Pharmaceutical compositions, as well as their manufacturing methods and uses.

Abstract

The present invention provides a pharmaceutical composition that can suppress the crystallization of amorphous active ingredients, improve storage stability, and suppress the formation of related substances. [Solution] A pharmaceutical composition is prepared by combining an amorphous active ingredient with a pharmaceutically acceptable carrier and a pharmaceutically acceptable acidic additive. The carrier comprises at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives. The active ingredient may be cabozantinib or a pharmaceutically acceptable salt thereof. The (meth)acrylic polymer may include a (meth)acrylic polymer having aminoalkyl methacrylate units. The cellulose derivative may include cellulose carboxyalkyl alkyl ethers (in particular carboxymethyl ethyl cellulose). The acidic additive may include an organic acid.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing an amorphous active ingredient, a method for producing the same, and uses thereof.

Background Art

[0002] Cabozantinib has the chemical name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and is a compound represented by the following formula.

[0003]

Chemical formula

[0004] Cabozantinib is used as a multi-kinase inhibitor effective for the treatment of unresectable or metastatic renal cell carcinoma, unresectable hepatocellular carcinoma that has worsened after cancer chemotherapy, and the like.

[0005] As a medicine containing cabozantinib, Patent No. 6342456 (Patent Document 1) discloses a medicine for treating renal cancer containing malate of cabozantinib and the salt being in a crystalline form, and Patent No. 6542429 (Patent Document 2) discloses a medicine for treating liver cancer containing malate of cabozantinib and the salt being in a crystalline form.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0007] However, since the cabozantinib malate described in Patent Documents 1 and 2 is crystalline, there is room for improvement in terms of dissolution and bioavailability. Generally, amorphous active ingredients are superior to crystalline active ingredients in terms of dissolution and bioavailability, but they have lower storage stability, so it is important to suppress the formation of related substances. Furthermore, it is difficult to amorphousize highly crystalline active ingredients such as cabozantinib malate, and even if amorphous, they tend to revert to a crystalline state, making it difficult to maintain a stable amorphous state.

[0008] Therefore, the object of the present invention is to provide a pharmaceutical composition that can suppress the crystallization of amorphous active ingredients and improve storage stability, as well as a method for producing the same and its uses.

[0009] Another object of the present invention is to provide a pharmaceutical composition that can suppress the crystallization of amorphous active ingredients, improve storage stability, and suppress the generation of related substances, as well as a method for producing the same and its uses. [Means for solving the problem]

[0010] As a result of diligent research to achieve the above objectives, the inventors have discovered that by preparing a pharmaceutical composition comprising an amorphous active ingredient and an acidic additive, or a pharmaceutical composition comprising an amorphous active ingredient and a pharmaceutically acceptable carrier comprising at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives (in particular, a pharmaceutical composition comprising an amorphous active ingredient, a pharmaceutically acceptable carrier comprising at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives, and an acidic additive), the crystallization of the amorphous active ingredient can be suppressed and storage stability can be improved, thus completing the present invention.

[0011] In other words, the present invention includes the following embodiments.

[0012] Embodiment [1]: A pharmaceutical composition comprising an amorphous active ingredient, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable acidic additive, A pharmaceutical composition comprising, as the carrier, at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives.

[0013] Embodiment [2]: The pharmaceutical composition according to Embodiment [1], wherein the active ingredient comprises cabozantinib or a pharmaceutically acceptable salt thereof.

[0014] Embodiment [3]: A pharmaceutical composition comprising an amorphous active ingredient and a pharmaceutically acceptable carrier, The active ingredient comprises cabozantinib or a pharmaceutically acceptable salt thereof, and A pharmaceutical composition comprising, as the carrier, at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives.

[0015] Embodiment [4]: ​​The pharmaceutical composition according to any one of Embodiments [1] to [3], wherein the proportion of the carrier is 10 to 1000 parts by mass per 100 parts by mass of the active ingredient.

[0016] Embodiment [5]: The pharmaceutical composition according to any one of Embodiments [1] to [4], wherein the (meth)acrylic polymer comprises an (meth)acrylic polymer having an aminoalkyl methacrylate unit, and the cellulose derivative comprises cellulose carboxyalkyl alkyl ethers.

[0017] Embodiment [6]: The pharmaceutical composition according to any one of Embodiments [1] to [5], wherein the cellulose derivative comprises carboxymethyl ethyl cellulose.

[0018] Embodiment [7]: A pharmaceutical composition comprising an amorphous active ingredient and a pharmaceutically acceptable acidic additive, A pharmaceutical composition comprising the active ingredient cabozantinib or a pharmaceutically acceptable salt thereof.

[0019] Aspect [8]: The pharmaceutical composition according to aspect [1], [2] or [7], wherein the proportion of the acidic additive is 0.01 to 100 parts by mass with respect to 100 parts by mass of the active ingredient.

[0020] Aspect [9]: The pharmaceutical composition according to aspect [1], [2], [7] or [8], wherein the acidic additive contains an organic acid.

[0021] Aspect

[10] : The pharmaceutical composition according to aspect [9], wherein the organic acid contains citric acid.

[0022] Aspect

[11] : The pharmaceutical composition according to any one of aspects [1] to

[10] , wherein the pharmaceutical composition is a solid dispersion.

