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|Prucalopride succinate; 179474-85-2; Resolor; Prucalopride (succinate); UNII-4V2G75E1CK; R-108512;|
|Molecular Weight:||485.95838 g/mol|
Drug Name：Prucalopride Succinate
Trade Name：Resolor®, MOA：Serotonin (5-HT4) receptor agonist, Indication：Chronic constipation
Company：Shire (Originator) , Johnson & Johnson
APPROVED EU 2009-10-15
Prucalopride (brand name Resolor, developed by Johnson & Johnson and licensed to Movetis) is a drug acting as a selective, high affinity 5-HT4 receptor agonist which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements. Prucalopride was approved for use in Europe in 2009, in Canada (named Resotran) on December 7, 2011 and in Israel in 2014 but it has not been approved by the Food and Drug Administration for use in the United States. The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.
Mechanism of action
Prucalopride, a first in class dihydro-benzofuran-carboxamide, is a selective, high affinity serotonin (5-HT4) receptor agonist with enterokinetic activities. Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force for defecation.
The observed effects are exerted via highly selective action on 5-HT4 receptors: prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors. Prucalopride differs from other 5-HT4 agonists such as tegaserod and cisapride, which at therapeutic concentrations also interact with other receptors (5-HT1B/D and the cardiac human ether-a-go-go K+ or hERG channelrespectively) and this may account for the adverse cardiovascular events that have resulted in the restricted availability of these drugs. Clinical trials evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.
Prucalopride is rapidly absorbed (Cmax attained 2–3 hours after single 2 mg oral dose) and is extensively distributed. Metabolism is not the major route of elimination. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in feces).Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours, and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.
In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products.
The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week. Further measures are improvements in PAC-QOL (a quality of life measure) and PAC-SYM (a range of stool,abdominal, and rectal symptoms associated with chronic constipation). Infrequent bowel movements, bloating, straining, abdominal pain, and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.
In three large clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than with placebo. There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants). The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.
Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are headache andgastrointestinal symptoms (abdominal pain, nausea or diarrhea). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.
In the European Economic Area, prucalopride was originally approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Subsequently, it has been approved by the European Commission for use in adults – that is, including male patients – for the same indication.
Prucalopride is contraindicated where there is hypersensitivity to the active substance or to any of the excipients, renal impairment requiring dialysis, intestinal perforation orobstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn’s disease, and ulcerative colitis and toxic megacolon/megarectum.
Prucalopride succinate, a first-in-class dihydrobenzofurancarboxamide, is a selective serotonin (5-HT4) receptor agonist.86–94 The drug, marketed under the brand name Resolor, possesses enterokinetic activity and was developed by the Belgian-based pharmaceutical firm Movetis. Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation, triggering the central propulsive force for defecation.95–97 The preparation of prucalopride succinate begins with the commercially available salicylic aniline 124 (Scheme 18). Acidic esterification, acetylation of the aniline nitrogen atom, and ambient-temperature chlorination via sulfuryl chloride (SO2Cl2) converted aminophenol 124 to acetamidoester 125 in 83% yield over the course of three steps.98–102 An unique set of conditions involving sodium tosylchloramide (chloramine T) trihydrate and sodium iodide were then employed to convert 125 to o-phenolic iodide 126, which then underwent sequential Sonogashira/cyclization reaction utilizing TMS-acetylene with tetramethylguanidine (TMG) in the presence of silica gel to furnish the benzofuran progenitor of 127.103 Hydrogenation of this intermediate benzofuranyl Sonagashira product saturated the 2,3-benzofuranyl bond while leaving the chlorine atom intact, ultimately delivering dihydrobenzofuran 127 in excellent yield for the two step sequence. Base-induced saponification and acetamide removal gave rise to acid 128. This acid was activated as the corresponding mixed anhydride and treated with commercial piperidine 129 to construct prucalopride which was stirred at room temperature for 24 h in ethanolic succinic acid to provide prucalopride succinate (XI). The yield for the formation of the salt was not provided.
86. Briejer, M. R.; Bosmans, J. P.; Van Daele, P.; Jurzak, M.; Heylen, L.; Leysen, J. E.;Prins, N. H.; Schuurkes, J. A. J. Eur. J. Pharmacol. 2001, 423, 71.
