CN115124419B - Rhein and cytisine eutectic crystal, preparation method, composition and application thereof - Google Patents
Rhein and cytisine eutectic crystal, preparation method, composition and application thereof Download PDFInfo
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- CN115124419B CN115124419B CN202110317195.2A CN202110317195A CN115124419B CN 115124419 B CN115124419 B CN 115124419B CN 202110317195 A CN202110317195 A CN 202110317195A CN 115124419 B CN115124419 B CN 115124419B
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- rhein
- cytisine
- crystal
- eutectic
- cocrystal
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C66/00—Quinone carboxylic acids
- C07C66/02—Anthraquinone carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/24—Anthracenes; Hydrogenated anthracenes
Abstract
The invention discloses a rhein and cytisine eutectic compound, a preparation method, a composition and application thereof. Belongs to the technical field of medicines. Specifically, the invention discloses a rhein and cytisine eutectic substance which takes a lead compound rhein as a medicinal active ingredient and cytisine as a eutectic substance ligand; a preparation method of rhein and cytisine eutectic; the use of cocrystal of rhein and cytisine as pharmaceutical active ingredients in preparing anti-inflammatory, anti-infectious and anti-osteoarthritis medicines is provided.
Description
Technical Field
The invention discloses a rhein and cytisine eutectic compound, a preparation method, a composition and application thereof; specifically, the invention discloses a eutectic substance formed by rhein and cytisine; a preparation method of rhein and cytisine eutectic; pharmaceutical compositions comprising a co-crystal of rhein and cytisine or a solid mixture comprising any non-zero ratio of rhein to cytisine; the application of rhein and cytisine eutectic as the effective components in preparing medicine for treating inflammation, infection, osteoarthritis, etc belongs to the field of medicine technology.
Background
Rhein belongs to anthraquinone compounds, and has wide pharmacological activities of inhibiting tumor cell metabolism and proliferation, resisting bacteria and inflammation, regulating blood lipid, inhibiting immunity, etc. However, the use of the water-soluble polymer has not been successfully applied to clinic until now because of extremely poor water solubility. Therefore, the improvement of rhein water solubility is of great significance. Chinese patent CN102603575a reports the preparation method, purification method and application of rhein and arginine cocrystal (rhein) in preparing medicine for treating diabetic complications [1] The method comprises the steps of carrying out a first treatment on the surface of the Chinese patent CN10255121a reports the preparation process of rhein and lysine cocrystal (lys rhein) and its application in tumor treatment [2] . In addition, other co-crystal reports of rhein have not been found so far.
The invention takes Rhein (Rhein) as active substance, the chemical name of the Rhein is 1, 8-dihydroxyl-3-carboxyanthraquinone, and the molecular formula is C 15 H 8 O 6 The structural formula is shown as formula a; uses cytisine (Aloperine) as eutectic substance, and has molecular formula of C 11 H 14 N 2 O has a structural formula shown in a formula b, and a rhein and cytisine eutectic substance and a preparation method thereof are found through a pharmaceutical eutectic screening technology, and compared with rhein bulk drugs, the rhein and cytisine eutectic substance has obviously improved solubility. In addition, the water solubility of rhein and eusine co-crystals is better than that of the reported rhein arginine co-crystals.
Disclosure of Invention
The invention aims to solve the technical problems:
the invention provides a state and a characterization mode of a cocrystal of rhein and cytisine.
The second technical problem to be solved by the invention is: provides a preparation method of a cocrystal of rhein and cytisine.
The third technical problem to be solved by the invention is: provided are a mixed solid substance containing pure cocrystal of rhein and cytisine, or cocrystal of rhein and cytisine in any non-zero ratio, and a pharmaceutical composition thereof.
The invention aims to solve the fourth technical problem: pharmaceutical compositions using co-crystals of rhein and cytisine as pharmaceutically active ingredients are provided in an amount ranging from 0.5 to 300mg per administration. The pharmaceutical composition comprises bone joint cavity injection, tablets, capsules, pills, injection and slow-release or controlled-release preparation medicines.
The invention solves the technical problems: compared with rhein and cytisine eutectic substances, the rhein and cytisine eutectic substances have the advantage of better solubility compared with rhein raw materials.