[0023] Aspect

[12] : A method for producing a pharmaceutical composition containing the amorphous active ingredient by dissolving the active ingredient, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable acidic additive in a solvent and then distilling off the solvent, wherein the carrier contains at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives.

[0024] Aspect

[13] : A method for suppressing crystallization of the active ingredient and formation of related substances of the active ingredient by formulating the active ingredient with a pharmaceutically acceptable carrier and a pharmaceutically acceptable acidic additive to prepare a pharmaceutical composition containing the amorphous active ingredient, wherein the carrier contains at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives.

[0025] Aspect

[14] : A method for suppressing crystallization of the active ingredient by formulating the active ingredient with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition containing the amorphous active ingredient, wherein the active ingredient contains cabozantinib or a pharmaceutically acceptable salt thereof, and the carrier contains at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives.

[0026] Embodiment

[15] : A method for suppressing the generation of related substances of the active ingredient by preparing a pharmaceutical composition containing an amorphous active ingredient by compounding the active ingredient with a pharmaceutically acceptable acidic additive, A method comprising the active ingredient cabozantinib or a pharmaceutically acceptable salt thereof.

[0027] In this disclosure, the numerical range represented by "A to B" means "A or greater and B or less," and is used to include the numbers A and B at both ends of that range. [Effects of the Invention]

[0028] In the present invention, a pharmaceutical composition comprising an amorphous active ingredient and an acidic additive, or a pharmaceutical composition comprising an amorphous active ingredient and a pharmaceutically acceptable carrier comprising at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives (in particular, a pharmaceutical composition comprising an amorphous active ingredient, a pharmaceutically acceptable carrier comprising at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives, and an acidic additive) is prepared, thereby suppressing the crystallization of the amorphous active ingredient and improving storage stability. In particular, crystallization of amorphous cabozantinib or its pharmaceutically acceptable salt can be suppressed, storage stability is improved, and the formation of related substances can also be suppressed. [Brief explanation of the drawing]

[0029] [Figure 1] Figure 1 is a graph showing the X-ray diffraction measurement results of the pharmaceutical composition, which is a solid dispersion obtained in Example 3, before and after storage. [Modes for carrying out the invention]

[0030] [Pharmaceutical composition] The pharmaceutical composition of the present invention may contain an amorphous active ingredient, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable acidic additive.

[0031] (Active ingredients) The active ingredients can be either conventional or novel, and examples include tonics and health supplements, antipyretics, analgesics and anti-inflammatory agents, antipsychotics, anxiolytics, antidepressants, hypnotics and sedatives, antispasmodics, gastrointestinal agents, antacids, antitussives and expectorants, dental and oral agents, antihistamines, cardiac agents, antiarrhythmics, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, choleretics, anticancer agents, antituberculosis agents, antibiotics, antivirals, chemotherapy agents, antidiabetic agents, osteoporosis agents, and skeletal muscle relaxants. These active ingredients can be used alone or in combination of two or more.

[0032] Among these active ingredients, those that readily crystallize are preferred because they allow the effects of the present invention to be easily expressed, and cabozantinib or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "cabozantinib or its salt") is particularly preferred.

[0033] The salt of cabozantinib is not particularly limited as long as it is a pharmaceutically acceptable salt, and may be a salt with an acid (such as an addition salt).

[0034] The acid used to form the salt may be an inorganic acid or an organic acid.

[0035] Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0036] Examples of organic acids include saturated aliphatic monocarboxylic acids such as acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, caproic acid, and trifluoroacetic acid; saturated aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, succinic anhydride, and glutaric acid; unsaturated aliphatic dicarboxylic acids such as maleic acid and fumaric acid; aromatic monocarboxylic acids such as benzoic acid; hydroxyaliphatic monocarboxylic acids such as lactic acid; hydroxyaromatic monocarboxylic acids such as salicylic acid; hydroxyaliphatic polycarboxylic acids such as malic acid, tartaric acid, and citric acid; alkanesulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid; aromatic sulfonic acids such as p-toluenesulfonic acid; acidic amino acids such as glutamic acid and aspartic acid; and ascorbic acid and gluconic acid.

[0037] These acids can be used individually or in combination of two or more. Of these, hydroxyaliphatic polycarboxylic acids such as malic acid are preferred.

[0038] The active ingredient may be in the form of a solvate in the pharmaceutical composition. Examples of solvents that form the solvate include water and alcohols (e.g., ethanol, 1-propanol, 2-propanol, etc.). 1-4 Examples of solvents include alkanols, ketones (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), nitriles (e.g., acetonitrile, propionitrile), esters (e.g., ethyl acetate, isopropyl acetate), ethers (e.g., diethyl ether, t-butyl methyl ether), aliphatic hydrocarbons (e.g., n-pentane, n-hexane, cyclohexane, n-heptane, isooctane), aromatic hydrocarbons (e.g., toluene), amides (e.g., N,N-dimethylformamide, dimethylacetamide), and sulfoxides (e.g., dimethyl sulfoxide). These solvents may be used individually or in combination of two or more. As solvates, for example, hydrates may be used.

