JP2003252751A5 - - Google Patents

Claims (28)

A method for producing a microsphere with improved dispersibility, comprising adding an osmotic pressure regulator to an outer aqueous phase when producing the microsphere by an underwater drying method. The process according to claim 1, wherein the improved dispersibility is such that about 400 to about 700 mg of microspheres can be dispersed in 1.5 mL of injectable dispersion medium in less than 2 minutes. The production method according to claim 1, wherein a W / O / W emulsion is used for the underwater drying method. The production method according to claim 3, further comprising a drug-retaining substance in the inner aqueous phase. The production method according to claim 1, wherein an O / W emulsion is used for the underwater drying method. The process according to claim 1, wherein an S / O / W emulsion is used for the underwater drying method. Contains an osmotic pressure regulator, a W / O emulsion containing a liquid containing a physiologically active substance or a salt thereof as an inner aqueous phase and a lactic acid polymer having a weight average molecular weight of 15,000 to 50,000 or a salt thereof as an oil phase. A method for producing microspheres, characterized by being dispersed in an outer aqueous phase and subjected to an underwater drying method. The production method according to claim 7, wherein the content of the polymer having a weight average molecular weight of 5000 or less in the lactic acid polymer or a salt thereof is about 10% by weight or less. The production method according to claim 7, wherein the content of the polymer having a weight average molecular weight of 5000 or less in the lactic acid polymer or a salt thereof is about 5% by weight or less. The production method according to claim 7, wherein the content of the polymer having a weight average molecular weight of 3000 or less in the lactic acid polymer or a salt thereof is about 1.5% by weight or less. The production method according to claim 7, wherein the content of the polymer having a weight average molecular weight of 1000 or less in the lactic acid polymer or a salt thereof is about 0.1% by weight or less. The process according to claim 7, wherein the lactic acid polymer or a salt thereof has a weight average molecular weight of 15,000 to 40,000. The production method according to claim 7, wherein the lactic acid polymer or a salt thereof has a weight average molecular weight of 17000 to 26000. The production method according to claim 1 or 7, wherein the osmotic pressure regulator is an alcohol, a saccharide, an amino acid, a peptide, a protein, a salt of a water-soluble amino acid, a derivative thereof, or a mixture thereof. The production method according to claim 1 or 7, wherein the osmotic pressure regulator is mannitol. The method according to claim 1 or 7, wherein the concentration of the osmotic pressure regulator in the outer aqueous phase is such that the osmotic pressure of the outer aqueous phase is about 1/50 to about 5 times the osmotic pressure of physiological saline. The production method according to claim 7, wherein the physiologically active substance is a water-soluble physiologically active substance. The method according to claim 7, wherein the physiologically active substance is a physiologically active peptide. The method according to claim 7, wherein the physiologically active substance is an LH-RH derivative. LH-RH derivative is formula
5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z
[Wherein Y represents DLeu, DAla, DTrp, DSer (tBu), D2Nal or DHis (ImBzl), and Z represents NH—C ₂ H ₅ or Gly-NH ₂ . The production method according to claim 7, which is a peptide represented by the formula: A microsphere obtained by the production method according to claim 1 or 7. A sustained release composition comprising the microsphere according to claim 21. The sustained-release composition according to claim 22, which is used for the prevention, treatment or contraception of prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids, uterine fibroma, precocious puberty, dysmenorrhea or breast cancer. The sustained release composition according to claim 22, which is for injection. The sustained-release composition according to claim 22, further comprising mannitol. The sustained-release composition according to claim 22, comprising about 70% by weight or more of microspheres based on the whole composition. In order to produce microspheres with improved dispersibility, an osmotic pressure regulator is present in the outer aqueous phase when an emulsion containing a physiologically active substance or a salt thereof and a polymer is dried in water. And how to. Use of an osmotic pressure regulator in an outer aqueous phase when an emulsion containing a physiologically active substance or a salt thereof and a polymer is dried in water to produce microspheres with improved dispersibility.