WO2013013143A1 - Fixed dose combination of bimatoprost and brimonidine - Google Patents

Fixed dose combination of bimatoprost and brimonidine Download PDF

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Publication number
WO2013013143A1
WO2013013143A1 PCT/US2012/047586 US2012047586W WO2013013143A1 WO 2013013143 A1 WO2013013143 A1 WO 2013013143A1 US 2012047586 W US2012047586 W US 2012047586W WO 2013013143 A1 WO2013013143 A1 WO 2013013143A1
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WO
WIPO (PCT)
Prior art keywords
composition
brimonidine
bimatoprost
glaucoma
intraocular pressure
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2012/047586
Other languages
French (fr)
Inventor
Richard S. Graham
Chetan P. Pujara
Anuradha V. Gore
Kevin S. Warner
Sesha NEERVANNAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Inc
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
Priority to EP12741222.9A priority Critical patent/EP2734206A1/en
Priority to CA2841969A priority patent/CA2841969A1/en
Priority to PH1/2014/500179A priority patent/PH12014500179A1/en
Priority to JP2014521822A priority patent/JP2014520895A/en
Priority to BR112014001118A priority patent/BR112014001118A2/en
Priority to MX2014000781A priority patent/MX2014000781A/en
Priority to RU2014103544/15A priority patent/RU2014103544A/en
Priority to AU2012283895A priority patent/AU2012283895A1/en
Application filed by Allergan Inc filed Critical Allergan Inc
Priority to KR1020147004214A priority patent/KR20140056280A/en
Priority to US14/235,746 priority patent/US20140249153A1/en
Priority to CN201280041251.3A priority patent/CN103747786A/en
Publication of WO2013013143A1 publication Critical patent/WO2013013143A1/en
Priority to IL230450A priority patent/IL230450A0/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present appl ication is directed to composition comprising combinations of brimonidine and bimatoprost useful for lowering intraocular pressure in a patient and the treatment of glaucoma.
  • Topically applied formulations are frequently used in ophthalmology to treat acute and chronic conditions because they are considered to be safer relative to systemically del ivered formulations. While topically applied formulations may not produce a high systemic exposure of the active pharmaceutical ingredient, there is still the potential for adverse events (e.g., conjunctival hyperemia) due to topical exposure.
  • Improving the side effect profile while stil l maintaining and possibly improving efficacy can be accomplished via the fol lowing: 1 ) reduce the concentration of the API to the lowest effective dose; 2) include a second API with a mechanism of action known to minimize the adverse event of the first API ; 3) Include a second API which will provide a synergistic effect thereby improving the overall efficacy; and 4) improve patient compliance by reducing the number of different medications that need to be delivered.
  • this invention discloses the fixed dose combination of bimatoprost and brimonidine in an appropriate formulation vehicle.
  • bimatoprost/brimonidine are described as follows:
  • the present invention is intended for use in patients who requ ire more than one intraocular pressure lowering agent and/or to improve patient compliance for patients undergoing concurrent bimatoprost and brimoindine monotherapy.
  • “About” is defined as variations in amounts in either active compounds or excipients that would be considered bioequivalent by a regulatory agency such as the FDA or the E EA.
  • an “effective amount” of a compound is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease. Where recited in reference to a disease treatment, an “effective amount” may also be referred to as a “therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • Na-C C means sodium carboxymethyl cellulose and can be either low density, medium density or high density CMC and mixtures thereof.
  • pharmaceutically acceptable salts is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • Soluplus® refers to the solubilizer sold by BASF known as polyvinyl capralactam- polyvinyl acetate-polyethylene glycol graft copolymer (PCA-PVA-PEG).
  • topical in the context of methods described herein relates in the customary sense to the administration of a compound or pharmaceutical composition which is incorporated into a suitable pharmaceutical carrier and administered at a topical treatment site of a subject. Accordingly, the term “topical pharmaceutical composition” includes those pharmaceutical forms in which the compound is administered externally by direct contact with a topical treatment site, e.g., the eye or the skin.
  • topical ocular a topical treatment site
  • composition refers to a pharmaceutical composition suitable for administering directly to the eye.
  • treating refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
  • a topical composition for use in lowering 10P in a patient comprising an effective amount of bimatoprost and brimonidine and a pharmaceutically acceptable carrier.
  • the brimonidine is brimonidine tartrate and is present in the concentration range of 0.005 - 0.2% w/w.
  • composition of embodiments 1 - 3 wherein the composition further comprises excipients selected from the group of excipients listed in Table 1 , Table 2 and Table 3.
  • a method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering the composition of embodiment 3.
  • a method of lowering intraocular pressure or treating glaucoma in a human patient comprising adm inistering a composition of embodiments 1 - 6.
  • a method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering one of the compositions l isted in Table 1 .
  • a method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering one of the compositions listed in Table 2 or Table 3.
  • a topical composition for ophthalmic application for use in lowering intraocular pressure in a patient comprising about 0.01 % w/w bimatoprost and about 0. 1 % w/w brimonidine.
  • concentration of 0.01 % w/w and brimonidine is brimonidine tartrate and is present in the amount of 0. 1 % w/w in an aqueous vehicle.
  • composition of embodiment 1 2 further comprising buffers selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
  • compositions of embodiment 12 further comprising tonicity agents wherein the tonicity agents are selected from the group consisting of NaCI and glycerin.
  • composition of embodiment 12 further comprising preservat ives wherein the preservatives are selected from the group consisting of benzalkoniun chloride and Purite.
  • compositions are a solution and is administered at least once a day.
  • compositions 12 - 1 7 wherein the composition is useful in treating glaucoma wherein the glaucoma is selected from the group consisting of open-angle glaucoma, closed-angle glaucoma, angle-closure glaucoma, normal- tension glaucoma, and congenital glaucoma.