[0039] In the pharmaceutical composition, the active ingredient is in an amorphous form. As for the type of active ingredient, one that crystallizes easily is preferred because it facilitates the manifestation of the effects of the present invention.

[0040] The proportion of the active ingredient (especially cabozantinib or its salt) can be selected from a range of about 10 to 90% by mass in the pharmaceutical composition, for example, 20 to 80% by mass, preferably 25 to 75% by mass, more preferably 30 to 70% by mass, more preferably 35 to 60% by mass, and most preferably 40 to 55% by mass. If the proportion of the active ingredient is too low, the dissolution of the active ingredient may decrease, and if it is too high, the stability of the active ingredient may decrease.

[0041] (carrier) The carrier includes at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives, as a pharmaceutically acceptable carrier. In this invention, the inclusion of a (meth)acrylic polymer and / or cellulose derivative in the carrier suppresses the crystallization of amorphous active ingredients.

[0042] The (meth)acrylic polymer may be a single (meth)acrylic monomer (such as (meth)acrylic acid, (meth)acrylic acid ester monomer, N,N-dialkylaminoethyl (meth)acrylate, ammonia (meth)acrylate, etc.) or a copolymer of a (meth)acrylic monomer and a copolymerizable monomer (such as vinyl ester monomers, heterocyclic vinyl monomers, polymerizable unsaturated dicarboxylic acids or their derivatives).

[0043] Examples of (meth)acrylic monomers alone or as copolymers include methacrylate-ethyl acrylate copolymer (methacrylate copolymer LD), methacrylate-butyl acrylate copolymer, methacrylate-methyl methacrylate copolymer (methacrylate copolymer S), methyl methacrylate-dimethylaminoethyl methacrylate copolymer (methacrylate copolymer E), methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, and ethyl acrylate-methyl methacrylate-methacrylate acid salt trimethylammonium ethyl (ammonium methacrylate) copolymer (methacrylate copolymers RS, RL).

[0044] These (meth)acrylic polymers can be used individually or in combination of two or more.

[0045] Among these (meth)acrylic polymers, basic (meth)acrylic polymers are preferred because they easily suppress the crystallization of amorphous active ingredients, (meth)acrylic polymers having aminoalkyl methacrylate units such as dimethylaminoethyl methacrylate are even more preferred, and (meth)acrylic polymers containing dimethylaminoethyl methacrylate units such as methacrylic acid copolymer E (or aminoalkyl methacrylate copolymer E) and methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer are even more preferred.

[0046] The cellulose derivative may be any of cellulose ethers, cellulose esters, or cellulose ether esters.

[0047] Examples of cellulose ethers include cellulose alkyl ethers such as isopropylcellulose and butylcellulose; cellulose alkylalkyl ethers (cellulose alkyl-alkyl mixed ethers) such as ethylmethylcellulose and ethylpropylcellulose; cellulose carboxyalkylalkyl ethers (cellulose carboxyalkyl-alkyl mixed ethers) such as carboxymethylethylcellulose (CMEC); cellulose aralkyl ethers such as benzylcellulose; and cellulose cyanoalkyl ethers such as cyanoethylcellulose.

[0048] Examples of cellulose esters include cellulose acetate butyrate, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose phthalate, and cellulose acetate phthalate.

[0049] Examples of cellulose ether esters include hydroxymethylcellulose acetate succinate, hydroxypropylcellulose phthalate, and hydroxypropylmethylcellulose phthalate (HPMCP).

[0050] These cellulose derivatives can be used individually or in combination of two or more.

[0051] Among these cellulose derivatives, cellulose ethers are preferred, cellulose carboxyalkyl alkyl ethers are more preferred, and CMEC is even more preferred, as they easily suppress the crystallization of amorphous active ingredients.

[0052] Among these water-insoluble polymers, cellulose derivatives are preferred due to their excellent handling properties, and CMEC is the most preferred.

[0053] The water-insoluble polymer constituting the carrier may include other water-insoluble polymers in addition to (meth)acrylic resins and cellulose derivatives. Examples of other water-insoluble polymers include vinyl resins such as polyvinyl acetate phthalate and polyvinyl acetal diethylaminoacetate.

[0054] The proportion of (meth)acrylic polymer and cellulose derivative may be 50% by mass or more of the water-insoluble polymer, preferably 80% by mass or more, more preferably 90% by mass or more, more preferably 95% by mass or more, and most preferably 99% by mass or more. The water-insoluble polymer may be a water-insoluble polymer consisting only of (meth)acrylic polymer and / or cellulose derivative.

[0055] The proportion of water-insoluble polymers in the carrier may be 50% by mass or more, preferably 80% by mass or more, more preferably 90% by mass or more, more preferably 95% by mass or more, and most preferably 99% by mass or more. The carrier may consist solely of water-insoluble polymers.

[0056] The proportion of the carrier can be selected from a range of approximately 1 to 10,000 parts by mass (particularly 10 to 1,000 parts by mass) per 100 parts by mass of the active ingredient, for example, 15 to 500 parts by mass, preferably 20 to 300 parts by mass, more preferably 30 to 200 parts by mass, more preferably 50 to 150 parts by mass, and most preferably 80 to 120 parts by mass. If the proportion of the carrier is too low, there is a risk that the crystallization of the amorphous active ingredient cannot be suppressed, and conversely, if it is too high, there is a risk that the elution properties of the active ingredient will decrease.

