Olaparib solid dispersions and methods of making same

Abstract

The application discloses a solid dispersion of olaparib and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The solid dispersion of olaparib adopts polyvinyl alcohol or polyvinyl alcohol and a plasticizer or polyvinyl alcohol and copolymerized povidone or polyvinyl alcohol, copolymerized povidone and an anti-sticking agent as a matrix polymer carrier, can effectively protect the olaparib raw material, reduce the degradation, and improve the drug loading of the solid dispersion. The solid dispersion of olaparib has small hygroscopicity, reduces the requirement of the environment humidity during the storage of the intermediate product of the olaparib preparation, reduces the energy consumption during the preparation process, and significantly improves the stability and effectiveness of the preparation.

Description

[0001] This application claims priority to Chinese Patent Application No. 202211097593.9, filed on September 8, 2022, entitled "An Olaparib Solid Dispersion and a Method for Preparing the Same", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical formulation technology, and in particular to an olaparib solid dispersion and its preparation method. Background Technology

[0003] Olaparib, chemical name: 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)4-fluoro-benzyl]-2H-phthalazine-1-one, has the following structural formula:

[0004]

[0005] Olaparib is the first oral poly(ADP-ribose) polymerase (PARP) inhibitor that targets and inhibits the DNA damage repair enzyme (PARP) to kill cancer cells. It was later classified as an ADP-ribose polymerase inhibitor, specifically a phthalazinone class. It is used for maintenance therapy in adult patients with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have a complete or partial response to platinum-based chemotherapy.

[0006] Olaparib is a weakly acidic compound with a pKa of 12.5. It is essentially neutral within the physiological pH range. Its solubility in aqueous buffers (pH 1–9) is approximately 0.10 mg / mL. In real and simulated gastrointestinal media, its solubility increases to 0.12–0.20 mg / mL. The highest solubility in simulated intestinal fluid after a meal is 0.20 mg / mL. Therefore, olaparib is a poorly soluble drug that is not easily absorbed by the human body, which makes formulation difficult.

[0007] Patent application 200980150172.4 (publication number CN 102238945A) utilizes a solid dispersion to enhance the dissolution of olaparib. The matrix is ​​selected from various polymers, including copovidone, povidone 17PF, povidone K25, povidone K30, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl-β-cyclodextrin, and hydroxypropyl methylcellulose. Copovidone was ultimately chosen, and the most effective copovidone was a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a 6:4 mass ratio (model VA64). Claim 1 specifies the weight ratio of olaparib to copovidone as 1:2 to 4.

[0008] Example 12 of 201510143738.8 (publication number CN106137998A) discloses the preparation of a solid dispersion by combining olaparib with copovidone and povidone K172 in a ratio of 1:1.3:0.7.

[0009] Paper 201611263795.0 (publication number CN106692066A) discloses the preparation of a solid dispersion by mixing olaparib with copovidone and povidone K30 and using a hot melt extrusion method.

[0010] Paper 202010143408.X (publication number CN113350349A) discloses the preparation of a solid dispersion by combining olaparib with copovidone and a dissolution accelerator, wherein the dissolution accelerator is selected from water-soluble cyclodextrin derivatives.

[0011] Paper 202110154649.9 (publication number CN112843007A) discloses the composition of olaparib with copovidone and povidone K17, and the weight percentage ratio of olaparib:copovidone:povidone K17 is 1:(2.0~1.5):(0.3~0.8).

[0012] However, when olaparib formulations were prepared using the hot melt extrusion method, the number of degradation impurities increased by more than 6, with a total exceeding 0.2%. The reason for this is that during the high-temperature hot melt extrusion process, the copovidone, acting as the single polymer carrier, could not effectively protect the olaparib molecules, leading to the generation of a series of degradation impurities at high temperatures (above 180°C).

[0013] As is well known, a large number of impurities in pharmaceutical preparations are the main factor causing adverse drug reactions and the main reason for problems with drug safety.

[0014] Therefore, there is an urgent need for a solid dispersion and its preparation process that can improve the impurity level of olaparib tablets while ensuring the drug dissolution and release effect. Summary of the Invention

[0015] In view of this, the technical problem to be solved by the present invention is to provide an olaparib solid dispersion and a method for preparing the same. The olaparib solid dispersion has low hygroscopicity and high stability.

[0016] This invention provides a novel olaparib solid dispersion composed of olaparib and a matrix polymer carrier, wherein the matrix polymer carrier is polyvinyl alcohol, or a combination of polyvinyl alcohol and a plasticizer, or a combination of polyvinyl alcohol and copolyvinyl ketone.

[0017] Specifically, the solid dispersion is composed of olaparib and polyvinyl alcohol in a weight ratio of 1:0.4 to 2.3.

[0018] Preferably, the weight ratio of olaparib to polyvinyl alcohol is 1:1.0 to 2.2.

[0019] More preferably, the weight ratio of olaparib to polyvinyl alcohol is 1:1.2 to 1.8.

[0020] More preferably, the weight ratio of olaparib to polyvinyl alcohol is 1:1.2 to 1.6.

[0021] Specifically, the solid dispersion is composed of olaparib, polyvinyl alcohol and plasticizer in a weight ratio of 1:0.4 to 2.3:0.1 to 0.6.

[0022] Preferably, the weight ratio of olaparib, polyvinyl alcohol and plasticizer is 1:1.0-2.2:0.1-0.4.

[0023] More preferably, the weight ratio of olaparib, polyvinyl alcohol and plasticizer is 1:1.2-1.8:0.2-0.4.

[0024] More preferably, the weight ratio of olaparib, polyvinyl alcohol and plasticizer is 1:1.2-1.6:0.2-0.3.

