JP2012500788A - Composition - Google Patents

Abstract

  A solid pharmaceutical taxane composition for oral administration comprising a substantially amorphous taxane, a carrier and a surfactant, wherein the substantially amorphous taxane is obtained by solvent evaporation and, in particular, A composition prepared by spray drying. Also included are methods of preparing the composition and uses of the composition.

Description

  The present invention relates to a pharmaceutical composition. In particular, but not exclusively, the present invention relates to compositions for treating neoplastic diseases.

  Administration of drugs in oral form offers a number of advantages. The availability of oral anticancer drugs, such as 5-fluorouracil (5-FU) prodrugs (eg, capecitabine) and drugs that interfere with signal transduction pathways or angiogenic processes, is long-term so that treatment is optimally effective. It is important when it must be applied to (Non-Patent Document 1). In addition, oral medications can be administered on an outpatient basis or at home, increasing convenience and patient quality of life and potentially reducing costs by reducing hospitalization (Non-Patent Document 2). ). For this reason, it is beneficial to try to administer anticancer drugs orally.

  In general, oral administration of drugs is convenient and practical. However, the vast majority of anticancer drugs unfortunately have low and variable oral bioavailability (1). Typical examples are docetaxel and paclitaxel, which are widely used taxanes, which have an oral bioavailability of less than 10% (Non-Patent Documents 3 and 4). Several other anticancer agents with higher bioavailability show higher variability. Examples include topoisomerase I inhibitors, vinca alkaloids, and mitoxantrone (Non-Patent Documents 1, 5, and 6). Given the narrow therapeutic concentration range, variable bioavailability can result in unpredictable toxicity or reduced efficacy if therapeutic plasma levels are not achieved. In a study, Hellriegel et al. Demonstrated that plasma levels after oral administration were generally more variable than after intravenous administration (Non-Patent Document 7). Proper oral bioavailability is important when drug exposure duration is a major determinant of anticancer therapy (Non-Patent Document 8). Proper oral bioavailability is also important to prevent high local drug concentrations in the gastrointestinal tract that can cause local toxicity.

  Thus, a problem associated with the prior art is that it has not been possible to develop oral compositions containing taxanes that have high bioavailability with low variability. Clinical trials using oral paclitaxel (eg, non-patent document 3) and clinical trials using oral docetaxel (eg, non-patent document 9) were conducted by the present inventors. In these studies, intravenous administration of taxanes Preparations (further containing excipients such as Cremophor EL and ethanol, or polysorbate 80 and ethanol) were taken orally. Nausea, vomiting, and unpleasant taste were frequently reported by patients.

  Chen et al. (Non-Patent Document 13) conducted an experiment that attempted to improve the solubility of the anticancer drug docetaxel to improve its bioavailability. Chen et al. Attempted to use a solid dispersion of docetaxel with various carriers: glyceryl monostearate, PVP-K30 or poloxamer 188. Chen et al. Have reported that the solubility of docetaxel to about 3.3 μg / mL after 20 minutes (in the standard dissolution test) and about poloxamer 188 using a 5:95 docetaxel to poloxamer ratio It was found to increase up to about 5.5 μg / mL after 120 minutes (see FIG. 7 in Chen's paper). PVP-K30 only increased the solubility of docetaxel to about 0.8 μg / mL after 20 minutes and up to about 4.2 μg / mL after about 300 minutes (see FIG. 2). Glycerol monostearate did not increase the solubility of docetaxel at all. Thus, the solubility and dissolution rate of docetaxel could not be increased to a particularly high level. In order to achieve superior oral bioavailability, the drug should be substantially free so that there is a sufficiently high amount of drug available for absorption in solution within the first about 0.5-1.5 hours. It must have a high solubility and dissolution rate.

Demario MD, Ratain MJ. J Clin Oncol 1998; 16: 2557-2567. Liu G, Franssen E, Fitch MI et al. J Clin Oncol 1997; 15: 110-115. Meerum Terwogt JM, Beijnen JH, ten Bokkel Huinink WW et al. Lancet 1998; 352: 285. Sparreboom A, van Asperen J, Mayer U et al. Proc Natl Acad Sci USA 1997; 94: 2031 -2035. Kuhn J, Rizzo J, Eckhardt J et al. Proc Am Soc Clin Oncol 1995; 14: 474. Schellens JHM, Creemers GJ, Beijnen JH et al. Br J Cancer 1996; 73: 1268-1271. Hellriegel ET, Bjornnson TD, Hauck WW.Clin Pharmacol Ther 1996; 60: 601 -607. Huizing MT, Giaccone G, van Warmerdam LJC et al. J Clin Oncol 1997; 15: 317-329. Malingre MM, Richel DJ, Beijnen JH et al. J Clin Oncol 2001; 19: l160-1166. Chen J, et al. Drug Development and Industrial Pharmacy 2008; 34: 588-594.

  In a first aspect, the present invention provides a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane, a hydrophilic carrier and a surfactant, wherein the amorphous taxane is prepared by a solvent evaporation method. A solid pharmaceutical composition is provided.

  An advantage provided by the composition of the present invention is that the solubility of the taxane, the dissolution rate of the taxane, and / or the amount of time that the taxane remains in the solution before it begins to crystallize is increased to a surprising degree. These factors result in a significant increase in taxane bioavailability. This is believed to be due, at least in part, to the fact that the taxane is in a more amorphous state compared to a pseudo-amorphous taxane that is less likely to be truly amorphous produced by other methods. It is done. Crystalline taxanes have very low solubility.

  The carrier helps to maintain the taxane in an amorphous state. Furthermore, when the taxane is placed in an aqueous medium, the carrier helps to maintain the taxane in a supersaturated state in solution. This stops the taxane from crystallizing or increases the length of time before the taxane begins to crystallize in solution. For this reason, the solubility and dissolution rate of the taxane remain high. Furthermore, the carrier provides excellent physical and chemical stability to the composition. This helps to prevent the taxane from decomposing and also helps to prevent the amorphous taxane from changing to a substantially more crystalline structure over time in the solid state. Excellent physical stability ensures that the solubility of the taxane remains high.

  Surfactants also help maintain the taxane in an amorphous state when placed in an aqueous medium and, surprisingly, the solubility of the taxane compared to a composition comprising an amorphous taxane and a carrier. Is substantially increased.

  The term “substantially amorphous” means that there should be little or no sequence of positions over a long distance of the taxane molecule. The majority of molecules must be randomly oriented. A completely amorphous structure never has a long range of rows, and no matter what it is, it contains no crystalline structure: this is the opposite of a crystalline solid. However, for some solids, it may be difficult to obtain a completely amorphous structure. For this reason, many “amorphous” structures are not completely amorphous and still contain a certain amount of long-range rows or crystallinity. For example, solids are primarily amorphous but have pockets of crystalline structure or may contain very small crystals, thus approximating true amorphousness. Thus, the term “substantially amorphous” includes solids that have some amorphous structure but also some crystalline structure. The crystallinity of the substantially amorphous taxane must be less than 50%. Preferably, the crystallinity of the substantially amorphous taxane is less than 40%, even more preferably less than 30%, even more preferably less than 25%, even more preferably less than 20%, even more preferably 15%. %, Even more preferably less than 12.5%, even more preferably less than 10%, even more preferably less than 7.5%, even more preferably less than 5%, and most preferably less than 2.5%. . Since crystalline taxanes have low solubility, the lower the crystallinity of the substantially amorphous taxane, the better the solubility of the substantially amorphous taxane.

  Substantially amorphous taxanes can be prepared using any suitable solvent evaporation method. Suitable solvent evaporation methods are, for example, the spray drying method and the vacuum drying method described in [18]. Preferably, the solvent evaporation method is a spray drying method. Surprisingly, the process of preparing an amorphous taxane using a solvent evaporation method, particularly a spray-drying method, is exceptionally superior compared to compositions prepared using other methods. It has been found to produce a composition that has solubility, dissolution rate, and / or stays in solution for a longer time before crystallization begins. This is believed to be due to the solvent evaporation method that produces more amorphous taxanes than other methods.

  Compositions for oral administration are in solid form. The solid composition may be in any suitable form as long as the taxane is in a substantially amorphous state. For example, the composition can include a physical mixture of an amorphous taxane, a carrier and a surfactant. In certain embodiments, the carrier and / or surfactant is also in a substantially amorphous state. Preferably, the taxane and the carrier are in the form of a solid dispersion. The term “solid dispersion” is well known to those skilled in the art and means that the taxane is partially molecularly dispersed within the carrier. More preferably, the taxane and the carrier are in the form of a solid solution. The term “solid solution” is well known to those skilled in the art and means that the taxane is substantially completely molecularly dispersed within the support. Solid solutions are considered to be essentially more amorphous than solid dispersions. Methods for preparing solid dispersions and solid solutions are well known to those skilled in the art [11,12]. Using these methods, both the taxane and the carrier are in an amorphous state. When the taxane and carrier are in the form of a solid dispersion or solid solution, the solubility and dissolution rate of the taxane is greater than the physical mixture of the amorphous taxane and the carrier. When the taxane is in a solid dispersion or solid solution, the taxane is naturally considered to be in a more amorphous state compared to the pseudo-amorphous taxane. This is believed to result in improved solubility and dissolution. The crystallinity of the solid dispersion or solid solution must be less than 50%. Preferably, the crystallinity of the solid dispersion or solid solution is less than 40%, even more preferably less than 30%, even more preferably less than 25%, even more preferably less than 20%, even more preferably less than 15%, Even more preferably less than 12.5%, even more preferably less than 10%, even more preferably less than 7.5%, even more preferably less than 5%, and most preferably less than 2.5%.

  When the taxane and carrier are in a solid dispersion, the surfactant may be in a physical mixture with the solid dispersion or solid solution. Preferably, however, the composition comprises a taxane, a carrier and a surfactant in the form of a solid dispersion, or more preferably a solid solution. The advantage of having all three components in a solid dispersion or solid solution is that it allows the use of smaller amounts of surfactant to achieve the same improvement in solubility and dissolution rate. Preferably, the taxane, carrier and surfactant are all in a substantially amorphous state.

  The taxane and carrier; or the solid dispersion or solid solution of the taxane, carrier and surfactant can be prepared using any suitable solvent evaporation method as described above. Preferably, the solid dispersion or solid solution is prepared by spray drying. Surprisingly, the process of preparing a solid dispersion or solid solution using a solvent evaporation method, particularly a spray-drying method, results in a composition having exceptionally good solubility properties, so that taxanes are other methods. Has been found to have superior solubility, dissolution rate and / or stay in solution for a longer time before crystallization begins. This is believed to be due to the solvent evaporation method that produces a composition in which all components are in a more amorphous state compared to other methods. In other methods, one or more of the components can still be found to have some crystalline properties, which have reduced solubility characteristics and / or physical stability in solution. It is thought to give rise to a composition.

  In one embodiment, the composition can be contained in a capsule for oral administration. Capsules can be filled in a number of different ways. For example, amorphous taxanes can be prepared by spray drying, pulverizing, combining with carriers and surfactants, and then dispensing into capsules.

  In yet another embodiment, the composition can be compressed into tablets. For example, an amorphous taxane can be prepared by spray drying, powdering, combining with a carrier and surfactant (and optionally other excipients), and then compressing the appropriate amount into a tablet. Can do.

  Taxanes are diterpene compounds originating from plants of the genus Taxus. However, some taxanes are currently produced synthetically or semi-synthetically. Taxanes are used to treat cancer because they inhibit cell proliferation by stopping cell division. Taxanes stop cell division by disrupting microtubule formation. Taxanes can also act as angiogenesis inhibitors. As used herein, the term “taxane” includes all diterpentanes, functional derivatives and pharmaceutically acceptable salts or esters that bind to tubulin, whether produced naturally or artificially produced. Is included.

  Derivatives of taxanes containing groups for modifying physiochemical properties are also included within the scope of the present invention. Thus, taxane polyalkylene glycols (eg, polyethylene glycol) or saccharide conjugates with improved or modified solubility characteristics are included.

  The taxane of the composition may be any suitable taxane as defined above. Preferred taxanes are docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof. BMS-275183 is a C-3'-t-butyl-3'-Nt-butyloxycarbonyl analog of paclitaxel [10]. More preferably, the taxane is selected from docetaxel, paclitaxel, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof.

