High-strength oral taxane compositions and methods

Abstract

To provide, considering potential clinical oral dosing regimens for taxanes, improved tablet formulations of taxanes having higher dosage strength and higher bioavailability.SOLUTION: The invention relates to high-strength, high-bioavailability, ready-to-administer oral compositions of taxanes to be manufactured by readily scalable methods. The ready-to-administer oral composition can comprise a solid dispersion of taxanes and a hypromellose acetate succinate (HPMCAS) carrier, which is compressed into a tablet form with high taxane loading.SELECTED DRAWING: Figure 9

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 569,258, filed October 6, 2017. These and all other referenced external materials are incorporated herein by reference in their entirety. In the event that the definition or usage of a term in a document incorporated by reference is inconsistent with or contradicts the definition of the term provided herein, the definition of the term provided herein shall be deemed controlling.

[0002] (Technical field) The field of the invention is pharmaceutical compositions and scalable methods for producing dosage forms that provide oral delivery of taxanes with high bioavailability and potency. [Background technology]

[0003] The following description contains information that may be useful in understanding the present invention. It is not an admission that any of the information presented herein is prior art or relevant to the present invention, or that any publication specifically or implicitly referenced is prior art.

[0004] The background description includes information that may be useful in understanding the present invention. None of the information presented herein is admitted to be prior art or relevant to the invention claimed herein, or that any publication specifically or implicitly referenced is prior art.

[0005] Taxanes are an important class of cytotoxic drugs, including paclitaxel (Taxol®), docetaxel (Taxotere® or Docecad), cabazitaxel, larotaxel, ortataxel, tesetaxel, etc. Paclitaxel is a diterpene isolated from the Pacific yew (Taxus brevifolia). Paclitaxel binds to tubulin, allowing it to inhibit cell division. Therefore, paclitaxel has been approved for the treatment of ovarian cancer, breast cancer, lung cancer, head and neck cancer, and pancreatic cancer. In addition, paclitaxel can effectively treat other diseases, such as malaria and kidney disease. However, paclitaxel has poor solubility in water, making it difficult to formulate safe and effective treatments.

[0006] In one known approach to improving the solubility of injectable taxanes, paclitaxel formulations include Cremophor® EL (Kolliphor® EL, polyoxyl 35 castor oil) or Tween® 80 (polysorbate 80) and ethanol. When administered in such formulations, Cremophor® EL (or Tween® 80) is independently toxic and exhibits side effects such as vasodilation, hypotension, dyspnea, fatigue, anaphylactoid hypersensitivity reactions, hyperlipidemia, abnormal lipoprotein patterns, red blood cell aggregation, and peripheral neuropathy. One option to avoid these side effects is to administer the pharmaceutical composition orally. Unfortunately, when administered orally, such paclitaxel formulations suffer from very low bioavailability and absorption.

[0007] Docetaxel is a derivative of paclitaxel that is approved for the treatment of breast, lung, prostate, gastric, and head and neck cancers. Docetaxel is also typically formulated with surfactants for parenteral delivery, and like paclitaxel, the bioavailability of orally administered docetaxel is very low.

[0008] One factor contributing to low bioavailability may be that taxanes are excreted from target cells by multidrug transporters such as P-glycoprotein (PGP). To address this issue, attempts have been made to co-administer taxanes with PGP inhibitors (e.g., HM30181A, ritonavir, and ketoconazole). See, for example, U.S. Patent No. 6,245,805 (Broder et al.), U.S. Patent No. 7,041,640 (Broder et al.), and U.S. Patent No. 7,115,565 (Gao et al.).

[0009] Another factor contributing to low bioavailability is the low aqueous solubility of taxanes. Various techniques have been developed to attempt to enhance the solubility of taxanes. For example, U.S. Patent Application Publication No. 2011 / 0,207,804 A1 (Slotervaart Participaties BV: Patent Document 4) describes a solid dispersion formulation filled into capsules, and Chinese Patent Application No. 103083240 A (Shenyang Pharmaceutical University: Patent Document 5) describes the use of a poor solvent and a liquid bridging solvent to form an emulsion, which is then used to form a dispersion of solid microspheres.

[0010] While many of these compositions can improve the supersaturated solubility and bioavailability of taxanes to some extent, such formulations do not represent practical and convenient final dosage forms for clinical administration. Generally, solid powder dispersions are considered "intermediate products" rather than "final products," and are inherently very light and fluffy due to their low bulk density. When filled into capsules, only very limited active substance loadings can be achieved per capsule due to the limited volume of powder that can be accommodated in an oral capsule of practical dimensions. For example, U.S. Patent Application Publication No. 2011 / 0,207,804 A1 (Slotervaart Participaties BV) describes a solid dispersion formulation in a capsule that provides only 15 mg of docetaxel per capsule.

[0011] Alternatively, the dosage form can be a tablet if the compressibility of the excipients allows for a higher active ingredient loading per unit dosage form than solid dispersion powders in capsules. For example, a 1 g tablet capable of providing a 10% active ingredient loading may be achievable with a 100 mg taxane active substance loading. For example, the approach employed in Chinese Patent Application No. CN103083240A requires the use of a poor solvent and a liquid bridging solvent to form an emulsion, which is used to form a dispersion of solid microspheres. Unfortunately, such microspheres are not suitable for compression into high-dose forms. The microspheres obtained from such a process are hollow, and compression affects their structural integrity, which in turn negatively impacts the release of the active ingredient. As a result, such microspheres are typically filled into capsules without compression. In addition, the formulation disclosed in Chinese Patent Application No. CN103083240A relies on the inclusion of a "dispersant" (such as porous silica) to increase the bioavailability of the active ingredient. In preferred embodiments, silica contents of up to 35% are required. The need to include substantial amounts of this excipient (or similar excipients) necessarily limits the ability of such formulations to achieve high active loadings. It should be understood that the preferred liquid bridging solvent is methylene chloride. This organic solvent is classified as a Class 2 solvent by the Food and Drug Administration (https: / / www.fda.gov / downloads / drugs / guidances / ucm073395.pdf). According to this guidance, the use of Class 2 solvents should be limited in pharmaceutical products to a permissible daily exposure (PDE) of 6 mg / day due to inherent toxicity. Additionally, the good solvent / poor solvent method taught for producing microspheres is relatively slow and non-scalable, and therefore not suitable for large-scale manufacturing.

