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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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SUGAMMADEX (Org 25969, Bridion)


SUGAMMADEX

CAS number 343306-71-8
Weight Average: 2002.12
Monoisotopic: 2000.408874758
Chemical Formula C72H112O48S8

WATCH OUT POST WILL BE UPDATED………

Sugammadex sodium.svg

SUGAMMADEX

343306-71-8 cas  free

Sugammadex sodium

343306-79-6
MF: C72H104O48S8.8Na
MW: 2178.01

Image result for SUGAMMADEX SYNTHESIS

Bridion; UNII-ERJ6X2MXV7; Suγdex Sodium; Suγdex; 343306-79-6; Org 25969;Org25969; Org-25969; Org 25969; 361LPM2T56

Sugammadex (Org 25969, Bridion) is chemically known as Cyclooctakis-(l-→4)-[6-S-(2-carboxyethyl)-6-thio-a-D-glucopyranosyl].

SugammadexSugammadex sodium 3D front view.png

Sugammadex sodium343306-79-6

CAS No.:343306-71-8 free

Molecular Weight:2178.01

Molecular Formula:C72H104Na8O48S8

CAS 343306-79-6 sodium salt
Octanatrium-3,3′,3”,3”’,3””,3””’,3”””,3”””’-{[(1S,3S,5S,6S,8S,10S,11S,13S,15S,16S,18S,20S,21S,23S,25S,26S,28S,30S,31S,33S,35S,36S,38S,40S,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53 ;R,54R,55R,56R)-41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hexadecahydroxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39-hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31 .233,36]hexapentacontan-5,10,15,20,25,30,
Octasodium 3,3′,3”,3”’,3””,3””’,3”””,3”””’-{[(1S,3S,5S,6S,8S,10S,11S,13S,15S,16S,18S,20S,21S,23S,25S,26S,28S,30S,31S,33S,35S,36S,38S,40S,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R ;,54R,55R,56R)-41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hexadecahydroxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39-hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31 .233,36]hexapentacontane-5,10,15,20,25,30,
Sugammadex Sodium
D05940, 
SUYDEX SODIUM
UNII-ERJ6X2MXV7
Sugammadex (brand name Bridion) is marketed by Merck Sharp and Dohme, and was approved by the United States FDA on December 15, 2015.

Sugammadex sodium was first approved by European Medicine Agency (EMA) on July 25, 2008, then approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jan 20, 2010, and approved by the US. food and drug administration (FDA) on Dec 15, 2015. It was developed and marketed as Bridion® by Merck Sharp & Dohme.

Sugammadex is reversal of neuromuscular blockade without relying on inhibition of acetylcholinesterase. It is the first selective relaxant binding agent (SRBA). It is indicated in neuromuscular blockade induced by rocuronium or vecuronium in adults.

Bridion® is available as injection solution for intravenous use, containing 100 mg /mL of free Sugammadex. The recommended dose is 4 mg/kg for adults if recovery has reached at least 1-2 post-tetanic counts (PTC) following rocuronium or vecuronium induced blockade.

Sugammadex (Org 25969, tradename Bridion) is an agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA).

Sugammadex.png

Sugammadex Sodium is the sodium salt form of the biologically inert, selective relaxant binding agent (SRBA) sugammadex, a modified, anionic gamma cyclodextrinderivative containing a hydrophilic exterior and a hydrophobic core, with neuromuscular blocking drug (NMBD) reversal activity. Upon administration, the negatively charged carboxyl-thio-ether groups of sugammadex selectively and reversibly bind to the positively charged quaternary nitrogen of a steroidal NMBD, which was administered at an earlier time for anesthetic purposes. The encapsulation of the NMBD by sugammadex blocks its ability to bind to nicotinic receptors in the neuromuscular junction and thereby reverses the NMBD-induced neuromuscular blockade. Sugammadex binds rocuronium, vecuronium, and to a lesser extent pancuronium.

 Sugammadex is a selective relaxant binding agent indicated for reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide during surgery in adults. Rocuronium bromide and vecuronium bromide are neuromuscular blocking medications that cause temporary paralysis and are especially useful for general anesthesia, ventilation, or tracheal intubation that patients may require for surgery. Sugammadex provides a new treatment option to reverse the effects of those medications and possibly help patients recover sooner post-surgery. Sugammadex (brand name Bridion) is marketed by Merck Sharp and Dohme, and was approved by the United States FDA on December 15, 2015.

Sugammadex is used to reverse neuromuscular blockade after administration of non-depolarizing neuromuscular-blocking agentssuch as vecuronium or rocuronium.

Image result for sugammadex chemical reviews

Pharmacology

Pharmacodynamics

Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery. This gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions. These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the quaternary nitrogen of the target as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex’s binding encapsulation of rocuronium is one of the strongest among cyclodextrins and their guest molecules. The rocuronium molecule (a modified steroid) bound within sugammadex’s lipophilic core, is rendered unavailable to bind to the acetylcholine receptor at the neuromuscular junction.

Schematic diagram of sugammadex encapsulating a rocuronium molecule
Sugammadex sodium 3D three quarters view.png
Left: Schematic of a sugammadex molecule encapsulating a rocuronium molecule.
Right: Space-filling model of a sugammadex sodium molecule in the same orientation.

Sugammadex, unlike neostigmine, does not inhibit acetylcholinesterase so cholinergic effects are not produced and co-administration of an antimuscarinicagent (glycopyrronium bromide or atropine) is not needed. Sugammadex might therefore be expected to have fewer adverse effects than the traditional reversal agents.

When muscle relaxant with rapid onset and short duration of action is required, there has been little choice apart from suxamethonium but this drug has important contraindications; for example, it can trigger malignant hyperthermia in susceptible individuals, it has a prolonged duration of action in patients with pseudocholinesterase deficiency and it causes an increase in plasma potassium concentration which is dangerous in some circumstances. Rocuronium has a comparably quick onset in high dose (0.6 mg kg−1 to 1 mg kg−1) and can be rapidly reversed with sugammadex (16 mg kg−1), so this drug combination offers an alternative to suxamethonium.

‘Recurarisation’, a phenomenon of recurrence of neuromuscular block, may occur where the reversal agents wear off before a neuromuscular blocking drug is completely cleared. This is very unusual with all but the longest acting neuromuscular blocking drugs (such as gallamine, pancuronium or tubocurarine). It has been demonstrated to occur only rarely with sugammadex, and only when insufficient doses were administered.[1] The underlying mechanism is thought to be related to redistribution of relaxant after reversal. It may occur for a limited range of sugammadex doses which are sufficient for complex formation with relaxant in the central compartment, but insufficient for additional relaxant returning to central from peripheral compartments.[2]

Sugammadex has been shown to have affinity for two other aminosteroid neuromuscular blocking agents, vecuronium and pancuronium. Although sugammadex has a lower affinity for vecuronium than for rocuronium, reversal of vecuronium is still effective because fewer vecuronium molecules are present in vivo for equivalent blockade: vecuronium is approximately seven times more potent than rocuronium. Sugammadex encapsulates with a 1:1 ratio and therefore will adequately reverse vecuronium as there are fewer molecules to bind compared to rocuronium.[3] Shallow pancuronium blockade has been successfully reversed by sugammadex in phase III clinical trials.[4]

Efficacy

A study was carried out in Europe looking at its suitability in rapid sequence induction. It found that sugammadex provides a rapid and dose-dependent reversal of neuromuscular blockade induced by high-dose rocuronium.[5]

A Cochrane review on sugammadex concluded that “sugammadex was shown to be more effective than placebo (no medication) or neostigmine in reversing muscle relaxation caused by neuromuscular blockade during surgery and is relatively safe. Serious complications occurred in less than 1% of the patients who received sugammadex. The results of this review article (especially the safety results) need to be confirmed by future trials on larger patient populations”.[6]

Tolerability

Sugammadex was generally well tolerated in clinical trials in surgical patients or healthy volunteers. In pooled analyses, the tolerability profile of sugammadex was generally similar to that of placebo or neostigmine plus glycopyrrolate.[7]

History

Sugammadex was discovered by the pharmaceutical company Organon at the Newhouse Research Site in Scotland.[8] Organon was acquired by Schering-Plough in 2007; Schering-Plough merged with Merck in 2009. Sugammadex is now owned and sold by Merck.

The US Food and Drug Administration (FDA) initially rejected Schering-Plough’s New Drug Application for sugammadex in 2008,[9] but finally approved the medication for use in the United States on December 15, 2015.[10] Sugammadex was approved for use in the European Union on July 29, 2008.[11]

SYNTHESIS

Sugammadex (Trade name: Bridion) is first disclosed in US6670340 assigned to Akzo Nobel. Sugammadex sodium was approved in EMEA as an agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia in 2008 and is the first selective relaxant binding agent (SRBA).

Figure imgf000002_0001

Sugammadex sodium contains 8 recurring glucose units each with 5 asymmetric carbon atoms, in total 40 asymmetric carbon atoms for the whole molecule. Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery. The gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions.

The US Patent 6670340 assigned to Akzo Nobel discloses a process for preparing Sugammadex sodium as depicted in Scheme-I:

Scheme-I

Figure imgf000003_0001

Sugammadex Sodium The first step in the process in the scheme-I involves the preparation of Vilsmeier Hack reagent by the reaction , of DMF, triphenylphosphine and Iodine. The triphenylphosphine oxide is formed as a byproduct of the first step. Removal of triphenylphosphine oxide from the product is very difficult from the reaction mass as it requires repeated washing with DMF under argon atmosphere, which leads to inconsistency in yield of final product Sugammadex. The second step involves the reaction of 6-perdeoxy-6-per-Iodo-Gamma cyclodextrin with 3-mercapto propionic acid in presence of alkali metal hydrides in an organic solvent to give 6-per-deoxy-6-per-(2-carboxyethyl)thio-y- cyclodextrin sodium salt.

The PCT publication WO2012/025937 discloses preparation of Sugammadex involving the reaction of gamma cyclodextrin with phosphorous halide in presence of organic solvent, thereby overcomes the formation of triphenyl phosphine oxide. The publication also discloses the use of 6-per deoxy-6-per- chloro-y-cyclodextrin in the preparation of the Sugammadex.

The purification techniques in the prior arts employ column chromatographic / membrane dialysis techniques which are costly and not convenient in large scale operations.

Image result for SUGAMMADEX SYNTHESIS

File:Sugammadex synthesis.svg

Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery.

Figure imgf000002_0001

Sugammadex (designation Org 25969, trade name Bridion) is an agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA). This gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth earbon positions. These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the positively charged ammonium group as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex’s binding encapsulation of rocuronium is one of the strongest among cyclodextrins and their guest molecules. The rocuronium molecule (a modified steroid) bound within Sugammadex’s lipophilic core, is rendered unavailable to bind to the acetylcholine receptor at the neuromuscular junction. Sugammadex sodium contains 8 recurring glucose units each with 5 asymmetric carbon atoms, in total 40 asymmetric carbon atoms for the whole molecule.

The Sugammadex was disclosed in US6670340 by Akzo Nobel. The process for preparing Sugammadex is there outlined as follows: (Scheme-I)

Figure imgf000004_0001
Figure imgf000004_0002

Scheme – 1 Suggamadex

above process step-1 involves the preparation of Vilsmeier Hack reagent by the reaction of DMF, triphenylphosphine and Iodine. Drawback associated with this step is formation of triphenylphosphine oxide as a byproduct. Removal of triphenylphosphine oxide is very difficult from the reaction; it requires repeated washing with DMF under argon atmosphere and leads to inconsistency in yield of final product. Due to this, process is lengthy and not feasible on commercial scale.

PATENT

https://www.google.com/patents/WO2012025937A1?cl=en

Image result for SUGAMMADEX SYNTHESIS

Figure imgf000006_0002

Suggamadex

The process of the invention is depicted in following

Figure imgf000007_0001

Formula – 1 Formula – lla

Scheme – III

scheme-IV

Figure imgf000008_0001

Suggamadex

Scheme – IV

[0018] The alkali metal hydrides are selected from the group consisting of sodium hydride, lithium hydride, potassium hydride preferably sodium hydride. [0019] The advantage of the present process is there that there is no formation of by product such as triphenylphosphine oxide, as present in prior art process. So, purification is not required which leads to better purity and yields for the intermediate as well as for final product.

[0020] Another advantage of the present invention is the significant difference between molecular weight of 6-per deoxy-6-per-chloro-y-cyclodextrin (Mol. wt. 1444) and the final product (Mol. wt. 2178). The use of 6-per deoxy-6-per- chforo-y-cyclodextrin instead of 6-per deoxy-6-per-bromo-y-cyclodextrin (Mol. wt. 1800) in the final stage of the process would extend the scope of selection of appropriate dialysis membranes with precise molecular weight cut off and there by facilitate efficient purification of Sugammadex. The invention is further illustrated with following non-limiting examples:

Example: 1 Preparation of 6-perdeoxy-6-per-bromo Gamma Cyclodextrin

[0021] A portion of phosphorous pentachloride (256.5 g) was added in DMF (300 ml) at 0-5°C. Mixture was stirred at 20-25°C for lhr. A solution of gamma- cyclodextrin (50 g) in DMF (400ml) was added to above solution at 5-10°C under nitrogen. Mixture was stirred at 65 -70°C 14 hrs. The reaction mixture was cooled to 20 – 25°C and DMF was removed under vacuum. The viscous residue was diluted with water. 5M NaOH solution was added dropwise to the above solution at 5-10°C until PH=8, the resulting slurry was stirred for one hour at 20-25°C. The slurry was filtered under vacuum and washed with water and dried. The crude product was diluted with water and resulting slurry was stirred at 20-25uC for one hour. The slurry was filtered under vacuum and the solid dried at 55- 60°C under vacuum for 12hrs. (Yield – 94 – 98%, purity-98.5% by HPLC) Example: 2 Preparation of Sugammadax

[0022] To a mixture of sodium hydride (24.4 g) in DMF (150 ml) at 0-5°C, a solution of 3-mercapto propionic acid (23.7 ml, 10 eq) in DMF (50 ml) was added slowly under argon maintaining the temperature below 10 C. The resulting mixture was stirred at 20 -25°C for 30 mins. Then 6-deoxy-6-chloro gamma cyclodextrin (40 g) in DMF (400 ml) was added slowly at 5-10°C under argon and the resulting mixture was heated to 70-75°C for 12 hrs. Reaction mixture was cooled to 20 -25°C and DMF removed partially under vacuum and the reaction mixture is diluted with ethanol (600 ml). The resulting precipitate was stirred at 20 – 25°C for 1 hr and filtered under vacuum and the solid dried to afford the crude Sugammadex (wet) (100 g). The crude product was purified over silica gel and sephadex G-25 column using water as eluent. (Yield 60%)

CLIP

Sugammadex Sodium

    • Synonyms:ORG-25969
    • ATC:V03AB35
  • Use:Lorem
  • Chemical name:Lorem ipsum dolor sit amet, consetetur sadipscing elitr, sed diam
  • Formula:Lorem ipsum dolor sit amet,
    • MW:2178.02 g/mol
    • CAS-RN:343306-79-6

    Derivatives

    free acid

    • Formula:C72H112O48S8
    • MW:2002.17 g/mol
    • CAS-RN:343306-71-8

    Substance Classes

    Synthesis Path

    Substances Referenced in Synthesis Path

    CAS-RN Formula Chemical Name CAS Index Name
    17465-86-0 C48H80O40 γ-cyclodextrin
    107-96-0 C3H6O2S 3-mercaptopropionic acid Propanoic acid, 3-mercapto-
    53784-84-2 C48H72Br8O32 6A,6B,6C,6D,6E,6F,6G,6H-octabromo-A,6B,6C,6D,6E,6F,6G,6H-octadeoxy-γ-cyclodextrin
    168296-33-1 C48H72I8O32 6A,6B,6C,6D,6E,6F,6G,6H-octadeoxy-A,6B,6C,6D,6E,6F,6G,6H-octaiodo-γ-cyclodextrin

    Trade Names

    Country Trade Name Vendor Annotation
    D Lorem Lorem ,2008
    GB Lorem Lorem ,2008
    USA Lorem Lorem

    Formulations

    • Loremipsumdolor

    References

      • Adam, J. M. et al.: J. Med. Chem. (JMCMAR) 45, 1806-1818 (2002).
      • Bom, A. et al.: Angew. Chem. Int. Ed. (ACIEF5) 41, 266-270 (2002)
      • US 9 999 999 (Akzo Nobel; 30.12.2003; appl. 19.8.2002; EP-prior. 29.11.1999)

    PATENT

    http://www.google.co.in/patents/WO2001040316A1?cl=en

    str1

    PATENT

    https://www.google.com/patents/WO2014125501A1?cl=enhttps://www.google.com/patents/WO2014125501A1?cl=en

    EXAMPLES Example: 1 Preparation of 6-perdeoxy-6-per-chloro Gamma Cyclodextrin

    256.8 g (0.62 Moles) of Phosphorous pentachloride was added to 400 ml of Dimethyformamide (DMF) at 25-30 °C and mixture was maintained for 1 hour at the same temperature. 100 g (0.04 Moles) of Gamma-cyclodextrin was gradually added to the reaction mixture at 25-30 °C under nitrogen. The temperature of the reaction mixture was raised to 65 -70 °C and maintained at the same temperature for 14 to 16 hrs. The reaction mixture was then slowly added to chilled water at 0- 15 °C. The pH of the reaction mass was adjusted to 7-8 with 30% solution of sodium hydroxide in water. The contents were stirred at 25-30 °C at 2 hours. The resultant solid was filtered and washed with water (200 ml). The wet solid was repeatedly washed with purified water at 25-30 °C and dried at 65-70 °C till the moisture level was reduced to less than 4.0%. The yield of the obtained product was 90% Example: 2 Preparation of Sugammadex sodium

    To a mixture of 1 10.2 g, (15 equ.) 3-mercapto propionic acid and 800 ml Dimethyl formamide (DMF) , a 30% solution of sodium methoxide (373.9 g, 30 equ) in methanol was added at 20-25°C and stirred for 1 hour at the same temperature. The compound from example- 1 (100 g) was added to the reaction mixture at 25-30°Cand heated to 75-80°C and maintained at the 75-80°C for 12 to 14 hours. After completion of the reaction, the reaction mass was cooled to 20- 25°C, then methanol (1000 ml) was added to the reaction mass and stirred for 2 hours at the same temperature. The resultant solid was filtered, washed with methanol (200 ml) and dried for 60-65°C for 8 hrs.

