CN115124532B - Rhein and matrine eutectic crystal, preparation method, composition and application thereof - Google Patents
Rhein and matrine eutectic crystal, preparation method, composition and application thereof Download PDFInfo
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- CN115124532B CN115124532B CN202110317165.1A CN202110317165A CN115124532B CN 115124532 B CN115124532 B CN 115124532B CN 202110317165 A CN202110317165 A CN 202110317165A CN 115124532 B CN115124532 B CN 115124532B
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- rhein
- matrine
- eutectic
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- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- 239000012071 phase Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- HRLYFPKUYKFYJE-UHFFFAOYSA-N tetraoxorhenate(2-) Chemical compound [O-][Re]([O-])(=O)=O HRLYFPKUYKFYJE-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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- 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
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- 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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Abstract
The invention discloses a rhein and matrine eutectic compound, a preparation method, a composition and application thereof. Specifically, the invention discloses a rhein and matrine eutectic substance which takes a lead compound rhein as a medicinal active ingredient and matrine as a eutectic substance ligand; a preparation method of rhein and matrine eutectic; the application of rhein and matrine eutectic as medicine active components in preparing medicine for treating inflammation, infection, osteoarthritis, etc belongs to the field of medicine technology.
Description
Technical Field
The invention discloses a rhein and matrine eutectic compound, a preparation method, a composition and application thereof. Specifically, the invention discloses a eutectic substance formed by rhein and matrine; a preparation method of rhein and matrine eutectic; a pharmaceutical composition comprising a co-crystal of rhein and matrine or a mixed solid comprising any non-zero ratio of rhein to matrine co-crystal; the invention also relates to application of the rhein and matrine eutectic as the active ingredients of the medicines in preparing anti-inflammatory, anti-infection and anti-osteoarthritis medicines, belonging to the technical field of medicines.
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; matrine (Matrine) is used as eutectic substance, and molecular formula is C 15 H 24 N 2 O has a structural formula shown in a formula b, and a rhein and matrine eutectic substance and a preparation method thereof are discovered through a pharmaceutical eutectic screening technology, and compared with rhein bulk drugs, the rhein and matrine eutectic substance has obviously improved solubility. In addition, compared with the reported rhein arginine eutectic, rhein lysine eutectic has better water solubility and unexpected technical effect.
Disclosure of Invention
The invention aims to solve the technical problems:
one of the technical problems to be solved by the invention is as follows: provides the existence state and characterization mode of the cocrystal of rhein and matrine.
The second technical problem to be solved by the invention is: provides a preparation method of a rhein and matrine eutectic.
The third technical problem to be solved by the invention is: provides a mixed solid substance containing pure rhein and matrine eutectic substance or mixed solid substance containing rhein and matrine eutectic substance with any non-zero proportion and a pharmaceutical composition thereof.
The invention aims to solve the fourth technical problem: a pharmaceutical composition using a cocrystal of rhein and matrine as pharmaceutically active ingredients is provided, which has a dose per administration in the range of 0.5-300 mg. 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: provides rhein with better solubility advantage compared with matrine eutectic substance rhein.
The invention solves the technical problems: provides rhein and matrine which can improve the blood concentration in the body to play a therapeutic role due to the formation of eutectic substances in the course of treating diseases.
The invention solves the technical problems: the rhein and matrine 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. morphological characteristics of rhein and matrine eutectic samples:
1.1 the rhein and matrine eutectic substance designed by the invention is a eutectic substance formed by rhein and matrine in a molar ratio of 2:1 by non-covalent bonds.
1.2 Co-crystals of rhein and matrine according to the present invention, cuK was used when powder X-ray diffraction analysis was used α Diffraction peak position under radiation experimental conditions: 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 pattern and data of physical mixture of rhein and matrine are shown in Table 2 and figure 2. The powder X-ray diffraction patterns of the cocrystal of rhein and matrine and the physical mixture of rhein and matrine have obvious differences in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topological graph and the like, which indicates that the cocrystal of rhein and matrine and the physical mixture of rhein and matrine are neither identical nor equivalent.
