Composition having improved solubility and bioavailability of olaparib

Abstract

To provide an oral composition comprising olaparib, which is a poorly soluble drug, the composition having improved solubility and bioavailability.SOLUTION: The present invention provides an oral composition comprising: a solid dispersion that comprises olaparib, a polymethacrylate copolymer, and D-α-tocopheryl polyethylene glycol succinate, the polymethacrylate copolymer being poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), the solid dispersion comprising 1 to 2.5 pts.wt. of the polymethacrylate copolymer based on 1 pt.wt. of olaparib, and comprising 0.01 to 1 pt.wt. of D-α-tocopheryl polyethylene glycol succinate based on 1 pt.wt. of olaparib; and one or more pharmaceutically acceptable additives.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to an oral composition containing the poorly soluble drug olaparib and having improved solubility and bioavailability, and a method for producing 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 pKa of 12.07, very low aqueous solubility (0.1-0.13 mg / mL), and its permeability is not particularly high, making it classified as BCS Class 4. Due to the low solubility and bioavailability of the active drug ingredient, formulation has been problematic, and various improvement methods have been attempted, including changing the crystalline form and producing salt forms.

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

[0004] Therefore, in order to improve patient compliance, it is necessary to increase the bioavailability and at the same time reduce the single dosage unit by increasing the drug content in the formulation, and various studies are currently underway. Summary of the Invention [Problem to be solved by the invention]

[0005] A first object of the present invention is to provide a solid dispersion comprising olaparib with improved solubility (aqueous solubility) and bioavailability.

[0006] Another object of the present invention is to provide oral compositions comprising olaparib with improved solubility and bioavailability.

[0007] It is yet another object of the present invention to provide a method for preparing an olaparib-containing oral solid dosage form having improved solubility and bioavailability. [Means for solving the problem]

[0008] One aspect of the invention relates to a solid dispersion comprising olaparib; and a polymethacrylate copolymer. In one embodiment, the olaparib is olaparib monohydrate. In one embodiment, the polymethacrylate copolymer is a cationic polymer comprising dimethylaminoethyl methacrylate. In one embodiment, the polymethacrylate copolymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate). In one embodiment, the polymethacrylate copolymer has a weight average molecular weight of 3,000 to 200,000 g / mol. In one embodiment, the solid dispersion contains 0.05 to 10 parts by weight of a polymethacrylate copolymer relative to 1 part by weight of olaparib. In one embodiment, the solid dispersion comprises D-α-tocopheryl polyethylene glycol. Further includes rusuccinate. In one embodiment, the solid dispersion further comprises 0.001 to 2 parts by weight of D-α-tocopheryl polyethylene glycol succinate relative to 1 part by weight of olaparib. In one embodiment, the solid dispersion is obtained by spray drying. In one embodiment, the solid dispersion is amorphous.

[0009] Another aspect of the invention relates to a method for preparing a solid dispersion comprising dissolving or dispersing olaparib together with a polymethacrylate copolymer in a solvent and then removing the solvent from the resulting dispersion or solution. In one embodiment, the removal of the solvent is carried out by spray drying.

[0010] Yet another aspect of the present invention relates to an oral composition comprising the solid dispersion and one or more pharmaceutically acceptable excipients.

[0011] 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 one or more pharmaceutically acceptable excipients. [Effects of the Invention]

[0012] The olaparib composition disclosed in the present invention is an oral formulation that can stably amorphousize the drug, increase its solubility and dissolution rate, and thereby improve the in vivo absorption rate of the drug. Compared to commercially available products, the use of additives can be reduced and the drug content in the formulation can be increased, thereby reducing the number of dosage units taken at one time and improving patient compliance. Furthermore, by adopting a composition and manufacturing process suitable for manufacturing, advantages can be expected in terms of productivity, such as manufacturing and packaging. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows the XRPD patterns of the solid dispersions and olaparib API (active ingredient) prepared in Examples 1 to 3, respectively, and shows that the olaparib API used to prepare the solid dispersions is itself in crystalline form, while the olaparib contained in the solid dispersions prepared in Examples 1 to 3 is all amorphous. [Figure 2] FIG. 1 shows the dissolution patterns of the tablets produced in Examples 5 to 8 and Comparative Example 1 in a pH 1.2 solution. [Figure 3] FIG. 1 shows the dissolution patterns of Example 5 and Comparative Examples 1 and 4 in water (distilled water, DW) and a pH 6.8 solution. DETAILED DESCRIPTION OF THE INVENTION

[0014] Meaning of the term Unless otherwise stated, several terms used throughout this specification may be defined as follows: In this specification, unless otherwise specified, the terms "comprise" or "contain" refer to the inclusion of a specific component (or constituent) without any particular limitation, and are not to be construed as excluding the addition of other components (or constituents).

