High-strength oral taxane compositions and methods

Abstract

The present invention provides compositions and methods for preparing high-dose, highly bioavailable oral taxane compositions. The oral taxanes can be prepared as amorphous solid dispersions and provided in compressed tablet form. Surprisingly, the oral bioavailability of the taxanes prepared and provided herein is high even in the absence of surfactants.

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 a definition or usage of a term in a document incorporated by reference does not match or conflict with the definition of the term provided herein, the definition of the term provided herein shall be deemed to control.

[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(s) 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). Because paclitaxel binds to tubulin, paclitaxel has the ability 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 low solubility in water, which makes it difficult to formulate a safe and effective treatment.

[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 poor 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. Typically, docetaxel is also formulated with a surfactant for parenteral delivery, and like paclitaxel, the bioavailability of orally administered docetaxel is very low.

[0008] One of the reasons for the 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 of low bioavailability is the low solubility of taxanes in water. Various techniques have been developed to try to enhance the solubility of taxanes. For example, US Patent Application Publication No. 2011 / 0,207,804 A1 (Slotervaart Participaties BV: Patent Document 4) describes a solid dispersion formulation filled in a capsule, and Chinese Patent Application No. 103083240A (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] Although many of these compositions can improve the supersaturated solubility and bioavailability of taxanes to some extent, such formulations do not present a practical and convenient final dosage form 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 loading per capsule can be achieved due to the limited volume of powder that can be accommodated in an oral capsule of practical dimensions. For example, US Patent Application Publication No. 2011 / 0,207,804 A1 (Slotervaart Participaties BV: Patent Document 4) describes a solid dispersion formulation in capsules that provides only 15 mg of docetaxel per capsule.

[0011] Alternatively, the dosage form may 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, it is believed that a 100 mg taxane active loading may be achievable in a 1 g tablet that can provide a 10% active ingredient loading. For example, the approach taken in Chinese Patent Application No. CN103083240A requires the use of a poor solvent and a liquid bridging solvent to form an emulsion that 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 their compression affects their structural integrity. This 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 formulations disclosed in Chinese Patent Application No. CN103083240A rely on the inclusion of a "dispersing agent" (such as porous silica) to increase the bioavailability of the active ingredient. In a preferred embodiment, a silica content of up to 35% is required. The need to include substantial amounts of this excipient (or similar excipients) necessarily limits the ability of such formulations to achieve high active loading content. 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 of the Federal Government Department of Health and Human Services (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 in inherent toxicity. In addition, 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. WO 2015 / 152433 A1 (Hanmi Phar.Co.Ltd: Patent Document 6). Unfortunately, a strength of only 30 mg paclitaxel in a total tablet weight of 750 mg was achieved. Naturally, tablets intended for human use typically do not exceed 1 g to ensure that they can be easily swallowed. The total dose of taxanes administered intravenously is 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 ng / kg), the total oral dose required per patient can be expected to exceed 300 mg in some cases. With known taxane capsules having 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 ingest. [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] U.S. Patent Application Publication No. 2011 / 0,207,804Al [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 THEINVENTION [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 since higher concentrations of taxanes would impair solubility and therefore bioavailability. [Means for solving the problem]

[0016] (Summary of the invention) The subject matter of the present invention provides high strength and high bioavailability ready to administer oral compositions of taxanes that are manufactured by an easily scalable process. The ready to administer oral compositions may include a solid dispersion of taxane and a hypromellose acetate succinate (HPMCAS) carrier, which is compressed into a tablet form with high taxane loading. Preferably, the taxane includes 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% by weight, at least 10% by weight, or at least 13% by weight. Although the disclosure herein is directed to oral compositions that include HPMCAS as a polymeric carrier, it is envisioned that other commercially suitable carriers may be used (e.g., hydroxypropyl methylcellulose phthalate, Eudragit®, etc.), which allows for high taxane loading and high bioavailability. Generally, the weight of the polymeric carrier comprises up to 90% by weight, up to 92% by weight, up to 94% by weight, up to 96% by weight, or up to 98% by weight of the total weight of the pharmaceutical composition.

[0017] The taxane and carrier may be present in the solid dispersion and final tablet form in any suitable ratio, 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 advantageous and surprisingly capable of providing high active agent 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 subject 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 more).

