Pharmaceutical compositions and methods for fabrication of solid masses comprising polypeptides and/or proteins

Abstract

Embodiments of the invention provide shaped masses (SM) comprising one or more drugs such as proteins or polypeptides and methods for forming and delivering such SM's. One embodiment provides a SM comprising a drug e.g., a protein or polypeptide having a biological activity in the body of a mammal. The SM is formed by compression of a precursor material (PM) comprising the drug wherein an amount of biologically active drug in the SM is a minimum level to that in the PM. Drugs which may be incorporated into the SM include insulin, incretins and immunoglobulins e.g., interleukin neutralizing antibodies or TNF-α-inhibiting antibodies. Embodiments of the invention are particularly useful for the oral delivery of drugs which would be degraded within the GI tract, wherein the SM containing the drug is formed as or incorporated into a tissue penetrating member which is inserted into the intestinal wall after oral ingestion.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of priority to U.S. Provisional No. 62 / 156,105 (Attorney Docket No. 42197-733.101), filed May 1, 2015, the entire content of which is incorporated herein by reference in its entirety; this Application is also a continuation-in-part of the following U.S. patent application Ser. Nos. 14 / 714,120, 14 / 714,126, 14 / 714,136, and 14 / 714,146, all filed on May 15, 2015, which are incorporated hereby by reference in their entirety.[0002]This application is also related to U.S. Application Serial; Ser. No. 13 / 532,589, now U.S. Pat. No. 9,149,617, entitled “Device, System And Methods For The Oral Delivery Of Therapeutic Compounds” filed Jun. 25, 2012, which is incorporated by reference herein for all purposes.FIELD OF THE INVENTION[0003]Embodiments described herein relate to pharmaceutical compositions and methods of fabrication of pharmaceutical compositions comprising solid masses comprising proteins and polypeptid...

AI Technical Summary

Benefits of technology

[0008]In various embodiments, the shaped mass may be in the form of a tablet, micro-tablet, pill or slug shape. Other shapes are also considered including spherical. In particular embodiments, the shaped mass can also be in the form of a bead or micro-bead which is inserted or otherwise formulated into embodiments of a tissue penetrating member described herein. Multiple such beads may formulated into the tissue penetrating member, with different beads formulated to have different drug release (e.g. by elution) profiles so as to achieve a bi-modal or other multi-modal release profile (e.g., tri-modal etc.). Multiple bead embodiments can also be configured so as to have beads comprising different drugs so as to deliver different drugs (e.g., a first and second antibody). In use, such embodiments allow for the simultaneous delivery of multiple drugs (e.g. such as those used to in a multidrug regimen to treat a particular condition or conditions) as well as achieve a varied release profile of drug e.g., to have a fast (e.g. minutes) and a slower (e.g. hours) release of drug.

[0015]In various embodiments where the drug sequestering polymer (ds-polymer) has a hydrophobic cavity to complex the drug so as to form an inclusion complex (inclusion compound) the ds-polymer may correspond to a cyclic oligosaccharide such as various cyclodextrins. In preferred embodiments the cyclodextrin comprises beta cyclo-dextrin (having a seven membered sugar ring), however cyclodextrins are also considered including alfa and gamma-cyclodextrins (having six and 8 membered sugar rings respectively). Further, in additional or alternative embodiments the cyclodextrin molecule can be copolymerized with a long chain organic molecule such that the copolymer has multiple cyclodextrin inclusion sites on a single copolymer molecule allowing for the formation of multiple inclusion complexes on a single such copolymer. In use such copolymerized molecules allow for one or more of: i) a greater degree of complexing with a smaller quantity of the ds-molecule; ii) greater control over the release rate of the drug (due to increased complexing); and iii) a further reduction in the release rate of the drug and thus an increase in the release period.

[0017]In one embodiment, the drug in the shaped mass comprises insulin or an analogue for the treatment of diabetes or other glucose regulation disorder. The insulin may be obtained from any suitable source (e.g. human insulin and / or that generated using recombinant DNA methods) and may correspond to basal or fast acting insulin or a combination of both. In another application, the drug comprises an incretin such as exenatide for the treatment of a glucose regulation disorder. In these and related embodiments the compression or other molding process is configured to preserve the biological activity of the insulin or incretin so as to be able to allow the drug to treat diabetes or other glucose regulation disorder once released into the body of a patient.

[0020]Still other embodiments provide methods of preparing a shaped mass comprising a drug wherein an outer coating or layer is formed over the drug using 3-D printing methods so as to produce a selectively shaped mass. Use of 3-D printing methods allow the shaped mass to be formed without the application of pressure and / or force on the mass. In use, such methods improve the yield of the drug in the final shaped mass due to decreased protein denaturation and / or other degradative effects on the drug. This in turn improves the bioactivity of the drug in the final shaped mass. Use of 3-printing also allows a variety of shapes to be produced without use of a mold or other related device reducing the potential for contamination and improving sterility. Such shapes may include for example, an arrow head shape, rectangle, pyramidal, spherical, hemispherical, conical and others. 3 D printing methods also allow for rapid customization of the drug mass shape and size for individual patient parameters, for example one or more of a patient's weight, medical condition and particular medical regimen (e.g. taking of medication once day, twice etc.). In still other embodiments, 3-D printing methods can be used to produce shaped masses configured to have a bimodal form of delivery, e.g. fast release and slow release.

Problems solved by technology

While there has been an increasing development of new drugs for the treatment of a variety of diseases, many including proteins, antibodies and peptides have limited application because they cannot be given readily formed into solid shapes for oral or other form of delivery and / or encapsulated.

One challenge in this area is that the process of fabrication of a drug comprising a protein, peptide or antibody into tablet or other solid form can result in loss in the bioactivity of the drug due to disruption of the structure of the protein from the fabrication process.

This is due to the fact that many proteins have complex internal structures that define their biological activity.

Disruption in the structure of a protein and / or polypeptide can result in its deactivation or considerable decline of its bioactivity.

Such disruption can result from fabrication processes such as molding, compression, milling, grinding or encapsulation or other related process.

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