[0015] Discovering the technical means To improve the solubility of poorly soluble drugs, various methods can be applied, including modifying the drug itself, such as producing salts, crystalline forms, or prodrugs, producing micro- or nano-emulsions or solid dispersions, micronizing or nanoizing the drug through particle size reduction, and forming micelles. These physical property improvements are difficult to achieve because each drug has different characteristics, such as solubility, pH, pKa, melting point, molecular weight, functional groups, three-dimensional structure, crystallinity, permeability, absorption site, degradation rate, and effective drug dosage, and therefore, one technique cannot be universally applied to all drugs. Therefore, it is necessary to find methods that are effective for specific drugs.

[0016] The present inventors have made great efforts to evaluate the effects of various substances on the solubility of olaparib, and have finally found a solid dispersion and an oral composition using the same that have excellent effects in improving the solubility and bioavailability of olaparib.

[0017] Detailed Description One aspect of the invention provides a solid dispersion comprising: olaparib; and a polymethacrylate copolymer.

[0018] The "olaparib" may be olaparib base (a free base drug without a separate salt), or a pharmaceutically acceptable salt thereof, an isomer thereof, or a mixture thereof. In each case, it may also form various hydrates, and in each case, various crystalline forms. For example, it may be a crystalline form of olaparib hydrate or anhydrous olaparib, or an amorphous form thereof, or a mixture thereof.

[0019] In one embodiment, the olaparib may be olaparib monohydrate.

[0020] The olaparib may be in various forms, for example, a micronized form having a size of several to several tens of micrometers, more preferably a micronized form having a size of several micrometers, and even more preferably a nano-sized form having a size of several hundred nanometers. As the particle size of the drug decreases, the dissolution rate increases, thereby improving solubility and bioavailability.

[0021] 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). The poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) may be a polymer containing each monomer in a molar ratio of 1:2:1.

[0022] As a specific example, the polymethacrylate copolymer may be Eudragit® EPO (manufactured by Evonik, Germany) or Eudragit® E100 (manufactured by Evonik, Germany). Eudragit® E polymer is a conventional coating base that is used when a drug needs to be protected from moisture or when patient compliance is poor, encapsulates sensitive drugs, or masks the taste and odor of the drug to reduce patient resistance and provide a smooth, glossy surface that makes it easier for patients to swallow the drug. Meanwhile, in the present invention, it is used as a polymer to improve the solubility and bioavailability of olaparib.

[0023] 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 / mol. If the weight-average molecular weight of the polymethacrylate copolymer is less than 3,000 g / mol, the effect of improving water solubility may be low, and if the weight-average molecular weight is more than 200,000 g / mol, disintegration may be delayed.

[0024] There is no particular limitation on the state of the polymethacrylate copolymer, but it may be in the form of granules or powder.

[0025] In one embodiment, the amount of polymethacrylate copolymer contained in the solid dispersion may be, per 1 part by weight of olaparib, 0.05 parts by weight or more, 0.1 parts by weight or more, 0.5 parts by weight or more, 1 part by weight or more, or 1.5 parts by weight or more, or may be, but is not limited to, 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, or 3 parts by weight or less.

[0026] For example, the solid dispersion may contain 0.05 to 10 parts by weight, 0.1 to 6 parts by weight, 0.1 to 5 parts by weight, 0.5 to 4 parts by weight, 1 to 3 parts by weight, or 1.5 to 3 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 above-mentioned lower limit, the effects of improving the solubility and bioavailability of olaparib may be insufficient. If the content is more than the above-mentioned upper limit, the dosage form (e.g., capsule or tablet) may become too large, which may cause discomfort to patients when taken.

[0027] In one embodiment, the solid dispersion may further comprise a hydrophilic polymer.

