Co-amorphous compound containing olaparib, preparation method thereof, and pharmaceutical composition

Abstract

The present invention discloses a co-amorphous compound containing olaparib, a preparation method, and a pharmaceutical composition thereof. The co-amorphous compound is formed by combining olaparib with a nonsteroidal anti-inflammatory drug. The nonsteroidal anti-inflammatory drug in the co-amorphous compound includes component A: diclofenac or a pharmaceutically acceptable salt thereof; component B: ibuprofen or a pharmaceutically acceptable salt thereof; component C: flurbiprofen or a pharmaceutically acceptable salt thereof; component D: ketoprofen or a pharmaceutically acceptable salt thereof; and component E: indomethacin or a pharmaceutically acceptable salt thereof. The co-amorphous compound of olaparib and the nonsteroidal anti-inflammatory drug disclosed herein has one or more advantages, including significantly improved solubility, significantly improved dissolution rate, good physical stability over three months under long-term conditions, and significantly enhanced antitumor activity. Therefore, the co-amorphous compound of olaparib and the nonsteroidal anti-inflammatory drug is expected to become a new compound solid preparation for the treatment of related cancers.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a co-amorphous substance containing olaparib, a preparation method thereof, and a pharmaceutical composition. Background Art

[0002] Olaparib, whose structural formula is shown in Formula (I) below, is chemically known as 1-(cyclopropylcarboxyl)-4-[5-[(3,4-dihydro-4-oxophthalazin-1-yl)methyl]-2-fluorobenzoyl]piperazine. First developed by the British biotechnology company KuDOS Pharmaceuticals Ltd., it is a first-in-class, oral, potent inhibitor of poly (ADP-ribose) polymerase (PARP). It exploits defects in the DNA repair pathway to promote apoptosis in tumor cells. Furthermore, olaparib can enhance the efficacy of radiotherapy, as well as alkylating and platinum-based chemotherapy. After AstraZeneca acquired KuDOS in 2005, it continued to develop olaparib for the treatment of ovarian cancer. In 2014, olaparib received FDA approval in the United States as the first targeted drug specifically for ovarian cancer patients with BRCA mutations, suitable for patients previously treated with chemotherapy. However, it suffers from low permeability, low solubility, and low bioavailability. By improving its solubility and dissolution rate, its bioavailability can be improved and its therapeutic effect can be enhanced.

[0003]

[0004] Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, flurbiprofen, diclofenac, indomethacin, and ketoprofen, have the structural formula shown in Formula (II) below. They are a class of drugs with antipyretic, anti-inflammatory, and analgesic properties. They exert their pharmacological effects by inhibiting cyclooxygenase (COX), blocking the conversion of arachidonic acid into prostaglandins, prostacyclins, and thromboxane A2. They are widely used clinically to relieve various fevers and pain symptoms, as well as to treat autoimmune diseases such as osteoarthritis, rheumatic and rheumatoid arthritis, and ankylosing spondylitis. NSAIDs are currently the most widely used anti-inflammatory and analgesic drugs in clinical practice due to their advantages, such as no prescription restrictions, low price, and low risk of drug resistance and dependence. Furthermore, NSAIDs inhibit the occurrence, progression, and metastasis of tumors and synergize with other anti-tumor drugs, enhancing their anti-tumor effects and reducing recurrence and metastasis rates. However, most nonsteroidal anti-inflammatory drugs (NSAIDs) have poor water solubility, which limits their clinical application.

[0005]

[0006] Currently, the concept of combination therapy has been widely accepted in clinical practice. Combination therapy significantly improves tumor suppression rates and median survival in chemotherapy patients. It can also overcome drug resistance and reduce adverse reactions. NSAID-based therapy plays an important role in the treatment of aggressive cancers. A growing number of studies have shown that these drugs have a positive inhibitory effect on many solid tumors by regulating stromal cell-induced inflammation. Combination therapy with NSAIDs also offers synergistic anti-cancer benefits for cancer patients, which can be manifested in the following aspects:

[0007] (1) NSAIDs prevent and enhance the anti-tumor effects of anti-tumor drugs and reduce the recurrence and metastasis rate. The combination of non-steroidal anti-inflammatory drugs and chemotherapy drugs can improve the anti-tumor effect. For example, NSAIDs have been shown to inhibit the malignant transformation of several cancer cell lines, and regular use of non-steroidal anti-inflammatory drugs is associated with a reduced risk of colorectal cancer, gastrointestinal cancer, breast cancer, prostate cancer, and lung cancer. A large number of studies have shown that the use of NSAIDs can not only reduce the incidence and mortality of breast cancer, but also inhibit the development, metastasis, and recurrence of breast cancer. There are also studies showing that low-dose fentanyl combined with flurbiprofen axetil for postoperative analgesia after breast cancer can reduce the expression of VEGF-C, TNF-α, and IL-1β compared to the use of fentanyl alone, thereby reducing the risk of postoperative metastasis and recurrence. Ibuprofen has also been shown in relevant statistical studies to significantly reduce the risk of breast cancer recurrence.

[0008] (2) Relieve chemotherapy-related pain. Chemotherapy can cause peripheral neuropathy and neuropathic pain, in which COX-2 and phosphatidylinositol 3-kinase (PI3K) / Akt may play a mediating role. Animal experiments have found that oxaliplatin can increase the expression of COX-2 and Akt2 in the L4-5 dorsal root ganglion, while celecoxib can reduce nerve hypersensitivity by inhibiting their expression and increase oxaliplatin-induced apoptosis of human colon cancer HCT-116. Therefore, celecoxib can relieve oxaliplatin-related neuropathic pain while also enhancing its anti-tumor effect. In view of this, the combination of olaparib and non-steroidal anti-inflammatory drugs is a promising therapy for the treatment of breast cancer.

