Pharmaceutical compositions for delivering macrolides
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.
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.
5 . (Cancelled)
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.
18 - 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 . (Cancelled).
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.