Injectable Suspensions
The present invention relates to aseptic suspensions, physically stable and injectable through a 25 G needle or thinner, comprising crystalline, non-micronized 3-beta-hydroxy-5-alpha-pregnan-20-one particles, a mixture of acylglycerols and cholesterol, processes for preparing crystalline, non-micronized, 3-beta-hydroxy-5-alpha-pregnan-20-one suitable for such suspensions, as well as methods for manufacturing such suspensions.
1 . A sterile, pharmaceutical, physically stable and injectable suspension, injectable through a 25 G needle or thinner, comprising the following components:
non-micronized, sterile, crystalline, 3-beta-hydroxy-5-alpha-pregnan-20-one particles;
mixture of acylglycerols; and
cholesterol;
wherein said suspension is prepared by mixing said components under aseptic conditions within 24 hours or less.
2 . The suspension according to claim 1 , wherein said needle is a 27 G needle, or thinner.
3 . The suspension according to claim 1 , wherein the concentration of said 3-beta-hydroxy-5-alpha-pregnan-20-one is 10 mg/mL, or higher.
4 . The suspension according to claim 1 , wherein said suspension remains injectable after at least 12 months of storage without resuspending the suspension and with full or near full recovery of dose.
5 . (canceled)
6 . The suspension according to claim 1 , wherein said mixture of acylglycerols comprises comprises a medium-chain acylglycerol, sesame oil, or a mixture of a medium-chain acylglycerol and sesame oil.
7 . The suspension according to claim 6 , wherein said medium-chain acylglycerol is a medium chain triglyceride (MCT).
8 . (canceled)
9 . (canceled)
10 . The suspension according to claim 1 , wherein the amount of cholesterol is 0.1-2.5%.
11 . (canceled)
12 . A pre-filled syringe equipped with a 27 G needle, or thinner, comprising a suspension according to claim 1 .
13 . Crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles, produced by the method comprising:
(i) dissolving 3-beta-hydroxy-5-alpha-pregnan-20-one in an organic solvent solution with a water content of at least 0.1% (v/v), at a temperature of at least 45° C.;
(ii) adding the solution of step (i) into liquid alkane at a temperature of 10° C. or lower, and stirring said solution mixture to obtain precipitation of crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one; followed by;
(iii) filtering and drying the precipitated crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one obtained in step (ii); wherein any micronization step of said crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles is omitted.
14 . Crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles according to claim 13 , wherein said organic solvent solution is a tetrahydrofuran solution.
15 . Crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles according to claim 13 , comprising the additional step of grating and/or sieving the crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles obtained in step (iii).
16 . Crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles according to claim 13 , wherein said tetrahydrofuran solution has water content of from 0.5% to 1.5% (v/v).
17 . Crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles according to claim 16 , wherein said tetrahydrofuran solution with water content is held at a temperature of about 50° C.
18 . Crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles according to claim 13 , wherein said liquid alkane is held at a temperature of from −10° C. to −20° C.
19 . Crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles according to claim 13 , wherein said liquid alkane is liquid heptane.
20 . A sterile, pharmaceutical, physically stable and injectable suspension, injectable through a 25 G needle or thinner, comprising the following components:
sterile, crystalline, non-micronized 3-beta-hydroxy-5-alpha-pregnan-20-one particles;
mixture of acylglycerols; and
cholesterol;
wherein said suspension is prepared by a process comprising the steps of:
sterilizing crystalline, non-micronized 3-beta-hydroxy-5-alpha-pregnan-20-one particles with gamma irradiation;
mixing the mixture of acylglycerols with the cholesterol and stirring until the cholesterol is completely dissolved in the mixture of acylglycerols;
filtering the mixture of acylglycerols/cholesterol mixture aseptically into a sterile vessel, adding said sterilized 3-bet-hydroxy-5-alpha-pregnan-20-one particles, and mixing for 24 hours or less to form a suspension.
21 . (canceled)
22 . (canceled)