  • a method of treating elevated intraocular pressure the method comprising
  • composition comprises about 0.01 % w/w bimatoprost and about 0. 1 % w/w brimonidine tartrate.
  • composition comprises 0.01 % w/w bimatoprost and 0.1 % vv/w brimonidine.
  • composition further comprises a solubulizer selected from the group consisting of Na-CMC and Soluplus® and a buffer selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
  • solubulizer selected from the group consisting of Na-CMC and Soluplus®
  • a buffer selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
  • composition further comprises a preservative.
  • the formulations of the present invention can be topical ly administered once, twice or three times a day in order to lower intraocular pressure in a patient.
  • the present formulations may be preserved or preservative free.
  • concentrations of actives in Tables 1 and 2 are preferred, bimatoprost may be present in concentration ranges of 0.001 - 0.03 w/w and brimonidine may be present in 0.005 - 0.2% w/w.
  • Concentrations of actives and excipients may be present in about the concentrations listed herein, wherein "about” refers to variations of the concentrat ions considered to be bioequivalent by the FDA or EM EA in making similar or generic compositions.
  • Brimonidine includes pharmaceutically acceptable salts of brimonidone such as brimonidine tartrate.
  • Brimonidine tartrate is an alpha adrenergic agon ist represented by the following formula:
  • brimonidine 5-Bromo-6-(2-imizazoi idinyl ideeneamno) quinoxaline L-tartrate.
  • Bimatoprost is represented by the following chemical structure:
  • Bimatoprost's chemical name is (Z)-7-[( l R,2/? ; 3/?,5S)-3,5-Dihydroxy-2-[( l E,3S)-3- hydroxy-5- phenyl- l -pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 41 5.58. Its molecular and its formula is C25H37NO4. Table 3. Brimonidine/Bimatoprost Fixed Dose Combination Formulations for Stability Evaluation
  • Bimatoprost 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 (% w/w)
  • Formulation stability for the formulation shown in Table 3 was as follows:
  • Example 1 - A 58 year old Caucasian male with elevated intraocular pressure (“IOP") is unresponsive to both brimonidine (0.1 5% w/v and 0.01 % w/v) and bimatoprost monotherapy (both 0.03% w/v and 0.01 % w/v) and unable to adequately control his elevated IOP.
  • the 58 year old male administers Formulation 6, in Table 3 twice a day, once in the morning and once in the evening. Administration is 1 2 hours apart and every day. Within three days of use, the patient's IOP falls to cl in ically acceptable levels and remains at clinically acceptable levels as long as the patient applies Formula 6 twice a day.
  • Example 2 a 71 year old African American female with ocular hypertension is unresponsive to both brimonidine and bimatoprost monotherapy and unable to control her IOP through the use of conventional glaucoma medications.
  • the 7 1 year old patient administers Formulation 8, in Table 3, once each day. Within seven days of use, the patient's IOP falls to clinically acceptable levels and remains at cl inically acceptable levels for over 120 days of daily adm inistration of Formulation 8.
  • Example 3 A 68 year old Caucasian male with elevated intraocular pressure, open- angle glaucoma and with sensitivity to ophthalmic preservatives is administered Formulation 3 in Table 3 on a once dai ly basis.
  • Example 4 - A 73 Hispanic female suffering ocular hypertension ranging from 1 7 - 20 mm Hg is unresponsive to commercially available brimonidine and bimatoprost monotherapy.
  • the patient is administered Formulation 5 of Table 3 once a day and after two days the patient's intraocular pressure lowers to acceptable levels.
  • the patient continues administering Formulation 5 every day and intraocular pressure levels remained at therapeutically acceptable levels.
  • composition comprising combinations of brimonidine and bimatoprost useful for lowering intraocular pressure in a patient and the treatment of glaucoma.
  • Topically applied formulations are frequently used in ophthalmology to treat acute and chronic conditions because they are considered to be safer relative to systemically delivered formulations. While topically applied formulations may not produce a high systemic exposure of the active pharmaceutical ingredient, there is still the potential for adverse events (e.g., conjunctival hyperemia) due to topical exposure.
  • Improving the side effect profile while still maintaining and possibly improving efficacy can be accomplished via the following: 1) reduce the concentration of the API to the lowest effective dose; 2) include a second API with a mechanism of action known to minimize the adverse event of the first API; 3) Include a second API which will provide a synergistic effect thereby improving the overall efficacy; and 4) improve patient compliance by reducing the number of different medications that need to be delivered.
  • this invention discloses the fixed dose combination of bimatoprost and brimonidine in an appropriate formulation vehicle.
  • bimatoprost/brimonidine are described as follows:
  • the present invention is intended for use in patients who require more than one intraocular pressure lowering agent and/or to improve patient compliance for patients undergoing concurrent bimatoprost and brimoindine monotherapy.
  • ABSOR is defined as variations in amounts in either active compounds or excipients that would be considered bioequivalent by a regulator ⁇ ' agency such as the FDA or the EMEA.
  • an “effective amount” of a compound is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease. Where recited in reference to a disease treatment, an “effective amount” may also be referred to as a “therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • Na-CMC means sodium carboxymethyl cellulose and can be either low density, medium density or high density CMC and mixtures thereof.
  • pharmaceutically acceptable salts is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • Soluplus® refers to the solubilizer sold by BASF known as polyvinyl capralactam- polyvinyl acetate-polyethylene glycol graft copolymer (PCA-PVA-PEG).
  • topical in the context of methods described herein relates in the customary sense to the administration of a compound or pharmaceutical composition which is incorporated into a suitable pharmaceutical carrier and administered at a topical treatment site of a subject. Accordingly, the term “topical pharmaceutical composition” includes those
  • topical ocular pharmaceutical composition refers to a pharmaceutical composition suitable for topical treatment site, e.g., the eye or the skin.