[0009] In recent years, co-amorphous drug formulations have emerged as a promising new drug delivery system. Co-amorphous drug formulations can enhance the stability of amorphous drugs and improve the solubility and dissolution of poorly soluble drugs, potentially increasing bioavailability and enhancing drug efficacy. Nonsteroidal anti-inflammatory drugs (NSAIDs) and olaparib have poor solubility, and olaparib has low bioavailability. However, co-amorphous drug formulations can effectively enhance the stability of amorphous drugs, improve the solubility and dissolution of poorly soluble drugs, and enhance bioavailability. Furthermore, co-amorphous complexes of NSAIDs and olaparib have potential synergistic anticancer effects, enhancing efficacy while reducing drug dosage, reducing the occurrence of dose-related adverse reactions, and improving drug safety. Therefore, co-amorphous compounds have become an increasingly important topic in international pharmaceutical research, holding significant significance for extending the lifespan of original drugs and developing new drugs. To this end, co-amorphous compounds containing olaparib, methods for their preparation, and pharmaceutical compositions are provided. Summary of the Invention

[0010] The purpose of the present invention is to address the deficiencies of the prior art and provide a co-amorphous compound containing olaparib, a preparation method thereof, and a pharmaceutical composition thereof, so as to solve the problems raised by the above-mentioned background technology.

[0011] To achieve the above objectives, the present invention provides the following technical solutions: providing a co-amorphous compound containing olaparib, wherein the co-amorphous compound is formed by combining olaparib with a non-steroidal anti-inflammatory drug; the non-steroidal anti-inflammatory drug in the co-amorphous compound comprises component A: diclofenac or a pharmaceutically acceptable salt thereof; component B: ibuprofen or a pharmaceutically acceptable salt thereof; component C: flurbiprofen or a pharmaceutically acceptable salt thereof; component D: ketoprofen or a pharmaceutically acceptable salt thereof; and component E: indomethacin or a pharmaceutically acceptable salt thereof.

[0012] The present invention provides co-amorphous compounds containing olaparib, including olaparib-diclofenac co-amorphous compound, olaparib-ibuprofen co-amorphous compound, olaparib-flurbiprofen co-amorphous compound, olaparib-ketoprofen co-amorphous compound, and olaparib-indomethacin co-amorphous compound.

[0013] Furthermore, the co-amorphous material has no sharp crystal diffraction peak in its X-ray powder diffraction pattern using Cu-Kα radiation.

[0014] Further, when the co-amorphous material is formed by combining the olaparib component A;

[0015] The infrared absorption spectrum of the co-amorphous compound measured by KBr pellet was 3417.17 cm -l 、3008.67cm -l 、2901.03cm -l 、1714.71cm -l 、1638.34cm-l 、1495.94cm -l 、1451.88cm -l 、1354.88cm -l 、1285.55cm -l 、1225.97cm -l 、1171.43cm -l 、1117.60cm -l 、1092.15cm -l 、1011.43cm -l 、834.79cm -l 、773.47cm -l There is an absorption peak at; the glass transition temperature of the co-amorphous compound is 64.5℃;

[0016] Furthermore, the molar ratio of olaparib to diclofenac is 1:1-10:1, preferably 1:1-3:1;

[0017] Furthermore, when the co-amorphous material is formed by combining Olaparib and component B;

[0018] The infrared absorption spectrum obtained by KBr pellet measurement was 3418.73 cm -l 、3183.89cm -l 、3008.40cm -l 、2954.49cm -l 、2827.49cm -l 、1730.26cm -l 、1639.57cm -l 、1465.90cm -l 、1436.72cm -l 、1354.77cm -l 、1284.43cm -l 、1225.74cm -l 、1172.13cm -l 、1117.28cm -l 、1011.29cm -l 、789.5cm -l 1.772.35cm -l There is an absorption peak at; the glass transition temperature of the co-amorphous compound is 57.3℃;

[0019] Furthermore, the molar ratio of olaparib to ibuprofen is 1:1-10:1, preferably 1:1-3:1;

[0020] Further, when the co-amorphous material is formed by combining Olaparib and component C;

[0021] The infrared absorption spectrum obtained by KBr pellet measurement was 3178.34 cm -l 、3007.99cm -l 、2930.00cm -l 、1729.06cm -l 、1639.20cm -l 、1484.25cm -l 、1465.95cm -l 、1436.44cm -l 、1354.81cm -l 、1284.89cm -l 、1225.70cm -l 、1131.74cm -l 、1085.74cm -l 、1011.24cm -l 、925.85cm -l 、871.38cm -l 、838.38cm -l 、790.59cm -l 、768.72cm -l 、723.42cm -l 、698.78cm -l There is an absorption peak at; the glass transition temperature of the co-amorphous compound is 59.0℃;

[0022] Furthermore, the molar ratio of olaparib to flurbiprofen is 1:1-10:1, preferably 1:1-3:1;

[0023] Further, when the co-amorphous material is formed by combining Olaparib and component D;

[0024] The infrared absorption spectrum obtained by KBr pellet measurement was at 3417.40 cm -l 、3188.15cm -l 、3005.90cm -l 、2928.28cm -l 、1729.73cm -l 、1639.55cm -l 、1465.46cm -l 、1436.04cm -l 、1354.61cm -l 、1318.58cm -l 、1283.07cm -l 、1224.95cm -l 、1177.09cm -l 、1083.87cm-l 、1010.81cm -l 、805.07cm -l 、789.22cm -l 、770.70cm -l 、721.08cm -l 、701.73cm -l 、642.07cm -l There is an absorption peak at; the glass transition temperature of the co-amorphous compound is 58.0℃;

[0025] Further, the molar ratio of olaparib to ketoprofen is 1:1-10:1, preferably 1:1-3:1;

[0026] Further, when the co-amorphous compound is formed by combining Olaparib and component E;

[0027] The infrared absorption spectrum obtained by KBr pellet measurement was 3418.66 cm -l 、3005.90cm -l 、2927.55cm -l 、1638.81cm -l 、1477.52cm -l 、1436.66cm -l 、1356.32cm -l 、1323.99cm -l 、1288.95cm -l 、1224.52cm -l 、1174.83cm -l 、1147.52cm -l 、1174.83cm -l 、1088.11cm -l 、1067.52cm -l 、1035.44cm -l 、1012.37cm -l 、836.67cm -l 、804.00cm -l 、770.21cm -l 、754.78cm -l There is an absorption peak at; the glass transition temperature of the co-amorphous compound is 74.4℃;

[0028] Furthermore, the molar ratio of olaparib to indomethacin is 1:1-10:1, preferably 1:1-3:1.

