CN116999447A - Co-amorphous substance of mesalamine and arginine as well as preparation method and application thereof - Google Patents
Co-amorphous substance of mesalamine and arginine as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN116999447A CN116999447A CN202210493958.3A CN202210493958A CN116999447A CN 116999447 A CN116999447 A CN 116999447A CN 202210493958 A CN202210493958 A CN 202210493958A CN 116999447 A CN116999447 A CN 116999447A
- Authority
- CN
- China
- Prior art keywords
- mesalamine
- arginine
- amorphous
- pharmaceutically acceptable
- powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 title claims abstract description 169
- 229960004963 mesalazine Drugs 0.000 title claims abstract description 166
- 239000004475 Arginine Substances 0.000 title claims abstract description 149
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 title claims abstract description 148
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 title claims abstract description 113
- 239000000126 substance Substances 0.000 title abstract description 47
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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Abstract
The application relates to a co-amorphous substance of mesalamine and arginine or pharmaceutically acceptable salt thereof, wherein mesalamine and arginine are combined in a non-covalent bond way to form the co-amorphous substance, the co-amorphous substance is in a solid state, and the molar ratio of mesalamine to arginine is 1:5-5:1, or 1:3-3:1, 1:2-2:1, or 1:2, 1:1 or 2:1. The co-amorphous substance of mesalamine and arginine can prevent or treat enteritis, spinal arthritis, hyperuricemia or gout diseases and complications thereof.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a co-amorphous substance formed by mesalamine and arginine, a preparation method and application thereof.
Background
Mesalamine (Mesalazine), chemical name 5-aminosalicylic acid, has the following structural formula. Mesalazine is mainly used for treating active colitis clinically, and has the action principle of inhibiting prostaglandin synthesis in a dose-dependent manner and reducing the release of PGE2 in human colon mucous membrane. The content of prostaglandin E2 (PGE 2) and leukotriene B4 (LTB 4) in colonic mucosa of colonic patients is very high, mesalazine can inhibit the synthesis of the same, can inhibit the lipoxygenase activity of neutrophils, inhibit the migration, degranulation, phagocytosis, oxygen free radical synthesis and other functions of human neutrophils, and can inhibit the synthesis of Platelet Activating Factor (PAF) which plays an important role in inflammation generation, thereby playing the role of treating colonitis and having better connective tissue effect on intestinal wall with inflammation. Has better effect on connective tissue of inflamed intestinal wall, and can be used for treating ulcerative colitis, ulcerative proctitis, crohn's disease and spondyloarthritis. The clinical dosage of mesalamine is 1.5-3.0 g/day. At present, the repositioning research on the drug function shows that the drug can play a certain therapeutic role in treating hyperuricemia.
Arginine (Arginine), which belongs to basic amino acid and has protective effect on myocardial cells, lung tissue, liver, etc., can be used for treating male infertility by oral administration.
For the effect of mesalazine on enteritis and spinal arthritis, it is necessary to develop a drug with better effect. In addition, there is a need to develop unknown uses for mesalamine.
Disclosure of Invention
One or more embodiments of the present application provide co-amorphous forms of mesalamine and arginine, or pharmaceutically acceptable salts thereof, wherein mesalamine and arginine are non-covalently bound to form co-amorphous forms, the co-amorphous forms are in a solid state, and the molar ratio of mesalamine to arginine is 1:5 to 5:1.
In one or more embodiments, the molar ratio of mesalamine to arginine is 1:3 to 3:1 or 1:2 to 2:1.
In one or more embodiments, the molar ratio of mesalamine to arginine is 1:2, 1:1, or 2:1.
In one or more embodiments, the co-amorphous material does not contain a crystallization solvent or water of crystallization component.
In one or more embodiments, pi-pi stacking and/or van der Waals forces exist between the mesalamine and arginine.
In one or more embodiments, use is made of C u K α Powder X-ray diffraction analysis as a radiation source, the powder X-ray diffraction pattern exhibited diffuse diffraction peaks. In one or more embodiments, the diffuse diffraction peak-to-peak value is located at 21±0.3° to 24±0.3° as expressed by 2θ angle.