  • topical ocular pharmaceutical composition refers to a pharmaceutical composition suitable for topical treatment site
  • treating refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
  • a topical composition for use in lowering IOP in a patient comprising an effective amount of bimatoprost and brimonidine and a pharmaceutically acceptable carrier.
  • the brimonidine is brimonidine tartrate and is present in the concentration range of 0.005 - 0.2% w/w.
  • composition of embodiments 1 - 3 wherein the composition further comprises excipients selected from the group of excipients listed in Table 1 , Table 2 and Table 3.
  • a method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering the composition of embodiment 3.
  • a method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering a composition of embodiments 1 - 6.
  • a method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering one of the compositions listed in Table 2 or Table 3.
  • a topical composition for ophthalmic application for use in lowering intraocular pressure in a patient comprising about 0.01 % w/w bimatoprost and about 0.1% w/w brimonidine.
  • composition of embodiment 12 further comprising a solubulizer selected from the group consisting of Na-CMC and Soluplus®.
  • composition of embodiment 12 further comprising buffers selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
  • compositions of embodiment 12 further comprising tonicity agents wherein the tonicity agents are selected from the group consisting of NaCl and glycerin.
  • composition of embodiment 12 further comprising preservatives wherein the preservatives are selected from the group consisting of benzalkoniun chloride and Purite.
  • composition is a solution and is administered at least once a day.
  • compositions 12 - 17 wherein the composition is useful in treating glaucoma wherein the glaucoma is selected from the group consisting of open-angle glaucoma, closed-angle glaucoma, angle-closure glaucoma, normal- tension glaucoma, and congenital glaucoma.
  • composition of embodiment 12 wherein the composition of embodiment 12 lowers intraocular pressure more than either bimatoprost or brimonidine administered alone and with fewer side-effects.
  • a method of treating elevated intraocular pressure comprising
  • composition comprises about 0.01% w/w bimatoprost and about 0.1 % w/w brimonidine tartrate.
  • composition further comprises a solubulizer selected from the group consisting of Na-CMC and Soluplus® and a buffer selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
  • solubulizer selected from the group consisting of Na-CMC and Soluplus®
  • a buffer selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
  • composition further comprises a preservative.
  • the formulations of the present invention can be topically administered once, twice or three times a day in order to lower intraocular pressure in a patient.
  • compositions may be preserved or preservative free. Although the concentrations of actives in Tables 1 and 2 are preferred, bimatoprost may be present in
  • Concentrations of actives and excipients may be present in about the concentrations listed herein, wherein "about” refers to variations of the concentrations considered to be bioequivalent by the FDA or EMEA in making similar or generic compositions.
  • Brimonidine includes pharmaceutically acceptable salts of brimonidone such as brimonidine tartrate.
  • Brimonidine tartrate is an alpha adrenergic agonist represented by the following formula:
  • brimonidine 5-Bromo-6-(2-imizazolidinylideeneamno) quinoxaline L-tartrate.
  • Bimatoprost is represented by the following chemical structure:
  • Bimatoprost's chemical name is (Z)-7-[(li?,2i?,3i?,55)-3,5-Dihydroxy-2-[(lE,3S)-3- hydroxy-5- phenyl-l-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular and its formula is C25H37NO4.
  • Bimatoprost 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 (% w/w)
  • Formulation stability for the formulation shown in Table 3 was as follows:
  • Example 1 A 58 year old Caucasian male with elevated intraocular pressure (“IOP") is unresponsive to both brimonidine (0.15% w/v and 0.01% w/v) and bimatoprost
  • Example 2 - a 71 year old African American female with ocular hypertension is unresponsive to both brimonidine and bimatoprost monotherapy and unable to control her IOP through the use of conventional glaucoma medications.
  • the 71 year old patient administers Formulation 8, in Table 3, once each day. Within seven days of use, the patient's IOP falls to clinically acceptable levels and remains at clinically acceptable levels for over 120 days of daily administration of Formulation 8.
  • Example 3 A 68 year old Caucasian male with elevated intraocular pressure, open- angle glaucoma and with sensitivity to ophthalmic preservatives is administered Formulation 3 in Table 3 on a once daily basis. After several days of use, the patients intraocular pressure drops to therapeutically acceptable levels and stays at therapeutically acceptable levels so long as daily administration of Formulation 3 is continued. After 6 months of daily use of Formulation 3, there is no further worsening of the patient's glaucoma and no further detectable damage to the optic nerve.
  • Example 4 - A 73 Hispanic female suffering ocular hypertension ranging from 17 - 20 mm Hg is unresponsive to commercially available brimonidine and bimatoprost monotherapy.
  • the patient is administered Formulation 5 of Table 3 once a day and after two days the patient's intraocular pressure lowers to acceptable levels.
  • the patient continues administering Formulation 5 every day and intraocular pressure levels remained at therapeutically acceptable levels.

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Abstract

The present invention is directed to compositions comprising combinations of brimonidine and bimatoprost useful for lowering intraocular pressure in a patient and for the treatment of glaucoma.

Description

FIXED DOSE COM BINATION OF BI ATOPROST AND BRIMONI DI NE
By Inventors: Richard S. Graham, Chetan P Pujara, Sesha Neervannan,
Anuradha V. Gore, and Kevin S. Warner
Related Application
This application claims the benefit of U.S. Provisional Application Serial No.
61 /509,666, filed July 20, 201 1 , the disclosure of which is hereby incorporated in its entirety herein by reference.
Field of the Invent ion:
The present appl ication is directed to composition comprising combinations of brimonidine and bimatoprost useful for lowering intraocular pressure in a patient and the treatment of glaucoma.
