Pharmaceutical compositions for delivering macrolides

• US 20050049209A1
• Filed: 07/20/2004
• Published: 03/03/2005
• Est. Priority Date: 08/06/2003
• Status: Abandoned Application

• Current Assignee: SD Pharmaceuticals, Inc. (Savara, Inc.)
• Original Assignee: SD Pharmaceuticals, Inc. (Savara, Inc.)
• Inventors: Chen, Andrew Xian
• Application Number:
  US10/895,018
• Publication Number:
  US 20050049209A1
• Time in Patent Office: Days
• US Class Current: 514/28
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 31/04 Antibacterial agents

Abstract

The present invention provides injectable macrolide oil-in-water emulsions and lyophilized formulations thereof. The present invention also provides methods for preparing and using such oil-in-water emulsions and lyophilized formulations thereof.

Claims

1. An injectable oil-in-water emulsion comprising:

(a) a macrolide at a concentration of at least about 0.5% by weight,

(b) a vegetable oil at a concentration of at most 10% by weight,

(c) one or more phospholipids at a total concentration between about 1.2% to about 5% by weight, and

(d) water.

2. The injectable oil-in-water emulsion of claim 1 further comprising a medium chain triglyceride, wherein

(i) the total concentration of the vegetable oil and the medium chain triglyceride is at most 10% by weight, and

(ii) the weight ratio of the vegetable oil to the medium chain triglyceride is between about 9:

1 to about 1;

1.

3. The injectable oil-in-water emulsion of claim 1 wherein the macrolide is clarithromycin having the structure:

4. The injectable oil-in-water emulsion of claim 1 wherein the macrolide is at a concentration of about 2.5% by weight.

6. The injectable oil-in-water emulsion of claim 2 wherein the medium chain triglyceride is Miglyol 812, Crodamol GTCC-PN, or Neobees M-5 oil.

7. The injectable oil-in-water emulsion of claim 1 wherein the phospholipid is soy lecithin or egg lecithin.

8. The injectable oil-in-water emulsion of claim 1 further comprising a stabilizer.

9. The injectable oil-in-water emulsion of claim 8 wherein the stabilizer is glycine.

10. The injectable oil-in-water emulsion of claim 9 wherein the concentration of glycine is between about 0.1% and about 5% by weight.

11. The injectable oil-in-water emulsion of claim 8 wherein the stabilizer is ethylene diamine-tetraacetic acid (EDTA).

12. The injectable oil-in-water emulsion of claim 11 wherein the concentration of EDTA is between about 0.001% and about 0.01% by weight.

13. The injectable oil-in-water emulsion of claim 1 further comprising a tonicity modifier.

14. The injectable oil-in-water emulsion of claim 13 wherein the tonicity modifier is glycerol.

15. The injectable oil-in-water emulsion of claim 14 wherein the concentration of glycerol is between about 0.5% and about 2.5% by weight.

16. The injectable oil-in-water emulsion of claim 1 wherein the average size of the oil droplets in the emulsion is less than about 250 nm.

17. The injectable oil-in-water emulsion of claim 1 wherein the average size of the oil droplets in the emulsion does not increase more than 25% after storage at about 2-8°

C. for 6 months.

49. A lyophilized formulation of a macrolide, wherein the formulation, when hydrated, produces the injectable oil-in-water emulsion according to claim 1.

50. The lyophilized formulation of claim 49 wherein the lyophilized formulation is reconstituted in a liquid medium to produce a reconstituted emulsion, and wherein the average droplet size of the reconstituted emulsion is no more than 200% of the average droplet size of the emulsion before lyophilization.

5. (Cancelled)

18-23. -23. (Cancelled).

24. An injectable oil-in-water emulsion, comprising:

(a) a macrolide at a therapeutically effective concentration,

(b) a vegetable oil,

(c) a phospholipid, and

(d) water,

wherein the emulsion does not cause vein irritation and is stable for at least 3 months.

25. The injectable oil-in-water emulsion of claim 24 further comprising a medium chain triglyceride.

26-48. -48. (Cancelled).