TABLE 1X-ray diffraction peak of rhein and matrine eutectic powder
TABLE 2X-ray diffraction peak of powder of physical mixture of rhein and matrine
1.4 rhein and matrine co-crystals according to the present invention were analyzed by attenuated total reflection Fourier IR spectroscopy at 2928, 2743, 1717, 1672, 1626, 1562, 1452, 1367, 1262, 1192, 1159, 1060, 1006, 932, 896, 839, 799, 750, 724, 704cm -1 There is an infrared spectrum characteristic peak (FIG. 3), wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 。
1.5 the rhein and matrine eutectic compound of the present invention is characterized in that when the temperature is 30-250 ℃ and the heating rate is 10 ℃/min, 1 endothermic peak exists at 173+ -3 ℃ in DSC spectrum (figure 4). The DSC superposition diagram of rhein, matrine and the eutectic of rhein and matrine is shown in figure 5, and the obvious difference of rhein and matrine in the number and position of endothermic peaks can be seen from figure 5, which indicates that rhein and matrine form the eutectic.
2. The preparation method of the rhein and matrine eutectic and mixed solid is characterized in that:
2.1 the invention relates to a preparation method of rhein and matrine eutectic substance, which is characterized in that a liquid adding grinding method is adopted, rhein and matrine 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 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 preparation method of the rhein and matrine eutectic substance is characterized in that a suspension method is adopted, rhein is added into a reaction vessel, an organic solvent is added according to the solid-to-liquid ratio of 10-500 mg/mL, the mixture is stirred uniformly at the temperature of 25-30 ℃, matrine with a certain molar ratio is slowly added into the reaction vessel, and stirring is carried out while stirring, the stirring speed is 100 r/min-1000 r/min, 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 a 100 ℃ oven for 0.5-1 h to obtain rhein and matrine eutectic; the organic solvent is any one single solvent or a plurality of mixed solvents prepared by combining different proportions selected from ethanol, ethyl acetate, acetonitrile and acetone; the mol ratio of rhein to matrine is 1:1.5.
2.3 the mixed solid matter of the rhein and matrine eutectic compound is obtained by mixing rhein and matrine eutectic compound components prepared by the method with other chemical substances according to any non-zero proportion and a conventional method.
3. Pharmaceutical preparation composition containing rhein and matrine eutectic components, and administration dosage characteristics and pharmaceutical application thereof:
3.1 the pharmaceutical composition of the invention comprises a rhein and matrine eutectic and a pharmaceutically acceptable carrier. 3.2 the pharmaceutical composition of the invention comprises mixed solid matters of rhein and matrine 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 of the invention is characterized in that the pharmaceutical composition is various tablets, capsules, pills, injection, sustained release preparation or controlled release preparation and bone joint cavity injection.
3.5 the invention relates to the application of rhein and matrine eutectic, and the mixed solid or pharmaceutical composition of rhein and matrine eutectic in preparing anti-inflammatory, anti-infection, anti-osteoarthritis and other drugs.
The invention relates to a pharmaceutical composition taking rhein and matrine eutectic 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 can be made by combining the rhein and matrine 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 matrine eutectic mixture in the pharmaceutical composition is 10-90% by weight.
The rhein and matrine eutectic mixture and the solid mixture of rhein and matrine 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 matrine eutectic substance can be prepared into common preparations, slow-release preparations, controlled-release preparations and targeting preparations, various microparticle administration systems and bone joint cavity injection.