Background of the Invention:
Topically applied formulations (defined as formulations applied to the cornea, conjunctiva, etc.) are frequently used in ophthalmology to treat acute and chronic conditions because they are considered to be safer relative to systemically del ivered formulations. While topically applied formulations may not produce a high systemic exposure of the active pharmaceutical ingredient, there is still the potential for adverse events (e.g., conjunctival hyperemia) due to topical exposure. Improving the side effect profile while stil l maintaining and possibly improving efficacy can be accomplished via the fol lowing: 1 ) reduce the concentration of the API to the lowest effective dose; 2) include a second API with a mechanism of action known to minimize the adverse event of the first API ; 3) Include a second API which will provide a synergistic effect thereby improving the overall efficacy; and 4) improve patient compliance by reducing the number of different medications that need to be delivered. Specifically, this invention discloses the fixed dose combination of bimatoprost and brimonidine in an appropriate formulation vehicle.
Summary of the Invention:
Formulation development approaches to meet the above criteria for
bimatoprost/brimonidine are described as follows:
1 . Optimize the pH of the formulation to maximize the unionized fraction of
brimonidine in aqueous formulations;
2. Incorporation of viscosity agents in the formulation to increase solution viscosity; 3. Incorporat ion of ocularly acceptable permeability enhancers to improve tissue bioavailabil ity; and,
4. Non-aqueous based formulations.
The present invention is intended for use in patients who requ ire more than one intraocular pressure lowering agent and/or to improve patient compliance for patients undergoing concurrent bimatoprost and brimoindine monotherapy.
"About" is defined as variations in amounts in either active compounds or excipients that would be considered bioequivalent by a regulatory agency such as the FDA or the E EA.
"Effective amount" An "effective amount" of a compound is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease. Where recited in reference to a disease treatment, an "effective amount" may also be referred to as a "therapeutically effective amount." A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipient.
"Na-C C" means sodium carboxymethyl cellulose and can be either low density, medium density or high density CMC and mixtures thereof.
The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
"Soluplus®" refers to the solubilizer sold by BASF known as polyvinyl capralactam- polyvinyl acetate-polyethylene glycol graft copolymer (PCA-PVA-PEG).
The term "topical" in the context of methods described herein relates in the customary sense to the administration of a compound or pharmaceutical composition which is incorporated into a suitable pharmaceutical carrier and administered at a topical treatment site of a subject. Accordingly, the term "topical pharmaceutical composition" includes those pharmaceutical forms in which the compound is administered externally by direct contact with a topical treatment site, e.g., the eye or the skin. The term "topical ocular
pharmaceutical composition" refers to a pharmaceutical composition suitable for administering directly to the eye.
The terms "treating" or "treatment" refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
Some embodiments of the invention include:
1 ) A topical composition for use in lowering 10P in a patient comprising an effective amount of bimatoprost and brimonidine and a pharmaceutically acceptable carrier.
2) The composition of embodiment 1 wherein the bimatoprost is present in the
concentration range of 0.001 - 0.03 % w/w and the brimonidine is brimonidine tartrate and is present in the concentration range of 0.005 - 0.2% w/w.
3) The composition of embodiments 1 - 2 wherein the bimatoprost is present in the concentration of about 0.01 % w/w and the brimon idine is present in the amount of about 0.1 % w/w.
4) The composition of embodiments 1 - 3 wherein the composition further comprises excipients selected from the group of excipients listed in Table 1 , Table 2 and Table 3.
5) The compositions of embodiment 4 wherein the excipients are present in
concentrations at about the concentrations listed in Tables I, I I and I I I .
6) A method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering the composition of embodiment 3.
7) A method of lowering intraocular pressure or treating glaucoma in a human patient comprising adm inistering a composition of embodiments 1 - 6.
8) A method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering one of the compositions l isted in Table 1 .
9) A method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering one of the compositions listed in Table 2 or Table 3.
1 0) The method of embodiments 1 - 9 wherein the composition is administered once a day. 1 l ) The method of embodiments 1 - 9 wherein the composition is administered twice a day or more.
1 2) A topical composition for ophthalmic application for use in lowering intraocular pressure in a patient comprising about 0.01 % w/w bimatoprost and about 0. 1 % w/w brimonidine.
1 3) The composition of embodiment 12 wherein the bimatoprost is present in the
concentration of 0.01 % w/w and brimonidine is brimonidine tartrate and is present in the amount of 0. 1 % w/w in an aqueous vehicle.
14) The composit ion of embodiment 12 further comprising a solubul izer selected from the group consisting of Na-C C and Soluplus®.
1 5) The composition of embodiment 1 2 further comprising buffers selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
16) The compositions of embodiment 12 further comprising tonicity agents wherein the tonicity agents are selected from the group consisting of NaCI and glycerin.
1 7) The composition of embodiment 12 further comprising preservat ives wherein the preservatives are selected from the group consisting of benzalkoniun chloride and Purite.
1 8) The topical composition of embodiment 1 2 wherein the composition is a solution and is administered at least once a day.
1 9) The topical composition of embodiment 1 2 wherein the composition is adm inistered twice a day.
20) The topical composition of embodiments 12 - 1 7 wherein the composition is useful in treating glaucoma wherein the glaucoma is selected from the group consisting of open-angle glaucoma, closed-angle glaucoma, angle-closure glaucoma, normal- tension glaucoma, and congenital glaucoma.
21 ) The composition of embodiment 12 wherein the composition of embodiment 1 2
lowers intraocular pressure more than either bimatoprost or brimonidine administered alone and with fewer side-effects.
22) A method of treating elevated intraocular pressure the method comprising
administering a composition to a patient suffering elevated intraocular pressure wherein the composition comprises about 0.01 % w/w bimatoprost and about 0. 1 % w/w brimonidine tartrate. ) The method of embodiment 22 wherein the composition comprises 0.01 % w/w bimatoprost and 0.1 % vv/w brimonidine.
