Nanocrystal microparticles of poorly soluble drugs and methods of production and use thereof

#One of the main challenges in the treatment of lung diseases such as tuberculosis, cancer, and fungal infections is the poor water solubility of some of the most effective therapeutic compounds to treat these diseases, which causes low oral bioavailability of these therapeutic compounds. As a result, higher doses of these compounds must be used to treat these conditions effectively. However, these high doses can also cause significant adverse effects that decrease the quality of life of patients.

#For example, lung cancer is the leading cause of cancer death worldwide and accounts for 26-30% of all cancer deaths in the United States. The two major types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC); NSCLC accounts for 85-90% of lung cancers. From NSCLC, the adenocarcinoma is usually found in the bronchio-alveolar region of the lung. Surgery is the standard of care for stage I NSCLC, whereas for stage II and IIIA adjuvant, cisplatin-based chemotherapy remains the gold standard for completely resected NSCLC tumors. Chemotherapy is usually given systemically (oral or IV), with just a small fraction of the drug reaching the lung, while most is distributed elsewhere in the body. As a result, treatment usually involves administration of high doses, which results in severe side effects and decreased quality of life for the patient.

#Cancer chemotherapy is limited by the often poor solubility of drugs and by the toxicity caused by drugs, including (but not limited to) cytotoxic agents which are the most widely used anticancer therapies. To overcome the handicaps of cytotoxic agents, new molecular targeting therapies have been developed. Although they have an improved toxicity profile, administrations of these agents continuously over long time periods causes chronic toxicity, which still remains a key limiting factor.

#FIG. 1 shows SEM images of (a) SHetA2 nanocrystals (NCs) and (b) microparticles (MPs) produced from the SHetA2 NCs.

#FIG. 2 shows the size distribution of the respirable fraction of microparticles formed by SHetA2 NCs formulated into microparticles (NC-MPs). The sum of all bars adds to 95%.

#FIG. 3 shows concentration of SHetA2 in guinea pig BAL samples after administration of a 10 mg/kg dose of a SHetA2 suspension solution.

#The present disclosure, in at least certain non-limiting embodiments, is directed to the formation of drug microparticles by spray drying suspensions of drug nanocrystals suspended in a solvent, thereby reducing polydispersity and enabling customization of the size distribution and average size and volume of the microparticles so that specific lung regions (e.g., alveoli) can be targeted for improved therapy when the microparticles are administered, particularly as dry powder aerosols. Direct pulmonary administration of drugs formulated by the approach disclosed herein result in achieving drug concentrations in the lung that other routes of administration, such as oral or parenteral, cannot attain.

#Before further describing various embodiments of the compounds, compositions, and methods of the present disclosure in more detail by way of exemplary description, examples, and results, it is to be understood that the compounds, compositions, and methods of the present disclosure are not limited in application to the details of specific embodiments and examples as set forth in the following description. The description provided herein is intended for purposes of illustration only and is not intended to be construed in a limiting sense. As such, the language used herein is intended to be given the broadest possible scope and meaning, and the embodiments and examples are meant to be exemplary, not exhaustive. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting unless otherwise indicated as so. Moreover, in the following detailed description, numerous specific details are set forth in order to provide a more thorough understanding of the present disclosure. However, it will be apparent to a person having ordinary skill in the art that the present disclosure may be practiced without these specific details. In other instances, features which are well known to persons of ordinary skill in the art have not been described in detail to avoid unnecessary complication of the description. It is intended that all alternatives, substitutions, modifications, and equivalents apparent to those having ordinary skill in the art are included within the scope of the present disclosure. Thus, while the compounds, compositions, and methods of the present disclosure have been described in terms of particular embodiments, it will be apparent to those of skill in the art that variations may be applied to the compounds, compositions, and/or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit, and scope of the inventive concepts described herein.

#All patents, patent applications, and non-patent publications mentioned in the specification or referenced in any portion of this application are herein expressly incorporated by reference in their entirety to the same extent as if each individual patent, application, or publication was specifically and individually indicated to be incorporated by reference. Non-limiting examples thereof include U.S. Pat. Nos. 6,586,460; 7,612,107; 9,511,026; 9,750,696; and 9,795,562; and U.S. Provisional Patent Application No. 62/583,755.