[0012] Taxane tablet compositions are described in International Patent Application Publication No. 2015 / 152433A1 (Hanmi Phar. Co. Ltd.: Patent Document 6). Unfortunately, only a strength of 30 mg paclitaxel per 750 mg total tablet weight was achieved. Naturally, tablets intended for human use typically do not exceed 1 g to ensure easy swallowing. Total intravenously administered taxane doses are often 135-175 mg / m 2 (i.e., 1.70m 2 Because the bioavailability of orally administered taxanes is lower than that of intravenously administered taxanes (approximately 300 mg for an individual with a body surface area (BSA) of 100 mg), the total oral dose required per patient can be expected to exceed 300 mg in some cases. For known taxane capsules with strengths of 15-30 mg, the number of unit doses that need to be administered to a patient can easily exceed 10 capsules / tablets, which many patients would be unable or unwilling to consume. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] U.S. Patent No. 6,245,805 [Patent Document 2] U.S. Patent No. 7,041,640 [Patent Document 3] U.S. Patent No. 7,115,565 [Patent Document 4] US Patent Application Publication No. 2011 / 0,207,804A1 [Patent Document 5] Chinese Patent Application No. 103083240A [Patent Document 6] International Patent Application Publication No. 2015 / 152433Al [Non-patent literature]

[0014] [Non-Patent Document 1] https: / / www.fda.gov / downloads / drugs / guidances / ucm073395.pdf DISCLOSURE OF THE INVENTION [Problem to be solved by the invention]

[0015] Considering potential clinical oral dosing regimens for taxanes, there is a strong unmet need for improved tablet formulations of taxanes with higher dosage strengths and higher bioavailability, which is inherently technically challenging because higher concentrations of taxane are thought to impair solubility and therefore bioavailability. [Means for solving the problem]

[0016] (Summary of the Invention) The present subject matter provides high-strength, high-bioavailability, ready-to-administer oral compositions of taxanes, manufactured by a readily scalable process. The ready-to-administer oral compositions may comprise a solid dispersion of the taxane and a hypromellose acetate succinate (HPMCAS) carrier, compressed into a tablet form with a high taxane loading. Preferably, the taxane comprises at least one of paclitaxel, docetaxel, cabazitaxel, larotaxel, ortataxel, and tesetaxel, and is present in the tablet at a concentration of at least 6% by weight, more preferably at least 8%, at least 10%, or at least 13% by weight. While the disclosure herein is directed to oral compositions comprising HPMCAS as a polymeric carrier, it is contemplated that other commercially suitable carriers (e.g., hydroxypropyl methylcellulose phthalate, Eudragit®, etc.) may be used, allowing for high taxane loading and high bioavailability. Generally, the weight of the polymeric carrier constitutes 90% by weight or less, 92% by weight or less, 94% by weight or less, 96% by weight or less, or 98% by weight of the total weight of the pharmaceutical composition.

[0017] The taxane and carrier may be present in any suitable ratio in the solid dispersion and final tablet form, however, to reduce the number of tablets required per dose, it is preferred that the taxane and carrier(s) are present in a ratio of from 1:0.5 to 1:6, more preferably from 1:0.5 to 1:4.

[0018] It should be appreciated that the final dosage forms of oral taxanes described herein are advantageously and surprisingly capable of providing high active substance loading per dosage unit while maintaining high bioavailability, thereby enhancing patient tolerance of clinical oral dosing regimens for taxanes.

[0019] Furthermore, it is envisioned that when the oral composition of the present invention is orally administered, a supersaturated solubility of at least 70% (or even at least 80% or at least 90%) of the released taxane is maintained for a period of at least 2 hours (or at least 3 hours or even longer).

[0020] Although not required, in some embodiments, the oral composition may further comprise a surfactant such as polysorbate 80, polysorbate 20, polyethyoxylated castor oil, caprylocaproyl polyoxylglyceride, or sodium dodecyl sulfate (SDS). If included, the surfactant and taxane may be present in a ratio of 1:5 to 5:1, or any other suitable ratio (e.g., 1:1).

[0021] The subject invention also provides a method for preparing a ready-to-dose oral composition of a taxane. The method contemplated herein may include the steps of: (a) formulating a spray solution comprising the taxane and an HPMCAS carrier; (b) spray-drying the spray solution to form an amorphous solid dispersion powder; and (c) compressing the amorphous solid dispersion powder to form a tablet having a taxane concentration of at least 6% by weight, more preferably at least 10% by weight, and even more preferably at least 13% by weight.

[0022] That is, the present invention provides the following.

[0023] The present invention provides a ready-to-administer oral composition comprising: an amorphous solid dispersion comprising a taxane and a hypromellose acetate succinate (HPMCAS) carrier; the taxane and the HPMCAS are present in the oral composition in a ratio of greater than or equal to 1:0.5 to less than or equal to 1:4; and wherein the taxane is present in a concentration of at least 6% by weight of the oral composition; Preferably, upon oral administration of the composition, at least 70% supersaturated solubility of the liberated taxane is maintained for a period of at least 2 hours. Preferably, the taxane is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, larotaxel, ortataxel, and tesetaxel. Preferably, the solid dispersion is a spray-dried amorphous solid dispersion or amorphous granules produced by fluidized bed granulation. Preferably, the taxane is present in a concentration of at least 10% by weight of the oral composition. Preferably, the taxane is present in a concentration of at least 13% by weight of the oral composition. Preferably, the taxane and the HPMCAS are present in the oral composition in a ratio of greater than or equal to 1:2 to less than or equal to 1:3.5. Preferably, it further comprises a surfactant. Preferably, the surfactant is selected from the group consisting of polysorbate 80, polysorbate 20, polyethyoxylated castor oil, caprylocaproyl polyoxylglyceride, and sodium dodecyl sulfate (SDS), and the surfactant and the taxane are present in a ratio of 1:5 or more to 5:1 or less. Preferably, the composition does not contain a surfactant. Preferably, the solid dispersion is mixed with an intragranular excipient by wet granulation to form a mixture. Preferably, the blend is extragranularly blended with at least one of a lubricant, a filler, and a superdisintegrant to form a tablet blend, and the tablet blend is compressed to form a ready-to-dose oral composition. Preferably, the composition releases less than 50% of the taxane within 1 hour in simulated gastrointestinal fluid at a pH of less than 6.8. Preferably, the composition releases less than 50% of the taxane in simulated gastrointestinal fluid at a pH of less than 4 within 1 hour. Preferably, a majority of the taxane is released from the composition into the simulated gastrointestinal fluid when the pH of the simulated gastrointestinal fluid exceeds the dissolution pH of the HPMCAS carrier. Preferably, it further comprises a disintegrant or superdisintegrant.

[0024] The present invention provides a method for preparing a ready-to-administer oral composition, comprising the steps of: preparing a spray solution comprising a taxane and an HPMCAS carrier; spray drying the spray solution to form an amorphous solid dispersion powder; compressing the amorphous solid dispersion powder to form a tablet having a taxane concentration of at least 6% by weight, Preferably, the tablet is characterized by maintaining at least 70% supersaturated solubility of the released taxane for a period of at least 2 hours after oral administration. Preferably, the taxane is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, larotaxel, ortataxel, and tesetaxel. Preferably, the tablet does not contain a surfactant. Preferably, the spray solution further comprises a surfactant. Preferably, the method further comprises the step of mixing a surfactant with the amorphous solid dispersion powder prior to compression. Preferably, a first pharmaceutically acceptable solvent is used to dissolve the surfactant; Preferably, the first pharmaceutically acceptable solvent is selected from the group consisting of water, ethanol, acetone, and mixtures thereof. Preferably, the taxane is present in a concentration of at least 10% by weight of the tablet. Preferably, the method further comprises the step of adding a stabilizer before compression, wherein the stabilizer is selected from the group consisting of citric acid and ascorbic acid. Preferably, the method further comprises the step of adding a disintegrant or superdisintegrant prior to compression. Preferably, the taxane and the HPMCAS are present in the tablet in a ratio of greater than or equal to 1:2 to less than or equal to 1:3.5. Preferably, a second pharmaceutically acceptable solvent is used to dissolve the taxane or the HPMCAS carrier. Preferably, the second pharmaceutically acceptable solvent is selected from the group consisting of water, ethanol, acetone, and mixtures thereof. Preferably, the tablet is characterized by releasing less than 50% of the taxane within 1 hour in a simulated gastrointestinal fluid having a pH of less than 6.8. Preferably, the tablet is characterized by releasing less than 50% of the taxane within 1 hour in a simulated gastrointestinal fluid having a pH of less than 4. Preferably, the tablet is characterized by the release of a majority of the taxane into the simulated gastrointestinal fluid when the pH of the simulated gastrointestinal fluid exceeds the dissolution pH of the HPMCAS carrier.