[0025] This invention reduces the amount of copovidone while adding a small amount of polyvinyl alcohol as a matrix polymer carrier to prepare a solid dispersion. This solves the problem that reducing the amount of copovidone causes crystalline olaparib to not be completely converted into an amorphous state. At the same time, the addition of polyvinyl alcohol can effectively protect the olaparib raw material and reduce its degradation.

[0026] Specifically, the solid dispersion is composed of olaparib, copovidone, and polyvinyl alcohol in a weight ratio of 1:1.3-1.9:0.1-0.9.

[0027] Preferably, the weight ratio of olaparib, copovidone, and polyvinyl alcohol is 1:1.4-1.8:0.2-0.4.

[0028] More preferably, the weight ratio of olaparib, copovidone, and polyvinyl alcohol is 1:1.6-1.8:0.3-0.4.

[0029] More preferably, the weight ratio of olaparib, copovidone, and polyvinyl alcohol is 1:1.4-1.6:0.5-0.9.

[0030] More preferably, the weight ratio of olaparib, copovidone, and polyvinyl alcohol is 1:1.4-1.6:0.7-0.9.

[0031] In the above solid dispersion, the olaparib raw material is either crystalline or amorphous, preferably crystalline, and the crystalline form is preferably crystalline form A.

[0032] The polyvinyl alcohol is selected from polyvinyl alcohol with a degree of hydrolysis of 85% to 89%, preferably polyvinyl alcohol with a degree of hydrolysis of 86% to 89%, and more preferably polyvinyl alcohol with a degree of hydrolysis of 87% to 88%.

[0033] The plasticizer is mannitol, sorbitol, or trehalose.

[0034] The copolyvinylpyrrolidone is designated as VA64, which is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a 6:4 mass ratio.

[0035] Adding an anti-adhesion agent to the above solid dispersion is beneficial for the dissolution of olaparib tablets.

[0036] Preferably, the matrix polymer carrier further includes an anti-adhesion agent.

[0037] Preferably, the matrix polymer carrier comprises copovidone, polyvinyl alcohol, and an anti-adhesion agent.

[0038] The matrix polymer carrier is prone to swelling in solution, which leads to gel formation and affects the release of olaparib from the solid dispersion. Therefore, adding an anti-sticking agent to the polymer carrier can effectively slow down the formation of gel and help the release of olaparib.

[0039] Based on this, the present invention provides an olaparib solid dispersion comprising olaparib, copovidone, polyvinyl alcohol and an anti-adhesion agent.

[0040] Preferably, the anti-adhesion agent is selected from one or more of light calcium carbonate, colloidal silica, and gel silica.

[0041] Preferably, the weight ratio of olaparib, copovidone, polyvinyl alcohol, and anti-adhesion agent is 1:1.4-1.9:0.1-0.6:0.02-0.1.

[0042] Preferably, the weight ratio of olaparib to the anti-adhesion agent is 1:0.02 to 0.1; more preferably, it is 1:0.03 to 0.08; and even more preferably, it is 1:0.03 to 0.05.

[0043] Preferably, the weight ratio of olaparib to copovidone is 1:1.4 to 1.9; more preferably, it is 1:1.7 to 1.9; and even more preferably, it is 1:1.8 to 1.9.

[0044] Preferably, the weight ratio of olaparib to polyvinyl alcohol is 1:0.1 to 0.6; more preferably, it is 1:0.1 to 0.3; and even more preferably, it is 1:0.1 to 0.2.

[0045] In this invention, preferably, the method for preparing the above-mentioned solid dispersion includes the following steps:

[0046] Weigh each component according to the formula, mix them evenly, and obtain a solid dispersion by hot melt extrusion. The temperature during hot melt extrusion is preferably controlled at 180℃~220℃; the screw rotation speed is preferably 150~200rpm.

[0047] When preparing a solid dispersion containing olaparib, copovidone, polyvinyl alcohol and an anti-sticking agent, the temperature during hot melt extrusion is preferably controlled at 120°C to 220°C; more preferably at 180°C to 220°C.

[0048] The screw rotation speed is preferably 150-600 rpm; more preferably 150-200 rpm.

[0049] In the above preparation method, the crystalline olaparib raw material is completely transformed into an amorphous state through hot melt extrusion, thereby increasing the solubility of the solid dispersion.

[0050] The present invention also provides a formulation containing olaparib solid dispersion, the formulation comprising a tablet core and a coating, wherein the tablet core comprises the following components in parts by weight: 70-90 parts of the above-mentioned olaparib solid dispersion, 10-16 parts of filler, 0-20 parts of disintegrant, 1-3 parts of flow aid, and 1-3 parts of lubricant.

[0051] Preferably, the tablet core comprises the following components in parts by weight: 70-76 parts of the above-mentioned olaparib solid dispersion, 12-16 parts of filler, 8-12 parts of disintegrant, 1-3 parts of flow aid, and 1-3 parts of lubricant. The olaparib solid dispersion in the formulation comprises olaparib and polyvinyl alcohol, or olaparib, polyvinyl alcohol, and a plasticizer, or olaparib, polyvinyl alcohol, and copovidone.

[0052] In the above-mentioned formulations:

[0053] Preferably, the filler is mannitol.

[0054] Preferably, the disintegrant is sodium carboxymethyl starch, crospovidone, or low-substituted hydroxypropyl cellulose (L-HPC).

[0055] Adding a gliding agent facilitates the dissolution of olaparib tablets and improves the flowability and compressibility of the mixed powder.

[0056] Preferably, the flow aid is colloidal silica.

[0057] Preferably, the lubricant is sodium stearate fumarate.

[0058] The present invention also provides an olaparib tablet, which is composed of a tablet core and a coating. The components of the tablet core include: 62.5 to 90 parts of the above-mentioned olaparib solid dispersion, 10 to 37.5 parts of filler, 1 to 2.5 parts of flow aid, and 1 to 2.5 parts of lubricant.

