Bepotastine Besilate
ベポタスチンベシル酸塩
- Molecular FormulaC27H31ClN2O6S
- Average mass547.063 Da
HL-151
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- Use:antiallergic, antihistaminic
| 10 mg Tablets | For the treatment of allergic rhinitis | 27.03.2017 CDSCO
APPROVED |
USFDA
NDA 22-288 Bepotastine Besilate 1.5% Ophthalmic Solution ISTA Pharmaceuticals, Inc.
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/02228s000_ChemR.pdf
Drug Substance Bepotastine besilate is manufactured by Ube Industries and the information for the NDA is submitted through DMF #19966. Bepotastine besilate is a white crystalline powder with no odor and bitter taste. It is very soluble in but sparingly soluble in . It is stable when exposed to light, and optically active. The S-isomer is the active drug and is controlled as an impurity through synthesis. The distribution coefficient in 1-octanol is higher than in aqueous buffer in the pH 5-9 range. There are 10 potential impurities but only one impurity is above 0.1%. Two potential genotoxic impurities are controlled below . Residual is controlled below Bepotastine besilate is stable under long term storage conditions for (25ºC/60% RH) over 5 years
Bepotastine besilate was originally developed as an oral tablet dosage form and got approval in Japan in 2000 for allergic rhinitis. It is a non-sedating anti-allergic drug. The proposed NDA is an ophthalmic solution indicated for allergic conjunctivitis. Bepotastine besilate ophthalmic solution 1.5% is a sterile solution. It is an aqueous solution to be administered as drops at or near physiological pH range of tears. The formulation contains sodium chloride, monobasic sodium phosphate as dihydrate, benzalkonium chloride, sodium hydroxide and purified water; typically these components are used for , preservative action, pH adjustment,
INTRO
Bepotastine is a non-sedating, selective antagonist of the histamine 1 (H1) receptor. Bepotastine was approved in Japan for use in the treatment of allergic rhinitis and uriticaria/puritus in July 2000 and January 2002, respectively, and is marketed by Tanabe Seiyaku Co., Ltd. under the brand name Talion. It is available in oral and opthalmic dosage forms in Japan. The opthalmic solution is FDA approved since Sept 8, 2009 and is under the brand name Bepreve.
Tae Hee Ha, Chang Hee Park, Won Jeoung Kim, Soohwa Cho, Han Kyong Kim, Kwee Hyun Suh, “PROCESS FOR PREPARING BEPOTASTINE AND INTERMEDIATES USED THEREIN.” U.S. Patent US20100168433, issued July 01, 2010., US20100168433
BEPREVE® (bepotastine besilate ophthalmic solution) 1.5% is a sterile, topically administered drug for ophthalmic use. Each mL of BEPREVE contains 15 mg bepotastine besilate.
Bepotastine besilate is designated chemically as (+) -4-[[(S)-p-chloro-alpha -2pyridylbenzyl] oxy]-1-piperidine butyric acid monobenzenesulfonate. The chemical structure for bepotastine besilate is:
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Bepotastine besilate is a white or pale yellowish crystalline powder. The molecular weight of bepotastine besilate is 547.06 daltons. BEPREVE ophthalmic solution is supplied as a sterile, aqueous 1.5% solution, with a pH of 6.8.
The osmolality of BEPREVE (bepotastine besilate ophthalmic solution) 1.5% is approximately 290 mOsm/kg.
ベポタスチンベシル酸塩 JP17
Bepotastine Besilate
C21H25ClN2O3
C6H6O3S : 547.07
[190786-44-8]
Bepotastine (Talion, Bepreve) is a 2nd generation antihistamine.[1] It was approved in Japan for use in the treatment of allergic rhinitisand urticaria/pruritus in July 2000 and January 2002, respectively. It is currently marketed in the United States under the brand-name Bepreve, by ISTA Pharmaceuticals.