[0029] The preparation method of a co-amorphous material containing olaparib comprises the following steps: dissolving olaparib and component A, component B, component C, component D and component E in an organic solvent according to a proportion, filtering, and then performing reduced pressure rotary evaporation and drying on the filtrate.

[0030] The specific steps include:

[0031] 1. Dissolve olaparib and component A, component B, component C, component D or component E in an organic solvent according to the ratio to obtain a clear solution;

[0032] 2. The solution obtained in step 1 is subjected to reduced pressure rotary evaporation to obtain a solid product;

[0033] 3. The solid product obtained in step 2 is vacuum dried to remove the residual solvent to obtain a co-amorphous substance containing olaparib.

[0034] As a preferred technical solution of the present invention, the temperature of the reduced pressure rotary evaporation is 40-60°C; further preferably, the temperature of the reduced pressure rotary evaporation is 50-60°C.

[0035] As a preferred technical solution of the present invention, the organic solvent is selected from at least one of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, acetone and methyl isobutyl ketone, preferably methanol.

[0036] A pharmaceutical composition comprises the above-mentioned co-amorphous material containing olaparib, and further comprises a pharmaceutically acceptable carrier.

[0037] The pharmaceutical composition of the present invention is prepared by combining the above-mentioned amorphous form of olaparib as an active ingredient with a pharmaceutically acceptable carrier to prepare a medicament for administration.

[0038] The pharmaceutical composition can be in any form suitable for oral administration, such as tablets (including sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, etc.), capsules (including hard capsules, soft capsules and sustained-release capsules), oral liquids, granules, pills, powders, drops, lozenges, granules, ointments, pills, suspensions, powders, solutions, injections, suppositories, sprays, etc.

[0039] For the pharmaceutical composition of the present invention, its oral administration preparation may contain commonly used excipients such as binders, fillers, tableting agents, lubricants, colorants, flavoring agents and wetting agents.

[0040] The pharmaceutical composition can be prepared into a solid oral composition by mixing, filling, tableting, and other methods commonly used in the art.

[0041] A co-amorphous form or pharmaceutical composition containing olaparib is used as a drug for preparing a drug for treating a disease, wherein the disease is selected from the group consisting of treating and alleviating advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, or recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. The drug application comprises administering an effective dose of any one or a combination of the co-amorphous form of olaparib or its pharmaceutical composition of the present invention to a patient.

[0042] A combined use of an olaparib co-amorphous form or pharmaceutical composition and other drugs; the other drugs are cobicistat, abiraterone acetate, cediranib, paclitaxel, carboplatin, pembrolizumab, gemcitabine, enzalutamide, prednisone, pemetrexed, cisplatin, 5-fluorouracil, capecitabine, bevacizumab, folinic acid / leucovorin, durvalumab, docetaxel, etoposide, cediranib maleate, cediranib, chest radiotherapy, etc.

[0043] The beneficial effects of the present invention are:

[0044] 1. The powder X-ray diffraction pattern, DSC spectrum, and infrared spectrum of the co-amorphous material containing olaparib of the present invention are different from those of diclofenac, ibuprofen, flurbiprofen, ketoprofen, indomethacin, and the physical mixture of raw materials used to prepare the amorphous material. Therefore, the amorphous material is a new solid form that is completely different from the monomers and their physical mixtures.

[0045] 2. After olaparib and other components are made into an amorphous form, the solubility and dissolution rate of olaparib in the amorphous form are significantly improved compared with single olaparib crystals. It is expected to become a new solid form of raw material for compound preparations containing olaparib and has good development prospects.

[0046] 3. The amorphous complex of nonsteroidal anti-inflammatory drugs and olaparib has potential synergistic anti-cancer effects, which can improve the efficacy while reducing the drug dosage, reduce the occurrence of dose-related adverse reactions, and improve the safety of medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 Middle a- Figure 1 f in the middle are the powder X-ray diffraction test results of olaparib crystals, diclofenac crystals, flurbiprofen crystals, ibuprofen crystals, indomethacin and ketoprofen crystals respectively;

[0048] Figure 2 Middle a- Figure 2f in the middle are the powder X-ray diffraction test results of a physical mixture of olaparib crystals and indomethacin crystals in a molar ratio of 1:1, a physical mixture of olaparib crystals and diclofenac crystals in a molar ratio of 1:1, a physical mixture of olaparib crystals and flurbiprofen crystals in a molar ratio of 1:1, a physical mixture of olaparib crystals and ibuprofen crystals in a molar ratio of 1:1, a physical mixture of olaparib crystals and ketoprofen crystals in a molar ratio of 1:1, and five co-amorphous forms;

[0049] Figure 3 Middle a- Figure 3 f in the middle are the infrared spectra test results of olaparib crystals, ibuprofen crystals, indomethacin crystals, flurbiprofen crystals, diclofenac crystals and ketoprofen crystals respectively;

[0050] Figure 4 Middle a- Figure 4 e in the middle are the infrared spectroscopic test results of the physical mixture of olaparib crystals and flurbiprofen crystals, the physical mixture of olaparib crystals and diclofenac crystals, the physical mixture of olaparib crystals and ketoprofen crystals, the physical mixture of olaparib crystals and indomethacin crystals, and the physical mixture of olaparib crystals and ibuprofen crystals;

[0051] Figure 5 Middle a- Figure 5 e in the middle are the infrared spectra test results of the co-amorphous form of olaparib and flurbiprofen, the co-amorphous form of olaparib and diclofenac, the co-amorphous form of olaparib and ketoprofen, the co-amorphous form of olaparib and ibuprofen, and the co-amorphous form of olaparib and indomethacin;

[0052] Figure 6 Middle a- Figure 6 f in the middle are the differential scanning calorimetry test results of olaparib crystals, diclofenac crystals, flurbiprofen crystals, ibuprofen crystals, ketoprofen and indomethacin crystals;