) The method of embodiment 22 wherein the composition further comprises a solubulizer selected from the group consisting of Na-CMC and Soluplus® and a buffer selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
) The method of embodiments 22 - 24 wherein the composition of claim 1 1 lowers intraocular pressure more effectively than either brimonidine monotherapy (0.2%, 0. 1 5%, or 0.1 %) or bimatoprost monotherapy (0.03% or 0.01 %).
) The method of embodiments 22- 24 wherein the composition of claim 1 1 lowers intraocular pressure more effectively than either brimonidine monotherapy or bimatoprost monotherapy and with fewer overall ocular side effects than either brimonidine and bimatoprost monotherapy.
) The method of embodiments 22 - 24 wherein the method is effective in treating glaucoma.
) The method of embodiments 22 - 24 wherein the method is effective in lower ocular hypertension.
) The method of embodiments 22 - 24 wherein the composition further comprises a preservative.
) The method of embodiments 22 - 24 wherein the composit ion is administered at least once a day.
) The method of embodiment 22 wherein the composition is applied topically to the eye.
Detailed Description of the Invention:
Table 1. Formulation Examples:
Figure imgf000007_0001
Table 1. Formulation Examples Continued:
Figure imgf000008_0001
Tabic 2. Further Formulation Exam les:
Figure imgf000008_0002
The formulations of the present invention can be topical ly administered once, twice or three times a day in order to lower intraocular pressure in a patient.
The present formulations may be preserved or preservative free. Although the concentrations of actives in Tables 1 and 2 are preferred, bimatoprost may be present in concentration ranges of 0.001 - 0.03 w/w and brimonidine may be present in 0.005 - 0.2% w/w. Concentrations of actives and excipients may be present in about the concentrations listed herein, wherein "about" refers to variations of the concentrat ions considered to be bioequivalent by the FDA or EM EA in making similar or generic compositions.
Brimonidine includes pharmaceutically acceptable salts of brimonidone such as brimonidine tartrate. Brimonidine tartrate is an alpha adrenergic agon ist represented by the following formula:
Figure imgf000009_0001
The chemical name for brimonidine is 5-Bromo-6-(2-imizazoi idinyl ideeneamno) quinoxaline L-tartrate.
Bimatoprost is represented by the following chemical structure:
Figure imgf000009_0002
Bimatoprost's chemical name is (Z)-7-[( l R,2/?;3/?,5S)-3,5-Dihydroxy-2-[( l E,3S)-3- hydroxy-5- phenyl- l -pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 41 5.58. Its molecular and its formula is C25H37NO4. Table 3. Brimonidine/Bimatoprost Fixed Dose Combination Formulations for Stability Evaluation
Formulations 1 2 3 4 5 6 7 8
Active Ingredients Bimatoprost 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 (% w/w)
Brimonidine (190342-LF) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
Solubilizers Na-C C (Low viscosity 0.5 0.5
(% w/w) 7LFPH)
Soluplus® 1 1 1
Buffers (% w/w) Sodium phosphate dibasic
0.268 0.268 0.268 0.268 0.268 0.268 heptahydrate
Citric acid monohydrate 0.014 0.014 0.014 0.014 0.014 0.014
Sodium borate decahydrate 0.095 0.095
Boric acid 0.229 0.229
Target pH 7.7 (7.4-8.0) 7.7 (7.4-8.0) 7.7 (7.4-8.0) 7.7 (7.4-8.0) 7.0 (6.7-7.3) 7.0 (6.7-7.3) 7.0 (6.7-7.3) 7.7 (7.4-8.0)
1 Sodium Hydroxide/
QS to pH QS to pH QS to pH QS to pH QS to pH QS to pH QS to pH QS to pH 1 Hydrochloric Acid
Tonicity Modifiers NaCI
0.8 0.8 0.8 0.8 0.8 0.8 (% w/w)
Glycerin 2.3 2.3
Preservatives BAK
0.005 0.02 0.01 0.003 0.01 (% w/w)
Purite 0.01 0.01
Vehicle (% w/w) Purified Water Q.S. to 100 Q.S. to 100 Q.S. to 100 Q.S. to 100 Q.S. to 100 Q.S. to 100 Q.S. to 100 Q.S. to 100
Formulation stability for the formulation shown in Table 3 was as follows:
Formulation Stability
Table 4: Potency of Brimonidine in B2 Formulations (expressed as percent of label strength) over 3 months:
Figure imgf000011_0001
Table 5: Potency of Bimatoprost in B2 Formulations (expressed as percent of label strength) over 3 months
Figure imgf000011_0002
Note: Formulation 2 and 7 that contain purite were discontinued after 1 month pull due to drug degradation . Table 6: Brimonitlinc/Biniatoprost Fixed Dose Combinalion Formulations for Rabbit PK Assessments
Figure imgf000012_0001
Tabic 7: Brimonidine and Bimatoprost in Aq ueous Humor
Figure imgf000013_0001
Examples
Example 1 - A 58 year old Caucasian male with elevated intraocular pressure ("IOP") is unresponsive to both brimonidine (0.1 5% w/v and 0.01 % w/v) and bimatoprost monotherapy (both 0.03% w/v and 0.01 % w/v) and unable to adequately control his elevated IOP. The 58 year old male administers Formulation 6, in Table 3 twice a day, once in the morning and once in the evening. Administration is 1 2 hours apart and every day. Within three days of use, the patient's IOP falls to cl in ically acceptable levels and remains at clinically acceptable levels as long as the patient applies Formula 6 twice a day.
