Camptothecin and citric acid eutectic crystal, preparation method, composition and application thereof

Abstract

The invention belongs to the technical field of medicine. The invention discloses a camptothecin and citric acid eutectic crystal, a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention discloses a solid substance state of the camptothecin and citric acid eutectic substance. A preparation method of a camptothecin and citric acid eutectic solid substance sample; the invention relates to application of a camptothecin and citric acid eutectic substance as an active ingredient in preparation of medicines for treating malignant tumors and psoriasis. Camptothecin and citric acid eutectic molecular structural formula

Description

Technical Field

[0001] The present invention discloses a camptothecin-citric acid cocrystal, a preparation method, and a composition and use thereof. Specifically, the present invention discloses a cocrystal formed from camptothecin and citric acid; a preparation method for the camptothecin-citric acid cocrystal; and the use of the camptothecin-citric acid cocrystal as a pharmaceutical active ingredient in the preparation of a drug for treating malignant tumors and psoriasis, belonging to the field of pharmaceutical technology. Background Art

[0002] A pharmaceutical cocrystal is a crystalline substance formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) in a fixed stoichiometric ratio within the same crystal lattice, bound together by weak non-covalent bonds such as hydrogen bonds, π-π stacking, van der Waals forces, and halogen bonds. By forming a cocrystal with a suitable ligand, a drug can, on the one hand, significantly improve the physicochemical properties and clinical efficacy of APIs with poor water solubility, low bioavailability, and poor stability without changing the API's chemical structure, and on the other hand, provide secondary patent protection. For generic drugs, the study of pharmaceutical cocrystals can break the original drug's crystal form patent and enhance the market competitiveness of generic drugs.

[0003] The present invention uses camptothecin as the active substance, whose chemical name is (S)-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione, and its molecular formula is C 20 H 16 N2O4 is a light yellow powder. Its structural formula is shown in a. The organic acid used in the invention is citric acid, with a molecular formula of C6H8O7 and a structural formula shown in b.

[0004]

[0005] Camptothecin is a quinoline alkaloid antitumor drug with limited efficacy against malignancies such as gastrointestinal tumors, bladder cancer, liver cancer, and leukemia. Its cellular target is DNA topoisomerase I (Top1). It stabilizes the covalent complex between Top1 and DNA, disrupting the normal function of topoisomerase II, forming a ternary dissociable complex that affects DNA replication. Camptothecin is primarily sensitive to proliferating cells, arresting the cell cycle in the S and G2 phases, making it a cell cycle-specific drug. Currently, camptothecin is primarily available as an oral tablet or injection, which has drawbacks such as poor water solubility, low bioavailability, and significant toxicity.

[0006] Through domestic and foreign patent and literature searches, no other co-crystal patents or literature reports on camptothecin were found.

[0007] The present invention has discovered a solid material state and preparation method of a camptothecin and citric acid eutectic that is different from the contents reported in the above patents or literature studies.

[0008] The research objective of the present invention is to start from the study of the existence state of the solid substance of camptothecin, and through co-crystal screening technology, to find and discover the existence type and state characteristics of the solid substance of camptothecin co-crystal at the level of the active ingredient raw material of the drug, so as to provide basic scientific data for the medicinal co-crystal solid substance of camptothecin; at the same time, it also provides a scientific basis for applying for national or international intellectual property invention patent protection based on the camptothecin co-crystal solid pharmaceutical raw material. Summary of the Invention

[0009] The technical problems to be solved by the present invention are:

[0010] One of the technical problems to be solved by the present invention is to provide an existence state and characterization method of a eutectic of camptothecin and citric acid.

[0011] The second technical problem to be solved by the present invention is to provide a method for preparing a eutectic of camptothecin and citric acid.

[0012] The third technical problem to be solved by the present invention is to provide a mixed solid material containing a pure eutectic of camptothecin and citric acid, or a mixed solid material containing a eutectic of camptothecin and citric acid in any non-zero ratio, and a pharmaceutical composition thereof.

