Olaparib solid dispersion compositions with improved stability and bioavailability

Abstract

The present invention relates to an olaparib solid dispersion composition with improved stability and bioavailability, and more particularly to an olaparib solid dispersion which contains the poorly soluble drug olaparib, a polymethacrylate copolymer, and a cellulose-based polymer as essential ingredients, has excellent storage stability and thermal stability, exhibits uniform drug release under various pH conditions in the body, and has improved bioavailability, and an oral composition containing the same.

Description

[Technical Field]

[0001] The present invention relates to an olaparib solid dispersion composition with improved stability and bioavailability, and more particularly to an olaparib solid dispersion which contains the poorly soluble drug olaparib, a polymethacrylate copolymer, and a cellulose-based polymer as essential ingredients, has excellent storage stability and thermal stability, exhibits uniform drug release under various pH conditions in the body, and has improved bioavailability, and an oral composition containing the same. [Background technology]

[0002] Olaparib, a phthalazinone derivative drug, was the first PARP inhibitor approved in 2014 and is used to treat breast and ovarian cancer. Olaparib is a poorly soluble substance with a weak acidity of pKa 12.07, exhibiting very low aqueous solubility (0.1-0.13 mg / mL) in the physiological pH range. Its permeability is also not very high, making it a BCS Class 4. The low solubility and bioavailability of the active ingredient pose problems for formulation, and various methods for improvement have been attempted, including changing the crystalline form and producing salt forms.

[0003] The commercially available formulation, Lynparza® capsules, uses Gelucire® 44 / 14, a lipid excipient, to improve drug solubility. However, the formulation of olaparib 50 mg filled into size 0 hard capsules has a drug content of 10%, which means that a therapeutic dose of 400 mg requires the inconvenient administration of eight capsules at once.

[0004] To improve the solubility of poorly water-soluble drugs, various methods have been attempted, including modification of the drug itself (e.g., salts, crystalline forms, prodrug production), drug modification (e.g., prodrug production), microparticulation by reducing the particle size of the drug, and micelle formation. However, when improving these physical properties, drug properties such as solubility, pH, pKa, melting point, molecular weight, functional groups, conformation, crystallinity, permeability, absorption site, degradation rate, and effective drug dose vary from drug to drug, so no single technique can be universally applied to all drugs, and it is necessary to find a method suitable for each specific drug. From this perspective, in order to improve patient compliance with olaparib, various studies are currently underway to increase bioavailability and simultaneously reduce the dosage unit by increasing the drug content in the formulation. Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide an olaparib-containing solid dispersion that has excellent storage stability and thermal stability, exhibits uniform drug release properties under all of various pH conditions in the body, and has improved bioavailability, and a method for producing the same. Another object of the present invention is to provide an oral composition containing olaparib, which has excellent storage stability and thermal stability, exhibits uniform drug release properties under various pH conditions in the body, and has improved bioavailability, and a method for preparing the same. [Means for solving the problem]

[0006] One aspect of the present invention relates to a solid dispersion comprising olaparib; a polymethacrylate copolymer; and a cellulosic polymer.

[0007] In one embodiment, the polymethacrylate copolymer is a cationic polymer comprising dimethylaminoethyl methacrylate.

[0008] In one embodiment, the polymethacrylate copolymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate).

[0009] In one embodiment, the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, cellulose acetate, methyl cellulose, and mixtures thereof.

[0010] In one embodiment, the solid dispersion further comprises D-α-tocopheryl polyethylene glycol succinate.

[0011] In one embodiment, the solid dispersion is obtainable by spray drying.

[0012] In one embodiment, the solid dispersion comprises amorphous olaparib.

[0013] Another aspect of the present invention relates to a method for producing a solid dispersion, comprising: (1) dissolving or dispersing olaparib together with a polymethacrylate copolymer in a solvent; (2) adding a cellulose-based polymer to the solution or dispersion obtained in step (1) and mixing the mixture; and (3) removing the solvent from the solution or dispersion obtained in step (2).

[0014] In one embodiment, the removal of the solvent is carried out by spray drying.

[0015] Yet another aspect of the present invention relates to an oral composition comprising the solid dispersion; a pharmaceutically acceptable organic acid; and a pharmaceutically acceptable diluent.

[0016] In one embodiment, the pharmaceutically acceptable organic acid is selected from the group consisting of acrylic acid, tartaric acid, citric acid, malic acid, maleic acid, fumaric acid, acetic acid, succinic acid, lactic acid, succinic acid, malonic acid, glutaric acid, and mixtures thereof.