Example 2 - a 71 year old African American female with ocular hypertension is unresponsive to both brimonidine and bimatoprost monotherapy and unable to control her IOP through the use of conventional glaucoma medications. The 7 1 year old patient administers Formulation 8, in Table 3, once each day. Within seven days of use, the patient's IOP falls to clinically acceptable levels and remains at cl inically acceptable levels for over 120 days of daily adm inistration of Formulation 8. Example 3 - A 68 year old Caucasian male with elevated intraocular pressure, open- angle glaucoma and with sensitivity to ophthalmic preservatives is administered Formulation 3 in Table 3 on a once dai ly basis. After several days of use, the patients intraocular pressure drops to therapeutically acceptable levels and stays at therapeutically acceptable levels so long as daily adm inistration of Formulation 3 is continued. After 6 months of daily use of Formulation 3, there is no further worsening of the pat ient's glaucoma and no further detectable damage to the optic nerve.
Example 4 - A 73 Hispanic female suffering ocular hypertension ranging from 1 7 - 20 mm Hg is unresponsive to commercially available brimonidine and bimatoprost monotherapy. The patient is administered Formulation 5 of Table 3 once a day and after two days the patient's intraocular pressure lowers to acceptable levels. The patient continues administering Formulation 5 every day and intraocular pressure levels remained at therapeutically acceptable levels.
By Inventors: Richard S. Graham, Chetan P Pujara, Sesha Neervannan,
Anuradha V. Gore, and Kevin S. Warner
Related Application
This application claims the benefit of U.S. Provisional Application Serial No.
61/509,666, filed July 20, 2011, the disclosure of which is hereby incorporated in its entirety herein by reference.
Field of the Invention:
The present application is directed to composition comprising combinations of brimonidine and bimatoprost useful for lowering intraocular pressure in a patient and the treatment of glaucoma.
Background of the Invention:
Topically applied formulations (defined as formulations applied to the cornea, conjunctiva, etc.) are frequently used in ophthalmology to treat acute and chronic conditions because they are considered to be safer relative to systemically delivered formulations. While topically applied formulations may not produce a high systemic exposure of the active pharmaceutical ingredient, there is still the potential for adverse events (e.g., conjunctival hyperemia) due to topical exposure. Improving the side effect profile while still maintaining and possibly improving efficacy can be accomplished via the following: 1) reduce the concentration of the API to the lowest effective dose; 2) include a second API with a mechanism of action known to minimize the adverse event of the first API; 3) Include a second API which will provide a synergistic effect thereby improving the overall efficacy; and 4) improve patient compliance by reducing the number of different medications that need to be delivered. Specifically, this invention discloses the fixed dose combination of bimatoprost and brimonidine in an appropriate formulation vehicle.
Summary of the Invention:
Formulation development approaches to meet the above criteria for
bimatoprost/brimonidine are described as follows:
1. Optimize the pH of the formulation to maximize the unionized fraction of
brimonidine in aqueous formulations;
2. Incorporation of viscosity agents in the formulation to increase solution viscosity;
1 bioavailability; and,
4. Non-aqueous based formulations.
The present invention is intended for use in patients who require more than one intraocular pressure lowering agent and/or to improve patient compliance for patients undergoing concurrent bimatoprost and brimoindine monotherapy.
"About" is defined as variations in amounts in either active compounds or excipients that would be considered bioequivalent by a regulator}' agency such as the FDA or the EMEA.
"Effective amount" An "effective amount" of a compound is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease. Where recited in reference to a disease treatment, an "effective amount" may also be referred to as a "therapeutically effective amount." A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipient.
"Na-CMC" means sodium carboxymethyl cellulose and can be either low density, medium density or high density CMC and mixtures thereof.
The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
"Soluplus®" refers to the solubilizer sold by BASF known as polyvinyl capralactam- polyvinyl acetate-polyethylene glycol graft copolymer (PCA-PVA-PEG).
The term "topical" in the context of methods described herein relates in the customary sense to the administration of a compound or pharmaceutical composition which is incorporated into a suitable pharmaceutical carrier and administered at a topical treatment site of a subject. Accordingly, the term "topical pharmaceutical composition" includes those
2 with a topical treatment site, e.g., the eye or the skin. The term "topical ocular pharmaceutical composition" refers to a pharmaceutical composition suitable for
administering directly to the eye.
The terms "treating" or "treatment" refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
Some embodiments of the invention include:
1) A topical composition for use in lowering IOP in a patient comprising an effective amount of bimatoprost and brimonidine and a pharmaceutically acceptable carrier.
2) The composition of embodiment 1 wherein the bimatoprost is present in the
concentration range of 0.001 - 0.03 % w/w and the brimonidine is brimonidine tartrate and is present in the concentration range of 0.005 - 0.2% w/w.
3) The composition of embodiments 1 - 2 wherein the bimatoprost is present in the concentration of about 0.01% w/w and the brimonidine is present in the amount of about 0.1%) w/w.
4) The composition of embodiments 1 - 3 wherein the composition further comprises excipients selected from the group of excipients listed in Table 1 , Table 2 and Table 3.
5) The compositions of embodiment 4 wherein the excipients are present in
concentrations at about the concentrations listed in Tables I, II and III.
6) A method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering the composition of embodiment 3.
7) A method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering a composition of embodiments 1 - 6.
8) A method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering one of the compositions listed in Table 1.
9) A method of lowering intraocular pressure or treating glaucoma in a human patient comprising administering one of the compositions listed in Table 2 or Table 3.
10) The method of embodiments 1 - 9 wherein the composition is administered once a day. day or more.
) A topical composition for ophthalmic application for use in lowering intraocular pressure in a patient comprising about 0.01 % w/w bimatoprost and about 0.1% w/w brimonidine.
) The composition of embodiment 12 wherein the bimatoprost is present in the concentration of 0.01% w/w and brimonidine is brimonidine tartrate and is present in the amount of 0.1 % w/w in an aqueous vehicle.
) The composition of embodiment 12 further comprising a solubulizer selected from the group consisting of Na-CMC and Soluplus®.