[0057] (Acid additive) The pharmaceutical composition of the present invention, by including an acidic additive, can improve the storage stability of the pharmaceutical composition and suppress the formation of related substances. In particular, by including the carrier and the acidic additive in combination, it is possible to suppress both the crystallization of the amorphous active ingredient and the formation of related substances, thereby improving the storage stability of the amorphous active ingredient.

[0058] The acidic additive is not particularly limited as long as it is a pharmaceutically acceptable and acidic compound, but an acid is preferred. Examples of acids include inorganic acids and organic acids, which are examples of acids used to form salts of the active ingredients. The acids can be used alone or in combination of two or more.

[0059] Of the aforementioned acids, organic acids are preferred, hydroxyaliphatic polycarboxylic acids are more preferred, and hydroxyaliphatic dicarboxylic acids such as citric acid are even more preferred.

[0060] The proportion of the acidic additive can be selected from a range of approximately 0.01 to 100 parts by mass per 100 parts by mass of the active ingredient, for example, 0.1 to 80 parts by mass, preferably 1 to 50 parts by mass, more preferably 5 to 40 parts by mass, more preferably 10 to 30 parts by mass, and most preferably 15 to 25 parts by mass. If the proportion of the acidic additive is too low, the storage stability of the pharmaceutical composition may not be improved, and conversely, if it is too high, the mechanical properties of the pharmaceutical composition may deteriorate.

[0061] (Other ingredients) The pharmaceutical composition of the present invention may further contain conventional additives used in oral formulations. Examples of conventional additives include excipients, disintegrants, binders, lubricants, plasticizers, surfactants, pH adjusters, colorants, sweeteners or flavoring agents, antioxidants, preservatives or antiseptics, wetting agents, antistatic agents, disintegration aids, fluidizing agents, and shielding agents.

[0062] These additives can be used individually or in combination of two or more. The total proportion of these additives may be 30% by mass or less in the pharmaceutical composition, for example, 20% by mass or less (e.g., 0.01 to 20% by mass), preferably 10% by mass or less (e.g., 0.1 to 10% by mass), more preferably 5% by mass or less, and more preferably 1% by mass or less.

[0063] Such pharmaceutical compositions of the present invention may contain an amorphous active ingredient, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable acidic additive, and their form and state are not particularly limited, but a solid dispersion form (state) is preferred.

[0064] (A pharmaceutical composition comprising cabozantinib or a salt thereof and the carrier) When the active ingredient of the pharmaceutical composition contains cabozantinib or a salt thereof, the pharmaceutical composition of the present invention may be a pharmaceutical composition that does not contain an acidic additive, i.e., a pharmaceutical composition that contains cabozantinib or a salt thereof and the pharmaceutically acceptable carrier. This pharmaceutical composition is identical to the pharmaceutical composition containing both the carrier and the acidic additive described above, except that it does not contain an acidic additive. Although this pharmaceutical composition does not contain the acidic additive, the acidic additive may be incorporated in the process of preparing a formulation using the pharmaceutical composition. In that case, the proportion of the acidic additive to be incorporated into the pharmaceutical composition can be selected from a range of about 0.01 to 100 parts by mass per 100 parts by mass of cabozantinib or a salt thereof, for example, 0.1 to 80 parts by mass, preferably 1 to 50 parts by mass, more preferably 5 to 40 parts by mass, more preferably 10 to 30 parts by mass, and most preferably 15 to 25 parts by mass.

[0065] A pharmaceutical composition comprising cabozantinib or a salt thereof and the pharmaceutically acceptable carrier is also not particularly limited in form or state, but a solid dispersion form (state) is preferred.

[0066] (A pharmaceutical composition comprising cabozantinib or a salt thereof and the aforementioned acidic additive) If the active ingredient of the pharmaceutical composition contains cabozantinib or a salt thereof, the pharmaceutical composition of the present invention may be a pharmaceutical composition that does not contain the pharmaceutically acceptable carrier, i.e., a pharmaceutical composition that contains cabozantinib or a salt thereof and the acidic additive. This pharmaceutical composition is identical to the pharmaceutical composition containing both the carrier and the acidic additive described above, except that it does not contain the carrier. The form or state of the pharmaceutical composition containing cabozantinib or a salt thereof and the acidic additive is not particularly limited, but a solid dispersion form (state) is preferred.

[0067] (Characteristics and manufacturing methods of pharmaceutical compositions) The pharmaceutical composition of the present invention may be in granular form. The shape of the pharmaceutical composition may include powder, granular, spherical or substantially spherical, ellipsoidal, polyhedral, plate-like, fibrous, irregular, or amorphous. Of these, powder and granular or irregular shapes are preferred. The shape of the pharmaceutical composition may be hollow, but a solid shape is preferred.

[0068] The pharmaceutical composition of the present invention can be produced by conventional methods, such as solvent distillation, melting, and mixing / grinding. However, a solvent distillation method is preferred because it facilitates the production of a pharmaceutical composition containing amorphous active ingredients. This method involves dissolving the active ingredients, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable acidic additive in a solvent, and then distilling off the solvent to produce a pharmaceutical composition containing amorphous active ingredients.

