WO2012015996A2 - Preservative free bimatoprost solutions - Google Patents

Preservative free bimatoprost solutions Download PDF

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Publication number
WO2012015996A2
WO2012015996A2 PCT/US2011/045652 US2011045652W WO2012015996A2 WO 2012015996 A2 WO2012015996 A2 WO 2012015996A2 US 2011045652 W US2011045652 W US 2011045652W WO 2012015996 A2 WO2012015996 A2 WO 2012015996A2
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WO
WIPO (PCT)
Prior art keywords
bimatoprost
composition
solution
eye
preservative
Prior art date
Application number
PCT/US2011/045652
Other languages
French (fr)
Other versions
WO2012015996A3 (en
Inventor
Sukhon Likitlersuang
Ajay P. Parashar
Chetan P. Pujara
William F. Kelly
Original Assignee
Allergan, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Allergan, Inc. filed Critical Allergan, Inc.
Priority to CA2806973A priority Critical patent/CA2806973A1/en
Priority to US13/812,594 priority patent/US20130245124A1/en
Priority to AU2011282679A priority patent/AU2011282679A1/en
Priority to EP20110745859 priority patent/EP2598117A2/en
Publication of WO2012015996A2 publication Critical patent/WO2012015996A2/en
Publication of WO2012015996A3 publication Critical patent/WO2012015996A3/en
Priority to US14/308,320 priority patent/US20150099807A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present application is directed to preservative-free formulations of bimatoprost.
  • Bimatoprost is a prostamide, a synthetic analog of prostaglandin F 2a (PGF 2a ) with potent ocular hypotensive activity.
  • Bimatoprost lowers intraocular pressure (IOP) in patients with glaucoma or ocular hypertension by increasing outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes.
  • IOP intraocular pressure
  • Use of preservative containing eye drops has been implicated in the development or worsening of ocular surface disease. Management of open angle glaucoma and ocular hypertension require long term treatment with eye drops containing preservatives. Symptoms and signs of ocular surface disease such as ocular surface breakdown, irritation, burning, foreign body sensation, dryness, inadequate quantity of tears etc are prevalent in a large proportion of patients with open angle glaucoma and ocular hypertension.
  • preservative-free eye drops induce significantly fewer ocular symptoms and signs of irritation in patients, such as pain or discomfort, foreign body sensation, stinging or burning, and dry eye sensation.
  • Benzalkonium chloride also may be absorbed by the soft contact lenses therefore patients wearing soft contact lenses are advised to remove lenses prior to administration and wait at least 15 minutes before reinserting them.
  • the present invention is directed to bimatoprost formulations (e.g., solutions) without benzalkonium chloride which are superior from a safety, tolerability and patient compliance standpoint while maintaining and/or improving its efficacy of IOP lowering and be available for use by patients hypersensitive to benzalkonium chloride and be convenient for patients wearing soft contact lenses.
  • Bimatoprost ophthalmic solution without preservative is a clear, isotonic, sterile solution.
  • the drug product contains bimatoprost as the active ingredient.
  • the inactive ingredients are tonicity and buffer agents, and purified water. Suitable buffers such as sodium phosphate dibasic heptahydrate and citric acid monohydrate and suitable tonicity agents such as sodium chloride may be included.
  • the final solution would be an aqueous solution having a pH value within the range of about 7 to 8 , preferably 7.3 and osmolality in range of 280-370 mOsmol/kg.
  • the present invention can be made generally according to the teachings of US Patent No. 5,688,819, which is hereby incorporated by reference in its entirety.
  • a preservative free bimatoprost composition for lowering intraocular pressure in a patient comprising the following formulation: about 0.03% w/v bimatoprost; about 0.268% w/v sodium phosphate heptahydrate; about 0.014 % w/v citric acid monohydrate; about 0.83% w/v sodium chloride; water and having a pH of about 7.3.
  • a preservative free bimatoprost composition for lowering intraocular pressure in a human patient comprising the following formulation: 0.03% w/v bimatoprost; 0.268% w/v sodium phosphate heptahydrate; 0.014 % w/v citric acid monohydrate; 0.83% w/v sodium chloride; water, hydrochloric acid, sodium hydroxide and having a pH of about 7.3.
  • the bimatoprost composition of claim 3 wherein the solution is contained in a unit dose kit form.
  • the bimatoprost composition of paragraphs 1 - 4 wherein the composition is a solution and is applied once a day to each eye.
  • the bimatoprost solution of paragraphs 1 - 4 wherein the composition is a solution and is applied twice a day to each eye.
  • the bimatoprost composition of claim 1 wherein the composition is a solution and has greater bioavailability of bimatoprost in the eye of the patient with fewer side-effects than bimatoprost preserved with benzalkonium chloride.
  • the composition of paragraph 1 wherein the composition may be a solution, emulsion, dispersion, suspension, reverse emulsion and microemulsion.
  • composition of paragraph 1 wherein the composition is contained in a unit-dose vial.
  • composition of paragraph 1 wherein the composition is contained in a multi-dose vial which has anti-preservative properties such as metal-ions imbedded in its dispensing tip.
  • metal ions are silver ions
  • Table 1 Example of a bimatoprost ophthalmic solution without preservative according to the present invention:
  • the present invention is directed to the same bimatoprost formulation as commercially available LUMIGAN 0.03 but without benzalkonium chloride as a preservative and in unit-dose or multi-dose form.
  • the present invention results in greater bioavailability of the active ingredient bimatoprost in the eye without the unwanted side- effects associated with the preservative benzalkonium chloride such as hyperemia.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention is directed to preservative-free solutions of bimatoprost for lowering intra-ocular pressure and treatment of glaucoma.