The invention solves the technical problems: rhein and cytisine have therapeutic effects due to the formation of eutectic substances in treating diseases, thereby increasing blood concentration in vivo.
The invention solves the technical problems: the rhein and cytisine eutectic is used as the effective component in preparing medicine for treating inflammation, infection, osteoarthritis, etc.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. rhein and cytisine eutectic sample morphological characteristics:
1.1A cocrystal of rhein and cytisine according to the present invention is characterized in that a cocrystal of rhein and cytisine is formed at a molar ratio of 1:1.
1.2 Co-crystals of rhein and Caragana according to the present invention, cuK was used when powder X-ray diffraction analysis was used α Diffraction peak position under radiation experimental conditions: diffraction peak position: 2-Theta (°) value orValue, diffraction peak relative intensity: peak height value [ ]Height%) or peak Area value (Area%) has the following expression (table 1, fig. 1). Powder X-ray diffraction patterns and data of physical mixtures of rhein and cytisine are shown in Table 2 and FIG. 2. The powder X-ray diffraction patterns of the cocrystal of rhein and cytisine and the physical mixture of rhein and cytisine have obvious differences in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topological pattern and the like, which indicates that the cocrystal of rhein and cytisine and the physical mixture of rhein and cytisine are neither identical nor equivalent.
TABLE 1X-ray diffraction peak of rhein and cytisine eutectic powder
TABLE 2 powder X-ray diffraction peak of physical mixture of rhein and cytisine
。
1.3 Co-crystals of rhein and cytisine according to the present invention were analyzed by attenuated total reflection Fourier IR spectroscopy at 3666, 3428, 3292, 2968, 2813, 2632, 2382, 1994, 1671, 1648, 1625, 1592, 1548, 1472, 1449, 1410, 1366, 1348, 1298, 1276, 1260, 1210, 1155, 1119, 1102, 1079, 1069, 1047, 1018, 1005, 979, 953, 900, 884, 866, 840, 820, 797, 775, 751, 731, 671, 658cm -1 There is an infrared spectrum characteristic peak (FIG. 3), wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 。
1.4 the rhein and cytisine eutectic crystal according to the present invention is characterized in that when analyzed by differential scanning calorimetry, 1 endothermic peak exists at 141 ℃ + -3 ℃ in the DSC spectrum at a temperature rising rate of 10 ℃/min in the range of 30 to 180 ℃ (FIG. 4). The DSC superposition diagram of rhein, cytisine and the eutectics of rhein and cytisine is shown in fig. 5, and the obvious difference between the eutectics of rhein and cytisine and rhein and the eutectics of rhein and cytisine in the aspects of the number and the positions of endothermic peaks and the like can be seen from fig. 5, so that the rhein and the cytisine form the eutectics.
2. The preparation method of rhein and cytisine eutectic and mixed solid substances is characterized in that:
2.1 the invention relates to a preparation method of rhein and cytisine eutectic, which is characterized in that the method adopts a liquid adding grinding method, the rhein and the cytisine are added according to a molar ratio of 1:1, and the addition amount of a solvent is 0.5-50 ml per gram of sample; grinding time is 0.05-10 h, drying temperature is 80-100 ℃, and drying time is 0.5-1 h; the comprehensive filling rate of the bowl body by the liquid adding grinding method is 10-50%, and the reciprocating speed is 20-70 m/min; the shearing impact energy of the ball mill by the liquid adding ball milling method is 10 kw-800 kw, and the comprehensive filling rate is 20-60%; the ball-material ratio is 1:1-10:1, preferably 6:1-10:1; the ball milling rotating speed is 20 r/min-400 r/min.
2.2 the method for preparing the eutectics of rhein and cytisine is characterized in that a suspension method is adopted, rhein is added into a reaction vessel, an organic solvent is added according to the proportion of 10-500 mg/mL of solid-to-liquid ratio, the mixture is stirred uniformly at the temperature of 25-30 ℃, then the cytisine with a certain molar ratio is slowly added into the reaction vessel, and the stirring speed is 100-1000 r/min while stirring until the bright yellow solution is completely changed into reddish brown. The stirring time is 24-72 h. Filtering the suspension, and drying the filter cake in an oven at 80-100 ℃ for 0.5-1 h to obtain rhein and cytisine eutectic.