[0059] The olaparib solid dispersion containing an anti-adhesion agent comprises: olaparib, copovidone, polyvinyl alcohol, and an anti-adhesion agent.

[0060] In some specific embodiments of the present invention, preferably, the content of each component of the core includes: 25 parts of olaparib, 35-47.5 parts of copovidone, 2.5-15 parts of polyvinyl alcohol, 0.5-2.5 parts of anti-adhesion agent, 10-37.5 parts of filler, 1-2.5 parts of lubricant, and 1-2.5 parts of flow aid.

[0061] More preferably, the components of the core include: 25 parts of olaparib, 40-47.5 parts of copovidone, 2.5-10 parts of polyvinyl alcohol, 0.75-2 parts of anti-adhesion agent, 15-30 parts of filler, 1-2 parts of lubricant, and 1-2 parts of flow aid.

[0062] More preferably, the components of the core include: 25 parts of olaparib, 42.5 to 47.5 parts of copovidone, 2.5 to 7.5 parts of polyvinyl alcohol, 0.75 to 2 parts of anti-adhesion agent, 15 to 30 parts of filler, 1 to 2 parts of lubricant, and 1 to 2 parts of flow aid.

[0063] More preferably, the components of the core include: 25 parts of olaparib, 45-47.5 parts of copovidone, 2.5-5 parts of polyvinyl alcohol, 0.75-1.25 parts of anti-adhesion agent, 17.5-22.5 parts of filler, 1-1.5 parts of lubricant, and 1-1.5 parts of flow aid.

[0064] In the above-mentioned olaparib tablets, the filler is preferably siliconized microcrystalline cellulose or mannitol.

[0065] The lubricant is preferably sodium stearate fumarate or glyceryl behenate.

[0066] The flow aid is preferably colloidal silica or gel silica.

[0067] The coating powder is preferably a stomach-soluble film coating premix.

[0068] The preparation method of the above-mentioned formulation containing olaparib solid dispersion and olaparib tablets includes the following steps: weighing each component according to the ratio, mixing them, compressing them into tablets, and coating them with a film to obtain the olaparib formulation and olaparib tablets.

[0069] Compared with existing technologies, the olaparib solid dispersion provided by this invention uses polyvinyl alcohol, or polyvinyl alcohol and plasticizer, or polyvinyl alcohol and copovidone, or polyvinyl alcohol, copovidone and anti-adhesion agent as the matrix polymer carrier, which can effectively protect the olaparib active pharmaceutical ingredient, reduce its degradation, and increase the drug loading of the solid dispersion. The olaparib solid dispersion of this invention has low hygroscopicity, reducing the humidity requirements for storing intermediate olaparib formulations, reducing energy consumption in the formulation production process, and significantly improving the stability and efficacy of the formulation. Attached Figure Description

[0070] Figure 1 Differential scanning calorimetry of olaparib active pharmaceutical ingredient;

[0071] Figure 2 X-ray powder diffraction pattern of olaparib active pharmaceutical ingredient;

[0072] Figure 3 X-ray powder diffraction pattern of blank excipient;

[0073] Figure 4 X-ray powder diffraction pattern of olaparib solid dispersion (Example 9);

[0074] Figure 5 X-ray powder diffraction pattern of olaparib tablet (Comparative Example 9);

[0075] Figure 6 X-ray powder diffraction pattern of olaparib tablets (Example 15);

[0076] Figure 7 Raman spectra of the olaparib active pharmaceutical ingredient, blank excipient, olaparib solid dispersion (Example 9), and olaparib tablets (Example 15) used in this invention. Detailed Implementation

[0077] To further illustrate the present invention, the following detailed description of the olaparib solid dispersion and its preparation method provided by the present invention is provided in conjunction with embodiments.

[0078] In the following examples, the Olaparib A crystal form is the raw material Olaparib. The Olaparib solid dispersions obtained are all transformed into an amorphous state through hot melt extrusion during the preparation process.

[0079] In the following examples and comparative examples, olaparib is calculated based on the 150 mg specification.

[0080] All the raw materials listed below are commercially available products. The polyvinyl alcohol is selected from the polyvinyl alcohol (model MXP) produced by Merck with a degree of alcoholysis of 85% to 88%, and the copolyvinyl ketone is selected from the copolyvinyl ketone (model VA64) produced by BASF.

[0081] 1. Description of some instruments:

[0082] 1) Particle size detection is performed using a laser particle size analyzer.

[0083] 2) Twin-screw extruder, model Thermo Scientific TM Process 11, purchased from Thermo Fisher Scientific.

[0084] 2. The unit of weight can be mg, g, or kg.

[0085] 3. The following gastric-soluble film-coating premix was purchased from the market.

[0086] Example 1

[0087] Olaparib solid dispersion 1

[0088] Raw material composition: Composed of olaparib and polyvinyl alcohol, see Table 1.

[0089] Table 1: Solid Dispersion 1 (Unit: parts by weight)

[0090] Olaparib A crystal form Polyvinyl alcohol (Merck MXP) 1 2.3 1 2.2 1 2.0 1 1.8 1 1.6 1 1.4 1 1.2 1 1.0 1 0.8

[0091] Example 2

[0092] Olaparib solid dispersion 2

[0093] Raw material composition: Composed of olaparib, polyvinyl alcohol and plasticizer, see Table 2.

[0094] Table 2: Solid Dispersion 2 (Unit: parts by weight)

[0095]

[0096] Example 3

[0097] Olaparib solid dispersion 3

[0098] Raw material composition: Composed of olaparib, copovidone, and polyvinyl alcohol, as shown in Table 3.