87. Briejer, M. R.; Prins, N. H.; Schuurkes, J. A. J. Neurogastroenterol. Motil. 2001, 13,465.
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Synlett 1993, 269
Chem. Pharm. Bull. 1998, 46,42.
In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ±5° C. N,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10° C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10° C. The resulting mixture was added dropwise over a 20-min period to a solution of 1-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCl3. The filtrate was separated in it’s layers. The separated organic layer was washed with water (50 ml)+a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50° C.), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-N- 1-(3-methoxypropyl)-4-piperidinyl!-7-benzofurancarboxamide monohydrochloride (comp. 1).
EXPERIMENTAL PART EXAMPLE 1
In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ±5° C. N,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10° C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10° C. The resulting mixture was added dropwise over a 20-min period to a solution of 1-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCl3. The filtrate was separated in it’s layers. The separated organic layer was washed with water (50 ml)+ a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50° C.), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-N- 1-(3-methoxypropyl)-4-piperidinyl!-7-benzofurancarboxamide monohydrochloride (comp. 1).
EP-0,389,037-A, published on September 26, 1990, N-(3-hydroxy-4-piperidin- yl) (dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide derivatives are disclosed as having gastrointestinal motility stimulating properties. In our EP-0,445,862-A, published on September 11, 1991, N-(4-piperidinyl) (dihydrobenzo¬ furan or dihydro-2H-benzopyran)carboxamide derivatives are disclosed also having gastrointestinal motility stimulating properties.
The compound subject to the present application differs therefrom by showing superior enterokinetic properties.
The present invention concerns a compound of formula
and the pharmaceutically acceptable acid addition salts thereof.
The chemical name of the compound of formula (I) is 4-amino-5-chloro-2,3-dihydro-N- [l-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide.
In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ± 5 °C. H,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10 °C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10°C. The resulting mixture was added dropwise over a 20-min period to a solution of l-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCI3. The filtrate was separated in it’s layers. The separated organic layer was washed with water (50 ml) + a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50 °C), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-M-[ 1 -(3-methoxypropyl)-4-piperidinyl]-7- benzofurancarboxamide monohydrochloride (comp. 1).
A mixture of 4-amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)-7-benzofuran- carboxamide(O.Olmol), l-chloro-3-methoxypropane (0.012mol), M,M-diethyl- ethanamine (2Jml) and KI (catalytic amount) in N,M-dimethylformamide (75ml) was stirred overnight at 50°C. The reaction mixture was cooled. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3/(CH3OH/NH3) 97/3). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried (vacuum; 80°C), yielding 1.40g (35%) of 4-amino-5-chloro-2,3-dihydro-N-[l-(3-methoxypropyl)- 4-piperidinyl]-7-benzofurancarboxamide monohydrochloride (comp. 1).
Chinese Journal of Pharmaceuticals 2012, 43, 5-8.
Chinese Patent CN 103012337 A report is as follows:
Pharmaceutical & Clinical Research 2011, 19, 306-307.
US5374637 (CN1045781, EP389037) and J. Het Chem, 1980,17 (6): 1333-5 reported synthetic route, as follows:
Chinese Patent CN 104016949 A synthetic route reported as follows:
1. Preparation of Compound II
Compound I (167. lg, Imol), triethylamine (111. lg, I. Imol) and methylene chloride (KMOg) added to the reaction flask, nitrogen cooled to 5 ° C, was slowly added dropwise trifluoroacetic anhydride (220. 5g, 1.05mol) / methylene chloride (150g) solution, maintaining the temperature throughout 5~15 ° C, dropping was completed, the reaction after 3 hours at room temperature, TLC (DCM = MeOH = 25: 1) The reaction was monitored to complete the reaction; the reaction mixture was slowly poured into ice water (560g) and stirred for 20 minutes, standing layer, the aqueous phase was separated, the organic phase was washed with saturated aqueous sodium bicarbonate (IOOg) wash sash; IM hydrochloric acid (IlOg) wash sash, then with saturated brine (200g) washed sash, magnesium sulfate (40g) dried, filtered and concentrated to give compound II (250. Ig), yield: 952%.
 2. Preparation of Compound III
 Chloroacetyl chloride (101. 7g, 0. 9mol), nitrobenzene (20g) and dichloroethane (580 g) added to the reaction flask, nitrogen cooled to 5 ° C, was slowly added anhydrous trichloro aluminum powder (359. 2g, 2. 7mol), to keep the whole temperature 5~20 ° C, plus complete, insulation 15~25 ° C for 30 minutes to obtain a mixture A.