  The hydrophilic carrier of the composition is an organic compound that can be at least partially dissolved in an aqueous medium at pH 7.4 and / or can swell or gel in such an aqueous medium. The carrier can be any suitable hydrophilic carrier that ensures that the taxane remains in the amorphous state in the composition and increases the solubility and dissolution rate of the taxane. Preferably the carrier is polymeric. Preferably, the carrier is: polyvinyl pyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol (PVA); crospovidone (PVP-CL); polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA); cellulose derivatives such as methylcellulose; Hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose (HPMC), cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate; polyacrylates; polymethacrylates; sugars, polyols and their polymers such as mannitol, sucrose, sorbitol, dextrose And chitosan; and cyclodextrins. More preferably, the carrier is selected from PVP, PEG and PVP-VA, and even more preferably the carrier is selected from PVP and PVP-VA. In one embodiment, the carrier is PVP. In another embodiment, the carrier is PVP-VA.

  Where the support is PVP, it can be any suitable PVP [16] that functions as a support and helps maintain the taxane in an amorphous state. For example, the PVP may be selected from PVP-K12, PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60, PVP-K90 and PVP-K120. Preferably, the PVP is selected from PVP-K30, PVP-K60 and PVP-K90. Most preferably, the PVP is PVP-K30.

  When the carrier is PEG, it can be any suitable PEG [16] that functions as a carrier and helps maintain the taxane in an amorphous state. For example, the PEG can be selected from PEG 1500, PEG 6000 and PEG 20000. Preferably, the PEG is selected from PEG 1500 and PEG 6000, and most preferably the PEG is PEG 1500.

  When the support is PVP-VA, it can be any suitable PVP-VA [16] that functions as a support and helps maintain the taxane in an amorphous state. For example, the PVP-VA may be PVP-VA64.

  The composition can contain any suitable amount of carrier relative to the amorphous taxane so that the carrier maintains the amorphous taxane in its amorphous state. Preferably, the weight ratio of taxane to carrier is from about 0.01: 99.99 (w / w) to about 75:25 (w / w). More preferably, the weight ratio of taxane to carrier is about 0.01: 99.99 (w / w) to about 50:50 (w / w), even more preferably about 0.01: 99.99 (w / W) to about 40:60 (w / w), more preferably about 0.01: 99.99 (w / w) to about 30:70 (w / w), even more preferably about 0.1. : 99.9 (w / w) to about 20:80 (w / w), even more preferably about 1:99 (w / w) to about 20:80 (w / w), even more preferably about 2.5: 97.5 (w / w) to about 20:80 (w / w), even more preferably about 2.5: 97.5 (w / w) to about 15:85 (w / w) Even more preferably from about 5:95 (w / w) to about 15:85 (w / w), and most preferably from about 10:90 (w / w).

  The surfactant may be any suitable pharmaceutically acceptable surfactant and such surfactants are well known to those skilled in the art. For example, the surfactant may be an anionic, cationic or nonionic surfactant. Preferably, the surfactant is a cationic or anionic surfactant. More preferably, the surfactant is an anionic surfactant.

  In one embodiment, the surfactant preferably has an HLB (Hydrophilic Lipophilic Balance) value greater than about 2. More preferably, the HLB value is greater than about 4, even more preferably the HLB value is greater than about 10, even more preferably the HLB value is greater than about 14, more preferably the HLB value is greater than about 20, even more Preferably the HLB value is greater than about 25, more preferably the HLB value is greater than about 30, and most preferably the HLB value is greater than about 35. Preferably, the HLB value should be less than about 45.

Preferably, the surfactant is triethanolamine, sunflower oil, stearic acid, monobasic sodium phosphate, sodium citrate dihydrate, propylene glycol alginate, oleic acid, monoethanolamine, mineral oil and lanolin alcohols, methylcellulose, medium Chain triglycerides, lecithin, hydrolanolin, lanolin, hydroxypropyl cellulose, glyceryl monostearate, ethylene glycol pamitostearate, diethanolamine, lanolin alcohols, cholesterol, cetyl alcohol, cetostearyl alcohol, castor oil, sodium dodecyl Sulfate (SDS), sorbitan esters (sorbitan fatty acid esters), polyoxyethylene stearates, poly Xylethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene alkyl ethers, poloxamer, glyceryl monooleate, docusate sodium, cetrimide, benzylbenzoate, benzalkonium chloride, benzethonium chloride, hypromellose, nonionic Emulsifying wax, anionic emulsifying wax and triethyl citrate (these compounds are listed as emulsifiers and surfactants in the Handbook of Pharmaceutical Excipients (4 ^th Edition, editors: RC Rowe, PJ Sheskey, PJ Weller)) Selected from. More preferably, the surfactant is sodium dodecyl sulfate (SDS), sorbitan esters (sorbitan fatty acid esters), polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene castor oil derivatives, Oxyethylene alkyl ethers, poloxamers, glyceryl monooleate, docusate sodium, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromellose, nonionic emulsifying wax, anionic emulsifying wax and triethyl citrate (these compounds) It is ^{the Handbook of Pharmaceutical Excipients (4 th} Edition, editors: RC Rowe, PJ Sheskey, PJ Weller) is selected from the displayed as a surfactant) in the. More preferably, the surfactant is selected from sodium dodecyl sulfate (SDS), sorbitan esters (sorbitan fatty acid esters), and polyoxyethylene sorbitan fatty acid esters. In one embodiment, the surfactant may be cetylpyridinium chloride (CPC). In yet another embodiment, the surfactant is selected from SDS, CPC, polyoxyethylene (20) sorbitan monooleate (polysorbate 80) and polysorbitan monooleate. Preferably, the surfactant is selected from SDS, CPC and polysorbate 80. More preferably, the surfactant is selected from SDS and CPC. Most preferably, the surfactant is SDS.

  Any suitable amount of surfactant can be used in the composition to improve the solubility and dissolution rate of the taxane. Preferably, the weight ratio of surfactant to combined taxane and carrier is from about 1:99 (w / w) to about 50:50 (w / w), more preferably about 1:99 (w / w). To about 44:56 (w / w), even more preferably from about 1:99 (w / w) to about 33:67 (w / w), even more preferably from about 2:98 (w / w) to About 33:67 (w / w), more preferably about 2:98 (w / w) to about 17:83 (w / w), even more preferably about 5:95 (w / w) to about 17 : 83 (w / w), and most preferably about 9:91 (w / w).

  Alternatively, the weight ratio of surfactant to taxane is preferably from about 1: 100 (w / w) to about 60: 1 (w / w), more preferably from about 1:50 (w / w) to about 40: 1 (w / w), even more preferably from about 1:20 (w / w) to about 20: 1 (w / w), even more preferably from about 1:10 (w / w) to about 10: 1 (W / w), even more preferably from about 1: 5 (w / w) to about 5: 1 (w / w), even more preferably from about 1: 3 (w / w) to about 3: 1 (w / W), even more preferably from about 1: 2 (w / w) to about 2: 1 (w / w), and most preferably about 1: 1 (w / w).

  In one embodiment, the composition includes an enteric coating. Any suitable enteric coating can be used, such as cellulose acetate phthalate, polyvinyl acetate phthalate and suitable acrylic derivatives such as polymethacrylates. The enteric coating prevents the release of the taxane in the stomach, thereby preventing acid-mediated degradation of the taxane. In addition, the enteric coating allows targeted delivery of the taxane to the intestine where the taxane is absorbed, thereby absorbing a limited time during which the taxane is present in solution (before crystallization begins). Guarantees spending only where it is possible.

  In one embodiment, the composition can further comprise one or more additional pharmaceutically active ingredients. Preferably, the one or more additional pharmaceutically active ingredients are CYP3A4 inhibitors. Suitable CYP3A4 inhibitors are grapefruit juice or St. John's wort (or any component), ritonavir, lopinavir or imidazole compounds such as ketoconazole. Preferably, the CYP3A4 inhibitor is ritonavir.

  Where the composition includes one or more additional pharmaceutically active ingredients, the pharmaceutically active ingredients can be included in the composition as a physical mixture. Alternatively, the pharmaceutically active ingredient may be in an amorphous form. The pharmaceutically active ingredient may be in an amorphous form in a physical mixture with other amorphous and / or non-amorphous ingredients. Alternatively, the pharmaceutically active ingredient may be in a taxane; a taxane and a carrier; or a solid dispersion or preferably a solid solution with the taxane, carrier and surfactant. If the additional pharmaceutically active ingredient is in the amorphous state, or is in a solid dispersion or solid solution, the additional pharmaceutically active ingredient may be removed using a solvent evaporation method, for example, spray drying. Must be prepared.

  Where the composition is in tablet form and includes one or more additional pharmaceutically active ingredients, the one or more additional pharmaceutically active ingredients are preferably the amorphous taxane and In the same tablet, ie in a single tablet with the other ingredients.

  The pharmaceutical composition can include additional pharmaceutically acceptable excipients, adjuvants and vehicles, which are well known to those skilled in the art. Pharmaceutically acceptable excipients, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present invention include ion exchangers, alumina, aluminum stearate, serum proteins such as human serum albumin, buffer substances such as phosphate, glycerin. , Sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, eg protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium Including but not limited to trisilicate and wool fat.

  The pharmaceutical composition can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders or coated granules. Tablets can be prepared to be immediate release, sustained release, repeated release or sustained release. The tablets may additionally or alternatively be effervescent, bilayer and / or coated tablets. Capsules can be prepared to be immediate release, sustained release, repeated release or sustained release. A lubricant, such as magnesium stearate, is also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. For tablets and capsules, the pharmaceutical excipients that can be added are binders, fillers, fillers / binders, adsorbents, wetting agents, tablet disintegrants, lubricants, glidants and the like. Tablets and capsules can be coated to change the appearance or properties of the tablets and capsules, for example to change the taste of the tablets or capsules, or to color coat.

  Other pharmaceutically acceptable additives that can be added to the composition are well known to those skilled in the art.

  The present invention further provides a composition as described above for use in therapy.

  Furthermore, the present invention provides the above composition for use in the treatment of neoplastic diseases.

  The neoplastic disease to be treated according to the present invention is preferably a solid tumor. Solid tumors are preferably breast, lung, stomach, colorectal, head and neck, esophagus, liver, kidney, pancreas, bladder, prostate, testis, cervix, endometrium, ovarian cancer and non-Hodgkin (non-Hodgkin) -Hodgkin's) selected from lymphoma (NHL). The solid tumor is more preferably selected from breast, stomach, ovary, prostate, head and neck and non-small cell lung cancer.

  Another neoplastic disease that can be treated by the present invention is multiple myeloma, chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and Kapsoi's sarcoma. Further, the disease range includes myelodysplastic syndrome (MDS).

  The present invention further provides a method of treating a neoplastic disease comprising administering an effective amount of the above composition to a subject in need of such treatment.

  Preferably, the method is used to treat a human subject.

The present invention provides a method for preparing the above composition comprising:
Preparing an amorphous taxane using a solvent evaporation method;
Combining the amorphous taxane with a hydrophilic carrier and a surfactant to produce the composition is further provided.

  Amorphous taxanes can be produced by any suitable solvent evaporation method, such as those described above. Preferably, the amorphous taxane can be produced by spray drying.

  The preparation of the amorphous taxane and the combination of it with the support and / or surfactant can be carried out in a single step, for example, the taxane and the support and / or surfactant together (eg a solid dispersion Alternatively, it is subjected to an amorphization process (to form a solid solution).

  Preferably, the method includes the steps of preparing a solid dispersion comprising a taxane and a hydrophilic carrier and combining the solid dispersion with the surfactant.

  More preferably, the method includes the step of preparing a solid dispersion comprising a taxane, a hydrophilic carrier, and a surfactant.

  In another aspect, the present invention provides a pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a hydrophilic carrier, wherein the substantially amorphous taxane is obtained by a spray drying method. Provided is a pharmaceutical composition to be prepared.

The present invention is a method for preparing a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a hydrophilic carrier comprising:
Preparing an amorphous taxane by spray drying;
Combining the amorphous taxane with a hydrophilic carrier to produce the composition is further provided.

  The advantage provided by the present composition is that the solubility of the taxane, the dissolution rate of the taxane, and / or the amount of time that the taxane remains in solution before it begins to crystallize is increased to a surprising degree. This is believed to be because the solvent evaporation method produces a much more amorphous taxane compared to other methods of producing an amorphous taxane where the taxane is less likely to be truly amorphous. It is done. It is believed that the more amorphous nature of the taxane provides increased solubility characteristics.

  Additional optional features of the composition are the same as those comprising an amorphous taxane, a carrier and a surfactant. For example, the present composition comprising a substantially amorphous taxane and a carrier, wherein the substantially amorphous taxane is prepared by spray drying, preferably comprises a surfactant. In addition. The taxane, the carrier, the crystallinity of the taxane, the ratio of the taxane to the carrier, the preferred embodiments of the taxane and the carrier state, and the like are as defined above.