[0053] Figure 7 Middle a- Figure 7 e in the middle are the differential scanning calorimetry test results of the co-amorphous form of olaparib and flurbiprofen, the co-amorphous form of olaparib and ibuprofen, the co-amorphous form of olaparib and diclofenac, the co-amorphous form of olaparib and indomethacin, and the co-amorphous form of olaparib and ketoprofen;

[0054] Figure 8 The dissolution test results of olaparib crystals, physical mixture of olaparib crystals and diclofenac crystals (molar ratio 1:1), and co-amorphous powder of olaparib and diclofenac are shown respectively;

[0055] Figure 9The dissolution test results of olaparib crystals, physical mixture of olaparib crystals and ibuprofen crystals (molar ratio 1:1), and co-amorphous powder of olaparib and ibuprofen are shown respectively;

[0056] Figure 10 The dissolution test results of olaparib crystals, a physical mixture of olaparib crystals and flurbiprofen crystals (molar ratio 1:1), and a co-amorphous powder of olaparib and flurbiprofen are shown.

[0057] Figure 11 The dissolution test results of olaparib crystals, physical mixture of olaparib crystals and ketoprofen crystals (molar ratio 1:1), and co-amorphous powder of olaparib and ketoprofen are shown respectively;

[0058] Figure 12 The dissolution test results of olaparib crystals, a physical mixture of olaparib crystals and indomethacin crystals (molar ratio 1:1), and a co-amorphous powder of olaparib and indomethacin are shown.

[0059] Figure 13 Middle a- Figure 13 Middle e are the powder diffraction patterns of the co-amorphous form of olaparib and flurbiprofen, the co-amorphous form of olaparib and indomethacin, the co-amorphous form of olaparib and ketoprofen, the co-amorphous form of olaparib and ibuprofen, and the co-amorphous form of olaparib and diclofenac under long-term conditions in a stability test chamber (25°C / 60%RH) for 3 months;

[0060] Figure 14 Middle a- Figure 14 Figure e in the middle are the powder diffraction patterns of the co-amorphous form of olaparib and flurbiprofen, the co-amorphous form of olaparib and indomethacin, the co-amorphous form of olaparib and ibuprofen, the co-amorphous form of olaparib and diclofenac, and the co-amorphous form of olaparib and ketoprofen under accelerated conditions (40°C / 75% RH) in a stability test chamber for one month. DETAILED DESCRIPTION

[0061] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0062] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0063] The present invention will be described in detail below through examples, but the protection scope of the present invention is not limited thereto.

[0064] Example 1: Preparation of Olaparib and Diclofenac Co-amorphous (OLA-DIC);

[0065] Weigh 1 mmol (434.46 mg) of olaparib (OLA) and 1 mmol (296.15 mg) of diclofenac (DIC), mix them in a round-bottom flask in a molar ratio of 1:1, add 12 ml of methanol, and slowly stir for 30 minutes in a water bath at 60°C until clear. Then, remove the organic solvent methanol by rotary evaporation under reduced pressure to obtain a co-amorphous form of olaparib and diclofenac (OLA-DIC), which is then vacuum dried at 35°C for 24 hours to obtain a white solid powder.

[0066] Example 2: Preparation of Olaparib and Indomethacin Co-amorphous Form (OLA-IND);

[0067] Weigh 1 mmol (434.46 mg) of olaparib (OLA) and 1 mmol (357.79 mg) of indomethacin (IND), mix them in a round-bottom flask at a molar ratio of 1:1, add 12 ml of methanol, and slowly stir for 30 minutes in a water bath at 60°C until clear. Then, remove the organic solvent methanol by rotary evaporation under reduced pressure to obtain a co-amorphous form of olaparib and indomethacin (OLA-IND), which is then vacuum dried at 35°C for 24 hours to obtain a yellow solid powder.

[0068] Example 3: Preparation of Olaparib and Flurbiprofen Co-amorphous (OLA-FLU);

[0069] Weigh 1 mmol (434.46 mg) of olaparib (OLA) and 1 mmol (244.26 mg) of flurbiprofen (FLU), mix them in a round-bottom flask in a molar ratio of 1:1, add 12 ml of methanol, and slowly stir for 30 minutes in a water bath at 60°C until clear. Then, remove the organic solvent methanol by rotary evaporation under reduced pressure to obtain a co-amorphous form of olaparib and flurbiprofen (OLA-FLU), which is then vacuum dried at 35°C for 24 hours to obtain a white solid powder.

[0070] Example 4: Preparation of Olaparib and Ketoprofen Co-amorphous (OLA-KET);

[0071] Weigh 1 mmol (434.46 mg) of olaparib (OLA) and 1 mmol (254.28 mg) of ketoprofen (KET), mix them in a round-bottom flask at a molar ratio of 1:1, add 12 ml of methanol, and slowly stir for 30 minutes in a water bath at 60°C until clear. Then, remove the organic solvent methanol by rotary evaporation under reduced pressure to obtain a co-amorphous form of olaparib and ketoprofen (OLA-KET), which is then vacuum dried at 35°C for 24 hours to obtain a white solid powder.

[0072] Example 5: Preparation of Olaparib and Ibuprofen Co-amorphous (OLA-IBU);

[0073] Weigh 1 mmol (434.46 mg) of olaparib (OLA) and 1 mmol (206.28 mg) of ibuprofen (IBU), mix them in a round-bottom flask at a molar ratio of 1:1, add 12 ml of methanol, and slowly stir for 30 minutes in a water bath at 60°C until clear. Then, remove the organic solvent methanol by rotary evaporation under reduced pressure to obtain a co-amorphous form of olaparib and ibuprofen (OLA-IBU), which is then vacuum dried at 35°C for 24 hours to obtain a white solid powder.

[0074] Example 6: Powder X-ray diffraction test;

[0075] The five co-amorphous materials, the raw materials for preparing the amorphous materials, and the physical mixtures of the raw materials prepared in Examples 1-5 were tested using powder X-ray diffraction. The X-ray powder diffractometer was manufactured by PANalytical (Netherlands), model X'Pert PRO MPD, Cu-K(α), tube voltage 40 kV, tube current 40 mA, and scan speed 2° / min.