    The crude product was dissolved in water (294 ml) and methanol (294 ml), treated with activated carbon (39.2 g, 20 % w/w) and was filtered through celite, washed the carbon cake with purified water (98 ml). The filtrate was heated to 50-55°C and slowly methanol (2646 ml) was added at the same temperature. The contents were cooled to 20 to 25°C and stirred for 2 hours at the same temperature. The resulted solid was washed with methanol (200 ml) and dried under vacuum at 60-65°C for 14 hours. The obtained product had yield of 70.34% and HPLC purity of 99.43 %.

    Example-3

    The Sugammadex prepared from example-2 was, dissolved in water ( 150 ml) and methanol (1 50 ml), treated with activated carbon (20 g) and filtered the carbon cake through celite bed and the carbon cake was washed with purified water (50 mL). The filtrate was heated to 50-55°C and added methanol (1350 ml) at the same temperature. The contents were cooled to 20 to 25°C and stirred for 2 hours at the same temperature. The resultant solid was washed with methanol (200 ml) and dried in vacuum at 70 – 75°C for 24 hrs. The obtained yield was 63%.

    CLIP
    ugammadex [6A,6B,6C,6D,6E,6F,6G,6H-octakis-S- (2-carboxyethyl)-6A,6B,6C,6D,6E,6F,6G,6H- octathio-γ-cyclodextrin octasodium salt] is a modified γ-cyclodextrin [Figure 1]. Chemical formula is C 72 H 104 Na 8 O 48 S 8. “Su” stands for sugar and “gammadex” stands for structural molecule gamma-cyclodextrin. [1] Cyclodextrins are cyclic dextrose units joined through 1-4 glycosyl bonds that are produced from starch or starch derivates using cyclodextrin glycosyltransferase. The three natural unmodified cyclodextrins are α-, β-or γ-cyclodextrin. Compared with α-and β-cyclodextrins, γ-cyclodextrin exhibits more favorable properties in terms of the size of its internal cavity, water solubility and bioavailability. To have a better fit of the larger rigid structure of the aminosteroid muscle relaxant molecule (e.g., rocuronium or vecuronium) within the cavity of γ-cyclodextrin, the latter was modified by adding eight side chains to extend the cavity. This modification allowed the four hydrophobic steroidal rings of rocuronium to be better accommodated within the hydrophobic cavity. In addition, adding negatively charged carboxyl groups at the end of the eight side chains served two purposes. First, the repellent forces of the negative charges keep propionic acid side chains from being disordered, thereby allowing the cavity to remain open and maintain structural integrity. Second, adding these negatively charged carboxyl groups enhances electrostatic binding to the positively charged quaternary nitrogen of rocuronium [Figure 1]. Three-dimensional structure resembles a hollow, truncated cone or a doughnut. [9]
    Clip
    Sugammadex (Bridion®)
    Schering-Plough’s sugammadex sodium, the first selective relaxant binding agent (SRBA), was approved last year
    in the European Union. Sugammadex is a drug-specific cyclodextrin designed specifically to reverse the effects of the muscle relaxant rocuronium bromide (Esmeron®/Zemuron®) when used as a component of general anesthesia during surgical procedures. Unlike other reversal agents, sugammadex can achieve reversal following rocuronium bromide administration within three minutes, regardless of the depth of block. Schering-Plough, which acquired the product via its acquisition of Organon BioSciences in late 2007, began marketing sugammadex in Sweden in September, 2008.
    There are several reports on the syntheses of sugammadex, all following a similar three-step procedure [72-74]. Bromination of 􀀁-cyclodexdrin 127 with the Vilsmeier-Haack reagent prepared by reaction of bromine with triphenylphospine in DMF gave the per-6-bromo-􀀁-cyclodextrin 128 in 95-98% yield [73]. Nucleophilic displacement of the bromines of 128 with methyl 3-mercaptopropionate (129) and cesium carbonate at 50 °C in DMF gave 6-perdeoxy-6-per(2-methoxycarbonylethyl) thio-􀀁-cyclodextrin 130 as a white powder.
    Saponification of the esters of 130 was accomplished by reaction with aqueous sodium hydroxide solution to provide
    sugammadex (XVII) as a glassy solid in 52% yield for the 2 steps [72,74].
    Adam, J. M.; Bennett, D. J.; Bom, A.; Clark, J. K.; Feilden, H.;
    72 Hutchinson, E. J.; Palin, R.; Prosser, A.; Rees, D. C.; Rosair, G.M.; Stevenson, D.; Tarver, G. J.; Ming-Qiang Zhang, M.-Q. Cyclodextrin-Derived Host Molecules as Reversal Agents for the Neuromuscular
    Blocker Rocuronium Bromide: Synthesis and Structure􀀁Activity Relationships J. Med. Chem., 2002, 45, 1806-
    1816.
    [73] Gorin, B. I.; Riopelle, R. J.; Thatcher, G. R. J. Efficient perfacial derivatization of cyclodextrins at the primary face. Tetrahedron Lett., 1996, 37, 4647-4650.
    [74] Zhang, M.-Q.; Palin, R.; Bennet, D. J. 6-Mercaptocyclodextrin derivatives, their preparation, and the use as reversal agents for drug-induced neuromuscular block. WO 0140316 A1, 2001.

     

     

    PATENT
    SEE
    CN 105348412
    NEW PATENT, SUGAMMADEX, WO 2016194001
    WO2016194001,  PROCESSES FOR PREPARATION OF SUGAMMADEX AND INTERMEDIATES THEREOF
    ALAPARTHI, Lakshmi Prasad; (IN).
    PAL, Palash; (IN).
    GINJUPALLI, Sadasiva Rao; (IN).
    SHARMA, Uday; (IN).
    CHOWDARY, Talluri Bhushaiah; (IN).
    MANTRI, Anand Vijaykumar; (IN).
    GADE, Bharath Reddy; (IN).
    KULKARNI, Gaurav; (IN)
    LINK

    Sugammadex (Org 25969, Bridion) is chemically known as Cyclooctakis-(l-→4)-[6-S-(2-carboxyethyl)-6-thio-a-D-glucopyranosyl]. Sugammadex is an agent for reversal of neuromuscular blockade by the neuromuscular blocking agents (NMBAs) rocuronium, vecuronium, pancuronium in general anesthesia. It is the first selective relaxant binding agent (SRBA). SRBAs are a new class of drugs that selectively encapsulates and binds NMBAs.

    The word Sugammadex is derived from Su= Sugar and Gamma cyclodex = Cyclodextrin. Sugammadex is inert chemically and does not bind to any receptor. It acts by rapidly encapsulating steroidal NMBDs to form a stable complex at a 1 : 1 ratio and thus decreasing the free concentration of the drug from the plasma. This creates a concentration gradient favoring the movement of the remaining rocuronium molecules from the neuromuscular junction back into the plasma, where they are encapsulated by free Sugammadex molecules. The latter molecules also enter the tissues and form a complex with rocuronium. Therefore, the neuromuscular blockade of rocuronium is terminated rapidly by the diffusion of rocuronium away from the neuromuscular junction back into the plasma.

    NMBDs are quaternary ammonium compounds with at least one charged nitrogen atom. Cyclodextrins have a lipophilic center but a hydrophilic outer core, attributable to negatively charged ions on their surface. These negatively charged ions on the surface of Sugammadex attract the positive charges of the quaternary ammonium relaxant, drawing the drug in to the central core of the cyclodextrin. The binding of the guest molecule into the host cyclodextrin occurs because of vander waal’s forces, hydrophobic and electrostatic interactions. The structure of the cyclodextrin is such that all four hydrophobic rings of the steroidal relaxant fit tightly within the concentric doughnut forming an inclusion complex. This has been confirmed by calorimetry and X-ray crystallography. Such a reaction occurs in the plasma not at the neuromuscular junction and the concentration of free rocuronium in the plasma decrease rapidly after Sugammadex administration.

    [0004] US 6670340 disclose process for preparation of Sugammadex sodium. The process as disclosed in example 4 of this patent involves reaction of iodo γ-cyclodextrin intermediate with 3-mercapto propionic acid in presence of sodium hydride and DMF to give 6-per-deoxy-6-per-(3-carboxyethyl)thio-Y-cyclodextrin, sodium salt (Sugammadex sodium). The preparation of iodo intermediate, 6-per-deoxy-6-per-iodo-y-cyclodextrin is as given in example 3 which involves reaction of γ-cyclodextrin with iodine in presence of triphenylphosphine (PPh3) and DMF. In practice, and to develop a process that has to be taken from lab scale to manufacturing scale, purity is one of the most important criteria. Since this process involves use of triphenylphosphine reagent there is formation of triphenylphosphine oxide as a by-product. Removal of triphenylphosphine oxide from the reaction mass is very difficult as it requires repeated washing with the solvent, which leads to inconsistency in yield of final product Sugammadex sodium. Furthermore, the product was dialysed for 36 hours to get pure compound. The dialysis purification is expensive and provides product in lower yield and hence such processes are not feasible and economical at industrial scale.

    [0005] Another process for preparing the intermediate compound, 6-perdeoxy-6-per-chloro gamma cyclodextrin as disclosed in WO2012025937 involves use of phosphorous halide in particular, phosphorous pentachloride. WO2012025937 also disclose process for preparation of Sugammadex sodium using this intermediate which involves a) reaction of gamma-cyclodextrin with phosphorous pentachloride and dimethylformamide to obtain 6-perdeoxy-6-per-chloro gamma cyclodextrin and b) reaction of 6-perdeoxy-6-per-chloro gamma cyclodextrin with 3-mercapto propionic acid in presence of alkali metal hydrides and an organic solvent to give Sugammadex sodium. Preparation of chloro gamma cyclodextrine intermediate using phosphorous pentachloride is associated with formation of phosphorous impurities during the reaction, which are difficult to remove and also it involves tedious workup procedure.

    [0006] WO2014125501 discloses preparation of 6-perdeoxy-6-per-chloro gamma cyclodextrin using phosphorous pentachloride (see example 1). The process as given in example 1 of this patent application was repeated by the present inventors. The first step provided yellow to brown mass which lacked the powder form and the flow properties. The mass was pasty at times and difficult to filter. Thus the process was unclean and tedious. Overall, no consistent product was obtained. WO2014125501 also disclose preparation of Sugammadex sodium using this intermediate which involves reaction of 6-perdeoxy-6-per-halo-gamma-cyclodextrin with 3-mercapto propionic acid in presence of alkali metal alkoxide such as sodium methoxide and organic solvent, the drawback of this this reaction is that it needs anhydrous conditions for completion of the reaction.

    [0007] It has been reported that the generation of impurities and obtaining less pure compounds are major concerns with Sugammadex. Applicant Nippon Organon K.K.in their “Report on the Deliberation Results” submitted to Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, mentions as follows:

    For related substances, specifications for 14 different related substances (Related Substance A, Org 48301, Related Substance B, Related Substance D, Related Substance E, Related Substance F, Related Substance G, Related Substance H, Related Substance I, Related Substance J, Related Substance K, Related Substance L, Related Substance M, Related Substance N), other individual related substances, and total related substances have been set. In the course of regulatory review, the specifications limit for 4 different related substances (Related Substance A, Related Substance D, Related Substance F, Related Substance G) have been changed based on the results of batch analyses. For related substances (degradation products), specifications for Related Substance E, Related Substance I, Related Substance C, Related Substance G, Related Substance D, Related Substance K, other individual degradation products, and total degradation products have been established. In the course of regulatory review, a specification for Impurity A which arises in *** (hidden part) step has been newly set and the specification limits for individual degradation products have been changed based on the results of batch analyses and stability studies.

    The cause for change of the colour of the drug product (the light yellow-brown colour darkened) was investigated using liquid chromatography -ultraviolet-visible spectrophotometry (LC-UV/VIS) and liquid chromatography-mass spectrometry (LC-MS), which suggested that trace amounts of varieties of unspecified degradation products (unidentified), instead of a single degradation product, were involved and in addition to *** investigated in formulation development, *** and *** content of the drug substance, *** and *** during the manufacture of the drug product, and *** were considered to affect the color of the drug product. Therefore, *** and *** have been included in the drug substance specification and the relevant manufacturing process steps have been improved.

    [0008] In view of the above it is clear that Sugammadex is not only prone to degradation but traces of degradation impurities affect and change the colour to yellowish brown and makes it unacceptable in quality. Therefore, it is crucial to carefully select the process to prepare pure Sugammadex sodium.

    [0009] The reported purification techniques for Sugammadex sodium employ column chromatographic and membrane dialysis which are costly and not convenient in large scale operations. Therefore, the reported processes for preparation of Sugammadex sodium as discussed herein are time consuming and not economically and industrially viable.

    Thus, there exist a need to provide a process of preparation of Sugammadex sodium which is simple, convenient, with easy work up procedure, economically efficient and the one which provides Sugammadex sodium in good yield and high purity.

    str0

    Figure 2 is 1HNMR of 6-perdeoxy-6-per-chloro gamma cyclodextrin

    str0

    Figure 6 is 1HNMR of Sugammadex prepared according to example 6

    str0

    Figure 7 is 13CNMR of Sugammadex prepared according to example 6

    str0

    Figure 12 is 1HNMR of Sugammadex prepared according to example 8

    SEE PATENT PLEASE

    Figure 13 is HPLC profile of Sugammadex prepared according to process of example 1 of WO2014125501.

    scheme 1.

    scheme 2.

    the process for preparation of Sugammadex sodium comprising reaction of 6-perdeoxy-6-per-chloro gamma cyclodextrin (Formula II) with 3-mercaptopropionic acid in presence of alkali metal amide selected from lithium amide, sodium amide (sodamide) or potassium amide to get Sugammadex sodium.

    Sugammadex Sodium

    scheme 4.

    the present invention provides process for preparation of Sugammadex comprising reacting the acid of Sugammadex of formula (IV) with sodium hydroxide to form Sugammadex sodium of formula (I).

    Formula IV Formula I

    Scheme 6

    scheme 7.

    scheme 8.

    scheme 9.

    Examples

    Example 1

    [0079] Preparation of 6-perdeoxy-6-per-chloro gammacyclodextrin

    In a four-neck round bottomed flask (2L) equipped with mechanical stirrer, thermometer pocket in a tub charged anhydrous DMF (250ml) under nitrogen atmosphere. Triphosgene (36.5g, 0.123mol) was added to the flask at 0-15°C and the mixture was stirred for lh. Dry gamma cyclodextrin (20g, 0.015mol) was added to the obtained slurry with stirring for 30 min followed by addition of DMF (50ml). The reaction mixture was heated at 65-70°C 16 h. After the completion of reaction, the reaction mixture was cooled and diisopropyl ether (800ml) was charged to the mixture to precipitate out the material. The solvent mixture of DMF and diisopropyl ether was decanted off from the reaction mixture to obtain gummy brown mass. The reaction mass was treated with saturated sodium bicarbonate solution (800ml) which leads to precipitation of the solid. The precipitated solid was filtered, washed with the water (250x3ml) and dried. This compound was used for the next step without any purification.

    Yield: 95%, HPLC Purity: 99%

    Example 2

    [0080] Preparation of 6-perdeoxy-6-per-chloro gamma-cyclodextrin

    In a 5L four-necked flask equipped with stirrer, dropping funnel, nitrogen inlet, and thermometer with pocket, oxalyl chloride (293.8g, 198.5ml, 2315mmol) was added to DMF (1200 ml) and maintained the mixture at 0-5°C under nitrogen followed by stirring at 20-25°C for lhr. A solution of gamma-cyclodextrin (lOOg, 77.16mmol) in DMF (500ml) was added to above mixture at 5-10°C under nitrogen. The mixture was stirred at 65-70°C for 14- 16 hr. After the completion of reaction, the reaction mixture was cooled to 20-25°C and diluted with diisopropyl ether (1.2L). The organic layer was decanted and the viscous residue was treated with 10% NaOH solution at 5- 10°C until PH = 8. The resulting slurry was stirred for one hour at 20-25°C. The slurry was filtered under vacuum and the solid was washed with water (3 x 500ml) and dried under vacuum. The crude material was suspended in methanol (750ml), stirred for 30min, filtered under vacuum and washed with diisopropyl ether (500ml). The solid obtained was dried at 55- 60°C in an oven for 12-16hr to afford the titled compound (95g).

    Yield: 85%, Purity: 98%, melting point: 226-228°C

    lH NMR (400 MHz, DMSO-d6): δ 6.0 (br s., 16 H), 4.99 (m, 8 H), 4.04 (d, J = 10 Hz, 8 H), 3.87

    – 3.78 (m, 16H), 3.64 – 3.56 (m, 8 H), 3.46 – 3.34 (m, 16 H) ppm.

    13C NMR (100 MHz, DMSO-d6): δ 101.98, 82.93, 72.30, 72.16, 71.11, 44.92 ppm.

    Mass: m/z (M+Na)+ calcd for
    1463.14; found: 1463.06.

    Example 3

    [0081] Preparation of 6-perdeoxy-6-per-chloro gamma-cyclodextrin

    In a clean, dried 50L glass reactor equipped with stirrer, dropping funnel, nitrogen inlet, and thermometer with pocket was charged anhydrous dimethylformamide (15L, moisture content NMT 0.4%) while maintaining the temperature at 0-5°C (using dry ice acetone bath). Oxalyl chloride (2L, 23635mmol, 30eq) was added slowly over a period 4-5hr (while maintaining the temperature below 5°C) and stirring was continued for lhr at the same temperature. A solution of dry gamma-cyclodextrin (1.0kg, 770.94mmol) dissolved in dimethylformamide (5L) was added slowly into the above reaction mixture. The solution was heated at 65-70°C for 16hr. The reaction was monitored by TLC at regular intervals. After the completion of reaction, the reaction mixture was cooled to room temperature and diisopropyl ether (10L) was added to the reaction mixture with stirring. The gummy solid precipitate out. The upper layer solvent was decanted, the gummy brown material was cooled to 0 to 5°C and was neutralized (pH 8.0) with slow addition of aqueous sodium hydroxide solution (20%, 5L) with stirring. The slurry obtained was stirred for lhr at temperature 0 to 5°C. The precipitate was filtered, washed with the water (3 x 2L) and dried under vacuum. The wet cake was suspended into methanol (10L), stirred, filtered, washed with diisopropyl ether (2L) and dried in oven at 60°C for 14-16hr to give the titled compound (980g). Yield: 87.9%, Purity: 98.1% as measured by HPLC.