) The composition of embodiment 12 further comprising buffers selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
) The compositions of embodiment 12 further comprising tonicity agents wherein the tonicity agents are selected from the group consisting of NaCl and glycerin.
) The composition of embodiment 12 further comprising preservatives wherein the preservatives are selected from the group consisting of benzalkoniun chloride and Purite.
) The topical composition of embodiment 12 wherein the composition is a solution and is administered at least once a day.
) The topical composition of embodiment 12 wherein the composition is administered twice a day.
) The topical composition of embodiments 12 - 17 wherein the composition is useful in treating glaucoma wherein the glaucoma is selected from the group consisting of open-angle glaucoma, closed-angle glaucoma, angle-closure glaucoma, normal- tension glaucoma, and congenital glaucoma.
) The composition of embodiment 12 wherein the composition of embodiment 12 lowers intraocular pressure more than either bimatoprost or brimonidine administered alone and with fewer side-effects.
) A method of treating elevated intraocular pressure the method comprising
administering a composition to a patient suffering elevated intraocular pressure wherein the composition comprises about 0.01% w/w bimatoprost and about 0.1 % w/w brimonidine tartrate.
4 bimatoprost and 0.1% w/w brimonidine.
) The method of embodiment 22 wherein the composition further comprises a solubulizer selected from the group consisting of Na-CMC and Soluplus® and a buffer selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
) The method of embodiments 22 - 24 wherein the composition of claim 11 lowers intraocular pressure more effectively than either brimonidine monotherapy (0.2%, 0.15%, or 0.1%) or bimatoprost monotherapy (0.03% or 0.01%).
) The method of embodiments 22- 24 wherein the composition of claim 11 lowers intraocular pressure more effectively than either brimonidine monotherapy or bimatoprost monotherapy and with fewer overall ocular side effects than either brimonidine and bimatoprost monotherapy.
) The method of embodiments 22 - 24 wherein the method is effective in treating glaucoma.
) The method of embodiments 22 - 24 wherein the method is effective in lower ocular hypertension.
) The method of embodiments 22 - 24 wherein the composition further comprises a preservative.
) The method of embodiments 22 - 24 wherein the composition is administered at least once a day.
) The method of embodiment 22 wherein the composition is applied topically to the eye.
5 Table 1. Formulation Examples:
Figure imgf000020_0001
6 Example # 12 13 14 15
Active Ingredients % (w/w)
Bimatoprost 0.01
Brimonidine 0.1
Excipients % (w/w)
White petrolatum QS 100
Mineral Oil 30-40 5-10
Lanolin 5-15 5-15
Beeswax 10-20 10-30
ST-Wax 30 8-12 5-10
Cetyl Alcohol 5-10
Castor Oil QS 100 QS 100
Jojoba Seed Oil 5-10
Silky Wax 10 5-15
QS 100
Cyclomethicone 5-NF
5-15
Caprylic/ capric
triglyceride
5-15
Isopropyl myristate
Table 2. Further Formulation Exam les:
Figure imgf000021_0001
The formulations of the present invention can be topically administered once, twice or three times a day in order to lower intraocular pressure in a patient.
The present formulations may be preserved or preservative free. Although the concentrations of actives in Tables 1 and 2 are preferred, bimatoprost may be present in
7 w/w. Concentrations of actives and excipients may be present in about the concentrations listed herein, wherein "about" refers to variations of the concentrations considered to be bioequivalent by the FDA or EMEA in making similar or generic compositions.
Brimonidine includes pharmaceutically acceptable salts of brimonidone such as brimonidine tartrate. Brimonidine tartrate is an alpha adrenergic agonist represented by the following formula:
Figure imgf000022_0001
The chemical name for brimonidine is 5-Bromo-6-(2-imizazolidinylideeneamno) quinoxaline L-tartrate.
Bimatoprost is represented by the following chemical structure:
Figure imgf000022_0002
Bimatoprost's chemical name is (Z)-7-[(li?,2i?,3i?,55)-3,5-Dihydroxy-2-[(lE,3S)-3- hydroxy-5- phenyl-l-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular and its formula is C25H37NO4.
8 Table 3. Brimonidine/Bimatoprost Fixed Dose Combination Formulations for Stability Evaluation
Formulations 1 2 3 4 5 6 7 8
Active Ingredients Bimatoprost 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 (% w/w)
Brimonidine (190342-LF) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
Solubilizers Na-CMC (Low viscosity 0.5 0.5
(% w/w) 7LFPH)
Soluplus® 1 1 1
Buffers (% w/w) Sodium phosphate dibasic
0.268 0.268 0.268 0.268 0.268 0.268 heptahydrate
Citric acid monohydrate 0.014 0.014 0.014 0.014 0.014 0.014
Sodium borate decahydrate 0.095 0.095
Boric acid 0.229 0.229
Target pH 7.7 (7.4-8.0) 7.7 (7.4-8.0) 7.7 (7.4-8.0) 7.7 (7.4-8.0) 7.0 (6.7-7.3) 7.0 (6.7-7.3) 7.0 (6.7-7.3) 7.7 (7.4-
1 N Sodium Hydroxide/
QS to pH QS to pH QS to pH QS to pH QS to pH QS to pH QS to pH QS to 1 N Hydrochloric Acid
Tonicity Modifiers NaCI
0.8 0.8 0.8 0.8 0.8 0.8 (% w/w)
Glycerin 2.3 2.3
Preservatives BAK
0.005 0.02 0.01 0.003 0.01 (% w/w)
Purite 0.01 0.01
Vehicle (% w/w) Purified Water Q.S. to 100 Q.S. to 100 Q.S. to 100 Q.S. to 100 Q.S. to 100 Q.S. to 100 Q.S. to 100 Q.S. to 1
Formulation stability for the formulation shown in Table 3 was as follows:
Formulation Stability
Table 4: Potency of Brimonidine in B2 Formulations (expressed as percent of label strength) over 3 months:
Figure imgf000024_0001
Table 5: Potency of Bimatoprost in B2 Formulations (expressed as percent of label strength) over 3 months
Figure imgf000024_0002
Note: Formulation 2 and 7 that contain purite were discontinued after 1 month pull due to drug degradation
10 Table 6: Brimonidine/Bimatoprost Fixed Dose Combination Formulations for Rabbit PK Assessments
Figure imgf000025_0001
11 Table 7: Brimonidine and Bimato rost in A ueous Humor
Figure imgf000026_0001
Examples
Example 1 - A 58 year old Caucasian male with elevated intraocular pressure ("IOP") is unresponsive to both brimonidine (0.15% w/v and 0.01% w/v) and bimatoprost
monotherapy (both 0.03%> w/v and 0.01% w/v) and unable to adequately control his elevated IOP. The 58 year old male administers Formulation 6, in Table 3 twice a day, once in the morning and once in the evening. Administration is 12 hours apart and every day. Within three days of use, the patient's IOP falls to clinically acceptable levels and remains at clinically acceptable levels as long as the patient applies Formula 6 twice a day.