 Compound II (. 236. 7g, 0 9mol) and dichloroethane (500g) added to the reaction flask, nitrogen cooled to 15 ° C; the mixture was added Compound II A quick solution, plus complete, rapid heating 65~75 ° C, 1 hours later once every 15 minutes in the control, monitoring TLC (DCM = MeOH = 50: 1) to complete the reaction; the reaction mixture was immediately poured into ice water (800g) and stirred for 30 minutes, controlling the temperature between 15~25 ° C, the organic phase was separated, the organic phase washed with water (180g) was washed with saturated brine (240g), dried over magnesium sulfate (45g) was dried, filtered and concentrated to give crude compound III (303 . 2g).
 Take the crude compound III (291. 3g) / ethanol 1 dichloromethane: 1 solution (1500ml) was dissolved, and then adding activated carbon (14. 5g) was refluxed for one hour, cooled to room temperature filtered and the filtrate concentrated at room temperature to 600~ 650g, stop and concentrated down to 5~10 ° C, filtered to give a yellow solid (204. 7g); the resulting yellow solid (207. 6g) in tetrahydrofuran (510g) was purified, reduced to 10~15 ° C, filtered, The filter cake was washed with tetrahydrofuran (90g) dip, dried under vacuum to give compound III (181. 3g), yield: 61.7% billion
 3. Preparation of Compound IV
 Compound 111 (! 169.68,0.5 11〇1), methanol (5,801,111) and sodium acetate (123.38,1.5111〇1) was added to the reaction flask. After 6 hours of reaction, began TLC (DCM: MeOH = 30: 1 ) the reaction was monitored to completion of the reaction; the reaction mixture was cooled to room temperature, concentrated, and the residue with ethyl acetate (500g) and water (200g) was dissolved, the organic phase was separated, the organic phase was washed with 2M sodium hydrogen carbonate (120g) was washed, then with saturated brine (IOOg), dried over magnesium sulfate (50g) was dried, filtered and concentrated to 250~280g, cooled to room temperature with stirring was added cyclohexane (200 g of), after stirring for 1 hour and then filtered and dried to obtain compound IV (126. 7g), yield: 83.4% billion
 4. Preparation of Compound V
 Compound IV (12L 2g, 0. 4mol), methanol (380g) and Raney-Ni (12. 5g) added to the autoclave, purged with nitrogen, hydrogen is introduced (3. Ompa), the reaction was heated to 45 ° C after 8 hours, TLC (DCM = MeOH = 30: 1) to monitor the reaction, to complete the reaction, cooled to room temperature and pressure, and then purged with nitrogen, the reaction solution was filtered and concentrated to give crude compound V (103. 7g), taking compound V crude product (103g) was refluxed with ethyl acetate (420g) (1 hour) was purified, cooled to room temperature and stirred for 30 minutes and filtered to give a yellow solid was dried in vacuo to give compound V (76 8g.), yield: 663 %.
 5. Preparation of Compound VI
 Compound ¥ (57.88,0.2111〇1), 1 ^ dimethylformamide (4.58) and acetonitrile (30 (^) was added to the reaction flask and heated 74~76 ° C; solution of N- chlorosuccinimide imide (. 26. 7g, 0 2mol) and acetonitrile (45g) was added dropwise over 30 minutes and maintaining the temperature finished 76~82 ° C, dropping was completed, the reaction was kept, after one hour the reaction started TLC (DCM: MeOH = 30: 1) to monitor the reaction, the reaction is complete the reaction solution cooled to 5~8 ° C, the filter cake was washed with water (210g) washed stirred, filtered, and dried in vacuo to give compound VI (57. 6g), yield. rate of 89.1%.
6. Preparation of Compound VII
Compound VI (48. 5g, 0. 15mol) and methanol (80g) added to the reaction flask, stirring at room temperature was added dropwise 4M aqueous sodium hydroxide (HOg), dropwise complete, for the reaction, 25 ° C~35 after 4 hours of reaction ° C, samples of about 7:00 adjust PH TLC (DCM = MeOH = 30: 1) to monitor the reaction, until the reaction was complete, down to 5~10 ° C, with 6M hydrochloric acid solution PH ~ 7. 5, half the solution was concentrated, then 2M hydrochloric acid solution PH ~ 7, reduced to 15~20 ° C was stirred for 30 minutes, filtered, the filter cake with methyl tert-butyl ether (70g) beating, filtration, and dried in vacuo to give compound VII (28. 7g), yield: 903%.
