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Amorphous efavirenz and the production thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Matrices, Synthetic PolymerAmorphous efavirenz and the production thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070026073, Amorphous efavirenz and the production thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Pat. App. No. 60/703,374, filed Jul. 28, 2005, the contents of which are hereby incorporated by reference. BACKGROUND OF THE INVENTION [0002] The present invention is directed to compositions containing amorphous efavirenz and methods for producing amorphous efavirenz. More particularly, the present invention relates to compositions and methods for preparing amorphous efavirenz utilizing at least one solubility-enhancing polymer. In accordance with one embodiment, the efavirenz is dissolved in a solvent containing the polymer. In yet another embodiment, a blend of solvent/non-solvent for the polymer is employed. The amorphous efavirenz product can be produced by any method suitable to the composition. When necessary, solvent can be removed from compositions to yield the amorphous efavirenz product. In one further development of the invention, efavirenz-polymer-solvent (or a solvent/non-solvent blend) is spray dried to produce efavirenz in a form that exhibits improved bioavailability. The bioenhanced efavirenz composition can be prepared by methods other than spray drying as recognized by those skilled in the art. Those methods include, without limitation: melt extrusion, spray congealing, granulation and freeze drying. In accordance with particular embodiments of the invention, a significant portion of the efavirenz is provided in the amorphous state. In accordance with certain embodiments, the efavirenz is converted almost entirely to the amorphous state. In one preferred embodiment of the invention, the efavirenz is converted to the completely amorphous state. [0003] Efavirenz is (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,- 1-benzoxazin-2-one. It is a benzoxazinone useful as a non-nucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI) and may be used in combination with other anti-retroviral agents for the treatment of HIV-1 infection in children and adults. Methods for the synthesis of efavirenz are disclosed in the U.S. Pat. Nos. 5,519,021; 5,663,169; 5,665,720 and 5,811,423, the disclosures of which are hereby incorporated by reference. [0004] Efavirenz is currently available in dosage forms containing 50 mg, 100 mg, 200 mg, and 600 mg of active. These dosage forms contain efavirenz in microcrystalline form and one or more disintegrants such as croscarmellose sodium to aid in tablet disintegration and dissolution. As described in WO99/64405, crystalline efavirenz exists in several physical forms that can be characterized by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). [0005] It is desirable to provide methods of producing efavirenz exhibiting enhanced bioavailability compared to the crystalline form of the compound. By converting a substantial portion of crystalline efavirenz to the amorphous state, the aqueous solubility and bioavailability are increased. Furthermore, efavirenz presented as an amorphous solid may facilitate manufacturing of both the active ingredient and the finished product and enable the use of reduced size dosage forms. Moreover, the selective customization of the properties of particles comprising efavirenz can offer intriguing opportunities for pharmaceutical production and drug delivery. The morphology of individual particles plays a central role in this pursuit, since morphology directly influences bulk powder properties, such as density, residual solvent content, and flowability. In addition, techniques that modify particle shape and interior structure may profoundly affect pharmacokinetic properties, such as drug release rate, solubility, and bioavailability. Thus, the ability to design particle morphology has significant implications for the production process and product attributes. SUMMARY OF THE INVENTION [0006] The present invention provides compositions and methods for producing amorphous efavirenz. A composition comprising a solid dispersion of efavirenz and at least one solubility-enhancing polymer wherein the efavirenz in the dispersion is substantially amorphous is provided in certain embodiments of the present invention. In one aspect, the disclosed invention describes the conversion of crystalline efavirenz to the amorphous state. One method for producing this conversion is through solvent spray drying. Other techniques that accomplish this conversion include, without limitation: flash solvent evaporation, melt-congeal spraying, freeze drying, and melt-extrusion. These methods can use a single solubility-enhancing polymer or blends of polymers. The degree of efavirenz amorphous conversion depends on various factors, including, but not limited to, polymer type and amount and processing conditions. In accordance with certain aspects of the invention, a single organic solvent, blends of solvents, or solvent/non-solvent blends can be used. [0007] In one aspect, the invention relates to spray-dried powders or granulated products comprising amorphous efavirenz. In addition, the resulting powders produced in accordance with certain embodiments typically possess lower residual solvent content and higher tap density than their