[0028] The hydrophilic polymer may be, for example, one or more selected from the group consisting of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Soluplus®), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), carboxymethylcellulose (sodium salt and calcium salt), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymer (e.g., Kollidon® VA64, manufactured by BASF), Polycoat IR, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof, but is not limited to these. Alternatively, the hydrophilic polymer may be polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (eg, Soluplus®), hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

[0029] In one embodiment, the hydrophilic polymer may be contained in the solid dispersion in an amount of, for example, 0.1 to 10 parts by weight, 0.1 to 5 parts by weight, 0.1 to 3 parts by weight, 0.5 to 3 parts by weight, or 1 to 3 parts by weight, per 1 part by weight of olaparib. If the content of the hydrophilic polymer is less than the above-mentioned lower limit, the improvement in the solubility and bioavailability of olaparib may be insufficient. If the content of the hydrophilic polymer exceeds the above-mentioned upper limit, the formulation (e.g., capsule or tablet) may become too large, which may cause discomfort to patients when taken.

[0030] 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.

[0031] 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 content of TPGS is less than the above-mentioned lower limit, the improvement in the solubility and bioavailability of olaparib may be insufficient, and the effect may be reduced. If the content of TPGS exceeds the above-mentioned upper limit, the coating layer may become sticky, which may make production, film formation, and storage difficult.

[0032] In one embodiment, the solid dispersion may be spray-dried. Because the solid dispersion is not in the form of a coated inactivated core, it can be used to manufacture tablets so that as much olaparib as possible is contained in the smallest possible tablet size, thereby preventing a sudden increase or decrease in disintegration rate and dissolution rate.

[0033] 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.

[0034] The term "solid dispersion" as used in the present invention refers to a form in which a dispersed substance (generally a drug) is dispersed in a crystalline or amorphous form in an amorphous polymer (continuous phase). Preferably, the solid dispersion is a form in which an amorphous drug is dispersed in an amorphous polymer. The solid dispersion generally contains a drug and a polymer, and in some cases, further contains other additives for the drug, such as a surfactant, plasticizer, disintegrant, etc.

[0035] In one embodiment, the solid dispersion may be surfactant-free.

[0036] In one embodiment, the solid dispersion may further comprise a surfactant.

[0037] The surfactant may be, for example, an anionic surfactant, such as sodium dodecyl sulfate, sodium lauryl sulfate, sodium N-lauroyl sarcosylate, N-long-chain acyl glutamate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, polyoxyethylene and polyoxypropylene copolymer, or a combination thereof, or sodium dodecyl sulfate.

[0038] Another aspect of the invention provides a method for preparing a solid dispersion, comprising dissolving or dispersing olaparib together with a polymethacrylate copolymer in a solvent, and then removing the solvent from the resulting dispersion or solution.

[0039] 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. The water-miscible organic solvent may be, for example, but is not limited to, an alcohol, acetone, tetrahydrofuran, acetic acid, acetonitrile, dioxane, or a combination thereof. The water-miscible organic solvent may be, for example, a low-cost alcohol having 1 to 5 carbon atoms, acetone, or a mixture thereof, or ethanol, acetone, or a mixture thereof, or ethanol.

[0040] The removal of the solvent can be accomplished by using vacuum drying, spray drying, tray drying, freeze drying, or other drying techniques. 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 dryers.

[0041] The solid dispersion prepared as above can be mixed with other additional components and powdered or granulated, or the mixture can be compressed into tablets or filled into capsules for encapsulation.

[0042] Another aspect of the present invention provides an oral composition with improved solubility and bioavailability, comprising the solid dispersion and one or more pharmaceutically acceptable excipients.

[0043] Yet another aspect of the present invention is a method for preparing a pharmaceutical composition comprising the solid dispersion and one or more pharmaceutically acceptable additives. A method for producing an oral composition with improved solubility and bioavailability is provided, which comprises a mixing step.

[0044] The oral composition may be for treating cancer.

[0045] In one embodiment, the cancer is selected from breast cancer and ovarian cancer.

[0046] The oral composition may be in the form of a solid oral formulation, for example in the form of a tablet, capsule, granules or powder, in particular a tablet or capsule. In one embodiment, the oral composition is a tablet.

[0047] The oral composition may contain the solid dispersion in an amount of 0.01 to 0.9 parts by weight, 0.01 to 0.8 parts by weight, 0.05 to 0.8 parts by weight, 0.1 to 0.7 parts by weight, 0.3 to 0.7 parts by weight, or 0.4 to 0.7 parts by weight, per part by weight of the total composition. If the oral composition contains a solid dispersion in an amount exceeding the above range, it will be difficult to formulate the composition due to poor tabletability, while if the amount is less than the above range, the size of the formulation will be too large, which may cause discomfort to patients when taking the composition.