[0025] The present invention provides a method for preparing a ready-to-dose oral composition, comprising the steps of: preparing a solution comprising a taxane and an HPMCAS carrier; applying the solution to intragranular excipients using a fluid bed granulation system to form an amorphous solid comprising the taxane and the HPMCAS carrier; drying the amorphous solid; and compressing the amorphous solid to form a tablet having a taxane concentration of at least 6% by weight, Preferably, the intragranular excipient is microcrystalline cellulose. Preferably, the method further comprises the step of adding extragranular excipients before drying. Preferably, the extragranular excipient is selected from the group consisting of cross-linked polyvinylpyrrolidone, amorphous silicon dioxide, sodium stearyl fumarate, and microcrystalline cellulose. Preferably, the tablet is characterized by providing at least 70% supersaturated solubility of the liberated taxane, maintained for a period of at least 2 hours after oral administration. Preferably, the taxane is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, larotaxel, ortataxel, and tesetaxel. Preferably, the tablet does not contain a surfactant. Preferably, the solution further comprises a surfactant. Preferably, the method further comprises the step of mixing a surfactant with the amorphous granules prior to compression. Preferably, the taxane is present in a concentration of at least 10% by weight of the tablet. Preferably, the method further comprises the step of adding a stabilizer before compression, wherein the stabilizer is selected from the group consisting of citric acid and ascorbic acid. Preferably, the method further comprises the step of adding a disintegrant or superdisintegrant prior to compression. Preferably, the taxane and the HPMCAS are present in the tablet in a ratio of greater than or equal to 1:2 to less than or equal to 1:3.5. Preferably, the solvent is selected from the group consisting of water, ethanol, acetone, and mixtures thereof. Preferably, the tablet is characterized by releasing less than 50% of the taxane within 1 hour at a pH of less than 6.8. Preferably, the tablet is characterized by releasing less than 50% of the taxane within 1 hour at a pH of less than 4. Preferably, the tablet is characterized by liberating a majority of the taxane into the aqueous medium with which it is in contact when the pH of the aqueous medium exceeds the dissolution pH of the HPMCAS carrier.

[0026] Various objects, features, aspects and advantages of the inventive subject matter are set forth in the following preferred embodiments taken in conjunction with the accompanying drawings. This will become more apparent from the detailed description of the preferred embodiments, in which like numerals represent like components. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 shows typical dissolution profiles of amorphous solid dispersions of docetaxel:povidone K-30:SDS (ASD Examples 1-3). [Figure 2A] FIG. 2A is a typical dissolution profile of amorphous solid dispersions of docetaxel:HPMCP-50:SDS and HPMCP-55 (ASD Examples 4 and 5). [Figure 2B] FIG. 2B is a typical dissolution profile of amorphous solid dispersions of docetaxel: HPMCP-50 and HPMCP-55 (no SDS, ASD Examples 6 and 7). [Figure 3A] FIG. 3A is a typical dissolution profile of amorphous solid dispersions of docetaxel:Eudragit:SDS (ASD Examples 8-10). [Figure 3B] FIG. 3B is a typical dissolution profile of docetaxel:Eudragit amorphous solid dispersions (no SDS, ASD Examples 11 and 12). [Figure 4A] FIG. 4A is a typical dissolution profile of amorphous solid dispersions of docetaxel:HPMCAS:SDS (ASD Examples 13-17). [Figure 4B] FIG. 4B is a typical dissolution profile of an amorphous solid dispersion of docetaxel:HPMCAS (no SDS, ASD Examples 18-20). [Figure 5] FIG. 5 is a typical dissolution profile of an amorphous solid dispersion (ASD) of paclitaxel:HPMCAS:SDS (ASD Example 21). [Figure 6A]FIG. 6A is a typical X-ray diffractogram of docetaxel amorphous solid dispersion (ASD Example 20) and crystalline docetaxel drug substance. [Figure 6B] FIG. 6B is a representative X-ray diffractogram of paclitaxel amorphous solid dispersion (ASD Example 21) and crystalline paclitaxel drug substance. [Figure 7A] FIG. 7A is a typical dissolution profile of a docetaxel tablet prepared from an amorphous solid dispersion of the inventive concepts: Docetaxel Tablet Example 1. [Figure 7B] FIG. 7B is a typical dissolution profile of a docetaxel tablet prepared from an amorphous solid dispersion of the inventive concepts: Docetaxel Tablet Example 2. [Figure 7C] FIG. 7C is a typical dissolution profile of a docetaxel tablet prepared from an amorphous solid dispersion of the inventive concepts: Docetaxel Tablet Example 3. [Figure 7D] FIG. 7D is a typical dissolution profile of a docetaxel tablet prepared from an amorphous solid dispersion of the inventive concepts: Docetaxel Tablet Example 4. [Figure 7E] FIG. 7E is a typical dissolution profile of a docetaxel tablet prepared from an amorphous solid dispersion of the inventive concepts: Docetaxel Tablet Example 5. [Figure 7F] FIG. 7F is a typical dissolution profile of docetaxel tablets prepared from amorphous solid dispersion D: Docetaxel Tablet Example 6. [Figure 8A] FIG. 8A is a typical dissolution profile of a paclitaxel tablet prepared from an amorphous solid dispersion: Paclitaxel Tablet Example 1. [Figure 8B] FIG. 8B is a typical dissolution profile of a paclitaxel tablet prepared from an amorphous solid dispersion: Paclitaxel Tablet Example 2. [Figure 8C] FIG. 8C is a typical dissolution profile of a paclitaxel tablet prepared from an amorphous solid dispersion: Paclitaxel Tablet Example 3. [Figure 8D]FIG. 8D is a typical dissolution profile of a paclitaxel tablet prepared from an amorphous solid dispersion: Paclitaxel Tablet Example 4. [Figure 8E] FIG. 8E is a typical dissolution profile of a paclitaxel tablet prepared from an amorphous solid dispersion of the inventive concepts: Paclitaxel Tablet Example 5. [Figure 9] FIG. 9 is a comparative dissolution profile of paclitaxel prepared from an amorphous solid dispersion of the inventive concept (Paclitaxel Tablet Example 5), a prior art paclitaxel tablet (Paclitaxel Tablet Comparator 1), and a prior art paclitaxel capsule (Paclitaxel Capsule Comparator 2). [Figure 10] FIG. 10 is a typical dissolution profile of paclitaxel amorphous granules of the inventive concept produced by fluid bed granulation. [Figure 11] FIG. 11 is a representative X-ray diffractogram of the paclitaxel solid granule dispersion of the inventive concept and crystalline paclitaxel drug substance produced by fluid bed granulation. [Figure 12A] FIG. 12A shows a typical dissolution profile of a 30 mg strength paclitaxel tablet made from amorphous granules of the inventive concepts produced by fluid bed granulation. [Figure 12B] FIG. 12B shows a typical dissolution profile of a 90 mg strength paclitaxel tablet of the inventive concept manufactured from amorphous granules produced by fluid bed granulation. DETAILED DESCRIPTION OF THE INVENTION