[0017] In one embodiment, the pharmaceutically acceptable diluent is a water-soluble diluent.

[0018] In one embodiment, the water-soluble diluent is selected from the group consisting of sugar alcohols, sugars, and mixtures thereof.

[0019] In one embodiment, the oral composition is for treating cancer.

[0020] Yet another aspect of the present invention relates to a method for producing an oral composition, comprising the step of mixing the solid dispersion with a pharmaceutically acceptable organic acid and a pharmaceutically acceptable diluent. [Effects of the Invention]

[0021] The solid dispersion and oral composition containing the same disclosed in the present invention can stably amorphousize olaparib, thereby exhibiting excellent storage stability and thermal stability, uniform drug release properties under various pH conditions in the body, and increasing the solubility and dissolution rate of olaparib, thereby improving the in vivo absorption rate and bioavailability of the drug. Furthermore, compared to commercially available products, the use of fewer additives and an increased drug content in the formulation can reduce the number of dosage units taken at one time, improving patient compliance. Furthermore, the application of a composition and manufacturing process suitable for formulation is expected to be advantageous in terms of productivity, such as manufacturing and packaging. [Brief explanation of the drawings]

[0022] [Figure 1]FIG. 1 shows XRPD patterns of the solid dispersions and olaparib API (active pharmaceutical ingredient) prepared in Example 1, Example 2, and Comparative Example 1, respectively. It can be seen that the olaparib API used to prepare the solid dispersions is crystalline, whereas the olaparib contained in the solid dispersions prepared in Example 1, Example 2, and Comparative Example 1 is all amorphous. [Figure 2] FIG. 1 shows the dissolution patterns of the tablets prepared in Example 3 in pH 1.2 solution, pH 4.0 solution, pH 6.8 solution and water (distilled water, DW). [Figure 3] FIG. 1 shows the dissolution patterns of the tablets prepared in Example 4 in pH 1.2 solution, pH 4.0 solution, pH 6.8 solution and water (distilled water, DW). [Figure 4] FIG. 1 shows the dissolution patterns of the tablets prepared in Comparative Example 2 in pH 1.2 solution, pH 4.0 solution, pH 6.8 solution and water (distilled water, DW). [Figure 5] FIG. 1 shows the dissolution patterns of the tablets prepared in Comparative Example 3 in pH 1.2 solution, pH 4.0 solution, pH 6.8 solution and water (distilled water, DW). BEST MODE FOR CARRYING OUT THE INVENTION

[0023] Unless otherwise stated, several terms used throughout this specification may be defined as follows:

[0024] Throughout this specification, unless otherwise stated, "comprise" or "contain" means to comprise, without particular limitation, a certain component (or components), and is not to be interpreted as excluding the addition of other components (or components).

[0025] The present invention will now be described in more detail.

[0026] One aspect of the present invention relates to a solid dispersion comprising olaparib; a polymethacrylate copolymer; and a cellulosic polymer.

[0027] The "olaparib" may be olaparib base (a free base drug without a separate salt), a pharmaceutically acceptable salt thereof, an isomer thereof, or a mixture thereof. In each case, various hydrates may be formed, and various crystalline forms may be formed. For example, it may be a crystalline form of olaparib hydrate (e.g., monohydrate) or anhydrous olaparib, or an amorphous form thereof, or a mixture thereof.

[0028] The olaparib may be in various forms, for example, in the form of microparticles having a size of several μm to several tens of μm. More preferably, it may be in the form of microparticles having a size of several μm (e.g., 1 to 9 μm). Even more preferably, it may be in the form of nanoparticles having a size of several hundred nanometers (e.g., 100 to 900 nanometers). The smaller the particle size of the drug, the faster the dissolution rate, and the higher the solubility and bioavailability.

[0029] In one embodiment, the polymethacrylate copolymer may be a cationic polymer containing dimethylaminoethyl methacrylate, more specifically, poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), which may be a polymer containing each monomer in a molar ratio of 1:2:1.

[0030] As a specific example, the polymethacrylate copolymer may be Eudragit® EPO (Evonik, Germany) or Eudragit® E100 (Evonik, Germany). Eudragit® E polymer is a conventional coating agent used when it is necessary to protect drugs from moisture. When patient compliance is poor, its purpose is to reduce patient resistance by encapsulating sensitive drugs, masking the taste and odor of drugs, and providing a smooth, glossy surface for easier swallowing. Meanwhile, in the present invention, it is used as a polymer to improve the solubility and bioavailability of olaparib.