For the preparation of the solid mixture of rhein and matrine co-crystals and rhein and matrine co-crystals of the present invention into tablets, various excipients known in the art, including diluents, binders, wetting agents, disintegrants, lubricants and glidants, may 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 prepare the administration unit into a capsule, the active ingredient rhein and matrine eutectic substance can be mixed with a diluent and a glidant, the mixture is directly placed into a hard capsule or a soft capsule, or the active ingredient rhein and matrine eutectic substance can be firstly prepared into particles or pellets with the diluent, an adhesive and a disintegrating agent, and then placed into the hard capsule or the soft capsule. The various diluents, adhesives, wetting agents, disintegrants and glidants used for preparing the rhein and matrine eutectic substance tablet of the invention can also be used for preparing capsules of the rhein and matrine eutectic substance 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 dosage of the pharmaceutical composition of the co-crystal of rhein and matrine 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 matrine eutectic or composition of the invention can be taken alone or combined with other therapeutic drugs or symptomatic drugs. When the rhein and matrine eutectic compound of the invention and other therapeutic drugs have synergistic effect, the dosage of the rhein and matrine eutectic compound should be adjusted according to the actual situation.
4. The beneficial technical effects of the invention are as follows: the rhein and matrine eutectic has the advantages of safety and solubility characteristics 4.1. The rhein and matrine eutectic does not contain any solvent, and has good safety and patent medicine advantages. 4.2 the rhein and matrine eutectic of the invention has the pharmacological activity of rhein, has great improvement on solubility, and is far superior to rhein. In addition, the water solubility was better and unexpected technical effects were obtained compared to the reported rhein arginine cocrystal (fig. 6).
4.3 the advantage and application of the cocrystal of rhein and matrine in preventing and treating diseases through the maximum concentration value in gastrointestinal tract or blood after oral administration (figure 7) are specifically embodied in that the cocrystal of rhein and matrine has the advantages of high absorption speed, high blood concentration and prolonged action platform.
Drawings
FIG. 1 powder X-ray diffraction pattern of rhein and matrine eutectic
FIG. 2 powder X-ray diffraction pattern of physical mixture of rhein and matrine
FIG. 3 is an infrared absorption spectrum of a co-crystal of rhein and matrine
FIG. 4 differential scanning calorimetric diagram of rhein and matrine co-crystals
FIG. 5 differential scanning calorimetric contrast map of rhein, matrine and rhein eutectic crystal
FIG. 6 solubility curves of rhein and matrine cocrystal, rhein and arginine cocrystal and rhein
FIG. 7 rhein and rhein co-crystals in rhesus monkey oral absorption for 0-24h
FIG. 8 stability investigation of sodium hyaluronate solution as rhein and matrine eutectic
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 matrine eutectic substance:
weighing rhein and matrine samples with a molar ratio of 1:1, placing the rhein and matrine samples into a mortar, adding a proper amount of organic solvent, grinding the rhein and matrine samples until the solvent is volatilized, drying the rhein and matrine samples in a 100 ℃ oven for a certain time, and carrying out powder X-ray diffraction analysis on the rhein and matrine samples, wherein a diffraction pattern of the rhein and matrine samples is consistent with that of figure 1, and the obtained rhein and matrine samples are cocrystals. As shown in table 3:
preparation method 2 of rhein and matrine eutectic substance:
weighing rhein and matrine samples with a molar ratio of 1:1, putting the rhein and matrine 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 for a certain time in a 100 ℃ oven. Powder X-ray diffraction analysis is carried out on the rhein, the diffraction pattern of the rhein is consistent with that of figure 1, and the obtained sample is rhein and matrine eutectic. As shown in table 4:
a preparation method of a rhein and matrine eutectic substance 3:
weighing a proper amount of rhein, putting the rhein into a clean container, adding a proper amount of organic solvent, uniformly stirring at 25-30 ℃, slowly adding matrine with a molar ratio of 1:1.5 into a reaction bottle, filtering the obtained suspension, and drying a filter cake in a 100 ℃ oven. Powder X-ray diffraction analysis is carried out on the rhein, the diffraction pattern of the rhein is consistent with that of figure 1, and the obtained sample is rhein and matrine eutectic. As shown in table 5:
example 2
The solubility characteristics of rhein, rhein and matrine co-crystals (rhein) and arginine co-crystals (rhein) in a pure water system were examined. The dissolution curve comparison adopts a model independent similarity factor (f 2) method by referring to measurement of common oral solid preparation dissolution test technical guidelines, and the similarity of dissolution curves of the rhein and matrine eutectic substance, rhein and arginine eutectic substance (rhein) and rhein bulk drug in pure water with pH=7.0 is compared through calculation of f 2. When f2 is higher than 50, the two curves are considered similar, and when f2 is lower than 50, the two curves are considered to be different. The experiment uses rhein bulk drug as reference, and calculates model independent similarity factor f2 value. The dissolution amount is calculated by an external standard method by measuring the rhein content at 254nm wavelength by adopting a high performance liquid phase method. Dissolution curves were drawn with time as the abscissa and dissolution amount as the ordinate (fig. 8). The specific 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 matrine eutectic substance in a pure water system is improved by about 40 times, the dissolution rate is obviously improved, the rhein and matrine eutectic substance is easy to be absorbed more rapidly to reach effective blood concentration, and the disease treatment effect of the medicine can be better realized.