[0028] (Detailed Description of the Invention) The subject matter of the invention provides high-strength, ready-to-dose oral compositions of taxanes and methods for their manufacture. The ready-to-dose oral compositions described herein include compressed tablets with high taxane loadings, which can be prepared from amorphous solid dispersions (ASDs) of taxanes formed from a solution of the taxane and a hypromellose acetate succinate (HPMCAS) carrier. A simple, commercial-scale method suitable for production is also described. Suitable taxanes include diterpene compounds having a taxadiene core, such as paclitaxel, docetaxel, and cabazitaxel. In chemotherapy, taxanes are typically administered as an infusion over one to several hours.

[0029] The inventors have unexpectedly discovered that hypromellose acetate succinate (HPMCAS) can be used to provide solid dispersions of taxanes that offer high solubility in aqueous solutions and high bioavailability. While not wishing to be bound by theory, the inventors believe that the improved bioavailability is at least partially due to the pH-dependent dissolution of the HPMCAS carrier, which in turn results in at least partially selective release of the active ingredient (e.g., taxane) of the composition in the later portions of the gastrointestinal tract after ingestion (e.g., the small intestine and / or large intestine, which have higher pH than the stomach). Different grades of HPMCAS dissolve at dissolution pHs ranging from about 5 to about 6, or about 6.8 or higher. As a result, release of most, or at least about half, of the taxane active ingredient of a composition of the inventive concepts placed in aqueous solution occurs after a shift from a highly acidic pH (i.e., below pH 5) to a pH of about 5 or higher (e.g., above about pH 5, above about pH 5.5, above about pH 6, and / or above about pH 6.5). The solid dispersion can be prepared as an amorphous solid, which can then be compressed into a tablet, caplet, or similar orally administrable form that provides the taxane in a form and amount suitable for chemotherapy. In some embodiments, the amorphous solid can be prepared using spray drying techniques. In other embodiments, the amorphous solid can be prepared by granulation methods such as fluidized bed granulation and / or top-down spray granulation.

[0030] In some embodiments, additional compounds can be incorporated into the solid dispersion. For example, in addition to the taxane and hypromellose acetate succinate, one or more surfactants can be included. Suitable surfactants include anionic surfactants, cationic surfactants, and zwitterionic surfactants. In some embodiments, the surfactant can be a hydrocarbon chain with a sulfate group (such as dodecyl sulfate) or a salt thereof.

[0031] Methods used in the production of amorphous solids, such as spray drying and / or fluidized bed granulation, generally incorporate the use of solvents during the manufacturing process. These solvents are removed or substantially removed in the drying step. Specific exemplary solvents are described below, but any solvent suitable for pharmaceutical use can be used. Examples of such solvents include Class 2 and Class 3 solvents as described in the FDA published Q3C-Tables and List Guidance for Industry. This document is available at www.fda.gov / downloads / drugs / guidances / ucm073395.pdf (the contents of which are incorporated herein by reference). In compositions of the inventive concepts, the concentration of Class 2 solvent remaining after completion of processing should be an amount that provides a PDE less than the recommended daily dose described therein using an effective dosing schedule. Similarly, in compositions of the inventive concepts, the amount of Class 3 solvent remaining after completion of processing should be an amount that provides less than 50 mg per day using an effective dosing schedule.

[0032] High-strength formulation - High-bioavailability taxane tablet composition

[0033] Preparation of amorphous taxane dispersions by spray drying.

[0034] Spray drying method A spray solution containing one or more taxanes and a polymeric carrier (e.g., HPMCAS) was prepared by first dissolving the taxane(s) in a pharmaceutically acceptable organic solvent system. Suitable organic solvent systems include ethanol, acetone, tetrahydrofuran, and aqueous solutions of such organic solvents. Although not required, in some embodiments, a surfactant can be added to the spray solution.

[0035] The spray solution was fed to a spray dryer (e.g., a Buchi Mini Spray Dryer B290™) connected to a dehumidifier (e.g., a Buchi Dehumidifier) ​​and an inert loop (e.g., a Buchi Inert Loop B295™) that allowed the spray dryer to work safely with organic solvents to produce amorphous solid dispersion powders.

[0036] The formation of an amorphous solid dispersion is affected by factors such as the inlet temperature, outlet temperature, and atomization flow rate. In a typical operation, an inlet temperature of 80°C to 120°C and an outlet temperature of 40°C to 80°C can be used, provided that the outlet temperature is lower than the inlet temperature. In some embodiments, the temperature difference between the inlet and outlet temperatures can be in the range of about 5°C, about 7°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, or about 40°C. The atomization flow rate can be in the range of about 10% to about 20% at 100% suction. For example, a spray solution can be provided to a spray dryer under the following conditions: an inlet temperature of 100°C, an outlet temperature of 59°C, and an atomization flow rate of 15% at 100% suction.

[0037] The resulting spray-dried amorphous solid dispersion is preferably stored under low moisture / humidity conditions, for example, such a spray-dried amorphous solid dispersion can be stored in an airtight container containing silica gel.

[0038] In embodiments utilizing a surfactant, the surfactant was either spray dried as part of the spray solution or physically mixed (e.g., using a blender) with the amorphous solid dispersion prepared from the taxane and polymeric carrier as described above prior to storage.

[0039] Dissolution testing of spray-dried amorphous solid dispersions The supersaturated solubility, physical stability, and release of taxane from the composition were investigated using a USP2011 dissolution apparatus II (Copley, UK) using dissolution media equilibrated at 37±0.5° C. in combination with simulated gastrointestinal fluid in the form of aqueous buffers having various pH values ​​representative of various portions of the human gastrointestinal tract (e.g., stomach, small intestine, large intestine, and / or portions thereof). The following exemplary 3-pH dissolution test method was used at pH values ​​of 4, 6.8, and 7.5 to simulate the varying pH conditions and elapsed time along the gastrointestinal tract. (a) The amorphous solid dispersion powder is filled into size 0 gelatin capsule(s); (b) the stirring speed of the dissolution paddle is set at 100 revolutions per minute (RPM); (c) the capsule(s) (in a sinker apparatus) are introduced into a dissolution vessel containing pH 4.0 dissolution medium for 1 hour, then adjusted to pH 6.8 (by addition of NaOH) for 1 hour, and then adjusted to pH 7.5 (by addition of NaOH) for 2 hours; (d) samples are collected at the following time points—0, 10, 20, 30, and 60 minutes for pH 4; 70, 80, 90, and 120 minutes for pH 6.8; and 130, 140, 150, 180, 210, and 240 minutes for pH 7.5, which are then replaced with an equal volume of fresh dissolution medium to compensate for losses due to each sampling; (e) the collected samples are centrifuged, and the supernatant is used for HPLC analysis. In some embodiments, such supernatants can be diluted with a suitable organic solvent (eg, 1:1 in methanol) prior to HPLC analysis.

