Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use

• US 20040013704A1
• Filed: 06/30/2003
• Published: 01/22/2004
• Est. Priority Date: 07/15/2002
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Alcon Incorporated
• Inventors: Kabra, Bhagwati P., Howie, Janet D.
• Granted Patent: US 7,678,827 B2
• Time in Patent Office: Days
• US Class Current: 424/427
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

Solid or semi-solid intraocular implant compositions are disclosed. The compositions contain a lipophilic compound but lack a polymeric ingredient.

Claims

1. An intraocular implant composition comprising a lipophilic compound having a molecular weight of 150-4000 and a pharmaceutically effective amount of a drug, but lacking a polymeric ingredient and an organic solvent that is miscible with or dispersible in water, wherein the composition is solid or semi-solid at temperatures ≦

37°

C. and the lipophilic compound is of the formula

2. The intraocular implant composition of claim 1 wherein the composition is solid or semi-solid at temperatures ≦

34°

C.

3. The intraocular implant composition of claim 1 wherein the molecular weight of the lipophilic compound of formula (I) is ≦

2000.

4. The intraocular implant composition of claim 3 wherein the molecular weight of the lipophilic compound of formula (I) is ≦

1000.

5. The intraocular implant composition of claim 1 wherein the composition comprises a mixture of two or more lipophilic compounds of formula (I).

6. The intraocular implant composition of claim 1 wherein the lipophilic compound of formula (I) has a melting point ≧

34°

C.

7. The intraocular implant composition of claim 5 wherein at least one lipophilic compound of formula (I) has a melting point <

34°

C. but the mixture has a melting point ≧

34°

C.

8. The intraocular implant composition of claim 1 wherein

R¹ is, —

C_nH_2n+1-2m, —

COOC_nH_2n+1-2m, —

COO(CH₂CH₂O)_nCH₂CH₂OH, —

CH₂R³, or

R^2, R³ and R⁴ are independently —

H, —

OH, —

COOH, —

C_nH_2n+1-2m, —

OOCC_nH_2n+1-2m, —

COOC_nH_2n+1-2m, —

COO(CH₂CH₂O)_nCH₂CH₂OH, —

C_nH_2n+1-2mCOO(CH₂CH₂O)_nCH₂CH₂OH, or —

OOCC_nH_2n+1-2mCOOC_n′

H<sub>2n′

+1-2m′</sub>

;

n, n′ and

n″

are independently 0-40; and

m, m′ and

m″

are independently 0-5.

9. The intraocular implant composition of claim 8 wherein

R¹ is

R^2, R³ and R⁴ are independently —

H, —

OH, —

COOH, —

C_nH_2n+1-2m, or —

OOCC_nH_2n+1-2m;

n, n′ and

n″

are independently 0-30; and

m, m′ and

m″

are independently 0-3.

10. The intraocular implant composition of claim 1 wherein the lipophilic compound of formula (I) is selected from the group consisting of diethylene glycol monostearate;

propylene glycol monostearate;

glyceryl monostearate;

glyceryl monolinoleate;

glyceryl monooleate;

glyceryl monopalmitate; and

mixtures thereof.

11. The intraocular implant composition of claim 1 wherein the lipophilic compound of formula (I) is selected from the group consisting of:

glyceryl monolaurate;

glyceryl dilaurate;

glyceryl monomyristate;

glyceryl dimyristate;

glyceryl monopalmitate;

glyceryl dipalmitate;

glyceryl monostearate;

glyceryl distearate;

glyceryl monooleate;

glyceryl dioleate;

glyceryl monolinoleate;

glyceryl dilinoleate;

glyceryl monoarachidate;

glyceryl diarachidate;

glyceryl monobehenate; and

glyceryl dibehenate.

12. The intraocular implant composition of claim 1 wherein the composition comprises at least 10% (wt.) of the lipophilic compound of formula (I).

13. The intraocular implant composition of claim 12 wherein the composition comprises at least 30% (wt.) of the lipophilic compound of formula (I).

14. The intraocular implant composition of claim 13 wherein the composition comprises at least 50% (wt.) of the lipophilic compound of formula (I).

15. The intraocular implant composition of claim 1 wherein the drug is selected from the group consisting of anti-glaucoma agents;

anti-infective agents;

non-steroidal and steroidal anti-inflammatory agents;

growth factors;

immunosuppressant agents;

neuroprotectant agents;

angiogenesis-inhibiting agents and anti-allergy agents.

16. The intraocular implant composition of claim 1 wherein the composition further comprises one or more excipients selected from the group consisting of surfactants, preservatives, and stabilizers.

17. The intraocular implant composition of claim 16 wherein the composition comprises a surfactant selected from the group consisting of tyloxapol;

polysorbate 20;

polysorbate 60; and

polysorbate 80.

18. The intraocular implant composition of claim 16 wherein the composition comprises a preservative selected from the group consisting of quaternary ammonium preservatives.

19. The intraocular implant composition of claim 16 wherein the composition comprises a stabilizer selected from the group consisting of chelating agents;

and antioxidants.

20. The intraocular implant composition of claim 1 wherein the composition is fashioned into a cylindrical, conical and spherical shape.

21. A method of delivering an ophthalmically acceptable drug to the eye comprising the steps of

(a) preparing an intraocular implant composition comprising a lipophilic compound having a molecular weight of 150-4000 and a pharmaceutically effective amount of a drug, but lacking a polymeric ingredient and an organic solvent that is miscible with or dispersible in water, wherein the composition is solid or semi-solid at temperatures ≦

34°

C. and the lipophilic compound is of the is formula

 

wherein

R¹ is —

H, —

OH, —

COOH, —

C_nH_2n+1-2m, —

COOC_nH_2n+1-2m, —

COO(CH₂CH₂O)_nCH₂CH₂OH, —

CH₂R³, or

R^2, R³ and R⁴ are independently —

H, —

OH, —

COOH, —

C_nH_2n+1-2m, —

OOCC_nH_2n+1-2m, —

COOC_nH_2n+1-2m, —

COO(CH₂CH₂O)_nCH₂CH₂OH, —

C_nH_2n+1-2mCOO(CH₂CH₂O)_nCH₂CH₂OH, —

OOCC_nH_2n+1-2mCOOC_n′

H_2n+1-2m′

, —

COO⁻

Na⁺, —

COO⁻

K⁺, —

SO₃H, —

SO₃⁻

Na⁺, —

SO₃⁻

K⁺, —

NH₂, —

Cl,

n, n′ and

n″

are independently 0-50; and

m, m′ and

m″

are independently 0-10; and

(b) implanting the composition prepared in step (a) in the eye.

22. The method of claim 21 wherein in step (b) the composition prepared in step (a) is implanted in a site selected from the group consisting of the conjunctival cul-de-sac;

punctum;

lacrimal canaliculus;

anterior segment;

posterior segment;

sub-Tenon'"'"'s space;

suprachoroidal space; and

subconjunctival space.

23. The method of claim 21 wherein the composition is warmed to a temperature above room temperature and administered through a cannula.

24. The method of claim 21 wherein the composition is administered as a solid or semi-solid.

25. The method of claim 21 wherein the intraocular implant composition of step (a) is suspended in a liquid carrier and implanted in the eye in step (b) by administration through a cannula.