[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 of making 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] Various objects, features, aspects and advantages of the subject invention will become more apparent from the following detailed description of preferred embodiments, taken in conjunction with the accompanying drawings, in which like numerals represent like components. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 is a typical dissolution profile 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 amorphous solid dispersions of docetaxel:HPMCAS (no SDS, ASD Examples 18-20). [Diagram 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 typical 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 D amorphous solid dispersion: 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 concept produced by fluid bed granulation. [Figure 12B] FIG. 12B shows a typical dissolution profile of a 90 mg strength paclitaxel tablet of the inventive concepts manufactured from amorphous granules produced by fluid bed granulation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] 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 loading, 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 method suitable for simple and commercial scale manufacture is also described. Suitable taxanes include diterpene compounds having a taxadiene core, such as paclitaxel, docetaxel, and cabazitaxel. In chemotherapy, taxanes are generally administered as an infusion over one to several hours.

[0025] Surprisingly, the inventors have found that hypromellose acetate succinate (HPMCAS) can be used to provide solid dispersions of taxanes that provide high solubility in aqueous solutions and high bioavailability. Without wishing to be bound by theory, the inventors believe that the bioavailability is at least partially improved by 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 part of the digestive tract after ingestion (e.g., the small intestine and / or large intestine, which have a 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, the release of most or at least about half of the taxane active ingredient of the composition of the inventive concept placed in aqueous solution occurs after a shift from a highly acidic pH (i.e., less than pH 5) to a pH of about 5 or higher (e.g., greater than about pH 5, greater than about pH 5.5, greater than about pH 6, and / or greater than 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.

[0026] In some embodiments, additional compounds can be incorporated into the solid dispersion. For example, in addition to 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 salts thereof.

[0027] Methods used in the manufacture of amorphous solids, such as spray drying and / or fluid 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 the compositions of the inventive concept, the concentration of Class 2 solvent remaining after completion of processing should be an amount that provides less than the recommended PDE per day as described therein with an effective dosing schedule. Similarly, in the compositions of the inventive concept, the amount of Class 3 solvent remaining after completion of processing should be an amount that provides less than 50 mg per day with an effective dosing schedule.

[0028] High strength formulation - High bioavailability taxane tablet composition

[0029] Preparation of amorphous taxane dispersions by spray drying.

[0030] 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 pharma- ceutically 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.

[0031] 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 allows the spray dryer to work safely with organic solvents to produce amorphous solid dispersion powders.

[0032] The formation of the amorphous solid dispersion is influenced by factors such as the inlet temperature, the outlet temperature, and the 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 temperature and the outlet temperature 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, the spray solution can be provided to the spray dryer under the following conditions: inlet temperature 100°C, outlet temperature 59°C, and atomization flow rate 15% at 100% suction.

[0033] The resulting spray dried solid amorphous dispersion is preferably stored under low moisture / humidity conditions, for example, such a spray dried solid amorphous dispersion can be stored in an airtight container with silica gel.

[0034] 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.

[0035] Dissolution testing of spray-dried amorphous solid dispersions The supersaturation solubility, physical stability, and release of taxanes from the compositions were investigated using a USP2011 dissolution apparatus II (Copley, UK) using dissolution media equilibrated at 37±0.5° C. in combination with simulated gastrointestinal fluids in the form of aqueous buffers having various pH values ​​representative of various parts of the human gastrointestinal tract (e.g., stomach, small intestine, large intestine, and / or parts 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 time course 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 the sinker apparatus) is 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, and 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.

[0036] In an exemplary HPLC analysis of docetaxel formulations by dissolution testing (as described above), the 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 for liquid chromatography (e.g., C18.5 μm particle size). 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℃ Gradient system:

[0037] TIFF0007597984000001.tif115161

[0038] In an exemplary HPLC analysis of paclitaxel formulations by dissolution testing (as described above), the 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 for liquid chromatography (e.g., C18.5 μm particle size). 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:

[0039] TIFF0007597984000002.tif91161

[0040] 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) carried out over 120 minutes.