    Example 4

    [0082] Preparation of Sugammadex sodium

    In a four-neck round bottomed flask (3L) equipped with mechanical stirrer, thermometer pocket in a tub under the nitrogen atmosphere, anhydrous DMF (300ml) and 3-Mercaptopropionic acid (18.3g, 0.172mol) were charged at 0-5°C followed by addition of sodamide (20g, O.38mol). The reaction mixture was stirred at the same temperature for lh. 6-perdeoxy-6-per-chloro gamma cyclodextrin (25g, 0.017mol, as obtained in example 1) was charged slowly. The reaction mixture was heated at 90-95°C for 16h. After completion of reaction, the reaction mixture was cooled to room temperature and methanol (300ml) was added to it. The mixture was stirred and the precipitated material was filtered off. The precipitated material was dissolved in a mixture of methanol (50ml) and water (50ml) and re-precipitated with the excess addition of methanol (450ml). The solid was filtered and dried. Yield: 76%

    The dried solid was purified by the preparative HPLC method using formic acid buffer in mixture of acetonitrile and water (80:20%) followed by lyophilization to get acid of Sugammadex which is further converted to Sugammadex sodium using sodium hydroxide.

    Example 5

    [0083] Preparation of Sugammadex sodium

    In a four-neck round bottomed flask (5L) equipped with mechanical stirrer, thermometer pocket in a tub under the nitrogen atmosphere, anhydrous DMF (1500ml) and 3-mercaptopropionic acid (HOg, 1038mmol) were charged at 0-5°C followed by addition of sodamide (81g, 2077mmol). The mixture was stirred at the same temperature for lh. 6-perdeoxy-6-per-chloro gamma cyclodextrin (lOOg, 69.25mmol, as obtained in example 1) was charged slowly. Extra DMF (500ml) was added to the mixture. The temperature of the mixture was raised to 80-85°C and maintained for 16h. After completion of reaction, the reaction mixture was cooled to room temperature and methanol (1500 ml) was added to it. The mixture was stirred and the precipitated material was filtered off. The precipitated material (wet cake) was dissolved in a mixture of methanol (800ml) and water (800ml). Charcoal (50g) was added and the mixture was stirred for 30mins at 50-55°C. The solution was filtered off through a pad of celite. Methanol (2500ml) was added the solution and precipitated solid was filtered and dried furnishing the titled compound (105g). Yield: 69.6%, Purity: 85.3%.

    Example 6

    [0084] Preparation of Sugammadex sodium

    A clean, dried 10L four neck flask equipped with stirrer, dropping funnel, nitrogen inlet, and thermometer with pocket, was charged with a solution of sodium hydroxide (83g, 2077mmol) dissolved in water (100ml) followed by addition of anhydrous DMF (2L) maintained under inert atmosphere using nitrogen. A solution of 3-mercapto propionic acid (HOg, 1037mmol) in DMF (1L) was added slowly under nitrogen maintaining the temperature between 0-5°C. The mixture was stirred for another lhr at this temperature. A mixture of 6-deoxy-6-chloro gamma cyclodextrin (lOOg, 69mmol) in DMF (1L) was added slowly at 5-10°C. The resulting mixture was heated to 75-80°C for 16-20hr. After the completion of reaction, the reaction mixture was cooled to 25-30°C and methanol (1.5L) was added into the reaction mixture, the resulting precipitate was stirred at 20-25°C, filtered, and dried under vacuum. The dried solid was dissolved in water (1L), treated with activated carbon (50 g, 5%) at 50°C, stirred and filtered through celite. The filtrate was stirred at 60°C and excess methanol (2.5L) was added slowly to the filtrate to get the precipitate. The precipitated material was filtered under vacuum as white solid, washed with methanol (500ml) and dried in oven to give pure Sugammadex sodium (90 g).

    Yield: 90 g, Purity: 91.2%.

    lU NMR (400 MHz, D20): δ 5.09 (m, 8H); 3.98-3.94 (m, 8H); 3.88-3.83 (m, 8H); 3.58-3.52 (m, 16H); 3.07-3.01 (m, 8H); 2.92-2.87 (m, 8H); 2.78-2.74 (m, 16H); 2.34-2.47 (m, 16H) ppm.

    13C NMR (100 MHz, D20): δ 180.18, 100.60, 81.96, 72.14, 71.84, 70.72, 37.24, 32.83, 29.06 ppm. Mass: m/z (M-Na7+H6)+ calcd for C72HnoNa048S8: 2023.12; found: 2023.39.

    Example 7

    Preparation of Sugammadex acid (Compound of formula IV)

    In a clean, dried 5L four neck flask equipped with stirrer, dropping funnel, nitrogen inlet, and thermometer with pocket was charged dimethylformamide (1500ml) followed by addition of potassium hydroxide (194.0 g, 3464mmol) and the mixture maintained at 0-5°C. A solution of 3-mercapto propionic acid (186.35g, 153.0ml, 1756mmol) in DMF (500ml) was added to the reactor over a period of 30 minutes under nitrogen while maintaining the temperature between 0-5°C. The

    resulting mixture was stirred at this temperature for 60 minutes. A solution of 6-deoxy-6-chloro gamma cyclodextrin (lOOg, 69.22mmol) in DMF (500ml) was added to the flask. The resulting mixture was heated at 110-120°C for 1.5-2hr while monitoring the progress of the reaction through HPLC. After completion of the reaction, the temperature of the reaction mixture was brought to 40-50°C and methanol (1000ml) was added to the mixture. The resulted precipitate was stirred at 20-25°C for lhr, filtered under vacuum and washed with methanol (500ml). The wet solid was dissolved in water (2000ml) with vigorous stirring and the solution was acidified with concentrated hydrochloric acid to give the white solid precipitate. The precipitated solid was filtered and suspended in ethyl acetate (500 ml), stirred for 30 minutes and filtered. The solid was dried to afford the titled compound (75g).

    Yield: 55%, Purity: 95.8% as measured by HPLC.

    lH NMR (400 MHz, DMSO-d6): δ 5.94 (br. s, 16H), 3.82-3.73 (m, 8H), 3.63-3.54 (m, 8H), 3.43-3.32 (m, 16H), 3.08-3.02 (m, 8H), 2.89-2.81 (m, 8H), 2.78-2.72 (m, 16H), 2.55-2.43 (m, 16H) ppm.

    13C NMR (100 MHz, DMSO-d6): δ 173.00, 102.01, 83.94, 72.45, 72.33, 71.36, 34.53, 33.08, 27.87 ppm.

    Mass: m/z (M-H2+K) + calcd for C72Hno048S8K: 2039.24; found: 2039.26.

    Example 8

    Preparation of Sugammadex Sodium

    In a clean, dried 3L four neck flask equipped with stirrer, dropping funnel, nitrogen inlet, and thermometer with pocket, the compound (75g) as obtained in example 4 was dissolved in solution of sodium hydroxide (37.5g, 0.937mol) in water (100ml) and methanol (100ml). The pH of resultant mixture was maintained between 8-10. To this mixture methanol (1.5L) was slowly added at room temperature and the mixture was stirred for additional 30 minutes. The precipitated white solid was filtered off under vacuum and thoroughly washed with methanol (500ml). The solid was dried at 50°C under vacuum oven for 24hr to afford Sugammadex sodium (79g).

    Yield: 96.9%, Purity: 95.5% measured by HPLC.

    PATENT
    Cited Patent Filing date Publication date Applicant Title
    WO2012025937A1 Aug 23, 2011 Mar 1, 2012 Ramamohan Rao Davuluri Improved process for preparation of sugammadex
    US5569756 * Mar 21, 1995 Oct 29, 1996 American Maize-Products Company Purification of chemically modified cyclodextrins
    US6670340 Nov 23, 2000 Dec 30, 2003 Akzo Nobel 6-Mercapto-cyclodextrin derivatives:reversal agents for drug-induced neuromuscular block
    Cited Patent Filing date Publication date Applicant Title
    WO2001040316A1 * Nov 23, 2000 Jun 7, 2001 Akzo Nobel N.V. 6-mercapto-cyclodextrin derivatives: reversal agents for drug-induced neuromuscular block
    US6670340 Nov 23, 2000 Dec 30, 2003 Akzo Nobel 6-Mercapto-cyclodextrin derivatives:reversal agents for drug-induced neuromuscular block
    Reference
    1 * KAZIMIERZ CHMURSKI ET AL.: “An Improved Synthesis of 6-Deoxyhalo Cyclodextrins via Halomethylenemorpholinium Halides Vilsmeier-Haack Type Reagents.“, TETRAHEDRON LETTERS, vol. 38, no. 42, 1997, pages 7365 – 7368, XP004111215
    2 * See also references of EP2609120A4
    Citing Patent Filing date Publication date Applicant Title
    WO2014125501A1 Apr 8, 2013 Aug 21, 2014 Neuland Laboratories Limited An improved process for preparation of sugammadex sodium
    WO2015181224A1 May 27, 2015 Dec 3, 2015 Universitaet Des Saarlandes Novel water soluble 6-thioalkyl-cyclodextrins and uses thereof

    FDA Orange Book Patents

    FDA Orange Book Patents: 1 of 3
    Patent 6949527
    Expiration Jan 27, 2021
    Applicant ORGANON SUB MERCK
    Drug Application N022225 (Prescription Drug: BRIDION. Ingredients: SUGAMMADEX SODIUM)
    FDA Orange Book Patents: 2 of 3
    Patent 7265099
    Expiration Aug 7, 2020
    Applicant ORGANON SUB MERCK
    Drug Application N022225 (Prescription Drug: BRIDION. Ingredients: SUGAMMADEX SODIUM)
    FDA Orange Book Patents: 3 of 3
    Patent RE44733
    Expiration Jan 27, 2021
    Applicant ORGANON SUB MERCK
    Drug Application N022225 (Prescription Drug: BRIDION. Ingredients: SUGAMMADEX SODIUM)

    References

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    14: Karalapillai D, Kaufman M, Weinberg L. Sugammadex. Crit Care Resusc. 2013 Mar;15(1):57-62. Review. PubMed PMID: 23432503.

    15: Øberg E, Claudius C. [Possible clinical potential in reverting muscular block with sugammadex in anaesthesia and surgery]. Ugeskr Laeger. 2013 Feb 11;175(7):428-32. Review. Danish. PubMed PMID: 23402253.

    16: Della Rocca G, Di Marco P, Beretta L, De Gaudio AR, Ori C, Mastronardi P. Do we need to use sugammadex at the end of a general anesthesia to reverse the action of neuromuscular bloking agents? Position Paper on Sugammadex use. Minerva Anestesiol. 2013 Jun;79(6):661-6. Epub 2012 Nov 29. Review. PubMed PMID: 23192221.

    17: Stair C, Fernandez-Bustamante A. Sugammadex, the first selective relaxant binding agent for neuromuscular block reversal. Drugs Today (Barc). 2012 Jun;48(6):405-13. doi: 10.1358/dot.2012.48.6.1813474. Review. PubMed PMID: 22745926.

    18: Baldo BA, McDonnell NJ, Pham NH. The cyclodextrin sugammadex and anaphylaxis to rocuronium: is rocuronium still potentially allergenic in the inclusion complex form? Mini Rev Med Chem. 2012 Jul;12(8):701-12. Review. PubMed PMID: 22512555.

    19: Fuchs-Buder T, Meistelman C, Schreiber JU. Is sugammadex economically viable for routine use. Curr Opin Anaesthesiol. 2012 Apr;25(2):217-20. doi: 10.1097/ACO.0b013e32834f012d. Review. PubMed PMID: 22157200.

    20: Baldo BA, McDonnell NJ, Pham NH. Drug-specific cyclodextrins with emphasis on sugammadex, the neuromuscular blocker rocuronium and perioperative anaphylaxis: implications for drug allergy. Clin Exp Allergy. 2011 Dec;41(12):1663-78. doi: 10.1111/j.1365-2222.2011.03805.x. Epub 2011 Jul 7. Review. PubMed PMID: 21732999.

     

    BRIDION (sugammadex) injection, for intravenous use, contains sugammadex sodium, a modified gamma cyclodextrin chemically designated as 6A,6B,6C,6D,6E,6F,6G,6H-Octakis-S-(2-carboxyethyl)6A,6B,6C,6D,6E,6F,6G,6H-octathio-γ-cyclodextrin sodium salt (1:8) with a molecular weight of 2178.01. The structural formula is:

    Gamma cyclodextrin - Structural Formula Illustration

    BRIDION is supplied as a sterile, non-pyrogenic aqueous solution that is clear, colorless to slightly yellow-brown for intravenous injection only. Each mL contains 100 mg sugammadex, which is equivalent to 108.8 mg sugammadex sodium. The aqueous solution is adjusted to a pH of between 7 and 8 with hydrochloric acid and/or sodium hydroxide. The osmolality of the product is between 300 and 500 mOsmol/kg.

    BRIDION may contain up to 7 mg/mL of the mono OH-derivative of sugammadex [see CLINICAL PHARMACOLOGY]. This derivative is chemically designated as 6A,6B,6C,6D,6E,6F,6G-Heptakis-S-(2carboxyethyl)-6A,6B,6C,6D,6E,6F,6G-heptathio-γ-cyclodextrin sodium salt (1:7) with a molecular weight of 2067.90. The structural formula is:

    Sugammadex - Structural Formula Illustration
    Sugammadex
    Sugammadex sodium.svg
    Sugammadex sodium 3D front view.png
    Clinical data
    AHFS/Drugs.com International Drug Names
    License data
    Routes of
    administration
    Intravenous
    Legal status
    Legal status
    Identifiers
    CAS Number 343306-79-6 
    ATC code V03AB35 (WHO)
    PubChem CID 6918584
    ChemSpider 5293781 
    UNII 361LPM2T56 Yes
    KEGG D05940 Yes
    ChEBI CHEBI:90952 
    Chemical data
    Formula C72H104Na8O48S8
    Molar mass 2178 g/mol
    3D model (Jmol) Interactive image

    /////////SUGAMMADEX, Sugammadex Sodium, D05940, SUYDEX SODIUM, UNII-ERJ6X2MXV7, fda 2015, bridion, Org25969,  Org-25969, Org 25969,  361LPM2T56

    O[C@@H]1[C@@H](O)[C@@H]2O[C@H]3O[C@H](CSCCC(O)=O)[C@@H](O[C@H]4O[C@H](CSCCC(O)=O)[C@@H](O[C@H]5O[C@H](CSCCC(O)=O)[C@@H](O[C@H]6O[C@H](CSCCC(O)=O)[C@@H](O[C@H]7O[C@H](CSCCC(O)=O)[C@@H](O[C@H]8O[C@H](CSCCC(O)=O)[C@@H](O[C@H]9O[C@H](CSCCC(O)=O)[C@@H](O[C@H]1O[C@@H]2CSCCC(O)=O)[C@H](O)[C@H]9O)[C@H](O)[C@H]8O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O

    O=C(O[Na])CCSC[C@@H]1OC(O[C@@H]2[C@H]([C@H](O)C(O[C@H]3[C@H](CSCCC(O[Na])=O)OC(O[C@H]4[C@H](CSCCC(O[Na])=O)OC5[C@@H](O)[C@@H]4O)[C@@H](O)[C@@H]3O)O[C@H]2CSCCC(O[Na])=O)O)[C@@H](O)[C@H](O)[C@H]1OC(O[C@@H](CSCCC(O[Na])=O)[C@H](OC6[C@@H](O)[C@H](O)[C@@H](OC7[C@@H](O)[C@H](O)[C@@H](OC8[C@@H](O)[C@H](O)[C@@H](O5)[C@H](CSCCC(O[Na])=O)O8)[C@H](CSCCC(O[Na])=O)O7)[C@H](CSCCC(O[Na])=O)O6)[C@H]9O)[C@H]9O

    C(CSCC1C2C(C(C(O1)OC3C(OC(C(C3O)O)OC4C(OC(C(C4O)O)OC5C(OC(C(C5O)O)OC6C(OC(C(C6O)O)OC7C(OC(C(C7O)O)OC8C(OC(C(C8O)O)OC9C(OC(O2)C(C9O)O)CSCCC(=O)[O-])CSCCC(=O)[O-])CSCCC(=O)[O-])CSCCC(=O)[O-])CSCCC(=O)[O-])CSCCC(=O)[O-])CSCCC(=O)[O-])O)O)C(=O)[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]

    A PRESENTATION

     

    Image result for waitThe presentation will load below

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    Asfotase alfa


     STR1

    > Asfotase Alfa Sequence
    LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQL
    HHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERS
    RCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEAL
    SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLDLVDTWK
    SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEMVVVAI
    QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTLTVVTA
    DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVSMVDYA
    HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACIGANLGHC
    APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV
    KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE
    KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
    TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKDIDDDD
    DDDDDD

    Asfotase alfa

    Indicated for the treatment of patients with perinatal/infantile and juvenile onset hypophosphatasia (HPP).

    (Strensiq®)Approved

    A mineralized tissue targeted fusion protein used to treat hypophosphatasia.