  In yet another aspect, the present invention further provides a pharmaceutical composition comprising a taxane, a hydrophilic carrier and a surfactant in solution. The above description relating to the identity, properties, etc. of the taxane, carrier and surfactant is equally applicable to this aspect of the invention. In such a composition, all three components of the composition are in solution.

  The pharmaceutical composition may be in the form of a beverage liquid for administration to a subject. Alternatively, the pharmaceutical composition can be placed in a capsule, for example, in a gelatin capsule to form a liquid-filled capsule containing the solution.

  This composition can be obtained by the process of dissolving the solid composition described above in a suitable solvent. Thus, in one embodiment, the present composition is obtainable by dissolving the solid composition described above in a suitable solvent, such as triacetin. In one embodiment, the solvent is an aqueous solvent.

  In another aspect, the invention provides a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane and one or more pharmaceutically acceptable excipients, A solid pharmaceutical composition is provided in which an amorphous amorphous taxane is prepared by spray drying.

The properties and preferred characteristics of the composition are as described above for other compositions of the invention.
The invention will now be described by way of example only with reference to the accompanying drawings.

It is a figure which shows the result of a dissolution test with the physical mixture of a paclitaxel solid dispersion and a paclitaxel (conditions: 900 mL WfI, 37 degreeC, 75 rpm). It is a figure which shows the result of the dissolution test of the paclitaxel (PCT) solid dispersion capsule with and without sodium dodecyl sulfate (conditions: 900 mL WfI, 37 ° C., 75 rpm). FIG. 4 is a diagram showing the results of a dissolution test of a paclitaxel solid dispersion containing sodium dodecyl sulfate incorporated into a solid dispersion or added to a capsule (conditions: 500 mL WfI, 37 ° C., 75 rpm (added to capsule 100 rpm for the obtained SDS)). It is a figure which shows the result of the dissolution test of the paclitaxel solid dispersion containing various support | carriers (conditions: 500 mL WfI, 37 degreeC, 100 rpm). It is a figure which shows the result of the dissolution test of the paclitaxel / PVP-K17 solid dispersion containing various drug-carrier ratios (conditions: 25 mL WfI, 37 ° C., 7,200 rpm). FIG. 6 shows the results of dissolution testing of paclitaxel solid dispersion in various media (conditions: 500 mL FaSSIF (light gray), 37 ° C., 75 rpm; or 500 mL SGF _sp and 629 mL SIF _sp , 37 ° C., 75 rpm (dark gray)). FIG. 5 shows docetaxel solubility of five different preparations (see Table 13). A: anhydrous docetaxel; B: amorphous docetaxel; C: physical mixture of anhydrous docetaxel, PVP-K30 and SDS; D: physical mixture of amorphous docetaxel, PVP-K30 and SDS; E: amorphous docetaxel , PVP-K30 and SDS solid dispersion (dissolution conditions: ± 6 mg docetaxel, 25 mL WfI, 37 ° C., 720 rpm). It is a figure which shows the docetaxel solubility of the solid dispersion containing a different support | carrier (refer Table 13). E: solid dispersion of amorphous docetaxel, PVP-K30 and SDS; F: solid dispersion of amorphous docetaxel, HPβ-CD and SDS (dissolution conditions: ± 6 mg docetaxel, 25 mL WfI, 37 ° C., 720 rpm ). FIG. 13 shows docetaxel solubility of solid dispersions containing PVP of various chain lengths (see Table 13). E: solid dispersion of amorphous docetaxel, PVP-K30 and SDS; G: solid dispersion of amorphous docetaxel, PVP-K12 and SDS; H: solid dispersion of amorphous docetaxel, PVP-K17 and SDS I: A solid dispersion of amorphous docetaxel, PVP-K25 and SDS; J: A solid dispersion of amorphous docetaxel, PVP-K90 and SDS (dissolution conditions: ± 6 mg docetaxel, 25 mL WfI, 37 ° C., 720 rpm). FIG. 11 shows docetaxel solubility of solid dispersions containing various drug loads (see Table 13). E: 1/11 docetaxel; K: 5/7 docetaxel; L: 1/3 docetaxel; M: 1/6 docetaxel; N: 1/21 docetaxel (dissolution conditions: ± 6 mg docetaxel, 25 mL WfI, 37 ° C., 720 rpm). The figure which shows the dissolution test result regarding the docetaxel of the solid dispersion of docetaxel, PVP-K30, and SDS compared with literature data about the solid dispersion of docetaxel and PVP-K30 (Chen et al, [13]). It is. Shows dissolution test results for dissolved absolute amounts of docetaxel in solid dispersions of docetaxel, PVP-K30 and SDS compared to literature data for solid dispersions of docetaxel and PVP-K30 (Chen et al. [13]). FIG. It is a figure which shows the result of the dissolution test of the docetaxel capsule (15 mg docetaxel (DXT) per capsule containing PVP-K30 + SDS) compared with literature data (Chen et al. [13]). It is a figure which shows the result of the dissolution test regarding the absolute amount which the solid dispersion of docetaxel, PVP-K30, and SDS melt | dissolved. The dissolution test was performed in Simulated Intestinal Fluid sine Pancreatin (SIF _sp ). It is a figure which shows the result of the dissolution test regarding the relative amount which the solid dispersion of docetaxel, PVP-K30, and SDS melt | dissolved. The dissolution test was performed in simulated intestinal juice sign pancreatin. It is a figure which shows the docetaxel pharmacokinetic curve of the patient who took the docetaxel and ritonavir simultaneously in the 1st cycle. In the second cycle, the patient took docetaxel and ritonavir simultaneously at t = 0, and then took an additional booster dose of ritonavir at t = 4h. FIG. 4 shows the pharmacokinetic curves of 4 patients who took a liquid preparation of docetaxel and / or a solid dispersion containing docetaxel (referred to as MODRA). FIG. 5 shows the pharmacokinetic curve of a patient taking a liquid oral preparation of docetaxel compared to a patient taking a solid oral preparation of docetaxel (MODRA). It is a figure which shows the pharmacokinetic curve after an intravenous and oral administration of a docetaxel. Both intravenous and oral administration were combined with the administration of ritonavir. Note: Calculated bioavailability is corrected for the dose administered. FIG. 5 shows the average dissolution curve of five docetaxel preparations containing different types of surfactants (n = 3). FIG. 5 shows the average dissolution curve of docetaxel preparations containing various amounts of SDS surfactant (n = 3). FIG. 3 shows the average dissolution rate of 0-10 minutes of four docetaxel preparations containing various amounts of surfactant (n = 3). It is a figure which shows the X-ray powder diffraction pattern of freeze-drying and crystalline docetaxel. FIG. 4 shows freeze-dried and crystalline docetaxel DSC (Differential Scanning Calorimetry) thermograms. FIG. 2 shows an X-ray powder diffraction pattern of a physical mixture of crystalline and amorphous docetaxel. FIG. 2 shows a DSC thermogram of a physical mixture of crystalline and amorphous docetaxel. It is a figure which shows the peak area in 165 degreeC in a total heat flow thermogram with respect to crystalline docetaxel content. Black line is the linear regression line with a ^{R 2} of 0.990. It is a figure which shows the X-ray powder diffraction pattern of freeze-drying and crystalline paclitaxel. FIG. 2 shows a DSC thermogram of lyophilized and crystalline paclitaxel. It is a figure which shows the X-ray powder diffraction pattern of docetaxel, PVP-K30, and SDS. It is a figure which shows the DSC thermogram of PVP-K30, SDS, and docetaxel. FIG. 2 shows X-ray powder diffraction spectra of a physical mixture and solid dispersion comprising 1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS. FIG. 11 shows DSC thermograms of physical mixture and solid dispersion with 1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS. It is a figure which shows the X-ray powder diffraction spectrum of the solid dispersion manufactured by the freeze-drying method and the spray-drying method. It is a figure which shows the DSC thermogram of the solid dispersion manufactured by the freeze-drying method and the spray-drying method. It is a figure which shows the average dissolution screening curve of the solid dispersion (n = 4) manufactured by the freeze-drying method and the spray-drying method. FIG. 4 shows an average dissolution screening curve of a solid dispersion of docetaxel containing PVP-K30 (n = 4), PEG 1500 (n = 2), PEG 6000 (n = 2) and PEG 20000 (n = 2). FIG. 6 shows an average dissolution screening curve of a solid dispersion of docetaxel containing PVP-K30 (n = 4) and PVP-VA64 (n = 2). It is a figure which shows the average dissolution curve of a 20 mg docetaxel tablet (n = 2) and a 10 mg docetaxel capsule (n = 6). FIG. 10 shows the average release rate of docetaxel for 0-10 minutes of 20 mg docetaxel tablets (n = 2) and 10 mg docetaxel capsules (n = 6). FIG. 6 shows DSC thermograms of amorphous (spray dry) and crystalline ritonavir. It is a figure which shows the DSC thermogram of the spray-drying method solid dispersion powder of the combination of docetaxel, ritonavir, PVP-K30, and SDS. FIG. 5 shows the dissolution profile of docetaxel / ritonavir / PVP-K30 / SDS capsules in 1,000 mL of 0.1N HCl at 37 ° C. and 50 RPM.

Paclitaxel Oral Preparation 1.1: Solid Dispersion and Physical Mixture In this experiment, the solubility and dissolution rate of a composition comprising paclitaxel mixed with SDS and a solid dispersion of PVP-K17 was compared with anhydrous paclitaxel, PVP-K17. And compared to a physical mixture of SDS.

5 mg capsules of paclitaxel solid dispersion in PVP-K17 Solid dispersion of 20% paclitaxel in PVP-K17 dissolves 100 mg paclitaxel in 10 mL t-butanol and 400 mg PVP-K17 in 6.67 mL water It was prepared by letting. The paclitaxel / t-butanol solution was added to the PVP-K17 / water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by freeze-drying (see Table 1 for conditions). 25 mg of 20% paclitaxel / PVP-K17 solid dispersion (= 5 mg paclitaxel) was mixed with 125 mg lactose, 30 mg sodium dodecyl sulfate, and 30 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 2).

5 mg capsules of paclitaxel in physical mixture with PVP-K17 The physical mixture is 5 mg anhydrous paclitaxel mixed with 20 mg PVP, 125 mg lactose, 30 mg sodium dodecyl sulfate, and 30 mg croscarmellose sodium It was prepared by. The resulting powder mixture was encapsulated.

Dissolution Test Both capsule preparations were tested in 900 mL of water for injection maintained at 37 ° C. in a USP2 (paddle) dissolution apparatus with a rotational speed of 75 rpm. In the first experiment, one capsule of each preparation was used. In the second experiment, two capsules of each preparation were used. Samples were taken at various time points and analyzed by HPLC-UV (see Table 4).

Results and Conclusions The results are shown in FIG. The amount of dissolved paclitaxel was displayed in comparison with the label contents (5 and 10 mg). It can be clearly seen that the dissolution of paclitaxel is greatly improved by the incorporation of PVP into the solid dispersion. The maximum amount of dissolved paclitaxel remains below 20% when the physical mixture is used compared to the label description. If a solid dispersion is used, the solubility is about 65% (5 mg paclitaxel) or greater than 70% (10 mg paclitaxel). For the 10 mg paclitaxel experiment, this corresponds to an absolute solubility of about 8 μg / mL, which is achieved after about 15 minutes. Thus, solid dispersions significantly increase solubility and also provide a rapid dissolution rate, both of which are important for bioavailability.

  In solid solutions or solid dispersions, the amorphous state of the support is made possible through the mixing of the support and the taxane. The carrier prevents crystallization during storage as well as during dissolution in an aqueous medium.

1.2: Addition of sodium dodecyl sulfate to the capsule preparation In this experiment, the effect of the presence or absence of the surfactant SDS in the capsule on the solubility was determined.

20% Paclitaxel Solid Dispersion in PVP-K17 A solid dispersion was prepared by dissolving 100 mg paclitaxel in 10 mL t-butanol and 400 mg PVP-K17 in 6.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 / water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

5 mg paclitaxel capsules without sodium dodecyl sulfate 25 mg 20% paclitaxel / PVP-K17 solid dispersion (= 5 mg paclitaxel) was mixed with 125 mg lactose and filled into capsules (see Table 5).

5 mg paclitaxel capsule with sodium dodecyl sulfate 25 mg 20% paclitaxel / PVP-K17 solid dispersion (= 5 mg paclitaxel) was mixed with 125 mg lactose, 30 mg sodium dodecyl sulfate, and 30 mg croscarmellose sodium . The resulting powder mixture was encapsulated (see Table 6).