[0031] The weight-average molecular weight of the polymethacrylate copolymer may be 3,000 to 200,000, 5,000 to 150,000, 10,000 to 100,000, 20,000 to 80,000, or 37,000 to 57,000 g / mole. If the weight-average molecular weight of the polymethacrylate copolymer is less than 3,000 g / mole, the effect of improving water solubility may be low, and if the weight-average molecular weight is more than 200,000 g / mole, disintegration may be delayed.

[0032] The state of the polymethacrylate copolymer is not particularly limited, and it may be in the form of granules or powder.

[0033] In one embodiment, the amount of the polymethacrylate copolymer contained in the solid dispersion of the present invention may be, relative to 1 part by weight of olaparib, 0.05 parts by weight or more, 0.1 parts by weight or more, 0.15 parts by weight or more, 0.2 parts by weight or more, or 0.5 parts by weight or more, or may be 10 parts by weight or less, 9 parts by weight or less, 8 parts by weight or less, 7 parts by weight or less, 6 parts by weight or less, 5 parts by weight or less, 4 parts by weight or less, 3 parts by weight or less, or 2 parts by weight or less, but is not limited thereto.

[0034] For example, the solid dispersion of the present invention may contain 0.05 to 10 parts by weight, 0.1 to 6 parts by weight, 0.2 to 4 parts by weight, or 0.5 to 2 parts by weight of the polymethacrylate copolymer per 1 part by weight of olaparib. If the content of the polymethacrylate copolymer in the solid dispersion is less than the lower limit, the effect of improving the solubility and bioavailability of olaparib may be insufficient, whereas if the content exceeds the upper limit, the formulation (e.g., capsule or tablet) may become too large, potentially causing discomfort to patients when taken.

[0035] In one embodiment, the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), ethyl cellulose (EC), cellulose acetate (CA), methyl cellulose, and mixtures thereof, more specifically selected from the group consisting of hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), and mixtures thereof, even more specifically selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and mixtures thereof, and most preferably hydroxypropyl methylcellulose (HPMC).

[0036] In one embodiment, the amount of the cellulose-based polymer contained in the solid dispersion of the present invention may be, relative to 1 part by weight of olaparib, 0.05 parts by weight or more, 0.1 parts by weight or more, 0.15 parts by weight or more, or 0.2 parts by weight or more, or may be 10 parts by weight or less, 9 parts by weight or less, 8 parts by weight or less, 7 parts by weight or less, 6 parts by weight or less, 5 parts by weight or less, 4 parts by weight or less, 3 parts by weight or less, 2 parts by weight or less, or 1 part by weight or less, but is not limited thereto.

[0037] For example, the solid dispersion of the present invention may contain the cellulose-based polymer in an amount of 0.05 to 10 parts by weight, 0.1 to 6 parts by weight, 0.2 to 4 parts by weight, or 0.2 to 1 part by weight per part by weight of olaparib. If the content of the cellulose-based polymer in the solid dispersion is less than the lower limit, the effect of improving the temperature stability of the solid dispersion may be insufficient, whereas if the content exceeds the upper limit, the dissolution rate may be too slow, affecting drug release into the body.

[0038] In one embodiment, the solid dispersion of the present invention may further comprise a hydrophilic polymer other than the cellulose-based polymer.

[0039] Examples of the additional hydrophilic polymer include, but are not limited to, one or more selected from the group consisting of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Soluplus®), polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymer (e.g., Kollidon® VA64, manufactured by Basp), Polycoat IR, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof.

[0040] In one embodiment, when the additional hydrophilic polymer is used, it may be contained in the solid dispersion in an amount of, for example, but not limited to, 0.01 to 10 parts by weight, or 0.1 to 7 parts by weight, or 0.1 to 5 parts by weight, or 0.1 to 3 parts by weight, relative to 1 part by weight of olaparib.

[0041] In one embodiment, the solid dispersion may further include D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS or TPGS), which can provide excellent effects in improving the solubility and dissolution rate of olaparib.

[0042] The TPGS may be contained in the solid dispersion in an amount of, for example, 0.001 to 2 parts by weight, 0.001 to 1 part by weight, 0.005 to 1 part by weight, or 0.01 to 0.1 part by weight relative to 1 part by weight of olaparib. If the TPGS content is less than the lower limit, the improvement in the solubility and bioavailability of olaparib may be insufficient, resulting in reduced effectiveness. If the TPGS content exceeds the upper limit, the coating layer may become too sticky, making film formation, storage, and production difficult.