In one or more embodiments, the powder X-ray diffraction pattern does not exhibit sharp diffraction peaks.
In one or more embodiments, the molar ratio of mesalamine to arginine of 1:1, 1:2, or 2:1 has a powder X-ray diffraction pattern of the co-amorphous of mesalamine and arginine as shown in fig. 1, 2, or 3, respectively.
In one or more embodiments, the co-amorphous forms of mesalamine and arginine of the present application are analyzed using attenuated total reflectance fourier infrared spectroscopy, with infrared spectral characteristic peaks at 3333±2, 3062±2, 2956±2, 2869±2, 2575±2, 1984±2, 1621±2, 1573±2, 1488±2, 1451±2, 1407±2, 1376±2, 1352±2, 1309±2, 1267±2, 1242±2, 1192±2, 1136±2, 929±2, 900±2, 824±2, 816±2, 809±2, 773±2, 703±2, 683±2cm "1.
One or more embodiments of the present application provide a method for preparing a co-amorphous of mesalamine and arginine of the present application, comprising mixing mesalamine and arginine in a molar ratio of 1:5 to 5:1, 1:3 to 3:1, or 1:2 to 2:1 (e.g., 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, or 5:1) to prepare the co-amorphous by a mechanochemical method or a co-solvent drying method.
In one or more embodiments, the crystalline form of mesalamine is mixed with arginine.
In one or more embodiments, the mechanochemical process is a mechanical ball milling process. In one or more embodiments, the ball to material ratio is 1:1 to 10:1 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1); ball milling rotation speed is 20 r/min-400 r/min (for example, 20, 50, 100, 200, 300, 400 r/min); grinding time is 0.1 to 70 hours (e.g., 0.1, 1, 10, 20, 30, 40, 50, 60, 70 hours); drying mesalamine and arginine in an oven at 50-70 ℃ (e.g., 60 ℃) for 12-72 hours (e.g., 15, 20, 30, 40, 50, 60, 70 hours) prior to milling; the ambient humidity during grinding is less than 30% (e.g., 10%, 20%, 30%).
In one or more embodiments, in the co-solvent drying method, the suspending is performed with a solvent selected from the group consisting of methanol, ethanol, acetonitrile, n-propanol, isopropanol, n-butanol, ethyl acetate, and/or acetone.
In one or more embodiments, in the co-solvent drying method, the solvent with methanol, ethanol, n-propanol, and/or isopropanol is used for confusion.
In one or more embodiments, in the co-solvent drying method, the resulting suspension is dried under vacuum at 30-80 ℃ (e.g., 30, 40, 50, 60 ℃) for 12-72 hours (e.g., 12, 20, 30, 40, 50, 60, 72 hours) to obtain a solid powder.
One or more embodiments of the present application provide a solid mixture comprising the co-amorphous of mesalamine and arginine of the present application, or a pharmaceutically acceptable salt thereof, wherein the amount of the co-amorphous of mesalamine and arginine is 1-99.9 wt%, such as 10-99.9 wt%, 50-99.9 wt%, 90-99.9 wt%, still such as 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 20 wt%, 30 wt%, 40 wt%, 50 wt%, 60 wt%, 70 wt%, 80 wt%, 90 wt% of the solid mixture.
One or more embodiments of the present application provide a pharmaceutical composition comprising a co-amorphous of mesalamine according to the present application with arginine or a pharmaceutically acceptable salt thereof or a solid mixture of the present application, and a pharmaceutically acceptable carrier.
In one or more embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, powder for injection, sustained release formulation, or controlled release formulation.
One or more embodiments of the present application provide the use of the co-amorphous form of mesalamine and arginine of the present application, or a pharmaceutically acceptable salt thereof, the solid mixture of the present application, or the pharmaceutical composition of the present application in the manufacture of a medicament for preventing or treating enteronitis, spinal arthritis, hyperuricemia or gout diseases, and complications of the above diseases.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of mesalamine and arginine 1:1 co-amorphous.
FIG. 2 is a powder X-ray diffraction pattern of mesalamine and arginine 1:2 co-amorphous.
FIG. 3 is a powder X-ray diffraction pattern of mesalamine and arginine 2:1 co-amorphous.