[0076] The test results of Olaparib crystals are as follows Figure 1 As shown in a, the test results of diclofenac crystals are as follows Figure 1 As shown in b, the test results of flurbiprofen crystals are as follows Figure 1 As shown in c, the test results of ibuprofen crystals are as follows Figure 1 As shown in Figure d, the test results of indomethacin are as follows Figure 1 As shown in e, the test results of ketoprofen crystals are as follows Figure 1 As shown in Figure f; the test results of the physical mixture of Olaparib crystals and indomethacin crystals (molar ratio 1:1) are as follows Figure 2 As shown in a, the test results of the physical mixture of Olaparib crystals and diclofenac crystals (molar ratio 1:1) are as follows Figure 2 As shown in b, the test results of the physical mixture of Olaparib crystals and Flurbiprofen crystals (molar ratio 1:1) are as follows Figure 2As shown in c, the test results of the physical mixture of Olaparib crystals and ibuprofen crystals (molar ratio 1:1) are as follows Figure 2 As shown in Figure d, the test results of the physical mixture of Olaparib crystals and Ketoprofen crystals (molar ratio 1:1) are as follows Figure 2 As shown in Figure e, the test results of the co-amorphous form of olaparib and flurbiprofen, the co-amorphous form of olaparib and diclofenac, the co-amorphous form of olaparib and ketoprofen, the co-amorphous form of olaparib and ibuprofen, and the co-amorphous form of olaparib and indomethacin are as follows. Figure 2 As shown in f.

[0077] As can be seen from the figure, the spectra of the co-amorphous materials prepared in Examples 1-5 do not have sharp diffraction peaks, which are completely different from the spectra of the raw materials for preparing the amorphous materials and the physical mixture of the raw materials for preparing the amorphous materials.

[0078] Example 7: Infrared spectrum detection;

[0079] The five co-amorphous materials, the raw materials for preparing the amorphous materials, and the physical mixtures of the raw materials prepared in Examples 1-5 were detected by infrared spectroscopy (FT-IR). The Fourier transform infrared spectrometer was a Vertex 70 manufactured by Bruker, Germany, with an absorption wavelength of 4000-500 cm -l , KBr tablets.

[0080] Test results: The test results of Olaparib crystals are as follows Figure 3 As shown in a, the test results of ibuprofen crystals are as follows Figure 3 As shown in b, the test results of indomethacin crystals are as shown in the figure Figure 3 As shown in c, the test results of flurbiprofen crystals are as follows Figure 3 As shown in Figure d, the test results of diclofenac crystals are as follows Figure 3 As shown in e, the test results of ketoprofen crystals are as follows Figure 3 As shown in f; the test results of the physical mixing of Olaparib crystals and flurbiprofen crystals are as follows Figure 4 As shown in a, the test results of the physical mixing of Olaparib crystals and diclofenac crystals are as follows Figure 4 As shown in b, the test results of the physical mixing of Olaparib crystals and Ketoprofen crystals are as follows Figure 4 As shown in c, the test results of the physical mixing of olaparib crystals and indomethacin crystals are as follows Figure 4 As shown in (d), the infrared spectrum test results of the physical mixture of Olaparib crystals and ibuprofen crystals are as follows Figure 4 As shown in e; the test results of the co-amorphous compound of Olaparib and Flurbiprofen are as follows Figure 5 In a, the test results of the co-amorphous product of olaparib crystals and diclofenac crystals are as follows: Figure 5As shown in b, the test results of the co-amorphous compound of Olaparib and Ketoprofen are as follows Figure 5 As shown in c, the test results of the co-amorphous compound of Olaparib and ibuprofen are as follows Figure 5 As shown in Figure d, the test results of the co-amorphous compound of Olaparib and Indomethacin are as follows: Figure 5 As shown in e.

[0081] As can be seen from the figure, the infrared spectrum wave number of the co-amorphous form of Olaparib and diclofenac is: 3417.17 cm -l 、3008.67cm -l 、2901.03cm -l 、1714.71cm -l 、1638.34cm -l 、1495.94cm -l 、1451.88cm -l 、1354.88cm -l 、1285.55cm -l 、1225.97cm -l 、1171.43cm -l 、1117.60cm -l 、1092.15cm -l 、1011.43cm -l 、834.79cm -l 、773.47cm -l The infrared spectrum wave number of the co-amorphous compound of olaparib and ibuprofen is: 3418.73 cm -l 、3183.89cm -l 、3008.40cm -l 、2954.49cm -l 、2827.49cm -l 、1730.26cm -l 、1639.57cm -l 、1465.90cm -l 、1436.72cm -l 、1354.77cm -l 、1284.43cm -l 、1225.74cm -l 、1172.13cm -l 、1117.28cm -l 、1011.29cm -l 、789.51cm -l 、772.35cm -l The infrared spectrum wave number of the co-amorphous compound of Olaparib and Flurbiprofen is: 3178.34 cm -l、3007.99cm -l 、2930.00cm -l 、1729.06cm -l 、1639.20cm -l 、1484.25cm -l 、1465.95cm -l 、1436.44cm -l 、1354.81cm -l 、1284.89cm -l 、1225.70cm -l 、1131.74cm -l 、1085.74cm -l 、1011.24cm -l 、925.85cm -l 、871.38cm -l 、838.38cm -l 、790.59cm -l 、768.72cm -l 、723.42cm -l 、698.78cm -l The infrared spectrum wave number of the co-amorphous compound of olaparib and ketoprofen is: 3417.40 cm -l 、3188.15cm -l 、3005.90cm -l 、2928.28cm -l 、1729.73cm -l 、1639.55cm -l 、1465.46cm -l 、1436.04cm -l 、1354.61cm -l 、1318.58cm -l 、1283.07cm -l 、1224.95cm -l 、1177.09cm -l 、1083.87cm -l 、1010.81cm -l 、805.07cm -l 、789.22cm -l 、770.70cm -l 、721.08cm -l 、701.73cm -l 、642.07cm -l The infrared spectrum wave number of the co-amorphous compound of olaparib and indomethacin is: 3418.66 cm -l、3005.90cm -l 、2927.55cm -l 、1638.81cm -l 、1477.52cm -l 、1436.66cm -l 、1356.32cm -l 、1323.99cm -l 、1288.95cm -l 、1224.52cm -l 、1174.83cm -l 、1147.52cm -l 、1174.83cm -l 、1088.11cm -l 、1067.52cm -l 、1035.44cm -l 、1012.37cm -l 、836.67cm -l 、804.00cm -l 、770.21cm -l 、754.78cm -l .