[0013] The fourth technical problem to be solved by the present invention is to provide a pharmaceutical composition using a cocrystal of camptothecin and citric acid as the active ingredient, with a pharmaceutical dosage ranging from 1 to 3000 mg. The pharmaceutical composition includes tablets, capsules, pills, injectable preparations, granules, powders, pellets, dropping pills, suppositories, films, patches, aerosols, sprays, sustained-release preparations, or controlled-release preparations.

[0014] The fifth technical problem to be solved by the present invention is to provide a eutectic of camptothecin and citric acid, which has superior properties to camptothecin in terms of solubility.

[0015] The sixth technical problem to be solved by the present invention is to provide a co-crystal of camptothecin and citric acid, which can improve the bioavailability in the body during the treatment of diseases and exert an effective therapeutic effect of the drug due to the co-crystal.

[0016] The seventh technical problem to be solved by the present invention: Application of camptothecin and citric acid cocrystal as an active pharmaceutical ingredient in the preparation of drugs for treating malignant tumors and psoriasis.

[0017] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0018] 1. Sample morphology characteristics of camptothecin and citric acid eutectic:

[0019] 1.1 The camptothecin and citric acid eutectic of the present invention is a eutectic formed by camptothecin and citric acid in a molar ratio of 1:2.

[0020] 1.2 The camptothecin and citric acid eutectic of the present invention is analyzed by powder X-ray diffraction using CuK α Under radiation experimental conditions, diffraction peak position: 2-Theta value (°) or d value Diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) has the following characteristics (Table 1, Figure 1 ); The powder X-ray diffraction pattern and data of the physical mixture of camptothecin and citric acid eutectic are shown in Table 2, Figure 2 The powder X-ray diffraction patterns of the cocrystal of camptothecin and citric acid and the physical mixture of camptothecin and citric acid showed obvious differences in the number of diffraction peaks, diffraction peak positions, diffraction peak intensities, and diffraction peak topology patterns, indicating that the cocrystal of camptothecin and citric acid and the physical mixture of camptothecin and citric acid are neither the same nor identical.

[0021] Table 1 Powder X-ray diffraction peaks of camptothecin and citric acid cocrystal

[0022]

[0023]

[0024] Table 2 Powder X-ray diffraction peaks of physical mixture of camptothecin and citric acid

[0025]

[0026] 1.4 The camptothecin and citric acid eutectic of the present invention was analyzed by attenuated total reflection Fourier transform infrared spectroscopy. The results were as follows: 3532, 3494, 3389, 3283, 3122, 2990, 2927, 2635, 2556, 1740, 1712, 1648, 1615, 1580, 1562, 1549, 1503, 1474, 1443, 1417, 139 1. 1359, 1328, 1307, 1293, 1225, 1161, 1141, 1105, 1082, 1044, 1006, 967, 944, 920, 903, 890, 861, 816, 803, 784, 768, 722, 709, 698, 666, 641, 613, 594, 543, 520, 507, 484, 435cm -1 There is an infrared spectrum characteristic peak at the position where the allowable deviation of the infrared spectrum characteristic peak is ±2cm -1 ( Figure 3 ).

[0027] 1.5 The camptothecin and citric acid cocrystal of the present invention, when analyzed using differential scanning calorimetry, has three endothermic peaks at 150°C ± 3°C, 222°C ± 3°C, and 266°C ± 3°C in the DSC spectrum when the heating rate is 10°C per minute ( Figure 4 The DSC superposition patterns of camptothecin, citric acid and their cocrystals are shown in Figure 5 The DSC spectra of the cocrystal of camptothecin and citric acid were significantly different from those of camptothecin and citric acid in terms of the number and position of endothermic / exothermic peaks, indicating that a new substance was formed between camptothecin and citric acid.