Bepotastine besilate is a second-generation antihistamine that was launched in a tablet formulation under a collaboration between Tanabe Seiyaku and Ube in 2000 and in 2002 for the treatment of allergic rhinitis including sneeze, mucus discharge and solidified mucus, and for the treatment of urticaria, respectively. An orally disintegrating tablet was made available in Japan in 2006, while a dry syrup formulation for the treatment of allergic rhinitis was studied in clinical trials at Tanabe Seiyaku for the treatment of allergic rhinitis
Originally developed at Ube, bepotastine besilate was later licensed to Tanabe Seiyaku as part of a collaboration agreement. In 2010, rights were licensed to Dong-A and Mitsubishi Tanabe Pharma in Korea for the treatment of eye disorders.
Pharmacology
Bepotastine is available as an ophthalmic solution and oral tablet. It is a direct H1-receptor antagonist that inhibits the release of histamine from mast cells.[2] The ophthalmic formulation has shown minimal systemic absorption, between 1 and 1.5% in healthy adults.[3] Common side effects are eye irritation, headache, unpleasant taste, and nasopharyngitis.[3] The main route of elimination is urinary excretion, 75-90% excreted unchanged.[3]
Marketing history
It is marketed in Japan by Tanabe Seiyaku under the brand name Talion. Talion was co-developed by Tanabe Seiyaku and Ube Industries, the latter of which discovered bepotastine. In 2001, Tanabe Seiyaku granted Senju, now owned by Allergan, exclusive worldwide rights, with the exception of certain Asian countries, to develop, manufacture and market bepotastine for ophthalmic use. Senju, in turn, has granted the United States rights for the ophthalmic preparation to ISTA Pharmaceuticals.
Sales and patents
In 2011, ISTA pharmaceuticals experienced a 2.4% increase in net revenues from 2010, which was driven by the sales of Bepreve. Their net revenue for 2011 was $160.3 million.[4] ISTA Pharmaceuticals was acquired by Bausch & Lomb in March 2012 for $500 million.[5] Bausch & Lomb hold the patent for bepotastine besilate (https://www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm. On November 26, 2014, Bausch & Lomb sue Micro Labs USA for patent infringement.[6] Bausch & Lomb was recently bought out by Valeant Pharmaceuticals in May 2013 for $8.57 billion, Valeant’s largest acquisition to date, causing the company’s stock to rise 25% when the deal was announced.[7]
Clinical trials
A Phase III clinical trial was carried out in 2010 to evaluate the effectiveness of bepotastine besilate ophthalmic solutions 1.0% and 1.5%.[8] These solutions were compared to a placebo and evaluated for their ability to reduce ocular itchiness. The study was carried out with 130 individuals and evaluated after 15 minutes, 8 hours, or 16 hours. There was a reduction in itchiness at all-time points for both ophthalmic solutions. The study concluded that bepotastine besilate ophthalmic formulations reduced ocular itchiness for at least 8 hours after dosing compared to placebo. Phase I and II trials were carried out in Japan.
Studies have been performed in animals and bepotastine besilate was not found to be teratogenic in rats during fetal development, even at 3,300 times more that typical use in humans.[3] Evidence of infertility was seen in rats at 33,000 times the typical ocular does in humans.[3] The safety and efficacy has not been established in patients under 2 years of age and has been extrapolated from adults for patients under 10 years of age.[3]
SYN
EP 0335586; JP 1989242574; JP 1990025465; JP 1993294929; US 4929618
The reaction of 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) with ethyl 4-bromobutyrate (II) by means of K2CO3 in refluxing acetone gives the corresponding condensation product (III), which is then hydrolyzed with NaOH in ethanol/water yielding compound (IV).
SYN 2
JP 1998237070; JP 2000198784; WO 9829409
A new synthesis of betotastine has been developed: The racemic 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) is submitted to optical resolution with N-acyl amino acids such as N-acetyl-L-phenylalanine (preferred), N-acetyl-L-leucine, N-(benzyloxycarbonyl)-L-phenylalanine, N-(benzyloxycarbonyl)-L-valine, N-(benzyloxycarbonyl)-L-threonine, N-(benzyloxycarbonyl)-L-serine or with (2R,3R)-3-(5-chloro-2-nitrophenylsulfanyl)-2-hydroxy-3-(4-methoxyphenyl)propionic acid (preferred) or (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionic acid as chiral intermediates, yielding the (S)-isomer (II). The condensation of (II) with ethyl 4-bromobutyrate (III) by means of a base such as Na2CO3, NaHCO3, K2CO3 or KHCO3 gives the expected 4-(1-piperidinyl)butyric acid ester (IV), which is finally hydrolyzed with NaOH or KOH in aqueous ethanol or methanol.