Chem Pharm Bull 46 (1), 42-52 (1998) and Pharmaceutical and clinical study based on 2011 (4) 306-307 reported synthetic route is as follows:
|Description||Prucalopride is a selective, high affinity 5-HT4 receptor agonist, inhibiting human 5-HT(4a) and 5-HT(4b) receptor with Ki value of 2.5 nM and 8 nM, respectively.|
|Targets||5-HT4A ||5-HT4B |
|IC50||2.5 nM(Ki)||8 nM(Ki)|
|In vitro||Prucalopride induces contractions in a concentration-dependent manner with pEC50 of 7.5. Prucalopride (1 mM) significantly amplifies the rebound contraction of the guinea-pig proximal colon after electrical field stimulation. Prucalopride induces relaxation of the rat oesophagus preparation of rat oesophagus tunica muscularis mucosae with pEC50 of 7.8, yielding a monophasic concentration–response curve.  Prucalopride (0.1 μM) concentration-dependently increases the amplitude of submaximal cholinergic contractions and of acetylcholine release induced by electrical field stimulation in pig gastric circular muscle, and the effect is induced and enhanced IBMX (10 μM).  Prucalopride (1 μM) significantly enhances the electrically induced cholinergic contractions in pig descending colon, and the facilitating effect is significantly enhanced by Rolipram. |
|In vivo||Prucalopride alters colonic contractile motility patterns in a dose-dependent fashion by stimulating high-amplitude clustered contractions in the proximal colon and by inhibiting contractile activity in the distal colon of fasted dogs. Prucalopride also causes a dose-dependent decrease in the time to the first giant migrating contraction (GMC); at higher doses of prucalopride, the first GMC generally occurres within the first half-hour after treatment. |
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×||mouse Km(3)||= 11.2 mg/kg|
Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)
|NCT02806206||Not yet recruiting||Gastrointestinal Hemorrhage|Crohn Disease|Celiac Disease|Intestinal Diseases|Inflammatory Bowel Diseases||University of British Columbia||July 2016||Phase 4|
|NCT02781493||Not yet recruiting||Prucalopride Plus Polyethylene Glycol in Bowel Preparation for Colonoscopyp||Shandong University|Binzhou Peoples Hospital|Taian People …more||June 2016||Phase 4|
|NCT02538367||Recruiting||Functional Constipation||Yuhan Corporation||August 2015||Phase 1|Phase 2|
|NCT02228616||Recruiting||Constipation||Xian-Janssen Pharmaceutical Ltd.||October 2014||Phase 4|
|NCT02425774||Recruiting||Postoperative Ileus||Katholieke Universiteit Leuven|Universitaire Ziekenhuizen …more||July 2014||Phase 4|
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- Digestive Remedies in Israel
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- McCrea, G. L.; Miaskowski, C.; Stotts, N. A.; MacEra, L.; Paul, S. M.; Varma, M. G. (2009). “Gender differences in self-reported constipation characteristics, symptoms, and bowel and dietary habits among patients attending a specialty clinic for constipation”.Gender Medicine 6 (1): 259–271. doi:10.1016/j.genm.2009.04.007. PMID 19467522.
- Pare, P.; Ferrazzi, S.; Thompson, W. G.; Irvine, E. J.; Rance, L. (2001). “An epidemiological survey of constipation in Canada: definitions, rates, demographics, and predictors of health care seeking”. The American Journal of Gastroenterology 96 (11): 3130–3137. doi:10.1111/j.1572-0241.2001.05259.x. PMID 11721760.
- Wald, A.; Scarpignato, C.; Kamm, M. A.; Mueller-Lissner, S.; Helfrich, I.; Schuijt, C.; Bubeck, J.; Limoni, C.; Petrini, O. (2007). “The burden of constipation on quality of life: results of a multinational survey”. Alimentary Pharmacology & Therapeutics 26 (2): 227–236. doi:10.1111/j.1365-2036.2007.03376.x. PMID 17593068.