[0041] Composition of spray-dried amorphous solid dispersions (ASD) The compositions of the above amorphous solid dispersions mainly comprised a taxane active ingredient, a polymeric carrier, and (in some embodiments) an optional surfactant component. Since the aim is to develop a tablet composition that provides a high taxane active loading, it is necessary to keep the proportion of excipients as low as possible compared to the active ingredient. For amorphous solid dispersions, the proportion of polymeric carriers should also be minimized. However, this idea is contrary to conventional formulation principles, since it is usually believed that a higher polymeric carrier to taxane ratio is required to maintain the supersaturated solubility of the active ingredient. This is evident from the data shown 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, for example, US2011 / 0207804A1 and PCT / KR2014 / 002734). Figure 1 showing the corresponding dissolution profiles (ASD Examples 1-3) clearly shows that the content of PVP K-30 must be high compared to the active taxane ingredient (e.g., as high as in the composition ratio of docetaxel:PVP K-30:SDS=1:9:1 (ASD Example 3)) so that supersaturated solubility can be maintained in the described dissolution model. Due to the high percentage 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.

[0042] [Table 1]

[0043] 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 or without SDS as a surfactant component, respectively. 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 increases rapidly with increasing pH to 6.8. This is seen consistently with formulations of the inventive concept. Figure 2A shows that at a docetaxel:HPMCP:SDS ratio of 1:3:1, sustained supersaturated solubility is not achieved. As shown in Figure 2B, in the absence of SDS, the release is also very slow, reaching maximum release about 3 hours after dissolution of the HPMCP polymer.

[0044] [Table 2A]

[0045] [Table 2B]

[0046] 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. It is clear from Figure 3A that the minimum docetaxel:Eudragit L100-55:SDS ratio that can successfully maintain 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, the release of docetaxel 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.

[0047] [Table 3A]

[0048] [Table 3B]

[0049] 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% supersaturation of docetaxel 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 of time.

[0050] [Table 4A]

[0051] [Table 4B]

[0052] A further unexpected observation from FIG. 4B was that in compositions with HPMCAS content selected to provide a 1:3 docetaxel:HPCMAS ratio (ASD Example 20), SDS (i.e., surfactant component) can be omitted from the high dose tablet taxane formulation composition while retaining its ability to maintain sustained supersaturated concentrations. As shown in the 1:3 and higher docetaxel:HPMCAS formulation compositions, 80% supersaturated solubility of liberated docetaxel can be maintained for at least 3 hours. This is in contrast to previous observations using other polymers mentioned above (e.g., PVP K-30, Eudragit, and HPMCP) where surfactant is an essential component. Surprisingly, this is not the case with HPMCAS. The absence of the need for a surfactant component provides an additional advantage in terms of active ingredient loading for high loading tablets.

[0053] 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 amorphous solid dispersion based on paclitaxel also produced a sustained supersaturation state at a ratio of 1:3:1.

[0054] [Table 5]

[0055] X-ray diffraction analysis X-ray powder diffraction analysis of docetaxel and paclitaxel amorphous solid dispersions prepared using the spray drying method and each drug substance was carried out 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 the angular range of 5° to 50° in 2θ.

[0056] 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 in comparison 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 during the process of manufacturing these amorphous solid dispersions.

[0057] Method for making tablets using spray-dried amorphous solid dispersions

[0058] 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. A coarse mass screen 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.

[0059] Composition of docetaxel tablets from spray-dried amorphous solid dispersions Table 6 shows the compositions of docetaxel tablets made 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).

[0060] [Table 6]

[0061] Based on a 1:3:1 ratio docetaxel:HPMCAS:surfactant solid dispersion, Figures 7A-7F show the dissolution curves of docetaxel tablet Examples 1-6, containing 6.66%-13.89% docetaxel. Figure 7F shows that even when docetaxel loading was increased to 13.89% (docetaxel tablet Example 6), the formulation containing HPMCAS was able to maintain a high supersaturation concentration of 80-90% for at least 3 hours. It should be appreciated 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 about 14% active ingredient by weight in the tablet. This is about a 3.5-fold increase in loading compared to the prior art formulation. The inventors believe that with further optimization, higher loadings are possible. 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 concentrations of HPMCAS (e.g., up to about 40% tablet loading, as seen in docetaxel tablet Examples 5 and 6), the tablets have a tendency to form a gel layer that may retard the release of the active ingredient if the concentration of the superdisintegrant is not adjusted accordingly (see FIG. 7E). Thus, for higher loadings of active ingredients, a concentration of at least 10% superdisintegrant is preferred. Polyvinylpolypyrrolidone (PVPP), cross-linked modifications of polyvinylpyrrolidone, and croscarmellose sodium have also been identified as effective superdisintegrants to ensure effective release of the active. It is contemplated that these disintegrants can be incorporated either intragranularly or extragranularly, or both. It is also worth noting that while the preferred tablet composition of taxane described in WO 2015 / 152433 A1 (Hanmi Phar.Co.Ltd) can achieve 30 mg of active substance in a tablet weight of 750 mg, the tablet 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 the prior art examples.

