Ophthalmic formulation with novel gum composition

• US 20030232089A1
• Filed: 02/20/2003
• Published: 12/18/2003
• Est. Priority Date: 02/22/2002
• Status: Active Grant

• Current Assignee: Pharmacia Corporation (Pfizer Inc.)
• Original Assignee: Pharmacia Corporation (Pfizer Inc.)
• Inventors: Singh, Satish K., Bandyopadhyay, Paramita
• Granted Patent: US 7,128,928 B2
• Time in Patent Office: Days
• US Class Current: 424/488
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

There is provided a pharmaceutical composition suitable for topical administration to an eye, the composition comprising (a) a pharmacologically effective concentration of an active agent and (b) a combination of at least two ophthalmically compatible polymers comprising a novel gum system. In preferred embodiments of the present invention, the compositions increase the retention time of the active agent in the eye, when compared to compositions with other gums or gum systems.

Claims

1. A pharmaceutical composition suitable for topical administration to an eye, comprising:

(a) a pharmacologically effective concentration of an active agent; and

(b) a set of at least two ophthalmically compatable polymers selected from the group consisting of konjac, scleroglucan, hydroxypropyl guar, propylene glycol alginate, sodium alginate, Carbopol, pectin, agarose hydroxypropylmethyl cellulose, and derivatives thereof.

2. The pharmaceutical composition of claim 1, wherein the set of at least two ophthalmically compatable polymers is selected from the group consisting of:

konjac and sodium alginate;

konjac and hydroxy propyl guar;

konjac and propylene glycol alginate;

konjac and Carbopol 971;

konjac and sodium alginate;

hydroxy propyl guar and agarose;

propylene glycol alginate and agarose;

propylene glycol alginate and scleroglucan;

propylene glycol alginate and agarose; and

scleroglucan and hydroxypropylmethyl cellulose.

3. The composition of claim 1, wherein the active agent is a steroid.

4. The composition of claim 1, wherein the active agent is an NSAIDS compound.

5. The composition of claim 1, wherein the active agent is an oxazolidinone antibiotic drug.

6. The composition of claim 5 wherein the oxazolidinone antibiotic drug of a compound of formula (I):

7. The composition of claim 6 wherein, in formula (I), R¹ is CH₃;

R² and R³ are independently selected from H and F but at least one of R² and R³ is F;

R⁴ and R⁵ are each H;

n is 1; and

X is selected from O, S and SO₂.

8. The composition of claim 5 wherein the oxazolidinone antibiotic drug is selected from the group consisting of:

linezolid, eperezolid, N-((5S)-3-(3-fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide, (S)-N-[[3-[5-(3-pyridyl)thiophen-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide, (S)-N-[[3-[5-(4-pyridyl)pyrid-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride and N-[[(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-5-oxazoldinyl]methyl]acetamide.

9. The composition of claim 5 wherein the oxazolidinone antimicrobial drug is linezolid.

10. The composition of claim 1, further comprising a cyclodextrin compound in a concentration sufficient to ensure that essentially all of the active agent in the composition is in solution.

11. The composition of claim 10 wherein the cyclodextrin compound is selected from the group consisting of α

-cyclodextrin, β

-cyclodextrin, γ

-cyclodextrin, an alkylcyclodextrin, a hydroxyalkylcyclodextrin, a carboxyalkylcyclodextrin, and sulfoalkylether cyclodextrin.

12. The composition of claim 10 wherein the cyclodextrin compound is selected from the group consisting of hydroxypropyl-β

-cyclodextrin and sulfobutylether-β

-cyclodextrin.

13. The composition of claim 10 wherein the cyclodextrin concentration is about 1 mg/ml to about 500 mg/ml.

14. The composition of claim 1, wherein the set of at least two ophthalmically compatible polymers reduces the rate of removal of the composition from the eye by lacrimation, such that a concentration of the active agent in lacrimal fluid of the eye is maintained above the MIC₉₀ for at least about 2 hours following topical application to the eye.

15. A method of treating and/or preventing a disease or infection in a an eye of a warm-blooded subject, the method comprising administering to the eye of the subject a therapeutically or prophylactically effective amount of the composition of claim 1.

16. A method of use of a composition of claim 1 in manufacture of a medicament for topically treating or preventing a disease or infection of an eye of a warm-blooded subject.

17. A pharmaceutical composition suitable for topical administration to an eye, comprising:

(a) an oxazolidinone antimicrobial drug in a concentration effective for treatment and/or prophylaxis of a gram-positive bacterial infection of at least one tissue of the eye;

(b) a pharmaceutically acceptable cyclodextrin compound in a cyclodextrin concentration sufficient to maintain the linezolid in solution; and

(c) a set of at least two ophthalmically compatible polymers selected from the group consisting of konjac, scleroglucan, hydroxypropyl guar, propylene glycol alginate, sodium alginate, Carbopol, pectin, hudroxypropylmethyl cellulose, agarose, and derivatives thereof.

18. The pharmaceutical composition of claim 17, wherein the set of at least two ophthalmically compatible polymers is selected from the group consisting of:

konjac and sodium alginate;

konjac and hydroxy propyl guar;

konjac and propylene glycol alginate;

konjac and Carbopol 971;

konjac and sodium alginate;

hydroxy propyl guar and agarose;

propylene glycol alginate and agarose;

propylene glycol alginate and scleroglucan;

propylene glycol alginate and agarose; and

scleroglucan and hydroxypropylmethyl cellulose.

19. The composition of claim 17 wherein the oxazolidinone antibiotic drug of a compound of formula (I):

20. The composition of claim 19 wherein, in formula (I), R¹ is CH₃;

R² and R³ are independently selected from H and F but at least one of R² and R³ is F;

R⁴ and R⁵ are each H;

n is 1; and

X is selected from O, S and SO₂.

21. The composition of claim 19 wherein the oxazolidinone antibiotic drug is selected from the group consisting of:

linezolid, eperezolid, N-((5S)-3-(3-fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide, (S)-N-[[3-[5-(3-pyridyl)thiophen-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide, (S)-N-[[3-[5-(4-pyridyl)pyrid-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride and N-[[(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.

22. The composition of claim 19 wherein the oxazolidinone antimicrobial drug is linezolid.

23. The composition of claim 22, wherein the linezolid concentration is about 0.01 mg/ml to about 100 mg/ml.

24. The composition of claim 17 wherein the cyclodextrin compound is selected from the group consisting of β

-cyclodextrin, β

-cyclodextrin, β

-cyclodextrin, an alkylcyclodextrin, a hydroxyalkylcyclodextrin, a carboxyalkylcyclodextrin, and sulfoalkylether cyclodextrin.

25. The composition of claim 17 wherein the cyclodextrin compound is selected from the group consisting of hydroxypropyl-β

-cyclodextrin and sulfobutylether-β

-cyclodextrin.

26. The composition of claim 17 wherein the cyclodextrin compound is present at a concentration of about 1 mg/ml to about 500 mg/ml.