[0069] The active ingredient used as a raw material may be crystalline or amorphous, but amorphous is preferred because it is easier to manufacture pharmaceutical compositions containing amorphous active ingredients.

[0070] While there are no particular restrictions on the solvent, water and aqueous solvents can be used for manufacturing safety reasons. Examples of aqueous solvents include lower alcohols (e.g., ethanol, isopropanol, etc.). 2-4 Examples include alkanols and aliphatic ketones (e.g., acetone). These solvents can be used individually or in combination of two or more.

[0071] These solvents can be appropriately selected depending on the type of active ingredient, and among the solvents, when the active ingredient is cabozantinib or a salt thereof, aliphatic ketones such as acetone are preferred.

[0072] The proportion of the solvent is, for example, 100 to 50,000 parts by mass, preferably 500 to 30,000 parts by mass, more preferably 1,000 to 20,000 parts by mass, more preferably 3,000 to 15,000 parts by mass, and most preferably 5,000 to 10,000 parts by mass, per 100 parts by mass of the active ingredient.

[0073] The method for removing the solvent (drying method) is not particularly limited, but examples include vacuum drying using a concentration centrifuge.

[0074] [formulation] The present invention encompasses formulations containing the aforementioned pharmaceutical composition. The formulation is preferably an oral formulation, as it readily exhibits the effects of the present invention. Examples of oral formulations include liquids, suspensions, powders, dry syrups, fine granules, granules, lozenges, tablets, pills, and capsules. Of these, tablets are preferred.

[0075] Examples of tablets include sugar-coated tablets, gelatin-coated tablets, film-coated tablets, enteric-coated tablets, core-containing tablets (compression-coated tablets), and multilayer tablets (two-layer or three-layer tablets, etc.). Of these, film-coated tablets are preferred.

[0076] The shape (surface shape) of the tablet is not particularly limited and can be circular, elliptical, or polygonal (square, rectangular, hexagonal, etc.), but circular and elliptical shapes are preferred.

[0077] The tablet diameter (average diameter) is, for example, 3 to 12 mm, preferably 4 to 11.5 mm, more preferably 4.5 to 11 mm, more preferably 5 to 10 mm, and most preferably 5.5 to 9 mm. If the tablet has an anisotropic shape, the tablet diameter is the average of the long and short diameters.

[0078] The thickness of the tablet is, for example, 1 to 5 mm, preferably 1.5 to 4.8 mm, more preferably 2.5 to 4.7 mm, more preferably 2.8 to 4.5 mm, and most preferably 3 to 4.3 mm.

[0079] The formulation (especially tablets) may be formed solely from the pharmaceutical composition, or from a combination of the pharmaceutical composition and conventional additives. Of these, the formulation of the present invention is preferably formed from a combination of the pharmaceutical composition (especially a solid dispersion) and components other than the pharmaceutical composition. In particular, for tablets, it is preferable that the tableting composition (tableting mixture) includes a combination of the pharmaceutical composition and a post-compound component.

[0080] Examples of the final ingredients include conventional additives as exemplified as other components of the pharmaceutical composition. The proportion of the final ingredients is, for example, 1 to 300 parts by mass, preferably 10 to 200 parts by mass, more preferably 50 to 100 parts by mass, more preferably 60 to 90 parts by mass, and most preferably 70 to 80 parts by mass, per 100 parts by mass of the pharmaceutical composition.

[0081] Examples of commonly used additives include those exemplified as other components of a pharmaceutical composition. These additives can be used alone or in combination of two or more. Among these additives, excipients, disintegrants, binders, lubricants, plasticizers, and colorants are commonly used.

[0082] Examples of excipients include sugars (lactose, glucose, fructose, maltose, sucrose, white sugar, powdered reduced maltose syrup, etc.), sugar alcohols [sorbitol such as D-sorbitol, mannitol such as D-mannitol, reduced maltose syrup (maltitol), reduced starch syrup, xylitol, reduced palatinose, tetrasaccharides obtained by fermenting glucose (e.g., erythritol, etc.)], celluloses (crystalline cellulose, microcrystalline cellulose, powdered cellulose, etc.), and alkylcelluloses (methylcellulose, ethylcellulose, etc.). These excipients can be used alone or in combination of two or more. Of these, sugar alcohols such as D-mannitol are preferred.

[0083] The proportion of the excipient is, for example, 10 to 200 parts by mass, preferably 30 to 100 parts by mass, and more preferably 50 to 70 parts by mass, per 100 parts by mass of the pharmaceutical composition.

[0084] Examples of disintegrants include polysaccharides [starchs such as corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, oxidized starch, dextrin, cyclodextrin, hydroxypropyl starch, carboxymethyl starch, and sodium carboxymethyl starch; cellulose ethers such as carboxymethylcellulose (carmellose or CMC), sodium carmellose, calcium carmellose, carboxymethyl ethylcellulose (CMEC), sodium croscarmellose, and low-substituted hydroxypropylcellulose (L-HPC); agar, carrageenan, gum arabic, alginic acid, sodium alginate, propylene glycol alginate, guar gum, locust bean gum, tragacanth gum, pullulan, xanthan gum, hyaluronic acid, pectin, and sodium chondroitin sulfate], proteins (gelatin, casein, soy protein, etc.), and cross-linked polyvinylpyrrolidones (crospovidone, etc.). These disintegrants can be used individually or in combination of two or more. Among these disintegrants, starches such as corn starch and partially pregelatinized starch, and carboxyalkylcelluloses such as carmellose and croscarmellose sodium are preferred, and cross-linked carboxyalkylcellulose such as croscarmellose sodium is preferred. 1-3 Alkylcellulose is particularly preferred.