FIG. 4 is a powder X-ray diffraction pattern of a physical mixture of mesalamine and arginine raw materials at 1:1.
Fig. 5 is a powder X-ray diffraction pattern of a physical mixture of mesalamine and arginine raw materials 1:2.
FIG. 6 is a powder X-ray diffraction pattern of a physical mixture of mesalamine and arginine raw material 2:1.
FIG. 7 is a chart showing the infrared absorption spectrum of co-amorphous mesalamine and arginine.
FIG. 8 is a graph of plasma concentration versus time in rats for co-amorphous mesalamine and arginine.
FIG. 9 shows uric acid lowering effects of mesalamine in vivo with arginine 1:1 co-amorphous.
Detailed Description
In one or more embodiments, mesalamine and arginine are prepared into co-amorphous solid substances with specific non-covalent acting force, so that new substances different from mesalamine, arginine and simple combined application of the mesalamine and arginine are formed, and the application of the new amorphous solid substances in preparing medicines capable of preventing or treating enteritis, spondyloarthritis, hyperuricemia, wind pain and other diseases and complications thereof is found.
In one or more embodiments, the presence and characterization of co-amorphous forms of mesalamine and arginine are provided.
In one or more embodiments, a method of preparing a co-amorphous of mesalamine and arginine is provided.
In one or more embodiments, a pharmaceutical composition comprising a co-amorphous of mesalamine and arginine as pharmaceutically active ingredients is provided in an amount ranging from 10 to 1000mg per administration. In one or more embodiments, the pharmaceutical composition is a tablet, capsule, pill, injection, sustained release formulation, or controlled release formulation.
In one or more embodiments, the co-amorphous form of mesalamine and arginine, due to the combination of both, increases the blood concentration in the organism to exert a more efficacious therapeutic effect of the drug in the treatment of the disease.
In one or more embodiments, there is provided use of mesalamine and arginine co-amorphous and mixed crystal solid substances thereof as raw materials of pharmaceutical active ingredients in the preparation of drugs capable of preventing or treating enteritis, spondyloarthritis, hyperuricemia, gout and other diseases and complications thereof.
In one or more embodiments, mesalamine and arginine co-amorphous form in a non-covalent bond, the molar ratio of mesalamine to arginine being 1:5 to 5:1, such as 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, or 5:1.
In one or more embodiments, the co-amorphous of mesalamine and arginine does not comprise a crystallization solvent or a crystallization water component, forming the co-amorphous at a mesalamine to arginine molar ratio of 1:2 to 2:1. When powder X-ray diffraction analysis is used, cuK is used α Under radiation experimental conditions, the powder X-ray spectrum of the powder X-ray spectrum shows diffuse diffraction peaks, wherein the most dominant diffuse diffraction peak value is positioned at 21+/-0.3-24+/-0.3 degrees. Fig. 1, 2 and 3 show powder X-ray diffraction patterns of co-amorphous forms with molar ratios of mesalamine to arginine of 1:1, 1:2 and 2:1, respectively. The positions of the main diffuse diffraction peaks in fig. 1, 2 and 3 are 23.1±0.3°, 21.2±0.3° and 23.6±0.3°, respectively.
In one or more embodiments, the powder X-ray diffraction patterns of the co-amorphous of mesalamine and arginine and the physical mixture of mesalamine and arginine starting materials differ significantly in terms of number of diffraction peaks, positions of diffraction peaks, intensities of diffraction peaks, topology of diffraction peaks, etc., indicating that the co-amorphous of mesalamine and arginine is a different material than the physical mixture of mesalamine and arginine starting materials. Fig. 4, 5 and 6 are powder X-ray diffraction patterns of physical mixtures having molar ratios of mesalamine starting material (crystals) to arginine starting material (crystals) of 1:1, 1:2 and 2:1, respectively, with powder X-ray diffraction peaks shown in tables 1, 2 and 3, respectively.