- Camilleri, M; Beyens, G; Kerstens, R; Vandeplassche, L (2009). “Long-term follow-up of safety and satisfaction with bowel function in response to oral prucalopride in patients with chronic constipation [Abstract]”. Gastroenterology 136 (Suppl 1): 160. doi:10.1016/s0016-5085(09)60143-8.
- Van Outryve, MJ; Beyens, G; Kerstens, R; Vandeplassche, L (2008). “Long-term follow-up study of oral prucalopride (Resolor) administered to patients with chronic constipation [Abstract T1400]”. Gastroenterology 134 (4 (suppl 1)): A547. doi:10.1016/s0016-5085(08)62554-8.
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|Systematic (IUPAC) name|
|Trade names||Resolor, Resotran|
|AHFS/Drugs.com||International Drug Names|
|ATC code||A06AX05 (WHO)|
|Molar mass||367.870 g/mol|
//////////Prucalopride succinate, Resolor, R-093877, R-108512, Resolor®, Resolor, Resotran, UNII:0A09IUW5TP, 179474-81-8 , R-093877, R-108512, Shire , Johnson & Johnson, 179474-85-2, UNII-4V2G75E1CK, SHIRE, 2010, LAUNCHED, JANNSEN , PHASE 3, IRRITABLE BOWL SYNDROME
International nonproprietary name: Filgrastim
Chemical name: N-L- Methionyl colony-stimulating factor (human genetically engineered); non-glycated protein consisted of 175 amino acids.
Chemical name: N-L- Methionyl colony-stimulating factor (human genetically engineered); non-glycated protein consisted of 175 amino acids.
Filgrastim is a granulocyte colony-stimulating factor (G-CSF) analog used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. The G-CSF then produced by E. coli is different from G-CSF naturally made in humans.
Hematopoietic growth factor. Interacting with receptors on the surface of hematopoietic cells it regulates production and release of neutrophils from the bone marrow to the peripheral blood. Dose dependant number growth of neutrophils with normal or increased functional activity is passing for 24 hours.
Filgrastim is marketed under several brand names, including Neupogen (Amgen), Imumax(Abbott Laboratories), Grafeel (Dr. Reddy’s Laboratories), Neukine (Intas Biopharmaceuticals), Emgrast (Emcure Pharmaceuticals), Religrast (Reliance Life Sciences), Zarzio (Sandoz), Nufil (Biocon) and others.
Apricus Biosciences is currently developing and testing a product under the brand nameNupen which can deliver filgrastim through the skin to improve post-chemotherapy recovery of neutrophil counts.
Filgrastim is also used to increase the number of hematopoietic stem cells in the blood before collection by leukapheresis for use in hematopoietic stem cell transplantation.Filgrastim is used to treat neutropenia, stimulating the bone marrow to increase production of neutrophils. Causes of neutropenia include chemotherapy and bone marrow transplantation.
Filgrastim should not be used in patients with known hypersensitivity to E. coli-derived proteins.
The most commonly observed adverse effect is mild-to-moderate bone pain after repeated administration and local skin reactions at the site of injection. Other observed adverse effects include serious allergic reactions (including a rash over the whole body, shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating), ruptured spleen (sometimes resulting in death), alveolar hemorrhage, acute respiratory distress syndrome, and hemoptysis. Severe sickle cell crises, in some cases resulting in death, have been associated with the use of filgrastim in patients with sickle cell disorders.
Drug interactions between filgrastim and other drugs have not been fully evaluated. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.
Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes; this should be considered when interpreting bone-imaging results.
Filgrastim has not been studied in pregnant women and its effects on unborn babies is unknown. If taking filgrastim while pregnant, it is possible that traces of the drug could be found in the baby’s blood. It is not known if the drug can get into human breast milk.
- Beveridge, R. A.; Miller, J. A.; Kales, A. N.; Binder, R. A.; Robert, N. J.; Harvey, J. H.; Windsor, K.; Gore, I. et al. (1998). “A Comparison of Efficacy of Sargramostim (Yeast-Derived RhuGM-CSF) and Filgrastim (Bacteria-Derived RhuG-CSF) in the Therapeutic Setting of Chemotherapy-Induced Myelosuppression”. Cancer Investigation 16 (6): 366–373. doi:10.3109/07357909809115775.PMID 9679526. edit
- Crawford, J.; Glaspy, J. A.; Stoller, R. G.; Tomita, D. K.; Vincent, M. E.; McGuire, B. W.; Ozer, H. (2005). “Final Results of a Placebo-Controlled Study of Filgrastim in Small-Cell Lung Cancer: Exploration of Risk Factors for Febrile Neutropenia”. Supportive Cancer Therapy 3 (1): 36–46. doi:10.3816/SCT.2005.n.023. PMID 18632435. edit
- Neupogen “Neupogen: Patient Information Leaflet”. Amgen. Retrieved 24 June 2013.
