FIELD OF THE INVENTION

The present invention relates to stable pharmaceutical compositions of pegylated carfilzomib compounds, methods for preparing the compositions, and uses thereof for treating cancer including hematologic malignancies, such as multiple myeloma, and solid tumors.

BACKGROUND OF THE INVENTION

Cancer is one of the most widespread diseases and a leading cause of death worldwide. In the United States alone, cancer is the second leading cause of death, surpassed only by heart disease. Cancer is often characterized by deregulation of normal cellular processes or unregulated cell proliferation.

Multiple myeloma (MM) is a progressive and malignant neoplastic type of cancer originating from plasma cells. It is characterized by abnormal accumulation of malignant plasma cells within bone marrow, and it accounts for approximately 13% of all hematologic cancers (Palumbo and Anderson, 2011). In 2015, about 26,850 new cases were expected to be diagnosed with MM, and about 11,240 people were expected to die from the disease in the United States (ACS, 2015). The incidence of MM has increased steadily due to increased life expectancy of the general population in the United States (Warren et al., 2013). The disease most commonly affects the elderly population, with the median age of incidence around 69 years old (Howlander et al., 2013; ACS, 2015).

The therapeutic goals of management of MM are to provide symptomatic relief, achieve disease control and provide prolonged remissions (Kurtin, 2013). Conventionally, a combination of high dose chemotherapeutic agents (melphalan, vincristine, cyclophosphamide, doxorubicin, liposomal doxorubicin, bendamamustine) followed by autologous stem-cell transplantation (ASCT) has been utilized to treat young, treatment-naïve and medically fit patients (less than 65 years of age) (Palumbo et al., 2011). Age, comorbid conditions and geriatric assessment are the major criteria for deciding patients' eligibility to tolerate high-dose therapy (HDT) followed by ASCT (Palumbo et al., 2014). For elderly patients ineligible for HDT and ASCT, melphalan plus prednisone had been the standard therapy for several decades (Palumbo et al., 2011; Rodriguez et al., 2012). During the last decade, treatment algorithm of MM underwent a paradigm change with the introduction of novel immunomodulatory agents (such as thalidomide, lenalidomide, and pomalidomide) and targeted proteasome inhibitors (bortezomib and carfilzomib) (Richardson et al., 2007; Dmoszynska, 2008; Gupta et al., 2013).

Carfilzomib is a tetrapeptide epoxy ketone proteosome inhibitor that binds selectively and irreversibly to the constitutive proteosome and immunoproteosome. More specifically, the epoxyketone electrophilic warhead binds to the catalytic threonine residue of the β5 subunit of the proteasome protein. CFZ is well tolerated with acceptable toxicity profile. Carfilzomib, polymorphic forms, methods of making, formulations, its use and other carfilzomib attributes are described in US20050245435, US20140105921 and PCT publications WO2006017842, WO2009045497, WO2014169897, WO2013169282, WO2014011695, WO2006063154, WO2014015016, and WO2010048298, each specification of which is hereby incorporated herein by reference in its entirety.

Carfilzomib has shown an encouraging overall response rates, progression free survival (PFS) and overall survival (OS) in patients with relapsed and refractory MM and with newly diagnosed patients with MM. Carfilzomib was first approved (as Kyprolis®) for treatment in patients with relapsed and refractory MM in July 2012 as a single agent therapy. More recently Kyprolis was approved in combination with lenalidomide and dexamethasone (July 2015) and in combination with dexamethasone (January 2016) for the treatment of patients with relapsed and refractory MM who have received one to three lines of therapy. The approved treatment regimen for carfilzomib is to administer it to the patient by infusion, either over a short 10 minute period or over a slower, longer 30 minute duration of time. This infusion is to occur for 2 consecutive days per week for three consecutive weeks in a 28 day cycle. Thus, to comply with this treatment schedule, patients need to drive or be driven two times per week on consecutive days to an authorized Kyprolis® administration center, such as a doctor's office, a clinic or a hospital, where it can be properly and safely administered. This may be inconvenient or impractical, or may simply be a burden to some patients. This burden increases the likelihood of reduced or decreased compliance with, or even complete non-compliance of, the full and complete course of the prescribed Kyprolis® therapeutic regimen.

Carfilzomib is rapidly metabolized and cleared in humans. Carfilzomib, a small tetrapeptide compound, exhibits a short half-life in-vivo of about 60 minutes or less in humans. One mechanism of carfilzomib clearance is via hepatic blood flow, resulting in the relatively brief half-life for carfilzomib. Drug products possessing short half lives or rapid clearance in general tend to exhibit reduced target coverage leading to decreased and/or shortened biological inhibitory activity. To overcome such shortfalls, additional drug is typically administered to provide more drug and prolonged efficacy at the biological site of action. Hence, both the rapid clearance and the twice weekly frequency of dosing of carfilzomib leave room for possible improvements in efficacy, delivery and/or patient compliance.

Carfilzomib, as currently approved (Kyprolis®), is a sterile lyophilized amorphous solid formulation comprising sulfabutylether beta cyclodextrin (SBECD) and a sodium citrate buffer. Immediately prior to administration, the lyophilate is reconstituted with sterile water, and infused or injected into the patient. The SBECD excipient acts primarily as a solubilizing additive for carfilzomib, and forms a complex with carfilzomib thereby improving carfilzomib water solubility.