[0040] In an exemplary HPLC analysis of docetaxel formulations by dissolution testing (as described above), HPLC was performed using the following conditions: Column: A stainless steel column (inner diameter 4.6 mm and length 15 cm) packed with a dimethyl-n-octadecylsilane stationary phase bonded to a porous silica support (e.g., C18.5 μm particle size) for liquid chromatography. Mobile phase: A: 0.1% formic acid in ultrapure water B: 0.1% formic acid in acetonitrile Detector: UV absorption detector (absorbance at 230 nm) Flow rate: 1.2mL / min Injection volume: 20 μL Column temperature: 45°C Gradient system:

[0041] TIFF0007813969000001.tif115161

[0042] In an exemplary HPLC analysis of paclitaxel formulations by dissolution testing (as described above), HPLC was performed using the following conditions: Column: A stainless steel column (inner diameter approximately 4.6 mm and length 15 cm) packed with a dimethyl-n-octadecylsilane stationary phase bonded to a porous silica support (e.g., C18.5 μm particle size) for liquid chromatography. Mobile phase: A: ultrapure water, B: acetonitrile Detector: UV-absorption detector (absorbance at 227 nm) Flow rate: 1.2mL / min Injection volume: 20 μL Column temperature: 30℃ Gradient system:

[0043] TIFF0007813969000002.tif91161

[0044] This "3-pH dissolution model" spanning 240 minutes is considered to be a more stringent screen for evaluating the effectiveness of amorphous compositions in preventing precipitation of taxanes at supersaturated concentrations compared to the single pH dissolution method previously disclosed in PCT / KR2014 / 002734 (Hanmi Pharm. Co, Ltd), which is carried out over 120 minutes.

[0045] Composition of spray-dried amorphous solid dispersions (ASD) The compositions of the above amorphous solid dispersions primarily comprised a taxane active ingredient, a polymeric carrier, and (in some embodiments) an optional surfactant component. Because the goal was to develop tablet compositions that provided high taxane active loadings, it was necessary to keep the proportion of excipients as low as possible relative to the active ingredient. For amorphous solid dispersions, the proportion of polymeric carrier also needed to be minimized. However, this concept runs counter to conventional formulation principles, since a higher polymeric carrier-to-taxane ratio is typically considered necessary to maintain supersaturated solubility of the active ingredient. This is evident from the data presented in Table 1, which summarizes various compositions using polyvinylpyrrolidone K-30 (PVP K-30), a polymeric carrier used in known formulations of amorphous solid dispersions of taxanes (see, e.g., US 2011 / 0207804 A1 and PCT / KR2014 / 002734). Figure 1, which shows the corresponding dissolution profiles (ASD Examples 1-3), clearly demonstrates that the PVP K-30 content must be high relative to the active taxane ingredient (e.g., comparable to a composition ratio of docetaxel:PVP K-30:SDS=1:9:1 (ASD Example 3)) to maintain supersaturated solubility in the described dissolution model. Due to the high proportion of PVP K-30 required, PVP K-30 is not suitable for use as an amorphous dispersion polymer carrier for high-strength taxane tablet formulations.

[0046] [Table 1]

[0047] Tables 2A and 2B show the compositions of ASD Examples 4-7, using hydroxypropyl methylcellulose phthalate HPMCP (50) and (55), respectively, as alternative polymer carriers, with and without SDS as a surfactant component. Figures 2A and 2B show the corresponding dissolution profiles of these compositions. It should be noted that dissolution is minimal (substantially less than 50%) at the first, relatively acidic pH 4 step, and rapidly increases with increasing pH to 6.8. This is consistently observed for formulations of the inventive concept. Figure 2A shows that sustained supersaturated solubility is not achieved at a docetaxel:HPMCP:SDS ratio of 1:3:1. As shown in Figure 2B, release in the absence of SDS is also very slow, reaching maximum release approximately 3 hours after dissolution of the HPMCP polymer.

[0048] [Table 2A]

[0049] [Table 2B]

[0050] Tables 3A and 3B show compositions using Eudragit L100-55 with and without SDS, respectively, and Figures 3A and 3B show the corresponding dissolution profiles. Figure 3A reveals that the minimum docetaxel:Eudragit L100-55:SDS ratio that successfully maintains supersaturated solubility is 1:4:1 (ASD Example 9). Figure 3B shows that while Eudragit L100-55 can be an effective polymer when formulated without SDS, docetaxel release is slow, beginning and reaching a maximum concentration only after 180 minutes. Thus, it appears that SDS may be a desirable ingredient in taxane compositions containing Eudragit and may aid in the release of docetaxel in such formulations.

[0051] [Table 3A]

[0052] [Table 3B]

[0053] Tables 4A and 4B show compositions using HPMCAS with and without SDS, respectively, and Figures 4A and 4B show the corresponding dissolution profiles. Figure 4A shows that, surprisingly, at very low proportions of HPMCAS (docetaxel:HPMCAS:SDS ratio of 1:1.67:0.67, as in ASD Example 16), >70% docetaxel supersaturation can be achieved for more than 3 hours. Even more surprisingly, when the ratio of HPMCAS to SDS in the composition is increased slightly to docetaxel:HPMCAS-LG:SDS=1:3:1 (ASD Example 13), near 100% supersaturation of liberated docetaxel can be maintained for extended periods.

[0054] [Table 4A]

[0055] [Table 4B]

[0056] A further unexpected observation from Figure 4B is that in compositions with HPMCAS content selected to yield a 1:3 docetaxel:HPMCAS ratio (ASD Example 20), SDS (i.e., surfactant component) can be omitted from high-dose tablet taxane formulations while retaining its ability to maintain sustained supersaturated concentrations. As shown in 1:3 and higher docetaxel:HPMCAS formulations, 80% supersaturated solubility of liberated docetaxel can be maintained for at least 3 hours. This contrasts with previous observations using other polymers mentioned above (e.g., PVP K-30, Eudragit, and HPMCP) in which surfactant is an essential component. Surprisingly, this is not the case with HPMCAS. The elimination of the need for a surfactant component provides an additional advantage in terms of active ingredient loading for high-load tablets.

[0057] Table 5 and Figure 5 show an example of the composition of an amorphous solid dispersion of paclitaxel:HPMCAS:SDS of the inventive concept, as well as a typical corresponding dissolution profile. As observed with docetaxel, the paclitaxel-based amorphous solid dispersion also produced a sustained supersaturation state at a ratio of 1:3:1.

[0058] [Table 5]

[0059] X-ray diffraction analysis X-ray powder diffraction analysis of the amorphous solid dispersions of docetaxel and paclitaxel prepared using the spray-drying method and each drug substance was performed using an X'Pert PRO X-ray diffraction system (Malvern Panalytical, UK). Samples were mounted in a sample holder and successive scans were performed over an angular range of 5° to 50° in 2θ.

[0060] Figures 6A and 6B, which show the X-ray diffractograms of the amorphous solid dispersions of docetaxel and paclitaxel, show sequential X-ray diffraction patterns compared to the X-ray diffractogram of the drug substance, confirming that conversion of the drug substance from a crystalline form to an amorphous form occurs in the process of making these amorphous solid dispersions.