[0043] In one embodiment, the solid dispersion may be spray-dried. Because the solid dispersion is not in the form of an inactivated core coating, it can be used to prepare tablets so that as much olaparib as possible can be contained in as small a tablet size as possible, and a sudden increase or decrease in the disintegration rate and dissolution rate can be prevented.

[0044] In one embodiment, the solid dispersion is amorphous. When the solid dispersion is amorphous, the solubility is higher than that of a crystalline form, which has the advantage of further increasing the bioabsorption rate.

[0045] The term "solid dispersion" as used in the present invention refers to a form in which a crystalline or amorphous dispersed substance (generally a drug) is dispersed in an amorphous polymer (continuous phase). More preferably, it refers to a form in which an amorphous drug is dispersed in an amorphous polymer. The solid dispersion generally contains a drug and a polymer, and may optionally further contain additives for the drug, such as a surfactant, plasticizer, or disintegrant.

[0046] Thus, in one preferred embodiment, the solid dispersion comprises amorphous olaparib.

[0047] In one embodiment, the solid dispersion does not contain a surfactant.

[0048] In another embodiment, the solid dispersion may further comprise a surfactant.

[0049] The surfactant may be, for example, an anionic surfactant, such as sodium dodecyl sulfate, sodium lauryl sulfate, sodium N-lauroyl sarcosinate, N-long-chain acyl glutamate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, a copolymer of polyoxyethylene and polyoxypropylene, or a combination thereof, or sodium dodecyl sulfate.

[0050] The surfactant can be used in an amount of, for example, 0.0001 to 1 part by weight, or 0.0005 to 0.5 parts by weight, or 0.001 to 0.1 parts by weight, or 0.001 to 0.01 parts by weight, or 0.001 to 0.005 parts by weight, relative to 1 part by weight of olaparib.

[0051] The solvent used in the solution for producing the solid dispersion may be a water-miscible organic solvent, water, or a mixture thereof. Examples of water-miscible organic solvents that can be used include, but are not limited to, alcohol, acetone, tetrahydrofuran, acetic acid, acetonitrile, dioxane, and combinations thereof. Examples of water-miscible organic solvents include lower alcohols having 1 to 5 carbon atoms, acetone, or mixtures thereof, such as ethanol, acetone, or mixtures thereof, or ethanol.

[0052] In the case of solid dispersions produced by a coating method, the thickness of the coating layer can be measured using a scanning electron microscope (SEM) or other method after cutting the edge of the coated particles. The average thickness can be calculated by averaging measurements taken at five or more locations. Finally, when the edge of the coating layer of the coated particles is observed, the average thickness may be 10 μm to 500 μm, or 20 μm to 400 μm, or 50 μm to 300 μm, or 80 μm to 200 μm. If the average thickness of the coating layer is below this range, the drug content in the particles will be reduced, requiring a larger amount of inert core, which may result in a larger formulation size. If the average thickness of the coating layer exceeds this range, dissolution will be delayed and the processing time will be too long, making it impossible to achieve the desired objectives.

[0053] In the coating procedures described above, various biologically inert ingredients may be further used for additional purposes such as coating efficiency, drug stability, appearance, color, protection, retention, binding, performance improvement, and manufacturing process improvement.

[0054] Another aspect of the present invention relates to a method for producing a solid dispersion, comprising: (1) dissolving or dispersing olaparib together with a polymethacrylate copolymer in a solvent; and (2) adding a cellulose-based polymer to the solution or dispersion obtained in step (1) and mixing the mixture; and (3) removing the solvent from the solution or dispersion obtained in step (2).

[0055] In one embodiment, the solvent used to prepare the solid dispersion may be a water-miscible organic solvent, water, or a mixture thereof, or may contain a supercritical fluid. Examples of the water-miscible organic solvent include, but are not limited to, alcohol, acetone, tetrahydrofuran, acetic acid, acetonitrile, dioxane, and combinations thereof. Examples of the water-miscible organic solvent include low-cost alcohols having 1 to 5 carbon atoms, acetone, or a mixture thereof, or ethanol.

[0056] The removal of the solvent can be accomplished by vacuum drying, spray drying, tray drying, freeze drying, or other drying techniques, and in one embodiment, the removal of the solvent is accomplished by spray drying, which can be accomplished using a spray dryer, a fluidized bed dryer, or other dryer.