History has revealed that attempts to solve weaknesses of drug products and/or to improve upon delivery, use or there aspects of a given drug product, have led to the preparation of alternative forms of these active pharmaceutical ingredients (API or medicinal compounds) and/or new formulations of them. Some alternative compound forms have included discovery of pro-drugs, designed to enhance the pK and/or PD properties of the API. For instance, Greenwald et al disclose Prodrugs of Amine Containing Compounds (J. Med Chem.,1999, 42, 3657-3667). WO2005063777 discloses benzylphosphate and substituted benzylphosphate prodrugs for the treatment of pulmonary inflammation. WO20090152160 discloses inhaled carbaprotacyclin and prostacyclin prodrugs for the treatment of arterial hypertension. US patent publication no. 20040100225 discloses acyloxymethyl pro-drugs of imatinib (Gleevec®). Also, PCT publication WO2011084846 discloses acyloxymethyl pro-drugs of risperidone. These pro-drug disclosures teach alkyl-acyloxymethyl linked pro-drugs.

Modifications to carfilzomib have also been made to improve upon its properties or other attributes as an active pharmaceutical ingredient and drug product. US patent application publication no. US20140105921 describes carfilzomib and other epoxyketone proteasome inhibitor pro-drugs having an acyloxymethyl linker connecting the inhibitor to polyethylene glycol units (PEG). However, these carfilzomib pro-drug compounds have been found to release quinone methide byproducts during metabolism in vivo, which may be potentially toxic and may present a human safety risk. It is desirable to identify formulations and/or pharmaceutical compositions of modified carfilzomib compounds to suitably deliver them to patients while maintaining or possibly improving the stability, shelf-life, efficacy and/or safety of the currently approved carfilzomib treatments.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides novel pharmaceutical compositions of pegylated carfilzomib compounds, i.e., stable formulations of peg-carfilomib, that deliver therapeutic anti-cancer benefits to the patient while maintaining comparable or longer carfilzomib plasma concentrations and exposure to the proteasome protein. To this end, the formulations of the present invention provide proteosomal inhibitory activity comparable to that of the currently approved carfilzomib cyclodextrin IV formulation. The present invention further provides pegylated carfilzomib formulations that do not include use of a cyclodextrin as a carfilzomib solubilizing agent.

Particularly, the present invention provides stable, isotonic, cyclodextrin free, lyophilized and liquid formulations of pegylated carfilzomib compounds. The solid lyophilized formulations may be reconstituted, such as with sterile water, and administered via parenteral methods including intravenous administration, injection and also via sub-cutaneous administration. These formulations are useful to treat various types of cancer, including without limitation, multiple myeloma. More particularly, the formulations provided herewith maintain or exhibit suitable bioavailability. The present invention further provides a method of preparing the pharmaceutical compositions, and methods of administering the compositions, such as parenterally by infusion or injection, or subcutaneously, for treating various forms of cancer such as multiple myeloma.

In one aspect, the invention provides a pharmaceutical composition comprising (a) a pegylated carfilzomib compound; (b) at least one excipient selected from the group consisting of sucrose, sorbital, glycerin, maltose, lactose, erythrose, dextrose, lactobiose, cyclodextrin, proline, glycine, arginine, histidine, aspartic acid, valine, leucine, alanine, methionine, proline, glutamic acid, glutamate, and a salt selected from the group consisting of sodium chloride, potassium chloride, ammonium sulfate, potassium chlorate, calcium chloride, zinc chloride, guanidine hydrochloride, ammonium chloride, potassium sulfate, ammonium aspartate, arginine-HCl, lysine-HCl, magnesium chloride and barium sulfate; (c) a buffering agent selected from the group consisting of glutamate, histidine, acetate, and Tris-HCl, or a combination thereof; and (d) optionally a bulking agent selected from the group consisting of mannitol, trehalose, PVP, cyclodextrin, glycine, dextrose, dextran, sucrose, proline, PEG 33350 and PEG 400, (e) optionally an amino acid selected from the group consisting of lysine, arginine, histidine, aspartic acid, valine, leucine, alanine, methionine, proline, glutamic acid and glutamate, (f) optionally a surfactant selected from the group consisting of polysorbate 20, polysorbate 80, pluronic F68, docusate sodium, benzaconium chloride, triton X100, tetrafunctional block O polymers, alcohols, SDS, protamine sulfate and butane, or a combination of (d), (e) and (f). The pharmaceutical compositions of the present invention provide suitable solubility, permeability, pharmacokinetics (pK) and/or pharmacodynamics (PD) properties to the pegylated carfilzomib compounds when compared with the corresponding approved carfilzomib product.

The pharmaceutical compositions provided by the present invention further provide potential drug product benefits including, without limitation, shelf stability, storage capability, safe use after a number of days as a liquid preparation, frozen formulations, dry lyophilized formulations, and other conveniences for the safe maintenance, storage and use of a carfilzomib based drug product. The improved compostions of the present invention facilitate various modes of administration, such as for example intravenously by infusion or injection. The compositions can also be administered subcutaneously under the skin. The invention also provides compositions including hyaluronidase, which may facilitate subcutaneous administration. The compositions are useful for treating cancers, including without limitation, multiple myeloma and solid tumors.

