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FDA Issues Draft Guidance on NCE Exclusivity Determinations
| Feb 25, 2014 |
Source: FDA.gov
see below
The Food and Drug Administration (FDA or the Agency) is issuing this guidance to set forth a change in the Agency’s interpretation of the 5-year new chemical entity (NCE) exclusivity provisions as they apply to certain fixed-combination drug products (fixed-combinations).
Historically, FDA has interpreted these provisions such that a fixed-combination was ineligible for 5-year NCE exclusivity if it contained a previously approved active moiety, even if the product also contained a new active moiety (i.e., an active moiety that the Agency had not previously approved).
The Agency recognizes that fixed-combinations have become increasingly prevalent in certain therapeutic areas (including cancer, cardiovascular, and infectious disease) and that these products play an important role in optimizing adherence to
dosing regimens and improving patient outcomes.
As further discussed below, we are therefore revising our historical interpretation of the 5-year NCE exclusivity provisions to further incentivize the development of certain fixed-combination products.
If the new interpretation is adopted, FDA intends to apply the new interpretation prospectively.Therefore, this guidance does not apply to fixed-combination drug products that were approvedprior to adopting the new interpretation.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required. read at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM386685.pdf
FDA Guidance on Polymorphic Compounds in Generic Drugs
The guidance issued by the US Food and Drug Administration advises companies on how to treat polymorphic drug compounds—those that exhibit multiple structural forms—in filing abbreviated new drug applications (ANDAs). The bottom line, according to the guidance, is that generic drug products containing the polymorphs be the “same” as the reference listed drug (RLD) in active ingredients, bioavailability, and bioequivalence.
The guidance pertains to orally available drugs that are either solid- or suspension-dosage products.
Polymorphisms arise when compounds are identical chemically, but not structurally. This can happen when two solids take on different crystalline forms—such as graphite and diamond; when molecules are disordered and fail to produce a repeatable crystal lattice, as is the case for the molecules in glass; or when solvent is trapped inside the crystal structure—as in hydrates, where water molecules are found within crystals.
The guidance notes that different polymorphisms may alter physical properties of compounds and affect their solubility, which in turn can alter their bioavailability or bioequivalence. In addition, polymorphic forms of a compound may alter the way the compound behaves during production, which again, may alter the finished drug’s biological activities.
On this latter point, the guidance specifically states, “Since an ANDA applicant should demonstrate that the generic drug product can be manufactured reliably using a validated process, we recommend that you pay close attention to polymorphism as it relates to pharmaceutical processing.”
The guidance also emphasizes the effect polymorphisms may have on drug stability, which again, may alter the drug’s biological activity. But the guidance goes on to say that “it is the stability of the drug product and not stability of the drug substance polymorphic form that should be the most relevant measure of drug equality.” Otherwise, a generic drug can be considered the “same” as the active ingredient in an RLD if the generic compound conforms to the standards set out in a United States Pharmacopeia (USP) monograph, if one exists for that particular drug substance.
These standards generally include the chemical name, empirical formula, and molecular structure of the compound. However, the “FDA may prescribe additional standards that are material to the sameness of a drug substance.” But as concerns polymorphisms, the guidance goes on to say “…differences in drug substance polymorphic forms do not render drug substances different active ingredients for the purposes of ANDA approvals….”
Finally, the guidance reminds ANDA applicants that the biological performance characteristics of a drug are also dependent on the drug’s formulation and advises applicants to consider the properties of both the drug substance and formulation excipients, when assessing “sameness.”
A sponsor of an Abbreviated New Drug Application (ANDA) must have information to show that the proposed generic product and the innovator product are both pharmaceutically equivalent and bioequivalent, and therefore, therapeutically equivalent.
Many pharmaceutical solids exist in several crystalline forms and thus exhibit polymorphism. Polymorphism may result in differences in the physico-chemical properties of the active ingredient and variations in these properties may render a generic drug product to be bioinequivalent to the innovator brand. For this reason, in ANDAs, careful attention is paid to the effect of polymorphism in the context of generic drug product equivalency.
This review ..Adv Drug Deliv Rev. 2004 Feb 23;56(3):397-414……discusses the impact of polymorphism on drug product manufacturability, quality, and performance. Conclusions from this analysis demonstrate that pharmaceutical solid polymorphism has no relevance to the determination of drug substance “sameness” in ANDAs.
Three decision trees for solid oral dosage forms or liquid suspensions are provided for evaluating when and how polymorphs of drug substances should be monitored and controlled in ANDA submissions. Case studies from ANDAs are provided which demonstrate the irrelevance of polymorphism to the determination of drug substance “sameness”. These case studies also illustrate the conceptual framework from these decision trees and illustrate how their general principles are sufficient to assure both the quality and the therapeutic equivalence of marketed generic drug products.
read
ANDAs: Pharmaceutical Solid Polymorphism – Food and Drug … click here
also
Issues of Polymorphism and Abbreviated New Drug Applications click here
and
POLYMORPHISM OF DRUGS – Seventh Street Development Group click here
An Overview of Solid Form Screening During Drug … – ICDD..http://www.icdd.com/ppxrd/10/presentations/PPXRD-10_Ann_Newman.pdf
http://www.ivtnetwork.com/sites/default/files/Polymorphism_01.pdf
Although polymorph/salt screening should ideally be performed to select the optimum solid form upon selection of the lead compound prior to animal pharmacokinetic (PK) studies, these screening study can be costly and time consuming. But the consequences of late discovery of a thermodynamic form are grave, so there must be a strategy to minimize the risk without spending a large amount of resources.
We find this right strategy based on early BCS classification of new compounds. We tailor the upfront polymorph/salt studies based on the risk in bioavailability, stability and manufacture-ability. Since regulatory agencies worldwide require the use of the same salt across preclinical and clinical studies, for insoluble or unstable compounds, salt screening is done early to enable further compound development.
Once salt is selected, the polymorph screening of the selected salt if soluble may be done a little later after animal study. However it is paramount to confirm 1) the polymorph in use is stable in the toxicological vehicle, 2) no changes of solid forms during shipping and storage, 3) no significant degradation upon storage.
Should there be polymorphic changes such as formation of a hydrate in the animal vehicle resulting in lowered solubility and precipitation of the hydrate, or formation of a hydrate when exposed to humidity during shipping and storage, early discovery of the stable forms will enable consistent animal exposure and avoid study repeats and delays in timelines.
Therefore, although most companies do not perform comprehensive polymorph screening until late in the development cycle, we recommend identification of a thermodynamic stable form within the confine of not only the API manufacture processes but also in the designated animal and human formulations.
For instance, for a drug product manufactured by direct compression, the solidstate properties of the active ingredient will likely be critical to the manufacture of the drug product, particularly when it constitutes the bulk of the tablet mass.
On the other hand, for a drug product manufactured by wet granulation, the solidstate properties of the active ingredient may no longer be important but the potential for polymorphic conversion is high in the presence of high moisture contents. In the context of the effect of polymorphism on pharmaceutical processing, what is most relevant is the ability to consistently manufacture a drug product that conforms to applicable in-process controls and release specifications.
This upfront work is especially critical to insoluble compounds prone to varied oral bioavailability in animal and human.
Why FDA Supports a Flexible Approach to Drug Development
We all know that just as every person is different, so too is every disease and every drug. And so we weren’t surprised by the results of a new study published in the Journal of … Continue reading →
Vorapaxar …FDA advisory panel votes to approve Merck & Co’s vorapaxar
VORAPAXAR
Thrombosis, Antiplatelet Therapy, PAR1 Antagonists , MERCK ..ORIGINATOR
Ethyl N-[(3R,3aS,4S,4aR,7R,8aR,9aR)-4-[(E)-2-[5-(3-fluorophenyl)-2-pyridyl]vinyl]-3-methyl-1-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-3H-benzo[f]isobenzofuran-7-yl]carbamate
618385-01-6 CAS NO
Vorapaxar (formerly SCH 530348) is a thrombin receptor (protease-activated receptor, PAR-1) antagonist based on the natural product himbacine. Discovered by Schering-Plough and currently being developed by Merck & Co., it is an experimental pharmaceutical treatment for acute coronary syndrome chest pain caused by coronary artery disease.[1]
In January 2011, clinical trials being conducted by Merck were halted for patients with stroke and mild heart conditions.[2] In a randomized double-blinded trial comparing vorapaxar with placebo in addition to standard therapy in 12,944 patients who had acute coronary syndromes, there was no significant reduction in a composite end point of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. However, there was increased risk of major bleeding.[3]
A trial published in February 2012, found no change in all cause mortality while decreasing the risk of cardiac death and increasing the risk of major bleeding.[4]
SCH-530348 is a protease-activated thrombin receptor (PAR-1) antagonist developed by Schering-Plough and waiting for approval in U.S. for the oral secondary prevention of cardiovascular events in patients with a history of heart attack and no history of stroke or transient ischemic attack. The drug candidate is being investigated to determine its potential to provide clinical benefit without the liability of increased bleeding; a tendency associated with drugs that block thromboxane or ADP pathways. In April 2006, SCH-530348 was granted fast track designation in the U.S. for the secondary prevention of cardiovascular morbidity and mortality outcomes in at-risk patients.
Vorapaxar was recommended for FDA approval on January 15, 2014.[5]
VORAPAXAR17 JAN 2014
FDA advisory panel votes to approve Merck & Co’s vorapaxar REF 6
VORAPAXAR SULPHATE
CAS Number: 705260-08-8
Molecular Formula: C29H33FN2O4.H2O4S
Molecular Weight: 590.7
Chemical Name: Ethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)pyridin-2- yl]ethenyl]-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamate sulfate
Synonyms: Carbamic acid, [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2- pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-,ethyl ester,sulfate; SCH-530348
Vorapaxar Sulfate (SCH 530348) a thrombin receptor (PAR-1) antagonist for the prevention and treatment of atherothrombosis.
……………………
GENERAL INTRO
SIMILAR NATURAL PRODUCT
+ HIMBACINE
Himbacine is an alkaloid muscarinic receptor antagonist displaying more potent activity associated with M2 and M2 subtypes over M1 or M3. Observations show himbacine bound tightly to various chimeric receptors in COS-7 cells as well as possessed the ability to bind to cardiac muscarinic receptors allosterically. Recent studies have produced series of thrombin receptor (PAR1) antagonists derived from himbacine Himbacine is an inhibitor of mAChR M2 and mAChR M4.
| Physical State: | Solid |
| Derived from: | Australian pine Galbulimima baccata |
| Solubility: | Soluble in ethanol (50 mg/ml), methanol, and dichloromethane. Insoluble in water. |
| Storage: | Store at -20° C |
| Melting Point: | 132-134 °C |
| Boiling Point: | 469.65 °C at 760 mmHg |
| Density: | 1.08 g/cm3 |
| Refractive Index: | n20D 1.57 |
| Optical Activity: | α20/D +51.4º, c = 1.01 in chloroform |
| Application: | An alkaloid muscarinic receptor antagonist |
| CAS Number: | 6879-74-9 |
| Molecular Weight: | 345.5 |
| Molecular Formula: | C22H35NO2 |
general scheme:
……………………………
SYNTHESIS
THE EXACT BELOW COMPD IS 14
Example 2
Step 1 :
Phosphonate 7, described in US 6,063,847, (3.27 g, 8.1 mmol) was dissolved in THF (12 ml) and C(O)Oled to 0 °C, followed by addition of 2.5 M n- BuLi (3.2 ml, 8.1 mmol). The reaction mixture was stirred at 0 °C for 10 min and warmed up to rt. A solution of aldehyde 6, described in US 6,063,847, in THF (12 ml) was added to the reaction mixture. The reaction mixture was stirred for 30 min. Standard aqueous work-up, followed by column chromatography (30-50% EtOAc in hexane) afforded product 8. 1HNMR (CDCI3): δ 0.92-1.38 (m, 31 H), 1.41 (d, J= 6 Hz, 3H), 1.40-1.55 (m, 2H), 1.70-1.80 (m, 2H), 1.81-1.90 (m, 2H), 2.36 (m, 2H), 2.69 (m, 1 H), 3.89 (m, 4H), 4.75 (m, 1 H), 6.28-6.41 (m, 2H), 7.05-7.15 (m, 2H), 8.19 (br s, 1 H). Step 2:
Compound 8 (2.64 g, 4.8 mmol) was dissolved in THF (48 ml). The reaction mixture was C(O)Oled to 0 °C followed by addition of 1 M TBAF (4.8 ml). The reaction mixture was stirred for 5 min followed by standard aqueous work-up. Column chromatography (50% EtOAc/hexane) afforded product 9 (1.9 g, 100%). 1HNMR (CDCI3): δ 1.15-1.55 (m, 6H), 1.41 (d, J= 6 Hz, 3H), 1.70-1.82 (m, 3H), 1.85-1.90 (m, 1 H), 2.36 (m, 2H), 2.69 (m, 1 H), 3.91 (m, 4H), 4.75 (m, 1 H), 6.18- 6.45 (m, 2H), 7.19 (br s, 2H), 8.19 (br s, 1 H). Step 3:
To a solution of compound 9 (250 mg, 0.65 mmol) in pyridine (5 ml) C(O)Oled to 0 °C was added Tf2O (295 μL, 2.1 mmol). The reaction mixture was stirred overnight at rt. Standard aqueous work-up followed by column chromatography afforded product 10 (270 mg, 80%). 1HNMR (CDCI3): δ 1.15-1.55 (m, 6H), 1.41 (d, J= 6 Hz, 3H), 1.70-1.82 (m, 3H), 1.85-1.90 (m, 1 H), 2.36 (m, 2H), 2.69 (m, 1 H), 3.91 (m, 4H), 4.75 (m, 1 H), 6.42-6.68 (m, 2H), 7.25 (m, 1 H), 7.55 (m, 1 H), 8.49 (d, J= 2.8 Hz, 1 H).
