Patent Application
20130023536
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.
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.
Formulation development approaches to meet the above criteria for 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.
“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 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 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 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.
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 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 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:
The chemical name for brimonidine is 5-Bromo-6-(2-imizazolidinylideeneamno) quinoxaline L-tartrate.
Bimatoprost is represented by the following chemical structure:
Bimatoprost's chemical name is (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular and its formula is C25H37NO4.
Formulation stability for the formulation shown in Table 3 was as follows:
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.
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.
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.
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.
This application claims the benefit of U.S. Provisional Application Ser. No. 61/509,666, filed Jul. 20, 2011, the disclosure of which is hereby incorporated in its entirety herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 61509666 | Jul 2011 | US |