Description

PRESERVATIVE FREE BIMATOPROST SOLUTIONS
By Inventors: Sukhon Likitlersuang, Ajay Parashar,
Chetan P. Pujara, and William F. Kelly
CROSS REFERENCE TO RELATED APPLICATIONS
This Application claims the benefit of US Provisional Patent Application Serial No. 61/368,688 which was filed on July 29, 2010 and is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present application is directed to preservative-free formulations of bimatoprost.
BACKGROUND OF THE INVENTION
Bimatoprost is a prostamide, a synthetic analog of prostaglandin F2a (PGF2a) with potent ocular hypotensive activity. Bimatoprost lowers intraocular pressure (IOP) in patients with glaucoma or ocular hypertension by increasing outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes. Use of preservative containing eye drops has been implicated in the development or worsening of ocular surface disease. Management of open angle glaucoma and ocular hypertension require long term treatment with eye drops containing preservatives. Symptoms and signs of ocular surface disease such as ocular surface breakdown, irritation, burning, foreign body sensation, dryness, inadequate quantity of tears etc are prevalent in a large proportion of patients with open angle glaucoma and ocular hypertension.
Compared to eye drops preserved with benzalkonium chloride, preservative-free eye drops induce significantly fewer ocular symptoms and signs of irritation in patients, such as pain or discomfort, foreign body sensation, stinging or burning, and dry eye sensation.
Patients experiencing hypersensitivity reactions with benzalkonium chloride cannot use the commercial bimatoprost product containing benzalkonium chloride such as LUMIGAN which is preserved with 0.005% w/v benzalkonium chloride. Benzalkonium chloride also may be absorbed by the soft contact lenses therefore patients wearing soft contact lenses are advised to remove lenses prior to administration and wait at least 15 minutes before reinserting them. SUMMARY OF THE INVENTION
The present invention is directed to bimatoprost formulations (e.g., solutions) without benzalkonium chloride which are superior from a safety, tolerability and patient compliance standpoint while maintaining and/or improving its efficacy of IOP lowering and be available for use by patients hypersensitive to benzalkonium chloride and be convenient for patients wearing soft contact lenses.
Bimatoprost ophthalmic solution without preservative is a clear, isotonic, sterile solution. The drug product contains bimatoprost as the active ingredient. The inactive ingredients are tonicity and buffer agents, and purified water. Suitable buffers such as sodium phosphate dibasic heptahydrate and citric acid monohydrate and suitable tonicity agents such as sodium chloride may be included. The final solution would be an aqueous solution having a pH value within the range of about 7 to 8 , preferably 7.3 and osmolality in range of 280-370 mOsmol/kg.
The present invention can be made generally according to the teachings of US Patent No. 5,688,819, which is hereby incorporated by reference in its entirety.
Some of the embodiments of the present invention are as follows: ) A preservative free bimatoprost composition for lowering intraocular pressure in a patient comprising the following formulation: about 0.03% w/v bimatoprost; about 0.268% w/v sodium phosphate heptahydrate; about 0.014 % w/v citric acid monohydrate; about 0.83% w/v sodium chloride; water and having a pH of about 7.3. ) A preservative free bimatoprost composition for lowering intraocular pressure in a human patient comprising the following formulation: 0.03% w/v bimatoprost; 0.268% w/v sodium phosphate heptahydrate; 0.014 % w/v citric acid monohydrate; 0.83% w/v sodium chloride; water, hydrochloric acid, sodium hydroxide and having a pH of about 7.3. ) The bimatoprost composition of paragraphs 1 and 2 wherein the composition is a solution and is useful for treating glaucoma. ) The bimatoprost composition of claim 3 wherein the solution is contained in a unit dose kit form. ) The bimatoprost composition of paragraphs 1 - 4 wherein the composition is a solution and is applied once a day to each eye. ) The bimatoprost solution of paragraphs 1 - 4 wherein the composition is a solution and is applied twice a day to each eye. ) The bimatoprost composition of claim 1 wherein the composition is a solution and has greater bioavailability of bimatoprost in the eye of the patient with fewer side-effects than bimatoprost preserved with benzalkonium chloride. ) The composition of paragraph 1 wherein the composition may be a solution, emulsion, dispersion, suspension, reverse emulsion and microemulsion. ) The composition of paragraph 1 wherein the composition is contained in a unit-dose vial. 0) The composition of paragraph 1 wherein the composition is contained in a multi-dose vial which has anti-preservative properties such as metal-ions imbedded in its dispensing tip. 1) The composition of paragraph 12 wherein the metal ions are silver ions
DETAILED DESCRIPTION OF THE INVENTION
One bimatoprost ophthalmic formulation of the present invention without preservative shown in Table- 1.
Table 1 : Example of a bimatoprost ophthalmic solution without preservative according to the present invention:
Figure imgf000004_0001
The present invention is directed to the same bimatoprost formulation as commercially available LUMIGAN 0.03 but without benzalkonium chloride as a preservative and in unit-dose or multi-dose form. As a result of the removal of benzalkonium chloride, the present invention results in greater bioavailability of the active ingredient bimatoprost in the eye without the unwanted side- effects associated with the preservative benzalkonium chloride such as hyperemia. This results in a formulation with the same or improved efficacy of the product in lowering IOP per dosage unit, fewer side-effects and superior patient compliance. Other side effects which may be avoided include visual disturbance, ocular burning, foreign, body sensation, eye pain, blepharitis, cataract, superficial punctate keratitis, eyelid erythema, ocular irritation, eye discharge, tearing, photophobia, allergic conjunctivitis, asthenopia, conjunctival edema, conjunctival hemorrhage, and intraocular inflammation.