[0099] Table 3: Solid Dispersions 3 (Unit: Parts by Weight)

[0100]

[0101]

[0102] Preparation method: The solid dispersions provided in Examples 1, 2, and 3 were prepared by mixing olaparib with the matrix polymer carrier in the proportions shown in Tables 1, 2, or 3, and then feeding the mixture into a twin-screw extruder (ThermoScientific).TM In Pharma 11), the extrusion temperature of the twin-screw extruder is controlled between approximately 180 and 220°C for melt extrusion, and the screw speed is approximately 150 rpm to 200 rpm. The extruded solid dispersion is cooled and pulverized to obtain an amorphous solid dispersion composition.

[0103] Example 4

[0104] Olaparib tablet core containing solid dispersion

[0105] The solid dispersion from Example 1 and the excipients in Table 4 are mixed evenly according to the ratio and directly compressed into tablets to obtain the olaparib tablet core.

[0106] Table 4: Prescription composition of Olaparib tablets

[0107]

[0108] Example 5

[0109] Olaparib tablet core containing solid dispersion

[0110] The olaparib solid dispersion from Example 3 is composed of mannitol, colloidal silica, sodium stearate fumarate, and cross-linked polyvinylpyrrolidone. The mixture is thoroughly mixed according to the proportions in Table 5 and directly compressed into tablets to obtain the olaparib tablet core.

[0111] Table 5: Prescription composition of Olaparib tablets

[0112]

[0113] Example 6

[0114] Olaparib tablet core containing solid dispersion

[0115] The olaparib solid dispersion from Example 2 is composed of mannitol, colloidal silica, sodium stearate fumarate, and low-substituted hydroxypropyl cellulose. The mixture is prepared according to the proportions in Table 6 and then directly compressed into tablets to obtain the olaparib tablet core.

[0116] Table 6: Prescription Composition of Olaparib Tablets

[0117]

[0118] Example 7

[0119] Olaparib tablet core containing solid dispersion

[0120] Olaparib tablet cores are obtained by mixing any olaparib solid dispersion from Example 1 or 2 with mannitol, colloidal silica, sodium stearate fumarate, and sodium carboxymethyl starch according to the proportions in Table 7, and then directly compressing the mixture into tablets.

[0121] Table 7: Prescription Composition of Olaparib Tablets

[0122]

[0123] Examples 8-13

[0124] Preparation of Olaparib solid dispersion containing anti-adhesion agent

[0125] 1. Composition: See Table 8

[0126] Table 8: Olaparib solid dispersions in Examples 8-13 (unit: parts by weight)

[0127]

[0128]

[0129] Note: Examples 8-13 are calculated based on the 150mg dosage of olaparib.

[0130] Preparation method: Mix olaparib, copovidone, polyvinyl alcohol, and anti-sticking agent evenly according to the formulation ratio shown in Table 8, and then feed the mixture into the feed hopper of a twin-screw extruder. The extrusion temperature in each zone of the twin-screw extruder is controlled between 125℃ and 220℃, and the screw speed is controlled between 150 rpm and 600 rpm. Specifically:

[0131] Regarding temperature, the first temperature zone is 125℃, and the temperatures of the second to sixth temperature zones are 15℃ higher than the previous temperature zone. The seventh temperature zone is 210℃, and the eighth temperature zone is 220℃.

[0132] For the first 3 minutes after the start of hot melt extrusion, the screw speed is controlled at 150 rpm. Then, the screw speed is increased by 150 rpm every 1 minute. When the screw speed reaches 600 rpm, this screw speed is maintained to continuously extrude the solid dispersion.

[0133] After the extruded solid dispersion is cooled to room temperature, it is pulverized to make its particle size D90 between 150 and 210 μm, thus obtaining olaparib solid dispersion powder.

[0134] Comparative Examples 1-4

[0135] Preparation of Olaparib solid dispersion

[0136] 1. Composition: The embodiments shown in paragraph 0217 and section 4.8 of specification 200980150172.4 are used as comparative examples 1 to 3 of this patent; in addition, based on the embodiments shown in the original patent, the colloidal silica in the formulation is removed, polyvinyl alcohol is increased and the amount of copovidone is reduced as comparative example 4, as detailed in Table 9.

[0137] Table 9: Olaparib Solid Dispersions (Unit: parts by weight)

[0138] specific ingredients Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Olapalli 25 25 25 25 Copolyvinylpyrrolidone 57.5 57.5 57.5 47.5 Polyvinyl alcohol / / / 10 colloidal silica / 1 1.8325 / total 82.5 83.5 84.3325 82.5

[0139] Preparation method: Same as the preparation method in Examples 8-13.

[0140] Experimental Example 1

[0141] Raw material testing

[0142] Paragraph 123 of the specification of 200980150172.4 states that the compound used in the formulation is in crystal form A. For relevant information regarding crystal form A, see 200780038855.1 (publication number CN101528714A), where the characteristic peaks of the X-ray powder diffraction pattern are shown in claim 1 (12.0, 17.8, 21.1, 22.3, 29.2, 10.5, 14.0, 21.7, 24.3, 26.1) and... Figure 3 Differential scanning calorimetry (DSC) detection is described in [link to DSC]. Figure 5 (210.0℃±1℃).

[0143] 1. Samples: The olaparib raw material used in Comparative Examples 1-4 and Examples 1-13 of this invention was prepared by the applicant, Zhengzhou Antu Industrial Group Co., Ltd. (batch number: 2209001).

[0144] 2. Detection method:

[0145] 2.1 Differential Scanning Calorimetry (DSC): Take about 3 mg of sample into an aluminum crucible, select nitrogen as the purge gas, set the temperature program to 30℃, equilibrate for 30 min, cool to 0℃, heat to 120℃ at 10℃ / min, cool to 0℃, and then heat to 400℃ at 5℃ / min for detection.