[0057] The solid dispersion prepared as described above can be mixed with other additional components and then powdered and granulated, or the mixture can be compressed into tablets or filled into capsules for encapsulation.

[0058] According to the present invention, olaparib, a crystalline drug, is produced as an amorphous solid dispersion, which improves the solubility and dissolution rate and thereby the bioavailability. Furthermore, the combined use of a polymethacrylate copolymer and a cellulose-based polymer can enhance the physical safety of the solid dispersion.

[0059] Yet another aspect of the present invention relates to an oral composition comprising the above-described solid dispersion of the present invention; a pharmaceutically acceptable organic acid; and a pharmaceutically acceptable diluent.

[0060] The oral composition may be for treating cancer.

[0061] In one embodiment, the cancer is selected from breast cancer and ovarian cancer.

[0062] Yet another aspect of the present invention is to provide a method for treating the solid dispersion with a pharmaceutically acceptable organic acid and

[0063] and a pharmaceutically acceptable diluent.

[0064] The oral composition may be a solid oral formulation, such as a tablet, capsule, granules, or powder, in particular in the form of a tablet or capsule. In one embodiment, the oral composition is a tablet.

[0065] In one embodiment, the content of the solid dispersion in the oral composition may be, relative to 1 part by weight of the oral composition, 0.01 part by weight or more, 0.05 part by weight or more, 0.1 part by weight or more, 0.15 part by weight or more, 0.2 part by weight or more, 0.25 part by weight or more, or 0.3 part by weight or more, or may be 0.9 part by weight or less, 0.85 part by weight or less, 0.8 part by weight or less, 0.75 part by weight or less, or 0.7 part by weight or less, but is not limited thereto. If the content of the solid dispersion in the oral composition is too high, the tablet size may be too large, and if the content is too low, the formulation may be too large, making it difficult to consistently achieve the desired bioabsorption rate.

[0066] In one embodiment, the pharmaceutically acceptable organic acid is selected from the group consisting of acrylic acid, tartaric acid, citric acid, malic acid, maleic acid, fumaric acid, acetic acid, lactic acid, succinic acid, malonic acid, glutaric acid, and mixtures thereof, more specifically selected from the group consisting of malic acid, maleic acid, tartaric acid, citric acid, fumaric acid, and mixtures thereof, even more specifically selected from the group consisting of fumaric acid, maleic acid, malic acid, and mixtures thereof, and most preferably fumaric acid.

[0067] In one embodiment, the content of the pharmaceutically acceptable organic acid in the oral composition may be, but is not limited to, 0.01 parts by weight or more, 0.02 parts by weight or more, 0.03 parts by weight or more, 0.04 parts by weight or more, or 0.05 parts by weight or more, or 0.5 parts by weight or less, 0.45 parts by weight or less, 0.4 parts by weight or less, 0.35 parts by weight or less, 0.3 parts by weight or less, or 0.2 parts by weight or less, per part by weight of the oral composition. If the content of the pharmaceutically acceptable organic acid in the oral composition is too high, exceeding the above range, the stability of the formulation may be affected, and if the content is too low, the stability of the formulation against pH changes may be reduced.

[0068] The pharmaceutically acceptable diluent may be a water-soluble diluent or a water-insoluble diluent, such as, but not limited to, one or more selected from the group consisting of lactose (anhydrous or hydrated, e.g., monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, low-substituted hydroxypropyl cellulose (L-HPC), starch, pregelatinized starch, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, and mixtures thereof.

[0069] In one embodiment, the pharmaceutically acceptable diluent is a water-soluble diluent.

[0070] In one embodiment, the water-soluble diluent is selected from the group consisting of sugar alcohols, sugars, and mixtures thereof.

[0071] In one embodiment, the sugar alcohols may be mannitol, maltitol, sorbitol, xylitol, or a combination thereof, and the sugars may be lactose, dextrose, maltose, sucrose, glucose, proctose, maltodextrin, or a combination thereof.

[0072] In one embodiment, the water-insoluble diluent may be one or more selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and mixtures thereof.

[0073] In one embodiment, the oral composition may be free of water-insoluble diluents.