2.3 the mixed solid matter of the rhein and cytisine eutectic substance, which is prepared by the method, is prepared by mixing rhein and cytisine eutectic substance components obtained by the method and other chemical substances according to any non-zero proportion and a conventional method.
3. Pharmaceutical formulation composition containing rhein co-crystal component, dosing characteristics and pharmaceutical use:
3.1 the pharmaceutical composition of the invention comprises a co-crystal of rhein and cytisine and a pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition of the invention comprises mixed solid matter of rhein and eulexine eutectic substance and pharmaceutically acceptable carrier.
3.3 the pharmaceutical composition related by the invention has the daily dosage of rhein within the range of 0.5-300 mg.
3.4 the pharmaceutical composition is characterized in that the pharmaceutical composition is bone joint cavity injection, tablet, capsule, pill, injection, sustained release preparation or controlled release preparation.
3.5 the use of the cocrystal of rhein and cytisine, the mixed solid or the pharmaceutical composition of the cocrystal of rhein and cytisine in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other drugs.
The invention relates to a pharmaceutical composition which takes the cocrystal of rhein and cytisine as active ingredients. The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use may be formulated by combining the rhein and cytisine co-crystals of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the mixed solid of the rhein and the eutectine eutectic compound in the pharmaceutical composition is in the range of 10-90% by weight.
The rhein and cytisine eutectic mixture and the mixed solid of rhein and cytisine eutectic mixture can be administered in unit dosage form, and the administration route can be oral administration, bone joint cavity injection, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs, respiratory tract, skin, vagina, rectum and the like.
The administration form of the present invention is preferably a solid preparation and an osteoarticular cavity injection form. The solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and spray.
The mixed solid of rhein and cytisine eutectic can be prepared into common preparations, slow-release preparations, controlled-release preparations, targeted preparations and various particle administration systems.
For the preparation of the rhein and cytisine co-crystals and the mixed solid of rhein and cytisine co-crystals into tablets, various excipients known in the art, including diluents, binders, wetting agents, disintegrants, lubricants and glidants, can be widely used. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
In order to make the administration unit into capsule, the active ingredient rhein and eutectics of cytisine are mixed with diluent and glidant, and the mixture is directly placed into hard capsule or soft capsule. Or mixing the active ingredients of rhein and cytisine cocrystal with diluent, binder, and disintegrating agent, granulating or making into pellet, and making into hard capsule or soft capsule. Various diluents, binders, wetting agents, disintegrants and glidants used for preparing the rhein and cytisine eutectic tablet of the invention can also be used for preparing the capsule of the rhein and cytisine eutectic mixed solid of the invention.
In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The administration amount of the pharmaceutical composition of rhein and cytisine cocrystal of the present invention may 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 administration route and dosage form, etc. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.
The rhein and cytisine cocrystal or composition of the invention can be taken alone or combined with other therapeutic drugs or symptomatic drugs. When the rhein and the eutectics of the cytisine and other therapeutic drugs have synergistic effect, the dosage of the rhein and the eutectics of the cytisine and other therapeutic drugs is adjusted according to actual conditions.
4. The beneficial technical effects of the invention are as follows: safety and solubility characteristic advantages of rhein and cytisine eutectic
4.1 the rhein and cytisine eutectic of the invention does not contain any crystallization solvent, and has the advantage of good safety patent medicine.
4.2 the rhein and cytisine eutectic has the pharmacological activity of rhein, and the rhein and cytisine eutectic has greatly improved solubility and far superior rhein. In addition, the water solubility of rhein and eusine co-crystals was better than that of the reported rhein arginine co-crystals, and unexpected technical effects were obtained (fig. 6).
Drawings
FIG. 1 powder X-ray diffraction pattern of rhein and cytisine co-crystals
FIG. 2 powder X-ray diffraction pattern of physical mixture of rhein and cytisine
FIG. 3 is an infrared absorption spectrum of a co-crystal of rhein and cytisine
FIG. 4 differential scanning calorimetric diagram of rhein and cytisine co-crystals
FIG. 5 differential scanning calorimetric comparison pattern of rhein, cytisine and co-crystals of rhein and cytisine
FIG. 6 solubility curves of rhein and eulexine co-crystals, rhein and arginine co-crystals and rhein
Detailed Description
The following examples are given for better illustration of the technical solution of the present invention, but the present invention is not limited thereto.