Compound 10 (560 mg, 1.1 mmol), 3-fluorophenyl boronic acid (180 mg, 1.3 mmol) and K2CO3 (500 mg, 3.6 mmol) were mixed with toluene (4.4 ml), H2O (1.5 ml) and EtOH (0.7 ml) in a sealed tube. Under an atmosphere of N2, Pd(Ph3P)4 (110 mg, 0.13 mmol) was added. The reaction mixture was heated at 100 °C for 2 h under N2. The reaction mixture was C(O)Oled down to rt, poured to EtOAc (30 ml) and washed with water (2X20 ml). The EtOAc solution was dried with NaHCO3 and concentrated at reduced pressure to give a residue. Preparative TLC separation of the residue (50% EtOAc in hexane) afforded product 11 (445 mg, 89%). 1HNMR (CDCI3): δ 1.15-1.59 (m, 6H), 1.43 (d, J= 6 Hz, 3H), 1.70-1.79 (m, 2H), 1.82 (m, 1H), 1.91 (m, 2H), 2.41 (m, 2H), 2.69 (m, 1 H), 3.91 (m, 4H), 4.75 (m, 1 H), 6.52-6.68 (m, 2H), 7.15 (m, 1 H), 7.22 (m, 2H), 7.35 (m, 1 H), 7.44 (m, 1 H), 7.81 (m, 1 H), 8.77 (d, J= 1.2 Hz, 1 H). Step 5:
Compound 11 (445 mg, 0.96 mmol) was dissolved in a mixture of acetone (10 ml) and 1 N HCI (10 ml). The reaction mixture was heated at 50 °C for 1 h.
Standard aqueous work-up followed by preparative TLC separation (50% EtOAc in hexane) afforded product 12 (356 mg, 89%). 1HNMR (CDCI3): δ 1.21-1.45 (m, 2H), 1.47 (d, J= 5.6 Hz, 3H), 1.58-1.65 (m, 2H), 2.15 (m, 1 H), 2.18-2.28 (m, 2H), 2.35- 2.51 (m, 5H), 2.71 (m, 1 H), 4.79 (m, 1 H), 6.52-6.68 (m, 2H), 7.15 (m, 1 H), 7.22 (m, 2H), 7.35 (m, 1 H), 7.44 (m, 1 H), 7.81 (m, 1 H), 8.77 (d, J= 1.2 Hz, 1 H). Step 6:
Compound 12 (500 mg, 4.2 mmol) was dissolved in EtOH (40 ml) and CH2CI2 (15 ml) NH3 (g) was bubbled into the solution for 5 min. The reaction mixture was C(O)Oled to 0 °C followed by addition of Ti(O/‘Pr)4 (1.89 ml, 6.3 mmol). After stirring at 0 °C for 1 h, 1 M TiCI (6.3 ml, 6.3 mmol) was added. The reaction mixture was stirred at rt for 45 min and concentrated to dryness under reduced pressure. The residue was dissolved in CH3OH (10 ml) and NaBH3CN (510 mg, 8 mmol) was added. The reaction mixture was stirred overnight at rt. The reaction mixture was poured to 1 N NaOH (100 ml) and extracted with EtOAc (3x 100 ml). The organic layer was combined and dried with NaHC03. Removal of solvent and separation by PTLC (5% 2 M NH3 in CH3OH/ CH2CI2) afforded β-13 (spot 1 , 30 mg, 6%) and α-13 (spot 2, 98 mg, 20%). β-13: 1HNMR (CDCI3): δ 1.50-1.38 (m, 5H), 1.42 (d, J= 6 Hz, 3H), 1.51-1.75 (m, 5H), 1.84 (m, 2H), 2.38 (m, 1 H), 2.45 (m, 1 H), 3.38 (br s, 1 H), 4.78 (m, 1 H), 6.59 (m, 2H), 7.15 (m, 1 H), 7.26 (m, 2H), 7.36 (m, 1 H), 7.42 (m, 1 H), 7.82 (m, 1 H), 8.77 (d, J= 2 Hz, 1 H). α-13:1HNMR (CDCI3): δ 0.95 (m, 2H), 1.02-1.35 (m, 6H), 1.41 (d, J= 6 Hz, 3H), 1.82-1.95 (m, 4H), 2.37 (m; 2H), 2.69 (m, 2H), 4.71 (m, 1 H), 6.71 (m, 2H), 7.11 (m, 1 H), 7.25 (m, 2H), 7.38 (m, 1 H), 7.42 (m, 1 H), 7.80 (m, 1 H), 8.76 (d, J= 1.6 Hz, 1 H). Step 7:
Compound α-13 (300 mg, 0.71 mmol) was dissolved in CH2CI2 (10 ml) followed by addition of Et3N (0.9 ml). The reaction mixture was C(O)Oled to 0 °C and ethyl chloroformate (0.5 ml) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was directly separated by preparative TLC (EtOAc/ hexane, 1 :1) to give the title compound (14) VORAPAXAR (300 mg, 86%). MS m/z 493 (M+1).
HRMS Calcd for C29H34N2O4F (M+1 ): 493.2503, found 493.2509.
…………………
SYNTHESIS 1
http://www.google.com/patents/WO2006076564A1
VORAPAXAR= COMPD A
Example 6 – Preparation of Compound A
To a three-neck flask equipped with an agitator, thermometer and nitrogen inertion was added 7A (13.0 g), THF (30 mL). The mixture was cooled to below -200C after which lithium diisopropylamide (2M, 20 mL) was slowly added. The reaction mixture was agitated for an additional hour (Solution A). To another flask was added 6 (10.0 g) and THF (75 mL) . The mixture was stirred for about 30 minutes and then slowly transferred into the solution A while maintaining the temperature below 200C. The mixture was stirred at below -200C for an additional hour before quenching the reaction by adding 20 mL of water. The reaction mixture was warmed to 00C and the pH was adjusted to about 7 by addition of 25% HaSO4 (11 mL). The mixture was further warmed to 200C and then diluted with 100 mL of ethyl acetate and 70 mL of water. The two phases that had formed were separated and the aqueous layer was extracted with 50 mL of ethyl acetate. The solvents THF and ethyl acetate were then replaced with ethanol, and the Compound A was precipitated out as a crystalline solid from ethanol with seeding at 35 to 4O0C. After cooling to O0C, the suspension was stirred for an additional hour and then the product was filtered and washed with cold ethanol. The product was dried at 50 – 600C under vacuum to provide an off-white solid. VORAPAXAR
Yield: 12.7 g, (90%). m.p. 104.90C (DSC onset point).
1H NMR (CDCl3) δ 8.88 (d, J = 2.4 Hz, IH), 8.10 (dd, J = 8.2, 2.4 Hz, IH), 7.64 (IH), 7.61 (d, J = 8.8 Hz, IH), 7.55 (m, J = 8.2, 6.2 Hz, IH), 7.51 (d, J = 8.0 Hz, IH), 7.25 (dt, J = 9.0, 2.3 Hz, IH), 7.08 (d, J = 8.0 Hz, IH), 6.68 (dd, J = 15.4, 9.4 Hz, IH), 6.58 (d, J = 9.6 Hz, IH), 4.85 (dd, J = 14.2, 7.2 Hz, IH), 3.95 (dd, J = 14.2, 7.1 Hz, 2H), 3.29 (m, IH), 2.66 (m, J = 12.0, 6.4 Hz, IH), 2.33 (m, 2H), 1.76 (m, 4H), 1.30 (d, J = 5.6 Hz, 3H), 1.19 (m, 4H), 1.14 (t, J = 7.2 Hz, 3H), 0.98 (m, IH), 0.84 (m, IH). MS (EI) m/z: calcd. 492, found 492.
BISULPHATE SALT
Example 7 – Preparation of an Acid Salt (bisulfate) of Compound A:
Compound IA (5 g) was dissolved in about 25 mL of acetonitrile.
The solution was agitated for about 10 minutes and then heated to about 50 0C. About 6 mL of 2M sulfuric acid in acetonitrile was added into the heated reaction mixture. The solid salt of Compound A precipitated out during the addition of sulfuric acid in acetonitrile. After addition of sulfuric acid solution, the reaction mixture was agitated for 1 hour before cooling to room temperature. The precipitated solid was filtered and washed with about 30 mL of acetonitrile. The wet solid was dried under vacuum at room temperature for 1 hour and at 80 0C for about 12 hours to provide about 5 g white solid (yield 85%). m.p. 217.0 0C. 1H NMR (DMSO) 9.04 (s, IH), 8.60 (d, J = 8.1 Hz, IH), 8.10 (d, J = 8.2 Hz, IH), 7.76 (d, J = 10.4, IH), 7.71 (d, J = 7.8 Hz, IH), 7.60 (dd, J = 8.4, 1.8 Hz, IH), 7.34 (dd, 8.4, 1.8 Hz, IH), 7.08 (d, J = 8.0 Hz, IH), 7.02 (m, IH), 6.69 (d, J = 15.8 Hz, IH), 4.82 (m, IH), 3.94 (dd, J = 14.0, 7.0 Hz, 2H), 3.35 (brs, IH), 2.68 (m, IH), 2.38 (m, 2H), 1.80-1.70 (m, 4H), 1.27 (d, J = 5.8 Hz, 3H), 1.21 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H), 0.95 (m, IH, 0.85 (m, IH). MS (EI) m/z calcd. 590, found 492.
INTERMEDIATE 6
Example 5- Preparation of Compound 6
To a three-neck flask equipped with an agitator, thermometer and nitrogen inert were added the crude product solution of Compound 5 (containing about 31 g. of Compound 5 in 300 mL solution) and anhydrous DMF (0.05 mL). After the mixture was agitated for 5 minutes, oxalyl chloride (12.2 mL) was added slowly while maintaining the batch temperature between 15 and 25°C. The reaction mixture was agitated for about an hour after the addition and checked by NMR for completion of reaction. After the reaction was judged complete, the mixture was concentrated under vacuum to 135 mL while maintaining the temperature of the reaction mixture below 300C. The excess oxalyl chloride was removed completely by two cycles of vacuum concentration at below 500C with replenishment of toluene (315 mL) each time, resulting in a final volume of 68 mL. The reaction mixture was then cooled to 15 to 25°C, after which THF (160 mL) and 2,6-lutidine (22 mL) were added. The mixture was agitated for 16 hours at 20 to 25°C under 100 psi hydrogen in the presence of dry 5% Pd/C (9.0 g). After the reaction was judged complete, the reaction mixture was filtered through celite to remove catalyst. More THF was added to rinse the hydrogenator and catalyst, and the reaction mixture was again filtered through celite. Combined filtrates were concentrated under vacuum at below 25°C to 315 mL. MTBE (158 mL) and 10% aqueous solution of phosphoric acid (158 mL) were added for a thorough extraction at 100C to remove 2,6- lutidine. Then phosphoric acid was removed by extracting the organic layer with very dilute aqueous sodium bicarbonate solution (about 2%), which was followed by a washing with dilute brine. The organic solution was concentrated atmospherically to a volume of 90 mL for solvent replacement. IPA (315 mL) was added to the concentrated crude product solution. The remaining residual solvent was purged to <_ 0.5% of THF (by GC) by repeated concentration under vacuum to 68 mL, with replenishment of IPA (315 mL) before each concentration. The concentrated (68 mL) IPA solution was heated to 50°C, to initiate crystallization. To this mixture n-heptane (68 mL) was added very slowly while maintaining the batch temperature at 50°C. The crystallizing mixture was cooled very slowly over 2.5 hours to 25°C. Additional n- heptane (34 mL) was added very slowly into the suspension mixture at 250C. The mixture was further cooled to 200C, and aged at that temperature for about 20 hours. The solid was filtered and washed with a solvent mixture of 25% IPA in n-heptane, and then dried to provide
19.5 g of a beige colored solid of Compound 6. (Yield: 66%) m.p. 169.30C. IH NMR (CD3CN) δ 9.74 (d, J = 3.03 Hz, IH), 5.42 (br, IH), 4.69 (m, IH), 4.03 (q, J = 7.02 Hz, 2H), 3.43 (qt, J = 3.80, 7.84 Hz, IH), 2.67 (m, 2H), 2.50 (dt, J = 3.00, 8.52 Hz, IH), 1.93 (d, J = 12.0 Hz, 2H), 1.82 (dt, J = 3.28, 9.75 Hz, 2H), 1.54 (qd, J = 3.00, 10.5 Hz, IH), 1.27 (d, J = 5.97 Hz, 3H), 1.20 (m, 6H), 1.03 – 0.92 (m, 2H). MS (ESI) m/z (M++1): calcd. 324, found 324.