[0074] In one embodiment, the content of the pharmaceutically acceptable diluent in the oral composition may be, but is not limited to, 0.01 parts by weight or more, 0.03 parts by weight or more, 0.05 parts by weight or more, 0.07 parts by weight or more, or 0.1 parts by weight or more, or 0.5 parts by weight or less, 0.45 parts by weight or less, 0.4 parts by weight or less, 0.35 parts by weight or less, or 0.3 parts by weight or less, per 1 part by weight of the oral composition. If the content of the pharmaceutically acceptable diluent in the oral composition is too high, the tablets may be too large and may cause discomfort to patients when taken, while if the content is too low, the tablets may be difficult to produce into tablets due to poor tableting properties.

[0075] The oral composition of the present invention may further contain one or more pharmaceutically acceptable additives other than the above components (ie, a pharmaceutically acceptable organic acid and a pharmaceutically acceptable diluent).

[0076] The one or more additional pharmaceutically acceptable additives may be, for example, a disintegrant, a lubricant, a surfactant, a coating agent, or a combination thereof.

[0077] The disintegrant may be, for example, one or more selected from the group consisting of croscarmellose sodium (CrosCMC-Na), carboxymethylcellulose, crospovidone (cross-linked polyvinylpyrrolidone), L-HPC (low-substituted hydroxypropylcellulose), starch (wheat, rice, corn, or potato starch), sodium carboxymethyl starch, sodium naglycolate of potato starch, partially hydrolyzed starch, and mixtures thereof, but is not limited thereto. Preferably, the disintegrant is croscarmellose sodium (CrosCMC-Na), sodium naglycolate of starch, L-HPC (low-substituted hydroxypropylcellulose), or a mixture thereof.

[0078] In one embodiment, the disintegrant can be used in an amount of, for example, 1 to 30 parts by weight, preferably 2 to 20 parts by weight, per 100 parts by weight of the total tablet weight. If the amount of disintegrant is less than the lower limit, delayed dissolution due to delayed disintegration may become a problem, while if the amount of disintegrant is more than the upper limit, productivity problems such as tableting problems may occur.

[0079] The lubricant may be, for example, one or more selected from the group consisting of magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn, or potato starch), talc, highly dispersed (colloidal) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, and mixtures thereof, but is not limited thereto. Preferably, it may be magnesium stearate.

[0080] In one embodiment, the lubricant can be used in an amount of, for example, 0.1 to 3 parts by weight, preferably 0.2 to 3 parts by weight, and more preferably 0.5 to 2 parts by weight, relative to 100 parts by weight of the total tablet weight. If the amount of lubricant is less than the lower limit, productivity problems such as tableting problems may occur, while if the amount is more than the upper limit, delayed dissolution and productivity problems may occur.

[0081] The surfactant may be, but is not limited to, one or more selected from the group consisting of anionic surfactants (such as sodium lauryl sulfate and docusate sodium), cationic surfactants (such as cetyltrimethylammonium bromide (CTAB) and benzethonium chloride), nonionic surfactants (such as polysorbate 80, 40 and 20, lauryldimethylamine N-oxide (LDAO)), Cremophor RH40 (registered trademark), polyoxyethylene stearate, poloxamer, and mixtures thereof. Preferably, the surfactant is sodium lauryl sulfate.

[0082] In one embodiment, the surfactant can be used in an amount of, for example, 0.1 to 10 parts by weight, preferably 0.5 to 7 parts by weight, and more preferably 1 to 5 parts by weight, per 100 parts by weight of the total weight of the formulation. If the amount of surfactant is less than the lower limit, it is difficult to obtain a sufficient solubility-enhancing effect, and if the amount is more than the upper limit, the stability of the formulation may be affected.

[0083] The coating agent may be, as a hydrophilic polymer, one or more selected from the group consisting of, but not limited to, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (sodium salt and calcium salt), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low-substituted HPC), polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers (e.g., Kollidon® VA64, manufactured by BASF), Polycoat IR, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof. Preferably, the coating agent is polyvinyl acetate (PVA) or hydroxypropyl methylcellulose (HPMC).

[0084] In one embodiment, the coating agent can be used in an amount of, for example, 0.2 to 10 parts by weight, preferably 1 to 7 parts by weight, and more preferably 3 to 5 parts by weight, per 100 parts by weight of the uncoated tablets (plain tablets). If the amount of coating agent is less than the lower limit, the entire surface of the plain tablets may not be completely coated with the coating agent, whereas if the amount is more than the upper limit, the dissolution rate may become excessively slow.

[0085] In order to facilitate understanding of the present invention, preferred examples are given below. However, the following examples are for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention.

