Microencapsulated 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
AssigneeAlkermes Controlled Therapeutics Inc. II
InventorsJean Mesens, Michael E. Rickey, Thomas J. Atkins
Life of this patent
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Abstract
Sustained-release microparticle composition. The microparticle composition can be formulated to provide multi-phasic release. In one aspect, the composition includes microparticles having more than one rate of release. In another aspect, the composition includes microparticles that exhibit diffusional release and microparticles that exhibit biodegradation release.
Claims8
A sustained-release microparticle composition. comprising:
- a microparticle comprising a 1,2 benzazole of the formula
- 15
- and the pharmaceutically acceptable acid addition salts thereof, wherein
- R is hydrogen or alkyl of 1 to 6 carbon atoms;
- R1 and R2 are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyloxy of 1 to 6 carbon atoms, and C alkyl of 1 to 6 carbon atoms;
- X is O or S;
- Alk is C1-4 alkanediyl;
- and
- Q is a radical of formula
- 16
- wherein
- R3 is hydrogen or alkyl of 1 to 6 carbon atoms;
- Z is —S—, —CH2—, or —CR4═CR5—;
- where R4 and R5 are independently selected from the group consisting of hydrogen or alkyl of 1 to 6 carbon atoms;
- A is a bivalent radical —CH2—CH2—, —CH2—CH2—CH2— or CR6═CR7—;
- where R6 and R7 are independently selected from the group consisting of hydrogen, halo, amino or alkyl of 1 to 6 carbon atoms;
- and
- R8 is hydrogen or hydroxyl;
- and a biodegradable and biocompatible polymeric matrix that exhibits diffusional release of said 1,2 benzazole;
- and
- a microparticle comprising a 1,2 benzazole of the formula
- and the pharmaceutically acceptable acid addition salts thereof, wherein
- R is hydrogen or alkyl of 1 to 6 carbon atoms;
- R1 and R2 are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyloxy of 1 to 6 carbon atoms, and C alkyl of 1 to 6 carbon atoms;
- <X is O or S;
- Alk is C1-4 alkanediyl;
- and
- Q is a radical of formula
- 17
- wherein
- R3 is hydrogen or alkyl of 1 to 6 carbon atoms;
- Z is —S—, —CH2—, or —CR4═CR5—;
- where R4 and R5 are independently selected from the group consisting of hydrogen or alkyl of 1 to 6 carbon atoms;
- A is a bivalent radical —CH2—CH2—, —CH2—CH2—CH2— or CR6═CR7—;
- where R6 and R7 are independently selected from the group consisting of hydrogen, halo, amino or alkyl of 1 to 6 carbon atoms;
- and
- R8 is hydrogen or hydroxyl;
- and a biodegradable and biocompatible polymeric matrix that exhibits biodegradation release of said 1,2 benzazole.
The sustained-release microparticle composition of claim 21, wherein said 1,2 benzazole is selected from the group consisting of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and the pharmaceutically acceptable acid addition salts thereof.
The sustained-release microparticle composition of claim 21, wherein said 1,2 benzazole is selected from the group consisting of 3-[2-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyridol[1,2-a]pyrimidin-4-one and the pharmaceutically acceptable acid addition salts thereof.
A sustained-release microparticle composition, comprising:
- a first microparticle comprising a first active agent and a first biodegradable and biocompatible polymeric matrix, wherein said first active agent is selected from the group consisting of risperidone, 9-hydroxy-risperidone, and pharmaceutically acceptable acid addition salts of the foregoing, and wherein said first microparticle has a first rate of release of said active agent;
- and
- a second microparticle comprising a second active agent and a second biodegradable and biocompatible polymeric matrix, wherein said second microparticle has a second rate of release of said active agent different from said first rate of release.
A method of making a multi-phasic sustained-release microparticle composition, comprising:
- dissolving in a solvent an active agent and a biodegradable and biocompatible polymer to form an organic phase, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxy-risperidone, and pharmaceutically acceptable acid addition salts of the foregoing;
- extracting the solvent to form microparticles;
- and
- combining microparticles having a plurality of sizes to thereby form a composition that delivers the active agent in a multi-phasic manner.
A method of making a multi-phasic sustained-release microparticle composition, comprising:
- dissolving in a solvent an active agent and a biodegradable and biocompatible polymer to form an organic phase, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxy-risperidone, and pharmaceutically acceptable acid addition salts of the foregoing;
- extracting the solvent to form microparticles;
- and
- combining microparticles exhibiting diffusional release and microparticles exhibiting biodegradation release to thereby form a composition that delivers the active agent in a multi-phasic manner.
The sustained-release microparticle composition of claim 24, wherein said second active agent is the same as said first active agent.
The sustained-release microparticle composition of claim 24, wherein said second active agent is selected from the group consisting of risperidone, 9-hydroxy-risperidone and pharmaceutically acceptable acid addition salts of the foregoing.
Dependencies are inferred from the claim text.