In addition, the water solubility of rhein and matrine co-crystals was improved by about 10-fold compared to the already reported rhein arginine co-crystals (fig. 6). Therefore, the preparation process of the rhein and matrine eutectic compound adopted by the invention well improves the technical problem of poor rhein water solubility, has simple production process, is beneficial to batch production, and provides technical support for subsequent research and development of rhein.
Example 3
Absorption characteristics and blood concentration characteristics of large Huang Suangu matrine eutectic in rhesus monkey:
rhesus monkeys with the weight of 3.3-4.2 kg are selected as experimental animals, the administration dosage of rhein bulk drugs is 15mg/kg, and the administration dosage of rhein-matrine eutectic is 28.1mg/kg (the dosage converted into rhein is 15 mg/kg). Blood was taken at 0.333, 0.667, 1, 2, 3, 4, 6, 8, 12, 16 and 24h before and after administration, respectively, placed in heparinized centrifuge tubes, centrifuged at 4000r/min for 10min, and the supernatant was taken and stored in a refrigerator at-40 ℃. To 100. Mu.L of plasma sample, 20. Mu.L of 1. Mu.g/mL 7-hydroxyisoflavone (internal standard) and 20. Mu.L of 2M HCl and 1000. Mu.L ethyl acetate were added sequentially, vortex for 3min, centrifuge at 13400rpm for 10min, transfer all supernatant to 1.5mL EP tube, blow-dry with nitrogen, re-dissolve with 100. Mu.L of 30% acetonitrile solution, vortex for 3min, centrifuge at 13400rpm for 10min, and sample injection of supernatant was taken.
Detection conditions: the column was Agilent Poroshell SB-C18 (2.7 μm, 2.1X150 mm); the sample injection amount is 20 mu L; mobile phase: formic acid 0.02% aqueous solution and acetonitrile; the flow rate is 0.3mL/min; run time: for 10min; mass spectrum signal: ESI source (negative ion detection mode), ion for quantitative analysis m/z=283 (rhein), m/z=237 (7-hydroxyisoflavone), fragmentation voltage 100V (rhein), 140V (7-hydroxyisoflavone), gain factor 1.5, dry gas flow 11.0L/min, spray chamber voltage 35psig, dryer temperature 350 ℃, capillary voltage 3000V (positive), 3000V (negative), respectively.
Table 8 shows the blood concentration at various time points in the blood of rhesus monkeys after oral administration of rhein and matrine rhenate cocrystal samples; table 9 shows pharmacokinetic parameters of rhesus monkey on oral administration of rhein and matrine rhein eutectic samples for 0-24h, indicating that large Huang Suangu matrine eutectic has the advantageous biological characteristics of rapid absorption, high blood concentration and prolonged action platform (FIG. 7).