[0146] 2.2 Detection of X-ray Powder Diffraction Patterns - Detection using a powder X-ray diffractometer (XRPD)

[0147] Take about 200 mg of sample, grind it into a fine powder, place it on a sample holder, flatten the sample on the sample holder, and start the X-ray diffraction method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0451) for determination. Use Cu-Kα as the light source, the scanning speed is 10° per minute, the tube voltage and tube current are 30 kV and 10 mA respectively, the step size is 0.02°, and the diffraction angle (2θ) ranges from 3° to 60° to record the diffraction pattern.

[0148] 3. Test Results:

[0149] 3.1 Differential Scanning Calorimetry (DSC) Detection Results: See Figure 1

[0150] Figure 1 The invention shows that the raw materials used in this invention have a strong characteristic absorption peak at 210-219°C, which is a clear endothermic peak of crystallization and melting. This temperature corresponds to the melting point of the drug.

[0151] 3.2 X-ray powder diffraction detection: see Figure 2

[0152] Figure 2 The results show that the raw materials used in this invention have strong characteristic peak signals in multiple locations, and each characteristic peak is consistent with the olaparib raw material used in 200980150172.4.

[0153] The above results indicate that the olaparib raw material used in this invention has the same crystal form as the active pharmaceutical ingredient A used in 200980150172.4.

[0154] Experiment Example 2

[0155] Detection of solid dispersions

[0156] The evaluation of solid dispersions includes indicators such as appearance, moisture content, and related substances.

[0157] 1. Samples: Solid dispersions provided in Examples 8-13 and Comparative Examples 1-4.

[0158] 2. Detection Method

[0159] 2.1 Appearance: When observed with the naked eye, the uncrushed solid dispersion should be clear and transparent, without any insoluble particles.

[0160] 2.2 Moisture content determination: Using the Fischer method, take approximately 100 mg of this product, weigh it accurately, and determine the moisture content according to the method for moisture determination (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0832, Method I).

[0161] 2.3 Detection of related substances:

[0162] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0163] 1) Reference Standard

[0164] Main ingredient reference standard: Olaparib, content 99.6%.

[0165] Impurity reference standards: Olaparib acid, 99.7% purity; Olaparib Pip dimer, 98.6% purity; Defluorinated Olaparib, 97.2% purity; n-propyl Olaparib, 99.6% purity.

[0166] 2) Preparation of sample solvent: Water / acetonitrile = 1 / 1 (v / v) was selected as the sample solvent, and this solvent was also used as the blank solution.

[0167] 3) Preparation of the test solution: Weigh 30 mg of olaparib solid dispersion into a 20 mL volumetric flask, dissolve and dilute to the mark with the sample solvent, and mix well.

[0168] 4) Preparation of system suitability solution: Weigh appropriate amounts of olaparib, olaparib acid, olaparib Pip dimer, defluorinated olaparib and n-propyl olaparib, accurately weigh them, dissolve them in solvent and quantitatively dilute them to prepare a mixed solution containing 0.4 mg of olaparib and approximately 0.8 μg each of olaparib acid, olaparib Pip dimer, defluorinated olaparib and n-propyl olaparib per 1 mL.

[0169] 5) Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Waters Sunfire C18, 4.6 mm × 150 mm, 3.5 μm or equivalent column); 0.05% trifluoroacetic acid solution was used as mobile phase A, and 0.05% trifluoroacetic acid in acetonitrile solution was used as mobile phase B, with gradient elution according to Table 3; flow rate was 1.0 mL per minute; detection wavelength was 276 nm; column temperature was 30 °C; injection volume was 10 μL.

[0170] Table 10: Gradient Elution Table

[0171] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 90 10 20 60 40 28 5 95 30 5 95 31 90 10 40 90 10

[0172] 3. Test Results:

[0173] 3.1 Characteristics: See Table 11

[0174] Table 11: Properties of Solid Dispersions

[0175]

[0176] Table 11 shows that the solid dispersions prepared in Examples 8-13 and Comparative Examples 1-4 can all achieve a clear and transparent state, and Examples 8-13 and Comparative Examples 1-4 have all achieved the expected properties of olaparib solid dispersions.

[0177] This demonstrates that the solid dispersion formulation provided by this invention and the formulation shown in the original patent can both completely melt the active pharmaceutical ingredient into an amorphous form through the hot melt extrusion process mentioned in this invention, indicating good process feasibility.

[0178] 3.2 Moisture content test results: See Table 12

[0179] Table 12: Moisture content determination data

[0180]

[0181] Table 12 shows that Examples 8-13 and Comparative Example 4 had lower moisture content, while Comparative Examples 1-3 had higher moisture content.

[0182] Results analysis: The moisture data of Examples 8-13 and Comparative Example 4 showed that the moisture content of the solid dispersion decreased as the amount of copovidone in the formulation decreased; while the amount of copovidone used in the formulations of Comparative Examples 1-3 was greater than that in Examples 8-13 and Comparative Example 4, and their moisture content was also relatively high.

[0183] For olaparib tablets, the water content of the solid dispersion is positively correlated with the water content of the final formulation. A high water content increases the probability of the active ingredient changing from an amorphous state to a crystalline state, thereby further affecting the stability and efficacy of the formulation. Therefore, the solid dispersion provided by this invention shows superiority in terms of water content.

[0184] 3.3 Results related to substances: See Table 13

[0185] Table 13: Detection Results of Related Substances

[0186]

[0187] Table 13 shows that the solid dispersions prepared in Examples 8-13 and Comparative Example 4 have 2-3 times less total degradation impurities and 4-5 fewer impurities than the solid dispersions prepared in Comparative Examples 1-3.