Dissolution Test Both capsule preparations were tested in 900 mL of water for injection maintained at 37 ° C. in a USP2 (paddle) dissolution apparatus with a rotational speed of 75 rpm. Samples were taken at various time points and analyzed by HPLC-UV (see Table 4).

Results and Conclusions The results are shown in FIG. The amount of dissolved paclitaxel was displayed in comparison with the label description (in this case, 5 mg). The porosity of the lyophilized taxane and carrier solid dispersion was high enough to ensure rapid dissolution when in powder form (results not shown). However, when the powder was compressed into capsules, the wettability decreased dramatically. For this reason, when compressed into capsules or tablets, a surfactant is required to wet the solid dispersion.

  From FIG. 2 it can be clearly seen that the dissolution of paclitaxel is greatly improved by the addition of the surfactant sodium dodecyl sulfate. Previous experiments have shown that the addition of croscarmellose sodium, more lactose, or the use of larger capsules does not result in an increased dissolution rate of the capsule preparation. Furthermore, this experiment shows that the highest dissolution is achieved in about 10-15 minutes when using a surfactant such as SDS.

1.3: Addition of sodium dodecyl sulfate to the solid dispersion preparation In this experiment, the effect of the addition of SDS to the solid dispersion on the solubility was determined.

40% Paclitaxel Solid Dispersion in PVP-K17 A solid dispersion was prepared by dissolving 600 mg paclitaxel in 60 mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 / water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

40% paclitaxel solid dispersion in PVP-K17 and 10% sodium dodecyl sulfate The solid dispersion was 250 mg paclitaxel in 25 mL t-butanol and 375 mg PVP-K17 and 62.5 mg in 16.67 mL water. Prepared by dissolving sodium dodecyl sulfate (SDS). The paclitaxel / t-butanol solution was added to the PVP-K17 / sodium dodecyl sulfate / water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

Paclitaxel / PVP-K17 solid dispersion 25 mg paclitaxel capsule 62.5 mg 40% paclitaxel / PVP-K17 solid dispersion (= 25 mg paclitaxel) 160 mg lactose, 30 mg sodium dodecyl sulfate, and 10 mg croscarmellose Mixed with sodium. The resulting powder mixture was encapsulated (see Table 7).

25 mg paclitaxel capsule of paclitaxel / PVP-K17 / sodium dodecyl sulfate solid dispersion 68.75 mg 40% paclitaxel / PVP-K17 / 10% sodium dodecyl sulfate solid dispersion (= 25 mg paclitaxel) 160 mg lactose and 10 mg Of croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 8).

Dissolution Test Both capsule preparations were tested in 500 mL of water for injection maintained at 37 ° C. in a USP2 (paddle) dissolution apparatus. The rotation speed was set at 75 rpm for capsules containing paclitaxel / PVP-K17 / sodium dodecyl sulfate solid dispersion and 100 rpm for capsules containing paclitaxel / PVP-K17 solid dispersion. Samples were taken at various time points and analyzed by HPLC-UV (see Table 4).

Results and Conclusions The results are shown in FIG. The amount of dissolved paclitaxel was displayed in comparison with the label description (in this case 25 mg). It can be clearly seen that the dissolution of paclitaxel from a capsule containing sodium dodecyl sulfate incorporated in a solid dispersion is comparable to the dissolution of paclitaxel from a capsule containing sodium dodecyl sulfate added to the capsule. . An additional 6.25 mg of sodium dodecyl sulfate was used for incorporation into the solid dispersion, while 30 mg of sodium dodecyl sulfate was used as an additive to the capsule preparation. This shows that less surfactant is required when surfactants are incorporated into solid dispersions than when incorporated into capsules to achieve similar results. Another surprising result from this experiment is that both compositions provide an absolute paclitaxel solubility of about 26 μg / mL, this level reaching in 20-30 minutes. This result provides a higher solubility and faster dissolution rate than previously achieved.

1.4: Effect of the carrier The solid dispersion used in the experiment of Example 1.4 was made after the first experiment showed no obvious difference between drug loads. The 40% drug loading was chosen because these preparations function as well as the 20% drug loading preparations in the experiments described above and may deliver more taxanes in one tablet or capsule. It was because it provided.

40% paclitaxel solid dispersion in PVP-K12 A solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 375 mg PVP-K12 in 16.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K12 / water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

40% Paclitaxel Solid Dispersion in PVP-K17 A solid dispersion was prepared by dissolving 600 mg paclitaxel in 60 mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

40% paclitaxel solid dispersion in PVP-K30 The solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 375 mg PVP-K30 in 16.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K30 water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

40% Paclitaxel Solid Dispersion in HP-Cyclodextrin A solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 375 mg HP-cyclodextrin in 16.67 mL water. The paclitaxel / t-butanol solution was added to the HP-cyclodextrin water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

25 mg paclitaxel solid dispersion capsule 62.5 mg paclitaxel carrier / solid dispersion (= 25 mg paclitaxel) was mixed with 160 mg lactose, 30 mg sodium dodecyl sulfate, and 10 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 9).

Dissolution Test All capsule preparations were tested in 500 mL of water for injection maintained at 37 ° C. in a USP2 (paddle type) dissolution apparatus with a rotational speed of 100 rpm. Samples were taken at various time points and analyzed by HPLC-UV (see Table 4).

Results and Conclusions The average results of 2-3 experiments are shown in FIG. The amount of dissolved paclitaxel was displayed in comparison with the label description (in this case 25 mg). It can be clearly seen that the dissolution of paclitaxel from the PVP-K30 solid dispersion is as rapid as the dissolution of paclitaxel from the PVP-K17 solid dispersion. However, the amount of dissolved paclitaxel remained high throughout the 4 hour experiment in the case of PVP-K30 solid dispersion.

  The chain length of the polymeric carrier determines the time for crystallization in an aqueous environment.

1.5: Effect of drug / carrier ratio The solid dispersion used in the experiment of Example 1.5 was made after the first experiment showed no obvious difference between the carriers. These initial experiments were performed prior to the more detailed experiment of Example 1.4. As a result, PVP-K17 was chosen at will as the carrier for subsequent experiments.

10% paclitaxel solid dispersion in PVP-K17 A solid dispersion was prepared by dissolving 100 mg paclitaxel in 10 mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

25% paclitaxel solid dispersion in PVP-K17 A solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 750 mg PVP-K17 in 16.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

40% Paclitaxel Solid Dispersion in PVP-K17 A solid dispersion was prepared by dissolving 600 mg paclitaxel in 6.60 mL t-butanol and 900 mg PVP-K17 in 6.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

75% paclitaxel solid dispersion in PVP-K17 A solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol and 83 mg PVP-K17 in 16.67 mL water. The paclitaxel / t-butanol solution was added to the PVP-K17 water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

100% Paclitaxel Solid Dispersion A solid dispersion was prepared by dissolving 250 mg paclitaxel in 25 mL t-butanol. The paclitaxel / t-butanol solution was added to 16.67 mL of water with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

Dissolution test An amount of solid dispersion powder equivalent to approximately 4 mg of paclitaxel was placed in a 50 mL beaker. A magnetic stir bar and 25 mL of water were added to the beaker. This solution was stirred at 720 rpm. Samples were taken at various time points and analyzed by HPLC-UV (see Table 4).

Results and Conclusions The average results of 2-3 experiments are shown in FIG. The amount of dissolved paclitaxel (PCT) was displayed relative to the label description (in this case approximately 4 mg). The effect of the drug / carrier ratio is immediately apparent from FIG. The paclitaxel peak concentration value was inversely proportional to the drug / carrier ratio. The highest peak concentration reaches the lowest drug / carrier ratio (10%), while the lowest peak concentration reaches the highest drug / carrier ratio (100%). In addition, the 10% drug / carrier ratio solid dispersion had the highest AUC values, followed by 25, 40, 75 and 100% drug / carrier ratio solid dispersion.

  The amount of carrier relative to the amount of drug determines the time for crystallization in an aqueous environment.

1.6: Presence of enteric coating 40% paclitaxel solid dispersion in PVP-K17 and 10% sodium dodecyl sulfate The solid dispersion was in 250 ml paclitaxel and 16.67 ml water in 25 ml t-butanol. Prepared by dissolving 375 mg PVP-K17 and 62.5 mg sodium dodecyl sulfate (SDS). The paclitaxel / t-butanol solution was added to the PVP-K17 / sodium dodecyl sulfate / water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. Thereafter, t-butanol and water were removed by lyophilization (see Table 1).

25 mg paclitaxel capsule of paclitaxel / PVP-K17 / sodium dodecyl sulfate solid dispersion 68.75 mg of 20% paclitaxel / PVP-K17 / 10% sodium dodecyl sulfate solid dispersion (= 25 mg paclitaxel) with 160 mg lactose and 10 mg Mixed with croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 10).

Dissolution test These capsules were subjected to two different dissolution tests twice. The first test is a 2 hour dissolution test in 500 mL simulated gastric fluid without pepsin (SGF _sp ; see Table 11), followed by 629 mL simulated gastric fluid without pepsin (SIF _sp ; see Table 11) ) In a two-stage dissolution test. The second study was conducted in 500 mL fasted simulated intestinal fluid (FaSSIF; see Table 12) medium for 4 hours.

Both dissolution tests were performed in a USP2 (paddle type) dissolution apparatus with 500 mL media maintained at 37 ° C. and maintained at a paddle rotation speed of 75 rpm. The SGF _sp medium was changed to SIF _sp medium by adding 129 mL of switch medium. Samples were taken at various time points and analyzed by HPLC-UV (see Table 4).

Results and Conclusions The results are shown in FIG. The amount of dissolved paclitaxel was displayed in comparison with the label description (in this case 25 mg). The solubility of paclitaxel in fasted simulated intestinal fluid was approximately 20% higher than in simulated gastric fluid (SGF _sp ). The amount of paclitaxel in solution after 2 hours in SGF _sp increased only slightly when the medium was changed to simulated intestinal fluid (SIF _sp ).

  Enteric coatings prevent the release of taxanes in the stomach and thereby prevent degradation of the active ingredient. In addition, the enteric coating allows targeted delivery of the taxane to the intestine where the taxane is absorbed, thereby absorbing a limited time during which the taxane is present in solution (before crystallization begins). Guarantees spending only where it is possible.

Docetaxel Oral Preparation Materials and Methods The preparations used in the following experiments were prepared according to the methods outlined below and the compositions described in Table 13.

Pure anhydrous docetaxel Anhydrous docetaxel was used as received from ScinoPharm (Taiwan).

Pure amorphous docetaxel Docetaxel was amorphized by dissolving 300 mg of docetaxel anhydride in 30 mL of t-butanol. The docetaxel / t-butanol solution was added to 20 mL of WfI (water for injection) with constant stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm, size 1/9), after which t-butanol and water were removed by lyophilization (see Table 14).

Physical mixture The physical mixture was prepared by mixing 150 mg of docetaxel and the corresponding amount of carrier and surfactant (see Table 13) in a mortar and pestle.

Solid dispersion The solid dispersion was obtained by dissolving 300 mg of anhydrous docetaxel in 30 mL of t-butanol and the corresponding amount of carrier and surfactant (see Table 13) in 20 mL of water for injection. The docetaxel / t-butanol solution was added to the carrier / surfactant / WfI solution with constant stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm, size 1/9), after which t-butanol and water were removed by lyophilization (see Table 14).

2.1: Type of preparation In the first experiment, the effect of the type of preparation on the solubility of docetaxel was tested. Data from dissolution tests performed on preparations AE were compared. The results are shown in FIG. Preparation E was tested in quadruplicate and preparations AD were tested in duplicate.

Results Preparation A (pure docetaxel anhydride) reaches a maximum concentration of approximately 12 μg / mL (with 4.7% total docetaxel) after 5 minutes of stirring and approximately 6 μg / mL (2 %) Equilibrium concentration is reached.

  Preparation B (pure amorphous docetaxel) reaches a maximum of 32 μg / mL (13%) after 0.5 minutes, and the solubility after 10-60 minutes is comparable to Preparation A.

  Preparation C (physical mixture of anhydrous docetaxel, PVP-K30 and SDS) reaches a concentration of approximately 85 μg / mL (37%) after 5 minutes. After 15-25 minutes, the docetaxel concentration decreases rapidly from 85 μg / mL (37%) to 30 μg / mL (12%), and then further decreases to 20 μg / mL (9%) after another 60 minutes.

  Preparation D (a physical mixture of amorphous docetaxel, PVP-K30 and SDS) reaches a maximum docetaxel concentration of approximately 172 μg / mL (70%) after 7.5 minutes. After 7.5-20 minutes, the amount of docetaxel in the solution drops to 24 μg / mL (10%). After 60 minutes, an equilibrium concentration of 19 μg / mL (7%) is reached.