TABLE 1 powder X-ray diffraction peaks for physical mixtures of mesalamine starting material and arginine starting material in a 1:1 molar ratio
TABLE 2 powder X-ray diffraction peaks for physical mixtures of mesalamine starting material and arginine starting material in a 1:2 molar ratio
TABLE 3 powder X-ray diffraction peaks for physical mixtures of mesalamine starting material and arginine starting material in a 2:1 molar ratio
In one or more embodiments, the co-amorphous of mesalamine and arginine is analyzed using attenuated total reflection fourier infrared spectroscopy at 3333, 3062, 2956, 2869, 2575, 1984, 1621, 1573, 1488, 1451, 1407, 1376, 1352, 1309, 1267, 1242, 1192, 1136, 929, 900, 824, 816, 809, 773, 703, 683cm -1 There is an infrared spectrum characteristic peak, wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 (see FIG. 7).
In one or more embodiments, the co-amorphous form of mesalamine and arginine may also form various pharmaceutically acceptable salts, with various salt forms of the co-amorphous form.
In one or more embodiments, the method for preparing the co-amorphous substance of mesalamine and arginine comprises the steps of feeding the mesalamine and arginine according to a molar ratio of 1:5-5:1, and preparing the co-amorphous substance of mesalamine and arginine by adopting a mechanochemical method for controlling pressure and humidity. The mechanochemical process can be a ball milling process wherein the ball to material ratio is 1:1 to 10:1, for example 6:1 to 10:1; ball milling rotation speed is 20 r/min-400 r/min; the grinding time is, for example, 0.1 to 70 hours; the raw materials can be placed at a dry ventilation position before preparation, the environmental humidity can be ensured to be within a range of 10-30% in the sample preparation process, and the crystal form purity of the sample can be ensured.
In one or more embodiments, the molar ratio of mesalamine to arginine is from 1:5 to 5:1, such as from 1:3 to 3:1; suspending with methanol, ethanol, acetonitrile, n-propanol, isopropanol, n-butanol, ethyl acetate, acetone, etc.; the obtained suspension is dried by heating and vacuum drying at 30-80 ℃, for example 40-60 ℃ for 12-72 hours to obtain solid powder.
In one or more embodiments, a blended solid material is provided that contains co-amorphous of mesalamine and arginine and other ingredients.
In one or more embodiments, the co-amorphous of mesalamine and arginine described above is mixed with other chemical ingredients in any non-zero ratio and in a conventional manner.
In one or more embodiments, a pharmaceutical composition is provided that includes a therapeutically effective dose of a co-amorphous form of mesalamine and arginine and a pharmaceutically acceptable carrier.
In one or more embodiments, a pharmaceutical composition is provided wherein the co-amorphous form of mesalamine and arginine is administered at a daily dosage of 10mg to 1000mg.
In one or more embodiments, a pharmaceutical composition is provided in the form of a tablet, capsule, pill, powder for injection, sustained release formulation, or controlled release formulation.
In one or more embodiments, there is provided use of a co-amorphous form of mesalamine and arginine in the manufacture of a medicament for the prevention and/or treatment of diseases such as enteritis, spinal arthritis, hyperuricemia, gout, and the like, and complications thereof.
In one or more embodiments, a pharmaceutical composition comprising mesalamine and arginine co-amorphous as active ingredients is provided.
In one or more embodiments, the pharmaceutical compositions may be prepared according to methods well known in the art.
In one or more embodiments, any dosage form suitable for human or animal use may be made by combining a co-amorphous form of mesalamine and arginine with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
In one or more embodiments, the co-amorphous form of mesalamine and arginine comprises 10 to 90% by weight of the pharmaceutical composition.
In one or more embodiments, the co-amorphous form of mesalamine and arginine may be administered in unit dosage forms by the enteral or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, skin, vaginal, rectal, and the like.
In one or more embodiments, the dosage form may be a solid dosage 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.
In one or more embodiments, mesalamine and arginine co-amorphous, mixed solid materials containing mesalamine and arginine co-amorphous, can be formulated as conventional formulations, as well as sustained release formulations, controlled release formulations, targeted formulations, and various microparticle delivery systems.
In one or more embodiments, in order to tablet the co-amorphous of mesalamine and arginine, various excipients known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. 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 methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked 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.
In one or more embodiments, the tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bi-and multi-layer tablets.