Table 7 blood concentration at each time point (n=6,)
table 8 pharmacokinetic parameters of SD rhesus monkey after oral administration of rhein and matrine co-crystals
Example 4
Preparation method of combination pharmaceutical formulation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that a rhein and matrine eutectic substance or mixed solid substances containing rhein and matrine eutectic substance in any proportion are used as raw material medicines of the combined medicine, several 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 9:
preparation formula of table 9 rhein and matrine eutectic compound medicine tablet
The method for preparing the tablet preparation by taking the rhein and matrine eutectic as 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 matrine eutectic substance or a mixed solid substance containing rhein and matrine eutectic substance in any proportion is used as a raw material medicine of the combination medicine, several excipients are used as auxiliary material components for preparing the combination medicine capsule, a capsule sample with the dosage 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 10:
formula of bulk drug and auxiliary materials of table 10 rhein and matrine eutectic compound pharmaceutical capsule preparation
The method for preparing the rhein and matrine 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 the large Huang Suangu alkaloid eutectic substance with several excipient adjuvants without granulating, sieving, and directly encapsulating.
Preparation method of combined pharmaceutical preparation 3 (bone joint cavity injection)
A preparation method of a combined medicine bone joint cavity injection is characterized in that a rhein and matrine eutectic substance or a mixed solid substance containing rhein and matrine eutectic substance in any proportion is used as a raw material medicine of the combined medicine, sodium hyaluronate with molecular weight of 5000 is used as an auxiliary material component for preparing the combined medicine bone joint cavity injection, bone joint cavity injection samples are prepared according to a certain proportion, and stability examination results of bone joint cavity injections with different concentrations at room temperature at 25 ℃ are shown in table 11 (figure 8).
TABLE 11 stability of rhein and matrine hyaluronic acid solutions at different concentrations at room temperature at 25℃
| Time | 0.5％ | 0.6％ | 0.7％ | 0.8％ | 1.0％ |
| For 5 days | Stabilization | Stabilization | Stabilization | Stabilization | Stabilization |
| For 10 days | Stabilization | Stabilization | Stabilization | Stabilization | Stabilization |
The method for preparing the rhein and matrine eutectic compound into the bone joint cavity injection preparation comprises the following steps: weighing a certain amount of sodium hyaluronate, respectively preparing sodium hyaluronate solutions with mass concentrations of 0.5%, 0.6%, 0.7%, 0.8% and 1.0% (g/100 mL), precisely weighing 5mg of rhein and matrine eutectic substance equivalent to rhein raw material medicines, respectively adding into 5mL of sodium hyaluronate solutions with different concentrations, and continuously stirring for 12 hours to obtain sodium hyaluronate bone joint cavity injection with the concentration of 1mg/mL rhein and matrine eutectic substance.
Example 5
Dosage 1 (tablet) of rhein and matrine cocrystal combination drug:
the pharmaceutical composition is characterized in that the rhein and matrine eutectic is used as the active ingredients of the medicine, the daily administration dosage is 0.5-300mg, and 1-6 tablets containing 10, 100, 200, 300 and 500mg of the active ingredients can be prepared respectively.
Dosage 2 (capsule) of rhein and matrine eutectic compound drug:
the pharmaceutical composition is prepared and developed by using a rhein and matrine eutectic substance sample as a pharmaceutical active ingredient, and is characterized in that the rhein and matrine eutectic substance is used as the pharmaceutical active ingredient, the daily administration dosage is 10-3000mg, and 1-6 capsules containing 10, 100, 200, 300 and 500mg of the active ingredient can be prepared respectively.
Problems to be described: the pharmaceutical composition of the cocrystal of rhein and matrine 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 absorption and blood concentration differences between the rhein and matrine eutectic samples also result in the proper dosage range of 0.01-300mg/kg body weight, preferably 10-100mg/kg body weight, of rhein and matrine eutectic components per time of the present invention. When in use, the total dosage scheme of the active ingredients of the eutectics of the rhein and the matrine is formulated according to the actual requirements of different treatment conditions, and the eutectics can be completed in a mode of multiple times or one time.