INTERMEDIATE 7A
Example 4 – Preparation of Compound 7A
+ 1-Pr2NLi + (EtO)2POCI – + LiCI
7A
To a 10 L three-necked round bottomed flask equipped with an agitator, thermometer and a nitrogen inlet tube, was added 20Og of
Compound 8 (1.07 mol, from Synergetica, Philadelphia, Pennsylvania). THF (1000 mL) was added to dissolve Compound 8. After the solution was cooled to -80 0C to -50 0C, 2.0 M LDA in hexane/THF(1175 mL, 2.2 eq) was added while maintaining the batch temperature below -50 0C. After about 15 minutes of agitation at -800C to -50 0C, diethyl chlorophosphate (185 mL, 1.2 eq) was added while maintaining the batch temperature below -50 0C. The mixture was agitated at a temperature from -800C to – 50 0C for about 15 minutes and diluted with n-heptane (1000 mL). This mixture was warmed up to about -35 0C and quenched with aqueous ammonium chloride (400 g in 1400 mL water) at a temperature below -10 0C. This mixture was agitated at -150C to -10 0C for about 15 minutes followed by agitation at 150C to 25 0C for about 15 minutes. The aqueous layer was split and extracted with toluene (400 mL). The combined organic layers were extracted with 2N hydrochloric acid (700 mL) twice. The product-containing hydrochloric acid layers were combined and added slowly to a mixture of toluene (1200 mL) and aqueous potassium carbonate (300 g in 800 mL water) at a temperature below 30 0C. The aqueous layer was extracted with toluene (1200 mL). The organic layers were combined and concentrated under vacuum to about 600 ml and filtered to remove inorganic salts. To the filtrate was added n-heptane (1000 ml) at about 55 0C. The mixture was cooled slowly to 40 0C, seeded, and cooled further slowly to -10 0C. The resulting slurry was aged at about -10 0C for 1 h, filtered, washed with n- heptane, and dried under vacuum to give a light brown solid (294 g, 85% yield), m.p. 52 0C (DSC onset point).1H NMR (CDCl3) δ 8.73 (d, J = 1.5 Hz, IH), 7.85 (dd, Ji = 8.0 Hz, J2 = 1.5 Hz, IH), 7.49 (dd, Ji = 8.0 Hz, J2 = 1.3 Hz, IH), 7.42 (m, IH), 7.32 (d, J = 7.8 Hz, IH), 7.24 (m, IH), 7.08 (dt, Ji = 8.3 Hz, J2 = 2.3 Hz, IH), 4.09 (m, 4H), 3.48 (d, J = 22.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 6H). MS (ESI) for M+H calcd. 324, found 324.
Example 3 – Preparation of Compound 5:
4 5
To a three-necked round bottomed flask equipped with an agitator, thermometer and a nitrogen inlet tube was added a solution of Compound 4 in aqueous ethanol (100 g active in 2870 ml). The solution was concentrated to about 700 ml under reduced pressure at 350C to 40°C to remove ethyl alcohol. The resultant homogeneous mixture was cooled to 200C to 300C and its pH was adjusted to range from 12 to 13 with 250 ml of 25% sodium hydroxide solution while maintaining the temperature at 20-300C. Then 82 ml of ethyl chloroformate was slowly added to the batch over a period of 1 hour while maintaining the batch temperature from 200C to 300C and aged for an additional 30 minutes. After the reaction was judged complete, the batch was acidified to pH 7 to 8 with 10 ml of concentrated hydrochloric acid (37%) and 750 ml of ethyl acetate. The pH of the reaction mixture was further adjusted to pH 2 to 3 with 35% aqueous hydrochloric acid solution. The organic layer was separated and the aqueous layer was extracted again with 750 ml of ethyl acetate. The combined organic layers were washed twice with water (200 ml) . Compound 5 was isolated from the organic layer by crystallization from ethyl acetate and heptane mixture (1: 1 mixture, 1500 ml) at about 700C to 80 0C. The solid was filtered at 500C to 60 °C, washed with heptane and then dried to provide an off-white solid (yield 50%). m.p. 197.7°C. 1HNMR (CD3CN) δ 5.31 (brs, IH), 4.67 (dt, J = 16.1, 5.9 Hz, IH), 4.03 (q, J = 7.1 Hz, 2H), 3.41 (m, IH), 2.55 – 2.70 (m, 2H), 1.87 – 1.92 (m, IH), 1.32 – 1.42 (m, IH), 1.30 (d, J = 5.92 Hz, 3H), 1.30 – 1.25 (m, 6H), 0.98 (qt, J = 15.7, 3.18 Hz, 2H). MS (ESI) M+l m/z calculated 340, found 340.
Example 2 – Preparation of Compound 4;
3 4
7.4 kg of ammonium formate was dissolved in 9L of water at 15- 250C, and then cooled to 0-100C. 8.9 kg of Compound 3 was charged at 0-150C followed by an addition of 89L of 2B ethyl alcohol. The batch was cooled to 0-50C 0.9 kg of 10% Palladium on carbon (50% wet) and 9 L of water were charged. The batch was then warmed to 18-280C and agitated for 5 hours, while maintaining the temperature between 18-28 0C. After the reaction was judged complete, 7 IL of water was charged. The batch was filtered and the wet catalyst cake was then washed with 8OL of water. The pH of the filtrate was adjusted to 1-2 with 4N aqueous hydrochloric acid solution. The solution was used in the next process step without further isolation. The yield is typically quantiative. m.p. 216.40C. IH NMR (D2O+1 drop HCl) δ 3.15 (m, IH), 2.76 (m, IH), 2.62 (m, IH), 2.48 (dd,J-5.75Hz, IH), 1.94 (m, 2H), 1.78 (m, 2H), 1.38 (m, 2H), 1.20 (m, 6H), 1.18 (m, IH), 0.98 (q,J=2.99Hz, IH).
Example 1 – Preparation of Compound 3
2B 3
To a reactor equipped with an agitator, thermometer and nitrogen, were added about 10.5 kg of 2B, 68 L of acetone and 68 L of IN aqueous hydrochloric acid solution. The mixture was heated to a temperature between 50 and 600C and agitated for about 1 hour before cooling to room temperature. After the reaction was judged complete, the solution was concentrated under reduced pressure to about 42 L and then cooled to a temperature between 0 and 50C. The cooled mixture was agitated for an additional hour. The product 3 was filtered, washed with cooled water and dried to provide an off-white solid (6.9 kg, yield 76%). m.p. 2510C. Η NMR (DMSO) δ 12.8 (s, IH), 4.72 (m, J = 5.90 Hz, IH), 2.58 (m, 2H), 2.40 (m, J = 6.03 Hz, 2H), 2.21 (dd, J = 19.0, 12.8 Hz, 3H), 2.05 (m, IH), 1.87 (q, J = 8.92 Hz, IH), 1.75 (m, IH), 1.55 (m, IH), 1.35 (q, J = 12.6 Hz, IH), 1.27 (d, J = 5.88 Hz, 3H). MS (ESI) M+l m/z calcd. 267, found 267.
NOTE
Compound 7A may be prepared from Compound 8 by treating Compound 8 with diethylchlorophosphate:
Compound 8 may be obtained by the process described by Kyoku, Kagehira et al in “Preparation of (haloaryl)pyridines,” (API Corporation, Japan). Jpn. Kokai Tokkyo Koho (2004). 13pp. CODEN: JKXXAF JP
2004182713 A2 20040702. Compound 8 is subsequently reacted with a phosphate ester, such as a dialkyl halophosphate, to yield Compound 7A. Diethylchlorophosphate is preferred. The reaction is preferably conducted in the presence of a base, such as a dialkylithium amide, for example diisopropyl lithium amide.
…………………………………..
J Med Chem 2008, 51(11): 3061
http://pubs.acs.org/doi/abs/10.1021/jm800180e
The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.
Ethyl [(3aR,4aR,8aR,9aS)-9(S)-[(E)-2-[5-(3-fluorophenyl)-2-
pyridinyl]ethenyl]dodecahydro-1(R)-methyl-3-oxonaphtho[2,3-c]furan-6(R)-yl]carbamate (4).
4 (300 mg, 86%). MS m/z 493 (M+1).
HRMS Calcd for C29H34N2O4F
(M+1): 493.2503, found 493.2509; mp125 °C;
[]D20 6.6 (c 0.5, MeOH).
1HNMR (CDCl3):
http://pubs.acs.org/doi/suppl/10.1021/jm800180e/suppl_file/jm800180e-file002.pdf
0.88-1.18 (m, 5 H), 1.22-1.30 (m, 3 H), 1.43 (d, J = 5.85 Hz, 3 H), 1.88-2.10 (m, 4 H), 2.33-2.42 (m, 2 H),
2.75-2.67 (m, 1 H), 3.52-3.60 (m, 1 H), 4.06-4.14 (m, 2 H), 4.54-4.80 (m, 1 H), 4.71-4.77 (m, 1 H),
6.55-6.63 (m, 2 H), 7.07-7.12 (m, 1 H), 7.26-7.29 (m, 2 H), 7.34 (d, J = 8.05 Hz, 1 H), 7.41-7.46 (m, 1 H), 7.80-7.82 (m, 1 H), 8.76-8.71 (m, 1 H).
……………………..
References
- Samuel Chackalamannil; Wang, Yuguang; Greenlee, William J.; Hu, Zhiyong; Xia, Yan; Ahn, Ho-Sam; Boykow, George; Hsieh, Yunsheng et al. (2008). “Discovery of a Novel, Orally Active Himbacine-Based Thrombin Receptor Antagonist (SCH 530348) with Potent Antiplatelet Activity”. Journal of Medicinal Chemistry 51 (11): 3061–4.doi:10.1021/jm800180e. PMID 18447380.
- Merck Blood Thinner Studies Halted in Select Patients, Bloomberg News, January 13, 2011
- Tricoci et al. (2012). “Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes”. New England Journal of Medicine 366 (1): 20–33.doi:10.1056/NEJMoa1109719. PMID 22077816.
- Morrow, DA; Braunwald, E; Bonaca, MP; Ameriso, SF; Dalby, AJ; Fish, MP; Fox, KA; Lipka, LJ; Liu, X; Nicolau, JC; Ophuis, AJ; Paolasso, E; Scirica, BM; Spinar, J; Theroux, P; Wiviott, SD; Strony, J; Murphy, SA; TRA 2P–TIMI 50 Steering Committee and, Investigators (Apr 12, 2012). “Vorapaxar in the secondary prevention of atherothrombotic events.”. The New England Journal of Medicine 366 (15): 1404–13. doi:10.1056/NEJMoa1200933.PMID 22443427.
- “Merck Statement on FDA Advisory Committee for Vorapaxar, Merck’s Investigational Antiplatelet Medicine”. Merck. Retrieved 16 January 2014.
- http://www.forbes.com/sites/larryhusten/2014/01/15/fda-advisory-panel-votes-in-favor-of-approval-for-mercks-vorapaxar/
- SCH-530348 (Vorapaxar) is an investigational candidate for the prevention of arterial thrombosis in patients with acute coronary syndrome and peripheral arterial disease. “Convergent Synthesis of Both Enantiomers of 4-Hydroxypent-2-ynoic Acid Diphenylamide for a Thrombin Receptor Antagonist Sch530348 and Himbacine Analogues.” Alex Zaks et al.: Adv. Synth. Catal. 2009, 351: 2351-2357 Full text;
- Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity
J Med Chem 2008, 51(11): 3061
- Stu Borman (2005). “Hopes Ride on Drug Candidates: Researchers reveal potential new medicines for thrombosis, anxiety, diabetes, and cancer”. Chemical & Engineering News 83 (16): 40–44.