[0062] From Figures 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 following a shift in pH from 4 to 6.8. This advantageously preserves release of most of the taxane active ingredient 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.

[0063] The inventors believe that in some embodiments, tablets of the inventive concept may 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.

[0064] Composition of paclitaxel tablets prepared from spray-dried amorphous solid dispersions Table 7 shows the composition of paclitaxel tablets made from amorphous solid dispersions based on paclitaxel:HPMCAS:surfactant with paclitaxel loadings of 6.66% to 11.11%. Figures 8A-8E show the supersaturation of paclitaxel that can be maintained in these formulations for more than 3 hours, even when the tablet loading is greater than 10% (i.e., up to at least 11.11%). This is consistent with the data observed for docetaxel, where polyvinyl-polypyrrolidone and croscarmellose sodium are useful superdisintegrants that can be incorporated either intragranularly or extragranularly or at both stages.

[0065] [Table 7]

[0066] Comparison of dissolution and bioavailability of paclitaxel tablets of the present invention to prior art compositions The dissolution profiles and oral bioavailability of paclitaxel tablet Example 5, a prior art paclitaxel tablet formulation (paclitaxel tablet comparison standard 1), and a prior art paclitaxel capsule formulation (paclitaxel capsule comparison standard 2) were compared. A typical dissolution profile using the 3-pH method described above is shown in Figure 9. As described in Example 9 of WO 2015 / 152433 A1 (Hanmi Phar.Co.Ltd), paclitaxel tablet comparison standard 1 has an active substance loading of 30 mg and comprises an amorphous solid dispersion using PVP K-30 as a polymer carrier, and as described in Comparative Example 1 of WO 2015 / 152433 A1 (Hanmi Phar.Co.Ltd), paclitaxel capsule comparison standard 2 is a 30 mg strength capsule in which paclitaxel is dissolved in polysorbate 80.

[0067] For dissolution study, Paclitaxel Example 5 was prepared with tablet strength of 33.33 mg. Dissolution tests were then performed on Paclitaxel Tablet Example 5, Paclitaxel Tablet Comparative Standard 1, and Paclitaxel Capsule Comparative Standard 2. As shown in Figure 9, the paclitaxel tablet formulation of the inventive concept 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 the tablets of the present invention can maintain supersaturation of paclitaxel for more than 3 hours, while the supersaturation concentration of paclitaxel from Paclitaxel Comparative Standard Tablet 1 and Paclitaxel Capsule Comparative Standard 2 began to decrease after 1 hour, meaning that paclitaxel began to precipitate in these prior art compositions.

[0068] For pharmacokinetic studies, the oral bioavailability of Paclitaxel Tablet Example 5, Paclitaxel Tablet Comparator 1, and Paclitaxel Capsule Comparator 2 was investigated by co-administration of HM30181A tablets in naive beagle dogs. Twenty naive male beagle dogs (weight 9.5-10.5 kg) were treated according to the regimen shown in Table 8. For Paclitaxel Tablet Example 5, 80 mg strength tablets were manufactured, 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 animal. 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.

[0069] [Table 8]

[0070] Table 9, which summarizes the pharmacokinetic data, clearly shows that paclitaxel tablet Example 5 unexpectedly provides significantly improved oral absorption, as evidenced by the increase in Cmax, AUC0-t, AUC0-∞ and F(%). Most notably, the bioavailability F(%) of this composition described in the present invention is more than twice as high as both comparative benchmark formulations, even though it provides high active substance loading per unit dosage form (i.e., using less polymer carrier). Therefore, the results provided by the tablet composition described in the present invention are unexpected.

[0071] [Table 9]

[0072] Preparation and characterization of amorphous taxane compositions by fluidized bed granulation.