[0061] Tablet manufacturing method utilizing spray-dried amorphous solid dispersions

[0062] The spray-dried solid dispersion of the active ingredient was mixed with one or more intragranular excipients, which may include a superdisintegrant and a binder, and combined with water to form a wet mass using a wet granulation method. Coarse mass screening was performed with a #12 sieve. The resulting granules were dried at 50°C and subsequently screened with a #20 sieve. The mixture was then combined in an extragranular manner with the superdisintegrant, lubricant, and the extragranular portion of the filler. The final mixture was then compressed into tablets using a tablet press.

[0063] Composition of docetaxel tablets from spray-dried amorphous solid dispersions Table 6 shows the compositions of docetaxel tablets prepared from amorphous solid dispersions based on docetaxel:HPMCAS:surfactant ratios of 1:2:1 and 1:3:1 with various active ingredient loadings and various proportions of primary functional excipients (e.g., superdisintegrants).

[0064] [Table 6]

[0065] Based on a 1:3:1 ratio of docetaxel:HPMCAS:surfactant solid dispersion, Figures 7A-7F show the dissolution curves of docetaxel tablet Examples 1-6, containing 6.66% to 13.89% docetaxel. Figure 7F shows that even when the docetaxel loading was increased to 13.89% (Docetaxel Tablet Example 6), the HPMCAS-containing formulation was able to maintain a high supersaturation concentration of 80-90% for at least 3 hours. It should be noted that the formulation of the inventive concept was able to achieve 104.2 mg of active taxane in a 750 mg tablet (Docetaxel Tablet 6) for a loading of approximately 14% active ingredient by weight in the tablet. This is approximately a 3.5-fold increase in loading compared to prior art formulations. The inventors believe that higher loadings are possible with further optimization. Active ingredient loadings of up to about 5%, 10%, 15%, 20%, and 25%, as well as intermediate ranges between these values ​​(e.g., 10%-15%, 5%-20%, etc.), are contemplated. It has been noted that at higher HPMCAS concentrations (e.g., up to about 40% tablet loading, as seen in Docetaxel Tablet Examples 5 and 6), tablets tend to form a gel layer that can retard active ingredient release if the superdisintegrant concentration is not adjusted accordingly (see Figure 7E). Therefore, for higher active ingredient loadings, a superdisintegrant concentration of at least 10% is preferred. Polyvinylpolypyrrolidone (PVPP), cross-linked modifications of polyvinylpyrrolidone, and croscarmellose sodium have also been identified as effective superdisintegrants to ensure efficient release of the active. It is contemplated that these disintegrants can be incorporated either intragranularly or extragranularly, or both. It is also noteworthy that while the preferred tablet composition of taxanes described in International Patent Application Publication No. 2015 / 152433 A1 (Hanmi Phar. Co. Ltd.) can achieve 30 mg of active substance in a tablet weighing 750 mg, the tablets of the present invention (as described in Docetaxel Example 5) can actually achieve a strength of 104.2 mg of active substance in the same tablet weight of 750 mg. This represents up to a 3.47-fold increase in active substance loading per tablet compared to prior art examples.

[0066] 7A-7F, it can be seen that for formulations incorporating HPMCAS-LG (which dissolves above pH 5.5), release of a significant proportion of the active ingredient can occur after the pH shift from 4 to 6.8. This advantageously reserves release of most of the taxane active ingredient for later in the digestive process (e.g., after leaving the stomach). It should be understood that in some embodiments, the formulations can be co-administered with a p-glycoprotein inhibitor (e.g., P-glycoprotein), and thus, this release pattern provided by the formulations may actually be desirable, as absorption of the taxane may be maximized.

[0067] The inventors believe that in some embodiments, tablets of the inventive concepts can be enteric coated with an enteric polymer that dissolves at a pH above 5.5, such as HPMCAS-LG, hydroxypropyl methylcellulose phthalate, Eudragit L100-55, and / or Eudragit L100.

[0068] Composition of paclitaxel tablets prepared from spray-dried amorphous solid dispersions Table 7 shows the compositions of paclitaxel tablets made from amorphous solid dispersions based on paclitaxel:HPMCAS:surfactant at paclitaxel loadings ranging from 6.66% to 11.11%. Figures 8A-8E show that paclitaxel supersaturation can be maintained in these formulations for more than 3 hours, even at tablet loadings greater than 10% (i.e., up to at least 11.11%). This is consistent with data observed for docetaxel, where polyvinyl-polypyrrolidone and croscarmellose sodium are useful superdisintegrants, which can be incorporated either intragranularly or extragranularly, or both.

[0069] [Table 7]

[0070] Comparison of dissolution and bioavailability of paclitaxel tablets of the present invention to prior art compositions Paclitaxel Tablet Example 5, a prior art paclitaxel tablet formulation (Paclitaxel Tablet Comparator 1), and a prior art paclitaxel capsule formulation (Paclitaxel Capsule The dissolution profiles and oral bioavailability of Comparative Standard 2 were compared. Typical dissolution profiles using the 3-pH method described above are shown in Figure 9. Paclitaxel tablet Comparative Standard 1 has a loading of 30 mg of active substance and contains an amorphous solid dispersion using PVP K-30 as the polymer carrier, as described in Example 9 of International Patent Application Publication No. 2015 / 152433A1 (Hanmi Phar. Co. Ltd.). Paclitaxel capsule Comparative Standard 2 is a 30 mg capsule in which paclitaxel is dissolved in polysorbate 80, as described in Comparative Example 1 of International Patent Application Publication No. 2015 / 152433A1 (Hanmi Phar. Co. Ltd.).

[0071] For dissolution studies, a 33.33 mg tablet strength of Paclitaxel Example 5 was prepared. Dissolution tests were then performed on Paclitaxel Tablet Example 5, Paclitaxel Tablet Comparative 1, and Paclitaxel Capsule Comparative 2. As shown in Figure 9, the paclitaxel tablet formulation of the inventive concepts exhibits delayed release at acidic pH (e.g., pH 4.0 or below pH 6.8) and maintains a high level of saturation at pH 6.8 or above. Figure 9 clearly shows that while the tablets of the present invention were able to maintain paclitaxel supersaturation for more than 3 hours, the paclitaxel supersaturation concentrations from Paclitaxel Comparative Tablet 1 and Paclitaxel Capsule Comparative 2 began to decrease after 1 hour, indicating that paclitaxel began to precipitate in these prior art compositions.

[0072] For pharmacokinetic studies, the oral bioavailability of Paclitaxel Tablet Example 5, Paclitaxel Tablet Comparator 1, and Paclitaxel Capsule Comparator 2 was investigated in naive beagle dogs by coadministration with HM30181A tablets. Twenty naive male beagle dogs (weight 9.5-10.5 kg) were treated according to the regimen shown in Table 8. Paclitaxel Tablet Example 5 was manufactured as an 80 mg strength tablet, while Paclitaxel Tablet Comparator 1 and Paclitaxel Capsule Comparator 2 were available as 30 mg dosage units, with a target dose of 80-90 mg per dog. Thirty minutes prior to oral administration of each of these formulations, each dog was treated with a 15 mg HM30181A tablet. For the intravenous route, dogs received a single injection of 2 mL / kg of paclitaxel solution (1 mg / ml, 4.9% Solutol HS15) infused over 60 minutes.