PATENTS
- WO 2003089428
- WO 2006076452
- US 6063847
- WO 2006076565
- WO 2008005344
- WO2010/141525
- WO2008/5353
- US2008/26050
- WO2006/76564 mp, nmr
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3-21-2012
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EXO-SELECTIVE SYNTHESIS OF HIMBACINE ANALOGS
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10-14-2011
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EXO- AND DIASTEREO- SELECTIVE SYNTHESIS OF HIMBACINE ANALOGS
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8-3-2011
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Exo- and diastereo-selective syntheses of himbacine analogs
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3-18-2011
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COMBINATION THERAPIES COMPRISING PAR1 ANTAGONISTS WITH NAR AGONISTS
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8-11-2010
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Exo-selective synthesis of himbacine analogs
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6-4-2010
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SYNTHESIS Of DIETHYLPHOSPHONATE
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5-12-2010
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THROMBIN RECEPTOR ANTAGONISTS
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3-31-2010
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Synthesis of diethyl{[5-(3-fluorophenyl)-pyridine-2yl]methyl}phosphonate
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12-4-2009
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Local Delivery of PAR-1 Antagonists to Treat Vascular Complications
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12-2-2009
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SYNTHESIS OF HIMBACINE ANALOGS
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10-21-2009
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Exo- and diastereo- selective syntheses of himbacine analogs
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6-31-2009
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Synthesis of 3-(5-nitrocyclohex-1-enyl) acrylic acid and esters thereof
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6-3-2009
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Synthesis of himbacine analogs
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1-23-2009
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METHODS AND COMPOSITIONS FOR TREATING CARDIAC DYSFUNCTIONS
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9-26-2008
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REDUCTION OF ADVERSE EVENTS AFTER PERCUTANEOUS INTERVENTION BY USE OF A THROMBIN RECEPTOR ANTAGONIST
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2-8-2008
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IMMEDIATE-RELEASE TABLET FORMULATIONS OF A THROMBIN RECEPTOR ANTAGONIST
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1-32-2008
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SOLID DOSE FORMULATIONS OF A THROMBIN RECEPTOR ANTAGONIST
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12-5-2007
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Thrombin receptor antagonists
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11-23-2007
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THROMBIN RECEPTOR ANTAGONISTS
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8-31-2007
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THROMBIN RECEPTOR ANTAGONISTS AS PROPHYLAXIS TO COMPLICATIONS FROM CARDIOPULMONARY SURGERY
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8-31-2007
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CRYSTALLINE POLYMORPH OF A BISULFATE SALT OF A THROMBIN RECEPTOR ANTAGONIST
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6-27-2007
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Crystalline polymorph of a bisulfate salt of a thrombin receptor antagonist
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8-4-2006
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Preparation of chiral propargylic alcohol and ester intermediates of himbacine analogs
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9-31-2004
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Methods of use of thrombin receptor antagonists
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| US6063847 * | Nov 23, 1998 | May 16, 2000 | Schering Corporation | Thrombin receptor antagonists |
| US6326380 * | Apr 7, 2000 | Dec 4, 2001 | Schering Corporation | Thrombin receptor antagonists |
| US20030216437 * | Apr 14, 2003 | Nov 20, 2003 | Schering Corporation | Thrombin receptor antagonists |
| US20040176418 * | Jan 9, 2004 | Sep 9, 2004 | Schering Corporation | Crystalline polymorph of a bisulfate salt of a thrombin receptor antagonist |
| WO2011128420A1 | Apr 14, 2011 | Oct 20, 2011 | Sanofi | Pyridyl-vinyl pyrazoloquinolines as par1 inhibitors |
MIDAZOLAM
MIDAZOLAM
8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
59467-70-8 CAS NO OF FREE BASE
59467-94-6 MALEATE, Launched – 1982, Roche (Originator)
59467-96-8 (HCl)
A short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is used in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. The short duration and cardiorespiratory stability makes it useful in poor-risk, elderly, and cardiac patients. It is water-soluble at pH less than 4 and lipid-soluble at physiological pH.
Midazolam (/mɪˈdæzəlæm/, marketed in English-speaking countries and Mexico under the trade names Dormicum, Hypnovel, andVersed,) is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potentanxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties.[6][7][8] Midazolam has a fast recovery time and is the most commonly used benzodiazepine as a premedication for sedation; less commonly it is used for induction and maintenance of anesthesia.Flumazenil, a benzodiazepine antagonist drug, can be used to treat an overdose of midazolam, as well as to reverse sedation.[7] However, flumazenil can trigger seizures in mixed overdoses and in benzodiazepine-dependent individuals, so is not used in most cases.[9][10]
midazolam
Administration of midazolam by the intranasal or the buccal route (absorption via the gums and cheek) as an alternative to rectally administereddiazepam is becoming increasingly popular for the emergency treatment of seizures in children. Midazolam is also used for endoscopyprocedural sedation and sedation in intensive care. The anterograde amnesia property of midazolam is useful for premedication before surgery to inhibit unpleasant memories. Midazolam, like many other benzodiazepines, has a rapid onset of action, high effectiveness and low toxicity level. Drawbacks of midazolam include drug interactions, tolerance, and withdrawal syndrome, as well as adverse events including cognitive impairment and sedation. Paradoxical effects occasionally occur, most commonly in children and the elderly, particularly after intravenous administration. The drug has also recently been hastily introduced for use in executions in the USA in combination with other drugs.
Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of one to four hours; however, in the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10 percent of biological activity of midazolam. Midazolam is poorly absorbed orally with only 50 percent of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl− channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, hypnotic, anxiolytic, anterograde amnesia, muscle relaxation and anti-convulsant.Midazolam maleate is a benzodiazepine that is commercialized by Astellas Pharma and Roche as an intravenous or intramuscular injection for the long-term sedation of mechanically ventilated patients under intensive care. The drug is also available in a tablet formulation, and is currently distributed in various markets, including Germany, Japan, Switzerland and the U.K. In March 2002, two lots of a syrup formulation were recalled in the U.S. due to the potential presence of a crystalline precipitate of an insoluble complex of midazolam and saccharin. Subsequently, the injection and syrup formulations of the product were both withdrawn from the U.S. market. In 2010, a Pediatric Use Marketing Authorization (PUMA) was filed for approval in the E.U. by ViroPharma for the treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents, from 3 months to less than 18 years. In 2011, a positive opinion was assigned to the PUMA and final approval was assigned in June 2011. The product was launched in the U.S. in November 2011. This product was filed for approval in Japan in 2013 by Astellas Pharma for the conscious sedation in dentistry and dental surgery. In the same year the product was approved for this indication.
In terms of clinical development, a nasal formulation of the drug is in phase III clinical trials at Upsher-Smith for rescue treatment of seizures in patients on stable anti-epileptic drug regimens who require control of intermittent bouts of increased seizure activity (seizure clusters). The Hopitaux de Paris had been developing a sublingual tablet formulation of midazolam to be used in combination with morphine for the treatment of pain in children following bone fractures; however, no recent development has been reported for this indication. NovaDel Pharma had been developing the compound preclinically for the treatment of generalized anxiety, however no recent developments have been reported.
Midazolam achieves its therapeutic effect through interaction with the gamma-aminobutyric acid benzodiazepine (GABA-BZ) receptor complex. Subunit modulation of the GABA-BZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and post-synaptic neurons, opening ion channels and bringing about a hyperpolarization via either chloride or potassium ion flow.
In 2008, fast track designation was assigned to midazolam maleate in the U.S. for the treatment of seizure disorders.
In 2009, Orphan Drug Designation was received in the U.S. by for the treatment of seizure disorders in patients who require control of intermittent bouts of increased seizure activity (e.g. acute repetitive seizures, seizure clusters). This designation was assigned in the U.S. for the treatment of nerve agent-induced seizures.
In 2010, midazolam maleate was licensed to Upsher-Smith by Ikano Therapeutics for the treatment of acute repetitive seizure in patients with epilepsy. However, in 2010, Ikano closed and dissolved its business. Previously, Ikano had transferred to Upsher-Smith ownership of it nasal midazolam maleate program.
Midazolam is among about 35 benzodiazepines which are currently used medically, and was synthesised in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States.Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs.The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. As of 2010, it is the most commonly used benzodiazepine in anesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site.Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility.
Midazolam is a water-soluble benzodiazepine available as a sterile, nonpyrogenic parenteral dosage form for intravenous or intramuscular injection. Each mL contains midazolam hydrochloride equivalent to 1 mg or 5 mg midazolam compounded with 0.8% sodium chloride and 0.01% edetate disodium with 1% benzyl alcohol as preservative, and sodium hydroxide and/or hydrochloric acid for pH adjustment. pH 2.9-3.7.
Midazolam is a white to light yellow crystalline compound, insoluble in water. The hydrochloride salt of midazolam, which is formed in situ, is soluble in aqueous solutions. Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H– imidazo[1,5-a] [1,4] benzodiazepine hydrochloride. Midazolam hydrochloride has the molecular formula C18H13ClFN3•HCl, a calculated molecular weight of 362.25 and the following structural formula:
 |
In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances. In the United Kingdom, midazolam is a Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.
midaolam hydrochloride NDA 018654, 075154
REF
U.S. Pat. No. 4,280,957
U.S. Pat. No. 5,693,795
U.S. Pat. No. 6,512,114
Midazolam Maleate
Drugs Fut 1978, 3(11): 822
Bioorganic and Medicinal Chemistry, 2012 , vol. 20, 18 pg. 5658 – 5667
Journal of Heterocyclic Chemistry, 1983 , vol. 20, 3 pg. 551 – 558.. 32 maleate
WO 2001070744
WO 2001002402
WO 2012075286
US2011/275799 A1… no 5
Journal of Organic Chemistry, 1978 , vol. 43, p. 936,942, mp free base, nmr
| US4280957 | May 15, 1978 | Jul 28, 1981 | Hoffmann-La Roche Inc. | Imidazodiazepines and processes therefor |
| US6262260 * | Mar 23, 2000 | Jul 17, 2001 | Abbott Laboratories | Process for the preparation of midazolam |
| US6512114 | Jun 30, 1999 | Jan 28, 2003 | Abbott Laboratories | Process for the preparation of Midazolam |
……………………….
introduction
4H-imidazo[1,5-a][1,4]benzodiazepines or, more simply, imidazobenzodiazepines, are a class of benzodiazepines having the general formula (I),
wherein the 1,4-diazepine ring is fused with a 1,3-imidazole ring. The main compounds part of the 4H-imidazo[1,5-a][1,4]benzodiazepines are Midazolam of formula (IV):
an active ingredient currently commercially available as a hydrochloride salt under the name of Versed or Hypnovel for anaesthetic and sedative use and the maleate salt currently commercially available under the name Dormicum or Flormidal.
Other important compounds are Climazolam of formula (VII):
Imidazenil of formula (VIII):
1-Hydroxymidazolam of formula (IX):
and Desmethyl midazolam of formula (X):
all these being biologically active substances and having psychotropic and sedative action.
The synthesis of the Midazolam as described in U.S. Pat. No. 4,280,957 of Hoffmann-La Roche provides for the decarboxylation reaction of the 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of formula (VI) according to the following scheme:
The process for preparing the intermediate (VI) via basic hydrolysis of the corresponding ester is described in such patent publication and it is well known in the art.
The thermal decarboxylation reaction in high boiling solvent such as mineral oil at 230° C. for 5 min results in a mixture of products of Midazolam of formula (IV) and of Isomidazolam of formula (IV-bis), a non-pharmacologically active isomer, at a 80:20 ratio. The two products are separated by chromatography.
At industrial level, the formation of the Isomidazolam isomer impurity requires a further isomerisation reaction performed on the mixture of the two compounds to convert the isomer into the active product. The reaction mixture obtained from the thermal decarboxylation is thus subjected to basic treatment under the action of KOH in EtOH followed by an acid treatment which thus provides a mixture of Midazolam-Isomidazolam at a 95:5 ratio. The final removal of the Isomidazolam impurity from the product occurs through crystallisation of the product from AcOEt and EtOH. In order to limit this isomerisation treatment, in the subsequent U.S. Pat. No. 5,693,795 of Hoffmann-La Roche dated 1999, there is described a process for performing the decarboxylation of the compound of formula (VI) in n-butanol in a continuous tubular reactor with a 4 minutes permanence period with a yield between 47-77%. However, the reaction, performed at high temperature and pressure (280° C., 100 bars) results in the formation of a considerable percentage of Isomidazolam (85:15 Midazolam/Isomidazolam ratio) which still requires the basic isomerisation step.
Lastly, in U.S. Pat. No. 6,512,114 of Abbott Laboratories there is described the decarboxylation of the compound of formula (VI) in mineral oil or in N,N-Dimethylacetamide (DMA) at 160-230° C. for at least 3 hours obtaining a 3/1 to 6/1 Midazolam/Isomidazolam ratio with a yield of isolated product equal to just 54%.
Though performed using dedicated apparatus and in extreme conditions, the prior art processes do not allow selectively performing the decarboxylation reaction of the intermediate (VI) to Midazolam thus requiring a further synthetic passage followed by crystallisation with ensuing reduction of the overall yield.
Midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine) is represented by the following structural formula (I):
Midazolam is a central nervous system (CNS) depressant, used for short term treatment of insomnia. Like other benzodiazepines, midazolam binds to benzodiazepine receptors in the brain and spinal cord and is thus used as a short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is currently used in dentistry, cardiac surgery, endoscopic procedures, as a preanesthetic medication, as an adjunct to local anesthesia and as a skeletal muscle relaxant. Depending on the pH value, midazolam can exist in solution as a closed ring form (I) as well as an open ring form (IA), which are in equilibrium, as shown in Scheme 1:
The amount of the open ring form (IA) is dependent upon the pH value of the solution. At a pH value of about 3, the content of the open ring form (IA) can be 40%, while at pH value of 7.5, the closed ring form (I) can be more than 90%.
Clinical studies have demonstrated that there are no significant differences in the clinical activity between midazolam hydrochloride and midazolam maleate, however the use of intravenous midazolam hydrochloride has been associated, in some cases, with respiratory depression and arrest.
U.S Pat. No. 4,280,957 (hereinafter the ‘957 patent) describes a synthetic process for preparing midazolam, which is depicted in Scheme 2 below. This process includes reacting 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-bezodiazepine (II) with acetic anhydride in dichloromethane to produce 2-acetamido-methyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-bezodiazepine (III). The latter is heated with polyphosphoric acid at 150° C. to produce 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine of formula (IV), which is purified by column chromatography. Compound IV is then mixed with toluene and manganese dioxide and heated to reflux to afford midazolam base, which is crystallized from ether to yield a product with mp of 152-154° C.
The ‘957 patent further describes an alternative process which includes reacting 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-bezodiazepine (II) (optionally as a dimaleate salt) with triethylorthoacetate in ethanol and in the presence of p-toluenesulfonic acid to afford 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (IV). This product is dissolved in xylene and treated with activated manganese dioxide to afford the crude base, which is reacted in situ with maleic acid in ethanol and crystallized by addition of ether to produce the midazolam maleate having melting point of 148-151° C. The process is depicted in Scheme 3 below.
The preparation of midazolam maleate from the isolated midazolam base is also described in a further example of the ‘957 Patent, wherein a warm solution of midazolam base in ethanol is combined with a warm solution of maleic acid in ethanol. The mixture is diluted with ether and at least part of the solvents is evaporated using a steam bath to obtain crystalline midazolam maleate having melting point of 148-151° C. The yield and the purity of the obtained midazolam maleate are not disclosed.
U.S. Pat. No. 6,512,114 (hereinafter the ‘114 patent) describes another synthetic process for preparing midazolam, which is depicted in Scheme 4 below. According to this Process, the starting material 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid (V) is heated in mineral oil for 3 hours at 230° C. until it is decarboxylated, followed by treatment with potassium tert-butoxide, to afford midazolm (I), isomidazolam (VI) and a midazolam dimmer (VII). Midazolam base is obtained in 54.5% yield after two re-crystallizations from ethyl acetate and heptane; however, the purity of the product is not disclosed.
The preparation of midazolam by conventional routes is liable to produce impurities such as isomidazolam (VI) and a midazolam dimmer (VII), and possibly other impurities. There is, therefore, a need in the art for a midazolam purification process that will provide highly pure midazolam containing minimal amounts of impurities produced. The present invention provides such a process.
This example describes the preparation of midazolam base as taught in the ‘957 patent.
16 g (0.03 mol) of 2-aminomethyl-7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-bezodiazepine dimaleate was dissolved in 200 ml of toluene and 10 ml of 25% ammonium hydroxide solution was added and mixing was maintained for an hour. Then, the phases were separated and the toluene phase was dried by azeotropic distillation using a Dean Stark apparatus. 7 ml (0.038 mol) of triethylorthoacetate was added and the solution was heated to reflux for 4 hours, after which time the solution was left to cool to ambient temperature. 25 ml of methyl tert-butyl ether was added and the mixture was cooled overnight to produce 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine, which was isolated by filtration. The product was mixed with 200 ml of toluene and dried by azeotropic distillation using a Dean Stark apparatus. Then, 30 g of manganese dioxide was added and the mixture was heated to reflux for two hours. The excess manganese dioxide was filtered off to afford a solution of midazolam base in toluene, which was evaporated to obtain a product having 97.9% purity and containing 0.44% of impurity VIII and 1.14% of impurity IX (according to HPLC).
…………………………
EXAMPLE 28
2-Aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine dimaleate
A suspension of 17 g (0.05 m) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide in 200 ml of tetrahydrofuran and 100 ml of methanol was hydrogenated in presence of 17 g of Raney nickel at an initial pressure of 155 psi for 24 hrs. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in 50 ml of 2-propanol and warmed on the steambath. A warm solution of 17 g of maleic acid in 60 ml of ethanol was added and the salt was allowed to crystallize by cooling in the ice bath. The final product consisted of yellow crystals with mp 196
EXAMPLE 14
8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
Acetic anhydride, 7 ml., was added to a solution of 6.16 g. of crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 200 ml. of methylene chloride. The solution was layered with 200 ml. of saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium bicarbonate, dried over sodium sulfate and evaporated to leave 6.2 g. resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine. This material was heated with 40 g. of polyphosphoric acid at 150 water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue (5.7 g.) was chromatographed over 120 g. of silica gel using 20% methanol in methylene chloride. The clean fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[ 1,5-a][1,4]benzodiazepine. A mixture of this material with 500 ml. of toluene and 30 g. of manganese dioxide was heated to reflux for 11/2 hours. The manganese dioxide was separated by filtration over celite. The filtrate was evaporated and the residue was crystallized from ether to yield a product with m.p. 152 was recrystallized from methylene chloride/hexane
EXAMPLE 49
8-Chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine
Potassium t-butoxide, 0.625 g. (5.5 mmol), was added to a solution of 1.625 g. (5 mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 20 ml. of dimethylformamide cooled to -30 nitrogen for 10 min. at -30 ml. of glacial acetic acid and was then partitioned between aqueous bicarbonate and toluene/methylene chloride (3:1 v/v). The organic layer was separated, dried and evaporated. The residue was chromatographed over 60 g. of silica gel using 25% (v/v) methylene chloride in ethyl acetate. The less polar product was eluted first and was crystallized from ethylacetate/hexane to yield product with m.p. 180
EXAMPLE 50
8-Chloro-6-(2-fluorphenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
Potassium t-butoxide, 0.125 g. (1.1 mmol) was added to a solution of 0.325 g. (1 mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine in 20 ml. of dimethylformamide cooled to -30 -30 by addition of 0.2 ml. of glacial acetic acid and was partitioned between aqueous sodium bicarbonate and methylene chloridetoluene (1:3). The organic phase was washed with water, dried and evaporated. The residue was chromatographed over 20 g. of silica gel using ethyl acetate for elution. After elution of starting material, product was collected and crystallized from ether/hexane, m.p. 156
hyd and dihydrochloride
EXAMPLE 24
8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine dihydrochloride
A solution of 0.32 g (1 mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 5 ml of ethanol was treated with excess ethanolic hydrogen chloride. The salt was crystallized by addition of 2-propanol and ether. The colorless crystals were collected, washed with ether and dried to leave a final product with mp 290
EXAMPLE 258-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride
A solution of 0.325 g (1 mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 3 ml of ethanol was combined with a suspension of 0.4 g (1 mmol) of the dihydrochloride of this compound in 5 ml of ethanol. After filtration, the solution was treated with ether and heated on the steambath for 5 min to crystallize. The crystals were collected, washed with ether and dried to leave the monohydrochloride with mp 295
maleate
EXAMPLE 22
8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine maleate
A warm solution of 6.5 g (0.02 m) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 30 ml of ethanol was combined with a warm solution of 2.6 g (0.022 m) of maleic acid in 20 ml of ethanol. The mixture was diluted with 150 ml of ether and heated on the steam bath for 3 min. After cooling, the crystals were collected, washed with ether and dried in vacuo to yield a final product with mp 148
…
Synthesis
Midazolam, can be described according to scheme 4 indicated below:
was prepared according to processes known in the art (e.g. U.S. Pat. No. 4,280,957) which comprise the basic hydrolysis of the corresponding ester.For the reactions performed in the microreactor, the solutions containing the substrates to be decarboxylated were loaded into 5 and 10 mL gastight glass syringes (Hamilton, item n. 81527, 81627) mounted on syringe pumps (KD Scientifics, model KDS100). A pipe made of PTFE® (OD=1.58 mm, ID=0.8 mm, Supelco, item n. 58696-U) was used for making the reaction channel.A counterpressure valve sold by Swagelok (item n. SS-SS1-VH) was used for regulating the flow within the channel.Example 1Synthesis of the Compound of Formula (V)—Example of the Invention
50 g (0.135 mol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylic acid of formula (VI) and 250 mL of ethanol were loaded into a two-neck 500 mL flask, equipped with a magnetic stirrer. 40 mL of an aqueous solution of 1 M HCl are dripped in about 10 minutes. The open di-hydrochloride intermediate of formula (V) starts precipitating into the reaction environment already after 3 minutes from the beginning of the addition of the acid solution. The mixture is maintained stirred at RT for 3 hrs and then it is filtered on buckner washing the solid with ethanol. The moist product is dried in an oven under vacuum at 60° C. up to reaching a constant weight. A light yellow crystalline product is obtained (51.5 g, 83% yield). The crude product was used for the decarboxylation without further purifications.
ESI-MS [MeCN+0.1% HCOOH]: m/z 388 (V); 370 (VI).
1H-NMR (250 MHz, CD3OD): 2.52 (s, 3H); 4.27-4.41 (m, 2H); 7.22-8.1 (m, 7H). M.p.: 217° C.
Example 2
Synthesis of Midazolam of Formula (IV)—Performed in Batch—Example of the Invention
30 g (0.065 mol) of 5-(aminomethyl)-1-{(4-chloro-2-[(2-fluorophenyl)carbonyl]phenyl}-2-methyl-1H-imidazole-4-carboxylic acid dihydrochloride of formula (V) and 90 mL of NMP are loaded into a three-neck 250 mL flask, equipped with a magnetic stirrer and coolant. The mass is heated using an oil bath at T=195-203° C. for one hour. Thus, 1 mL of solution is collected for performing HPLC analysis. The reaction product is Midazolam having 82% titre (w/w) (determined via HPLC titre correcting it using the solvent) and it contains 1% of Isomidazolam. The product is extracted using Isopropyl acetate after raising the pH to 10 by adding aqueous Na2CO3.
Example 3
Synthesis of Midazolam of Formula (IV)—Performed in a Micro-Reactor—Example of the Invention
3.22 g (7 mmol) of 5-(aminomethyl)-1-{4-chloro-2-[(2-fluorophenyl)carbonyl]phenyl}-2-methyl-1H-imidazole-4-carboxylic acid dihydrochloride of formula (V) and 10 mL of NMP are loaded into a 10 mL flask equipped with a magnetic stirrer. In order to facilitate the complete solubilisation of the substrate, it is necessary to slightly heat the reaction mixture (about 40° C.) for a few minutes. The solution thus obtained is transferred into a 10 mL gastight glass syringe mounted on a KDS100 syringe pump (FIG. 1) and the flow is regulated at 1.0 mL/h so as to set a residence period of 30 minutes at 200° C. The reaction product is Midazolam having an 89% titre (w/w) (determined via HPLC titre correcting it using the solvent) and containing 3% (w/w) of Isomidazolam.
Example 4Synthesis of Midazolam of formula (IV)—Comparison of the InventionA table is reported which summarises the results of the decarboxylation of the compound of formula (V) and (V-bis) (for the latter see Examples 6 and 7) obtained according to some embodiments of the invention and those obtained by way of experiment through the decarboxylation of the intermediate of formula (VI) (process of the prior art) both performed in 3 volumes of NMP at 200° C., both in batch method (Example 4) and in continuous method with the microreactor (MR) made of PTFE of FIG. 1. (Examples 4-1, 4-2, 4-3).
| Example | substrate | Mode | Solv. | T° C. | t min. | Midazolam (p/p) | Isomidaz. (P/P) |
| 2 | (V) | Batch | NMP | 200 | 60 | 82 | 1 |
| 3 | (V) | MR | NMP | 200 | 30 | 89 | 3 |
| 7 | (V-bis) | Batch | NMP | 200 | 60 | 68 | 3 |
| 4 | (VI) | Batch | NMP | 200 | 60 | 78 | 18 |
| 4-1 | (VI) | MR | NMP | 200 | 38 | 81 | 17 |
| 4-2 | (VI) | MR | NMP | 200 | 20 | 77 | 18 |
| 4-3 | (VI) | MR | NMP | 200 | 15 | 58 | 22 |
| U.S. Pat. No. | (VI) | Tubular | n-BuOH | 290 | 4 | 85 * | 15 * |
| 5,693,795 | reactor | ||||||
| U.S. Pat. No. | (VI) | Batch | Olio | 230 | 180 | 75 * | 25 * |
| 6,512,114 | min. | 87.5 * | 12.5 * | ||||
| or DMA | |||||||
| * = Midazolam/Isomidazolam ratio only (other impurities not considered). | |||||||
The product of the comparative experiments 4, 4-1, 4-2, 4-3 and of the two USA patents should be subjected to a further isomerisation process to reduce the high amount of Isomidazolam so as to be able to obtain Midazolam free of Isomidazolam after further crystallization, which would not be required for the product obtained according to the invention (examples 2 and 3).