  Preparation E (a solid dispersion of amorphous docetaxel, PVP-K30 and SDS) has a maximum maximum concentration of 213 μg / mL (90%) reached after 5 minutes. After 10-25 minutes, the amount of docetaxel in the solution decreases rapidly, resulting in an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

Conclusion All preparations initially showed higher solubility, but these decrease to equilibrium solubility after 45-60 minutes of stirring. The decrease in solubility occurs due to crystallization of docetaxel as a result of the supersaturated solution. The degree of supersaturation depends on the physical state of the drug, i.e. whether the drug is amorphous or crystalline. When PVP-K30 is the carrier, the supersaturated state is maintained for a longer period of time so that docetaxel solubility does not decrease rapidly. Furthermore, these results show that the use of amorphous docetaxel significantly increases the solubility of docetaxel compared to anhydrous crystalline docetaxel. In addition, amorphous docetaxel exhibits a fairly high dissolution rate that peaks in about 5 to 7.5 minutes.

  This experiment shows that the amount of docetaxel in solution is even more significantly increased by physically mixing anhydrous docetaxel with PVP-K30 and SDS and by physically mixing amorphous docetaxel with PVP-K30 and SDS. Showed that to do. However, the greatest increase in solubility is achieved by incorporating docetaxel in the solid dispersion of PVP-K30 and SDS.

2.2: Type of carrier In the second experiment, the effect of the type of carrier on the solubility of docetaxel was tested. Data from dissolution tests performed on preparations E and F were compared. The results are shown in FIG. Preparation E was tested four times and Preparation F was tested twice.

Results Preparation E (a solid dispersion of amorphous docetaxel, PVP-K30 and SDS) has a maximum maximum concentration of 213 μg / mL (90% total docetaxel present) reached after 5 minutes. After 10-25 minutes, the amount of docetaxel in the solution decreases rapidly, resulting in an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

  Preparation F (in a solid dispersion of amorphous docetaxel, HPβ-CD and SDS) reaches a maximum docetaxel concentration of approximately 200 μg / mL (81%) after about 2 minutes. After 5-10 minutes, the amount of docetaxel in the solution drops to a value of 16 μg / mL (6%) and after 45 minutes an equilibrium concentration of 11 μg / mL (4%) is reached.

Conclusion This experiment showed that PVP-K30 and HPβ-CD increase the solubility of docetaxel. When PVP-K30 was used as a carrier compared to HPβ-CD, the maximum docetaxel concentration was slightly higher and the supersaturated state was maintained for a long time, so the solubility of docetaxel decreased rapidly over time. There wasn't. Furthermore, the equilibrium concentration reached after docetaxel sedimentation is higher when PVP-K30 is used compared to HPβ-CD.

2.3: Chain length In the third experiment, the effect of PVP chain length on the solubility of docetaxel was tested. Data from dissolution tests performed on preparations E and GJ were compared. The results are shown in FIG. Preparation E was tested in quadruplicate and preparations GJ were tested in duplicate.

Results Preparation G (PVP-K12) reaches a maximum docetaxel concentration of 206 μg / mL (77% of total docetaxel is present) after 5 minutes. After 5-30 minutes, the amount of docetaxel in the solution drops to a value of 20 μg / mL (7%), and after 45 minutes the docetaxel concentration is 17 μg / mL (6%).

  Preparation H (PVP-K17) reaches a maximum docetaxel concentration of 200 μg / mL (83%) after 5 minutes and this concentration is maintained for up to 10 minutes after which the amount of docetaxel in the solution is 44 μg after 15 minutes. / ML (18%) and rapidly drops to 22 μg / mL (9%) after 30 minutes. The equilibrium concentration after 45-60 minutes was approximately 21 μg / mL (8%).

  Preparation I (PVP-K25) reaches a maximum docetaxel concentration of 214 μg / mL (88%) after 5 minutes of stirring. The amount of docetaxel in the solution decreases to 22 μg / mL (9%) after 10-30 minutes, and after 60 minutes the concentration of docetaxel is 19 μg / mL (8%).

  Preparation E (PVP-K30) has a maximum docetaxel concentration of 213 μg / mL (90%), which is reached after 5 minutes. After 10-25 minutes, the amount of docetaxel in the solution decreases rapidly, resulting in an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

  Preparation J (PVP-K90) reaches a maximum docetaxel concentration of 214 μg / mL (88%) after 10 minutes of stirring. After 15 minutes, the amount of docetaxel in the solution is still 151 μg / mL (61%). After 60 minutes, the docetaxel concentration dropped to 19 μg / mL (7%).

Conclusion This experiment shows that the chain length of PVP affects both the degree of supersaturation and the period during which supersaturation is maintained. The use of a longer PVP chain length results in a higher maximum docetaxel concentration and a longer supersaturation period, where higher solubility over a longer period.

2.4: Drug loading In the fourth experiment, the effect of drug loading on the solubility of docetaxel was tested. Data from dissolution tests performed on preparations E and KN were compared. The results are shown in FIG. Preparation E was tested in quadruplicate and preparations K through N were tested in duplicate.

  Preparation N (1/21 docetaxel by weight of total composition; 5:95 (w / w) docetaxel vs. PVP) is the highest docetaxel of 197 μg / mL (79% of total docetaxel is present) after 10 minutes Reach concentration. After 15 minutes, the amount of docetaxel in the solution is still 120 μg / mL (48%), and after 15-30 minutes the docetaxel concentration decreases to 24 μg / mL (12%). After 60 minutes, the docetaxel concentration is 20 μg / mL (8%).

  Preparation E (1/11 docetaxel by weight of total composition; 10:90 (w / w) docetaxel vs. PVP) has a maximum docetaxel concentration of 213 μg / mL (90%) after 5 minutes. After 10-30 minutes, the amount of docetaxel in the solution decreases rapidly and reaches an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

  Preparation M (1/6 docetaxel by weight of total composition; 20:80 (w / w) docetaxel vs. PVP) has a docetaxel concentration of 196 μg / mL (80%) after 10 minutes of stirring. The amount of docetaxel in the solution decreases to 25 μg / mL (10%) after 10-30 minutes, and after 60 minutes the concentration of docetaxel is 18 μg / mL (7%).

  Preparation L (1/3 docetaxel by weight of total composition; 40:60 (w / w) docetaxel vs. PVP) reaches a docetaxel concentration of 176 μg / mL (71%). After 10-15 minutes, the amount of docetaxel in the solution drops rapidly to 46 μg / mL (18%), and after 60 minutes the docetaxel concentration in the solution is 18 μg / mL (7%).

  Preparation K (5/7 docetaxel by weight of total composition; 75:25 (w / w) docetaxel vs. PVP) reaches a maximum docetaxel value of 172 μg / mL (71%) after 5 minutes of stirring. After 5-10 minutes, the docetaxel concentration drops rapidly to 42 μg / mL (17%), and after 60 minutes a docetaxel concentration of 18 μg / mL (7%) is reached.

Conclusion This experiment shows that the amount of PVP-K30 compared to the amount of docetaxel used in the solid dispersion affects both the degree of supersaturation and the period during which the supersaturation is maintained. The use of a higher drug load results in a lower maximum docetaxel concentration and a shorter supersaturation period, where there is lower solubility over time.

2.5: Comparison of Solubility with Prior Art Compositions In this experiment, a composition containing a solid dispersion of 15 mg docetaxel, 135 mg PVP-K30 and 15 mg SDS is disclosed in Chen et al. [13]. Comparison with literature data for a composition containing 5 mg of docetaxel and a solid dispersion of PVP-K30. The solubility test results were obtained using the dissolution test described in Chen et al. [13] and displayed in FIGS. Dissolution tests were also performed in simulated intestinal fluid and compared to Chen literature data. The results are shown in FIG.

Results From FIG. 11, the Chen et al. Composition can dissolve up to about 80% of 5 mg of docetaxel in the composition in 900 mL of water. It took more than 5 hours to reach this maximum. The docetaxel, PVP-K30 and SDS composition dissolved 100% of 15 mg docetaxel in about 60 minutes.

  FIG. 12 shows the absolute concentration of docetaxel. The Chen composition produced a maximum docetaxel concentration of about 4.2 μg / mL after about 5 hours. The docetaxel, PVP-K30 and SDS composition resulted in a maximum docetaxel concentration of about 16.7 μg / mL after about 60 minutes.

  In FIG. 13, docetaxel capsules reach a solubility of 28 μg / mL (> 90% solubility). The solid dispersion described in Chen et al. (Docetaxel + PVP-K30) reaches a solubility of 4.2 μg / mL (less than 80% 5 mg docetaxel solid dispersion tested for dissolution in 900 mL). The capsule preparation thus reaches 6.6 times better solubility with a higher dissolution rate (the maximum dissolution rate was reached after 30 minutes compared to 90-120 minutes with Chen).

CONCLUSION From these results, docetaxel, PVP-K30 and SDS composition resulted in faster dissolution rate and higher solubility compared to Chen composition. For bioavailability, it is important to see how fast the drug dissolves and what solubility is reached in 0.5-1.5 hours.

  From the Chen results, one of ordinary skill in the art will not consider that increasing the amount of docetaxel in the composition will increase the absolute solubility of docetaxel. Because Chen's composition only dissolves 80% (ie, 4 mg) in 5 mg docetaxel in 900 mL water, increasing the amount of docetaxel to 15 mg will cause more than 4 mg of docetaxel to dissolve. You will not expect it. Thus, 15 mg docetaxel composition by Chen would be expected to dissolve up to about 27% docetaxel compared to 100% for docetaxel, PVP-K30 and SDS composition. For this reason, docetaxel, PVP-K30 and SDS compositions provide surprisingly superior results compared to Chen.

2.6: Dissolution test in simulated intestinal juice sign pancreatin (SIF _sp ) In this experiment, dissolution of capsules containing solid dispersions of docetaxel, PVP-K30 and SDS in simulated intestinal juice sign pancreatin (SIF _sp ) Tested. The capsule contained 15 mg of docetaxel according to Preparation E (see Table 13). SIF _sp was prepared according to USP28. Capsules containing 15 mg docetaxel were dissolved in 500 mL USP SIF _sp at 37 ° C. with stirring at 75 rpm. The results are shown in FIGS.

  Figures 14 and 15 show that almost 100% of docetaxel has dissolved. This is equivalent to an absolute docetaxel concentration of about 29 μg / mL and is achieved in about 30 minutes. Thus, the present composition provides a considerably higher solubility in a considerably shorter time.

2.7: Stability The solid dispersion of docetaxel, PVP-K30 and SDS according to Preparation E (see Table 13) and used in capsules for clinical trials (see examples below) It was found that both chemical (no degradation) and physical (no change in solubility properties) were stable over at least 180 days when stored at 4-8 ° C.

Data and Methods for Clinical Trials Using Preparations Ten patients participated in the ongoing Phase I clinical trials.

  These patients were given the following numbers: 301, 302, 303, 304, 305, 306, 307, 308, 309 and 310.

  These patients were given a drug consisting of a liquid preparation of docetaxel or a solid composition comprising a solid dispersion of docetaxel, PVP-K30 and SDS (hereinafter referred to as MODRA).

Liquid preparation Docetaxel dose: 30 mg for all patients (except patient 306 who took 20 mg of docetaxel). A 30 mg dose was prepared as follows: 3.0 mL Taxotere® premix for intravenous administration (polysorbate 80 (25 (v / v)%), ethanol (10 (w / w)%) ), And water) containing 10 mg of docetaxel per mL) were mixed with water to a final volume of 25 mL. This solution was taken orally by the patient with 100 mL of tap water.

MODRA
Docetaxel dose: 30 mg; 2 capsules containing 15 mg docetaxel per capsule were ingested. For subsequent studies of this clinical study, preparation E (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) from the previous example was selected. A new batch of Preparation E consists of 1,200 mg docetaxel anhydride in 120 mL t-butanol, and 10,800 mg PVP-K30 and 1,200 mg SDS in 80 mL water for injection (see Table 13). It was manufactured by dissolving. The docetaxel / t-butanol solution was added to the PVP-K30 / SDS / WfI solution with constant stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm, size 1/3), after which t-butanol and water were removed by lyophilization (see Table 14).

  A total of 60 gelatin capsules of size 0 were filled with an amount of solid dispersion equivalent to 15 mg docetaxel and the exact amount of docetaxel per mg solid dispersion was determined using an HPLC assay. This assay confirmed that the capsules contained 15 mg docetaxel.

  The patient took this drug orally when the morning stomach was empty with 100 mL of tap water.