Claims

A preservative free bimatoprost composition for lowering intraocular pressure in a patient comprising the following formulation: about 0.03% w/v bimatoprost; about 0.268% w/v sodium phosphate heptahydrate; about 0.014 % w/v citric acid monohydrate; about 0.83% w/v sodium chloride; water and having a pH of about 7.3.
A preservative free bimatoprost composition for lowering intraocular pressure in a human patient comprising the following formulation: 0.03% w/v bimatoprost; 0.268% w/v sodium phosphate heptahydrate; 0.014 % w/v citric acid monohydrate; 0.83% w/v sodium chloride; water, hydrochloric acid, sodium hydroxide and having a pH of about 7.3.
The bimatoprost composition of claim 1 wherein the composition is a solution and is useful for treating glaucoma.
The bimatoprost composition of claim 3 wherein the solution is contained in a unit dose kit form.
The bimatoprost composition of claim 1 wherein the composition is a solution and is applied once a day to each eye.
The bimatoprost solution of claim 2 wherein the composition is a solution and is applied twice a day to each eye.
The bimatoprost composition of claim 1 wherein the composition is a solution and has greater bioavailability of bimatoprost in the eye of the patient with fewer side-effects than bimatoprost preserved with benzalkonium chloride.
PCT/US2011/045652 2010-07-29 2011-07-28 Preservative free bimatoprost solutions WO2012015996A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA2806973A CA2806973A1 (en) 2010-07-29 2011-07-28 Preservative free bimatoprost solutions
US13/812,594 US20130245124A1 (en) 2010-07-29 2011-07-28 Preservative free bimatoprost solutions
AU2011282679A AU2011282679A1 (en) 2010-07-29 2011-07-28 Preservative free bimatoprost solutions
EP20110745859 EP2598117A2 (en) 2010-07-29 2011-07-28 Preservative free bimatoprost solutions
US14/308,320 US20150099807A1 (en) 2010-07-29 2014-06-18 Preservative free bimatoprost solutions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36868810P 2010-07-29 2010-07-29
US61/368,688 2010-07-29