[0073] [Table 8]

[0074] Table 9, which summarizes the pharmacokinetic data, clearly demonstrates that paclitaxel tablet Example 5 unexpectedly provides significantly improved oral absorption, as evidenced by increases in Cmax, AUC0-t, AUC0-∞, and F(%). Most notably, the bioavailability F(%) of this composition described in this invention, which provides a high active substance loading per unit dosage form (i.e., uses less polymer carrier), is more than twice that of both comparative benchmark formulations. Therefore, the results provided by the tablet composition described in this invention are unexpected.

[0075] [Table 9]

[0076] Preparation and characterization of amorphous taxane compositions by fluidized bed granulation

[0077] Fluidized bed granulation methodSimilar to spray drying, a spray solution containing a taxane can be prepared by first dissolving the taxane (e.g., paclitaxel) and HPMCAS in a suitable solvent system (e.g., aqueous ethanol). In some embodiments, a surfactant (e.g., sodium lauryl sulfate) can be added to the spray solution, while in other embodiments, the taxane formulation does not contain a surfactant. Fluid-bed granulation can be carried out using any suitable fluid-bed granulation system. Suitable fluid-bed granulation systems include a Vector™ FLM-3 (Vector Corporation, Marion, USA) top-spray fluid-bed granulator. In an exemplary embodiment, a solution of the taxane prepared as described above is prepared and sprayed into a product container containing an intragranular excipient (e.g., microcrystalline cellulose) and one or more extragranular excipient(s) (e.g., cross-linked polyvinylpyrrolidone, colloidal silicon dioxide, sodium stearyl fumarate, microcrystalline cellulose, etc.). The following parameters were used: spray rate in the range of 40-60 g / min, inlet temperature in the range of 60-70°C, exhaust temperature in the range of 30-38°C, and atomization air pressure in the range of 30-50 PSI. After the spraying process was completed, the granulation was dried until a loss on drying (LOD) value of 2.0% or less was achieved. When the taxane used was paclitaxel, the resulting solid dispersion contained free-flowing amorphous paclitaxel granules. While not wishing to be bound by theory, the inventors believe that the taxane active ingredient forms an amorphous matrix coating or layer in HPMCAS on the surface of the intragranular excipients. Such amorphous granules can be formed into tablets providing the desired unit dose of taxane (e.g., 1 mg to 100 mg or more). In such embodiments, one or more surfactants can be provided in the formulation, for example, by incorporating them into the spray solution or by adding them as a solution or solid prior to drying. Similarly, in such embodiments, one or more stabilizers may be incorporated by addition to the spray solution before drying or by addition as a solution or solid.Such embodiments may also incorporate one or more disintegrants and / or superdisintegrants, for example, by incorporating them into the spray solution prior to drying or by adding them as a solution or solid. It is contemplated that surfactants, stabilizers, and disintegrants / superdisintegrants suitable for use in spray drying may also be suitable for fluidized bed granulation. Table 10, for example, shows example compositions of 30 and 90 mg high-strength paclitaxel tablets produced using top-spray fluidized bed granulation.

[0078] [Table 10]

[0079] Dissolution testing of taxane formulations manufactured by fluidized bed granulation Dissolution testing of amorphous solid dispersions and tablet compositions prepared using spray drying was performed using the 3-pH model described above. By adding an additional dissolution step at pH 1.2, a similar 4-pH dissolution model was utilized to characterize the dissolution of amorphous taxane-containing granules and tablets prepared from amorphous taxane-containing granules prepared by fluidized-bed granulation. This provides a rigorous assessment of the physical testing and release of taxane from the composition, and also more closely simulates the changing pH of the GI tract experienced by such compositions after ingestion. It should be noted that dissolution is minimal (substantially less than 50%) in the first acidic pH 1.2 step and the second acidic pH 4.0 step, increasing rapidly as the pH increases to 6.8. This is consistently observed for formulations of the inventive concepts.

[0080] An exemplary 4-pH dissolution test method utilizing simulated gastrointestinal fluid (in the form of an aqueous buffer solution having various pH values ​​representative of various portions of the human gastrointestinal tract—e.g., stomach, small intestine, large intestine, and / or portions thereof) at pH values ​​of 1.2, 4.0, 6.8, and 7.5 can be performed as follows: (a) fill the amorphous solid granule dispersion into size 0 gelatin capsule(s) or, alternatively, form tablets containing the amorphous taxane-containing granule dispersion; (b) set the agitation speed of the dissolution paddle at 100 revolutions per minute (RPM); (c) introduce the capsules or tablets (in a sinker apparatus) into a dissolution vessel containing 720 ml of 0.1 N hydrochloric acid (pH 1.2); (d) after 1 hour at pH 1.2, dissolve the capsules or tablets in 180 ml of 0.25 M monobasic sodium phosphate (NaH ) containing 5% w / v polysorbate 80; 2 PO 4 ) solution to a final molar concentration of 0.05M NaH 2 PO 4 and polysorbate 80 at a concentration of 1% w / v and adjusted to pH 4.0 (by adding 20% ​​sodium hydroxide (NaOH, 1% w / v polysorbate 80 was used to keep the sinker apparatus submerged during dissolution), (e) after 1 hour at pH 4.0, adjust the pH of the solution to pH 6.8 (e.g., by adding 20% ​​NaOH), (f) after 1 hour at pH 6.8, adjust the pH of the solution to pH 7.5 (e.g., by adding 20% ​​NaOH) and stir for an additional 2 hours. Samples are collected at the following time points - pH 1.2 The following time points were used for the dissolution analysis: 0, 10, 20, 30, and 60 minutes for pH 4; 70, 80, 90, and 120 minutes for pH 4; 130, 140, 150, and 180 minutes for pH 6.8; and 190, 200, 210, 240, 270, and 300 minutes for pH 7.5. An equal volume of fresh dissolution solvent was added after sampling to compensate for volume loss. The collected samples were centrifuged, and the supernatants were subjected to HPLC analysis. In some embodiments, the supernatants can be diluted with a suitable organic solvent (e.g., 1:1 in methanol) prior to HPLC analysis.

[0081] To characterize the dissolution of an amorphous solid granule dispersion of paclitaxel equivalent to a high-strength tablet containing 90 mg of paclitaxel, 786 mg of amorphous paclitaxel granules were used, filled into four size 0 capsules, and analyzed according to the procedure described above. Figure 10 shows a typical dissolution profile of such an amorphous solid granule dispersion. It is clear that the granules can sustain a supersaturated concentration of more than 70% of the active ingredient (i.e., paclitaxel) released for at least 3 hours. From the improved solubility and supersaturation concentration achieved, it can be inferred that paclitaxel had been converted to an amorphous state using the fluidized-bed granulation process.

[0082] X-ray diffraction analysis of amorphous granules produced by fluidized bed granulation X-ray powder diffraction analysis of the amorphous solid granular paclitaxel dispersions and conventional paclitaxel drug substance was performed using an X'Pert PRO™ X-ray diffraction system (Malvern Panalytical, UK). Samples were mounted on a sample holder and sequentially scanned over an angular range of 5° to 50° in 2θ.