In one or more embodiments, in order to make the administration unit into a capsule, the co-amorphous of mesalamine and arginine as an active ingredient may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or mixing the co-amorphous substance of mesalamine and arginine with diluent, binder, and disintegrating agent, granulating or making into pellets, and making into hard capsule or soft capsule. Various diluents, binders, wetting agents, disintegrants and glidants used to prepare tablets of mesalamine and arginine co-amorphous ingredients can also be used to prepare capsules of mesalamine and arginine co-amorphous.
In one or more embodiments, colorants, preservatives, flavors, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
In one or more embodiments, the co-amorphous form of mesalamine and arginine, or pharmaceutical compositions thereof, may be administered by any known method of administration for the purpose of administration to enhance therapeutic effects.
In one or more embodiments, the dosage of mesalamine co-amorphous with arginine 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 route of administration and dosage form, and the like. 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.
In one or more embodiments, the co-amorphous of mesalamine and arginine may be taken alone or in combination with other therapeutic or symptomatic agents.
In one or more embodiments, when co-amorphous of mesalamine and arginine is co-acting with other therapeutic agents, its dosage should be adjusted according to the circumstances.
In one or more embodiments, mesalamine and arginine co-amorphous (may be simply referred to as co-amorphous) is distinguished from mesalamine alone in terms of metabolic characteristics in animals, has higher bioavailability and blood concentration at the same dosage administered, reaches a peak velocity increase of more than 50%, and has a 4-fold increase in blood concentration with a significant biological advantage (see fig. 8).
In one or more embodiments, a smaller amount of mesalamine can be used to reduce the occurrence of side effects caused by overdose of current drugs, which is more beneficial to reduce uric acid levels in the body, and effectively increase the biological activity of the drug in the body as compared to mesalamine in the prior art, while achieving the same therapeutic effect (see fig. 8 and 9).
In one or more embodiments, the dosage of the co-amorphous pharmaceutical composition of mesalamine and arginine at the active ingredient may be determined by a variety of factors, such as: the different uses for prevention and treatment cause different daily dosage; the different nature and severity of the illness cause the different daily dosage of the medicine; the sex, age and surface area of patients are different, and the administration route, the administration times and the treatment purpose are different, so that the daily administration dosage is different. In addition, the co-amorphous substance of mesalamine and arginine is used in a dosage of 0.003 to 300mg/kg body weight, or 0.03 to 30mg/kg body weight, in consideration of the difference in absorption and blood concentration between the crystal form samples. When in use, the total dosage scheme of the co-amorphous active ingredients of the mesalamine and the arginine is formulated according to the actual requirements of preventing and treating different conditions, and the mesalamine and the arginine can be completed in a mode of multiple times or one time of administration.
Examples
The following examples are given for better illustration of the technical solution of the present application, but the present application is not limited thereto.
The mechanochemical method or the co-solvent drying method of the present application is not particularly limited to the form of the reactant raw materials. That is, the co-amorphous product of the present application can be obtained by applying the mechanochemical method or the co-solvent drying method of the present application, regardless of the crystal form or amorphous mesalamine and arginine used as the reactant raw materials.
Polymorphic studies on mesalamine: the mesalamine currently found has a crystalline state [1-3] And the mesalamine bulk drug used in the patent is in a crystal form without water, and the mesalamine bulk drug is in the crystal form [1] 。
Polymorphic reports on arginine: arginine has been reported to have four crystalline states [4-7] Two of them are crystal-containing [4-7] Two are crystal-free [8,9] The patent uses a crystal-free material [9] 。
Example 1
Method 1: preparation of solid substance of co-amorphous substance in molar ratio of mesalamine to arginine of 1:1
According to the table below, mesalamine and arginine in a molar ratio of 1:1 were placed in a ball mill pot, the appropriate ball-to-material ratio was selected, the appropriate rotational speed was set, and grinding was performed for the appropriate time. Mesalamine forms co-amorphous with arginine at a 1:1 molar ratio when analyzed using powder X-ray diffraction with CuK α Under the radiation experimental condition, the powder X-ray diffraction pattern shows a dispersed diffraction peak, the position of the diffraction peak is 23.1+/-0.3 degrees in 2 theta value, and the diffraction pattern is shown in figure 1, so that the obtained sample is mesalamine and arginine 1:1 co-amorphous. Specific examples are shown in Table 4.