[0082] Example 8: Differential Scanning Calorimetry Detection;

[0083] The five co-amorphous materials and the raw materials for preparing the amorphous materials prepared in Examples 1-5 were tested by differential scanning calorimetry (DSC). The differential scanning calorimeter was a DSC 3500 Sirius model from NETZSCH, Germany. The present invention employed a nitrogen atmosphere with a heating rate of 10 K / min and a temperature range of 30-260°C.

[0084] Test results: The test results of Olaparib crystals are as follows Figure 6 As shown in a, the test results of diclofenac crystals are as follows Figure 6 As shown in b, the test results of flurbiprofen crystals are as follows Figure 6 As shown in c, the test results of ibuprofen crystals are as follows Figure 6 As shown in Figure d, the test results of ketoprofen crystals are as follows Figure 6 As shown in e, the test results of indomethacin crystals are as follows Figure 6 As shown in f; the test results of the amorphous compound of Olaparib and Flurbiprofen are as follows Figure 7 As shown in a, the test results of the co-amorphous compound of Olaparib and ibuprofen are as follows Figure 7 As shown in b, the test results of the amorphous compound of Olaparib and diclofenac are as follows: Figure 7 As shown in c, the test results of the amorphous compound of Olaparib and Indomethacin are as follows Figure 7As shown in Figure d, the test results of the amorphous compound of Olaparib and Ketoprofen are as follows: Figure 7 As shown in e.

[0085] As can be seen from the figure, the endothermic transition of olaparib is at 209.0°C, the endothermic transition of diclofenac is at 180.7°C, the endothermic transition of flurbiprofen is at 115.4°C, the endothermic transition of ibuprofen is at 77.0°C, the endothermic transition of ketoprofen is at 95.7°C, the endothermic transition of indomethacin is at 160.8°C, the glass transition temperature of the co-amorphous form of olaparib and flurbiprofen is 59.0°C, the glass transition temperature of the co-amorphous form of olaparib and ibuprofen is 57.3°C, the glass transition temperature of the co-amorphous form of olaparib and diclofenac is at 64.5°C, the glass transition temperature of the co-amorphous form of olaparib and indomethacin is at 74.4°C, and the glass transition temperature of the co-amorphous form of olaparib and ketoprofen is at 58.0°C.

[0086] Example 9: Solubility evaluation;

[0087] The equilibrium solubility of the five co-amorphous forms prepared in Examples 1-5 was determined and compared with the olaparib API and the mixture of materials used to prepare the raw materials, as follows:

[0088] The solubility determination method is as follows:

[0089] Determine the solubility of olaparib in water and various pH buffers. Measure 1 mL of each medium (purified water, pH 1.2 hydrochloric acid buffer solution, pH 4.5 acetic acid buffer solution, pH 6.8 phosphate buffer solution) and place it in a 5 mL EP tube. After adding an excess of the above-mentioned test substance, seal the EP tube and place it in a 37°C THZ-100 constant temperature shaker. Shake for 24 hours to reach equilibrium, let it stand for 30 minutes, remove the supernatant and filter it with a 0.45 μm microporous filter membrane. Take the subsequent filtration and inject it into high performance liquid chromatography (HPLC) to measure the solubility. Each group of samples was measured in parallel 3 times. The HPLC chromatographic conditions are as follows:

[0090] Liquid phase conditions:

[0091] Instrument: Agilent 1260 Infinity II;

[0092] Column: Agilent Poroshell 120EC-C 18 Column (4.6 mm × 100 mm, 4 μm);

[0093] UV detection wavelength: 276nm;

[0094] Mobile phase: acetonitrile: water (v / v, 50:50, containing 0.1% acetic acid)

[0095] Column temperature: 40°C;

[0096] Flow rate: 1 mL / min;

[0097] Injection volume: 10 μL.

[0098] The test results are as follows:

[0099] 1. Olaparib API. The equilibrium solubility (μg / mL) of the co-amorphous products of Olaparib and five nonsteroidal anti-inflammatory drugs prepared in Examples 1-5 in buffered saline solutions at different pH values ​​and ultrapure water is shown in Table 1.

[0100] Table 1: Equilibrium solubility of olaparib in buffered saline solutions at different pH values ​​(μg / mL)

[0101]

[0102]

[0103] Example 10: Dissolution evaluation;

[0104] The co-amorphous forms of olaparib and five nonsteroidal anti-inflammatory drugs, their physical mixtures, and the powder dissolution data of olaparib were compared.

[0105] Source of test samples: Co-amorphous forms of olaparib and five nonsteroidal anti-inflammatory drugs were prepared by the methods provided in Examples 1-5 of the present invention; the olaparib API was purchased from Shanghai Shengde Pharmaceutical Technology Co., Ltd. with a purity of 99%.

[0106] Powder dissolution test method: Olaparib, its co-amorphous form with five NSAIDs, and olaparib were ground and passed through 100 and 200 mesh sieves, respectively, to control the powder particle size to 75-150 μm. 70 mg of olaparib API, 70 mg equivalent of olaparib, and the co-amorphous form of the five NSAIDs were weighed and added to 300 mL of pH 6.8 phosphate buffer. 1 mL of the solution was sampled at intervals, filtered through a 0.45 μm microporous filter, and diluted to the appropriate multiple. Drug concentrations at various time points were monitored by high-performance liquid chromatography to generate powder dissolution curves for each sample. Each experiment was repeated three times.