SYN 3
A new synthesis of betotastine has been developed: The racemic 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) is submitted to optical resolution with N-acyl amino acids such as N-acetyl-L-phenylalanine (preferred), N-acetyl-L-leucine, N-(benzyloxycarbonyl)-L-phenylalanine, N-(benzyloxycarbonyl)-L-valine, N-(benzyloxycarbonyl)-L-threonine, N-(benzyloxycarbonyl)-L-serine or with (2R,3R)-3-(5-chloro-2-nitrophenylsulfanyl)-2-hydroxy-3-(4-methoxyphenyl)propionic acid (preferred) or (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionic acid as chiral intermediates, yielding the (S)-isomer (II). The condensation of (II) with ethyl 4-bromobutyrate (III) by means of a base such as Na2CO3, NaHCO3, K2CO3 or KHCO3 gives the expected 4-(1-piperidinyl)butyric acid ester (IV), which is finally hydrolyzed with NaOH or KOH in aqueous ethanol or methanol.
CLIP
A Novel Synthetic Method for Bepotastine, a Histamine H1 Receptor …
file:///C:/Users/91200291/Downloads/B130241_549.pdf
Scheme 1. Synthesis of bepotastine l-menthyl ester N-benzyloxycarbonyl-L-aspartic acid complex (3), bepotastine besilate (4) and bepotastine calcium (5). Reagents and conditions; i) 4-bromobutanoic acid l-menthyl ester, K2CO3, acetone, reflux, 7 h, 95-99%; ii) N-benzyloxycarbonyl-L-aspartic acid (NCbzLAA), ethyl acetate, rt, 12 h, 71-73%; iii) Ethyl acetate/H2O, NaHCO3, 97-99%; iv) EtOH:H2O = 1:1, NaOH, rt, 12 h, 3.0 N-HCl Neutralization, 92- 95%; v) AcOH, reflux, 12 h, racemization 97-100%; vi) Bezensulfonic acid, acetonitrile, rt, 12 h, 64-67%; vii) NaOH, H2O, CaCl2, rt, 12 h, 86-89%.
Synthesis of (S)-Bepotastine Besilate (4). Bepotastine (50 g, 0.13 mol) was dissolved in 500 mL of acetonitrile, and benzenesulfonic acid monohydrate (20 g, 0.11 mol) was added to the reaction mixture. Bepotastine besilate (0.5 g, 1.28 mmol) was seeded in the reaction mixture and stirred at rt for 12 h. The solid precipitate was filtered and dried. The product was obtained 38 g (yield: 64%, optical purity: 99.5% ee) as a pale white crystalline powder. Melting point: 161- 163 o C. Water: 0.2% (Karl-Fischer water determination). MS: m/z 389.1 [M+H]; 1 H-NMR (300 MHz, DMSO-d6) δ 9.2 (br s, 1H), 8.5 (d, J = 4.1 Hz, 1H), 7.8 (t, J = 7.7 Hz, 1H), 7.6 (m, 3H), 7.4 (m, 4H), 7.3 (m, 4H), 5.7 (s, 1H), 3.7 (br s, 2H), 3.3 (br s, 3H), 3.1 (br s, 2H), 2.3 (t, J = 14.1 Hz, 2H), 2.2 (m, 1H), 2.0 (m, 1H), 1.8 (m, 3H), 1.7 (m, 1H); IR (KBr, cm−1 ): 3422, 2996, 2909, 2735, 2690, 2628, 1719, 1592, 1572, 1488, 1470, 1436, 1411, 1320, 1274, 1221, 1160, 1123, 1066, 1031, 1014, 996, 849, 830, 771, 759, 727, 693, 612, 564
Synthesis
FDA Orange Book Patents
| FDA Orange Book Patents: 1 of 3 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 8784789 |
| Expiration | Sep 5, 2024 |
| Applicant | BAUSCH AND LOMB INC |
| Drug Application | N022288 (Prescription Drug: BEPREVE. Ingredients: BEPOTASTINE BESILATE) |
| FDA Orange Book Patents: 2 of 3 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 6780877 |