[0048] The one or more pharmaceutically acceptable additives may be, for example, a diluent, a disintegrant, a lubricant, a surfactant, a pH adjuster, a coating base, or a combination thereof. In one embodiment, the oral composition may include a diluent, a disintegrant, a lubricant, a pH adjuster, or a combination thereof.

[0049] The diluent may be, for example, one or more selected from the group consisting of lactose (anhydrous or hydrated, e.g., monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, and mixtures thereof, but is not limited thereto. Preferably, lactose, mannitol, microcrystalline cellulose, or a mixture thereof can be selected. Most preferably, microcrystalline cellulose or mannitol can be selected.

[0050] In this case, the diluent can be used in an amount of, for example, 1 to 70 parts by weight, 5 to 50 parts by weight, or 10 to 40 parts by weight per 100 parts by weight of the total weight of the tablet. If the amount of diluent is below the lower limit, tableting properties are poor and tablet production is difficult, while if it is above the upper limit, there will be too many tablets, which may cause discomfort to the patient when taking them.

[0051] 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 glycolate of potato starch, partially hydrolyzed starch, and mixtures thereof, but is not limited thereto. Preferably, the disintegrant is croscarmellose sodium (CrosCMC-Na), sodium glycolate of starch, L-HPC (low-substituted hydroxypropylcellulose), or a mixture thereof.

[0052] In this case, the disintegrant can be used in an amount of, for example, 1 to 30 parts by weight, 2 to 20 parts by weight, 2 to 10 parts by weight, or 2 to 6 parts by weight per 100 parts by weight of the total weight of the tablet. If the amount of the disintegrant is below the lower limit mentioned above, the problem of delayed dissolution rate due to delayed disintegration rate may occur. If the upper limit is exceeded, problems in productivity such as tableting problems may occur.

[0053] 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, magnesium stearate may be used alone as the lubricant.

[0054] In this case, the lubricant can be used in an amount of, for example, 0.1 to 3 parts by weight, 0.2 to 3 parts by weight, 0.5 to 2.5 parts by weight, or 0.5 to 2 parts by weight per 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 it is more than the upper limit, there is a possibility of delayed dissolution and productivity problems.

[0055] The pH adjuster refers to a compound that changes the acidity-basicity balance in the formulation, and specifically may be carboxylic acid, acrylic acid, tartaric acid, citric acid, malic acid, maleic acid, fumaric acid, acetic acid, succinic acid, lactic acid, succinic acid, malonic acid, glutaric acid, or a mixture thereof. The pH adjuster can be used to improve the solubility difference of the polymethacrylate copolymer depending on the pH of the aqueous solvent.

[0056] In one embodiment, the pH adjuster is an acidic compound, including an organic acid having a carboxylic acid, preferably, but not limited to, a dibasic acid having two carboxyl functional groups, such as, for example, maleic acid, tartaric acid, citric acid, fumaric acid, or a mixture thereof, and in one embodiment, the pH adjuster is fumaric acid, maleic acid, or a mixture thereof.

[0057] In one embodiment, the pH adjuster can be used in an appropriate amount depending on the properties of each component, such as pKa and stability, and can be used in an amount of, for example, 0.01 to 5 parts by weight, 0.05 to 3 parts by weight, 0.1 to 1 part by weight, 0.1 to 0.5 parts by weight, 0.1 to 0.3 parts by weight, 0.1 to 0.25 parts by weight, or 0.3 to 0.8 parts by weight per part by weight of polymethacrylate copolymer. If the amount of pH adjuster is less than the lower limit, the effect of reducing solubility due to pH change may be insufficient. If the amount of pH adjuster is more than the upper limit, the stability of the formulation may be affected due to the properties of highly reactive substances.

[0058] In other embodiments, the oral composition may be free of surfactants.

[0059] The coating base may be one or more hydrophilic polymers 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 Basp), Polycoat IR, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof. Preferably, polyvinyl acetate (PVA) or hydroxypropyl methylcellulose (HPMC) is used.

[0060] The coating base 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 base is less than the lower limit, the entire surface of the plain tablet may not be completely covered with the coating base, while if the amount is more than the upper limit, the dissolution rate may be excessively delayed.