[0083] Figure 11 shows a typical X-ray diffractogram of an amorphous solid granule dispersion of paclitaxel. The sequential appearance of the X-ray powder diffraction pattern further confirms the conversion of the crystalline form of the drug substance to the amorphous form in the solid granule dispersion when compared to normal crystalline paclitaxel.

[0084] Preparation of paclitaxel tablets from amorphous granules produced by fluidized bed granulation and their dissolution profiles In a typical process for preparing tablets from amorphous solid granules produced by fluidized bed granulation as described above, the granules are milled and blended with one or more excipients. Typical excipients include disintegrants, fillers, binders, etc., examples of which are provided in Table 10. Tablets can be manufactured by any suitable process, such as molding and / or compression. Tablets can be manufactured in any suitable shape that facilitates ingestion, such as round, oval, cylindrical, etc. Similarly, tablets can be manufactured at any suitable hardness or compression level required to provide suitable binding strength and size. In the provided example, 30 mg tablets are compressed to an average hardness of 8 kp, and 90 mg tablets are compressed to an average hardness of 12 kp.

[0085] The dissolution profiles of the 30 and 90 mg tablets (determined using the 4-pH step process as described above) are shown in Figures 12A and 12B, respectively. These dissolution profiles achieved maximum release of the active agent within 10 minutes of the tablet disintegrating and the HPMCAS polymer dissolving after the pH exceeded 4.0, again providing a release percentage of greater than 70%, which was sustainable for at least 3 hours.

[0086] Comparison of the bioavailability of paclitaxel tablets made from amorphous granules produced using fluid bed granulation with prior art compositions The oral bioavailability of paclitaxel tablets prepared from amorphous granules produced by fluidized-bed granulation (specifically, top-spray fluidized-bed granulation) using HPMCAS polymer and prior art paclitaxel tablets was investigated by co-administration of HM30181A tablets in naive beagle dogs. The prior art paclitaxel tablets had a loading of 30 mg of active ingredient and contained an amorphous solid dispersion prepared using PVP K-30 as the polymer carrier, as described in Example 9 of International Patent Application Publication No. WO 2015 / 152433 A1 (Hanmi Phar. Co. Ltd).

[0087] For the pharmacokinetic study, 15 naive male beagle dogs (weight 9.0-10.5 kg) were randomly divided into three groups of five animals each according to the study design shown in Table 11. Animals in groups 1 and 2 were treated with paclitaxel tablets prepared from amorphous granules produced by fluid-bed granulation using HPMCAS polymer or prior art paclitaxel tablets, respectively, co-administered with HM30181A for both tablet formulations in a crossover design, with the two phases separated by a one-week washout period. Animals in group 3 received paclitaxel intravenously in only one phase.

[0088] [Table 11]

[0089] The oral dose selected for this study was 60 mg per animal, which is lower than the 80-90 mg dose used in a previous pharmacokinetic study comparing inventive concept tablets manufactured by a spray-drying process. Therefore, two units of 30 mg strength tablets were used for paclitaxel tablets prepared from amorphous granules produced by fluid-bed granulation using HPMCAS polymer or prior art paclitaxel tablets when administered to each dog in the appropriate test group. Thirty minutes before oral administration of each of these formulations, each dog was treated with a 15 mg HM30181A tablet. For the intravenous route, dogs received a single 2 ml / kg infusion of paclitaxel solution (1 mg / ml, 4.9% Solutol HS15™) infused over 60 minutes.

[0090] Table 12 summarizes the pharmacokinetic data obtained, showing that paclitaxel tablets prepared from amorphous granules produced by fluid-bed granulation using HPMCAS polymer at a dose of 60 mg per animal also showed a significant improvement in AUC o-t , AUC o-∞ and F (%).

[0091] [Table 12]

[0092] Thus, various oral compositions of taxanes with high active substance loading and high bioavailability are presented herein. The described methods advantageously use spray-drying or fluid-bed granulation processes that do not involve the formation of emulsions, antisolvents, or liquid bridging solvents, as required by prior art processes. Instead, the processes described herein spray-dry dissolved taxanes, resulting in the formation of solid powder / granule amorphous solid dispersions. Such solid dispersions, unlike hollow microspheres, can be effectively compressed into tablets as discussed herein.

[0093] It should be understood that the compositions of the present invention can be effectively compressed into tablets, a property not shared by compositions in which the active ingredient is incorporated into hollow-core microspheres. Similarly, it should be understood that the compositions of the inventive concept can be produced by scalable means suitable for large-scale manufacturing and do not require the inclusion of a dispersing agent (e.g., porous silica) to enhance and / or provide adequate bioavailability. This provides a beneficial technical effect, as the elimination of such dispersing agents allows for higher loading of the active ingredient (e.g., taxane) in the final dosage form.

[0094] In some embodiments, the numerical parameters should be understood in terms of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as practicable. The numerical values ​​presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0095] As used throughout this specification and the claims that follow, the meanings of "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Also, as used herein, the meaning of "in" includes "on" unless the context clearly dictates otherwise.

[0096] Groupings of other elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the specification is intended to include the group as modified to satisfy all Markush group descriptions used in the appended claims.

[0097] It will be apparent to those skilled in the art that many further modifications beyond those already described are possible without departing from the inventive concepts herein. Accordingly, the inventive subject matter is not limited except as by the appended claims. Moreover, both in the specification and in the claims, all terms should be interpreted in the broadest manner consistent with the context. In particular, the terms "comprises" and "comprising" should be interpreted to refer non-exclusively to elements, components, or steps, meaning that a recited element, component, or step may be present in, utilized with, or combined with other elements, components, or steps not explicitly recited. When a specification or claim refers to at least one selected from the group consisting of A, B, C, ..., and N, the text should be interpreted as requiring only one element from that group, rather than A+N, or B+N, etc.

Claims

1. A ready-to-administer oral composition comprising: an amorphous solid dispersion comprising paclitaxel, a hypromellose acetate succinate (HPMCAS) carrier, and sodium dodecyl sulfate (SDS); the paclitaxel, the HPMCAS, and the SDS are present in the oral composition in a ratio of 1:3:1 to 1:4:1; and the paclitaxel is present in a concentration of at least 6.66% by weight of the oral composition; The oral composition maintains a supersaturated concentration of paclitaxel for at least 3 hours when mixed with a buffer solution having a pH of 6.8 to 7.

5.

2. The composition described in claim 1, wherein upon oral administration of the composition, a supersaturated solubility of at least 70% of the paclitaxel content of the oral composition is maintained in a dissolved state at pH 7.4 for at least 2 hours.

3. The composition of claim 1, wherein the oral composition is formulated as a compressed tablet.

4. 10. The composition of claim 1, wherein the solid dispersion is a spray-dried amorphous solid dispersion or amorphous granules produced by fluidized bed granulation.

5. The composition described in claim 1, wherein the paclitaxel is present at a concentration of up to 11.11% by weight of the oral composition.

6. A composition described in claim 1 for treating cancer in an individual being treated with HM30181A.

7. The composition described in claim 6, wherein the individual has previously been treated with HM30181A.

8. The composition described in claim 6, wherein the individual is treated with 15 mg of HM30181A.

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