Injectable suspension comprising 3-beta-hydroxy-5-alpha-pregnan-20-one, and a method for the manufacturing thereof
The present invention relates to aseptic suspensions, physically stable and injectable through a 25G 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 process of manufacturing non-micronized crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles, 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.
2. The process according to claim 1 , wherein said organic solvent solution is a tetrahydrofuran solution.
3. The process according to claim 1 , comprising the additional step of grating and sieving the crystalline 3-beta-hydroxy-5-alpha-pregnan-20-one particles obtained in step (iii).
4. The process according to claim 1 , wherein said tetrahydrofuran solution has water content of from 0.5% to 1.5% (v/v).
5. The process according to claim 4 , wherein said tetrahydrofuran solution with water content is held at a temperature of about 50° C.
6. The process according to claim 1 , wherein said liquid alkane is held at a temperature of from −10° C. to −20° C.
7. The process according to claim 1 , wherein said liquid alkane is liquid heptane.
8. A method of manufacturing a sterile suspension injectable through a 25G needle or thinner, comprising crystalline, non-micronized 3-beta-hydroxy-5-alpha-pregnan-20-one particles; mixture of acylglycerols; and cholesterol; 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 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-beta-hydroxy-5-alpha-pregnan-20-one particles and mixing for 24 hours, or less; and
filling sterile syringe barrels with the obtained suspension.
9. The method according to claim 8 , wherein said crystalline, 3-beta-hydroxy-5-alpha-pregnan-20-one particles are manufactured by a process comprising the steps of:
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.