Patient Treatment Patients 301, 302, 303, 304 and 305 received only liquid preparations.

  Patient 306 took the same drug except that he took 20 mg docetaxel plus ritonavir as a liquid preparation in the first cycle and additional ritonavir 4 hours after docetaxel in the second cycle.

  Patients 307, 308, 309 and 310 took liquid preparations and / or MODRA. Treatment cycles were administered at weekly intervals.

  All patients were treated with oral dexamethasone for both oral and intravenous docetaxel according to institutional guidelines. A dose of 4 mg of dexamethasone was administered 1 hour prior to the study drug, followed by 4 mg every 12 hours (twice). One hour prior to docetaxel treatment, the patient also took 1 mg of granisetron (Kytril®) to prevent nausea and vomiting.

  After drug administration, blood samples were taken for pharmacokinetic analysis. A blank sample was taken before administration. Blood samples were centrifuged and plasma was separated and stored immediately at −20 ° C. until analysis. The analysis was performed using a validated HPLC method in a GLP-certified laboratory (17).

Results Table 16 displays a summary of the individual pharmacokinetic study results.

Patients 301, 302, 303, 304, 305, 307, 309, and 310 took liquid preparations. Mean value of AUC and 95% confidence interval for mean value (extrapolated to infinity): 1156 (+348) ng * h / mL.
Inter-individual variability is 85%.

  Patient 306 took 20 mg docetaxel (as a liquid preparation) at the same time as 100 mg ritonavir in the first cycle and the same combination in the second cycle one week later, but after 4 hours of docetaxel additional dose 100 mg ritonavir was ingested. That is, two doses of ritonavir were taken at t = 0 for the first time and t = 4h for the second time. The pharmacokinetic curve is shown in FIG.

  Patients 307, 308, 309 and 310 took liquid preparations and / or MODRA. The pharmacokinetic curve is shown in FIG.

  FIG. 18 shows the pharmacokinetic curves of patients taking liquid preparations (307, 309 and 310) and the overall course (n = 6) of 4 patients taking MODRA (307, 308, 309 and 310). Yes.

The pharmacokinetic results of the liquid preparation vs. MODRA, both combined with 100 mg ritonavir, are summarized below.
Liquid preparation (30 mg docetaxel)
AUC _inf (95% confidence interval of the mean): 1156 (808-1504) ng * h / mL.
Inter-individual variability: 85% (n = 8)
MODRA (30 mg docetaxel)
AUC _inf (95% confidence interval for mean): 768 (568-968) ng * h / mL.
Inter-individual variability: 29% (n = 4)
Individual variability: 33% (n = 2)

  The average AUC for MODRA was calculated using 6 curves from 4 patients. Inter-individual variability was calculated using the first dose of MODRA administered to each patient. Intra-individual variability is based on data from patients 307 and 308 who took two doses of MODRA.

CONCLUSION The tested docetaxel liquid preparation yields an AUC value approximately 1.5 times higher than the same dose (30 mg) administered with the new capsule preparation (MODRA).

  Although the individual variability of the liquid preparation is high (85%), the variability of the capsule preparation is substantially low (29%). This is an important feature of the new capsule preparation and provides much better and predictable docetaxel exposure. Furthermore, for safety reasons, low inter-individual variability is very much desirable in an oral chemotherapy regimen.

  Intra-individual variability (limited data) is on the same level as inter-individual variability.

  A second boost dose of 100 mg ritonavir taken 4 hours after docetaxel administration increases the AUC of docetaxel by a factor of 1.5.

Comparison of Oral Capsule Preparation and Intravenous Administration FIG. 19 shows intravenous administration (20 mg docetaxel, Taxotere® (n = 5 patients) as an intravenous one hour infusion, and oral administration of docetaxel (30 mg Figure 2 shows pharmacokinetic curves after docetaxel; MODRA capsule, see above) (n = 4 patients; 6 courses) both intravenous and oral administration with 100 mg ritonavir (capsule, Norvir®). In accordance with institutional guidelines, all patients were treated with oral dexamethasone for both oral and intravenous docetaxel A dose of 4 mg dexamethasone was administered 1 hour before the study drug and every 12 hours thereafter (2 times) 1 hour before docetaxel treatment, patient prevents nausea and vomiting 1 mg of granisetron (Kytril®) was also taken for this purpose.

The bioavailability of MODRA capsules is:
(AUC 30 mg oral / AUC 20 mg IV) × (20/30) × 100% = 73% (SD 18%).

  This indicates that the bioavailability of the capsule is quite high, with low individual variability.

Additional characterization of oral preparations Important findings:
The preparation produced by the spray-drying method is sufficiently amorphous and has a prolonged supersaturation state after the dissolution test compared to the preparation produced by the freeze-drying method (see section 7 below).

  The equilibrium solubility of docetaxel after settling in the dissolution test was determined for the preparation with PVP-VA64 (40 μg) compared to the preparation with PVP-K30 (20 μg / mL) and the preparation without carrier (7 μg / mL). / ML) increase significantly (see section 8 below).

Summary of conclusions:
Effect of surfactant type on docetaxel dissolution (section 1):
• All surfactants tested (SDS, CPC, polysorbate 80 and sorbitan monooleate) increase the solubility of docetaxel.
-The effect of the surfactant on the dissolution rate of docetaxel appears to correlate with the HLB value of the surfactant.
SDS and CPC show a similar increase in the dissolution rate of docetaxel.

Effect of SDS amount on docetaxel dissolution (section 2):
A small amount of SDS (1/41) already increases the dissolution rate of docetaxel.
• Larger amounts of SDS (1/11) further increase the dissolution rate of docetaxel.
• The effect of surfactant appears to correlate with the compaction level of the powder, so the difference in docetaxel dissolution rate between the powder with and without the surfactant is expected to be greater for tablets .

The amorphous nature of docetaxel (section 3):
-Freeze-drying of docetaxel causes the disappearance of diffraction peaks in the X-ray powder diffraction spectrum.
• Freeze-drying of docetaxel causes the endothermic peak to disappear near 165 ° C and the appearance of a glass transition near 124 ° C.
The endothermic peak area near 165 ° C. correlates well with the amount of crystalline material in the physical mixture of amorphous and crystalline docetaxel.

The amorphous nature of paclitaxel (section 4):
-Lyophilization of paclitaxel causes the disappearance of diffraction peaks in the X-ray powder diffraction spectrum.
• Freeze drying of paclitaxel results in the disappearance of endothermic peaks near 58, 80 and 163 ° C, the appearance of endothermic peaks near 61 ° C and the glass transition near 154 ° C.

Characterization of solid dispersion of docetaxel (section 5):
Freeze-drying a mixture of docetaxel, PVP-K30 and SDS results in the disappearance of the diffraction peak belonging to docetaxel in the X-ray powder diffraction pattern.
The diffraction peak of docetaxel is present in the physical mixture of solid dispersion components.

Characterization of solid dispersion of paclitaxel (section 6):
• The paclitaxel solid dispersion system is comparable to the docetaxel solid dispersion system.

Effect of production method on properties and performance of docetaxel solid dispersion (Section 7):
-Spray drying of a mixture of docetaxel, PVP-K30 and SDS results in the disappearance of diffraction peaks belonging to docetaxel and SDS.
-Spray drying of a mixture of docetaxel, PVP-K30 and SDS causes the disappearance of endothermic peaks belonging to docetaxel and SDS in the DSC thermogram.
• Spray drying of a mixture of docetaxel, PVP-K30 and SDS results in a longer time to settling after dissolution testing compared to a lyophilized mixture of docetaxel, PVP-K30 and SDS.

Effect of carrier type on dissolution performance of docetaxel solid dispersion (section 8):
The use of polyethylene glycol (1500, 6000 or 20000) instead of PVP-K30 results in a shorter time to sedimentation and a lower equilibrium solubility of docetaxel after the dissolution test.
Use of PVP-VA64 instead of PVP-K30 results in comparable time to sedimentation and significantly higher equilibrium solubility of docetaxel after dissolution testing (40 μg / mL vs. 20 μg / mL, respectively).

Tablet production (section 9):
It is feasible to produce tablets with a dissolution rate that is at least as high as that of currently used capsules.
It is feasible to produce tablets with a higher docetaxel content than currently used capsules.

Materials and Methods General The preparations used in the following experiments were prepared according to the methods outlined below and the compositions described in Table 18, Table 19, Table 20 and Table 17. The drugs tested were paclitaxel and docetaxel.

Crystalline drugs:
The crystalline drug was used as received from the supplier.

Amorphous drug:
The drug was amorphized by dissolving the drug in 30 mL t-butanol. The drug / t-butanol solution was added to 20 mL of water for injection (WfI) with constant stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm, size 1/9), after which t-butanol and water were removed by lyophilization (see Table 20).

Physical mixture of the components of the solid dispersion The physical mixture was prepared by mixing 150 mg of docetaxel and the corresponding amount of carrier and surfactant (see Table 17) with a mortar and pestle.

Physical mixture of amorphous and crystalline docetaxel The physical mixture was prepared by mixing precisely metered amounts of crystalline and amorphous docetaxel (see Table 18).

Solid dispersion (freeze-dried)
The solid dispersion was obtained by dissolving docetaxel and the corresponding amount of carrier and surfactant (see Table 19) in 20 mL of water for injection in 30 mL of t-butanol. The docetaxel / t-butanol solution was added to the carrier / surfactant / WfI solution with constant stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm size 1/9), after which t-butanol and water were removed by lyophilization (see Table 20).

Solid dispersion (spray dry)
The solid dispersion was obtained by dissolving docetaxel in 45 mL ethanol and 5 mL WfI. After the drug was completely dissolved, PVP-K30 and SDS (see Table 21) were added to the drug / ethanol / WfI solution with constant stirring. The final mixture was transferred to a flask, after which ethanol and water were removed by spray drying (see Table 22).

Capsule (used in sections 1 and 2)
Capsules were made by weighing lyophilized solid dispersion powder (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) in an amount equivalent to 10-15 mg drug. The solid dispersion powder was pulverized with a mortar and pestle to a fine powder and filled into size 0 hard gelatin capsules using a manual capsule filling machine. The amount of docetaxel per capsule was estimated by subtracting the net capsule weight from the total capsule weight after manufacture and multiplying it by the docetaxel ratio of the solid dispersion powder (FIG. 19). The capsule content was confirmed by HPLC quality control.

Clinical trial capsule (used in Section 9)
Clinical trial capsules were lyophilized solid dispersion powder (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) in an amount equivalent to 10 mg drug, 110 mg lactose monohydrate and 1.1 mg Of colloidal silicon dioxide. All ingredients were mixed using a mortar and pestle until a homogeneous mixture was obtained. This mixture was encapsulated in size 0 hard gelatin capsules using a manual capsule filling device.

Tablet (used in section 9)
Tablets were spray-dried solid dispersion powder (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) equivalent to 20 mg docetaxel, 110 mg lactose monohydrate and 110 mg crosslinked polyvinylpyrrolidone. Was manufactured by weighing. All ingredients were mixed using a mortar and pestle until a homogeneous mixture was obtained. This mixture was compressed manually on an eccentric press equipped with a 13 mm flat tool. The filling amount was fixed at 13.5 mm, and the pressure was set to 10.5 mm. Tablets were weighed after compression and the amount of docetaxel was estimated by multiplying the tablet weight by the product of the weight fraction of drug in the solid dispersion powder and the weight fraction of solid dispersion powder in the tablet. The tablet content was confirmed by HPLC quality control.

Dissolution screening test An amount of powder equivalent to approximately 6 mg of drug was placed in a 50 mL beaker. A magnetic stir bar and 25 mL of water were added to the beaker. This solution was stirred at 720 rpm and maintained at approximately 37 ° C. Samples were taken at various time points and filtered using a 0.45 μm filter, after which they were diluted with a 1: 4 (v / v) mixture of methanol and acetonitrile. Filtered and diluted samples were then analyzed by HPLC-UV (see Table 23). The amount of drug dissolved was expressed as a concentration of μg / mL.

Dissolution test The capsule or tablet was placed in a type 2 (paddle type) dissolution apparatus filled with 500 mL of WfI at 37 ° C, and the rotational speed of the paddle was 75 rpm. Samples were taken at various time points and filtered using a 0.45 μm filter, after which they were diluted 1: 1 with a 1: 4 (v / v) mixture of methanol and acetonitrile. Filtered and diluted samples were then analyzed by HPLC-UV (see Table 23). The amount of docetaxel dissolved was expressed either as a concentration in μg / mL or as a percentage of the label content (% RLC). The label description is an estimated amount of drug present in each capsule or tablet after manufacture.