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/812,594 A-371-Of-International US20130245124A1 (en) 2010-07-29 2011-07-28 Preservative free bimatoprost solutions
US14/308,320 Continuation US20150099807A1 (en) 2010-07-29 2014-06-18 Preservative free bimatoprost solutions

Publications (2)

Publication Number Publication Date
WO2012015996A2 true WO2012015996A2 (en) 2012-02-02
WO2012015996A3 WO2012015996A3 (en) 2012-04-12

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Country Status (5)

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US (2) US20130245124A1 (en)
EP (1) EP2598117A2 (en)
AU (1) AU2011282679A1 (en)
CA (1) CA2806973A1 (en)
WO (1) WO2012015996A2 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR1008330B (en) * 2013-10-17 2014-10-20 "Φαρματεν Α.Β.Ε.Ε.", Preservative free pharmaceutical compositions for ophthalmic administration having improved physical characteristics and drop volume
WO2015055301A1 (en) 2013-10-15 2015-04-23 Pharmathen S.A. Preservative free pharmaceutical compositions for ophthalmic administration
US11400100B2 (en) 2019-12-11 2022-08-02 Somerset Therapeutics, Llc. Effective benzalkonium chloride-free bimatoprost ophthalmic compositions
WO2024003078A1 (en) * 2022-06-27 2024-01-04 Warszawskie Zaklady Farmaceutyczne Polfa Sa Preservative-free ophthalmic composition comprising a prostaglandin analogue

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL3103439T3 (en) 2015-06-09 2019-12-31 Medproject Pharma-Entwicklungs- Und Vertriebsgesellschaft Mbh Drippable ophthalmic bimatoprost gel
IL300064A (en) * 2016-12-02 2023-03-01 Univ Florida Preservative removal from eye drops

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5688819A (en) 1992-09-21 1997-11-18 Allergan Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents

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US7074827B2 (en) * 2002-10-24 2006-07-11 Sucampo Ag (Usa) Inc. Method for treating ocular hypertension and glaucoma
US7851504B2 (en) * 2005-03-16 2010-12-14 Allergan, Inc. Enhanced bimatoprost ophthalmic solution
FR2918891B1 (en) * 2007-07-20 2009-09-25 Thea Sa Lab OPHTHALMIC SOLUTION BASED ON PROSTAGLANDINS WITHOUT PRESERVATIVE
EP2127638A1 (en) * 2008-05-30 2009-12-02 Santen Pharmaceutical Co., Ltd Method and composition for treating ocular hypertension and glaucoma

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5688819A (en) 1992-09-21 1997-11-18 Allergan Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2598117A2

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015055301A1 (en) 2013-10-15 2015-04-23 Pharmathen S.A. Preservative free pharmaceutical compositions for ophthalmic administration
US10350161B2 (en) 2013-10-15 2019-07-16 Pharmathen S.A. Preservative free pharmaceutical compositions for ophthalmic administration
EP3973954A1 (en) * 2013-10-15 2022-03-30 Pharmathen S.A. Preservative free pharmaceutical compositions for ophthalmic administration
GR1008330B (en) * 2013-10-17 2014-10-20 "Φαρματεν Α.Β.Ε.Ε.", Preservative free pharmaceutical compositions for ophthalmic administration having improved physical characteristics and drop volume
US11400100B2 (en) 2019-12-11 2022-08-02 Somerset Therapeutics, Llc. Effective benzalkonium chloride-free bimatoprost ophthalmic compositions
US11786538B2 (en) 2019-12-11 2023-10-17 Somerset Therapeutics, Llc Low benzalkonium chloride bimatoprost ophthalmic compositions with effective penetration and preservation properties
WO2024003078A1 (en) * 2022-06-27 2024-01-04 Warszawskie Zaklady Farmaceutyczne Polfa Sa Preservative-free ophthalmic composition comprising a prostaglandin analogue

Also Published As

Publication number Publication date
US20130245124A1 (en) 2013-09-19
WO2012015996A3 (en) 2012-04-12
EP2598117A2 (en) 2013-06-05
AU2011282679A1 (en) 2013-03-07
US20150099807A1 (en) 2015-04-09
CA2806973A1 (en) 2012-02-02

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