counterparts produced by conventional methods, due to a change in the particle morphology and size. When applied to produce pharmaceutical products, a system of polymers can be used to modify not only particle morphology, but also the pharmacokinetic properties of the active. [0008] One aspect of the invention involves amorphous efavirenz prepared from compositions containing efavirenz and a solubility-enhancing polymer in a solvent or solvent blend. This solvent or solvent blend includes one or more solvents in which the polymer is soluble. The term "soluble" means that the attractive force between polymer and solvent molecules is greater than the competing inter- and intramolecular attractive forces between polymer molecules. For simplicity, this solvent is simply called "solvent." Compositions also are described in which the solvent blend contains a solvent for which the opposite is true: The attractive force between polymer and solvent molecules is less than the inter- and intramolecular attractive force between polymer molecules. This second solvent is termed the "non-solvent." The polymer may swell but does not dissolve in the non-solvent. In accordance with one embodiment of the invention, a solubility-enhancing polymer and a suitable solvent/non-solvent blend are provided. Additionally, the solvent possesses a lower boiling point than the non-solvent. Preferably, the solvent and non-solvent are miscible. The ratio of solvent to non-solvent is such that the polymer can be considered "dissolved" in the solvent system. [0009] Unique particle properties can be created by evaporating the solvent/non-solvent blend. For example, this evaporation can occur during the spray drying of the feed solution or granulation processes. Atomized droplets containing a blend of solvents will experience a change in the total solvent composition due to evaporation. The method appears to be independent of how the droplets are generated or atomized. Initially, the polymer exists in a dissolved state, due to a sufficient amount of the solvent. As it evaporates (the solvent boils at a lower temperature than the non-solvent), the concentration of non-solvent in the droplet increases. Eventually, the solvent composition is insufficient to maintain the polymer in solution. In doing so, the polymer collapses from solution. This change in polymer conformation can alter the evaporation dynamics of the droplet to create particle morphologies that influence final powder properties. [0010] The use of a solvent/non-solvent blend system has been found to provide additional benefits beyond the benefits obtained with a solvent only system. This solvent/non-solvent approach can produce a spray dried powder of lower residual solvent content and smaller particle size. A further consequence of this engineered particle morphology is the increase in bulk powder density. Increased powder density is an important attribute for many applications. The extent of polymer collapse--and therefore the net effect on the spray dried powder properties--depends on the polymer solvation factors, such as the initial ratio of solvent to non-solvent, the polymer chemical structure and the polymer molecular weight. In addition to reducing residual solvent content and increasing density, the primary polymer may be paired with the solvent/non-solvent system in order to affect not only the morphology of the particle, but also that of the efavirenz, and thereby affect the efavirenz loading, crystallinity, solubility, stability and release. [0011] The presence of additional polymers may contribute to the final particle morphology by their interaction with the first polymer and the solvent system. These additional polymers may also be advantageous to create special release properties of the active. For example, the primary polymer may be paired with the solvent/non-solvent system in order to affect particle morphology, and thereby residual solvent content and bulk powder density. Additional polymeric adjuvants may be added to serve additional purposes: further inhibit active recrystallization, further maximize active concentration, and further enhance/delay/retard dissolution rate. To accomplish these functionalities, it is necessary to suitably match the adjuvant solubilities with the solvent blend selected for the primary polymer. BRIEF DESCRIPTION OF THE DRAWINGS [0012] FIG. 1 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #1. [0013] FIG. 2 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #1 after storage for 196 days at 20.degree. C. and 40.degree. C. [0014] FIG. 3 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #3. [0015] FIG. 4 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #3 after storage for 216 days at 20.degree. C. and 40.degree. C. [0016] FIG. 5 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #5. [0017] FIG. 6 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #5 after storage for 92 days at 20.degree. C. and 40.degree. C. [0018] FIGS. 7A-B are photomicrograph images of particles from Examples #5 and #7. [0019] FIG. 8 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #8. [0020] FIG. 9 is a plot of percent efavirenz released in water as a function of time for spray dried product using solvent and solvent/non-solvent methods in accordance with Example #8. Continue reading about Amorphous efavirenz and the production thereof... 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