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US 12,599,562 B2Granted
Nanocrystal microparticles of poorly soluble drugs and methods of production and use thereof
AssigneeThe Board of Regents of the University of Oklahoma
InventorsLucila Garcia-Contreras, Sevim Manolya Hatipoglu, Doris Mangiaracina Benbrook
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Abstract
Microparticulate drug compositions comprising nanocrystals of poorly soluble drugs combined with a carrier are disclosed. Also disclosed are pharmaceutical compositions that include the microparticulate drug compositions. Further disclosed are methods of preparing and using the microparticulate drug compositions/pharmaceutical compositions.
Claims17
A method of producing a pharmaceutical composition comprising a dry powder formulation of a microparticulate drug composition, the method comprising the steps of:
- producing by controlled precipitation a batch of nanocrystals consisting of a poorly soluble drug, wherein the controlled precipitation of the nanocrystals is performed by:
- (1) providing the poorly soluble drug dissolved in an organic solvent at a drug concentration in a range of from about 30 mg/ml to about 75 mg/ml, wherein the organic solvent is miscible in an aqueous solvent,
- (2) combining the poorly soluble drug dissolved in the organic solvent with an aqueous solvent to form a mixture,
- (3) sonicating the mixture at a sonication power density in a range of 0.5-5.0 Watts/Liter, a frequency of 10-100 Hz, and an amplitude of 10-80% for a time in a range of from about 20 minutes to about 90 minutes, and
- (4) ultrasonicating the mixture for a time in a range of from about 10 minutes to about 60 minutes,
- wherein the poorly soluble drug is a heteroarotinoid or cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, wherein the nanocrystals thereby formed have an average geometric diameter of less than about 0.2 μm, and wherein a micronization method is not used in the production of the nanocrystals;
- dispersing the batch of nanocrystals into a carrier solution consisting of a carrier and an aqueous solvent, thereby forming a nanocrystal/carrier suspension having a feed concentration in a range of from about 0.10% to about 2% nanocrystals, and a carrier ratio in a range of from about 10% to about 75%;
- and
- spray drying the nanocrystal/carrier suspension at a spray drying temperature in a range of from about 80° C. to about 130° C. to form a microparticulate drug composition, wherein the microparticulate drug composition comprises microparticles consisting of the nanocrystals dispersed in the carrier, wherein the microparticles have an average geometric diameter in a range of about 1 μm to about 500 μm, and wherein the microparticles have a dissolution rate that is at least about 5-fold higher than that of an unprocessed form of the poorly soluble drug and at least about 2-fold higher than that of microparticles comprising an amorphous form of the poorly soluble drug, that consist of the poorly soluble drug.
6 more elements
A method of producing a pharmaceutical composition comprising a dry powder formulation of a microparticulate drug composition, the method comprising the steps of:
- producing by controlled precipitation a batch of nanocrystals consisting of a poorly soluble drug, wherein the controlled precipitation of the nanocrystals is performed by:
- (1) providing the poorly soluble drug dissolved in an organic solvent at a drug concentration in a range of from about 30 mg/ml to about 75 mg/ml, wherein the organic solvent is miscible in an aqueous solvent,
- (2) combining the poorly soluble drug dissolved in the organic solvent with an aqueous solvent to form a mixture,
- (3) sonicating the mixture at a sonication power density in a range of 0.5-5.0 Watts/Liter, a frequency of 10-100 Hz, and an amplitude of 10-80% for a time in a range of from about 20 minutes to about 90 minutes, and
- (4) ultrasonicating the mixture for a time in a range of from about 10 minutes to about 60 minutes,
- wherein the poorly soluble drug is a heteroarotinoid or cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, wherein the nanocrystals thereby formed have an average geometric diameter of less than about 0.2 μm, and wherein a micronization method is not used in the production of the nanocrystals;
- dispersing the batch of nanocrystals into a carrier solution consisting of a carrier and an aqueous solvent, thereby forming a nanocrystal/carrier suspension having a feed concentration in a range of from about 0.10% to about 2% nanocrystals, and a carrier ratio in a range of from about 10% to about 75%;
- and
- spray drying the nanocrystal/carrier suspension at a spray drying temperature in a range of from about 80° C. to about 130° C. to form a microparticulate drug composition, wherein the microparticulate drug composition comprises microparticles consisting of the nanocrystals dispersed in the carrier, wherein the microparticles have an average geometric diameter in a range of about 1 μm to about 500 μm, and wherein the microparticles have a dissolution rate that is at least about 5-fold higher than that of an unprocessed form of the poorly soluble drug and at least about 2-fold higher than that of microparticles comprising an amorphous form of the poorly soluble drug, that consist of the poorly soluble drug;
- and
- wherein the pharmaceutical composition is in the form of a capsule or tablet.
8 more elements
Dependencies are inferred from the claim text.