[0086] Example Example 1: Preparation of a solid dispersion of olaparib / Eudragit® E / HPMC (weight ratio 1:1.5:0.25) 2.0 g of olaparib hydrate (crystalline form), 3.0 g of Eudragit® EPO, and 0.1 g of TPGS were completely dissolved in 200 mL of EtOH. 0.5 g of HPMC was completely dissolved in 20 mL of water and then uniformly mixed with the solution containing olaparib and Eudragit® E. The resulting mixture was spray-dried to remove the solvent, yielding a solid dispersion.

[0087] Example 2: Preparation of a solid dispersion of olaparib / Eudragit® E / HPMC (weight ratio 1:1:1) 2.0 g of olaparib hydrate (crystalline form), 2.0 g of Eudragit® EPO, and 0.1 g of TPGS were completely dissolved in 200 mL of EtOH. 2.0 g of HPMC was completely dissolved in 80 mL of water, and then the solution containing olaparib and Eudragit® E was mixed uniformly. The resulting mixture was spray-dried to remove the solvent, yielding a solid dispersion.

[0088] Comparative Example 1: Preparation of a solid dispersion of olaparib and Eudragit® E (weight ratio 1:2) 2.0 g of olaparib hydrate (crystalline form), 4.0 g of Eudragit (registered trademark) EPO, and 0.1 g of TPGS were completely dissolved in 200 mL of EtOH, and then spray-dried to remove the solvent, thereby obtaining a solid dispersion.

[0089] Test Example 1: Measurement of solubility <Comparison of drug solubility between raw olaparib and solid dispersion> The solid dispersions of Examples 1 and 2 and Comparative Example 1 equivalent to 50 mg of olaparib were added to 150 mL of pH 1.2 buffer solution and shaken at 100 rpm for 1 hour in an incubator at 37°C. This test solution was filtered through an RC syringe filter (0.2 µm), and 1 mL of the filtrate was collected and diluted with 2 mL of diluent, and the content was measured according to the Olaparib Content Analysis Method. The results are shown in Table 1 below.

[0090] [Table 1]

[0091] Test Example 2: Crystallinity evaluation by XRPD analysis The solid dispersions of Examples 1 and 2 and Comparative Example 1 were each analyzed by XRPD to evaluate the crystallinity of olaparib within the solid dispersions. The XRPD patterns of the solid dispersions and olaparib API (raw active ingredient) prepared in Examples 1 and 2 and Comparative Example 1 are shown in Figure 1. The XRPD patterns in Figure 1 indicate that the olaparib API used to prepare the solid dispersions is itself crystalline, whereas the olaparib contained in the solid dispersions prepared in Examples 1 and 2 and Comparative Example 1 is all amorphous.

[0092] Test Example 3: Stability The solid dispersions of Examples 1 and 2 and Comparative Example 1 were filled into hard gelatin capsules in an amount equivalent to 150 mg of olaparib, which were then placed in aluminum pouches together with a desiccant, sealed, and stored for 6 months under accelerated storage conditions of 40°C and 75% RH. To observe changes in dissolution rate, the dissolution rates of the samples were measured before and after 6 months of storage.

[0093] Elution conditions A dissolution test was conducted on hard gelatin capsules filled with olaparib (150 mg of olaparib) under the following conditions: Samples were collected at 60 minutes, and the dissolution rate of the drug was measured by HPLC analysis. Test solution: pH 1.2 buffer solution 450 mL Stirring speed: 100 rpm Temperature: 37℃ Sampling times: 5, 10, 15, 30, 45, 60 minutes

[0094] [Table 2]

[0095] From the results in Table 2, it was confirmed that the solid dispersion of Comparative Example 1, which was prepared using only olaparib and Eudragit (registered trademark) E, had significantly reduced stability in the accelerated test.

[0096] Example 3: Preparation of Olaparib Tablets (Prototype) Mannitol, fumaric acid, croscarmellose sodium, and magnesium stearate were added to the solid dispersion of Example 1 according to the following composition to prepare olaparib tablets.

[0097] [Table 3]

[0098] Example 4: Preparation of Olaparib Tablets (Prototype) Mannitol, fumaric acid, croscarmellose sodium, and magnesium stearate were added to the solid dispersion of Example 1 according to the following composition to prepare olaparib tablets.

[0099] [Table 4]

[0100] Comparative Example 2: Production of Olaparib Tablets (Prototype) Microcrystalline cellulose, fumaric acid, croscarmellose sodium, and magnesium stearate were added to the solid dispersion of Example 1 according to the following composition to prepare olaparib tablets. [Table 5]

[0101] Comparative Example 3: Production of Olaparib Tablets (Prototype) Mannitol, croscarmellose sodium, and magnesium stearate were added to the solid dispersion of Example 1 according to the following composition to prepare olaparib tablets.