[0188] Results Analysis: The common feature of Examples 8-13 and Comparison 4 is that polyvinyl alcohol was added to the solid dispersion formulation, and the amount of polyvinyl alcohol was 2.5-10 parts. Therefore, adding polyvinyl alcohol to the olaparib solid dispersion can effectively protect the olaparib active pharmaceutical ingredient and reduce its degradation.

[0189] Examples 14-17

[0190] Preparation of Olaparib tablets

[0191] 1. Composition: See Table 14, wherein the olaparib solid dispersion is provided by Example 9.

[0192] Table 14: Olaparib Tablets (Unit: Parts by Weight)

[0193]

[0194] 2. Preparation method:

[0195] 1) Weigh out each ingredient according to the formula and set aside;

[0196] 2) Preparation of solid dispersion (same as Example 9): Mix 25 parts of olaparib, 47.5 parts of copovidone, 2.5 parts of polyvinyl alcohol, and 1 part of colloidal silica evenly, then feed the mixture into the feed hopper of a twin-screw extruder. The extrusion temperature in each zone of the twin-screw extruder is controlled between 125℃ and 220℃, and the screw speed is controlled between 150 and 600 rpm. Specifically:

[0197] Temperature: The first temperature zone is 125℃, and the temperatures of the second to sixth temperature zones are 15℃ higher than the previous temperature zone. The seventh temperature zone is 210℃, and the eighth temperature zone is 220℃.

[0198] For the first 3 minutes after the start of hot melt extrusion, the screw speed is controlled at 150 rpm. Then, the screw speed is increased by 150 rpm every 1 minute. When the screw speed reaches 600 rpm, this screw speed is maintained to continuously extrude the solid dispersion.

[0199] After the extruded solid dispersion is cooled to room temperature, it is pulverized to make its particle size D90 between 150 and 210 μm, thus obtaining olaparib solid dispersion powder.

[0200] 3) Mixing: The solid dispersion prepared in step 1) is mixed with diluent, glidant and lubricant using a wet mixing granulator. The stirring speed is set to 400 rpm and the cutter speed is set to 900 rpm. Force mixing is performed for 10 min.

[0201] 4) Tableting: Using a rotary tablet press, the main pressure is controlled within the range of 10-20KN and the filling depth is within the range of 7-11mm. The tablets are directly compressed to obtain the olaparib tablet core.

[0202] 5) Coating: Prepare a coating solution with a solid content of 12% and a theoretical weight gain of 4% to obtain olaparib tablets.

[0203] Comparative Examples 5-8

[0204] Preparation of Olaparib tablets

[0205] 1. Composition: See Table 15, wherein the solid dispersions in Comparative Examples 5, 6, 7 and 8 are the solid dispersions provided by Comparative Examples 1, 2, 3 and 4 respectively.

[0206] Table 15: Olaparib Tablets (Unit: Parts by Weight)

[0207]

[0208]

[0209] 2. Preparation method: The solid dispersions of Comparative Examples 5, 6, 7, and 8 were prepared using the same methods as those of Comparative Examples 1, 2, 3, and 4. The remaining preparation steps were the same as those in Examples 14-17.

[0210] Comparative Example 9

[0211] Commercially available formulations

[0212] Commercially available olaparib tablets are manufactured by AstraZeneca, batch number: RV418.

[0213] Experimental Example 3

[0214] Detection of active pharmaceutical ingredients in olaparib tablets

[0215] The samples were subjected to X-ray powder diffraction and Raman spectroscopy.

[0216] 1. Samples: Olaparib active pharmaceutical ingredient, blank excipients (made by pressing the remaining excipients without solid dispersions in Example 15 according to the preparation methods of Examples 14-17), olaparib solid dispersion provided in Example 9, and olaparib tablets provided in Comparative Example 9 and Example 15.

[0217] 2. Detection indicators

[0218] 2.1 Detection of X-ray powder diffraction pattern - Detection by powder X-ray diffractometer (XRPD): Same as in Experimental Example 1.

[0219] 2.2 Raman spectroscopy detection: Place the sample on the stage, set the excitation wavelength to 785 nm, and the scanning range to 3250–400 cm⁻¹. -1 The resolution is 1cm. -1 Scanning spectrum.

[0220] 3. Experimental Results:

[0221] 3.1 X-ray powder diffraction pattern: see Figure 3 , Figure 4 , Figure 5 and Figure 6 .

[0222] Figure 3 , Figure 4 , Figure 5 and Figure 6 The X-ray powder diffraction patterns are shown for the blank excipient, Example 9, Comparative Example 9, and Example 15, respectively. Figure 3 Characteristic diffraction peaks of the excipients can be observed; Figure 4 The appearance of diffused hump without obvious characteristic sharp peaks indicates that the A-crystal form of olaparib in the olaparib solid dispersion formulation has been transformed into an amorphous state through hot melt extrusion. Figure 5 (Comparative Example 9) and Figure 6 The X-ray powder diffraction pattern shown in Example 15 is consistent with that in Example 15, and the characteristic peaks in the pattern are located in the same positions as the characteristic peaks in the X-ray powder diffraction pattern of the blank sample.

[0223] comprehensive Figures 3-6 The information shown indicates that the olaparib tablets provided by this invention have the same material state as those in commercially available formulations, with the active pharmaceutical ingredient changing from a crystalline state to an amorphous state.

[0224] 3.2 Raman spectroscopy detection: see Figure 7 .

[0225] Figure 7 Raman spectra of the olaparib active pharmaceutical ingredient, blank excipient, olaparib solid dispersion (Example 9), and olaparib tablets (Example 15) used in this invention.