Reference to the literature
1. Chinese patent CN102603575a
2. Chinese patent CN10255121a.
Claims (13)
1. A rhein and matrine eutectic substance, which is characterized in that the rhein and matrine form the eutectic substance in a molar ratio of 2:1.
2. The co-crystal of rhein and matrine 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 matrine of claim 1, wherein when analyzed using attenuated total reflectance fourier infrared spectroscopy, at 2928, 2743, 1717, 1672, 1626, 1562, 1452, 1367, 1262, 1192, 1159, 1060, 1006, 932, 896, 839, 799, 750, 724, 704cm -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 matrine according to claim 1, wherein the rhein and matrine are characterized by having 1 endothermic peak at 173 ℃ ± 3 ℃ in a DSC profile when analyzed by differential scanning calorimetry at a temperature ranging from 30 ℃ to 250 ℃ and a heating rate of 10 ℃/min.
5. The method for preparing rhein and matrine eutectic substance as claimed in any one of claims 1-4, characterized in that, adding rhein and matrine in a molar ratio of 1:1 by adopting a liquid adding grinding method or a liquid adding ball milling method, continuously grinding until solvent volatilizes, drying in a high temperature oven at 100 ℃ to obtain rhein and matrine eutectic substance, wherein the organic solvent is selected from any one single solvent of 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 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 matrine eutectic substance according to any one of claims 1-4, 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 ℃, matrine with a certain molar ratio is slowly added into the reaction vessel, stirring is carried out while the stirring speed is 100 r/min-1000 r/min until the bright yellow solution is completely changed into reddish brown, the stirring time is 24-72 h, the obtained suspension is filtered, a filter cake is put into a 100 ℃ oven for drying for 0.5-1 h, and the rhein and matrine eutectic substance is obtained, wherein the organic solvent is any one single solvent or a mixed solvent prepared by combining a plurality of solvents with different proportions; the mol ratio of rhein to matrine is 1:1.5.
7. A mixed solid material comprising a co-crystal of rhein and matrine, characterized in that the content of the co-crystal of rhein and matrine according to any one of claims 1-4 is 1-99.9%.
8. A mixed solid material comprising a co-crystal of rhein and matrine, characterized in that the content of the co-crystal of rhein and matrine according to any one of claims 1-4 is 50-99.9%.
9. A mixed solid material comprising a co-crystal of rhein and matrine, characterized in that the content of the co-crystal of rhein and matrine according to any one of claims 1-4 is 85-99.9%.
10. A pharmaceutical composition comprising an effective amount of a co-crystal of rhein and matrine according to any one of claims 1-4 and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising an effective amount of the solid mixture comprising a co-crystal of rhein and matrine according to 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 matrine as claimed in any one of claims 1 to 4 or a mixed solid substance comprising a co-crystal of rhein and matrine as claimed in any one of claims 7 to 9 or a pharmaceutical composition as claimed in any one of claims 10 or 11 for the manufacture of an anti-inflammatory, anti-infective medicament.
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| 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 |
| CN101898962A (en) * | 2009-05-31 | 2010-12-01 | 中国医学科学院药物研究所 | Rhein crystal B-type solid matter, preparation method and use |
| 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 |
| CN107286035A (en) * | 2017-05-19 | 2017-10-24 | 华东师范大学 | A kind of 5 aminosalicylic acid pharmaceutical co-crystals and preparation method thereof |
| 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 (6)
| 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 |
| CN101898962A (en) * | 2009-05-31 | 2010-12-01 | 中国医学科学院药物研究所 | Rhein crystal B-type solid matter, preparation method and use |
| 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 |
| CN107286035A (en) * | 2017-05-19 | 2017-10-24 | 华东师范大学 | A kind of 5 aminosalicylic acid pharmaceutical co-crystals and preparation method thereof |
| 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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