    Research Code ALXN-1215; ENB-0040; sALP-FcD-10

    CAS No.1174277-80-5

    180000.0

    C7108H11008N1968O2206S56

    Company Alexion Pharmaceuticals Inc.
    Description Fusion protein incorporating the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP; ALPL) and a bone-targeting peptide
    Molecular Target
    Mechanism of Action Enzyme replacement therapy
    Therapeutic Modality Biologic: Fusion protein
    Latest Stage of Development Approved
    Standard Indication Metabolic (unspecified)
    Indication Details Treat hypophosphatasia (HPP); Treat hypophosphatasia (HPP) in children; Treat hypophosphatasia (HPP) in patients whose first signs or symptoms occurred prior to 18 years of age; Treat perinatal, infantile and juvenile-onset hypophosphatasia (HPP)
    Regulatory Designation U.S. – Breakthrough Therapy (Treat hypophosphatasia (HPP) in children);
    U.S. – Breakthrough Therapy (Treat hypophosphatasia (HPP) in patients whose first signs or symptoms occurred prior to 18 years of age);
    U.S. – Fast Track (Treat hypophosphatasia (HPP));
    U.S. – Orphan Drug (Treat hypophosphatasia (HPP));
    U.S. – Priority Review (Treat hypophosphatasia (HPP) in children);
    EU – Accelerated Assessment (Treat hypophosphatasia (HPP));
    EU – Accelerated Assessment (Treat hypophosphatasia (HPP) in children);
    EU – Orphan Drug (Treat hypophosphatasia (HPP));
    Japan – Orphan Drug (Treat hypophosphatasia (HPP));
    Australia – Orphan Drug (Treat hypophosphatasia (HPP)

    Asfotase Alfa is a first-in-class bone-targeted enzyme replacement therapy designed to address the underlying cause of hypophosphatasia (HPP)—deficient alkaline phosphatase (ALP). Hypophosphatasia is almost always fatal when severe skeletal disease is obvious at birth. By replacing deficient ALP, treatment with Asfotase Alfa aims to improve the elevated enzyme substrate levels and improve the body’s ability to mineralize bone, thereby preventing serious skeletal and systemic patient morbidity and premature death. Asfotase alfa was first approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on July 3, 2015, then approved by the European Medicine Agency (EMA) on August 28, 2015, and was approved by the U.S. Food and Drug Administration (FDA) on October 23, 2015. Asfotase Alfa is marketed under the brand name Strensiq® by Alexion Pharmaceuticals, Inc. The annual average price of Asfotase Alfa treatment is $285,000.

    Hypophosphatasia (HPP) is a rare inheritable disease that results from loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Therapeutic options for treating the underlying pathophysiology of the disease have been lacking, with the mainstay of treatment being management of symptoms and supportive care. HPP is associated with significant morbidity and mortality in paediatric patients, with mortality rates as high as 100 % in perinatal-onset HPP and 50 % in infantile-onset HPP. Subcutaneous asfotase alfa (Strensiq(®)), a first-in-class bone-targeted human recombinant TNSALP replacement therapy, is approved in the EU for long-term therapy in patients with paediatric-onset HPP to treat bone manifestations of the disease. In noncomparative clinical trials in infants and children with paediatric-onset HPP, asfotase alfa rapidly improved radiographically-assessed rickets severity scores at 24 weeks (primary timepoint) as reflected in improvements in bone mineralization, with these benefits sustained after more than 3 years of treatment. Furthermore, patients typically experienced improvements in respiratory function, gross motor function, fine motor function, cognitive development, muscle strength (normalization) and ability to perform activities of daily living, and catch-up height-gain. In life-threatening perinatal and infantile HPP, asfotase alfa also improved overall survival. Asfotase alfa was generally well tolerated in clinical trials, with relatively few patients discontinuing treatment and most treatment-related adverse events being of mild to moderate intensity. Thus, subcutaneous asfotase alfa is a valuable emerging therapy for the treatment of bone manifestations in patients with paediatric-onset HPP.

    FDA

    October 23, 2015

    Release

     Today, the U.S. Food and Drug Administration approved Strensiq (asfotase alfa) as the first approved treatment for perinatal, infantile and juvenile-onset hypophosphatasia (HPP).

    HPP is a rare, genetic, progressive, metabolic disease in which patients experience devastating effects on multiple systems of the body, leading to severe disability and life-threatening complications. It is characterized by defective bone mineralization that can lead to rickets and softening of the bones that result in skeletal abnormalities. It can also cause complications such as profound muscle weakness with loss of mobility, seizures, pain, respiratory failure and premature death. Severe forms of HPP affect an estimated one in 100,000 newborns, but milder cases, such as those that appear in childhood or adulthood, may occur more frequently.

    “For the first time, the HPP community will have access to an approved therapy for this rare disease,” said Amy G. Egan, M.D., M.P.H., deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research (CDER). “Strensiq’s approval is an example of how the Breakthrough Therapy Designation program can bring new and needed treatments to people with rare diseases.”

    Strensiq received a breakthrough therapy designation as it is the first and only treatment for perinatal, infantile and juvenile-onset HPP. The Breakthrough Therapy Designation program encourages the FDA to work collaboratively with sponsors, by providing timely advice and interactive communications, to help expedite the development and review of important new drugs for serious or life-threatening conditions. In addition to designation as a breakthrough therapy, the FDA granted Strensiq orphan drug designation because it treats a disease affecting fewer than 200,000 patients in the United States.

    Orphan drug designation provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Strensiq was also granted priority review, which is granted to drug applications that show a significant improvement in safety or effectiveness in the treatment of a serious condition. In addition, the manufacturer of Strensiq was granted a rare pediatric disease priority review voucher – a provision intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. Development of this drug was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.

    Strensiq is administered via injection three or six times per week. Strensiq works by replacing the enzyme (known as tissue-nonspecific alkaline phosphatase) responsible for formation of an essential mineral in normal bone, which has been shown to improve patient outcomes.

    The safety and efficacy of Strensiq were established in 99 patients with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies. Study results showed that patients with perinatal- and infantile-onset HPP treated with Strensiq had improved overall survival and survival without the need for a ventilator (ventilator-free survival). Ninety-seven percent of treated patients were alive at one year of age compared to 42 percent of control patients selected from a natural history study group. Similarly, the ventilator-free survival rate at one year of age was 85 percent for treated patients compared to less than 50 percent for the natural history control patients.

    Patients with juvenile-onset HPP treated with Strensiq showed improvements in growth and bone health compared to control patients selected from a natural history database. All treated patients had improvement in low weight or short stature or maintained normal height and weight. In comparison, approximately 20 percent of control patients had growth delays over time, with shifts in height or weight from the normal range for children their age to heights and weights well below normal for age. Juvenile-onset patients also showed improvements in bone mineralization, as measured on a scale that evaluates the severity of rickets and other HPP-related skeletal abnormalities based on x-ray images. All treated patients demonstrated substantial healing of rickets on x-rays while some natural history control patients showed increasing signs of rickets over time.

    The most common side effects in patients treated with Strensiq include injection site reactions, hypersensitivity reactions (such as difficulty breathing, nausea, dizziness and fever), lipodystrophy (a loss of fat tissue resulting in an indentation in the skin or a thickening of fat tissue resulting in a lump under the skin) at the injection site, and ectopic calcifications of the eyes and kidney.

    Strensiq is manufactured by Alexion Pharmaceuticals Inc., based in Cheshire, Connecticut.

    Patent Number Pediatric Extension Approved Expires (estimated)
    US7763712 No 2004-04-21 2026-07-15

    STRENSIQ is a formulation of asfotase alfa, which is a soluble glycoproteincomposed of two identical polypeptide chains. Each chain contains 726amino acids with a theoretical mass of 161 kDa. Each chain consists of the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP), the human immunoglobulin G1 Fc domain and a deca-aspartatepeptide used as a bone targeting domain. The two polypeptide chains are covalently linked by two disulfide bonds.

    STRENSIQ is a tissue nonspecific alkaline phosphatase produced byrecombinant DNA technology in a Chinese hamster ovary cell line. TNSALP is a metallo-enzyme that catalyzes the hydrolysis of phosphomonoesters with release of inorganic phosphate and alcohol. Asfotase alfa has a specific activity of 620 to 1250 units/mg. One activity unit is defined as the amount of asfotase alfa required to form 1 μmol of p-nitrophenol from pNPP per minute at 37°C.

    STRENSIQ (asfotase alfa) is a sterile, preservative-free, nonpyrogenic, clear, slightly opalescent or opalescent, colorless to slightly yellow, with few small translucent or white particles, aqueous solution for subcutaneous administration. STRENSIQ is supplied in glass single-use vials containing asfotase alfa; dibasic sodium phosphate, heptahydrate; monobasic sodium phosphate, monohydrate; and sodium chloride at a pH between 7.2 and 7.6. Table 5 describes the content of STRENSIQ vial presentations.

    Table 5: Content of STRENSIQ Vial Presentations

    INGREDIENT QUANTITY PER VIAL
    ASFOTASE ALFA 18 MG/0.45 ML 28 MG/0.7 ML 40 MG/ML 80 MG/0.8 ML
    Dibasic sodium phosphate, heptahydrate 2.48 mg 3.85 mg 5.5 mg 4.4 mg
    Monobasic sodium phosphate, monohydrate 0.28 mg 0.43 mg 0.62 mg 0.5 mg
    Sodium chloride 3.94 mg 6.13 mg 8.76 mg 7.01 mg

    REFERNCES

    http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003794/WC500194340.pdf

    1. Whyte MP: Hypophosphatasia – aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016 Apr;12(4):233-46. doi: 10.1038/nrendo.2016.14. Epub 2016 Feb 19. [PubMed:26893260 ]
    2. Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C: Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2016 Jan;101(1):334-42. doi: 10.1210/jc.2015-3462. Epub 2015 Nov 3. [PubMed:26529632 ]
    3. Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H: Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012 Mar 8;366(10):904-13. doi: 10.1056/NEJMoa1106173. [PubMed:22397652 ]

    //////Asfotase alfa, Strensiq, treat hypophosphatasia, ALXN-1215,  ENB-0040,  sALP-FcD-10, FDA 2015

    Patiromer


    Patiromer

    1260643-52-4 FREE FORM

    CAS 1208912-84-8

    (C10 H10 . C8 H14 . C3 H3 F O2 . 1/2 Ca)x

    2-​Propenoic acid, 2-​fluoro-​, calcium salt (2:1)​, polymer with diethenylbenzene and 1,​7-​octadiene

    RLY5016

    RELYPSA INNOVATOR

    Patiromer is a powder for suspension in water for oral administration, approved in the U.S. as Veltassa in October, 2015. Patiromer is supplied as patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion. Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium. The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol. Patiromer sorbitex calcium is an amorphous, free-flowing powder that is composed of individual spherical beads.

    Veltassa is a powder for suspension in water for oral administration. The active ingredient is patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion.

    Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium. The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol.

    Mechanism of Action

    Veltassa is a non-absorbed, cation exchange polymer that contains a calcium-sorbitol counterion. Veltassa increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, resulting in a reduction of serum potassium levels.

    patiromer1

    Treatment of Hyperkalemia

    Hyperkalemia is usually asymptomatic but occasionally can lead to life-threatening cardiac arrhythmias and increased all-cause and in-hospital mortality, particularly in patients with CKD and associated cardiovascular diseases (Jain et al., 2012; McMahon et al., 2012; Khanagavi et al., 2014). However, there is limited evidence from randomized clinical trials regarding the most effective therapy for acute management of hyperkalemia (Khanagavi et al., 2014) and a Cochrane analysis of emergency interventions for hyperkalemia found that none of the studies reported mortality or cardiac arrhythmias, but reports focused on PK (Mahoney et al., 2005). Thus, recommendations are based on opinions and vary with institutional practice guidelines (Elliot et al., 2010; Khanagavi et al., 2014). Management of hyperkalemia includes reducing potassium intake, discontinuing potassium supplements, treatment of precipitating risk factors, and careful review of prescribed drugs affecting potassium homeostasis. Treatment of life-threatening hyperkalemia includes nebulized or inhaled beta-agonists (albuterol, salbutamol) or intravenous (IV) insulin-and-glucose, which stimulate intracellular potassium uptake, their combination being more effective than either alone. When arrhythmias are present, IV calcium might stabilize the cardiac resting membrane potential. Sodium bicarbonate may be indicated in patients with severe metabolic acidosis. Potassium can be effectively eliminated by hemodialysis or increasing its renal (loop diuretics) and gastrointestinal (GI) excretion with sodium polystyrene sulfonate, an ion-exchange resin that exchanges sodium for potassium in the colon. However, this resin produces serious GI adverse events (ischemic colitis, bleeding, perforation, or necrosis). Therefore, there is an unmet need of safer and more effective drugs producing a rapid and sustained PK reduction in patients with hyperkalemia.

    In this article we review two new polymer-based, non-systemic oral agents, patiromer calcium (RLY5016) and zirconium silicate (ZS-9), under clinical development designed to induce potassium loss via the GI tract, particularly the colon, and reduce PK in patients with hyperkalemia.

    1. Patiromer calcium

    This metal-free cross-linked fluoroacrylate polymer (structure not available) exchanges cations through the gastrointestinal (GI) tract. It preferentially binds soluble potassium in the colon, increases its fecal excretion and reduces PK under hyperkalemic conditions.

    The development program of patiromer includes several clinical trials. An open-label, single-arm study evaluated a titration regimen for patiromer in 60 HF patients with CKD treated with ACEIs, ARBs, or beta blockers (clinicaltrials.gov identifier: NCT01130597). Another open-label, randomized, dose ranging trial determined the optimal starting dose and safety of patiromer in 300 hypertensive patients with diabetic nephropathy treated with ACEIs and/or ARBs, with or without spironolactone (NCT01371747). The primary outcomes were the change in PK from baseline to the end of the study. Unfortunately, the results of these trials were not published.

    In a double-blind, placebo-controlled trial (PEARL-HF, NCT00868439), 105 patients with a baseline PK of 4.7 mmol/L and HF (NYHA class II-III) treated with spironolactone in addition to standard therapy were randomized to patiromer (15 g) or placebo BID for 4 weeks (Pitt et al., 2011). Spironolactone, initiated at 25 mg/day, was increased to 50 mg/day on day 15 if PK was ≤5.1 mmol/L. Patients were eligible for the trial if they had either CKD (eGFR <60 ml/min) or a history of hyperkalemia leading to discontinuation of RAASIs or beta-blockers. Compared with placebo, patiromer decreased the PK (-0.22 mmol/L, while PK increased in the placebo group +0.23 mmol/L, P<0.001), and the incidence of hyperkalemia (7% vs. 25%, P=0.015) and increased the number of patients up-titrated to spironolactone 50 mg/day (91% vs. 74%, P=0.019). A similar reduction in PK and hyperkalemia was observed in patients with an eGFR <60 ml/min. Patiromer produced more GI adverse events (flatulence, diarrhea, constipation, vomiting: 21% vs 6%), hypokalemia (<4.0 mmol/L: 47% vs 10%, P<0.001) and hypomagnesaemia (<1.8 mg/dL: 24% vs. 2.1%), but similar adverse events leading to study discontinuation compared to placebo. Unfortunately, recruited patients had normokalemia and basal eGFR in the treatment group was 84 ml/min. Thus, this study did not answer whether patiromer is effective in reducing PK in patients with CKD and/or HF who develop hyperkalemia on RAASIs.

    A two-part phase 3 study evaluated the efficacy and safety of patiromer in the treatment of hyperkalemia (NCT01810939). In a single-blind phase (part A) 243 patients with hyperkalemia and CKD (102 with HF) on RAASIs were treated with patiromer BID for 4 weeks: 4.2 g in patients with mild hyperkalemia (5.1-<5.5 mmol/L, n=92) and 8.4 g in patients with moderate-to-severe hyperkalemia (5.5-<6.5 mmol/L, n=151). Part B was a placebo-controlled, randomized, withdrawal phase designed to confirm the maintained efficacy of patiromer and the recurrent hyperkalemia following that drug’s withdrawal. Patients (n=107) who completed phase A with a normal PK were randomized to continue on patiromer (27 with HF) or placebo (22 with HF) besides RAASIs for 8 weeks. The primary endpoint was the difference in mean PK between the patiromer and placebo groups from baseline to the end of the study or when the patient first had a PK <3.8 or ≥5.5 mmol/L. In part A patiromer produced a rapid reduction in PK that persisted throughout the study in patients with and without HF (-1.06 and -0.98 mmol/L, respectively; both P<0.001 vs. placebo); three-fourths of patients in both groups had normal PK (3.8-<5.1 mmol/L) at 4 weeks. In part B patiromer reduced PK (-0.64 mmol/L) in patients with or without HF (P<0.001). As compared with placebo, fewer patients, with or without HF, presented recurrent hyperkalemia in the patiromer group or required RAASI discontinuation regardless of HF status (Pitt, 2014). Patiromer was well-tolerated, with a safety profile similar to placebo even in HF patients. The most common adverse events were nausea, diarrhea, and hypokalemia.

    INDICATIONS AND USAGE

    Veltassa is a potassium binder indicated for the treatment of hyperkalemia.

    Veltassa should not be used as an emergency treatment for lifethreatening hyperkalemia because of its delayed onset of action.

    Patiromer (USAN, trade name Veltassa) is a drug used for the treatment of hyperkalemia (elevated blood potassium levels), a condition that may lead to palpitations and arrhythmia (irregular heartbeat). It works by binding potassium in the gut.[1][2]

     

    Medical uses

    Patiromer is used for the treatment of hyperkalemia, but not as an emergency treatment for life-threatening hyperkalemia, because it acts relatively slowly.[2] Such a condition needs other kinds of treatment, for example calcium infusions, insulin plus glucose infusions, salbutamol inhalation, and hemodialysis.[3]

    Typical reasons for hyperkalemia are renal insufficiency and application of drugs that inhibit the renin–angiotensin–aldosterone system (RAAS) – e.g. ACE inhibitors, angiotensin II receptor antagonists, or potassium-sparing diuretics – or that interfere with renal function in general, such as nonsteroidal anti-inflammatory drugs (NSAIDs).[4][5]

    Adverse effects

    Patiromer was generally well tolerated in studies. Side effects that occurred in more than 2% of patients included in clinical trials were mainly gastro-intestinal problems such as constipation, diarrhea, nausea, and flatulence, and also hypomagnesemia (low levels of magnesium in the blood) in 5% of patients, because patiromer binds magnesium in the gut as well.[2][6]

    Interactions

    No interaction studies have been done in humans. Patiromer binds to many substances besides potassium, including numerous orally administered drugs (about half of those tested in vitro). This could reduce their availability and thus effectiveness,[2] wherefore patiromer has received a boxed warning by the US Food and Drug Administration (FDA), telling patients to wait for at least six hours between taking patiromer and any other oral drugs.[7]

    Pharmacology

    Mechanism of action

    Patiromer works by binding free potassium ions in the gastrointestinal tract and releasing calcium ions for exchange, thus lowering the amount of potassium available for absorption into the bloodstream and increasing the amount that is excreted via the feces. The net effect is a reduction of potassium levels in the blood serum.[2][4]

    Lowering of potassium levels is detectable 7 hours after administration. Levels continue to decrease for at least 48 hours if treatment is continued, and remain stable for 24 hours after administration of the last dose. After this, potassium levels start to rise again over a period of at least four days.[2]

    Pharmacokinetics

    Patiromer is not absorbed from the gut, is not metabolized, and is excreted in unchanged form with the feces.[2]

    Physical and chemical properties

    The substance is a cross-linked polymer of 2-fluoroacrylic acid (91% in terms of amount of substance) with divinylbenzenes (8%) and 1,7-octadiene (1%). It is used in form of its calcium salt (ratio 2:1) and with sorbitol (one molecule per two calcium ions or four fluoroacrylic acid units), a combination called patiromer sorbitex calcium.[8]

    Patiromer sorbitex calcium is an off-white to light brown, amorphous, free-flowing powder. It is insoluble in water, 0.1 M hydrochloric acid, heptane, and methanol.[2][8]

    Hyperkalemia Is a Clinical Challenge

    Hyperkalemia may result from increased potassium intake, impaired distribution between the intracellular and extracellular spaces, and/or conditions that reduce potassium excretion, including CKD, hypertension, diabetes mellitus, or chronic heart failure (HF) (Jain et al., 2012). Additionally, drugs and nutritional/herbal supplements (Table 1) can produce hyperkalemia in up to 88% of hospitalized patients by impairing normal potassium regulation (Hollander-Rodríguez and Calvert, 2006; Khanagavi et al., 2014).