[0107] Powder dissolution conditions:

[0108] Dissolution medium: phosphate buffer solution, pH 6.8;

[0109] Stirring speed: 50 rpm;

[0110] Dissolution temperature: 37±0.5℃;

[0111] Sampling time: 1, 5, 10, 20, 30, 60, 120, 240, 480, 720, and 1440 minutes;

[0112] Liquid phase conditions: same as above;

[0113] The experimental results are attached. Figures 8-12 The powder dissolution curves are shown. As shown, the maximum apparent solubility of olaparib and its co-amorphous form with five NSAIDs (diclofenac, indomethacin, flurbiprofen, ibuprofen, and ketoprofen) are 111.66 μg / mL, 176.31 μg / mL, 225.30 μg / mL, 184.76 μg / mL, 168.83 μg / mL, and 190.16 μg / mL, respectively. Compared to the olaparib API, these increases are approximately 1.58-fold, 2.02-fold, 1.65-fold, 1.51-fold, and 1.70-fold, respectively. This indicates that the solubility of olaparib with NSAIDs is significantly superior to that of the olaparib API.

[0114] Example 11: Physical stability evaluation;

[0115] To investigate the physical stability of the co-amorphous form of olaparib and nonsteroidal anti-inflammatory drugs, the co-amorphous powders were treated under long-term conditions of 25°C / 60% RH for 3 months and accelerated conditions of 40°C / 75% RH for 1 month (stability test chamber, Yongsheng Instruments, Chongqing, China). Powder diffraction data of each sample were collected once a week in the first month (i.e., week 1, week 2, week 3, and week 4) and once a month for the other two months (i.e., at the end of month 2 and at the end of month 3) to determine the recrystallization trend. Figure 13 As shown in Figure 2, the powder diffraction test results show that the characteristic peaks of powder diffraction of OLA-IND, OLA-DIC, OLA-FLU, OLA-IBU and OLA-KET co-amorphous materials do not change under long-term conditions compared with the corresponding starting materials, indicating that OLA-IND, OLA-DIC, OLA-FLU, OLA-IBU and OLA-KET co-amorphous materials are physically stable under long-term conditions for 3 months. Figure 14 As shown in Figure 3, under accelerated conditions, the characteristic peaks of powder diffraction of OLA-IND and OLA-DIC co-amorphous did not change, indicating that OLA-IND and OLA-DIC co-amorphous were physically stable under accelerated conditions for 1 month.

[0116] Example 12: Evaluation of anticancer activity;

[0117] To investigate the synergistic anticancer effects of olaparib and NSAID co-amorphous compounds, the MTT assay was used to assess the cytotoxic activity of OLA, DIC, IND, FLU, IBU, KET, OLA-IND, OLA-DIC, OLA-FLU, OLA-IBU, and OLA-KET co-amorphous compounds against a human ovarian cancer cell line (Ovcar3). Cells were cultured in 96-well plates at a density of 5000 cells per well. Six different concentrations of OLA, DIC, IND, FLU, IBU, KET, OLA-IND, OLA-DIC, OLA-FLU, OLA-IBU, and OLA-KET co-amorphous compounds in DMSO (0, 0.01, 0.1, 1, 10, 100, and 1000 μM) were then added to the cells and incubated at 37°C in 5% CO₂ for 48 hours. MTT (2 mg / mL) was then added to each well, and the cells were incubated for an additional 4 hours. Then, the liquid in each well was removed and DMSO (150 μL) was added. The absorbance (OD value) at 490 nm was measured using a microplate reader (Biotek, SYNERGY HTX, VT, USA). Each experiment was repeated three times. The results are shown in Table 2.

[0118] Table 2: IC values ​​of olaparib and NSAIDs co-amorphously 50 result

[0119]

[0120] The co-amorphous form of olaparib and non-steroidal anti-inflammatory drugs provided by the present invention can be used to prepare drugs for preventing and / or treating cancer, and has broad application prospects.

[0121] The above embodiments merely illustrate several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, and all such variations and improvements fall within the scope of protection of the present invention.

Claims

1. A co-amorphous material containing olaparib, characterized in that: The co-amorphous material is formed by combining olaparib with a non-steroidal anti-inflammatory drug; the non-steroidal anti-inflammatory drug in the co-amorphous material is component A, component B, component C, component D or component E; component A is diclofenac; component B is ibuprofen; component C is flurbiprofen; component D is ketoprofen; and component E is indomethacin; the molar ratio of olaparib to the non-steroidal anti-inflammatory drug is 1:1; The co-amorphous material has the X-ray powder diffraction pattern shown in Figure 2f, wherein component A is the OLA-DIC co-amorphous material shown in the figure, component B is the OLA-IBU co-amorphous material shown in the figure, component C is the OLA-FLU co-amorphous material shown in the figure, component D is the OLA-KET co-amorphous material shown in the figure, and component E is the OLA-IND co-amorphous material shown in the figure.