- “NEUPOGEN® Patient Guide”. Amgen. Retrieved 24 June 2013.
- “Neupogen”. RxList. 4 June 2012. Retrieved 23 June 2013.
- Budiono Santoso; Chris J. van Boxtel; Boxtel, Christoffel Jos van (2001). Drug benefits and risks: international textbook of clinical pharmacology. New York: Wiley. ISBN 0-471-89927-5.
- “Neupogen information”. Retrieved 20 October 2005.
CUT PASTE OF INFO….
7 MAR 2013
The US Food and Drug Administration (FDA) has accepted for review AMAG Pharmaceuticals’ supplemental new drug application (sNDA) for Feraheme (ferumoxytol) injection for Intravenous (IV) use.
The sNDA filed is to expand the indication for ferumoxytol for the treatment of iron deficiency anemia (IDA) in adult patients with chronic kidney disease (CKD), who have failed or could not take oral iron treatment.
Ferumoxytol is currently indicated for oral use for the treatment of IDA in adult patients with CKD, according to the company.
The sNDA included the data from a global phase III program, which included two phase III clinical trials such as as IDA-301 (placebo comparator) and IDA-302 (active comparator).
The trials, which enrolled 1,400 patients, evaluated the use of ferumoxytol in a broad range of adult IDA patients, all of whom had failed or could not take oral iron treatment.
Both studies achieved the primary efficacy endpoints with statistically significant improvements in hemoglobin from baseline to the 35-day.
The studies, which also included patient-reported outcomes data as pre-specified secondary and exploratory endpoints, found no new safety signals, outside of those described in the current Feraheme (ferumoxytol) label, were observed with ferumoxytol treatment in these studies, claims the company.
In response to the application, the FDA said it will complete the review of Feraheme sNDA by 21 October 2013.
Feraheme, an iron replacement product, is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether. The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of Feraheme is Fe5874O8752-C11719H18682O9933Na414 with an apparent molecular weight of 750 kDa.
Feraheme injection is an aqueous colloidal product that is formulated with mannitol. It is a black to reddish brown liquid, and is provided in single use vials containing 510 mg of elemental iron. Each mL of the sterile colloidal solution of Feraheme injection contains 30 mg of elemental iron and 44 mg of mannitol, and has low bleomycin-detectable iron. The formulation is isotonic with an osmolality of 270-330 mOsm/kg. The product contains no preservatives, and has a pH of 6 to 8.
STRUCTURE SOURCE http://chem.sis.nlm.nih.gov/chemidplus/rn/1309-38-2
Polyglucose sorbitol carboxymethyl ether-coated non-stoichiometric magnetite. Ferumoxytol is a superparamagnetic iron oxide that is coated with a low molecular weight semi-synthetic carbohydrate, polyglucose sorbitol carboxymethyl ether. The iron oxide is a superparamagnetic form of non-stoichiometric magnetite with crystal size of 6.2 to 7.3 nm. In solution, the colloidal particle of ferumoxytol has a Stokes diameter of 18-20 nm. Molecular weight is approximately 308,000
Iron oxide (Fe3O4). It is a black ore of IRON that forms opaque crystals and exerts strong magnetism. The NANOPARTICLES; and MICROSPHERES of its mineral form, magnetite, have many biomedical applications.
Ferumoxytol is the generic ingredient in one branded drug marketed by Amag Pharms Inc and is included in one NDA. There are six patents protecting this compound and one Paragraph IV challenge. Additional information is available in the individual branded drug profile pages.
This ingredient has eleven patent family members in ten countries.
There is one drug master file entry for ferumoxytol. One supplier is listed for this compound.