    Although the prevalence of hyperkalemia in the general population is unknown, it is present in 1-10% of hospitalized patients depending on how hyperkalemia is defined (McMahon et al., 2012; Gennari, 2002). Hyperkalemia is a common problem in patients with conditions that reduce potassium excretion, especially when treated with beta-adrenergic blockers that inhibit Na+,K+-ATPase activity or RAAS inhibitors (RAASIs) [angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists or renin inhibitors] that decrease aldosterone excretion (Jain et al., 2012; Weir and Rolfe, 2010). The incidence of hyperkalemia with RAASIs in monotherapy is low (≤2%) in patients without predisposing factors, but increases with dual RAASIs (5%) and in patients with risk factors such as CKD, HF, and/or diabetes (5-10%) (Weir and Rolfe, 2010). Thus, hyperkalemia is a key limitation to fully titrate RAASIs in these patients who are most likely to benefit from treatment. Thus, we need new drugs to control hyperkalemia in these patients while maintaining the use of RAASIs.

     

    History

    Studies

    In a Phase III multicenter clinical trial including 237 patients with hyperkalemia under RAAS inhibitor treatment, 76% of participants reached normal serum potassium levels within four weeks. After subsequent randomization of 107 responders into a group receiving continued patiromer treatment and a placebo group, re-occurrence of hyperkalemia was 15% versus 60%, respectively.[9]

    Approval

    The US FDA approved patiromer in October 2015.[7] The drug is not approved in Europe as of January 2016.

    PATENT

    WO 2010132662

    PATENT

    WO 2010022383

    References

     

    • 1 Henneman, A; Guirguis, E; Grace, Y; Patel, D; Shah, B (2016). “Emerging therapies for the management of chronic hyperkalemia in the ambulatory care setting”. American Journal of Health-System Pharmacy 73 (2): 33–44. doi:10.2146/ajhp150457. PMID 26721532.
    • 2FDA Professional Drug Information for Veltassa.
    • 3Vanden Hoek TL, Morrison LJ, Shuster M, Donnino M, Sinz E, Lavonas EJ, Jeejeebhoy FM, Gabrielli A; Morrison; Shuster; Donnino; Sinz; Lavonas; Jeejeebhoy; Gabrielli (2010-11-02). “Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care”. Circulation 122 (18 Suppl 3): S829–61. doi:10.1161/CIRCULATIONAHA.110.971069. PMID 20956228.
    • 4Esteras, R.; Perez-Gomez, M. V.; Rodriguez-Osorio, L.; Ortiz, A.; Fernandez-Fernandez, B. (2015). “Combination use of medicines from two classes of renin-angiotensin system blocking agents: Risk of hyperkalemia, hypotension, and impaired renal function”. Therapeutic Advances in Drug Safety 6 (4): 166. doi:10.1177/2042098615589905. PMID 26301070.
    • 5Rastegar, A; Soleimani, M (2001). “Hypokalaemia and hyperkalaemia”. Postgraduate Medical Journal 77 (914): 759–64. doi:10.1136/pmj.77.914.759. PMC 1742191. PMID 11723313.
    • 6Tamargo, J; Caballero, R; Delpón, E (2014). “New drugs for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors — hype or hope?”. Discovery medicine 18 (100): 249–54. PMID 25425465.
    • 7″FDA approves new drug to treat hyperkalemia”. FDA. 21 October 2015.
    • 8RxList: Veltassa.
    • 9Weir, Matthew R.; Bakris, George L.; Bushinsky, David A.; Mayo, Martha R.; Garza, Dahlia; Stasiv, Yuri; Wittes, Janet; Christ-Schmidt, Heidi; Berman, Lance; Pitt, Bertram (2015). “Patiromer in Patients with Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors”. New England Journal of Medicine 372 (3): 211. doi:10.1056/NEJMoa1410853. PMID 25415805.

     

     

     

    Patiromer skeletal.svg
    Systematic (IUPAC) name
    2-Fluoropropenoic acid, cross-linked polymer with diethenylbenzene and 1,7-octadiene
    Clinical data
    Trade names Veltassa
    AHFS/Drugs.com entry
    Legal status
    Routes of
    administration
    Oral suspension
    Pharmacokinetic data
    Bioavailability Not absorbed
    Metabolism None
    Onset of action 7 hrs
    Duration of action 24 hrs
    Excretion Feces
    Identifiers
    CAS Number 1260643-52-4
    1208912-84-8 (calcium salt)
    ATC code None
    PubChem SID 135626866
    DrugBank DB09263
    UNII 1FQ2RY5YHH
    KEGG D10148
    ChEMBL CHEMBL2107875
    Synonyms RLY5016
    Chemical data
    Formula [(C3H3FO2)182·(C10H10)8·(C8H14)10]n

    [Ca91(C3H2FO2)182·(C10H10)8·(C8H14)10]n (calcium salt)

    ////

    Elotuzumab


     

    str2

    Elotuzumab

    Approved nov 30 2012

    A SLAMF7-directed immunostimulatory antibody used to treat multiple myeloma.

    (Empliciti®)

    HuLuc-63;BMS-901608

    cas 915296-00-3

     

     

     

    STR1

     

    Elotuzumab (brand name Empliciti, previously known as HuLuc63) is a humanized monoclonal antibody used in relapsed multiple myeloma.[1] The package insert denotes its mechanism as a SLAMF7-directed (also known as CD 319) immunostimulatory antibody.[2]

    Approvals and indications

    In May 2014, it was granted “Breakthrough Therapy” designation by the FDA. [3] On November 30, 2015, FDA approved elotuzumab as a treatment for patients with multiple myeloma who have received one to three prior medications.[1] Elotuzumab was labeled for use with lenalidomide and dexamethasone. Each intravenous injection of elotuzumab should be premedicated with dexamethasone, diphenhydramine, ranitidine and acetaminophen.[2]

     

    Elotuzumab is APPROVED for safety and efficacy in combination with lenalidomide and dexamethasone.

    Monoclonal antibody therapy for multiple myeloma, a malignancy of plasma cells, was not very clinically efficacious until the development of cell surface glycoprotein CS1 targeting humanized immunoglobulin G1 monoclonal antibody – Elotuzumab. Elotuzumab is currently APPROVED in relapsed multiple myeloma.

    Elotuzumab (HuLuc63) binds to CS1 antigens, highly expressed by multiple myeloma cells but minimally present on normal cells. The binding of elotuzumab to CS1 triggers antibody dependent cellular cytotoxicity in tumor cells expressing CS1. CS1 is a cell surface glycoprotein that belongs to the CD2 subset of immunoglobulin superfamily (IgSF). Preclinical studies showed that elotuzumab initiates cell lysis at high rates. The action of elotuzumab was found to be enhanced when multiple myeloma cells were pretreated with sub-therapeutic doses of lenalidomide and bortezomib. The impressive preclinical findings prompted investigation and analysis of elotuzumab in phase I and phase II studies in combination with lenalidomide and bortezomib.

    Elotuzumab As Part of Combination Therapy: Clinical Trial Results

    Elotuzumab showed manageable side effect profile and was well tolerated in a population of relapsed/refractory multiple myeloma patients, when treated with intravenous elotuzumab as single agent therapy. Lets’ take a look at how elotuzumab fared in combination therapy trials,

    In phase I trial of elotuzumab in combination with Velcade/bortezomib in patients with relapsed/refractory myeloma, the overall response rate was 48% and activity was observed in patients whose disease had stopped responding to Velcade previously. The trial results found that elotuzumab enhanced Velcade activity.
    A phase I/II trial in combination with lenalidomide and dexamethasone in refractory/relapsed multiple myeloma patients showed that 82% of patients responded to treatment with a partial response or better and 12% of patients showed complete response. Patients who had received only one prior therapy showed 91% response rate with elotuzumab in combination with lenalidomide and dexamethasone.


    Phase I/II trials of the antibody drug has been very impressive and the drug is currently into Phase III trials. Two phase III trials are investigating whether addition of elotuzumab with Revlimid and low dose dexamethasone would increase the time to disease progression. Another phase III trial (ELOQUENT 2) is investigating and comparing safety and efficacy of lenalidomide plus low dose dexamethasone with or without 10mg/kg of elotuzumab in patients with relapsed/refractory multiple myeloma.

    Elotuzumab is being investigated in many other trials too. It is being evaluated in combination with Revlimid and low-dose dexamethasone in multiple myeloma patients with various levels of kidney functions, while another phase II study is investigating elotuzumab’s efficacy in patients with high-risk smoldering myeloma.

    The main target of multiple myeloma drug development is to satisfy the unmet need for drugs that would improve survival rates. Elotuzumab is an example that mandates much interest in this area and should be followed with diligence.

     

    On November 30, 2015, the U. S. Food and Drug Administration approved elotuzumab (EMPLICITI, Bristol-Myers Squibb Company) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.
    Elotuzumab is a monoclonal antibody directed against Signaling Lymphocyte Activation Molecule Family 7 (SLAMF7). SLAMF7 is present on myeloma cells and is also present on natural killer cells.
    The approval was based on a multicenter, randomized, open-label, controlled trial evaluating progression-free survival (PFS) and overall response rate (ORR) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy.  A total of 646 patients were randomized (1:1) to receive elotuzumab in combination with lenalidomide and dexamethasone (n=321) or lenalidomide plus dexamethasone alone (n=325).  Patients continued treatment until disease progression or the development of unacceptable toxicity.
    The trial demonstrated a statistically significant improvement in both PFS and ORR, the trial’s co-primary endpoints.  The median PFS in the elotuzumab-containing arm was 19.4 months and 14.9 months in the lenalidomide plus dexamethasone alone arm (hazard ratio 0.70, 95% CI: 0.57, 0.85; p = 0.0004).  The ORR in the elotuzumab-containing arm was 78.5% (95% CI: 73.6, 82.9) compared to 65.5% (95% CI: 60.1, 70.7) in the lenalidomide plus dexamethasone alone arm (p=0.0002).
    The safety data reflect exposure in 318 patients to elotuzumab in combination with lenalidomide and dexamethasone and 317 patients to lenalidomide plus dexamethasone. The most common adverse reactions (greater than or equal to 20%), with an increased rate in the elotuzumab arm compared to the control arm, were fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, and pneumonia.
    Other important adverse reactions include infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with determination of complete response.  As elotuzumab is an IgG kappa monoclonal antibody, it can be detected in the serum protein electrophoresis and immunofixation assays used to assess response.
    Serious adverse events occurred in 65.4% of patients in the elotuzumab-containing arm compared to 56.5% in the lenalidomide plus dexamethasone alone arm. The most common serious adverse reactions were pneumonia, pyrexia, respiratory tract infection, anemia, pulmonary embolism, and acute renal failure.
    The recommended dose and schedule for elotuzumab is 10 mg/kg intravenously every week for the first two cycles and every 2 weeks, thereafter, until disease progression or unacceptable toxicity with lenalidomide 25 mg daily orally on days 1 through 21.  Dexamethasone is administered as follows: In weeks with elotuzumab infusion, dexamethasone is to be administered in divided doses, 8 mg intravenously prior to infusion and 28 mg orally; in weeks without elotuzumab infusion, dexamethasone is to be administered 40 mg orally.  Pre-medication with an H1 blocker, H2 blocker, and acetaminophen should be administered prior to elotuzumab infusion.
    Elotuzumab is being approved prior to the Prescription Drug User Fee Act (PDUFA) goal date of February 29, 2016.  This application was granted priority review and had breakthrough therapy designation.  A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

     

    Empliciti’s Cost

    Empliciti will be sold in the U.S. in two vials sizes: A smaller vial that contains 300 mg of the drug, and a larger vial that contains 400 mg.

    Bristol-Myers Squibb has informed The Beacon that the wholesale price per vial of Empliciti will be $1,776 for the 300 mg vial and $2,368 for the 400 mg vial.

    Using these prices and an assumed patient weight of between 154 and 176 pounds, Empliciti will cost $18,944 per four-week cycle for each of the first two cycles of treatment, and $9,472 per cycle there­after. This means, in turn, that Empliciti’s cost per year will be $142,080 in the first year and $123,136 in subsequent years.

    In comparison, Velcade costs between $4,800 and $8,500 per four-week cycle, depending on how often it is dosed. Ninlaro costs $8,670 per four-week cycle. And Kyprolis costs $10,500 per four-week cycle at the standard (20 – 27 mg/m2) dose.

    Additional details about the FDA approval of Empliciti can be found in this press release from the FDA, a related press release from Bristol-Myers Squibb and AbbVie, and the full Empliciti prescribing information.

    The results of the ELOQUENT-2 trial were published in Lonial, S. et al., “Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma,” The New England Journal of Medicine, June 2, 2015 (abstract). Slides from the ASCO presentation summarizing the ELOQUENT-2 results can be viewed here (PDF, courtesy of Dr. Lonial). This Beacon news article provides an in-depth look at the trial results.

     

    Elotuzumab
    Monoclonal antibody
    Type Whole antibody
    Source Humanized
    Target SLAMF7 (CD319)
    Clinical data
    Trade names Empliciti
    Pregnancy
    category
    • US: X (Contraindicated)
    Legal status
    Routes of
    administration
    IV
    Pharmacokinetic data
    Bioavailability 100% (IV)
    Identifiers
    CAS Number 915296-00-3 
    ATC code None
    IUPHAR/BPS 8361
    UNII 1351PE5UGS Yes
    Chemical data
    Formula C6476H9982N1714O2016S42
    Molecular mass 145.5 kDa

    References

     

    1 “Press Announcement—FDA approves Empliciti, a new immune-stimulating therapy to treat multiple myeloma”. U.S. Food and Drug Administration. Retrieved 3 December 2015.

    2“Empliciti (elotuzumab) for Injection, for Intravenous Use. Full Prescribing Information” (PDF). Empliciti (elotuzumab) for US Healthcare Professionals. Bristol-Myers Squibb Company, Princeton, NJ 08543 USA.

    3 “Bristol-Myers Squibb and AbbVie Receive U.S. FDA Breakthrough Therapy Designation for Elotuzumab, an Investigational Humanized Monoclonal Antibody for Multiple Myeloma” (Press release). Princeton, NJ & North Chicago, IL: Bristol-Myers Squibb. 2014-05-19. Retrieved 2015-02-05.

     

    ///////

    FDA approves new orphan drug Uptravi (selexipag) to treat pulmonary arterial hypertension


    Selexipag.svg

     

     KEEPING WATCHING THIS POSTS FOR SYNTHESIS UPDATES

    12/22/2015
    On December 21, the U.S. Food and Drug Administration approved Uptravi (selexipag) tablets to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive, and debilitating rare lung disease that can lead to death or the need for transplantation.

    December 22, 2015

    On December 21, the U.S. Food and Drug Administration approved Uptravi (selexipag) tablets to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive, and debilitating rare lung disease that can lead to death or the need for transplantation.

    “Uptravi offers an additional treatment option for patients with pulmonary arterial hypertension,” said Ellis Unger, M.D., director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research. “The FDA supports continued efforts to provide new treatment options for rare diseases.”

    PAH is high blood pressure that occurs in the arteries that connect the heart to the lungs. It causes the right side of the heart to work harder than normal, which can lead to limitations on exercise ability and shortness of breath, among other more serious complications.

    Uptravi belongs to a class of drugs called oral IP prostacyclin receptor agonists. The drug acts by relaxing muscles in the walls of blood vessels to dilate (open) blood vessels and decrease the elevated pressure in the vessels supplying blood to the lungs.

    Uptravi’s safety and efficacy were established in a long-term clinical trial of 1,156 participants with PAH. Uptravi was shown to be effective in reducing hospitalization for PAH and reducing the risks of disease progression compared to placebo. Participants were exposed to Uptravi in this trial for a median duration of 1.4 years.

    Common side effects observed in those treated with Uptravi in the trial include headache, diarrhea, jaw pain, nausea, muscle pain (myalgia), vomiting, pain in an extremity, and flushing.

    Uptravi was granted orphan drug designation. Orphan drug designation provides incentives such as tax credits, user fee waivers, and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

    Uptravi is marketed by San Francisco-based Actelion Pharmaceuticals US, Inc.

    Selexipag.svg

     

    Selexipag, Uptravi

    475086-01-2 CAS

    (C26H32N4O4S, Mr = 496.6 g/mol)

    A prostacyclin receptor (PGI2) agonist used to treat pulmonary arterial hypertension (PAH).

    NIPPON SHINYAKU….INNOVATOR

    Selexipag (brand name Uptravi) is a drug developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its active metabolite, ACT-333679 (MRE-269) (the free carboxylic acid), are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation.[1]

    The US FDA granted it Orphan Drug status[2] (for PAH). It was approved by the U.S. FDA on 22 December 2015.[2]

    ACT-333679 or MRE-269, the active metabolite of selexipag

     

     

     

    str1

     

     

    str1

     

    str1

     

     

    PATENT

    US2012/101276

    http://www.google.st/patents/US20120101276?hl=pt-PT&cl=en

    The present invention relates to a crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “compound A”).

     

     

    BACKGROUND OF THE INVENTION

    Compound A has an excellent PGI2 agonistic effect and shows a platelet aggregation inhibitory effect, a vasodilative effect, a bronchodilative effect, a lipid deposition inhibitory effect, a leukocyte activation inhibitory effect, etc. (see, for example, in WO 2002/088084 (“WO ‘084”)).