[0085] The proportion of the disintegrant is, for example, 1 to 100 parts by mass, preferably 3 to 50 parts by mass, and more preferably 5 to 20 parts by mass, per 100 parts by mass of the pharmaceutical composition.

[0086] Examples of binders include polyvinylpyrrolidones [polyvinylpyrrolidone (povidone), vinylpyrrolidone copolymers such as vinyl acetate-vinylpyrrolidone copolymer (copolyvidone), etc.], vinyl alcohol polymers (polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.), carboxyvinyl polymers, polyacrylic acid polymers (sodium polyacrylate, acrylic acid copolymer, etc.), polylactic acid, polyethylene glycol, polyvinyl acetate, and other synthetic polymers; hydroxyalkylcelluloses such as hydroxyethylcellulose, hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (hypromellose or HPMC); and cellulose esters such as cellulose acetate. These binders can be used alone or in combination of two or more. Of these, hydroxyalkylcelluloses (hydroxyalkylcellulose such as HPC or alkylhydroxyalkylcellulose such as HPMC) are preferred, and hydroxyC 2-4 Cellulose ethers having alkyl groups are more preferred, such as hydroxy C such as HPC. 3-4 C, such as alkylcellulose and HPMC 1-3 AlkylhydroxyC 3-4 Alkylcellulose is more preferred, and HPC is most preferred.

[0087] The proportion of the binder is, for example, 1 to 50 parts by mass, preferably 3 to 30 parts by mass, and more preferably 5 to 10 parts by mass, per 100 parts by mass of the pharmaceutical composition.

[0088] Examples of lubricants include fatty acids or their metal salts, such as stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, and sodium coconut oil fatty acid; silicon dioxide, such as hydrated silicon dioxide and silicon dioxide; polyorganosiloxanes, such as dimethylpolysiloxane; oils and fats, such as hydrogenated oil and cocoa butter; and waxes, such as beeswax, bleached beeswax, carnauba wax, lanolin, paraffin, and petrolatum. These lubricants can be used individually or in combination of two or more. Among these lubricants, fatty acid metal salts such as magnesium stearate are preferred.

[0089] The proportion of the lubricant is, for example, 0.1 to 10 parts by mass, preferably 0.5 to 8 parts by mass, and more preferably 1 to 5 parts by mass, per 100 parts by mass of the pharmaceutical composition.

[0090] Examples of plasticizers include hydrophilic plasticizers such as polyethylene glycol, propylene glycol, and glycerin; and lipid-soluble plasticizers such as triacetin, triethyl citrate, diethyl phthalate, dioctyl adipate, lauric acid, stearyl alcohol, and cetanol.

[0091] The proportion of the plasticizer is, for example, 0.1 to 10 parts by mass, preferably 0.5 to 8 parts by mass, and more preferably 1 to 5 parts by mass, per 100 parts by mass of the pharmaceutical composition.

[0092] Examples of colorants include yellow iron(III) oxide, iron(III) oxide, food blue No. 1, food blue No. 2, food yellow No. 4, food yellow No. 5, food green No. 3, food red No. 2, food red No. 3, food red No. 102, food red No. 104, food red No. 105, food red No. 106, food lake pigment, red iron oxide, turmeric extract, riboflavin, sodium riboflavin phosphate, carotene solution, tar dyes, and caramel. These colorants can be used individually or in combination of two or more.

[0093] The proportion of the coloring agent is, for example, 0.1 to 5 parts by mass, preferably 0.2 to 3 parts by mass, and more preferably 0.3 to 2 parts by mass, per 100 parts by mass of the pharmaceutical composition. [Examples]

[0094] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples. The raw materials and evaluation methods used in the following examples are shown below. Also, the mass of the raw materials used is the solid content mass.

[0095] [Raw materials] Amorphous cabozantinib malate CMEC: Carboxymethyl ethylcellulose, manufactured by Freund Industrial Co., Ltd. Eudragit E: Aminoalkyl methacrylate copolymer E, manufactured by Evonik, "Eudragit E100" Soluplus: Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, manufactured by BASF Japan Ltd. Kollidon: Copolividone, manufactured by BASF Japan Ltd., "Kollidon VA64" D-Mannitol: ROQUETTE's "PERLITOL 50C" Croscarmellose sodium: "Acdisol" manufactured by DuPont Nutrition USA Inc. Light anhydrous silicic acid: Manufactured by Fuji Silicia Chemical Co., Ltd. Magnesium stearate: "Plant-derived magnesium stearate (Taihei)" manufactured by Taihei Chemical Industry Co., Ltd. Hypromellose: "TC-5R" manufactured by Shin-Etsu Chemical Co., Ltd. Macrogol 6000: Manufactured by NOF Corporation Talc: "Tarukan Hayashi" manufactured by Hayashi Chemical Co., Ltd. Titanium dioxide: "Titanium Dioxide FG" manufactured by Freund Industrial Co., Ltd. Yellow iron(III) oxide: Manufactured by Kisshi Kasei Co., Ltd.