Example 2 - a 71 year old African American female with ocular hypertension is unresponsive to both brimonidine and bimatoprost monotherapy and unable to control her IOP through the use of conventional glaucoma medications. The 71 year old patient administers Formulation 8, in Table 3, once each day. Within seven days of use, the patient's IOP falls to clinically acceptable levels and remains at clinically acceptable levels for over 120 days of daily administration of Formulation 8.
12 Example 3 - A 68 year old Caucasian male with elevated intraocular pressure, open- angle glaucoma and with sensitivity to ophthalmic preservatives is administered Formulation 3 in Table 3 on a once daily basis. After several days of use, the patients intraocular pressure drops to therapeutically acceptable levels and stays at therapeutically acceptable levels so long as daily administration of Formulation 3 is continued. After 6 months of daily use of Formulation 3, there is no further worsening of the patient's glaucoma and no further detectable damage to the optic nerve.
Example 4 - A 73 Hispanic female suffering ocular hypertension ranging from 17 - 20 mm Hg is unresponsive to commercially available brimonidine and bimatoprost monotherapy. The patient is administered Formulation 5 of Table 3 once a day and after two days the patient's intraocular pressure lowers to acceptable levels. The patient continues administering Formulation 5 every day and intraocular pressure levels remained at therapeutically acceptable levels.
13

Claims

Claims:
I) A topical composition for ophthalmic application for use in lowering intraocular pressure in a patient comprising about 0.01 % w/w bimatoprost and about 0.1% w/w brimonidine.
2) The composition of claim 1 wherein the bimatoprost is present in the concentration of 0.01% w/w and brimonidine is brimonidine tartrate and is present in the amount of 0.1% w/w in an aqueous vehicle.
3) The composition of claim 2 further comprising a solubilizer selected from the group consisting of Na-CMC and Soluplus®.
4) The composition of claim 2 further comprising buffers selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
5) The compositions of claim 2 further comprising tonicity agents wherein the tonicity agents are selected from the group consisting of NaCl and glycerin.
6) The composition of claim 2 further comprising preservatives wherein the
preservatives are selected from the group consisting of benzalkoniun chloride and Purite.
7) The topical composition of claim 2 wherein the composition is a solution and is administered at least once a day.
8) The topical composition of claim 2 wherein the composition is administered twice a day.
9) The topical composition of claim 2 wherein the composition is useful in treating glaucoma wherein the glaucoma is selected from the group consisting of open-angle glaucoma, closed-angle glaucoma, angle-closure glaucoma, normal-tension glaucoma, and congenital glaucoma.
10) The composition of claim 2 wherein the composition of claim 2 lowers intraocular pressure more than either bimatoprost or brimonidine administered alone and with fewer side-effects.
I I) A method of treating elevated intraocular pressure the method comprising
administering a composition to a patient suffering elevated intraocular pressure wherein the composition comprises about 0.01 % w/w bimatoprost and about 0.1 % w/w brimonidine tartrate.
12) The method of claim 11 wherein the composition comprises 0.01% w/w bimatoprost and 0.1% w/w brimonidine .
14 13) The method of claim 11 wherein the composition further comprises a solubulizer selected from the group consisting of Na-CMC and Soluplus® and a buffer selected from the group consisting of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium borate decahydrate, sodium hydroxide and hydrochloric acid.
14) The method of claim 11 wherein the composition of claim 11 lowers intraocular pressure more effectively than either brimonidine monotherapy or bimatoprost monotherapy.
15) The method of claim 14 wherein the composition of claim 11 lowers intraocular pressure more effectively than either brimonidine monotherapy or bimatoprost monotherapy and with fewer overall ocular side effects than either brimonidine and bimatoprost monotherapy.
16) The method of claim 11 wherein the method is effective in treating glaucoma.
17) The method of claim 11 wherein the method is effective in lower ocular hypertension.
18) The method of claim 11 wherein the composition further comprises a preservative.
19) The method of claim 11 wherein the composition is administered at least once a day.
20) The method of claim 11 wherein the composition is applied topically to the eye.
15
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BR112014001118A BR112014001118A2 (en) 2011-07-20 2012-07-20 topical combination for ophthalmic application and use of bimatoprost and brimonidine
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AU2012283895A AU2012283895A1 (en) 2011-07-20 2012-07-20 Fixed dose combination of bimatoprost and brimonidine
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CA2841969A CA2841969A1 (en) 2011-07-20 2012-07-20 Fixed dose combination of bimatoprost and brimonidine
US14/235,746 US20140249153A1 (en) 2011-07-20 2012-07-20 Fixed dose combination of bimatoprost and brimonidine
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