    Specifically, compound A is useful as preventive or therapeutic agents for transient ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud’s disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), hypertension, pulmonary hypertension, ischemic disorder (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcer, pressure ulcer (bedsore), restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved [e.g., Renal diseases (e.g., tuburointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease), digestive diseases (e.g., hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer), cardiovascular diseases (e.g, myocardial fibrosis), bone and articular diseases (e.g, bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinary diseases (e.g., prostatic hypertrophy), other diseases (e.g., Alzheimer’s disease, sclerosing peritonitis; type I diabetes and organ adhesion after operation)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostata, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet disease), gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) (there is no particular limitation for the intestinal damage so far as it is damage appearing in duodenum, small intestine and large intestine and examples thereof include mucosal damage such as erosion and ulcer generated in duodenum, small intestine and large intestine), and symptoms associated with lumbar spinal canal stenosis (e.g., paralysis, dullness in sensory perception, pain, numbness, lowering in walking ability, etc. associated with cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffuse spinal canal stenosis or sacral stenosis) etc. (see, for example, in WO ‘084, WO 2009/157396, WO 2009/107736, WO 2009/154246, WO 2009/157397, and WO 2009/157398).

    In addition, compound A is useful as an accelerating agent for angiogenic therapy such as gene therapy or autologous bone marrow transplantation, an accelerating agent for angiogenesis in restoration of peripheral artery or angiogenic therapy, etc. (see, for example, in WO ‘084).

    Production of Compound A

    Compound A can be produced, for example, according to the method described in WO ‘084, and, it can also be produced according to the production method mentioned below.

     

     

    Step 1:

    6-Iodo-2,3-diphenylpyrazine can be produced from 6-chloro-2,3-diphenylpyrazine by reacting it with sodium iodide. The reaction is carried out in the presence of an acid in an organic solvent (e.g., ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or their mixed solvent). The acid to be used is, for example, acetic acid, sulfuric acid, or their mixed acid. The amount of sodium iodide to be used is generally within a range of from 1 to 10 molar ratio relative to 6-chloro-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the acid to be used, but may be generally within a range of from 60° C. to 90° C. The reaction time varies depending on the kinds of the solvent and the acid to be used and on the reaction temperature, but may be generally within a range of from 9 hours to 15 hours.

    Step 2:

    5,6-Diphenyl-2-[(4-hydroxybutyl(isopropyl)amino]pyrazine can be produced from 6-iodo-2,3-diphenylpyrazine by reacting it with 4-hydroxybutyl(isopropyl)amine. The reaction is carried out in the presence of a base in an organic solvent (e.g., sulfolane, N-methylpyrrolidone, N,N-dimethylimidazolidinone, dimethyl sulfoxide or their mixed solvent). The base to be used is, for example, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate or their mixed base. The amount of 4-hydroxybutyl(isopropyl)amine to be used may be generally within a range of from 1.5 to 5.0 molar ratio relative to 6-iodo-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from 170° C. to 200° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 5 hours to 9 hours.

    Step 3:

    Compound A can be produced from 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine by reacting it with N-(2-chloroacetyl)methanesulfonamide. The reaction is carried out in the presence of a base in a solvent (N-methylpyrrolidone, 2-methyl-2-propanol or their mixed solvent). The base to be used is, for example, potassium t-butoxide, sodium t-butoxide or their mixed base. The amount of N-(2-chloroacetyl)methanesulfonamide to be used may be generally within a range of from 2 to 4 molar ratio relative to 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from −20° C. to 20° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 0.5 hours to 2 hours.

    The compounds to be used as the starting materials in the above-mentioned production method for compound A are known compounds, or can be produced by known methods.

    PATENT

    WO 2002088084

    and

    http://www.google.fm/patents/WO2009157398A1?cl=en

    PAPER

    Bioorganic and Medicinal Chemistry, 2007 ,  vol. 15,   21  p. 6692 – 6704

    compd 31

    PAPER

    Bioorganic and Medicinal Chemistry, 2007 ,  vol. 15,   24  p. 7720 – 7725

    Full-size image (5 K)2a isthe drug

    N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and their potential as prodrug forms of the carboxylic acid was evaluated in vitro and in vivo. These compounds were converted to the active compound 1 by hepatic microsomes from rats, dogs, monkeys, and humans, and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys. These types of analogues, including NS-304 (2a), are potentially useful prodrugs of 1.

    http://www.sciencedirect.com/science/article/pii/S0968089607007614

    str1

    PATENT

    WO 2011024874

     

    Example 1 t- butylamine Form I crystal of the salt
    Compound A (40 mg) with 0.5mL dimethoxyethane (hereinafter, referred to as. “DME”) was dissolved in, and t- butylamine (1.1 eq) were added, 25 1 ° C. at 8 it was stirred for hours. Thereafter, the reaction solution was added t- butyl methyl ether (1mL), at -20 ° C. 3 and held hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried, I-form crystals of t- butylamine salt ( 3 to afford 9.9mg). B Powder X-ray diffraction spectrum of type I crystal obtained t- butylamine salt using the apparatus shown in Figure 1.
    Melting point: 152.5 ℃
    elemental analysis (C 3 0 H 4 3 N 5 O 4 S + 0.0 3 H 2 as O)
    calculated value (%) C: 6 3 .1 8 H: 7 . 6 1 N: 12 .2 8 measured value (%) C: 6 2. 8 5 H: 7 . 6 4 N: 12.52 1 H-NMR (DMSO-D 6 ): delta 8 .15 (s, 1H), 7 .55 – 7 . 8 0 (M, 2H), 7 .10- 7 . .45 (M, 10H), 4 7 . 0-4 8 5 (M, 1H), 3 . 6 6 (s, 2H), 3 .4 7 (t, 2H), 3 .45 (t, 2H), 2. 7 3 (s, 3 H), 1.50-1. 7 5 (M, 4H), 1.2 3 (s, 9H), 1.22 (D, 6 H)
    Example 2 I-form crystal of the potassium salt
    Compound A tetrahydrofuran with (40mg) 12mL (hereinafter, referred to as. “THF”) was dissolved in, 0.1M aqueous potassium hydroxide solution (1.1 eq) was added, 40 ℃ It was heated and stirred in for 15 minutes. After that, it was evaporated under reduced pressure, the solvent. The residue it was added ethyl acetate (200μL). While shaking the mixture heated to 50 ° C. 8 was allowed to cool to 25 ℃ over hours. After repeated two more times this step, at -20 ° C. 3 and held hours. The resulting precipitated crystals were collected by filtration under reduced pressure, and dried to obtain Form I crystal of the potassium salt. B Powder X-ray diffraction spectrum of type I crystal of the obtained potassium salt using the apparatus shown in Fig. 1 H-NMR (DMSO-D 6 ): delta 8 .14 (s, 1H), 7 .1 8 – 7 . 3 8 . (M, 10H), 4 7 . 2-4 8 4 (M, 1H) , 3 . 6 5 (s, 2H), 3 .4 7 (t, 2H), 3 .45 (t, 2H), 2. 7 2 (s, 3 H), 1.55-1. 7 0 ( M, 4H), 1.2 3 (D, 6 H)
    Example 3  II-form crystals of the potassium salt
    Compound A with (40mg) was dissolved in THF and 12mL, 0.1M aqueous potassium hydroxide solution (1.1 eq) was added and heated with stirring for 15 min at 40 ℃. After that, it was evaporated under reduced pressure, the solvent. The residue it was added ethyl acetate (200μL). While shaking the mixture heated to 50 ° C. 8 was allowed to cool to 25 ℃ over hours. This operation was repeated two more times, at -20 ° C. 3 and held hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, after drying, 40 ℃, relative humidity 7 while 5% of thermo-hygrostat 7 left for days to give crystalline Form II of the potassium salt. B Powder X-ray diffraction spectrum of crystalline Form II of the resulting potassium salt using the apparatus Fig 3 is shown in.

    Example 4 III type crystal of the potassium salt
    Compound A , in addition to (100mg) acetonitrile (1mL), and stirred with heating, Compound A was dissolved, followed by cooling to 20 ℃. To a solution 3 .5M potassium hydroxide / ethanol solution (1.1 eq) was added and stirred for 200 minutes at 20 ℃. While stirring the mixture 7 after a heated stirring for 1 hour to 0 ° C., and then cooled to 10 ℃ over 10 hours. Further heated while the mixture 6 is heated to 0 ℃, t- butyl methyl ether (0. 3 after adding mL), cooled to 20 ℃ over 10 hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried, III type crystal of the potassium salt ( 7 to afford 5mg). The powder X-ray diffraction spectrum of the type III crystal of the obtained potassium salt using R unit is shown in FIG. Furthermore, in differential scanning calorimetry, of about 7 endothermic peak was observed at around 4 ° C..
    Elemental analysis (C 2 6 H 3 1 N 4 O 4 . SK + 0 7 8 H 2 as O)
    calculated value (%) C: 5 6 .91 H: 5.9 8 N: 10.21
    measured value (%) C: 5 6 . 6 1 H: 5.55 N:. 10 3 6

    EXAMPLE 5 IV-type crystal of the potassium salt
    Compound A , in addition to (50mg) and ethyl acetate (1mL), and stirred with heating, Compound A was dissolved, followed by cooling to 20 ℃. To a solution 3 .5M potassium hydroxide / ethanol solution (2.2 eq) was added and 2 at 20 ° C. 3 and stirred for hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried to obtain Form IV crystal of the potassium salt (41mg). The powder X-ray diffraction spectrum of crystalline Form IV of the resulting potassium salt using R unit is shown in FIG. Furthermore, in differential scanning calorimetry, an endothermic peak was observed at around approximately 91 ℃.

    str1

    Selexipag (C26H32N4O4S, Mr = 496.6 g/mol) ist ein Diphenylpyrazin-Derivat. Es wird in der Leber zum aktiven Metaboliten ACT-333679 (MRE-269) biotransformiert. Selexipag unterscheidet sich strukturell von Prostazyklin und anderen Prostazylin-Rezeptor-Agonisten.

     

     

     

     

    References

     

     

    1. Kuwano et al. NS-304, an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007;322:1181-1188.
    2. Kuwano et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, NS-304, ameliorates rat pulmonary hypertension with unique relaxant responses of its active form MRE-269 on rat pulmonary artery. J Pharmacol Exp Ther 2008;326:691-699.
    3. Simonneau G, Lang I, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N. Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension Eur Respir J 2012; 40: 874-880
    4. Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.
    5. Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812. PMID 23204120.
    Patent Submitted Granted
    Methods of identifying critically ill patients at increased risk of development of organ failure and compounds for the treatment hereof [US8877710] 2009-12-30 2014-11-04
    Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and method for producing the same [US8791122] 2010-06-25 2014-07-29
    COMPOUNDS CAPABLE OF MODULATING/PRESERVING ENDOTHELIAL INTEGRITY FOR USE IN PREVENTION OR TREATMENT OF ACUTE TRAUMATIC COAGULOPATHY AND RESUSCITATED CARDIAC ARREST [US2015057325] 2013-03-26 2015-02-26
    INHIBITION OF NEOVASCULARIZATION BY SIMULTANEOUS INHIBITION OF PROSTANOID IP AND EP4 RECEPTORS [US2014275200] 2014-03-05 2014-09-18
    INHIBITION OF NEOVASCULARIZATION BY INHIBITION OF PROSTANOID IP RECEPTORS [US2014275238] 2014-03-05 2014-09-18
    Fibrosis inhibitor [US8889693] 2014-04-10 20
    Patent Submitted Granted
    Heterocyclic compound derivatives and medicines [US7205302] 2004-05-27 2007-04-17
    METHODS OF IDENTIFYING CRITICALLY ILL PATIENTS AT INCREASED RISK OF DEVELOPMENT OF ORGAN FAILURE AND COMPOUNDS FOR THE TREATMENT HEREOF [US2014322207] 2014-07-11 2014-10-30
    THERAPEUTIC COMPOSITIONS CONTAINING MACITENTAN [US2014329824] 2014-07-18 2014-11-06
    Sustained Release Composition of Prostacyclin [US2014303245] 2012-08-10 2014-10-09
    COMPOUNDS CAPABLE OF MODULATING/PRESERVING ENDOTHELIAL INTEGRITY FOR USE IN PREVENTION OR TREATMENT OF ACUTE TRAUMATIC COAGULOPATHY AND RESUSCITATED CARDIAC ARREST [US2013261177] 2011-09-30 2013-10-03
    METHODS OF TREATMENT OF PATIENTS AT INCREASED RISK OF DEVELOPMENT OF ISCHEMIC EVENTS AND COMPOUNDS HEREOF [US2013040898] 2011-04-29 2013-02-14
    Substituted Diphenylpyrazine Derivatives [US2013005742] 2010-08-06 2013-01-03
    USE OF FORM-I CRYSTAL OF 2–N-(METHYLSULFONYL)ACETAMIDE [US2014148469] 2014-01-22 2014-05-29
    CRYSTALS OF 2- {4- [N- (5,6-DIPHENYLPYRAZIN-2-YL) -N-ISOPROPYLAMINO]BUTYLOXY}-N- (METHYLSULFONYL) ACETAMIDE [US2014155414] 2014-01-22 2014-06-05
    PROSTACYCLIN AND ANALOGS THEREOF ADMINISTERED DURING SURGERY FOR PREVENTION AND TREATMENT OF CAPILLARY LEAKAGE [US2014044797] 2012-03-30 2014-02-13

     

     

     

    Selexipag
    Selexipag.svg
    Names
    IUPAC name

    2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide
    Other names

    ACT-293987, NS-304
    Identifiers
    475086-01-2 Yes
    ChEMBL ChEMBL238804 
    ChemSpider 8089417 Yes
    7552
    Jmol interactive 3D Image
    KEGG D09994 Yes
    PubChem 9913767
    UNII P7T269PR6S Yes
    Properties
    C26H32N4O4S
    Molar mass 496.6 g·mol−1

     

    SEE……….http://apisynthesisint.blogspot.in/2015/12/fda-approves-new-orphan-drug-uptravi.html

    //////////

    CC(C)N(CCCCOCC(=O)NS(=O)(=O)C)C1=CN=C(C(=N1)C2=CC=CC=C2)C3=CC=CC=C3

    FDA approves first emergency treatment for overdose of certain types of chemotherapy


    Uridine triacetate.svg
    12/11/2015 12:05 PM EST
    The U.S. Food and Drug Administration today approved Vistogard (uridine triacetate) for the emergency treatment of adults and children who receive an overdose of the cancer treatment fluorouracil or capecitabine, or who develop certain severe or life-threatening toxicities within four days of receiving these cancer treatments.

    December 11, 2015

    Release

    The U.S. Food and Drug Administration today approved Vistogard (uridine triacetate) for the emergency treatment of adults and children who receive an overdose of the cancer treatment fluorouracil or capecitabine, or who develop certain severe or life-threatening toxicities within four days of receiving these cancer treatments.

    “Treating cancer requires not only selecting which drug may be most effective and well tolerated, but ensuring the correct dose is given at proper intervals. While rare, unintentional overdose can occur,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval is a first-of-its-kind therapy that can potentially save lives following overdose or life-threatening toxicity from these chemotherapy agents.”

    Fluorouracil (taken by infusion) and capecitabine (taken orally) are similar types of chemotherapy that have been used for decades to treat several types of cancer, including breast and gastrointestinal cancers. An overdose of fluorouracil or capecitabine is rare, but when it occurs, the effects are serious and can be fatal.

    Vistogard, taken orally, blocks cell damage and cell death caused by fluorouracil chemotherapy. Patients should take Vistogard as soon as possible after the overdose (whether or not they have symptoms) or early-onset (within four days) of severe or life-threatening toxicity. The patient’s health care provider will determine when he or she should return to the prescribed chemotherapy after treatment with Vistogard.

    The efficacy and safety of Vistogard were studied in 135 adult and pediatric cancer patients who were treated in two separate trials and had either received an overdose of flourouracil or capecitabine, or had early-onset, unusually severe or life-threatening toxicities within 96 hours after receiving flourouracil (not due to an overdose). The studies’ primary measure was survival at 30 days or until chemotherapy could resume if prior to 30 days. Of those who were treated with Vistogard for overdose, 97 percent were still alive at 30 days. Of those treated with Vistogard for early-onset severe or life-threatening toxicity, 89 percent were alive at 30 days. In both studies, 33 percent of patients resumed chemotherapy in less than 30 days.

    Vistogard is not recommended for treating non-emergency adverse reactions associated with flourouracil or capecitabine because Vistogard may lessen the efficacy of these drugs. The safety and efficacy of Vistogard initiated more than 96 hours following the end of treatment with flourouracil or capecitabine have not been established.

    The most common side effects of treatment with Vistogard were diarrhea, vomiting and nausea.

    The FDA granted Vistogard orphan drug designation, which provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Vistogard was also granted priority review and fast track designations, which are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions.

    Vistogard is marketed by Wellstat Therapeutics Corporation based in Gaithersburg, Maryland.

     UPDATED IN SEPT 2016…………..
     ChemSpider 2D Image | uridine triacetate | C15H18N2O9
    2',3',5'-Tri-O-acetyluridine.png
    Uridine triacetate
    Uridine, 5-hydroxy-, 2′,3′,5′-triacetate
    2′,3′,5′-Tri-O-acétyluridine
    223-881-5 [EINECS]
    CAS 4105-38-8
    Priority review drug 
    Orphan drug
    FAST TRACK
    MF C15H18N2O9, MW 370.314
    [(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-2-yl]methyl acetate
    Vistogard [Trade name]
    Xuriden [Trade name]
    (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl diacetate
    Wellstat (Originator)
    PN-401; RG-2133; TAU
    MOA:Pyrimidine analog
    Indication:Hereditary orotic aciduria; Chemotherapy induced poisoning
    To treat patients with hereditary orotic aciduria
    Drug Name(s) XURIDEN
    FDA Application No. (NDA) 208169
    Active Ingredient(s) URIDINE TRIACETATE
    Company WELLSTAT THERAP
    Original Approval or Tentative Approval Date September 4, 2015

    FDA APPROVAL SUMMARY

    Chemotherapy induced poisoning, VISTOGARD, FDA 2015-12-11

    Hereditary orotic aciduria, Xuriden, FIRST APPROVAL, 2015-09-04

     Image result for SYNTHESIS, Uridine triacetate

    2′,3′,5′-tri-O-acetyluridine
    2′,3′,5′-Triacetyluridine
    Tri-O-acetyluridine
    Triacetyl uridine
    Triacetyluridine
    Uridine 2′,3′,5′-triacetate
    Vistonuridine
    External Identifiers
    • PN 401
    • PN-401
    • PN401
    • RG 2133
    • RG-2133
    • RG2133

    Uridine triacetate is a drug used in the treatment of hereditary orotic aciduria[1] and to treat patients following an overdose ofchemotherapy drugs 5-fluorouracil or capecitabine, or in patients exhibiting early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of 5-fluorouracil or capecitabine administration.[2][3]

    Uridine triacetate was developed, manufactured and distributed by Wellstat Therapeutics and it is marketed in USA by BTG. Also, It was granted breakthrough therapy designation by FDA in 2015.