[0096] [Method for evaluating crystallinity] Powder X-ray diffraction (XRD) was used to measure the crystallinity (presence or absence of crystals) of the sample by confirming characteristic peaks in the crystals based on the pattern obtained.

[0097] [Purity Test (Method for Measuring Related Substances)] Related substances were measured as follows: First, for each experimental example, the pharmaceutical composition or tablet was extracted with a fixed amount of extraction solvent (a mixture of 0.1% by mass formic acid aqueous solution and acetonitrile), and then centrifuged to obtain the sample solution.

[0098] The obtained sample solutions were subjected to purity testing by liquid chromatography under the following conditions. Specifically, the peak area of ​​each sample solution was measured using the automated integration method, their amounts were determined by the area percentage method, and the average value was calculated. The amount of related substances was measured by the RRT (relative retention time) of 1.3 (the amount of related substances detected at the point with a retention time 1.3 times that of the main peak) and the total amount. System suitability testing was performed as follows.

[0099] (Test conditions) Detector: UV absorbance spectrophotometer (measurement wavelength: 248 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm was packed with 3 μm octadecylsilylated silica gel for liquid chromatography. Column temperature: 40℃ Mobile phase A: A liquid prepared by dissolving ammonium formate in water and adjusting the pH by adding formic acid. Mobile phase B: Acetonitrile Flow rate: 1.0 mL per minute Area measurement range: 42 minutes after injection of sample solution. However, peaks originating from additives were excluded from the calculation.

[0100] (Reference example) Amorphous cabozantinib malate was stored under the storage conditions and in the storage form shown in Table 1 for the period shown in Table 1. After storage, its crystallinity was evaluated and the amount of related substances was measured. The results are shown in Table 1.

[0101] [Table 1]

[0102] As is clear from Table 1, amorphous cabozantinib malate, the active pharmaceutical ingredient, is quite unstable, and it was observed that it tends to crystallize and the amount of related substances increases when stored at higher temperatures and humidity.

[0103] Example 1 0.25 g of amorphous cabozantinib malate and 0.25 g of carboxymethyl ethyl cellulose (CMEC) were dissolved in 25 mL of acetone.

[0104] Next, the solvent was removed from the solution by vacuum drying to obtain a solid dispersion (pharmaceutical composition). A concentration centrifuge (Spin Dryer Light VC-36R) was used for vacuum drying. The centrifugation conditions were a temperature of 35°C and a rotation speed of 2000 rpm, and drying was performed using a vacuum pump.

[0105] The obtained solid was ground in a mortar and evaluated for crystallinity. No peaks characteristic of crystals were observed, and a halo pattern was seen, confirming that cabozantinib malate in the solid dispersion was amorphous. The amount of related substances was measured, and RRT1.3 was 0.128%, with a total amount of related substances of 0.291%.

[0106] After storing the aforementioned solid dispersion at 70°C for 9 days, its crystallinity was evaluated, confirming that it was amorphous. The amount of related substances was measured, and RRT1.3 was found to be 1.011%, with a total amount of related substances of 2.269%.

[0107] After storing the aforementioned solid dispersion at 40°C and 75% RH for two weeks, its crystallinity was evaluated, confirming that it was amorphous. The amount of related substances was measured, and RRT1.3 was found to be 0.178%, with a total amount of related substances of 0.774%.

[0108] After storing the aforementioned solid dispersion at 40°C and 75% RH for one month, its crystallinity was evaluated, and it was confirmed to be amorphous. The amount of related substances was measured, and RRT1.3 was found to be 0.208%, with a total amount of related substances of 0.990%.

[0109] These results are shown in Table 2.

[0110] Example 2 A solid dispersion as a pharmaceutical composition was prepared in the same manner as in Example 1, except that 0.25 g of aminoalkyl methacrylate copolymer E (Eudragit E) was used instead of 0.25 g of carboxymethyl ethyl cellulose. The results of evaluating the crystallinity and amount of related substances are shown in Table 2.

[0111] Comparative Example 1 A solid dispersion as a pharmaceutical composition was prepared in the same manner as in Example 1, except that 0.25 g of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) was used instead of 0.25 g of carboxymethyl ethyl cellulose. The results of evaluating the crystallinity and amount of related substances are shown in Table 2. Only a storage test was performed at 70°C for 9 days, but crystallization occurred.

[0112] Comparative Example 2 A solid dispersion as a pharmaceutical composition was prepared in the same manner as in Example 1, except that 0.25 g of copolyvidone (Kollidon) was used instead of 0.25 g of carboxymethyl ethylcellulose. The results of evaluating the crystallinity and amount of related substances are shown in Table 2. Only a storage test was performed at 70°C for 9 days, but crystallization occurred.

[0113] [Table 2]

[0114] As is clear from Table 2, in Examples 1 and 2, a solid dispersion of cabozantinib malate in an amorphous state was prepared and maintained its amorphous state after storage. In contrast, in Comparative Examples 1 and 2, a solid dispersion of cabozantinib malate in an amorphous state could not be prepared, and it remained crystalline even after storage at 70°C for 9 days.