A 4-neck RBF was charged under nitrogen flow with: 10 g of Midazolam (IV) (prepared according to example 2) and 40 mL of Ethanol. The slurry was stirred until complete dissolution at 25/30° C. In an other flask was prepared the following solution: 3.72 g of maleic acid are dissolved in 15 mL of Ethanol. The slurry was stirred until complete dissolution at 25/30° C. The maleic acid solution is dropped in 30/40 minutes and keeping T=25/30° C. into the solution containing Midazolam. The slurry was cooled down at −15° C. in one hour and kept at that temperature for at least 2 hours. The slurry was then filtered and the cake was washed with 40 mL of cool Ethanol. The filter was discharged and the product was dried at 40° C. under vacuum for 2 hours and then at 60° C. for 8 hours. 12.8 g of Midazolam Maleate as white solid were collected (Molar yield=94.5%). m.p.=149-152° C. (by DSC).
A 4-neck RBF was charged under nitrogen flow with: 1 g of Midazolam (IV) (prepared according to example 2) and 15 mL of Ethanol. The slurry was stirred until complete dissolution at 25/30° C. 5 mL of a ethanolic solution of Hydrochloric acid 2N were slowly added. 20 mL of Isopropanol were added over 30 minutes at RT. The slurry was cooled down at −15° C. in one hour and kept at that temperature for at least 2 hours. The slurry was then filtered and the cake was washed with 10 mL of cool isopropanol. The filter was discharged and the product was dried at 40° C. under vacuum for 2 hours and then at 60° C. for 8 hours. Midazolam dihydrochloride as white solid was collected.
MIDAZOLAM HYDROCHLORIDE
Example 10
Preparation of 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride (Midazolam hydrochloride)
A 4-neck RBF was charged under nitrogen flow with: 1 g of Midazolam (IV) (prepared according to example 2) and 10 mL of Ethanol. The slurry was stirred until complete dissolution at 25/30° C. In an other flask was prepared the following suspension: 1.22 g of Midazolam dihydrochloride (prepared according to example 9) and 15 mL of Ethanol. The Midazolam ethanolic solution was added to the Midazolam dihydrochloride suspension. After filtration, the solution was treated with MTBE and heated at 60° C. until crystallization. After cooling to RT, the slurry was filtered, the cake washed with MTBE and the product was dried to provide Midazolam (mono)hydrochloride as a white solid.
…..
NEW DRUG APPROVALS
ONE TIME
$10.00
TEDIGLUTIDE ..Glucagon-like peptide 2 (GLP-2) analog; protects small intestinal stem cells from radiation damage.
TEDUGLUTIDE
Glucagon-like peptide 2 (GLP-2) analog; protects small intestinal stem cells from radiation damage.
Gattex (teduglutide) is a recombinant analog of human glucagon-like peptide 2 for the treatment of adults with short bowel syndrome.
- (Gly2)GLP-2
- ALX 0600
- ALX-0600
- Gattex
- Gly(2)-GLP-2
- Teduglutide
- UNII-7M19191IKG
[Gly2]hGLP-2, [Gly2]-hGLP-2, ALX-0600,
Gattex, Revestive
| CAS number | 197922-42-2 |
|---|
L-histidylglycyl-L-α-aspartylglycyl-L-seryl-L-phenylalanyl-L-seryl-L-α-aspartyl-L-α-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L-isoleucyl-L-leucyl-L-α-aspartyl-L-asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-α-aspartyl-L-phenylalanyl-L-isoleucyl-L-asparaginyl-L-tryptophyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-isoleucyl-L-threonyl-L-aspartic acid
| Formula | C164H252N44O55S |
|---|---|
| Mol. mass | 3752.082 g/mol |
Gattex, ALX-0600, (Gly2)GLP-2, Gly(2)-GLP-2, ALX 0600, [Gly2]GLP-2, Glucagon-like peptide II (2-glycine) (human), UNII-7M19191IKG
LAUNCHED 2013, NPS Pharmaceuticals
APPROVAL FDA
Company: NPS Pharmaceuticals, Inc.
Date of Approval: December 21, 2012 FDA
NDA 203441
POWDER; SUBCUTANEOUS GATTEX
U-1320=TREATMENT OF ADULT PATIENTS WITH SHORT BOWEL SYNDROME WHO ARE DEPENDENT ON PARENTERAL SUPPORT
| Patent No | Patent Expiry Date | Patent use code |
|---|---|---|
| 5789379 | Apr 14, 2015 | U-1320 |
| 7056886 | Sep 18, 2022 | U-1320 |
| 7847061 | Nov 1, 2025 | U-1320 |
| Exclusivity Code | Exclusivity_Date |
|---|---|
| ORPHAN DRUG EXCLUSIVITY | Dec 21, 2019 |
| NEW CHEMICAL ENTITY | Dec 21, 2017 |
SEE FDA
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203441Orig1s000lbl.pdf
CLINICAL TRIALS
http://clinicaltrials.gov/search/intervention=Teduglutide+OR+ALX-0600
The active ingredient in GATTEX (teduglutide [rDNA origin]) for injection is teduglutide (rDNA origin), which is a 33 amino acid glucagon-like peptide-2 (GLP-2) analog manufactured using a strain of Escherichia coli modified byrecombinant DNA technology. The chemical name of teduglutide is L-histidyl-L-glycyl-L-aspartyl-L-glycyl-L-seryl-L-phenylalanyl-L-seryl-L-aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L-isoleucyl-L-leucyl-L-aspartyl-L-asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-aspartyl-L-phenylalanyl-L-isoleucyl-L-asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-isoleucyl-L-threonyl-L-aspartic acid. The structural formula is:
Figure 1: Structural formula of teduglutide
Teduglutide has a molecular weight of 3752 Daltons. Teduglutide drug substance is a clear, colorless to light-straw–colored liquid.
Each single-use vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for solution for subcutaneous injection. In addition to the active pharmaceutical ingredient (teduglutide), each vial of GATTEX contains 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium phosphate monohydrate, 3.434 mg dibasic sodium phosphate heptahydrate as excipients. No preservatives are present.
At the time of administration the lyophilized powder is reconstituted with 0.5 mL of Sterile Water for Injection, which is provided in a prefilled syringe. A 10 mg/mL sterile solution is obtained after reconstitution. Up to 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn for subcutaneous injection upon reconstitution.
Teduglutide (brand names Gattex and Revestive) is a 36-membered polypeptide andglucagon-like peptide-2 analog that is used for the treatment of short bowel syndrome. It works by promoting mucosal growth and possibly restoring gastric emptying and secretion.[1] In Europe it is marketed under the brand Revestive by Nycomed. It was approved by the United States under the name Gattex on December 21, 2012.
Teduglutide is a proprietary analogue of glucagon-like peptide 2 (GLP-2) which was approved in the U.S. in December 2012 for the once-daily treatment of short-bowel syndrome in adults who are dependent on parenteral support. Commercial launch took place in 2013.The product was filed for approval in the E.U. in 2011 by Nycomed for this indication. In June 2012, a positive opinion was received in the E.U. and final approval was assigned in September 2012.
At NPS Pharmaceuticals, the compound is in phase III clinical development for this indication in pediatric patients and in phase II clinical studies for the treatment of Crohn’s disease. Preclinical studies are also ongoing at the company for the treatment of chemotherapy-induced enterocolitis and for the prevention and treatment of necrotizing enterocolitis (NEC) in preterm infants.
Teduglutide has been found to induce intestinal hyperplasia, reduce apoptosis and inflammation and improve cell barrier integrity in animal models. In 2001, orphan drug designation was assigned to teduglutide for the treatment of short-bowel syndrome.
In 2007, the compound was licensed to Nycomed for development and commercialization outside the U.S., Canada and Mexico for the treatment of gastrointestinal disorders. In 2012, the product was licensed to Neopharm by NPS Pharmaceuticals in Israel for development and commercialization for the treatment of gastrointestinal disorders.
The estimated prevalence of short bowel syndrome (SBS) patients with non-malignant disease requiring home parenteral nutrition (HPN) is at least 40 per million of the U.S. population. SBS usually results from surgical resection of some or most of the small intestine for conditions such as Crohn’s disease, mesenteric infarction, volvulus, trauma, congenital anomalies, and multiple strictures due to adhesions or radiation. Surgical resection may also include resection of all or part of the colon. SBS patients suffer from malabsorption that may lead to malnutrition, dehydration and weight loss. Some patients can maintain their protein and energy balance through hyperphagia; more rarely they can sustain fluid and electrolyte requirements to become independent from parenteral fluid.
Although long-term parenteral nutrition (PN) is life saving in patients with intestinal failure, it is expensive, impairs quality of life and is associated with serious complications such as catheter sepsis, venous occlusions and liver failure. Treatments that amplify absolute intestinal absorption, and eliminate or minimize the need for PN have great potential significance to SBS patients.
The endogenous meal-stimulated hormone, glucagon-like peptide-2 (GLP-2), raises considerable interest for SBS patients. GLP-2 functions to slow gastric emptying, reduce gastric secretions, increase intestinal blood-flow and stimulate growth of the small and large intestine. In animal studies, GLP-2 administration induces mucosal epithelial proliferation in the stomach and small and large intestine by stimulation of crypt cell proliferation and inhibition of enterocyte apoptosis.
SBS patients with end-jejunostomy and no colon have low basal GLP-2 levels and limited meal-stimulated GLP-2 secretion due to removal of GLP-2 secreting L-cells, which are located primarily in the terminal ileum and colon. This GLP-2 deficiency results in a minimal adaptive response following resection and could explain the gastric hypersecretion, rapid intestinal transit and lack of intestinal adaptation observed in these SBS patients.
Jeppesen et al. (Gastroenterology 2001; 120:806-815) have described positive benefit in an open-label study using pharmacologic doses of native GLP-2 in SBS jejunostomy patients. There was significant improvement in intestinal wet weight absorption and a more modest improvement in energy absorption that led to an increase in body weight, lean body mass and a rise in urinary creatinine excretion.
In contrast, SBS patients with colon-in-continuity have elevated basal endogenous GLP-2 levels resulting in an adaptive response to resection characterized by improved wet weight gain and energy absorption. The potential for added benefit of pharmacologic doses of GLP-2 receptor agonists in these patients is not obvious and has not been studied.
TEDUGLUTIDE
- Jeppesen PB (May 2012). “Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome”. Therap Adv Gastroenterol 5 (3): 159–71. doi:10.1177/1756283X11436318. PMC 3342570. PMID 22570676.
- US 2013157954
- WO 2006050244
- WO 2005021022
- US 6586399
- WO 2002066062
- US 6297214
- US 2001021767
- WO 2001041779
- WO 1999058144
- WO 1998052600
Gattex Approved By FDA For Short Bowel Syndrome
Gattex (teduglutide) has been approved by the U.S. Food and Drug Administration to be used in patients that have short bowel syndrome and require parenteral nutrition.
The drug, once it is in the market, will compete against two others that have been approved by the FDA for this type of patient population. Those two medications are Nutrestore (glutamine) and Zorbtive (Somatropin).
Short bowel syndrome comes on following the removal surgically of part of the large or small intestine or part of both. Patients who are affected must have parenteral nutrition due to the poor absorption they have of nutrients and fluids. Teduglutide is injected one time each day and improves the absorption making it less important to have nutrition assistance.
The advisory committee for the FDA voted unanimously in October to recommend the drug’s approval after seeing the results from a pair of clinical trials that showed the advantage teduglutide had over just a placebo in at least a reduction of 20% in the amount of parenteral nutrition at 6 months.
During the first clinical trial, 46% of the patients that took the drug saw a level of reduction, which was compared to only 6% who had taken only a placebo. In the other study, the figure increased to 63%, while the placebo rated was up to 30%
The side effects most common found in those who use teduglutide during the trials included nausea, reactions around the injection site, abdominal pain abdominal distension and headaches.
………..
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| EP1231219A1 | Apr 11, 1997 | Aug 14, 2002 | 1149336 Ontario Inc. | GLucagon-like peptide-2 analogs |
| WO1997039031A1 | Apr 11, 1997 | Oct 23, 1997 | Allelix Biopharma | Glucagon-like peptide-2 analogs |
| WO1997039091A1 | Apr 16, 1997 | Oct 23, 1997 | Burckett St Laurent James Char | Mid-chain branched surfactants |
| WO2002066511A2 | Feb 15, 2002 | Aug 29, 2002 | Conjuchem Inc | Long lasting glucagon-like peptide 2 (glp-2) for the treatment of gastrointestinal diseases and disorders |
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DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
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Purslane – The Gourmet Weed
Health benefits of Purslane
- This wonderful green leafy vegetable is very low in calories (just 16 kcal/100g) and fats; nonetheless, it is rich in dietary fiber, vitamins, and minerals.