[0028] 2. Characteristics of the preparation method of camptothecin and citric acid eutectic and mixed solid material:

[0029] 2.1 The present invention relates to a method for preparing a eutectic of camptothecin and citric acid, wherein camptothecin and citric acid are added in a molar ratio of 1:2 and a mechanochemical method is used to prepare the eutectic of camptothecin and citric acid by controlling pressure and temperature. The mechanochemical method can be selected from a liquid addition grinding method or a liquid addition ball milling method, wherein the type of organic solvent added is any one or more mixed solvents prepared by combining in different proportions; the organic solvent is selected from any one or more mixed solvents prepared by combining in different proportions of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate and acetone; the amount of liquid added is 5 to 100 ml per gram of sample; the grinding time is 0.1 to 10 hours, the drying temperature is 40 to 60°C, and the drying time is 2 to 10 hours; the comprehensive filling rate of the bowl body in the liquid addition grinding method is 10% to 50%, and the reciprocating motion speed is 20 to 70 m / min; the shear impact energy of the ball mill in the liquid addition ball milling method is 10 kW to 800 kW, and the comprehensive filling rate is 20 to 60%; the ball-to-material ratio is 1:1 to 10:1, preferably 6:1 to 10:1; the ball milling speed is 20 r / min to 400 r / min, preferably 300 r / min to 400 r / min.

[0030] 2.2 The present invention relates to a method for preparing a eutectic of camptothecin and citric acid, comprising adding camptothecin and citric acid in a molar ratio of 1:2 into a clean container, adding an organic solvent to form a suspension, stirring at room temperature for 1 to 4 days at a stirring speed of 100 r / min to 400 r / min, and drying the obtained suspension by solvent evaporation, natural drying by filtration, or vacuum drying by filtration to obtain a eutectic of camptothecin and citric acid. The organic solvent is preferably a mixed solvent prepared by combining any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate, and acetone in different proportions; and maintaining the solid-liquid ratio of the total mass of camptothecin and citric acid to the organic solvent within the range of 10 mg / ml to 200 mg / ml.

[0031] 2.3 The mixed solid material containing the camptothecin and citric acid eutectic of the present invention is obtained by mixing the camptothecin and citric acid eutectic components prepared by the above method with other chemical substances in any non-zero ratio and in a conventional manner.

[0032] 3. Pharmaceutical preparation compositions containing camptothecin and citric acid eutectic components, dosage characteristics, and pharmaceutical uses:

[0033] 3.1 The pharmaceutical composition of the present invention comprises a cocrystal of camptothecin and citric acid and a pharmaceutically acceptable carrier.

[0034] 3.2 The pharmaceutical composition of the present invention comprises a mixed solid substance of camptothecin and citric acid eutectic and a pharmaceutically acceptable carrier.

[0035] 3.3 The pharmaceutical composition of the present invention has a daily dosage of camptothecin in the range of 1 to 3000 mg.

[0036] 3.4 The pharmaceutical composition involved in the present invention is characterized in that the pharmaceutical composition is various tablets, capsules, pills, injection preparations, granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols, sprays, sustained-release preparations or controlled-release preparations.

[0037] 3.5 The present invention relates to the use of a cocrystal of camptothecin and citric acid, a mixed solid substance containing the cocrystal of camptothecin and citric acid, or a pharmaceutical composition in the preparation of drugs for treating malignant tumors and psoriasis.

[0038] The present invention relates to a pharmaceutical composition comprising the camptothecin and citric acid cocrystal of the present invention as the active ingredient. The pharmaceutical composition can be prepared according to methods known in the art. The camptothecin and citric acid cocrystal of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to form any dosage form suitable for human or animal use. The content of the camptothecin and citric acid cocrystal of the present invention in the pharmaceutical composition is in the range of 10% to 90% by weight.

[0039] The camptothecin and citric acid cocrystal of the present invention can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0040] The dosage form of the present invention is preferably a solid dosage form. The solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.

[0041] The camptothecin and citric acid eutectic of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0042] In order to form the camptothecin and citric acid cocrystal of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropyl alcohol, etc.; binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, etc.; lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0043] The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0044] To prepare the dosing unit as a capsule, the active ingredient, camptothecin and citric acid eutectic of the present invention, can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard or soft capsule. Alternatively, the active ingredient, camptothecin and citric acid eutectic of the present invention, can be first prepared into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard or soft capsule. Various diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets of the camptothecin and citric acid eutectic of the present invention can also be used to prepare capsules of the camptothecin and citric acid eutectic of the present invention.