Example 1
Preparation method 1 of rhein and cytisine eutectic crystal:
weighing rhein and cytisine samples with the molar ratio of 1:1, putting the rhein and the cytisine samples into a mortar, adding a proper amount of organic solvent, grinding for a certain time, grinding until the solvent is volatilized, drying the mixture in an oven at 80-100 ℃ for a certain time, and carrying out powder X-ray diffraction analysis on the mixture, wherein the diffraction pattern of the mixture is consistent with that of figure 1, wherein the obtained sample is the rhein and cytisine eutectic. As shown in table 3:
preparation method 2 of rhein and cytisine eutectic compound:
weighing rhein and cytisine samples with the molar ratio of 1:1, putting the rhein and the cytisine samples into a ball milling tank, adding a proper amount of organic solvent, selecting a proper ball-material ratio, setting a proper rotating speed, grinding for a proper time, and drying in an oven at 80-100 ℃ for a certain time. Powder X-ray diffraction analysis is carried out on the sample, the diffraction pattern of the sample is consistent with that of figure 1, and the obtained sample is the rhein and cytisine eutectic. As shown in table 4:
preparation method 3 of rhein and cytisine eutectic compound:
weighing a proper amount of rhein, putting the rhein into a clean container, adding a proper amount of organic solvent, stirring uniformly at 25-30 ℃, slowly adding cytisine with a molar ratio of 1:1.5 into a reaction bottle, filtering the obtained suspension, and drying a filter cake in an oven at 80-100 ℃. Powder X-ray diffraction analysis is carried out on the sample, the diffraction pattern of the sample is consistent with that of figure 1, and the obtained sample is the rhein and cytisine eutectic. As shown in table 5:
example 2
The solubility characteristics of rhein, rhein and eutectics of cytisine, rhein and arginine (rhein) in pure water systems were examined. And (3) determining by referring to a general oral solid preparation dissolution test technical guidelines, comparing dissolution curves by adopting a model independent similarity factor (f 2) method, and comparing the similarity of dissolution curves in different solvent systems of rhein and cytisine eutectic, rhein and arginine eutectic (rhein) and rhein bulk drugs by calculating f2 values. The experiment uses rhein bulk drug as reference, and calculates model independent similarity factor f2 value. And (3) measuring the rhein content at the wavelength of 254nm by adopting a high performance liquid phase method, and calculating the dissolution amount by using an external standard method. Dissolution curves were drawn with time on the abscissa and percent dissolution on the ordinate, respectively (fig. 6). The data are shown in table 6:
TABLE 6 dissolution profile data of rhein co-crystals and rhein in pure water
Compared with rhein raw materials, the dissolution rate of the rhein and cytisine eutectic in a pure water system is improved by about 50 times, the dissolution rate is obviously improved, the rhein and cytisine eutectic is easy to be absorbed more quickly to achieve effective blood concentration, and the disease treatment effect of the medicine can be better realized.
In addition, the water solubility of rhein and cytisine co-crystals was improved by about 8-fold compared to the already reported rhein and arginine co-crystals (fig. 6). Therefore, the preparation process of the rhein and cytisine eutectic compound adopted by the invention well improves the technical problem of poor rhein water solubility, has simple production process, is beneficial to mass production, and provides technical support for subsequent research and development of rhein.
Example 3
Preparation method of combination pharmaceutical formulation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that a co-crystal of rhein and cytisine or a mixed solid substance containing the co-crystal of rhein and cytisine in any proportion is used as a raw material medicine of the combined medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, a tablet sample with the drug content of 0.5-150 mg of each tablet is prepared according to a certain proportion, and the formula proportion of the tablet is shown in table 7:
table 7 preparation formulation of pharmaceutical tablet of co-crystal of rhein and cytisine
The method for preparing the tablet preparation by taking the rhein and the eutectics of the cytisine as the raw material medicines comprises the following steps: mixing several excipients and raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into soft material, sieving, granulating, oven drying, sieving, granulating, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Preparation method 2 (capsule) of the combined pharmaceutical preparation:
a preparation method of a combination medicine capsule is characterized in that a rhein and cytisine eutectic substance or a mixed solid substance containing rhein and cytisine eutectic substance in any proportion is used as a raw material medicine of the combination medicine, a plurality of excipients are used as auxiliary material components for preparing the combination medicine capsule, a capsule sample with the drug content of 0.5-150 mg per tablet is prepared according to a certain proportion, and the formula proportion of the capsule is shown in table 8:
table 8 pharmaceutical raw material and auxiliary material formulation of rhein and cytisine eutectic compound pharmaceutical capsule preparation
The method for preparing the rhein and cytisine eutectic compound into the tablet preparation comprises the following steps: mixing several excipients with the raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into wet granule, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing rhein and cytisine eutectic substance with excipient adjuvants, sieving, and directly encapsulating.