Differential Scanning Calorimetry (DSC) Measurement DSC measurements were performed on a Q2000 DSC (TA Instruments, Newcastle, Del.). The thermometer and the heat flow meter were calibrated using indium. Approximately 10 mg of powder sample was transferred to a Tzero aluminum pan (TA instruments), sealed and placed in an autosampler. The program listed in Table 24 was used for all samples.

X-ray powder diffractometry X-ray powder diffractometry was performed on a Phlips X'pert pro diffractometer equipped with an X-celerator. A sample with a thickness of approximately 0.5 mm was placed in a metal sample holder, placed in a diffractometer, and scanned with the settings shown in Table 25.

Experimental Section 1: Effect of Surfactant Type on Docetaxel Dissolution Purpose To determine the effect of surfactant type on five preparations (Table 26) with different surfactants (see Table 26) 19, preparations 1-5) were prepared by lyophilization (see Table 20). Surfactant selection was based on surfactant class and HLB values. The selected surfactants represent all three surfactant classes (anionic, cationic and nonionic) and a wide range of HLB values (4.3-40). Each preparation had the same amount of docetaxel, PVP-K30 and surfactant. Three capsules were made from each preparation without any additives and subjected to dissolution testing.

Observations FIG. 20 shows that the amount of docetaxel dissolved in the preparation containing SDS in 0-5 minutes was less than 10% RLC, but the amount of docetaxel dissolved in the preparation containing CPC and polysorbate 80 was 30%. RLC was exceeded. At this point, approximately 17% RLC of docetaxel in the sorbitan monooleate preparation is dissolved. However, after 10 minutes, the difference in the amount of dissolved docetaxel between the SDS (63% RLC), CPC (75% RLC) and polysorbate 80 (68% RLC) preparations was significantly reduced, but from the sorbitan monooleate preparation The release of docetaxel remains fairly low at 48% RLC. After 15 minutes, the amount of docetaxel released from the preparation containing SDS is equivalent to the amount of docetaxel released from the preparation containing CPC. Polysorbate 80 and sorbitan monooleate preparations have lower released docetaxel amounts of 73% RLC and 63% RLC, but these numbers are still much more than docetaxel release from solid dispersion systems without surfactant. (37% RLC). After 60 minutes, the amount of docetaxel released from the CPC and SDS systems is 87% RLC and 89% RLC, respectively, while the release from the polysorbate 80 and sorbitan monooleate preparations is 77% RLC and 83% RLC, respectively. Low.

Conclusion All solid dispersion systems with surfactants increase docetaxel dissolution compared to the same solid dispersion system without surfactants. The effects of CPC and SDS on docetaxel dissolution are comparable, and the initial difference between these two surfactants is probably the result of variations in capsule shell dissolution. The HLB value of these surfactants appears to correlate well with the performance of the solid dispersion preparation.

  Furthermore, dissolution tests using capsules made from the paclitaxel solid dispersion system showed an even greater change in dissolution rate due to the incorporation of surfactant (SDS) into the solid dispersion. This difference may be related to the difference in action of the solubility of the active ingredient (paclitaxel versus docetaxel), so the difference between the various surfactants was produced from paclitaxel containing a solid dispersion system For formulations, it is likely to be large.

Section 2: Effect of Surfactant Amount on Docetaxel Dissolution Purpose To determine the effect of SDS amount, four solid dispersion powders containing docetaxel (see Table 19, Preparations 4-7) Was prepared by lyophilization (see Table 20). The amount of SDS varied between the four preparations, while the amount of docetaxel and PVP-K30 remained constant. Three capsules were made from each preparation without any additives and subjected to dissolution testing.

Observation FIG.21 and FIG.22 has shown the result of the dissolution test. In 0-5 minutes, docetaxel dissolution is limited in all four preparations. The initial slow solubility is due to the lag time caused by the dissolution of the capsule envelope. After the jacket has dissolved, the solid dispersion powder can begin to dissolve. Dissolution of docetaxel from the preparation without surfactant is considered to be slower than dissolution of docetaxel from the preparation with 1/11 SDS.

  The 1/11 SDS preparation reaches dissolved docetaxel in an amount of 90% RLC within 30 minutes, whereas the preparation without SDS dissolves in an amount of 70% RLC (compared to the label) after 60 minutes. Only reach the docetaxel. Furthermore, the variation in the release rate of docetaxel between capsules of the preparation without surfactant is much higher than the variation between capsules of the preparation with 1/11 SDS.

  20 and 21 also show the difference between various amounts of SDS. The dissolution of docetaxel is already improved by the addition of only 1/41 SDS to the solid dispersion system, but there is no clear difference between the dissolution patterns of 1/41 and 1/21 SDS. A certain amount of 1/11 SDS produces the best dissolution pattern of docetaxel compared to 1/21 SDS and 1/41 SDS.

Conclusion The higher amount of incorporation into SDS into the solid dispersion system results in a faster dissolution rate. Incorporation of 1/11 (w / w) SDS yields the fastest dissolution rate.

  Compression of the solid dispersion powder is likely to make the use of surfactants indispensable. Incorporation of surfactants will be even more necessary in solid dispersion tablets because tablet production results in higher compression than capsule production.

  Incorporation of SDS into the solid dispersion system ensures a homogeneous distribution of surfactant that improves the wettability of the solid dispersion powder after capsule filling and tableting.

Section 3: Amorphous Properties of Docetaxel Purpose The physical form of docetaxel after lyophilization was determined by differential scanning calorimetry (DSC) (see Table 24) and X-ray powder to determine crystallinity after lyophilization of docetaxel. Investigated by diffraction measurements (see Table 25).

Observations FIG. 23 shows the effect of the freeze-drying method on the X-ray powder diffraction pattern of docetaxel. Prior to lyophilization of docetaxel, the X-ray diffraction spectrum has a number of diffraction peaks between 10 and 40 ° 2θ, indicating that docetaxel is in the crystalline state. After lyophilization of docetaxel, there is an amorphous halo in the X-ray powder diffraction pattern, indicating that docetaxel is in an amorphous form.

  FIG. 24 shows the effect of freeze drying on the DSC thermogram of docetaxel. Prior to lyophilization of docetaxel, the DSC thermogram shows a large endothermic peak at 165 ° C. probably caused by rearrangement of the crystal structure of docetaxel. After lyophilization of docetaxel, the DSC thermogram has no endothermic peak at 165 ° C. However, a broad endothermic peak is present at approximately 50 ° C., which is caused by the evaporation method of water and t-butanol. Furthermore, the glass transition can be observed at 124 ° C., indicating that docetaxel is in an amorphous state.

  FIG. 25 shows X-ray powder diffraction spectra of various mixtures of amorphous (lyophilized) and crystalline docetaxel. A decrease in the crystalline docetaxel content in the mixture results in a decrease in the intensity and number of diffraction peaks in the X-ray powder diffraction spectrum. The X-ray diffraction pattern of the mixture containing 5% crystalline docetaxel does not have a diffraction peak, which indicates that the minimum detectable amount of crystalline docetaxel with X-ray powder diffraction is 5 (w / w)% (pure It is instructed to exceed the drug substance).

  FIG. 26 shows DSC thermograms for various mixtures of amorphous (lyophilized) and crystalline docetaxel. A decrease in the content of crystalline docetaxel in the mixture results in a decrease in the endothermic peak size at 165 ° C. and a broad endothermic peak increase at approximately 50 ° C. This is the difference in the size of the endothermic peaks at 50 and 165 ° C. in the thermograms of 0% crystalline docetaxel (pure lyophilized docetaxel) and 5% crystalline docetaxel, which is detectable for crystalline docetaxel containing DSC The minimum amount is 0-5 (w / w)% crystalline docetaxel (pure drug substance).

  FIG. 27 shows a plot of the peak area at 165 ° C. in the total heat flow thermogram against the amount of crystalline material in the physical mixture of crystalline and amorphous docetaxel (see Table 18). The amount of crystalline material in the amorphous and crystalline drugs is estimated to be 0-100 (w / w)% each. The regression line has a coefficient of determination of 0.990 and a coefficient of regression of 0.995, confirming that there is an intensity correlation between the peak size at 165 ° C. and the crystallinity.

Conclusions Lyophilization of docetaxel reduces crystallinity to such an extent that the X-ray powder diffraction spectrum of lyophilized docetaxel does not show diffraction peaks, and the DSC thermogram does not show endothermic peaks associated with crystal rearrangement. Give rise to Furthermore, in the DSC thermogram, a glass transition appears. This is all an indication that docetaxel is in an amorphous state after lyophilization.

  The peak area of the endothermic peak associated with crystal rearrangement correlates well with the content of crystalline docetaxel in the physical mixture of amorphous and crystalline docetaxel.

Section 4: Amorphous nature of paclitaxel Purpose The physical form of paclitaxel after lyophilization was investigated by X-ray powder diffraction and differential scanning calorimetry to determine the crystallinity of paclitaxel after lyophilization.

Findings FIG. 28 shows the effect of freeze drying on the X-ray powder diffraction pattern of paclitaxel. Prior to lyophilization of paclitaxel, the X-ray diffraction spectrum has a number of diffraction peaks between 10 and 40 ° 2θ, indicating that paclitaxel is in the crystalline state. After paclitaxel is lyophilized, there is an amorphous halo in the X-ray powder diffraction pattern, indicating that paclitaxel is in an amorphous form.

  FIG. 29 shows the effect of lyophilization on paclitaxel DSC thermogram. Prior to lyophilization of paclitaxel, the DSC thermogram shows large endothermic peaks at 58, 80 and 163 ° C. Both peaks at 58 and 80 ° C. are caused by the disappearance of water from the crystal lattice. The endothermic peak at 163 ° C. is probably caused by rearrangement of the crystal structure of paclitaxel. After lyophilization of paclitaxel, the DSC thermogram does not have an endothermic peak at 58, 80 or 163 ° C. instead of a broad endothermic peak at 61 ° C., and a glass transition at 154 ° C. can be observed.

Conclusions Lyophilization of paclitaxel results in a decrease in crystallinity to the extent that the X-ray powder diffraction spectrum of lyophilized paclitaxel does not show a diffraction peak, and the DSC thermogram does not show an endothermic peak associated with crystal rearrangement. Furthermore, in the DSC thermogram, a glass transition appears. This is all an indication that paclitaxel is in an amorphous state after lyophilization.

Section 5: Characterization of Solid Dispersion Containing Docetaxel Purpose To characterize the solid dispersion of docetaxel, X-ray powder diffractometry and DSC measurements were performed using physical mixtures and solid dispersions of docetaxel, PVP-K30 and SDS. Conducted above.

Observation FIG. 30 shows X-ray diffraction patterns of docetaxel, PVP-K30 and SDS which are components of the solid dispersion. Docetaxel is crystalline and has many diffraction peaks at 10 to 40 ° 2θ, SDS is crystalline and has a sharp diffraction peak between 20 and 22 ° 2θ, and PVP-K30 is It is amorphous and does not have a diffraction peak.

  FIG. 31 shows DSC thermograms of docetaxel, PVP-K30 and SDS which are components of the solid dispersion. Docetaxel has a large endothermic peak at 165 ° C. possibly caused by crystal rearrangement. PVP-K30 has a large endothermic peak caused by the evaporation of water near 76 ° C. and has a glass transition near 162 ° C. caused by the difference in heat capacity between the glass and rubber states. . SDS has a phase transition near 67 ° C., possibly caused by a small amorphous fraction, and a large endothermic region of 80-120 ° C. containing multiple peaks. These peaks are caused in part by melting the crystalline bulk of SDS and in part by unknown irreversible endothermic events.

  FIG. 32 is a diagram showing an X-ray powder diffraction spectrum of a physical mixture containing 1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS, and a solid dispersion system. The crystalline diffraction peaks of docetaxel and SDS appear in the X-ray powder diffraction spectrum of the physical mixture, but the docetaxel diffraction peak does not appear in the X-ray diffraction spectrum of the solid dispersion system.

  FIG. 33 shows a DSC thermogram of a physical mixture and solid dispersion system containing 1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS. The thermogram of the physical mixture is probably an endothermic drop near 200 ° C. caused by SDS; a small endothermic peak near 162 ° C. probably caused by crystalline docetaxel and possibly near 164 ° C. caused by PVP-K30. The glass transition of is shown. The thermogram of the solid dispersion system shows an endothermic peak near 113 ° C. possibly caused by SDS; and a glass transition near 155 ° C. caused by the combination of amorphous docetaxel and amorphous PVP-K30.