[0073] Fluidized bed granulation methodSimilar to the spray drying method, 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, and 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°C-70°C, exhaust temperature in the range of 30°C-38°C, and atomizing air pressure in the range of 30-50 PSI. After completion of the spraying process, the granulation was dried until a loss on drying (LOD) value of 2.0% or less was achieved. When the taxane used is paclitaxel, the resulting solid dispersion of such a process comprises free-flowing amorphous paclitaxel granules. Without wishing to be bound by theory, the inventors believe that the taxane active ingredient forms a coating or layer of amorphous matrix in HPMCAS on the intragranular excipient surface. Such amorphous granules can be formed into tablets that provide 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 incorporation into the spray solution or by addition 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 believed that surfactants, stabilizers, and disintegrants / superdisintegrants suitable for use in spray drying may be suitable for fluidized bed granulation. Table 10 shows example compositions of 30 and 90 mg high strength paclitaxel tablets manufactured using, for example, top spray fluidized bed granulation.

[0074] [Table 10]

[0075] Dissolution testing of taxane formulations produced by fluidized bed granulation. Dissolution testing of the amorphous solid dispersion and tablet compositions produced using spray drying techniques was performed using the 3-pH model as described above. By adding an additional step of dissolution at pH 1.2, a similar 4-pH dissolution model was utilized to characterize the dissolution of the amorphous taxane-containing granules and tablets produced from amorphous taxane-containing granules produced by fluid 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 that such compositions experience after ingestion. It should be noted that dissolution is minimal (substantially less than 50%) at the first acidic pH 1.2 step and the second acidic pH 4.0 step, and increases rapidly with increasing pH to 6.8. This is consistently seen with formulations of the inventive concept.

[0076] 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 a tablet containing the amorphous taxane-containing granule dispersion; (b) set the stirring speed of the dissolution paddle at 100 revolutions per minute (RPM); (c) introduce the capsule or tablet (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 capsule or tablet in 180 ml of 0.25 M monobasic sodium phosphate (NaH 2 O ) 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 a further 2 hours. Samples are collected at the following time points - pH 1.2 For pH 4, 0, 10, 20, 30, and 60 minutes; for pH 4, 70, 80, 90, and 120 minutes; for pH 6.8, 130, 140, 150, and 180 minutes; for pH 7.5, 190, 200, 210, 240, 270, and 300 minutes. An equal volume of fresh dissolution solvent is added after sampling to compensate for volume loss. The collected samples are centrifuged and the supernatant is subjected to HPLC analysis. In some embodiments, such supernatants can be diluted with a suitable organic solvent (e.g., 1:1 in methanol) before HPLC analysis.

[0077] To characterize the dissolution of the 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 above procedure. 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.

[0078] 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 the angular range of 5° to 50° in 2θ.

[0079] 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.

[0080] Preparation of paclitaxel tablets from amorphous granules produced by fluid bed granulation and their dissolution profile In a typical process for preparing tablets from the amorphous solid granules produced by fluid 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 produced by any suitable process, for example by molding and / or compression. Tablets can be produced in any suitable shape that facilitates ingestion, for example, round, oval, cylindrical, etc. Similarly, tablets can be produced at any suitable hardness or compression level required to provide suitable binding strength and size. In the examples provided, 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.

[0081] 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 active 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%, meaning that it was sustainable for at least 3 hours.

[0082] 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 fluid bed granulation using HPMCAS polymer (specifically, top spray fluid bed granulation) and prior art paclitaxel tablets was investigated with 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 WO 2015 / 152433 A1 (Hanmi Phar.Co.Ltd).

[0083] For the pharmacokinetic study, 15 naive male beagle dogs (body weight 9.0-10.5 kg) were randomly divided into 3 groups of 5 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 in which the two phases were separated by a 1-week washout period. Animals in group 3 were administered paclitaxel intravenously in a single phase only.

[0084] [Table 11]

[0085] 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 tablets of the inventive concept manufactured by a spray drying process. Thus, when administered to each dog in the appropriate test group, 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. 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, the dogs were given a single 2 ml / kg infusion of paclitaxel solution (1 mg / ml, 4.9% Solutol HS15™) infused over 60 minutes.

[0086] 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 significantly higher AUC o-t , AUC o-∞ and F (%).