[0115] Example 3 A solid dispersion for a pharmaceutical composition was prepared in the same manner as in Example 1, except that 0.25 g of amorphous cabozantinib malate and 0.25 g of carboxymethyl ethyl cellulose (CMEC) were dissolved in 25 mL of acetone along with 0.045 g of citric acid. The results of evaluating the crystallinity and amount of related substances are shown in Table 3. For comparison, the results of Example 1 are also shown in Table 3.

[0116] [Table 3]

[0117] As is clear from Table 3, in Example 3, by adding citric acid, an acidic additive, to the support, not only was crystallization suppressed, but the amount of related substances generated was also suppressed, and the stability of the solid dispersion was improved.

[0118] Furthermore, Figure 1 shows the results of X-ray diffraction measurements of the solid dispersion obtained in Example 3, initially, after storage at 70°C for 9 days (70°C 9D, sealed), after storage at 40°C 75%RH for 1 month (40°C 75%RH 1M, sealed), and after storage at 40°C 75%RH with a desiccant for 1 month (40°C 75%RH 1M, sealed + desiccant). In the pattern shown in Figure 1, no peaks characteristic of crystals were observed (the faintly visible peaks can be presumed to be citrate-derived peaks), and a halo pattern was observed, confirming that cabozantinib malate in the solid dispersion is amorphous.

[0119] Example 4 (Preparation of solid dispersions) Solid dispersions as pharmaceutical compositions were obtained in the proportions shown in Table 4, using the same method as in Example 1.

[0120] (Mixed tableting process) The obtained solid dispersions, along with D-mannitol, croscarmellose sodium, and light anhydrous silicic acid as the final components, were added to a diffusion mixer in the proportions shown in Table 4 and mixed to obtain a primary mixed powder. The obtained primary mixed powder and magnesium stearate as the final component were added to a diffusion mixer and mixed to obtain a tableting mixed powder. The obtained tableting mixed powder was compressed using a rotary tablet press to obtain uncoated tablets.

[0121] (Film coating (FC) process) A film coating solution was prepared by dispersing hypromellose, macrogol 6000, talc, titanium dioxide, and yellow ferric oxide in the proportions shown in Table 4 into purified water. The uncoated tablets were placed in a film coating machine, coated with the film coating solution, and then dried to obtain film-coated tablets (20 mg tablets containing the active ingredient cabosantinib).

[0122] [Table 4] [Industrial applicability]

[0123] The pharmaceutical composition of the present invention can suppress the crystallization of various active ingredients and improve storage stability, and therefore can be effectively used as a pharmaceutical composition containing active ingredients that are prone to crystallization.

Claims

1. A pharmaceutical composition comprising an amorphous active ingredient, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable acidic additive, A pharmaceutical composition comprising, as the carrier, at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives.

2. The pharmaceutical composition according to claim 1, wherein the active ingredient comprises cabozantinib or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising an amorphous active ingredient and a pharmaceutically acceptable carrier, The active ingredient comprises cabozantinib or a pharmaceutically acceptable salt thereof, and A pharmaceutical composition comprising, as the carrier, at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the proportion of the carrier is 10 to 1,000 parts by mass per 100 parts by mass of the active ingredient.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the (meth)acrylic polymer comprises a (meth)acrylic polymer having aminoalkyl methacrylate units, and the cellulose derivative comprises cellulose carboxyalkyl alkyl ethers.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cellulose derivative comprises carboxymethyl ethylcellulose.

7. A pharmaceutical composition comprising an amorphous active ingredient and a pharmaceutically acceptable acidic additive, A pharmaceutical composition comprising the active ingredient cabozantinib or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 1, 2, or 7, wherein the proportion of the acidic additive is 0.01 to 100 parts by mass per 100 parts by mass of the active ingredient.

9. The pharmaceutical composition according to claim 1, 2, or 7, wherein the acidic additive comprises an organic acid.

10. The pharmaceutical composition according to claim 9, wherein the organic acid comprises citric acid.

11. The pharmaceutical composition according to claim 1, 2, 3, or 7, wherein the pharmaceutical composition is a solid dispersion.

12. A method for producing an amorphous pharmaceutical composition containing an active ingredient, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable acidic additive by dissolving them in a solvent, and then removing the solvent by distillation, A method comprising a carrier containing at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives.

13. A method for suppressing crystallization of the active ingredient and the generation of related substances of the active ingredient by preparing a pharmaceutical composition containing an amorphous active ingredient by blending the active ingredient with a pharmaceutically acceptable carrier and a pharmaceutically acceptable acidic additive, A method comprising a carrier containing at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives.

14. A method for suppressing the crystallization of an active ingredient, comprising preparing a pharmaceutical composition containing an amorphous active ingredient by combining the active ingredient with a pharmaceutically acceptable carrier, The active ingredient comprises cabozantinib or a pharmaceutically acceptable salt thereof. A method comprising a carrier containing at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives.

15. A method for suppressing the generation of related substances of the active ingredient by preparing a pharmaceutical composition containing an amorphous active ingredient by compounding the active ingredient with a pharmaceutically acceptable acidic additive, A method comprising the active ingredient cabozantinib or a pharmaceutically acceptable salt thereof.

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