Conclusion The X-ray powder diffraction spectrum of the solid dispersion does not show a diffraction peak belonging to docetaxel, whereas the X-ray powder diffraction spectrum of the physical mixture containing docetaxel, PVP-K30 and SDS shows a diffraction peak belonging to docetaxel. The DSC thermogram of the lyophilized mixture of docetaxel, PVP-K30 and SDS shows a glass transition at 155 ° C. possibly caused by molecular mixing of amorphous docetaxel and PVP-K30, but contains docetaxel, PVP-K30 and SDS The DSC thermogram of the physical mixture shows the glass transition temperature at 163 ° C. probably caused by PVP-K30. In addition, the endothermic peak near 162 ° C. is only visible in the DSC thermogram of the physical mixture, but not in the DSC thermogram of the solid dispersion.

  SDS exists in a crystalline state in both the solid dispersion and the physical mixture, the diffraction peak between 20-22 ° 2θ in the X-ray diffraction spectra of both the solid dispersion and the physical mixture, and the physical mixture and the solid Each produces an endothermic peak near 100-113 ° C. in the DSC thermogram of the dispersion.

  Furthermore, although lyophilization of docetaxel alone produced amorphous docetaxel (see section 3), lyophilization of a mixture containing docetaxel is also very likely to produce amorphous docetaxel.

Section 6: Characterization of Paclitaxel Solid Dispersion Available data indicate that the paclitaxel solid dispersion system is comparable to the docetaxel solid dispersion system, ie, paclitaxel exists in an amorphous state after lyophilization but not SDS I have indicated that.

Section 7: Effect of Manufacturing Method on Docetaxel Solid Dispersion Properties and Performance Objectives To determine the effect of manufacturing method on solid dispersion properties, use both freeze-drying and spray-drying methods. A solid dispersion system with docetaxel, 9/11 PVP-K30 and 1/11 SDS was produced (see Table 19 and Table 21). Both systems were tested by X-ray diffraction, DSC and dissolution screening tests.

Observation FIG. 34 shows the X-ray powder diffraction spectrum of the solid dispersion produced by freeze-drying method and spray-drying method. The solid dispersion produced by the freeze-drying method (freeze-drying method) is partially crystalline because of the presence of diffraction peaks present in the spectrum of 20-22 ° 2θ. These diffraction peaks belong to SDS (FIG. 30). The solid dispersion produced by the spray drying method is sufficiently amorphous as can be concluded from the absence of diffraction peaks in the X-ray powder diffraction pattern.

  FIG. 35 shows DSC thermograms of solid dispersions produced by freeze drying and spray drying methods. The thermogram of the solid dispersion produced by the freeze-drying method is probably an endothermic peak near 113 ° C. caused by SDS; and near 155 ° C. caused by the combination of amorphous docetaxel and amorphous PVP-K30. The glass transition of is shown. The solid dispersion produced by the spray-drying process shows only a glass transition near 147 ° C., which is an indication of a sufficiently amorphous form.

  FIG. 36 shows dissolution screening curves for solid dispersions produced by freeze-drying and spray-drying methods. The solid dispersion produced by lyophilization reaches a peak docetaxel concentration after 5 minutes and begins to settle. The solid dispersion produced by the spray drying method reaches a peak docetaxel concentration after 10 minutes and begins to settle after 15 minutes.

Conclusion The use of the spray-drying method compared to the freeze-drying method in the preparation of docetaxel solid dispersions results in a more amorphous system that gives improved performance in dissolution screening tests for long-term supersaturation.

  Furthermore, the powder obtained after the spray drying process is less stationary and has a more uniform particle size, so it is more suitable for subsequent processing compared to the lyophilized product.

Section 8: Effect of Carrier Type on Dissolution Performance of Docetaxel Solid Dispersion To test the performance of different carriers on dissolution performance of solid dispersion of docetaxel. Various carriers were used in the production of solid dispersion systems containing I / 11 docetaxel, 9/11 carrier and 1/11 SDS (see Table 19, preparations 8-11). The entire system was subjected to a dissolution screening test.

Observations FIG. 37 shows dissolution screening curves for solid dispersion systems containing PVP-K30, PEG 1500, PEG 6000 or PEG 20000. All systems reach comparable peak concentrations of docetaxel after 5 minutes, but docetaxel sedimentation already begins after 5 minutes for all three PEG systems. Furthermore, the amount of docetaxel in the solution after settling is approximately 8 μg / mL in PEG containing the solid dispersion system, whereas the system containing PVP-K30 reaches the amount of docetaxel in the solution at 20 μg / mL after settling. .

  FIG. 38 shows a dissolution screening curve of a solid dispersion system containing PVP-K30 or PVP-VA64. For both systems, the same docetaxel peak concentration is reached after 5 minutes and for both systems docetaxel begins to settle after approximately 10 minutes. However, there is a significant difference in the amount of docetaxel in the solution after precipitation: PVP-VA64 (40 μg / mL) and PVP-K30 (20 μg / mL).

Conclusion Solid dispersion systems containing PEG perform worse than solid dispersion systems containing PVP-K30 in dissolution screening tests.

  The solid dispersion system containing PVP-VA64 reaches a significantly higher concentration of docetaxel after settling than the solid dispersion system containing PVP-K30.

  Furthermore, since paclitaxel has a lower solubility than docetaxel, the use of PVP-VA64 may be particularly useful in paclitaxel containing solid dispersion systems.

Section 9: Purpose of tablet production To investigate the feasibility of tablet production from a solid dispersion of docetaxel.

Findings FIG. 39 shows the mean dissolution curves of 20 mg docetaxel tablets and 10 mg docetaxel capsules currently used in clinical trials. FIG. 40 shows the average dissolution rate of tablets and capsules in 0-10 minutes. The tablets show a steady dissolution rate of 0-30 minutes until reaching a concentration of 35 μg / mL. The capsules show a steady dissolution rate of 0-10 minutes until reaching a concentration of approximately 16 μg / mL. In 0-10 minutes, the release rate of docetaxel from both capsules and tablets is approximately 0.8 mg / min.

Conclusion Manufacture of docetaxel tablets containing solid dispersion system is feasible. The dissolution rate of docetaxel tablets is comparable to the dissolution rate of docetaxel capsules currently used in clinical trials.

Addition of additional pharmaceutically active ingredients to a solid dispersion of docetaxel Preparation of amorphous ritonavir Solid ingredients:
300 mg ritonavir solvent:
45 mL of ethanol 5 mL of water for injection Ritonavir was dissolved in an ethanol / water mixture and spray dried using a Buchi 290 mini spray dryer (see Table 27).

Manufacturing solid components of a combined product of docetaxel, ritonavir, PVP and SDS:
1 g docetaxel anhydride 4 g ritonavir 25 g PVP-K30
5g of SDS
solvent:
900 mL of ethanol 100 mL of water for injection All solid components were dissolved in an ethanol-water mixture and spray dried using a Buchi 290 mini spray dryer (see Table 27). This resulted in a visually homogeneous white powder. This solid dispersion powder was equivalent to approximately 12.5 mg docetaxel and 50 mg ritonavir (per capsule) and was manually encapsulated in size 0 hard gelatin capsules.

  FIG. 41 shows DSC thermograms of amorphous (spray dry) and crystalline ritonavir. Amorphous ritonavir exhibits a Tg of approximately 25 ° C and the crystal exhibits a melting endotherm of approximately 122 ° C. It was concluded that the spray-drying method yielded amorphous ritonavir.

  FIG. 42 shows a DSC thermogram of a spray-dried solid dispersion powder of a combination of docetaxel, ritonavir, PVP-K30 and SDS. The thermogram showed a single Tg of approximately 117 ° C., but no melt endotherm for ritonavir, docetaxel, PVP-K30 or SDS.

  FIG. 43 shows the dissolution profile of docetaxel / ritonavir / PVP-K30 / SDS capsules in 1,000 mL of 0.1N HCl at 37 ° C. and 50 RPM. Each capsule contained approximately 12.5 mg docetaxel and approximately 50 mg ritonavir. Both docetaxel and ritonavir are completely released within 45 minutes (n = 3).

  The above examples are intended to illustrate certain embodiments of the present invention, but are not intended to limit the scope of the invention, which is covered by the appended claims. It is prescribed by. All documents mentioned in this specification are hereby incorporated by reference in their entirety.

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Claims (36)

  A solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane, a hydrophilic carrier and a surfactant, wherein the substantially amorphous taxane is prepared by a solvent evaporation method. Said solid pharmaceutical composition.   The composition according to claim 1, wherein the solvent evaporation method is a spray drying method.   The composition according to claim 1 or 2, wherein the taxane and the carrier are in the form of a solid dispersion.   The composition according to any one of claims 1 to 3, wherein the taxane, the carrier and the surfactant are in the form of a solid dispersion.   The composition according to claim 3 or 4, wherein the solid dispersion is prepared by a solvent evaporation method.   The composition according to claim 5, wherein the solvent evaporation method is a spray drying method.   7. The taxane according to any one of claims 1 to 6, wherein the taxane is selected from docetaxel, paclitaxel, BMS-275183, and functional derivatives thereof, and pharmaceutically acceptable salts or esters thereof. Composition.   8. The composition of claim 7, wherein the taxane is selected from docetaxel, paclitaxel, and functional derivatives thereof, and pharmaceutically acceptable salts or esters thereof.   The composition according to any one of claims 1 to 8, wherein the carrier is polymeric.   The composition according to any one of claims 1 to 9, wherein the carrier is selected from PVP, PVP-VA and PEG.   11. A composition according to any one of claims 1 to 10, wherein the carrier is PVP.   The composition according to claim 11, wherein the PVP is selected from PVP-K12, PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60 and PVP-K90.   The composition according to claim 12, wherein the PVP is selected from PVP-K30, PVP-K60 and PVP-K90.   The surfactant is sodium dodecyl sulfate (SDS), sorbitan esters (sorbitan fatty acid esters), polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene alkyl Ethers, poloxamer, glyceryl monooleate, docusate sodium, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromellose, nonionic emulsifying wax, anionic emulsifying wax and triethyl citrate The composition according to any one of claims 1 to 13.   The composition according to any one of claims 1 to 14, wherein the surfactant is selected from SDS, sorbitan esters (sorbitan fatty acid esters), polyoxyethylene sorbitan fatty acid esters, and CPC.   The composition according to claim 14, wherein the surfactant is SDS.   17. A composition according to any one of the preceding claims, wherein the weight ratio of taxane to carrier is from about 0.01: 99.99 (w / w) to about 75:25 (w / w). .   18. The composition of claim 17, wherein the taxane to carrier weight ratio is from about 0.01: 99.99 (w / w) to about 30:70 (w / w).   19. The weight ratio of surfactant to combined taxane and carrier is from about 1:99 (w / w) to about 50:50 (w / w). Composition.   20. The composition of claim 19, wherein the weight ratio of surfactant to combined taxane and carrier is between about 2:98 (w / w) to about 17:83 (w / w).   21. The composition according to any one of claims 1 to 20, further comprising one or more additional pharmaceutically active ingredients.   24. The composition of claim 21, wherein the one or more additional pharmaceutically active ingredients are CYP3A4 inhibitors.   23. The composition of claim 22, wherein the CYP3A4 inhibitor is ritonavir.   24. The taxane, the carrier, the surfactant, and the one or more additional pharmaceutically active ingredients are in the form of a solid dispersion. Composition.   25. The composition of claim 24, wherein the solid dispersion is prepared by a solvent evaporation method.   26. The composition of claim 25, wherein the solvent evaporation method is a spray drying method.   27. A composition according to any one of claims 1 to 26 for use in therapy.   27. A composition according to any one of claims 1 to 26 for use in the treatment of neoplastic diseases.   A method for treating a neoplastic disease, comprising the step of administering an effective amount of the composition according to any one of claims 1 to 26 to a subject in need of such treatment. In order to produce the composition,
Preparing an amorphous taxane using a solvent evaporation method;
A method for preparing a composition according to claim 1, comprising combining the amorphous taxane with a hydrophilic carrier and a surfactant.   A pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a hydrophilic carrier, wherein the substantially amorphous taxane is prepared by spray drying method object.   A pharmaceutical composition comprising a taxane, a hydrophilic carrier and a surfactant in solution.   33. The composition of claim 32, wherein the composition is in the form of a beverage liquid for administration to a subject.   The composition according to claim 32, wherein the composition is contained in a capsule.   32. The composition according to any one of claims 29 to 31, wherein the composition is obtainable by a step of dissolving the solid composition according to any one of claims 1 to 26 in a suitable solvent. Composition.   A solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane and one or more pharmaceutically acceptable excipients, wherein the substantially amorphous taxane is spray dried. The said solid pharmaceutical composition which is prepared by a method.