Launched – 2009, Anemia, iron deficiency
A superparamagnetic iron oxide (non-stoichiometric magnetite) coated with a low molecular weight semi-synthetic carbohydrate polyglucose carboxymethyl ether; USAN (OO-74) (Advanced Magnetics, Cambridge, MA, USA)
- C 7228
- Code 7228
Superparamagnetic iron oxide coated with a low molecular weight semi-synthetic carbohydrate polyglucose sorbitol carboxymethyl ether. The iron oxide is a superparamagnetic form of non-stoichiometric magnetite with crystal size of 6.2 to 7.3 nm. In solution, the colloidal particle has a Stokes diameter of 18-20 nm
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Feraheme, an iron replacement product, is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether. The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of Feraheme is Fe5874O8752C11719H18682O9933Na414 with an apparent molecular weight of 750 kDa.
Feraheme Injection is an aqueous colloidal product that is formulated with mannitol. It is a black to reddish brown liquid, and is provided in single use vials containing 510 mg of elemental iron. Each mL of the sterile colloidal solution of Feraheme Injection contains 30 mg of elemental iron and 44 mg of mannitol, and has low bleomycin-detectable iron. The formulation is isotonic with an osmolality of 270-330 mOsm/kg. The product contains no preservatives, and has a pH of 6 to 8.
Ferumoxytol is AMAG Pharmaceuticals’ lead investigational compound. In 2007, the company filed a regulatory application seeking approval in the U.S. for use as an intravenous iron replacement therapeutic in patients who may be on dialysis and are suffering from anemic chronic kidney disease (CKD). In 2009, FDA approval was assigned and the product became available on the market. A regulatory application was filed in the E.U. in 2010 for this indication and a positive opinion was received in 2012. Final E.U. approval was obtained in June 2012. In 2012, AMAG Pharmaceuticals submitted a supplemental NDA to the FDA for the treatment of patients with iron-deficiency anemia (IDA) who are not candidates for oral iron, for which they received a complete response letter in January 2014. In 2013, Takeda filed for approval for this indication in the E.U. This application was withdrawn in 2015 due to safety concerns.
In terms of clinical studies, phase II trials are underway at AMAG and at Oregon Health and Science University for use in magnetic resonance angiography (MRA). The National Cancer Institute is also conducting phase II trials for the imaging of primary high-grade brain tumors and/or cerebral metastases from lung or breast cancer. Phase I clinical trials are ongoing at Dana-Farber Cancer Institute for use in magnetic resonance imaging in pediatric and adult patients with malignant sarcoma.
The drug consists of intravenously administered bioavailable iron which allows for more efficient replenishment of the body’s iron stores than oral iron supplements, without their associated common side effects. Ferumoxytol is a blood pool agent, a true intravascular contrast agent that remains in the blood stream for an extended period of time. Based on this quality, the product may be useful as a contrast agent in a wide range of applications in MRI.
In 2008, fast track designation was received in the U.S. as a diagnostic agent for vascular-enhanced magnetic resonance imaging (VE-MRI) to improve the assessment of peripheral arterial disease in patients with known or suspected chronic kidney disease. In 2010, a license, development and commercialization agreement was established between Takeda and AMAG Pharmaceuticals in Asia Pacific countries (excluding Japan, China and Taiwan), Canada, Europe, the Commonwealth of Independent States and Turkey. However, in December 2014, both companies announced the termination of this license agreement. In 2011, orphan drug designation was assigned by the FDA for use in magnetic resonance imaging in brain metastases. This designation was assigned in 2012 for use in magnetic resonance imaging to assess, and monitor treatment of solid tumor malignancies previously diagnosed in pediatric patients (age 16 years and younger).
As announced in May 2008, we entered into a development and commercialization agreement with AMAG Pharmaceuticals, Inc. (“AMAG”) (NASDAQ:AMAG), a US biopharmaceutical company, for ferumoxytol, an intravenous iron replacement therapeutic agent being developed to treat iron deficiency anemia in CKD patients and in patients requiring hemodialysis.
Under the terms of the agreement, AMAG granted us exclusive rights to develop and commercialize ferumoxytol in the PRC, initially for CKD, and with an option to expand into additional indications. We will be responsible for the clinical development, registration, and commercialization of ferumoxytol in the PRC. We and AMAG will form a joint steering committee, with equal representation from both parties, to oversee and guide the development and commercialization of ferumoxytol in China. The agreement has an initial duration of 13 years and will be automatically renewed for a set term if minimum sales thresholds are achieved. AMAG will retain all manufacturing rights for ferumoxytol and will provide, under a separate agreement, commercial supply to us at a predetermined supply price.