- Fresh leaves contain surprisingly more omega-3 fatty acids (α-linolenic acid) than any other leafy vegetable plant. 100 grams of fresh purslane leaves provide about 350 mg of α-linolenic acid. Research studies show that consumption of foods rich in ω-3 fatty acids may reduce the risk of coronary heart disease, stroke, and help prevent the development of ADHD, autism, and other developmental differences in children.
- It is an excellent source of Vitamin A, (1320 IU/100 g, provides 44% of RDA) one of the highest among green leafy vegetables. Vitamin A is a known powerful natural antioxidant and is essential for vision. This vitamin is also required to maintain healthy mucus membranes and skin. Consumption of natural vegetables and fruits rich in vitamin A is known to help to protect from lung and oral cavity cancers.
- Purslane is also a rich source of vitamin C, and some B-complex vitamins like riboflavin, niacin, pyridoxine and carotenoids, as well as dietary minerals, such as iron, magnesium, calcium, potassium, and manganese.
- Furthermore, present in purslane are two types of betalain alkaloid pigments, the reddish beta-cyaninsand the yellow beta-xanthins. Both pigment types are potent anti-oxidants and have been found to have anti-mutagenic properties in laboratory studies. [Proc. West. Pharmacol. Soc. 45: 101-103 (2002)].
Portulaca oleracea (common purslane, also known as verdolaga, pigweed, little hogweed, or pursley, and moss rose) is an annual succulent in the family Portulacaceae, which may reach 40 cm in height.
Greek salad with Purslane
Approximately forty varieties currently are cultivated.[1] It has an extensive Old World distribution extending from North Africa through the Middle East and the Indian Subcontinentto Malesia and Australasia. The species status in the New World is uncertain: in general, it is considered an exotic weed, however, there is evidence that the species was in Crawford Lake deposits (Ontario) in 1430-89 AD, suggesting that it reached North America in the pre-Columbian era.[2] It is naturalised elsewhere and in some regions is considered an invasiveweed. It has smooth, reddish, mostly prostrate stems and alternate leaves clustered at stem joints and ends. The yellow flowers have five regular parts and are up to 6 mm wide. Depending upon rainfall, the flowers appear at anytime during the year. The flowers open singly at the center of the leaf cluster for only a few hours on sunny mornings. Seeds are formed in a tiny pod, which opens when the seeds are mature. Purslane has a taproot with fibrous secondary roots and is able to tolerate poor, compacted soils and drought.
A Purslane cultivar grown as a vegetable
Although purslane is considered a weed in the United States, it may be eaten as a leaf vegetable. It has a slightly sour and salty taste and is eaten throughout much of Europe, the middle east, Asia, and Mexico.[1][3] The stems, leaves and flower buds are all edible. Purslane may be used fresh as a salad, stir-fried, or cooked as spinach is, and because of its mucilaginous quality it also is suitable for soups and stews. Australian Aborigines use the seeds to make seedcakes. Greeks, who call it andrakla (αντράκλα) or glystrida (γλυστρίδα), fry the leaves and the stems with feta cheese, tomato, onion, garlic, oregano, and olive oil, add it in salads, boil it or add to casseroled chicken. In Turkey, besides being used in salads and in baked pastries, it is cooked as a vegetable similar to spinach. InAlbania it is called burdullak, and also is used as a vegetable similar to spinach, mostly simmered and served in olive oil dressing, or mixed with other ingredients as a filling for dough layers of byrek. In the south of Portugal (Alentejo), “baldroegas” are used as a soup ingredient.
Purslane contains more omega-3 fatty acids (alpha-linolenic acid in particular[4]) than any other leafy vegetable plant. Studies have found that Purslane has 0.01 mg/g ofeicosapentaenoic acid (EPA). This is an extraordinary amount of EPA for a land-based vegetable source. EPA is an Omega-3 fatty acid found mostly in fish, some algae, and flax seeds.[5] It also contains vitamins (mainly vitamin A, vitamin C, Vitamin E (alpha-tocopherol)[6] and some vitamin B and carotenoids), as well as dietary minerals, such asmagnesium, calcium, potassium, and iron. Also present are two types of betalain alkaloid pigments, the reddish betacyanins (visible in the coloration of the stems) and the yellow betaxanthins (noticeable in the flowers and in the slight yellowish cast of the leaves). Both of these pigment types are potent antioxidants and have been found to have antimutagenic properties in laboratory studies.[7]
100 Grams of fresh purslane leaves (about 1 cup) contain 300 to 400 mg of alpha-linolenic acid.[8] One cup of cooked leaves contains 90 mg of calcium, 561 mg of potassium, and more than 2,000 IUs of vitamin A. A half-cup of purslane leaves contains as much as 910 mg of oxalate, a compound implicated in the formation of kidney stones; however, many common vegetables, such as spinach, also can contain high concentrations of oxalates. Cooking purslane reduces overall soluble oxalate content by 27%, which is important considering its suggested nutritional benefits of being part of a healthy diet.[9]
When stressed by low availability of water, purslane, which has evolved in hot and dry environments, switches to photosynthesis usingCrassulacean acid metabolism (the CAM pathway): At night its leaves trap carbon dioxide, which is converted into malic acid (the souring principle of apples), and, in the day, the malic acid is converted into glucose. When harvested in the early morning, the leaves have ten times the malic acid content as when harvested in the late afternoon, and thus have a significantly more tangy taste.
Portulaca oleracea showing blooms
Seed pods, closed and open, revealing the seeds
Known as Ma Chi Xian (pinyin: translates as “horse tooth amaranth”) in traditional Chinese medicine, its active constituents include: noradrenaline, calcium salts, dopamine,DOPA, malic acid, citric acid, glutamic acid, asparagic acid, nicotinic acid, alanine, glucose, fructose, and sucrose.[10] Betacyanins isolated from Portulaca oleracea improved cognition deficits in aged mice.[11] A rare subclass of Homoisoflavonoids, from the plant, showed in vitro cytotoxic activities towards four human cancer cell lines.[12]Use is contraindicated during pregnancy and for those with cold and weak digestion.[10]Purslane is a clinically effective treatment for oral lichen planus,[13] and its leaves are used to treat insect or snake bites on the skin,[14] boils, sores, pain from bee stings, bacillary dysentery, diarrhea, hemorrhoids, postpartum bleeding, and intestinal bleeding.[10]
Portulaca oleracea efficiently removes bisphenol A, an endocrine-disrupting chemical, from a hydroponic solution. How this happens is unclear.[15]
Purslane, also known as Khulpha, Khursa in Hindi or Ghol in Marathi, is a water-retaining plant that can reach a height of 6″ – 12”. It’s smooth, reddish, thick leaves are wedge shaped. The leaves are alternately clustered at stem joints and are greenish on top and purplish on the underside.
The very tiny yellow flowers are around 6 mm wide and depending upon rainfall, the flowers appear at anytime during the year. Purslane has a taproot with fibrous secondary roots and is able to tolerate poor, compacted soils and drought.
It’s smooth, reddish, thick leaves are wedge shaped. The leaves are alternately clustered at stem joints and are greenish on top and purplish on the underside.
All that purslane needs to grow is part to full sun and clear ground. They are not picky about soil type or nutrition. If you decide to plant purslane seeds, simply scatter the seeds over the area that you plan on growing the purslane. Do not cover the seeds with soil. Purslane seeds need light to germinate, so they must stay on the surface of the soil. If you are using Purslane cuttings, lay them on the ground where you plan on growing purslane. Water the stems and they should take root in the soil in a few days.
About a month after the seeds are planted, the first flowers will begin to appear. Once the flowers open, the seeds will begin to set within about a week to ten days. Since the Purslane is an invasive plant, it is difficult to get rid of. This is because the plant has stored enough energy for the seeds to continue to mature even after you pull the plant. Therefore, if you are trying to get rid of purslane, don’t try to compost it. If the compost pile is not hot enough to destroy the seeds, you will end up with more plants you don’t want.
Purslane is ready to harvest in about 2 months from the time the seeds are sown. Make sure to harvest it regularly and be aware that it can become invasive. Harvesting before it develops flowers will help cut down on its spreading. Generally, you can harvest two or three times before the plants are exhausted.
The erect, tangy and succulent stems are high in Vitamin C. The leaves contain the highest concentration of Omega-3 fatty acids found in land plants. This is 5 times more than Spinach and 10 times more than any Lettuce or Mustard. It also contains Vitamin A, Vitamin C, and some Vitamin B and carotenoids as well as dietary minerals such as Magnesium, Calcium, Potassium and Iron.
100 Grams of fresh purslane leaves contain 300 to 400 mg of essential fatty acids (EFAs). One cup of cooked leaves contains 90 mg of Calcium, 561 mg of Potassium, and more than 2,000 IUs of Vitamin A.
As a companion plant, Purslane provides ground cover to create a humid microclimate for nearby plants, stabilizing ground moisture. Its deep roots bring up moisture and nutrients that those plants can use, and some, including corn, will “follow” purslane roots down through harder soil that they cannot penetrate on their own.
As a companion plant, Purslane provides ground cover to create a humid microclimate for nearby plants, stabilizing ground moisture. Its deep roots bring up moisture and nutrients that those plants can use, and some, including corn, will “follow” purslane roots down through harder soil that they cannot penetrate on their own (ecological facilitation). It is known as a beneficial weed in places that do not already grow it as a crop in its own right.
Widely used in East Mediterranean countries, archaeobotanical finds are common at manyprehistoric sites. In historic contexts, seeds have been retrieved from a protogeometric layer in Kastanas, as well as from the Samian Heraion dating to seventh century B.C. In the fourth century B.C., Theophrastus names purslane, andrákhne (ἀνδράχνη), as one of the several summer pot herbs that must be sown in April (H.P 7.12).[16] As portulaca it figures in the long list of comestibles enjoyed by the Milanese given by Bonvesin de la Riva in his “Marvels of Milan” (1288).[17]
In antiquity, its healing properties were thought so reliable that Pliny advised wearing the plant as an amulet to expel all evil (Natural History 20.120).[16]
A common plant in parts of India, purslane is known as Sanhti, Punarva, or Kulfa.
- The name verdolaga, associated with the plant that grows in South America is a nickname for Football clubs with green-white schemes in their uniforms, such as Colombia‘s Atletico Nacional and Argentina‘s Ferrocarril Oeste.
- Marlena Spieler (July 5, 2006). “Something Tasty? Just Look Down”. The New York Times.
- Byrne, R. and McAndrews, J. H. (1975). “Pre-Columbian puslane (Portulaca oleracea L.) in the New World”. Nature 253(5494): 726–727. doi:10.1038/253726a0.
- Pests in Landscapes and Gardens: Common Purslane. Pest Notes University of California Agriculture and Natural Resources Publication 7461. October 2003
- Jump up^ David Beaulieu. “Edible Landscaping With Purslane”. About.com.
- ARTEMIS P SIMOPOULOS Omega-3 Fatty Acids and Antioxidants in Edible Wild Plants. 2004. Biol Res 37: 263-277, 2004
- Simopoulos AP, Norman HA, Gillaspy JE, Duke JA. Common purslane: a source of omega-3 fatty acids and antioxidants. J Am Coll Nutr. 1992;11(4):374-82.
- Evaluation of the Antimutagenic Activity of Different Vegetable Extracts Using an In Vitro Screening Test
- A. P. Simopoulos, H. A. Norman, J. E. Gillaspy, and J. A. Duke. Common purslane: a source of omega-3 fatty acids and antioxidants. Journal of the American College of Nutrition, Vol 11, Issue 4 374-382, Copyright © 1992
- http://world-food.net/oxalate-content-of-raw-and-cooked-purslane/
- Tierra, C.A., N.D., Michael (1988). Planetary Herbology. Lotus Press. p. 199.
- Wang CQ. Yang GQ., “Betacyanins from Portulaca oleracea L. ameliorate cognition deficits and attenuate oxidative damage induced by D-galactose in the brains of senescent mice.,Phytomedicine. 17(7):527-32, 2010 Jun.
- Yan J, Sun LR, Zhou ZY, Chen YC, Zhang WM, Dai HF, Tan JW “Homoisoflavonoids from the medicinal plant Portulaca oleracea.” Phytochemistry. 2012 Aug;80:37-41
- Agha-Hosseini F, Borhan-Mojabi K, Monsef-Esfahani HR, Mirzaii-Dizgah I, Etemad-Moghadam S, Karagah A (Feb 2010). “Efficacy of purslane in the treatment of oral lichen planus”.Phytother Res. 24 (2): 240–4. doi:10.1002/ptr.2919.PMID 19585472.
