# US 12,599,562 B2 · Nanocrystal microparticles of poorly soluble drugs and methods of production and use thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,599,562 B2 - Document ID: US12599562B2 - Status: Granted - Kind: B2 - Application number: 18/145,334 - Filed: 2022-12-22 - Published: 2023-05-04 - Granted: 2026-04-14 - Earliest claimed: 2017-11-09 - Assignees: The Board of Regents of the University of Oklahoma - Applicants: The Board of Regents of the University of Oklahoma - Inventors: Lucila Garcia-Contreras; Sevim Manolya Hatipoglu; Doris Mangiaracina Benbrook - Web page: https://patentgrep.com/patent/US12599562B2 ## CPC - A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles} - A61K 9/1682: {Processes} - A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules} - A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates} - A61K 31/382: having six-membered rings, e.g. thioxanthenes (thiothixene A61K31/496) - A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles - A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone - A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine - A61K 31/502: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine - A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems - A61K 31/506: not condensed and containing further heterocyclic rings - A61K 31/519: ortho- or peri-condensed with heterocyclic rings - A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## 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. ## Claims ### Claim 1 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. ### Claim 2 (depends on 1) The method of claim 1, wherein at least one of: the frequency is in a range of about 50 Hz to about 60 Hz; the feed concentration is in a range of about 0.45% to about 0.75% nanocrystals; the carrier ratio is in a range of about 30% to about 50%; and/or the spray drying temperature is in a range of about 100° C. to about 120° C. ### Claim 3 (depends on 1) The method of claim 1, wherein at least one of: the mixture is sonicated for a time in a range of about 30 minutes to about 60 minutes; and/or the mixture is ultrasonicated for a time in a range of about 20 minutes to about 40 minutes. ### Claim 4 (depends on 1) The method of claim 1, wherein the microparticles comprise a ratio of the average volume diameter to the average geometric diameter in a range of about 1 to about 3. ### Claim 5 (depends on 1) The method of claim 1, wherein the carrier is a highly-soluble sugar. ### Claim 6 (depends on 1) The method of claim 1, wherein the heteroarotinoid is selected from SHetA2, SHetA3, SHetA4, SHetC2, SHetD3, SHetD4, SHetD5, SHet50, SHet65, SHet100, OHet72, NHet17, NHet86, and NHet90. ### Claim 7 (depends on 1) The method of claim 1, wherein the CDK4/6 inhibitor is selected from Palbociclib, Abemaciclib, Ribociclib, and ON123300. ### Claim 8 (depends on 1) The method of claim 1, wherein the aqueous solvent is water. ### Claim 9 (depends on 1) The method of claim 1, wherein the pharmaceutical composition is formulated for administration as a dry powder aerosol. ### Claim 10 (depends on 1) The method of claim 1, wherein the microparticles have an average geometric diameter in a range of about 1 μm to 40 about μm. ### Claim 11 (depends on 9) The method of claim 9, wherein the method further comprises disposing the pharmaceutical composition in an inhaler for pulmonary delivery of the pharmaceutical composition. ### Claim 12 (depends on 11) The method of claim 11, wherein the microparticles have an average geometric size that enables the pharmaceutical composition to target and be deposited in an alveolar region of at least one lung. ### Claim 13 (depends on 1) The method of claim 1, wherein the microparticles have an average geometric diameter in a range of about 50 μm to 500 about μm. ### Claim 14 (depends on 1) The method of claim 1, wherein the pharmaceutical composition is in the form of a capsule or tablet. ### Claim 15 (depends on 14) The method of claim 14, wherein at least one of: the pharmaceutical composition is packaged in a gelatin capsule; the pharmaceutical composition is combined with a methyl cellulose to produce the tablet; and/or the method further comprises the use of at least one compression process to produce the tablet. ### Claim 16 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. ### Claim 17 (depends on 16) The method of claim 16, wherein the microparticles have an average geometric diameter in a range of about 50 μm to 500 about μm.