[0045] Furthermore, if necessary, colorants, preservatives, perfumes, flavorings or other additives may be added to the pharmaceutical preparations.

[0046] To achieve the purpose of medication and enhance the therapeutic effect, the drug of the present invention can be administered by any known method of administration.

[0047] The dosage of the pharmaceutical composition of camptothecin and citric acid cocrystal of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. The above dosage can be administered as a single dosage unit or divided into several dosage units, depending on the physician's clinical experience and the dosage regimen including the use of other therapeutic modalities.

[0048] The camptothecin and citric acid cocrystal or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the camptothecin and citric acid cocrystal of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0049] 4. Beneficial technical effects of the present invention: The camptothecin and citric acid cocrystal has advantageous drug-making characteristics in terms of safety, stability and solubility.

[0050] 4.1 The camptothecin and citric acid eutectic of the present invention, according to its DSC spectrum ( Figure 4 ) It can be seen that before the melting endothermic peak of the cocrystal, there is no endothermic peak of loss of crystallization solvent or crystal water, indicating that the cocrystal of camptothecin and citric acid does not contain any crystallization solvent and has good safety advantages for drug development.

[0051] 4.2 Camptothecin is hygroscopic and easily inactivated by hydrolysis. The camptothecin and citric acid eutectic of the present invention can not only remain stable under high temperature and light conditions, but also remain stable under high humidity conditions, and has good stability as a drug ( Figure 6 ).

[0052] 4.3 The camptothecin and citric acid eutectic of the present invention has a solubility advantage, which is specifically reflected in that its solubility in pure aqueous solution at pH 7.0 is significantly better than that of camptothecin ( Figure 7 ). BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 Powder X-ray diffraction pattern of camptothecin and citric acid cocrystal

[0054] Figure 2 Powder X-ray diffraction pattern of physical mixture of camptothecin and citric acid

[0055] Figure 3 Infrared absorption spectrum of camptothecin and citric acid cocrystal

[0056] Figure 4 Differential scanning calorimetry of camptothecin and citric acid cocrystal

[0057] Figure 5 DSC superposition spectra of camptothecin, citric acid and cocrystal of camptothecin and citric acid

[0058] Figure 6 Stability experimental chart of camptothecin and citric acid cocrystal under high temperature, high humidity and light environment

[0059] Figure 7 Comparison of the solubility of camptothecin-citric acid eutectic and camptothecin in pH 7.0 pure aqueous solution DETAILED DESCRIPTION

[0060] In order to better illustrate the technical solutions of the present invention, the following examples are given, but the present invention is not limited thereto.

[0061] Example 1

[0062] Preparation method 1 of camptothecin and citric acid eutectic:

[0063] According to the table below, take appropriate amount of camptothecin and citric acid (molar ratio 1:2) and put them into a mortar, add appropriate amount of organic solvent, grind them manually for appropriate time, and dry them at a certain temperature. Figure 1 The results were consistent, indicating that the obtained sample was a eutectic of camptothecin and citric acid.

[0064] Table 3 Examples of experimental conditions for preparation method 1 of camptothecin and citric acid eutectic

[0065]

[0066] Preparation method 2 of camptothecin and citric acid eutectic:

[0067] According to the table below, take appropriate amount of camptothecin and citric acid (molar ratio 1:2) and put them into a ball mill, add appropriate amount of organic solvent, select appropriate ball-to-material ratio, set appropriate speed, grind for appropriate time, and dry at a certain temperature. Powder X-ray diffraction analysis is performed on it, and its diffraction pattern is the same as Figure 1 The results were consistent, indicating that the obtained sample was a eutectic of camptothecin and citric acid.

[0068] Table 4 Examples of experimental conditions for preparation method 2 of camptothecin and citric acid eutectic

[0069]

[0070] Preparation method 3 of camptothecin and citric acid eutectic:

[0071] As shown in the table below, appropriate amounts of camptothecin and citric acid (molar ratio 1:2) were placed in a clean container, and appropriate amounts of organic solvent were added. The mixture was stirred at room temperature for an appropriate time. The resulting suspension was filtered and the solid matter was dried at a certain temperature. The powder X-ray diffraction analysis was performed on the mixture, and the diffraction pattern was the same as Figure 1 The results were consistent, indicating that the obtained sample was a eutectic of camptothecin and citric acid.