- Bensky, Dan, et al. Chinese Herbal Medicine, Materia Medica. China: Eastland Press Inc., 2004.
- Watanabe I. Harada K. Matsui T. Miyasaka H. Okuhata H. Tanaka S. Nakayama H. Kato K. Bamba T. Hirata K.”Characterization of bisphenol A metabolites produced by Portulaca oleracea cv. by liquid chromatography coupled with tandem mass spectrometry.” , Biotechnology & Biochemistry. 76(5):1015-7, 2012.
- Megaloudi Fragiska (2005). “Wild and Cultivated Vegetables, Herbs and Spices in Greek Antiquity”.Environmental Archaeology 10 (1): 73–82.Noted by John Dickie, Delizia! The Epic History of Italians and Their Food (New York, 2008), p. 37.
- Noted by John Dickie, Delizia! The Epic History of Italians and Their Food (New York, 2008), p. 37.
“Portulaca oleracea”. FloraBase. Department of Environment and Conservation, Government of Western Australia.- Online Field guide to Common Saltmarsh Plants of Queensland
- Portulaca oleracea in West African plants – A Photo Guide.
- Purslane Recipes, Prairieland Community Supported Agriculture
| Nutritional value per 100 g (3.5 oz) | |
|---|---|
| Energy | 84 kJ (20 kcal) |
| Carbohydrates | 3.39 g |
| Fat | 0.36 g |
| Protein | 2.03 g |
| Water | 92.86 g |
| Vitamin A | 1320 IU |
| Thiamine (vit. B1) | 0.047 mg (4%) |
| Riboflavin (vit. B2) | 0.112 mg (9%) |
| Niacin (vit. B3) | 0.48 mg (3%) |
| Vitamin B6 | 0.073 mg (6%) |
| Folate (vit. B9) | 12 μg (3%) |
| Vitamin C | 21 mg (25%) |
| Vitamin E | 12.2 mg (81%) |
| Calcium | 65 mg (7%) |
| Iron | 1.99 mg (15%) |
| Magnesium | 68 mg (19%) |
| Manganese | 0.303 mg (14%) |
| Phosphorus | 44 mg (6%) |
| Potassium | 494 mg (11%) |
| Zinc | 0.17 mg (2%) |
| Link to USDA Database entry Percentages are roughly approximated using US recommendations for adults. Source: USDA Nutrient Database |
|
Preparation and serving methods
The stems and flower buds are also edible. Trim the tough stems near roots using a sharp knife. Cook under low temperature for a shorter period in order to preserve the majority of nutrients. Although antioxidant properties are significantly decreased on frying and boiling, its minerals, carotenes and flavonoids may remain intact with steam cooking.
India gift to the world
In fact, among the many names given to purslane around the world, there are some like the old Arabic baqla hamqa or the Spanish verdilacas or yerba orate that mean crazy plant. It is a reference not just to its appearance, but to the madly unrestrained way it grows, spreading rapidly in all directions at ground level in a mesh of stems, roots and leaves, which is one reason why for many gardeners purslane is one of the most annoying weeds.
Added to this is its remarkable resilience — it stores water it in its succulent stems and leaves, allowing it to tolerate hot, dry conditions, and can produce over 240,000 tiny seeds per plant, making it really hard to remove. It’s no surprise that purslane has spread remarkably widely, growing in different forms in most parts of the world and known by a wide variety of names such as portulaca or little door, from the way its seed pod opens, or the Hebrew regelah or foot, since that’s near where it grows, though the most unusual must be the term from Malawi that translates as ‘the buttocks of the chief’s wife”, an apparent reference to the fleshy rounded leaves of some forms.
Despite this wide range, most botanical studies give India as the origin for purslane, and some writers, like the American expert on wild food, Euell Gibbons, have even labelled it “India’s gift to the world.” But it is a gift that we have largely forgotten about, since few people here eat purslane these days, or even know that this weed is edible. It is rarely cultivated, but gathered from the wild and only rarely appears in places like Bhaji Gully because few know its value, other than old people or poor migrants from rural areas who have some memory of eating it.
One who did know the value of luni was Mahatma Gandhi, and while it’s a bit of a stretch to describe purslane as his favourite food, as some of its enthusiasts abroad have done, he did recommend it to several people and, in an article in his magazine Harijan, he wrote about “the nourishing properties of the innumerable leaves that are to be found hidden among the grasses that grow wild in India.” He had discovered these while living in Wardha and following a diet of uncooked food that required what he felt was an unreasonable amount of purchases from the local market. So he was delighted when an ashram resident “brought to me a leaf that was growing wild among the Ashram grasses. It was luni. I tried it, and it agreed with me.” It soon was a regular part of his diet.
Gandhi’s recommendations, of course, are no guide to taste, since he didn’t believe in enjoying food for its own sake. But luni has a pleasant lightly acid taste when raw, though with a slightly grassy, earthy undertone that does take some getting used to. It is probably never going to be one of those foods you have to try-before-you-die, but it is not bad at all to eat, either raw in a salad, or cooked. I find that the version we get here, which is rather less fleshy than purslane I’ve seen abroad, is worth stir-frying or adding to a dal, which brings out a nice, slightly peanutty taste. Another interesting way to cook it is in the Persian style, first sautéing it with onions and then cooking with eggs to make a firm omelette that has a nicely herbal taste when cut up and eaten cold.
The real reason for valuing purslane though is not taste, but health. It has always had a reputation for medicinal properties, with physicians over the centuries, from India to the Middle East to Europe, recommending it for everything from reducing fever, removing worms and soothing urinary infections. But modern science has made clear why it is of such value: apart from providing significant amounts of vitamins A, B and C. and decent amounts of protein, purslane probably contains more omega-3 fatty acids than any other commonly available vegetable source.
These fatty acids are essential for reducing cholesterol and heart diseases, but their most easily accessible source is oily fish, which makes it hard for vegetarians to get them. Some health conscious ones do force themselves to swallow fish oil capsules, or eat alsi (flax seeds) which are also a decent source of omega-3 acids. But purslane is probably a better source, and can be cooked and eaten as part of one’s meal. (The only caution is for people prone to kidney stones, since it also contains high levels of the oxalates which cause them). Luni may seem like a crazy thing to eat, but when people around the world are realising the value of this Indian plant, it is the way we are letting it become forgotten that may be what is really loony.
FDA okays Vifor Fresenius phosphate binder Velphoro
THERAPEUTIC CLAIM Oral phosphate binder, treatement of elevated
phosphate levels in patients undergoing dialysis
CHEMICAL DESCRIPTIONS
1. Ferric hydroxide oxide
2. Mixture of iron(III) oxyhydroxide, sucrose, starches
3. Polynuclear iron(III) oxyhydroxide stabilized with sucrose and starches
structure
O =Fe -OH
MOLECULAR FORMULA FeHO2•xC12H22O11•y(C6H10O5)n
SPONSOR Vifor (International) Inc.
CODE DESIGNATIONS PA21
CAS REGISTRY NUMBER 12134-57-5
sucroferric oxyhydroxide
Sucroferric oxyhydroxide nonproprietary drug name
1. February 27, 2013. N13/36. STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN (ZZ-19). SUCROFERRIC …
The US Food and Drug Administration has given the green light to Vifor Fresenius Medical Care Renal Pharma’s hyperphosphatemia drug Velphoro.
The approval for Velphoro (sucroferric oxyhydroxide), formerly known as PA21, is based on Phase III data demonstrated that the drug successfully controls the accumulation of phosphorus in the blood with the advantage of a much lower pill burden than the current standard of care in patients with chronic kidney disease on dialysis, namely Sanofi’s Renvela (sevelamer carbonate). read this at
http://www.pharmatimes.com/Article/13-11-28/FDA_okays_Vifor_Fresenius_phosphate_binder_Velphoro.aspx
Velphoro (PA21) receives US FDA approval for the treatment of hyperphosphatemia in Chronic Kidney Disease Patients on dialysis
Velphoro (sucroferric oxyhydroxide) has received US Food and Drug Administration (FDA) approval for the control of serum phosphorus levels in patients with Chronic Kidney Disease (CKD) on dialysis. Velphoro will be launched in the US by Fresenius Medical Care North America in 2014.
Velphoro (previously known as PA21) is an iron-based, calcium-free, chewable phosphate binder. US approval was based on a pivotal Phase III study, which met its primary and secondary endpoints. The study demonstrated that Velphoro® successfully controls hyperphosphatemia with fewer pills than sevelamer carbonate, the current standard of care in patients with CKD on dialysis. The average daily dose to control hyperphosphatemia was 3.3 pills per day after 52 weeks.
Velphoro was developed by Vifor Pharma. In 2011, all rights were transferred to Vifor Fresenius Medical Care Renal Pharma, a common company of Galenica and Fresenius Medical Care. In the US, Velphorowill be marketed by Fresenius Medical Care North America, a company with a strong marketing and sales organization, and expertise in dialysis care. The active ingredient of Velphoro is produced by Vifor Pharma in Switzerland.
Hyperphosphatemia, an abnormal elevation of phosphorus levels in the blood, is a common and serious condition in CKD patients on dialysis. Most dialysis patients are treated with phosphate binders. However, despite the availability of a number of different phosphate binders, up to 50% of patients depending on the region are still unable to achieve and maintain their target serum phosphorus levels. In some patients, noncompliance due to the high pill burden and poor tolerability appear to be key factors in the lack of control of serum phosphorus levels. On average, dialysis patients take approximately 19 pills per day with phosphate binders comprising approximately 50% of the total daily pill burden. The recommended starting dose of Velphoro is 3 tablets per day (1 tablet per meal).
Full results from the pivotal Phase III study involving more than 1,000 patients were presented at both the 50th ERA-EDTA (European Renal Association European Dialysis and Transplant Association) Congress in Istanbul, Turkey, in May 2013, and the American Society of Nephrology (ASN) Kidney Week in Atlanta, Georgia, in November 2013. Velphorowas shown to be a potent phosphate binder, with lower pill burden and a good safety profile.
Based on these data, Vifor Fresenius Medical Care Renal Pharma believes that Velphoro offers a new and effective therapeutic option for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.
The regulatory processes in Europe, Switzerland and Singapore are ongoing and decisions are expected in the first half 2014. Further submissions for approval are being prepared.
VBL Therapeutics announced FDA has granted Fast Track designation to its lead oncology drug VB-111
VB-111
VBL Therapeutics announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to its lead oncology drug VB-111, for prolongation of survival in patients with recurrent glioblastoma multiforme (rGBM).
VB-111 – highly targeted anti-angiogenic agent for the specific inhibition of tumor vascular growth
VB-111 is the first highly targeted anti-angiogenic agent for the specific inhibition of tumor vascular growth to use VTS™™, our proprietary platform technology, for cancer therapy. VB-111 is an IV-administered anti angiogenic agent that works in a manner akin to a “biological knife” to destroy tumor vasculature, thus cutting off blood vessels feeding the tumor.
Preclinical Insights
VB-111 has shown significant promise as a targeted cancer treatment with the potential to work synergistically in combination with conventional chemotherapy treatments to provide an effective treatment regimen for cancer patients. Pharmacological and toxicology studies of VB-111 have showed tissue specificity for the tumor tissue, no significant damage to normal non-cancerous tissues or to the normal vasculatures in the body and more than 90 percent tumor burden reduction in a metastatic lung cancer model with only one injection. Similar efficacy was shown in other tumor models.
Completed Clinical Trials
Phase 1 Clinical Trial – in a Phase 1 “all comers” dose escalation study in 33 patients with advanced metastatic cancer, therapeutic doses of VB-111 demonstrated antitumor activity and was found to be safe and well tolerated with no effect on liver function or major changes in complete blood count. Findings have been presented at the American Association of Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) annual meetings.
GSK obtains FDA approval for bird flu vaccine
GlaxoSmithKline (GSK) has received approval from the US Food and Drug Administration (FDA) for the first adjuvanted vaccine to prevent H5N1 influenza, also known as bird flu.
GSK obtains FDA approval for bird flu vaccine http://www.pharmaceutical-technology.com/news/newsgsk-obtains-fda-approval-bird-flu-vaccine?WT.mc_id=DN_News
26 November 2013
GlaxoSmithKline (GSK) has received approval from the US Food and Drug Administration (FDA) for the first adjuvanted vaccine to prevent H5N1 influenza, also known as bird flu.
The FDA cleared the pandemic Influenza A (H5N1) virus monovalent vaccine, adjuvanted (also referred to as Q-Pan H5N1 influenza vaccine), for use in people aged 18 and older who are at increased risk of exposure to the virus.
The vaccine is composed of monovalent, inactivated, split A/H5N1 influenza virus antigen and GSK’s AS03 adjuvant.
The company said that in clinical studies, the adjuvanted formulation stimulated the required immune response while using a smaller amount of antigen as compared with a formulation without adjuvant.
New Drug Approvals 