[0102] [Table 6]

[0103] Test Example 4: Dissolution test of olaparib tablets The dissolution rates over time of the tablets of Examples 3 and 4 and Comparative Examples 2 and 3 in buffer solutions of pH 1.2, pH 4.0, and pH 6.8 and in water (distilled water, DW) were measured, and the results are shown in Figures 2, 3, 4, and 5, respectively. From Figures 2 to 5, it was confirmed that the tablets of the Examples containing the solid dispersion according to the present invention were more uniformly dissolved under all test solution conditions than the tablets of the Comparative Examples.

[0104] Elution conditions Test solution: pH 1.2, pH 4.0, pH 6.8 buffer solution, water (distilled water, DW) 450 mL Stirring speed: 100 rpm Temperature: 37℃ Dissolution reference time points: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes Analysis method: HPLC analysis method

[0105] Study Example 5: Pharmacokinetic (PK) study of olaparib tablets To compare the pharmacokinetics of the tablets (formulations containing olaparib solid dispersion) of Examples 3 and 4 and Comparative Example 2, a pharmacokinetic study was conducted using beagle dogs as experimental animals. The beagle dogs were divided into three groups and administered the formulations. Each formulation contained 150 mg of olaparib, and one tablet per dog was orally administered with 20 mL of water to the fasted experimental animals. After administration, blood samples were collected at predetermined intervals up to 24 hours, and serum was separated from the blood samples and frozen for storage. The concentration was analyzed using an LC / MS / MS device to measure the blood concentration over time, and the AUC (area under the serum concentration-time curve) and C max The maximum blood concentration was determined, and the results are shown in Table 3 below.

[0106] [Table 7]

[0107] From the results of the pharmacokinetic test in Table 3, the formulations of Examples 3 and 4 containing the olaparib solid dispersion according to the present invention have improved solubility and systemic absorption of the olaparib raw material, resulting in improved AUC and C max is in the preferred range, whereas the formulation of Comparative Example 2 does not fall within the pharmacokinetically preferred range.

Claims

1. Olaparib; Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate); Hydroxypropyl methylcellulose; and D-α-tocopheryl polyethylene glycol succinate Including, the poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) is contained in an amount of 0.2 to 4 parts by weight relative to 1 part by weight of the olaparib; A solid dispersion comprising 0.1 to 6 parts by weight of the hydroxypropyl methylcellulose relative to 1 part by weight of the olaparib.

2. 2. The solid dispersion according to claim 1, obtained by spray drying.

3. 2. The solid dispersion of claim 1, comprising amorphous olaparib.

4. (1) dissolving or dispersing olaparib together with poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) and D-α-tocopheryl polyethylene glycol succinate in a solvent; (2) adding hydroxypropyl methylcellulose to the solution or dispersion obtained in the step (1) and mixing; and (3) removing the solvent from the solution or dispersion obtained in the step (2); the poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) is contained in an amount of 0.2 to 4 parts by weight relative to 1 part by weight of the olaparib; The hydroxypropyl methylcellulose is contained in an amount of 0.1 to 6 parts by weight relative to 1 part by weight of the olaparib. Method for producing a solid dispersion.

5. The method for producing a solid dispersion according to claim 4, wherein the solvent is removed by spray drying.

6. The solid dispersion according to any one of claims 1 to 3; a pharmaceutically acceptable organic acid; and a pharmaceutically acceptable diluent; An oral composition comprising:

7. 7. The oral composition of claim 6, wherein the pharmaceutically acceptable organic acid is selected from the group consisting of acrylic acid, tartaric acid, citric acid, malic acid, maleic acid, fumaric acid, acetic acid, succinic acid, lactic acid, succinic acid, malonic acid, glutaric acid, and mixtures thereof.

8. 7. The oral composition of claim 6, wherein the pharmaceutically acceptable diluent is a water-soluble diluent.

9. 9. The oral composition of claim 8, wherein the water-soluble diluent is selected from the group consisting of sugar alcohols, sugars, and mixtures thereof.

10. The oral composition according to claim 6, which is for the treatment of cancer.

11. A method for producing a composition for oral administration, comprising a step of mixing the solid dispersion according to any one of claims 1 to 3 with a pharmaceutically acceptable organic acid and a pharmaceutically acceptable diluent.

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