[0072] Table 5 Examples of experimental conditions for preparation method 3 of camptothecin and citric acid eutectic

[0073]

[0074]

[0075] Example 2

[0076] Stability characteristics of camptothecin and citric acid cocrystal:

[0077] Illumination test: 50 mg of camptothecin and citric acid cocrystal was placed under illumination for 5 days and 10 days, and then subjected to powder X-ray diffraction analysis. The diffraction pattern was the same as Figure 1 The results were consistent, indicating that the sample was a eutectic of camptothecin and citric acid, which was stable under light conditions.

[0078] High temperature test: 50 mg of camptothecin and citric acid cocrystal was placed under high temperature conditions for 5 days and 10 days, and the powder X-ray diffraction analysis was performed on it. The diffraction pattern was the same as Figure 1 The results are consistent, indicating that the sample is a eutectic of camptothecin and citric acid, which is stable under high temperature conditions.

[0079] High humidity test: 50 mg of camptothecin and citric acid cocrystal was placed under high humidity conditions for 5 days and 10 days, and the powder X-ray diffraction analysis was performed. The diffraction pattern was the same as Figure 1 The results are consistent, indicating that the sample is a eutectic of camptothecin and citric acid, which is stable under high humidity conditions.

[0080] Stability studies have shown that the cocrystal of camptothecin and citric acid remains stable under high temperature, high humidity and light conditions, and has the advantage of stable drug development.

[0081] Example 3

[0082] Solubility characteristics of camptothecin and citric acid eutectic:

[0083] Camptothecin is a drug with very poor water solubility. Compared with the raw material of camptothecin, the dissolution amount and dissolution rate of camptothecin and citric acid cocrystal in pure water solvent system at pH 7.0 are significantly improved ( Figure 7 ). The solubility determination method was referred to ("Technical Guidelines for Dissolution Test of Ordinary Oral Solid Preparations (Draft)", Drug Review Center, October 2012). High performance liquid chromatography was used to calculate the concentration of the dissolved sample using the chromatographic peak area data of the sample. The solubility curves were drawn with time as the horizontal axis and solvent concentration as the vertical axis. The data are shown in the following table:

[0084] Table 6 Dissolution curve data of camptothecin-citric acid eutectic and camptothecin in pH 7.0 aqueous solution

[0085]

[0086]

[0087] It can be seen from the experimental data that the dissolution behavior of the camptothecin and citric acid cocrystal of this patent in a pH 7.0 aqueous solution is significantly better than that of camptothecin. Specifically, the camptothecin and citric acid cocrystal has a faster dissolution rate and a higher dissolution amount, which is easy to be absorbed more quickly to reach an effective blood drug concentration. The total dissolution amount of the camptothecin and citric acid cocrystal is increased by more than 1.6 times compared with camptothecin, and the dissolution rate of the camptothecin and citric acid cocrystal is increased by about 1.6 times compared with camptothecin, which can better achieve the drug's disease therapeutic effect; the solubility curve of the camptothecin and citric acid cocrystal has a stable release platform, which can ensure a stable blood drug concentration during disease treatment.

[0088] Example 3

[0089] Preparation method 1 of combined pharmaceutical preparation (tablets):

[0090] A method for preparing a combination drug tablet comprises using a camptothecin and citric acid cocrystal and several excipients as auxiliary ingredients for preparing the combination drug tablet, and preparing tablet samples containing 1 to 500 mg of camptothecin and citric acid cocrystal per tablet according to a certain ratio. Table 7 shows the tablet formulation ratio:

[0091] Table 7 Preparation formula of camptothecin and citric acid eutectic tablets

[0092]

[0093] The method for preparing a tablet preparation using a cocrystal of camptothecin and citric acid as a raw material is as follows: several excipients are mixed evenly with the raw material and the tablets are directly compressed; or the excipients are mixed and dry granulated and then mixed evenly with the raw material and the tablets are compressed to obtain the tablet.