[0226] The results showed that the olaparib solid dispersion and olaparib tablets prepared using the formulation process described in this invention exhibited good performance at 2800–3000 cm⁻¹. -1 1400~1500cm -1 500-600cm -1 100-300cm -1 No characteristic spectral peaks of olaparib A crystal form were observed at any Raman shift, indicating that the self-made solid dispersion and the olaparib A crystal form raw material in the tablets were completely transformed into an amorphous state.

[0227] The above results further demonstrate that the formulation produced by the olaparib tablet formulation process provided by the present invention can achieve the same physicochemical state as commercially available olaparib tablets, and the active pharmaceutical ingredient olaparib in the formulation is converted from the A crystal form to the amorphous state.

[0228] Experiment Example 4

[0229] Quality testing of Olaparib tablets

[0230] The moisture content, related substances, and dissolution of olaparib tablets were examined.

[0231] 1. Sample:

[0232] Olaparib tablets and commercially available formulations (Comparative Example 9) prepared in Examples 14-17 and Comparative Examples 5-9.

[0233] 2. Testing Content and Methods:

[0234] 2.1 Moisture detection: The detection method is the same as in Experiment 2.

[0235] 2.2 Detection of related substances: The detection method is the same as in Experimental Example 2.

[0236] 2.3 Dissolution curve detection:

[0237] Dissolution and release were determined according to the method of determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method I).

[0238] pH-solubility experiments confirmed that olaparib is not pH-dependent in the pH range of 1.0–7.5. Therefore, water was chosen as the dissolution medium for dissolution curve determination.

[0239] Dissolution test method: Refer to the fourth method (basket method) of General Chapter 0931 of Part IV of Chinese Pharmacopoeia 2020. Take 12 tablets of olaparib (150mg specification), place each tablet in 900mL of water, the temperature is 37℃, the rotation speed is 75r / min, and samples are taken for testing after 10min, 20min, 30min, 45min, 60min and 90min respectively.

[0240] Test solution: Filter 5 mL of the sample and use the filtrate as the test solution;

[0241] Reference solution: Accurately weigh 17 mg of olaparib reference standard, place it in a 100 mL volumetric flask, add 25% acetonitrile to dissolve and dilute to the mark to prepare a sample solution containing approximately 0.17 mg of olaparib per mL;

[0242] Chromatographic column: ChromCore 120C18 3μm, 4.6×150mm; mobile phase: 0.1% trifluoroacetic acid solution-acetonitrile = 65:35; flow rate: 1mL / min; detection wavelength: 276nm; column temperature: 30℃; diluent: 25% acetonitrile; injection volume: 10μL.

[0243] Accurately measure 10 μL of the filtrate and inject it into the liquid chromatograph. Record the chromatogram and calculate the peak area using the external standard method.

[0244] 3. Test Results

[0245] 3.1 Moisture content test results: See Table 16

[0246] Table 16: Moisture content determination data

[0247]

[0248] Table 16 shows that the moisture content of Examples 14-17 and Comparative Example 8 was low (<2%), while the moisture content of Comparative Examples 5-7 and Comparative Example 9 was relatively high.

[0249] The results showed that, compared with the comparative example, the olaparib tablets prepared using the formulation process described in this invention had lower moisture content.

[0250] Therefore, the olaparib tablets provided by this invention exhibit superiority in terms of water content.

[0251] 3.2 Results of related substances detection: see Table 17.

[0252] Table 17: Related substance detection results of Examples 14-17 and Comparative Examples 5-9

[0253]

[0254] Table 17 shows that the total impurities in Examples 14-17 and Comparative Example 8 were relatively small, and the number of impurities was also low; while the total impurities in Comparative Examples 5-7 and Comparative Example 9 were relatively high, and the number of impurities was also high.

[0255] Based on the results in Table 17, the olaparib solid dispersion and formulation prepared using the formulation process described in this invention have relatively low levels of related substances. The impurity levels in the solid dispersion are positively correlated with the impurity levels in the formulation. Adding polyvinyl alcohol to the solid dispersion formulation can effectively reduce the impurity levels in the solid dispersion, thereby reducing the impurity levels in the formulation product.

[0256] Therefore, the olaparib tablets provided by this invention show superiority in terms of related substances.

[0257] 3.3 Dissolution test results: see Table 18.

[0258] Table 18: Dissolution curve data of Olaparib tablets

[0259]

[0260] Table 18 shows the results:

[0261] The dissolution curves of the olaparib tablets provided in Examples 14-17 were similar to those of the original formulation (Comparative Example 9), and the drug release behavior was basically the same.

[0262] Compared with the dissolution curve of the original formulation (Comparative Example 9), the drug dissolution amount of olaparib tablets provided by Comparative Examples 5 and 8, which did not contain an anti-adhesion agent (colloidal silica) in the solid dispersion, was significantly lower at each dissolution time point. Therefore, the addition of an anti-adhesion agent to the solid dispersion has a certain impact on the dissolution of olaparib tablets.

[0263] The dissolution curves of the olaparib tablets provided in Comparative Example 6 were similar to those of the original formulation (Comparative Example 9).

[0264] The dissolution curve of the olaparib tablets provided in Comparative Example 7, which did not contain a flow aid (colloidal silica) in the added excipients, was slightly slower than that of the original formulation (Comparative Example 9) and was not similar. Therefore, the addition of a flow aid has a certain impact on the dissolution of olaparib tablets. However, the method of adding the flow aid (colloidal silica) mentioned in paragraphs 0217 and 0242 of the original patent 200980150172.4 was not described.

[0265] The moisture content and number of related substances in Comparative Examples 6 and 9 are very similar, proving that the marketed formulation is similar to the formulation and preparation method of Comparative Example 6. In the formulation, colloidal silica acts as an anti-adhesion agent in the solid dispersion, and as a flow aid when added externally.

[0266] In summary, the olaparib tablets prepared using the formulation process provided by this invention have achieved the expected pharmaceutical effects.

