FIELD OF THE INVENTION

The present invention relates to methods for preparing stable amorphous dispersions of poorly soluble active pharmaceutical ingredients (APIs) via processing with a polymer, and compositions made thereby. The methods of the invention result in more complete amorphization, increased solubility, drug loading and stability.

BACKGROUND OF THE INVENTION

The formulation and delivery of poorly soluble drug candidates remains a challenge. One general strategy to overcome these challenges has been to stabilize the more soluble amorphous solid form of a drug with polymer and surfactant excipients, resulting in amorphous solid dispersions of drug with improved solubility and absorption in vivo. Solvent mediated techniques such as spray drying and solvent casting have emerged as options for preparing amorphous dispersions, but require that the materials used be soluble in organic solvent. Hot melt extrusion (HME) has also been established as a method for preparing amorphous dispersion of drug and polymer mixtures in the absence of solvent. However, HME requires large amounts of materials (>10 grams) and is not suitable for early formulation work in drug discovery, where the amount of material is limited.

Poor aqueous solubility can be a serious problem for achieving adequate drug bioavailability. In particular, poor solubility often limits oral absorption from the gastrointestinal (GI) tract. Drug solid state forms with optimal solubility and dissolution rates can result in better absorption from the GI tract. It follows that using a drug form with optimal solubility can also allow for similar plasma levels as seen with a larger dose of a less soluble form. Therefore, enhancing the dissolution, solubility and bioavailability of poorly soluble drugs is of great interest in the art.

In general, amorphous forms of a substance show a higher kinetic solubility and/or dissolution rate than crystalline forms of the same substance. The higher kinetic dissolution rate/solubility of amorphous phases as well as potential supersaturation can result in better bioavailability as compared to an associated crystalline form. More soluble amorphous phases are desirable for both human solid dosage forms and for use in formulations (suspensions) for preclinical toxicology studies, where large exposure margins often are required.

Frequently, amorphous drugs will convert to the lower energy crystalline phase, resulting in a drop in solubility (Hancock and Zografi,J. Pharm Sci.86:1-12 (1997)). It is known that crystallization can be suppressed by dissolving the drug into an amorphous polymer, thus forming a stabilized “amorphous solid dispersion”. Drug-polymer solid dispersions can be prepared via several means, including melt extrusion, solvent casting, and spray drying.

In view of the foregoing, there is a need for improving the process by which amorphous dispersion formulations are prepared, particularly for poorly organic soluble compounds and on smaller scales than those used for melt extrusion

SUMMARY OF THE INVENTION

The present invention relates to methods for preparing stable amorphous dispersions of pharmaceutically active substances with improved aqueous solubility comprising applying low frequency acoustic energy and heat to a mixture comprising an active pharmaceutical ingredient (API) and at least one polymer. The invention also provides amorphous dispersions made by the methods of the invention and compositions comprising said amorphous dispersions. The methods of the invention result in more complete amorphization, better physical stability and increased solubility and/or dissolution as compared to known solvent-free methods of preparing amorphous material. The methods of the invention are advantageous because they require a minimum amount of active pharmaceutical ingredients.

Thus, the present invention provides a method for producing a stable amorphous dispersion of a drug product comprising: (a) applying low frequency acoustic energy to a mixture comprising: (i) an API and (ii) at least one polymer; and (b) heating the mixture to a temperature above the glass transition or melting point temperatures of at least one of the polymer or the API to produce a stable amorphous dispersion of the drug product; wherein the low frequency acoustic energy and the heat are applied to the mixture for a period of time sufficient to form a stable amorphous dispersion of the drug product.

Vials of various composition, such as glass, plastic, or alloy, are loaded with drug and polymer solids in various scales, such as from 10-10,000 mg, they can be subjected to up to 100 G's of mixing intensity while being heated at various temperatures up to 200° C. It is shown herein that the methods of the invention are useful for producing amorphous dispersions of multiple compounds with different polymer systems, including Soluplus, Vit-E TPGS, PEG1500, Eudragit EPO, copovidone Kollidon® VA64, HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, Kolliphor EL, and Crospovidone.

Also provided is a high throughput method of preparing multiple amorphous solid dispersion samples simultaneously, the method comprising: (a) preparing, in each chamber of a multi-chambered apparatus, a mixture comprising: (i) an active pharmaceutical ingredient; and (ii) at least one polymer; (b) applying low frequency acoustic energy to said multi-chambered apparatus; and (c) heating the apparatus to a temperature above the glass transition or melting point temperature of the mixture in each chamber of the apparatus until said amorphous solid dispersion samples are formed.

The present invention is also directed to amorphous drug product produced by the methods of the invention. In certain embodiments, the amorphous drug product contains substantially no crystalline content, preferably less than 5%, 2% or 1%.

The present invention also relates to a formulation containing the amorphous drug product in the form of a liquid suspension or a solid dosage form.