[0094] Preparation method 2 of combined pharmaceutical preparation (tablets):

[0095] A method for preparing a combination drug tablet comprises using a cocrystal of camptothecin and citric acid and several excipients as auxiliary ingredients for preparing the combination drug tablet, and preparing tablet samples containing 1 to 500 mg of the cocrystal per tablet according to a certain ratio. Table 8 shows the tablet formulation ratios:

[0096] Table 8 Preparation formula of camptothecin and citric acid eutectic tablets

[0097]

[0098] The method for preparing a tablet preparation using a cocrystal of camptothecin and citric acid as a raw material is as follows: several excipients are uniformly mixed with the raw material, an appropriate amount of 1% sodium hydroxymethylcellulose solution is added to prepare a soft material, sieve and granulate the wet granules, dry the wet granules, sieve and refine the granules, add magnesium stearate and talc powder, mix uniformly, and press into tablets to obtain the tablet preparation.

[0099] Preparation method 3 of combined pharmaceutical preparation (capsules):

[0100] A method for preparing a combination drug capsule is characterized by using a cocrystal of camptothecin and citric acid as the API and several excipients as auxiliary ingredients for preparing the combination drug capsule. The mixture is prepared according to a certain ratio to produce capsule samples with a drug content of 1 to 100 mg per tablet. Table 9 shows the capsule formulation ratios:

[0101] Table 9 API and excipient formulas for capsule preparations of camptothecin and citric acid cocrystal combination

[0102]

[0103] The method for preparing capsules using the camptothecin and citric acid cocrystal as a raw material drug is as follows: several excipients are uniformly mixed with the raw material drug, an appropriate amount of 1% sodium hydroxymethyl cellulose solution is added to prepare wet granules, the wet granules are dried and sieved, magnesium stearate is added, the mixture is uniformly mixed, and the granules are inserted into capsules; or the granulation step is omitted, and the camptothecin and citric acid cocrystal raw material drug is directly mixed with several excipients and auxiliary materials, the mixture is sieved, and the mixture is directly filled into capsules.

[0104] Example 4

[0105] Dosage of the combination drug of camptothecin and citric acid cocrystal 1 (tablet):

[0106] A pharmaceutical composition is developed using a cocrystal of camptothecin and citric acid as the active ingredients of the drug. The composition is characterized in that the cocrystal of camptothecin and citric acid is used as the active ingredients of the drug, with a daily dosage of 20 mg, and can be prepared into two 5 mg ordinary tablets twice a day or one 20 mg tablet once a day.

[0107] Dosage of camptothecin and citric acid cocrystal combination drug 2 (capsule):

[0108] A pharmaceutical composition developed using a cocrystal of camptothecin and citric acid as the active ingredient of the drug is characterized in that a cocrystal of pioglitazone hydrochloride and para-aminosalicylic acid is used as the active ingredient of the drug, with a daily dosage of 100 mg, which can be prepared into one 100 mg capsule once a day or one 50 mg capsule twice a day.

[0109] Issues requiring clarification: The dosage of the active ingredient in the camptothecin and citric acid cocrystal pharmaceutical composition described herein is influenced by numerous factors, such as patient age, body surface area, route of administration, number of doses, and therapeutic objectives, which can lead to variations in each dose. Variations in absorption and blood concentrations between samples also contribute to the suitable dosage range for each dose of the camptothecin and citric acid cocrystal component used in the present invention being 0.02-1 mg / kg body weight, preferably 0.1-0.4 mg / kg body weight. Different total dosage regimens for the active ingredient of the camptothecin and citric acid cocrystal should be formulated based on the actual treatment needs, and can be administered in multiple doses or a single dose.

Claims

1. A camptothecin and citric acid eutectic, characterized in that: Camptothecin and citric acid form a cocrystal at a molar ratio of 1:

2.