[0087] [Table 12]

[0088] Thus, various oral compositions of taxanes with high loading of active substance and high bioavailability are presented herein.The described method advantageously uses a spray drying process or a fluidized bed granulation method that does not involve the formation of emulsions, anti-solvents, or liquid bridging solvents as required by the prior art processes.Instead, the process described herein spray dries the dissolved taxane, resulting in the formation of a solid powder / granule amorphous solid dispersion.Such solid dispersions, unlike hollow microspheres, can be effectively compressed into tablets as discussed herein.

[0089] It should be understood that the compositions of the present invention can be effectively compressed into tablets, a property that is not shared with compositions that incorporate active ingredients into hollow core microspheres.Similarly, it should be understood that the compositions of the inventive concept can be manufactured by scalable means suitable for large-scale manufacturing and do not require the inclusion of dispersing agents (e.g., porous silica) to enhance and / or provide adequate bioavailability.This provides a beneficial technical effect, since the elimination of such dispersing agents allows for higher loading of active ingredients (e.g., taxanes) in the final dosage form.

[0090] 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 some embodiments of the invention in broad scope 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.

[0091] As used throughout this specification and the claims which 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.

[0092] Groupings of alternative 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 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.

[0093] 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 concept herein. Accordingly, the subject matter of the invention is not limited except as set forth in the appended claims. Moreover, in both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms "comprises" and "comprising" should be interpreted to refer to elements, components, or steps in a non-exclusive manner, meaning that a referenced element, component, or step may be present, utilized, or combined with other elements, components, or steps not expressly referenced. When a specification 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, not A+N, or B+N, etc.

Claims

1. A ready to administer oral composition comprising: a solid dispersion of amorphous granules comprising at least 90 mg of a taxane, a hypromellose acetate succinate (HPMCAS) carrier, and a surfactant, the ratio of taxane:carrier:surfactant being 1:2:1 or 1:1.67:0.67; wherein the surfactant is sodium dodecyl sulfate, Upon oral administration, the oral composition maintains a supersaturated concentration of taxane of at least 70 μg / mL for at least 2 hours following dissolution of the solid dispersion of amorphous granules in 900 mL of pH 7.5 solution; A composition wherein said taxane is present in a concentration of at least 6% by weight of said oral composition.

2. 2. The composition of claim 1, wherein the taxane is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, larotaxel, ortataxel, and tesetaxel.

3. 3. The composition according to claim 1 or 2, wherein the solid dispersion of amorphous granules is prepared by fluid bed granulation.

4. mixing the solid dispersion of amorphous granules with intragranular excipients by wet granulation to form a mixture; the intragranular excipients are selected from the group consisting of lubricants, fillers and superdisintegrants to form a tablet blend; and The composition according to any one of claims 1 to 3, wherein the tablet blend is compressed into a tablet to form a ready-to-administer oral composition.

5. The composition according to any one of claims 1 to 4, further comprising a disintegrant or superdisintegrant.

6. 1. A method for preparing a ready-to-administer oral composition, comprising: preparing a solution comprising a taxane and a HPMCAS carrier; applying said solution to intragranular excipients using a fluid bed granulation system to form an amorphous solid comprising said taxane and said HPMCAS carrier; drying the amorphous solid; and and compressing the amorphous solid to form a tablet having a taxane concentration of at least 6% by weight. wherein the surfactant is mixed with the amorphous granules prior to compression; The method wherein the surfactant is sodium dodecyl sulfate and the ratio of taxane:carrier:surfactant is 1:2:1 or 1:1.67:0.

67.

7. The method of claim 6 , wherein the intragranular excipient is microcrystalline cellulose.

8. adding extragranular excipients prior to drying; 8. The method of claim 6 or 7, wherein the extragranular excipient is selected from the group consisting of cross-linked polyvinylpyrrolidone, amorphous silicon dioxide, sodium stearyl fumarate, and microcrystalline cellulose.

9. The method of any one of claims 6 to 8, wherein the taxane is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, larotaxel, ortataxel, and tesetaxel.

10. 10. The method according to any one of claims 6 to 9, comprising the step of adding a stabiliser before compression, said stabiliser being selected from the group consisting of citric acid and ascorbic acid.

11. 11. The method according to any one of claims 6 to 10, further comprising the step of adding a disintegrant or superdisintegrant before compression.

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