Ferumoxytol was approved in June 2009 by the U.S. Food and Drug Administration to treat iron deficiency anemia in CKD patients and launched commercially in the U.S. by AMAG in July 2009. Ferumoxytol received marketing approval in Canada in December 2011 and a positive recommendation for approval from the Committee for Medicinal Products for Human Use of the European Medicines Agency in April 2012.
We have submitted the application for a registrational clinical trial for ferumoxytol to SFDA, as announced in January 2010. Once approved by the SFDA, we will commence a multi-center randomized efficacy and safety study in China with approximately 200 CKD patients, measuring the mean change in hemoglobin from baseline at Day 35 after first dose.
Ferumoxytol is a newer parenteral iron formulation but limited information is available as to its efficacy and administration. See e.g., Landry et al. (2005) Am J Nephrol 25, 400-410, 408; and Spinowitz et al. (2005) Kidney Intl 68, 1801-1807; U.S. Pat. No. 6,599,498.
Another example of a preferred iron carbohydrate complex for use in the methods described herein is a carboxyalkylated reduced polysaccharide iron oxide complex (e.g., ferumoxytol, described in U.S. Pat. No. 6,599,498).
Another preferred iron carbohydrate complex for use in the methods described herein is a polyglucose sorbitol carboxymethyl ether-coated non-stoichiometric magnetite (e.g., “ferumoxytol”). Ferumoxytol is known in the art to be effective for treating anemia (at single unit doses lower than described herein). See e.g., Spinowitz et al. (2005) Kidney Intl 68, 1801-1807. Ferumoxytol is a superparamagnetic iron oxide that is coated with a low molecular weight semi-synthetic carbohydrate, polyglucose sorbitol carboxymethyl ether. Ferumoxytol and its synthesis are described in U.S. Pat. No. 6,599,498, incorporated herein by reference. Safety, efficacy, and pharmacokinetics of ferumoxytol are as described, for example, in Landry et al. (2005) Am J Nephrol 25, 400-410, 408; and Spinowitz et al. (2005) Kidney Intl 68, 1801-1807.
The iron oxide of ferumoxytol is a superparamagnetic form of non-stoichiometric magnetite with a crystal size of 6.2 to 7.3 nm. Average colloidal particle size can be about 30 nm, as determined by light scattering. Molecular weight is approximately 750 kD. The osmolarity of ferumoxytol is isotonic at 297 mOsm/kg and the pH is neutral. The blood half-life of ferumoxytol is approximately 10-14 hours. It has been previously reported that ferumoxytol can be given by direct intravenous push over 1-5 minutes in doses up to 1,800 mg elemental iron per minute, with maximal total dose up to 420 mg per injection. Landry et al. (2005) Am J Nephrol 25, 400-410, 408.
About Feraheme® (ferumoxytol)/Rienso
In the United States, Feraheme (ferumoxytol) Injection for Intravenous (IV) use is indicated for the treatment of iron deficiency anemia (IDA) in adult patients who have failed oral iron therapy. Feraheme received marketing approval from the FDA on June 30, 2009 for the treatment of IDA in adult chronic kidney disease (CKD) patients and was commercially launched by AMAG in the U.S. shortly thereafter.
Ferumoxytol is protected in the U.S. by five issued patents covering the composition and dosage form of the product. Each issued patent is listed in the FDA’s Orange Book. These patents are set to expire in March 2020; a request for patent term extension has been filed, which, if granted, may extend the patent term to June 2023 for one of the patents.
Ferumoxytol received marketing approval in Canada in December 2011, where it is marketed by Takeda as Feraheme, and in the European Union in June 2012 and Switzerland in August 2012, where it is marketed by Takeda as Rienso.
For additional U.S. product information, including full prescribing information, please visit www.feraheme.com.
AMAG now has five Orange Book-listed patents for ferumoxytol, with patent protection through March 2020, without patent term extension. AMAG has applied for a patent term extension for an Orange Book-listed ferumoxytol patent, which would lengthen that patent term through June 2023.
//////////Ferumoxytol, AMAG Pharmaceuticals, Phase II, 722492-56-0, Launched, 2009, Anemia, iron deficiency, 7228 , AMI-7228 , Code-7228