[0061] The solid dispersion can be mixed with other additional ingredients and powdered or granulated, or the mixture can be compressed into tablets or filled into capsules for encapsulation.

[0062] When the solid dispersion is used to produce an oral composition, for example, a tablet, a production method including, but not limited to, the steps of: mixing the solid dispersion, a diluent, and a pH adjuster; further mixing a disintegrant; further mixing a lubricant; and compressing the mixture into tablets can be used. [Example]

[0063] To facilitate understanding of the present invention, examples are provided below. However, the following examples are for the purpose of illustrating the present invention, and the scope of the present invention is not limited thereby in any way.

[0064] Example Examples 1-4: Preparation of solid dispersions containing olaparib Olaparib hydrate (crystalline form) (as monohydrate, same as below), Eudragit® EPO or Soluplus, and TPGS (D-α-tocopheryl polyethylene glycol succinate) were completely dissolved in EtOH in the amounts shown in Table 1 below, and the solvent was removed by spray drying to obtain a solid dispersion containing olaparib.

[0065] [Table 1]

[0066] Examples 5 to 8: Preparation of tablets containing olaparib solid dispersion The tablets of Examples 5 to 8 were produced using the solid dispersions produced in Examples 1 to 4. Specifically, the solid dispersion was first mixed with microcrystalline cellulose and fumaric acid according to the compositions shown in Table 2 below, followed by adding and mixing croscarmellose sodium, adding magnesium stearate as a lubricant, and then compressing the mixture to produce tablets with a total weight of 600 mg containing 100 mg of olaparib. The dissolution patterns of these tablets under in vivo pH conditions were confirmed.

[0067] Comparative Example 1 Commercially available Lynparza® (olaparib 50 mg) capsules were used.

[0068] [Table 2]

[0069] Comparative Examples 2 and 3: Preparation of Olaparib Simple Mixture (1:2.5 weight ratio) As a comparative example to Example 1, Comparative Example 2 was prepared by simply mixing 2.0 g of olaparib hydrate (crystalline form), 5.0 g of Eudragit (registered trademark) EPO, and 0.1 g of TPGS. Furthermore, as a comparative example to Example 4, Comparative Example 3 was prepared by simply mixing 2.0 g of olaparib hydrate (crystalline form), 5.0 g of Soluplus, and 0.1 g of TPGS. The prepared Comparative Examples 2 and 3 were used in the solubility analysis of Test Example 1.

[0070] Comparative Example 4: Preparation of organic acid-free olaparib solid dispersion tablets As a comparative example with Example 5, additives other than fumaric acid, which is a pH adjuster in the tablet composition containing the solid dispersion of Example 5, were mixed according to the composition ratios shown in the table below, and 100 mg olaparib tablets were compressed.

[0071] [Table 3]

[0072] Test Example 1: Comparison of drug solubility between a simple mixture of olaparib and a polymer and a solid dispersion To 20 mL of distilled water and pH 1.2 buffer, each of the solid dispersions of Examples 1 and 4 and a simple mixture of Comparative Examples 2 and 3 corresponding to 400 mg of olaparib were added, and the mixture was stirred in an incubator at 37°C and 100 rpm for 1 hour. 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 the following diluent, after which the content was measured by the olaparib content analysis method. The results are shown in Table 4.

[0073] Content analysis conditions 1) Preparation of dilution solution Diluent - Water (DW): Acetonitrile (CAN) = 1:1 2) Operation Detector: UV absorption spectrophotometer 254 nm Column: Nova-Pak C18 column, 60Å, 4μm, 3.9mm x 150mm Flow rate: 1.2mL / min Injection volume: 5μL Column temperature: 35℃ Run Time: 16 minutes mobile phase

[0074] [Table 4]

[0075] [Table 5]

[0076] Test Example 2: Measurement of drug crystallinity by XRPD analysis XRPD analysis was performed on Examples 1 to 3 and the olaparib raw material under the analytical conditions in Table 6 below, and the presence or absence of olaparib crystallinity in the solid dispersions is shown in Figure 1. As a result of the test, the solid dispersions of Examples 1 to 3 did not exhibit the crystalline peak of olaparib observed in the raw material, indicating that olaparib was present in an amorphous form.