Example 4
Dosage 1 (tablet) of rhein and cytisine co-crystal combination drug:
the pharmaceutical composition is prepared and developed by using a sample of the cocrystal of rhein and cytisine as the active ingredients, and is characterized in that the cocrystal of rhein and cytisine is used as the active ingredients of the medicine, and the daily administration dosage is 100mg, and the cocrystal of rhein and cytisine can be prepared into 50mg common tablets for 2 times per time per 1 tablet or 100mg tablets for 1 time per 1 tablet respectively.
Dosage of administration of rhein and cytisine cocrystal combination drug 2 (capsule):
the pharmaceutical composition is prepared and developed by using a sample of the cocrystal of rhein and cytisine as the active ingredients, and is characterized in that the cocrystal of rhein and cytisine is used as the active ingredients of the medicine, the daily administration dosage is 150mg, and the cocrystal of rhein and cytisine can be prepared into common tablets of 50mg for 3 times a day/1 granule/time or capsules of 150mg for 1 time a day/time.
Problems to be described: the pharmaceutical composition of rhein and cytisine cocrystal substance disclosed by the invention has a plurality of factors on the administration dosage of the active ingredients, such as: the age and body surface area of patients are different, and the dosage of each administration is different due to the different administration routes, administration times and treatment purposes; the presence of absorption and blood concentration differences between the rhein and cytisine co-crystals samples also results in the present invention at a suitable dosage range of 0.01-5mg/kg body weight, preferably 0.02-3mg/kg body weight, per time when the rhein and cytisine co-crystals components are used. When in use, different total dosage schemes of active ingredients of the cocrystal of rhein and cytisine are formulated according to the actual requirements of different treatment conditions, and the cocrystal of rhein and cytisine can be completed in a mode of multiple times or one time of administration.
Reference to the literature
1. Chinese patent CN102603575a.
2. Chinese patent CN10255121a.
Claims (13)
1. A co-crystal of rhein and cytisine, wherein the co-crystal is formed by rhein and cytisine in a molar ratio of 1:1.
2. The co-crystal of rhein and cytisine according to claim 1, wherein CuK is employed when powder X-ray diffraction analysis is used α Diffraction peak position under radiation experimental conditions: 2-Theta (°),Diffraction peak relative intensity: peak Height value (Height%), peak Area value (Area%) has the following characteristics:
。
3. the co-crystal of rhein and cytisine according to claim 1, wherein when analyzed using attenuated total reflectance fourier infrared spectroscopy, the co-crystal is characterized by the steps of 3666, 3428, 3292, 2968, 2813, 2632, 2382, 1994, 1671, 1648, 1625, 1592, 1548, 1472, 1449, 1410, 1366, 1348, 1298,1276、1260、1210、1155、1119、1102、1079、1069、1047、1018、1005、979、953、900、884、866、840、820、797、775、751、731、671、658cm -1 There is an infrared spectrum characteristic peak, wherein the deviation of the infrared spectrum characteristic peak is + -2 cm -1 。
4. The co-crystal of rhein and cytisine according to claim 1, wherein the co-crystal is characterized by having 1 endothermic peak at 141 ℃ ± 5 ℃ in a DSC profile when analyzed by differential scanning calorimetry at a temperature ranging from 30 ℃ to 180 ℃ and a heating rate of 10 ℃/min.