2. The camptothecin and citric acid eutectic according to claim 1, characterized in that When using powder X-ray diffraction with CuK α Under radiation experimental conditions, diffraction peak position: 2-Theta value (°) or d value Diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) has the following characteristics:

3. The camptothecin and citric acid eutectic according to claim 1, characterized in that When analyzed by attenuated total reflection Fourier transform infrared spectroscopy, the 8, 1307, 1293, 1225, 1161, 1141, 1105, 1082, 1044, 1006, 967, 944, 920, 903, 890, 8 61, 816, 803, 784, 768, 722, 709, 698, 666, 641, 613, 594, 543, 520, 507, 484, 435cm -1 There is an infrared spectrum characteristic peak at the position where the allowable deviation of the infrared spectrum characteristic peak is ±2cm -1 .

4. The camptothecin and citric acid eutectic according to claim 1, characterized in that When analyzed using differential scanning calorimetry technology, when the heating rate is 10°C per minute, there are three endothermic peaks at 150°C±3°C, 222°C±3°C, and 266°C±3°C in its DSC spectrum.

5. The method for preparing the camptothecin and citric acid eutectic according to any one of claims 1 to 4, characterized in that: Camptothecin and citric acid are added in a molar ratio of 1:2, and a mechanochemical method with controlled pressure and temperature is adopted to prepare a eutectic of camptothecin and citric acid.

6. The preparation method according to claim 5, characterized in that The mechanochemical method can be selected from a liquid addition grinding method or a liquid addition ball milling method, wherein the type of organic solvent added is any one or more mixed solvents prepared by combining in different proportions; the organic solvent is selected from any one or more mixed solvents prepared by combining in different proportions of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate and acetone; the amount of liquid added is 5 to 100 ml per gram of sample; the grinding time is 0.1 to 10 hours, the drying temperature is 40 to 60°C, and the drying time is 2 to 10 hours; the comprehensive filling rate of the bowl body in the liquid addition grinding method is 10% to 50%, and the reciprocating motion speed is 20 to 70 m / min; the shear impact energy of the ball mill in the liquid addition ball milling method is 10 kW to 800 kW, and the comprehensive filling rate is 20 to 60%; the ball-to-material ratio is 1:1 to 10:1, preferably 6:1 to 10:1; the ball milling speed is 20 r / min to 400 r / min, preferably 300 r / min to 400 r / min.

7. The method for preparing the camptothecin and citric acid eutectic according to any one of claims 1 to 4, characterized in that: The suspension method comprises adding camptothecin and citric acid in a molar ratio of 1:2 into a clean container, adding an organic solvent to form a suspension, stirring at room temperature for 1 to 4 days at a speed of 100 r / min to 400 r / min, and drying the obtained suspension by solvent evaporation, natural drying by filtration, or vacuum drying by filtration to obtain a eutectic of camptothecin and citric acid.

8. The method for preparing the camptothecin and citric acid eutectic according to claim 7, wherein: The organic solvent is selected from any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate and acetone, and is prepared as a mixed solvent by combining them in different proportions; the solid-liquid ratio of the total mass of camptothecin and citric acid to the organic solvent is maintained within the range of 10 mg / ml to 200 mg / ml.

9. A mixed solid material containing a eutectic of camptothecin and citric acid, characterized in that: The amount of the camptothecin and citric acid eutectic according to any one of claims 1 to 4 is 1-99.9%, preferably 10-99.9%, more preferably 50-99.9%, and most preferably 85-99.9%.

10. A pharmaceutical composition, characterized in that The invention also comprises an effective dose of the camptothecin and citric acid cocrystal according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition, characterized in that A mixed solid material containing a cocrystal of camptothecin and citric acid according to claim 9 containing an effective dose and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 10 or 11, characterized in that The daily dosage of camptothecin is in the range of 1 to 3000 mg.

13. The pharmaceutical composition according to claim 10 or 11, characterized in that The dosage form of the pharmaceutical composition is tablets, capsules, pills, injection preparations, granules, powders, pellets, dropping pills, suppositories, films, patches, aerosols, sprays, sustained-release preparations or controlled-release preparations.

14. Use of the camptothecin and citric acid eutectic according to any one of claims 1 to 4, or the mixed solid material containing the camptothecin and citric acid eutectic according to claim 9, or the pharmaceutical composition according to claim 10 or 11 in the preparation of a medicament for treating malignant tumors and psoriasis.

Images