    Uridine triacetate is a prodrug of uridine.[4]

    Uridine triacetate, formerly known as vistonuridine, is an orally active prodrug of the naturally occurring nucleoside uridine. It is used for the treatment of hereditary orotic aciduria (Xuriden), or for the emergency treatment of fluorouracil or capecitabine overdose or toxicity (Vistogard). It is provided in the prodrug form as uridine triacetate as this form delivers 4- to 6-fold more uridine into the systemic circulation compared to equimolar doses of uridine itself. When used for the treatment or prevention of toxicity associated with fluorouracil and other antimetabolites, uridine triacetate is utilized for its ability to compete with 5-fluorouracil (5-FU) metabolites for incorporation into the genetic material of non-cancerous cells. It reduces toxicity and cell-death associated with two cytotoxic intermediates: 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). Normally, FdUMP inhibits thymidylate synthase required for thymidine synthesis and DNA replication and repair while FUTP incorporates into RNA resulting in defective strands. As a result, these metabolites are associated with various unpleasant side effects such as neutropenia, mucositis, diarrhea, and hand–foot syndrome. Like many other neoplastic agents, these side effects limit the doses of 5-FU that can be administered, which also affects the efficacy for treatment. By pre-administering with uridine (as the prodrug uridine triacetate), higher doses of 5-FU can be given allowing for improved efficacy and a reduction in toxic side effects [3]. It can also be used as a rescue therapy if severe side effects present within 96 hours after initiation of therapy. Uridine triacetate is also used for the treatment of hereditary orotic aciduria, also known as uridine monophosphate synthase deficiency. This rare congenital autosomal recessive disorder of pyrimidine metabolism is caused by a defect in uridine monophosphate synthase (UMPS), a bifunctional enzyme that catalyzes the final two steps of the de novo pyrimidine biosynthetic pathway. As a result of UMPS deficiency, patients experience a systemic deficiency of pyrimidine nucleotides, accounting for most symptoms of the disease. Additionally, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Furthermore, orotic acid crystals in the urine can cause episodes of obstructive uropathy. When administered as the prodrug uridine triacetate, uridine can be used by essentially all cells to make uridine nucleotides, which compensates for the genetic deficiency in synthesis in patients with hereditary orotic aciduria. When intracellular uridine nucleotides are restored into the normal range, overproduction of orotic acid is reduced by feedback inhibition, so that urinary excretion of orotic acid is also reduced.

    Image result for SYNTHESIS, Uridine triacetate

    Marketed as the product Xuriden (FDA), uridine triacetate is indicated for the treatment of hereditary orotic aciduria. Marketed as the product Vistogard (FDA), uridine triacetate is indicated for the emergency treatment of adult and pediatric patients in the following situations: following a fluorouracil or capecitabine overdose regardless of the presence of symptoms; or who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration.

    Image result for SYNTHESIS, Uridine triacetateImage result for SYNTHESIS, Uridine triacetate

    Uridine Triacetate was approved by the U.S. Food and Drug Administration (FDA) on Sep 4, 2015. It was developed by Wellstat Therapeutics, then marketed as Xuriden® by Wellstat Therapeutics in US. Then it was also approved by FDA for overdose of certain types of chemotherapy on Dec 11, 2015 and marketed as Vistogard®.

    Uridine Triacetate is a prodrug of the nucleoside uridine used to treat hereditary orotic aciduria. Hereditary orotic aciduria is inherited from a recessive gene. The disease is due to a defective or deficient enzyme, which results in the body being unable to normally synthesize uridine, a necessary component of ribonucleic acid (RNA). Signs and symptoms of the disease include blood abnormalities (anemia, decreased white blood cell count, decreased neutrophil count), urinary tract obstruction due to the formation of orotic acid crystals in the urinary tract, failure to thrive, and developmental delays.

    Xuriden® is approved as oral granules that can be mixed with food or in milk or infant formula, and is administered once daily. The starting dosage is 60 mg/kg once daily; the dose may be increased to 120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy.

    Mechanism Of Action

    Uridine triacetate is an acetylated form of uridine. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases present throughout the body, yielding uridine in the circulation (Figure 1).

    Figure 1: Uridine Triacetate Conversion to Uridine

    Uridine Triacetate Conversion to Uridine - Illustration

    URIDEN provides uridine in the systemic circulation of patients with hereditary orotic aciduria who cannot synthesize adequate quantities of uridine due to a genetic defect in uridine nucleotide synthesis.

    Uridine triacetate is a synthetic uridine pro-drug that is converted to uridine in vivo. When used for the treatment or prevention of toxicity associated with fluorouracil and other antimetabolites, uridine triacetate is utilized for its ability to compete with 5-fluorouracil (5-FU) metabolites for incorporation into the genetic material of non-cancerous cells. It reduces toxicity and cell-death associated with two cytotoxic intermediates: 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). By pre-administering with uridine (as the prodrug uridine triacetate), higher doses of 5-FU can be given allowing for improved efficacy and a reduction in toxic side effects [A18578] such as neutropenia, mucositis, diarrhea, and hand–foot syndrome. Uridine triacetate is also used for replacement therapy in the treatment of hereditary orotic aciduria, also known as uridine monophosphate synthase (UMPS) deficiency. As a result of UMPS deficiency, patients experience a systemic deficiency of pyrimidine nucleotides, accounting for most symptoms of the disease. Additionally, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Furthermore, orotic acid crystals in the urine can cause episodes of obstructive uropathy. When administered as the prodrug uridine triacetate, uridine can be used by essentially all cells to make uridine nucleotides, which compensates for the genetic deficiency in synthesis in patients with hereditary orotic aciduria.

    Route 1

    Reference:1. J. Am. Chem. Soc. 1953, 75, 2017-2019.

    2. Angew. Chem. internat. Edit. 1971, 10, 75.

    3. US3116282.

    PATENT

    Production Example 1

    Figure US06900298-20050531-C00001

    5.6 g of uracil and 0.1 g of ammonium sulfate were dissolved in 22.4 ml of 1,1,1,3,3,3-hexamethyldisilazane and reacted at 120° C. for 2.5 hours. After the completion of the reaction, the reaction mixture was distilled to give 11.8 g of 2,4-bis(trimethylsilyloxy)-1,3-diazine. 1H-NMR (400 MHz, in C2D6CO): δ=0.29 (s, 9H), 0.31 (s, 9H), 6.35 (d, J=5.6 Hz, 1H), 8.19 (d, J=5.5Hz, 1H)

    Referential Example 11.21 g of 2,4-bis(trimethylsilyloxy)-1,3-diazine obtained in PRODUCTION EXAMPLE 1 and 1.15 g of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose were dissolved in 4.8 ml of acetonitrile and cooled to 5° C. Next, 0.94 g of SnCl4 was added dropwise thereinto at the same temperature. After stirring for 10 minutes at the same temperature, the mixture was heated to 50° C. and reacted for 3 hours. The reaction mixture was analyzed by HPLC. Thus, β-uridine triacetate was obtained with a reaction yield of 83%.

    Example 1

    Figure US06900298-20050531-C00002

    0.93 g of 2,4-bis(trimethylsilyloxy)-1,3-diazine obtained in PRODUCTION EXAMPLE 1 and 0.92 g of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose were dissolved in 4.7 ml of acetonitrile and cooled to 4° C. Then 0.49 g of FeCl3 was added thereto at the same temperature. After stirring for 10 minutes at the same temperature, the mixture was heated to 50° C. and reacted. The reaction was monitored by HPLC. After the completion of the reaction, the reaction mixture was added dropwise at 4° C. into a cold aqueous solution of sodium hydrogencarbonate which had been preliminarily prepared. After filtering off the catalyst residue, the filtrate was separated and the aqueous layer was extracted with 20 ml portions of ethyl acetate thrice. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After distilling off the solvent, 1.2 g (purity 80%) of the target compound was obtained as a viscous white solid.

    Namely, the target compound could be obtained at a yield comparable to REFERNTIAL EXAMPLE 1 wherein SnCl4 was employed as the catalyst. 1H-NMR (400 MHz, in CDCl3): δ=2.11 (s, 3H), 2.14 (s, 3H), 2.15 (s, 3H), 4.35 (m, 3H), 5.33 (m, 2H), 5.79 (d, J=8.2 Hz, 1H), 6.04 (d, J=4.9 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H)

    Image result for SYNTHESIS, Uridine triacetate

    CLIP

    12/11/2015 12:05 PM EST
    The U.S. Food and Drug Administration today approved Vistogard (uridine triacetate) for the emergency treatment of adults and children who receive an overdose of the cancer treatment fluorouracil or capecitabine, or who develop certain severe or life-threatening toxicities within four days of receiving these cancer treatments.

    December 11, 2015

    Release

    The U.S. Food and Drug Administration today approved Vistogard (uridine triacetate) for the emergency treatment of adults and children who receive an overdose of the cancer treatment fluorouracil or capecitabine, or who develop certain severe or life-threatening toxicities within four days of receiving these cancer treatments.

    “Treating cancer requires not only selecting which drug may be most effective and well tolerated, but ensuring the correct dose is given at proper intervals. While rare, unintentional overdose can occur,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval is a first-of-its-kind therapy that can potentially save lives following overdose or life-threatening toxicity from these chemotherapy agents.”

    Fluorouracil (taken by infusion) and capecitabine (taken orally) are similar types of chemotherapy that have been used for decades to treat several types of cancer, including breast and gastrointestinal cancers. An overdose of fluorouracil or capecitabine is rare, but when it occurs, the effects are serious and can be fatal.

    Vistogard, taken orally, blocks cell damage and cell death caused by fluorouracil chemotherapy. Patients should take Vistogard as soon as possible after the overdose (whether or not they have symptoms) or early-onset (within four days) of severe or life-threatening toxicity. The patient’s health care provider will determine when he or she should return to the prescribed chemotherapy after treatment with Vistogard.

    The efficacy and safety of Vistogard were studied in 135 adult and pediatric cancer patients who were treated in two separate trials and had either received an overdose of flourouracil or capecitabine, or had early-onset, unusually severe or life-threatening toxicities within 96 hours after receiving flourouracil (not due to an overdose). The studies’ primary measure was survival at 30 days or until chemotherapy could resume if prior to 30 days. Of those who were treated with Vistogard for overdose, 97 percent were still alive at 30 days. Of those treated with Vistogard for early-onset severe or life-threatening toxicity, 89 percent were alive at 30 days. In both studies, 33 percent of patients resumed chemotherapy in less than 30 days.

    Vistogard is not recommended for treating non-emergency adverse reactions associated with flourouracil or capecitabine because Vistogard may lessen the efficacy of these drugs. The safety and efficacy of Vistogard initiated more than 96 hours following the end of treatment with flourouracil or capecitabine have not been established.

    The most common side effects of treatment with Vistogard were diarrhea, vomiting and nausea.

    The FDA granted Vistogard orphan drug designation, which provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Vistogard was also granted priority review and fast track designations, which are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions.

    Vistogard is marketed by Wellstat Therapeutics Corporation based in Gaithersburg, Maryland.

    CLIP

    With support from Almac, Wellstat delivers for a rare disease.

    Proximity of API and finished drug development helps uridine triacetate to market for two indications

    By Rick Mullin

    “The initial contact was a cold call by Almac in 2010 or 2011,” recalls Mike Bamat, senior vice president of R&D at Wellstat Therapeutics, a small drug company in Gaithersburg, Md. “There were probably a couple of calls. It was one of those things where timing is everything.”

    Almac, a Craigavon, Northern Ireland-based pharmaceutical services company, was looking to get in on Wellstat’s development of uridine triacetate, a synthetic pyrimidine analog, as an antidote for fluorouracil and capecitabine toxicity and overdose in cancer patients receiving those chemotherapies. And the calls, which Almac records indicate followed some communication between the companies, happened to come just when Wellstat was looking to change service partners as it moved toward commercial development of the drug.


    Uridine triacetate

    Discovery: Wellstat Therapeutic’s research on the therapeutic potential of exogenous uridine leads to a determination that uridine triacetate is a safe means of delivering the agent
    Applications: Treatment of hereditary orotic aciduria (HOA), an extremely rare disease in which the body does not produce uridine, causing overproduction of orotic acid; emergency treatment of toxic reaction to or overdose of the cancer treatments fluorouracil and capecitabine
    Methods of action: Treating HOA, uridine triacetate restores intracellular nucleotide concentrations, normalizing orotic acid production; as a chemotherapy antidote, it increases intracellular levels of uridine to dilute fluorouracil and capecitabine
    Years in development: Since 2008 for chemotherapy antidote, and 2013 for HOA
    Approved: Xuriden for HOA, Sept. 4, 2015; Vistogard for chemotherapy antidote, Dec. 11, 2015


    The job went to Almac, as did work that sprang up as the result of another phone call to Wellstat—this one from the U.S. Food & Drug Administration.

    As Bamat explains, uridine triacetate caught FDA’s attention regarding another potential indication—an extremely rare and life-threatening disease called hereditary orotic aciduria, or HOA. A consequence of the body’s inability to produce uridine, a necessary component of ribonucleic acid, HOA can manifest in a range of symptoms including blood abnormalities, developmental delays, and urinary tract obstruction caused by overproduction of orotic acid. There have been 20 reported cases of HOA since the 1950s. Only four cases are currently known in the U.S., Bamat says, and likely fewer than 20 in the world.

    Wellstat landed approvals for Xuriden, the HOA treatment, in September of last year and Vistogard, the chemotherapy antidote, in December.

    The story of Xuriden centers on a raft of FDA incentives for super-rare diseases that enabled Wellstat to move forward on an expedited application for a drug that will never be made in any great volume. But bringing Xuriden and Vistogard to market may also be viewed as the story of a drug discovery firm becoming a commercial enterprise thanks to its partnership with a service provider.

    As Wellstat began late-stage development of the chemotherapy antidote, its research partner at the time, QS Pharma, was acquired by the service firm WIL Research. The look and feel of the partnership changed, according to Bamat.

    “We kind of lost the small, easy-to-work-with relationship we had with them,” he says. Wellstat also needed support on development and manufacturing of a finished drug product composed of granules delivered in packets or sachets. The drug is administered orally, usually sprinkled on food such as applesauce or yogurt.

    Almac was deemed a good fit because of its experience with developing drugs in granule form for “sachet presentation,” a packaging method more common in Europe than in the U.S. The Northern Ireland firm’s ability to develop and manufacture the active pharmaceutical ingredient (API) and the drug product in one location—at its headquarters—would also prove to be a significant advantage.

    The distance between Gaithersburg and Craigavon, however, was a concern, according to Bamat. “We debated it. Especially those of us who knew we would be going there,” he says. “We couldn’t just jump in a car and go. But we looked at a variety of things, including cost and value, and it was all very positive at Almac.”

    According to David Downey, vice president of commercial operations at Almac, bringing Wellstat’s work on uridine triacetate to commercial production posed several challenges, the first being to secure supply of uridine starting material, which is extracted from sugar beets by Euticals, an Italian firm. Next was developing a method to control particle size in both the API and the finished product. Almac also had to validate process equipment as it scaled up production.

    “Uridine triacetate is Wellstat’s first commercial product,” Downey says. “So we were provided with a process more fit for development than for commercial production.”

    The basic formulation of a granule drug product is simple, according to Downey: The API and excipient are mixed in a dry blender. The challenge is developing an analytical regimen to assure the granules are blended uniformly. Meeting the challenge required a high level of coordination between API and drug product process development.

    “Wellstat needed a partner that could support them from the API to the drug product,” Downey says. The physical proximity between the Almac facilities in Craigavon conducting API and drug product work was a key advantage, he claims.

    09414-cover-drugscxd
    Uridine triacetate is formulated into granules presented in packets and sprinkled on food.
    Credit: Wellstat Therapeutics

    “If you listen to our business development people, you’ll hear them use the term, ‘crossing car parks as opposed to crossing oceans,’ ” Downey says, explaining that many competitors who offer API and finished drug services run these operations thousands of kilometers apart from each other, sometimes on different continents.

    Before it signed on with Almac, Wellstat had been working with uridine triacetate for about 10 years. Its focus on developing the antidote drug started in 2008. Branching into the HOA treatment, however, upped the stakes.

    Clinical study development for an HOA therapy was expedited via a full house of regulatory incentives from FDA, according to Bamat. “We had orphan drug designation, rare pediatric designation, breakthrough therapy designation, and priority review,” he says. “So they really went all out in helping us develop this.”

    Although Wellstat was interested in developing a life saving drug for children, it was concerned about paying for it, given the tiny market. “At that time, the rare pediatric disease priority review voucher program was just on the radar,” Bamat says. “FDA said, ‘Consider this new program. Maybe it’s a way that at some risk you could recoup some of your costs.’ We looked at it and were willing to take the risk.”

    It paid off. Wellstat was able to sell its priority review voucher—which entitles a company that brings a rare pediatric drug to market to receive expedited review of a subsequent drug—to AstraZeneca last year for an undisclosed amount. Other vouchers sold in 2015 brought high sums, including $350 million for one that AbbVie bought from United Therapeutics in August.

    Bamat says Wellstat is not likely to change focus after its success with uridine triacetate. It continues to investigate new indications for the compound and will likely work with Almac on anything going into commercial development.

    He emphasizes the importance of maintaining an effective working relationship with an outsourcing partner. “My main consideration is that these are people we can really work with on a day-to-day, week-to-week basis,” Bamat says. “Will the communication be good? Will they be honest and transparent with us, and will we be the same for them? That was a key factor, and we felt it was a plus with Almac.”