| Expiration | Sep 19, 2019 |
| Applicant | BAUSCH AND LOMB INC |
| Drug Application | N022288 (Prescription Drug: BEPREVE. Ingredients: BEPOTASTINE BESILATE) |
| FDA Orange Book Patents: 3 of 3 (FDA Orange Book Patent ID) | |
|---|---|
| Patent | 8877168 |
| Expiration | Jul 30, 2023 |
| Applicant | BAUSCH AND LOMB INC |
| Drug Application | N022288 (Prescription Drug: BEPREVE. Ingredients: BEPOTASTINE BESILATE) |
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| Clinical data | |
|---|---|
| Trade names | Bepreve |
| AHFS/Drugs.com | International Drug Names |
| MedlinePlus | a610012 |
| Pregnancy category |
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| Routes of administration |
Oral, topical (eye drops) |
| ATC code |
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| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | High (oral) Minimal (topical) |
| Protein binding | ~55% |
| Excretion | Renal (75–90%) |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C21H25ClN2O3 |
| Molar mass | 388.88 g/mol |
| 3D model (JSmol) | |
References
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- EP 335 586 (Ube Ind.; appl. 22.3.1989; J-prior. 25.3.1988).
- EP 485 984 (Ube Ind.; appl. 13.11.1991; J-prior. 15.11.1990).
- WO 9 829 409 (Ube Ind.; appl. 25.12.1997; J-prior. 26.12.1996).
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racemization :
- JP 10 237 069 (Ube Ind.; appl. 21.2.1997).
References
- Jump up^ H. Takahashi; A. Ishida-Yamamoto; H. Iizuka (September 2004). “Effects of bepotastine, cetirizine, fexofenadine, and olopatadine on histamine-induced wheal-and flare-response, sedation, and psychomotor performance”. Clinical and Experimental Dermatology. 29: 526–532. doi:10.1111/j.1365-2230.2004.01618.x.
- Jump up^ “Bepotastine Monograph”. LexiComp.
- ^ Jump up to:a b c d e f “Bepreve prescribing Information” (PDF).
- Jump up^ [phx.corporate-ir.net/External.File?item…t=1 “2011 Net Revenues Increase to $160.3 Million On an Adjusted Cash Net Income Basis, ISTA Posts Second Year of Profitability Company Reaffirms 2012 Financial Guidance”] Check
|url=value (help). - Jump up^ “Bausch & Lomb to Buy ISTA Pharmaceuticals for $500 Million”. DealBook. Retrieved 2015-12-05.
- Jump up^ “Bausch & Lomb Inc. et al. v. Micro Labs USA, Inc. et al.”
- Jump up^ “Valenant pharmaceuticals eyes China with Bausch deal”.
- Jump up^ Macejko, Thomas T.; Bergmann, Mark T.; Williams, Jon I.; Gow, James A.; Gomes, Paul J.; McNamara, Timothy R.; Abelson, Mark B. (2010-07-01). “Multicenter Clinical Evaluation of Bepotastine Besilate Ophthalmic Solutions 1.0% and 1.5% to Treat Allergic Conjunctivitis”. American Journal of Ophthalmology. 150 (1): 122–127.e5. doi:10.1016/j.ajo.2010.02.007.
////////////Bepotastine Besilate, ベポタスチンベシル酸塩 ,Talion , tau284, TAU-284DS, TAU-284, DA-5206
HL-151 , SNJ-1773
C1CN(CCC1OC(C2=CC=C(C=C2)Cl)C3=CC=CC=N3)CCCC(=O)O.C1=CC=C(C=C1)S(=O)(=O)O