2. The co-amorphous material containing olaparib according to claim 1, characterized in that: When the co-amorphous compound is formed by combining olaparib and diclofenac, the infrared absorption spectrum of the co-amorphous compound measured by KBr tablet is 3417.17 cm -l 、3008.67cm -l 、2901.03cm -l 、1714.71cm -l 、1638.34cm -l 、1495.94cm -l 、1451.88cm -l 、1354.88cm -l 、1285.55cm -l 、1225.97cm -l 、1171.43cm -l 、1117.60cm -l 、1092.15cm -l 、1011.43cm -l 、834.79cm -l 、773.47cm -l There is an absorption peak at , and the glass transition temperature of the co-amorphous compound is 64.5℃; When the co-amorphous material is formed by combining olaparib and ibuprofen, the infrared absorption spectrum of the co-amorphous material measured by KBr tablet is 3418.73 cm -l 、3183.89cm -l 、3008.40cm -l 、2954.49cm -l 、2827.49cm -l 、1730.26cm -l 、1639.57cm -l 、1465.90cm -l 、1436.72cm -l 、1354.77cm -l 、1284.43cm -l 、1225.74cm -l 、1172.13cm -l 、1117.28cm -l 、1011.29cm -l 、789.51cm -l 、772.35cm -l There is an absorption peak at , and the glass transition temperature of the co-amorphous compound is 57.3℃; When the co-amorphous material is formed by combining olaparib and flurbiprofen, the infrared absorption spectrum of the co-amorphous material measured by KBr tablet is 3178.34 cm -l 、3007.99cm -l 、2930.00cm -l 、1729.06cm -l 、1639.20cm -l 、1484.25cm -l 、1465.95cm -l 、1436.44cm -l 、1354.81cm -l 、1284.89cm -l 、1225.70cm -l 、1131.74cm -l 、1085.74cm -l 、1011.24cm -l 、925.85cm -l 、871.38cm -l 、838.38cm -l 、790.59cm -l 、768.72cm -l 、723.42cm -l 、698.78cm -l There is an absorption peak at , and the glass transition temperature of the co-amorphous compound is 59.0℃; When the co-amorphous compound is formed by combining olaparib and ketoprofen, the infrared absorption spectrum of the co-amorphous compound measured by KBr pellet is 3417.40 cm -l 、3188.15cm -l 、3005.90cm -l 、2928.28cm -l 、1729.73cm -l 、1639.55cm -l 、1465.46cm -l 、1436.04cm -l 、1354.61cm -l 、1318.58cm -l 、1283.07cm -l 、1224.95cm -l 、1177.09cm -l 、1083.87cm -l 、1010.81cm -l 、805.07cm -l 、789.22cm -l 、770.70cm -l 、721.08cm -l 、701.73cm -l 、642.07cm -l There is an absorption peak at , and the glass transition temperature of the co-amorphous compound is 58.0℃; When the co-amorphous compound is formed by combining olaparib and indomethacin, the infrared absorption spectrum of the co-amorphous compound measured by KBr pellet is 3418.66 cm -l 、3005.90cm -l 、2927.55cm -l 、1638.81cm -l 、1477.52cm -l 、1436.66cm -l 、1356.32cm -l 、1323.99cm -l 、1288.95cm -l 、1224.52cm -l 、1174.83cm -l 、1147.52cm -l 、1174.83cm -l 、1088.11cm -l 、1067.52cm -l 、1035.44cm -l 、1012.37cm -l 、836.67cm -l 、804.00cm -l 、770.21cm -l 、754.78cm -l There is an absorption peak at , and the glass transition temperature of the co-amorphous compound is 74.4 °C.

3. A method for preparing a co-amorphous material containing olaparib according to any one of claims 1 to 2, characterized in that: The specific steps are as follows: dissolving olaparib and any one of component A, component B, component C, component D, and component E in an organic solvent according to a ratio, and then performing reduced pressure rotary evaporation and drying to prepare a co-amorphous material; the temperature of the reduced pressure rotary evaporation is 40-60° C.; specifically as follows: Preparation of co-amorphous OLA-DIC of olaparib and diclofenac; Weigh 1 mmol (434.46 mg) of olaparib (OLA) and 1 mmol (296.15 mg) of diclofenac (DIC), mix them in a 1:1 molar ratio in a round-bottom flask, add 12 ml of methanol, and slowly stir for 30 minutes in a 60°C water bath until the mixture becomes clear. Then, remove the organic solvent methanol by rotary evaporation under reduced pressure to obtain a co-amorphous OLA-DIC of olaparib and diclofenac, which is then dried in vacuo at 35°C for 24 hours to obtain a white solid powder. Preparation of olaparib and indomethacin co-amorphous OLA-IND; Weigh 1 mmol (434.46 mg) of olaparib (OLA) and 1 mmol (357.79 mg) of indomethacin (IND), mix them in a round-bottom flask at a molar ratio of 1:1, add 12 ml of methanol, and slowly stir for 30 minutes in a water bath at 60°C until the mixture becomes clear. Then, remove the organic solvent methanol by rotary evaporation under reduced pressure to obtain a co-amorphous form of olaparib and indomethacin (OLA-IND), which is then dried in vacuo at 35°C for 24 hours to obtain a yellow solid powder. Preparation of olaparib and flurbiprofen co-amorphous OLA-FLU; Weigh 1 mmol (434.46 mg) of olaparib OLA and 1 mmol (244.26 mg) of flurbiprofen FLU, mix them in a round-bottom flask at a molar ratio of 1:1, add 12 ml of methanol, and slowly stir for 30 minutes in a water bath at 60°C until clear. Then, remove the organic solvent methanol by rotary evaporation under reduced pressure to obtain a co-amorphous form of olaparib and flurbiprofen OLA-FLU, which is then dried in vacuo at 35°C for 24 hours to obtain a white solid powder. Preparation of Olaparib and ketoprofen co-amorphous OLA-KET; Weigh 1 mmol (434.46 mg) of olaparib (OLA) and 1 mmol (254.28 mg) of ketoprofen (KET), mix them in a round-bottom flask at a molar ratio of 1:1, add 12 ml of methanol, and slowly stir for 30 minutes in a water bath at 60°C until the mixture becomes clear. Then, remove the organic solvent methanol by rotary evaporation under reduced pressure to obtain a co-amorphous form of olaparib and ketoprofen (OLA-KET), which is then dried in vacuo at 35°C for 24 hours to obtain a white solid powder. Preparation of Olaparib and ibuprofen co-amorphous OLA-IBU; Weigh 1 mmol (434.46 mg) of olaparib OLA and 1 mmol (206.28 mg) of ibuprofen IBU, mix them in a round-bottom flask at a molar ratio of 1:1, add 12 ml of methanol, and slowly stir for 30 minutes in a water bath at 60°C until clear. Then, remove the organic solvent methanol by rotary evaporation under reduced pressure to obtain amorphous OLA-IBU of olaparib and ibuprofen, which is then dried in vacuo at 35°C for 24 hours to obtain a white solid powder.

4. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the co-amorphous material containing olaparib according to any one of claims 1 to 2, and further comprises a pharmaceutically acceptable carrier.

5. Use of the co-amorphous material containing olaparib according to any one of claims 1 to 2 or the pharmaceutical composition according to claim 4 in the preparation of a medicament for treating a disease, characterized in that: The disease is advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

6. A method for preparing a medicament for treating advanced epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, or recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, characterized in that: The drug comprises an effective dose of the olaparib-containing co-amorphous compound selected from any one of claims 1-2 or the pharmaceutical composition according to claim 4 in combination with other anti-tumor drugs.

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