    Uridine triacetate
    Uridine triacetate.svg
    Clinical data
    Trade names Vistogard, Xuriden
    Routes of
    administration
    Oral granules
    Legal status
    Legal status
    Pharmacokinetic data
    Metabolism Pyrimidine catabolic pathway
    Onset of action Tmax = 2-3 hours
    Biological half-life 2-2.5 hours
    Excretion Renal
    Identifiers
    DrugBank DB09144
    Chemical data
    Formula C15H18Cl0N2O9S0
    Molar mass 370.31 g·mol−1

    References

    1.  HIGHLIGHTS OF PRESCRIBING INFORMATION OF XURIDEN
    2. Jump up^ BTG Announces FDA Approval of VISTOGARD® (Uridine Triacetate) as Antidote to Overdose and Early Onset, Severe, or Life-Threatening Toxicities from Chemotherapy Drugs 5-Fluorouracil (5-FU) or Capecitabine
    3. Jump up^ “FDA Approved Drugs:Uridine Triacetate”. FDA. 2015-12-11. Retrieved 2016-04-29.
    4.  “Uridine triacetate”. DrugBank.
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    US5047520 1991-09-10 2′-alkylidenepyrimidine nucleoside derivatives, process for production thereof, and uses thereof
    EP0204264 1990-08-16 CONVERSION OF URACIL DERIVATIVES TO CYTOSINE DERIVATIVES
    WO8903837 1989-05-05 ACYLATED URIDINE AND CYTIDINE AND USES THEREOF
    US4754026 1988-06-28 Conversion of uracil derivatives to cytosine derivatives
    Patent ID Date Patent Title
    US7807654 2010-10-05 Compositions and methods for treatment of mitochondrial diseases
    US2010222296 2010-09-02 PYRIMIDINES, SUCH AS URIDINE, IN TREATMENTS FOR PATIENTS WITH BIPOLAR DISORDER
    US7737128 2010-06-15 Pyrimidines, such as uridine, in treatments for patients with bipolar disorder
    US2010098678 2010-04-22 Methods of Treatment of Mitochondrial Disorders
    US2010041620 2010-02-18 METHODS FOR IMPROVING FRONTAL BRAIN BIOENERGETIC METABOLISM
    US2010041621 2010-02-18 METHODS AND COMPOSITIONS FOR IMPROVING COGNITIVE PERFORMANCE
    US7582619 2009-09-01 Compositions and methods for treatment of mitochondrial diseases
    US2008226684 2008-09-18 METHOD AND PROCESS FOR THE PRODUCTION OF MULTI-COATED RECOGNITIVE AND RELEASING SYSTEMS
    US7105498 2006-09-12 Acylated uridine and cytidine and uses thereof
    US6956028 2005-10-18 Compositions and methods for treatment of mitochondrial diseases
    Patent ID Date Patent Title
    US2015307542 2015-10-29 MODIFIED NUCLEIC ACID MOLECULES AND USES THEREOF
    US2015167017 2015-06-18 ALTERNATIVE NUCLEIC ACID MOLECULES AND USES THEREOF
    US8821899 2014-09-02 Method and process for the production of multi-coated recognitive and releasing systems
    US8771713 2014-07-08 Method and process for the production of multi-coated recognitive and releasing systems
    US8741316 2014-06-03 Highly porous, recognitive polymer systems
    US2012294869 2012-11-22 Methods for Treating Fatty Liver Disease
    US2012078529 2012-03-29 DETERMINING THE SEVERITY OF 5-FLUOROURACIL OVERDOSE
    US8067392 2011-11-29 Compositions and methods for treatment of mitochondrial diseases
    US7915233 2011-03-29 Compositions and methods for treatment of mitochondrial diseases
    US7884202 2011-02-08 Nucleobase Having Perfluoroalkyl Group and Process for Producing the Same
    //////////174105-38-8Priority review drug , Orphan drug, FDA 2015,  Vistogard, uridine triacetate, fast track designations, PN-401, RG-2133,  TAU, XURIDEN
    CC(=O)OC[C@H]1O[C@H]([C@H](OC(C)=O)[C@@H]1OC(C)=O)N1C=CC(=O)NC1=O

    FDA approves new oral therapy to treat ALK-positive lung cancer


     

    12/11/2015 01:03 PM EST
    The U.S. Food and Drug Administration today approved Alecensa (alectinib) to treat people with advanced (metastatic) ALK-positive non-small cell lung cancer (NSCLC) whose disease has worsened after, or who could not tolerate treatment with, another therapy called Xalkori (crizotinib).

     

     

    December 11, 2015

    Release

    The U.S. Food and Drug Administration today approved Alecensa (alectinib) to treat people with advanced (metastatic) ALK-positive non-small cell lung cancer (NSCLC) whose disease has worsened after, or who could not tolerate treatment with, another therapy called Xalkori (crizotinib).

    Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015, according to the National Cancer Institute. An ALK (anaplastic lymphoma kinase) gene mutation can occur in several different types of cancer cells, including lung cancer cells. ALK gene mutations are present in about 5 percent of patients with NSCLC. In metastatic cancer, the disease spreads to new parts of the body. In ALK-positive NSCLC metastatic patients, the brain is a common place for the disease to spread.

    “Today’s approval provides a new therapy for a group of patients who would have few treatment options once their disease no longer responds to treatment with Xalkori,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “In addition to the primary effect on tumors in the lung, Alecensa clinical trials provide evidence of an effect on tumors that had spread to the brain, which is an important effect for clinicians to understand.”

    Alecensa is an oral medication that blocks the activity of the ALK protein, which may prevent NSCLC cells from growing and spreading.

    The safety and efficacy of Alecensa were studied in two single-arm clinical trials of patients with metastatic ALK-positive NSCLC whose disease was no longer controlled by treatment with Xalkori. Study participants received Alecensa twice daily to measure the drug’s effect on their lung cancer tumors. In the first study, 38 percent of participants experienced a partial shrinkage of their NSCLC tumors, an effect that lasted for an average of 7.5 months. In the second study, 44 percent of participants experienced a partial shrinkage of their NSCLC tumors, lasting for an average of 11.2 months. The trials also examined Alecensa’s effect on individuals’ brain metastases, a common occurrence in this population. Sixty-one percent of participants in the two trials who had measurable brain metastases experienced a complete or partial reduction in their brain tumors, lasting an average of 9.1 months.

    The most common side effects of Alecensa are fatigue, constipation, swelling (edema) and muscle pain (myalgia). Alecensa may cause serious side effects, including liver problems, severe or life-threatening inflammation of the lungs, very slow heartbeats and severe muscle problems. Treatment with Alecensa may cause sunburn when patients are exposed to sunlight.

    Alecensa was approved using the accelerated approval regulatory pathway, which allows the FDA to approve products for serious or life-threatening diseases based on evidence that the product has an effect on an outcome that is reasonably likely to predict clinical benefit. In the case of Alecensa, the tumor response to treatment, along with the duration of response, provided this evidence. Under the accelerated approval requirements, a confirmatory study is required to verify and describe the clinical benefit of Alecensa.

    The FDA granted the Alecensa application breakthrough therapy designation and priority review status. These are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions. Alecensa also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

    Alecensa is marketed by Genentech, based in San Francisco, California. Xalkori is marketed by Pfizer, based in New York, New York.

     

    Synthesis

     

    Read also

    https://newdrugapprovals.org/2014/07/08/japan-first-to-approve-alectinib-%E3%82%A2%E3%83%AC%E3%82%AF%E3%83%81%E3%83%8B%E3%83%96-%E5%A1%A9%E9%85%B8%E5%A1%A9-af-802-for-alk-nsclc/

     

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    FDA approves first recombinant von Willebrand factor to treat bleeding episodes


    12/08/2015 02:44
    The U.S. Food and Drug Administration today approved Vonvendi, von Willebrand factor (Recombinant), for use in adults 18 years of age and older who have von Willebrand disease (VWD). Vonvendi is the first FDA-approved recombinant von Willebrand factor, and is approved for the on-demand (as needed) treatment and control of bleeding episodes in adults diagnosed with VWD.
    Company Baxalta Inc.
    Description Recombinant human von Willebrand factor (vWF)
    Molecular Target von Willebrand factor (vWF)
    Mechanism of Action
    Therapeutic Modality Biologic: Protein
    Latest Stage of Development Registration
    Standard Indication Bleeding
    Indication Details Treat and prevent bleeding episodes in von Willebrand disease (vWD) patients; Treat von Willebrand disease (vWD)
    Regulatory Designation U.S. – Orphan Drug (Treat and prevent bleeding episodes in von Willebrand disease (vWD) patients);
    EU – Orphan Drug (Treat and prevent bleeding episodes in von Willebrand disease (vWD) patients);
    Japan – Orphan Drug (Treat and prevent bleeding episodes in von Willebrand disease (vWD) patients)

    December 8, 2015

    Release

    The U.S. Food and Drug Administration today approved Vonvendi, von Willebrand factor (Recombinant), for use in adults 18 years of age and older who have von Willebrand disease (VWD). Vonvendi is the first FDA-approved recombinant von Willebrand factor, and is approved for the on-demand (as needed) treatment and control of bleeding episodes in adults diagnosed with VWD.

    VWD is the most common inherited bleeding disorder, affecting approximately 1 percent of the U.S. population. Men and women are equally affected by VWD, which is caused by a deficiency or defect in von Willebrand factor, a protein that is critical for normal blood clotting. Patients with VWD can develop severe bleeding from the nose, gums, and intestines, as well as into muscles and joints. Women with VWD may have heavy menstrual periods lasting longer than average and may experience excessive bleeding after childbirth.

    “Patients with heritable bleeding disorders should meet with their health care provider to discuss appropriate measures to reduce blood loss,” said Karen Midthun, M.D., director of the FDA’s Center for Biologics Evaluation and Research. “The approval of Vonvendi provides an additional therapeutic option for the treatment of bleeding episodes in patients with von Willebrand disease.”

    The safety and efficacy of Vonvendi were evaluated in two clinical trials of 69 adult participants with VWD. These trials demonstrated that Vonvendi was safe and effective for the on-demand treatment and control of bleeding episodes from a variety of different sites in the body. No safety concerns were identified in the trials. The most common adverse reaction observed was generalized pruritus (itching).

    The FDA granted Vonvendi orphan product designation for these uses. Orphan product designation is given to drugs intended to treat rare diseases in order to promote their development.

    Vonvendi is manufactured by Baxalta U.S., Inc., based in Westlake Village, California.

    //////////

    FDA approves first drug to treat a rare enzyme disorder in pediatric and adult patients


    Sebelipase alfa
    CAS No. 1276027-63-4
    Synageva… innovator
    ALEXION
    EMA AUG 28 2015
    12/08/2015
    Today, the U.S. Food and Drug Administration approved Kanuma (sebelipase alfa) as the first treatment for patients with a rare disease known as lysosomal acid lipase (LAL) deficiency.

    December 8, 2015

    Release

    Today, the U.S. Food and Drug Administration approved Kanuma (sebelipase alfa) as the first treatment for patients with a rare disease known as lysosomal acid lipase (LAL) deficiency.

    Patients with LAL deficiency (also known as Wolman disease and cholesteryl ester storage disease [CESD]) have no or little LAL enzyme activity. This results in a build-up of fats within the cells of various tissues that can lead to liver and cardiovascular disease and other complications. Wolman disease often presents during infancy (around 2 to 4 months of age) and is a rapidly progressive disease. Patients with Wolman disease rarely survive beyond the first year of life. CESD is a milder, later-onset form of LAL deficiency and presents in early childhood or later. Life expectancy of patients with CESD depends on the severity of the disease and associated complications. Wolman disease affects one to two infants per million births, and CESD affects 25 individuals per million births.

    Today’s action involved approvals from two FDA centers. The Center for Veterinary Medicine (CVM) approved an application for a recombinant DNA (rDNA) construct in chickens that are genetically engineered (GE) to produce a recombinant form of human lysosomal acid lipase (rhLAL) protein in their egg whites. The FDA regulates GE animals under the new animal drug provisions of the Federal Food, Drug, and Cosmetic Act, because an rDNA construct introduced into an animal to change its structure or function meets the definition of a drug. The Center for Drug Evaluation and Research (CDER) approved the human therapeutic biologic (Kanuma), which is purified from those egg whites, based on its safety and efficacy in humans with LAL deficiency.

    “LAL deficiency is a rare inherited genetic disorder that can lead to serious and life-threatening organ damage, especially when onset begins in infancy,” said CDER Director Janet Woodcock, M.D. “Using this technology, these patients for the first time ever have access to a treatment that may improve their lives and chances of survival.”

    The new therapy, Kanuma, provides an rhLAL protein that functions in place of the missing, partially active or inactive LAL protein in the patient. Kanuma is produced by GE chickens containing an rDNA construct responsible for producing rhLAL protein in their egg whites. These egg whites are refined to extract the rhLAL protein that is eventually used to produce Kanuma and treat patients with LAL deficiency. The GE chickens are used only for producing the drug substance, and neither the chicken nor the eggs are allowed in the food supply.

    Kanuma is approved for use in patients with LAL deficiency. Treatment is provided via intravenous infusion once weekly in patients with rapidly progressive LAL deficiency presenting in the first six months of life, and once every other week in all other patients.

    CDER evaluated the safety and efficacy of Kanuma in an open-label, historically controlled trial in nine infants with rapidly progressive Wolman disease and in a double-blind, placebo-controlled trial in 66 pediatric and adult patients with CESD. In the trial in infants with Wolman disease, six of nine infants (67 percent) treated with Kanuma were alive at 12 months of age, whereas none of the 21 infants in the historical control group survived. In the trial in CESD patients, there was a statistically significant improvement in LDL-cholesterol levels and other disease-related parameters in those treated with Kanuma versus placebo after 20 weeks of treatment.

    The most common side effects observed in patients treated with Kanuma are diarrhea, vomiting, fever, rhinitis, anemia, cough, headache, constipation, and nausea.

    In its review of the GE chicken application, CVM assessed the safety of the rDNA construct, including the safety of the rDNA construct to the animals, as well as a full review of the construct and its stability in the genome of the chicken over several generations. No adverse outcomes were noted in the chickens. As required by the National Environmental Policy Act and its implementing regulations, CVM evaluated the potential environmental impacts of approval of the sponsor’s GE chickens and determined that the approval does not cause any significant impact on the environment, because the chickens are raised in highly secure indoor facilities.

    “We reviewed all of the data to ensure that the hens do produce rhLAL in their egg whites, without suffering any adverse health effects from the introduced rDNA construct. The company has taken rigorous steps to ensure that neither the chickens nor the eggs will enter the food supply, and we have confirmed their containment systems by inspecting the manufacturing facilities,” said CVM Director Bernadette Dunham, D.V.M., Ph.D.

    The FDA granted Kanuma orphan drug designation because it treats a rare disease affecting fewer than 200,000 patients in the United States. Orphan drug designation provides financial incentives for rare disease drug development such as clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Kanuma was also granted breakthrough therapy designation as it is the first and only treatment available for Wolman disease, the very severe infant form of the disease. The breakthrough therapy designation program encourages the FDA to work collaboratively with sponsors, by providing timely advice and interactive communications, to help expedite the development and review of important new drugs for serious or life-threatening conditions. The Kanuma application was also granted a priority review, which is granted to drug applications that show a significant improvement in safety or effectiveness in the treatment of a serious condition. The manufacturer of Kanuma was granted a rare pediatric disease priority review voucher –– a provision intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases.

    Kanuma is produced by Alexion Pharmaceuticals Inc., based in Cheshire, Connecticut.

     

    ///////// Kanuma, sebelipase alfa, rare disease, lysosomal acid lipase (LAL) deficiency,

    FDA approves first Factor X concentrate to treat patients with rare hereditary bleeding disorder


    10/20/2015
    The U.S. Food and Drug Administration today approved Coagadex, Coagulation Factor X (Human), for hereditary Factor X (10) deficiency. Until today’s orphan drug approval, no specific coagulation factor replacement therapy was available for patients with hereditary Factor X deficiency.

    October 20, 2015

    Release

    The U.S. Food and Drug Administration today approved Coagadex, Coagulation Factor X (Human), for hereditary Factor X (10) deficiency. Until today’s orphan drug approval, no specific coagulation factor replacement therapy was available for patients with hereditary Factor X deficiency.

    In healthy individuals, the Factor X protein activates enzymes to help with normal blood clotting in the body. Factor X deficiency is an inherited disorder, affecting men and women equally, where the blood does not clot as it should. Patients with the disorder are usually treated with fresh-frozen plasma or plasma-derived prothrombin complex concentrates (plasma products containing a combination of vitamin K-dependent proteins) to stop or prevent bleeding. The availability of a purified Factor X concentrate increases treatment options for patients with this rare bleeding disorder.

    “The approval of Coagadex is a significant advancement for patients who suffer from this rare but serious disease,” said Karen Midthun, M.D., director of the FDA’s Center for Biologics Evaluation and Research.

    Coagadex, which is derived from human plasma, is indicated for individuals aged 12 and older with hereditary Factor X deficiency for on-demand treatment and control of bleeding episodes, and for perioperative (period extending from the time of hospitalization for surgery to the time of discharge) management of bleeding in patients with mild hereditary Factor X deficiency.

    The safety and efficacy of Coagadex was evaluated in a multi-center, non-randomized study involving 16 participants (208 bleeding episodes) for treatment of spontaneous, traumatic and heavy menstrual (menorrhagic) bleeding episodes. Coagadex was demonstrated to be effective in controlling bleeding episodes in participants with moderate to severe hereditary Factor X deficiency. Coagadex was also evaluated in five participants with mild to severe Factor X deficiency who were undergoing surgery. The five individuals received Coagadex for perioperative management of seven surgical procedures. Coagadex was demonstrated to be effective in controlling blood loss during and after surgery in participants with mild deficiency. No individuals with moderate or severe Factor X deficiency received Coagadex for perioperative management of major surgery, and no safety concerns were identified in either study.

    The FDA granted Coagadex orphan product designation for these uses. Orphan product designation is given to drugs intended to treat rare diseases in order to promote their development. Coagadex was also granted fast track designation and priority review.

    Coagadex is manufactured by Bio Products Laboratory Limited in Elstree, Hertfordshire, United Kingdom.

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