5. The method for preparing the rhein-cytisine eutectic substance according to any one of claims 1-4, which is characterized in that a liquid adding grinding method or a liquid adding ball milling method is adopted, a proper amount of organic solvent is added according to the mole ratio of rhein to cytisine, and then the mixture is continuously ground until the solvent is volatilized, and the rhein-cytisine eutectic substance is obtained through drying in a high-temperature oven at 80-100 ℃, wherein the organic solvent is selected from any one single solvent of methanol, ethanol, ethyl acetate, acetonitrile and acetone or a mixed solvent prepared by combining a plurality of solvents in different proportions; the addition amount of the solvent is 0.5-50 ml per gram of sample; grinding time is 0.05-10 hours, drying temperature is 80-100 ℃, and drying time is 0.5-1 hour; the comprehensive filling rate of the bowl body by the liquid adding grinding method is 10-50%, and the reciprocating speed is 20-70 m/min; the shearing impact energy of the ball mill by the liquid adding ball milling method is 10 kw-800 kw, and the comprehensive filling rate is 20-60%; the ball-material ratio is 1:1-10:1; the ball milling rotating speed is 20 r/min-400 r/min.
6. The method for preparing rhein and cytisine eutectic substance according to any one of claims 1-4, characterized in that a suspension method is adopted, rhein is added into a reaction container, an organic solvent is added according to the proportion of 10-500 mg/mL of solid-to-liquid ratio, the mixture is stirred uniformly at the temperature of 25-30 ℃, then, the cytisine with a certain molar ratio is slowly added into the reaction bottle, the mixture is stirred while the mixture is being added, the stirring speed is 100 r/min-1000 r/min until the bright yellow solution is completely changed into reddish brown, the obtained suspension is filtered after the stirring is continued for 24-72 h, a filter cake is put into an oven at the temperature of 80-100 ℃ and dried for 0.5-1 h, and the rhein and cytisine eutectic substance is obtained, wherein the organic solvent is any one single solvent or a mixed solvent of a plurality of solvents prepared by different proportions; the mol ratio of rhein to cytisine is 1:1-1:1.5.
7. A mixed solid material comprising a cocrystal of rhein and cytisine, wherein the cocrystal of rhein and cytisine according to any one of claims 1 to 4 is contained in an amount of 1 to 99.9%.
8. A mixed solid material comprising a cocrystal of rhein and cytisine, wherein the cocrystal of rhein and cytisine according to any one of claims 1 to 4 is contained in an amount of 50 to 99.9%.
9. A mixed solid material comprising a co-crystal of rhein and cytisine, wherein the content of the co-crystal of rhein and cytisine according to any one of claims 1 to 4 is 85 to 99.9%.
10. A pharmaceutical composition comprising an effective amount of a co-crystal of rhein and cytisine according to any one of claims 1-4 and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising an effective amount of the co-crystal mixture of rhein and cytisine in accordance with any one of claims 7-9 and a pharmaceutically acceptable carrier.
12. Pharmaceutical composition according to any of claims 10 or 11, characterized in that the pharmaceutical composition is in the form of an osteoarticular cavity injection, an injection, a tablet, a capsule, a powder, a slow release formulation or a controlled release formulation.
13. Use of a co-crystal of rhein and cytisine according to any one of claims 1-4 or a mixed solid substance comprising a co-crystal of rhein and cytisine according to any one of claims 7-9 or a combination according to any one of claims 10 or 11 for the preparation of an anti-inflammatory, anti-infective medicament.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101255121A (en) * | 2008-04-15 | 2008-09-03 | 中国医学科学院医药生物技术研究所 | Preparation technique of lysine rhein and use thereof in tumour therapy |
| CN102603575A (en) * | 2012-01-04 | 2012-07-25 | 丛晓东 | Rhein-arginine eutectic compound, and preparation method, purification method and application thereof in preparation of medicines for treating diabetic complications |
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
| CN109810013A (en) * | 2017-11-22 | 2019-05-28 | 盘锦格林凯默科技有限公司 | A kind of preparation method of Rhein-amino acid conjugate |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101255121A (en) * | 2008-04-15 | 2008-09-03 | 中国医学科学院医药生物技术研究所 | Preparation technique of lysine rhein and use thereof in tumour therapy |
| CN102603575A (en) * | 2012-01-04 | 2012-07-25 | 丛晓东 | Rhein-arginine eutectic compound, and preparation method, purification method and application thereof in preparation of medicines for treating diabetic complications |
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
| CN109810013A (en) * | 2017-11-22 | 2019-05-28 | 盘锦格林凯默科技有限公司 | A kind of preparation method of Rhein-amino acid conjugate |
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