[0267] Experimental Example 5

[0268] Stability test

[0269] 1. Samples: Olaparib tablets provided in Example 15 and Comparative Example 9.

[0270] 2. Detection method:

[0271] The above samples were packaged in double aluminum blister packs and placed under accelerated testing conditions of 40℃ and 75%RH. Samples were taken in 0 months, 1 month, 2 months, 3 months and 6 months to test for dissolution, moisture and related substances.

[0272] (1) Dissolution curve detection: Water was used as the dissolution medium, and the method was the same as that used in Experiment 4.

[0273] (2) Moisture content: The test method is the same as in Experiment Example 2.

[0274] (3) Related substances: The testing method is the same as in Experiment Example 2.

[0275] 3. Test Results:

[0276] 3.1 Accelerated dissolution test results: see Table 19.

[0277] Table 19: Stability Test Data

[0278]

[0279]

[0280] Table 19 shows the results:

[0281] Dissolution results: The results of Example 15 and Comparative Example 9 were similar;

[0282] Moisture and related substances detection: Compared with Comparative Example 9, Example 15 had lower moisture content and lower related substances content.

[0283] The results showed that during the 6-month accelerated stability testing of the olaparib tablets provided by this invention, all key quality attributes remained consistent with the original formulation without significant changes. However, the moisture content and related substance levels of the formulation were lower than those of the original formulation. Therefore, the overall quality of the olaparib tablets prepared using the formulation process of this invention is superior to that of the original formulation.

[0284] In summary, by adding a certain amount of polyvinyl alcohol to the olaparib solid dispersion formulation shown in the original patent, and using copovidone as a matrix polymer carrier, the degradation of intermediate and finished products can be effectively reduced. Under the premise of ensuring effective release of the formulation, other key quality properties of the formulation are improved and the stability is better.

[0285] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. An olaparib tablet, comprising a tablet core and a coating, characterized in that, The core is composed of the following components in parts by weight: 25 parts olaparib, 42.5-47.5 parts copovidone, 2.5-7.5 parts polyvinyl alcohol, 0.75-2 parts anti-adhesion agent, 15-30 parts filler, 1-2 parts lubricant, and 1-2 parts flow aid, wherein the anti-adhesion agent is colloidal silica; The preparation method of the olaparib tablets includes: 1) The preparation method of the solid dispersion is as follows: Olaparib, copovidone, polyvinyl alcohol, and anti-sticking agent are mixed evenly, and then fed into the feed hopper of a twin-screw extruder. The extrusion temperature of each temperature zone of the twin-screw extruder is controlled between 125℃ and 220℃, and the screw speed is controlled between 150 rpm and 600 rpm. Specifically: Regarding temperature, the temperature of the first temperature zone is 125℃, and the temperature of the second to sixth temperature zones is 15℃ higher than the previous temperature zone. The temperature of the seventh temperature zone is 210℃, and the temperature of the eighth temperature zone is 220℃. For the first 3 minutes after the start of hot melt extrusion, the screw speed is controlled at 150 rpm. Then, the screw speed is increased by 150 rpm every 1 minute. When the screw speed reaches 600 rpm, this screw speed is maintained and the solid dispersion is continuously extruded. After the extruded solid dispersion is cooled to room temperature, it is pulverized to make its particle size D90 between 150 and 210 μm, thus obtaining olaparib solid dispersion powder. 2) Mixing: The solid dispersion prepared in step 1) is mixed with diluent, glidant and lubricant using a wet mixing granulator. The stirring speed is set to 400 rpm and the cutter speed is set to 900 rpm. Force mixing is performed for 10 min. 3) Tableting: Using a rotary tablet press, control the main pressure in the range of 10~20 KN and the filling depth in the range of 7~11 mm, and directly compress to obtain olaparib tablets.

2. The olaparib tablet according to claim 1, characterized in that, The core is composed of the following components in parts by weight: 25 parts olaparib, 45-47.5 parts copovidone, 2.5-5 parts polyvinyl alcohol, 0.75-1.25 parts anti-adhesion agent, 17.5-22.5 parts filler, 1-1.5 parts lubricant, and 1-1.5 parts flow aid.

3. The method for preparing olaparib tablets according to claim 1 or 2, characterized in that, The preparation methods include the following: 1) The preparation method of the solid dispersion is as follows: Olaparib, copovidone, polyvinyl alcohol, and anti-sticking agent are mixed evenly, and then fed into the feed hopper of a twin-screw extruder. The extrusion temperature of each temperature zone of the twin-screw extruder is controlled between 125℃ and 220℃, and the screw speed is controlled between 150 rpm and 600 rpm. Specifically: Regarding temperature, the temperature of the first temperature zone is 125℃, and the temperature of the second to sixth temperature zones is 15℃ higher than the previous temperature zone. The temperature of the seventh temperature zone is 210℃, and the temperature of the eighth temperature zone is 220℃. For the first 3 minutes after the start of hot melt extrusion, the screw speed is controlled at 150 rpm. Then, the screw speed is increased by 150 rpm every 1 minute. When the screw speed reaches 600 rpm, this screw speed is maintained and the solid dispersion is continuously extruded. After the extruded solid dispersion is cooled to room temperature, it is pulverized to make its particle size D90 between 150 and 210 μm, thus obtaining olaparib solid dispersion powder. 2) Mixing: The solid dispersion prepared in step 1) is mixed with diluent, glidant and lubricant using a wet mixing granulator. The stirring speed is set to 400 rpm and the cutter speed is set to 900 rpm. Force mixing is performed for 10 min. 3) Tableting: Using a rotary tablet press, control the main pressure in the range of 10~20 KN and the filling depth in the range of 7~11 mm, and directly compress to obtain olaparib tablets.

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