[0077] [Table 6]

[0078] Test Example 3: Stability Comparison Accelerated storage tests were conducted to evaluate the stability of the solid dispersions of the examples. The solid dispersions prepared in Example 1 were placed in aluminum pouches with desiccants and sealed, then stored under accelerated storage conditions of 40°C and 75% RH for 3 months. XRPD analysis was performed on the samples before storage, at 1 month, and at 3 months to confirm the crystallinity of the drug and measure the dissolution rate. The results are shown below. Elution conditions An amount of solid dispersion equivalent to 400 mg of olaparib was accurately weighed and subjected to dissolution testing under the following conditions. Samples were taken at 60 minutes and the dissolution rate of the drug was measured by HPLC analysis. In the case of Comparative Example 1, a low dissolution rate was observed at an early stage and crystalline form was formed, so no further testing was performed. Test solution: pH 1.2 buffer 900 mL Stirring speed: 100 rpm Temperature: 37℃

[0079] [Table 7]

[0080] Test Example 4: Dissolution test of olaparib solid dispersion tablets The dissolution rates as a function of time were measured for the tablets of Examples 5 to 8 and the tablet of Comparative Example 1 (Lynparza (registered trademark) capsule formulation) under solution conditions of pH 1.2, which is the same as gastric fluid, and the results are shown in FIG. Elution conditions Test solution: pH 1.2 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

[0081] Test Example 5: Dissolution test of olaparib solid dispersion tablets containing Eudragit® E in neutral pH solution The dissolution rates of the tablets of Example 5 and Comparative Example 4 as a function of time were measured in water at pH 6.8, and the results are shown in FIG. Elution conditions Test solution: Water, pH 6.8 solution 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

[0082] Study Example 6: Pharmacokinetic (PK) study of raparib solid dispersion To compare the in vivo behavior of Example 5 and Comparative Example 1, a pharmacokinetic study was conducted using SD rats as experimental animals. 15 SD rats were divided into groups, with 5 rats per group, with Group 1 as the control group and Group 2 as the sample group. For each group, the composition was dispersed to a concentration of 4 mg / mL as olaparib, and orally administered at a dose of 10 mg / kg to the fasted experimental animals. After administration, blood samples were collected at predetermined time intervals up to 24 hours, and plasma was separated from the blood samples and frozen and stored. The plasma was analyzed using an LC / MS / MS device for concentration analysis, and the drug concentration in the blood over time was measured. From the data, AUC (area under the plasma concentration-time curve) and Cmax (maximum blood concentration) were obtained. As a result, are shown in Table 8 below.

[0083] [Table 8]

[0084] The results of the pharmacokinetic study showed that the solid dispersion composition containing olaparib of the present invention has higher AUC and C values ​​than conventional hard capsule formulations containing olaparib currently on the market. max Shows the current It was confirmed that the drug has superior pharmacokinetic properties compared to currently available formulations.

Claims

1. olaparib; a polymethacrylate copolymer; and D-α-tocopheryl polyethylene glycol succinate, the polymethacrylate copolymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate); The polymethacrylate copolymer is contained in an amount of 1 to 2.5 parts by weight per 1 part by weight of the olaparib; A solid dispersion comprising 0.01 to 1 part by weight of the D-α-tocopheryl polyethylene glycol succinate relative to 1 part by weight of the olaparib.

2. The solid dispersion of claim 1, wherein the solid dispersion is amorphous.

3. dissolving or dispersing olaparib together with a polymethacrylate copolymer and D-α-tocopheryl polyethylene glycol succinate in a solvent, and then spray drying the resulting dispersion or solution; the polymethacrylate copolymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate); The polymethacrylate copolymer is contained in an amount of 1 to 2.5 parts by weight per 1 part by weight of the olaparib; A method for producing a solid dispersion comprising 0.01 to 1 part by weight of the D-α-tocopheryl polyethylene glycol succinate relative to 1 part by weight of the olaparib.

4. The method for producing a solid dispersion according to claim 3, wherein the solvent is ethanol.

5. 3. An oral composition comprising the solid dispersion according to claim 1 or 2 and one or more pharmaceutically acceptable additives.

6. The oral composition of claim 5, further comprising a diluent, a disintegrant, a lubricant, a pH adjuster, or a combination thereof.

7. A method for producing an oral composition, comprising the step of mixing the solid dispersion according to claim 1 or 2 with one or more pharmaceutically acceptable additives.

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