Table 4 specific examples of co-amorphous solid material preparation method 1 for mesalamine to arginine 1:1 molar ratio
Method 2: preparation of solid substance of co-amorphous substance in molar ratio of mesalamine to arginine of 1:2
According to the table below, mesalamine and arginine in a molar ratio of 1:2 were placed in a ball mill pot, the appropriate ball-to-material ratio was selected, the appropriate rotational speed was set, and grinding was performed for the appropriate time. Mesalamine forms co-amorphous with arginine at a 1:2 molar ratio when analyzed using powder X-ray diffraction with CuK α Under the radiation experimental condition, the powder X-ray diffraction pattern shows a dispersed diffraction peak, the position of the diffraction peak is 21.2+/-0.3 degrees in 2 theta value, and the diffraction pattern is shown in figure 2, so that the obtained sample is the co-amorphous substance of mesalamine and arginine. Specific examples are shown in Table 5.
Table 5 specific examples of co-amorphous solid material preparation method 2 for mesalamine to arginine 1:2 molar ratio
Method 3: co-amorphous substance co-dissolution drying preparation of mesalamine and arginine in molar ratio of 2:1
According to the table below, mesalamine and arginine in a molar ratio of 2:1 were placed in a container, a suitable single solvent and a mixed solvent were selected, a suitable temperature was set, and the mixture was dried for a suitable period of time. Mesalamine forms co-amorphous with arginine at a 2:1 molar ratio when analyzed using powder X-ray diffraction with CuK α Under the radiation experimental condition, the powder X-ray diffraction pattern shows dispersed diffraction peaks, the positions of the diffraction peaks are 7.5+/-0.3 DEG and 23.6+/-0.3 DEG in 2 theta values, and the diffraction pattern is shown in figure 3, which shows that the obtained sample isCo-amorphous of mesalamine and arginine. Specific examples are shown in Table 6.
Table 6 specific example of co-amorphous solid material preparation method 3 for mesalamine to arginine 2:1 molar ratio
Example 2
Method 1: preparation of the combination pharmaceutical formulation (tablet):
pure mesalamine and arginine co-amorphous substance or solid substance mixed with mesalamine and arginine co-amorphous substance in a proper proportion are used as raw material medicines of a combined drug, several excipients are used as auxiliary material components for preparing a combined drug tablet, a tablet sample with the drug content of 10-500 mg of each tablet is prepared according to a certain proportion, and the tablet formula proportion is shown in table 7:
table 7 formulation for preparing co-amorphous combination pharmaceutical tablet of mesalamine and arginine
The method for preparing the tablet preparation from pure mesalamine and arginine co-amorphous substance or solid substance bulk drug mixed by mesalamine and arginine co-amorphous substance with proper proportion comprises the following steps: mixing several excipients with the raw materials, and tabletting directly; or mixing the auxiliary materials, granulating by a dry method, uniformly mixing with the raw materials, and tabletting.
Method 2: preparation of the combination pharmaceutical formulation (tablet):
pure mesalamine and arginine co-amorphous substance or solid substance mixed with mesalamine and arginine co-amorphous substance in proper proportion is used as a raw material medicine of a combined medicine, several excipients are used as auxiliary material components for preparing a combined medicine tablet, a tablet sample with the drug content of 10-500 mg of each tablet is prepared according to a certain proportion, and the tablet formula proportion is shown in table 8:
table 8 formulation for preparing co-amorphous combination pharmaceutical tablets of mesalamine and arginine
The method for preparing the pure product bulk drug of the co-amorphous substance of mesalamine and arginine into the tablet preparation 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.
Method 3: preparation of the combination pharmaceutical formulation (capsule):
the pure product of mesalamine and arginine co-amorphous substance is used as the raw material medicine of the combined medicine, and several excipients are used as the auxiliary material components for preparing the combined medicine capsule, and the capsule sample with the drug content of 10-500 mg per tablet is prepared according to a certain proportion, and the formula proportion of the capsule is shown in the table 9:
table 9 Co-amorphous compound pharmaceutical capsule preparation of mesalamine and arginine bulk drug and auxiliary material formula
The method for preparing the tablet preparation from solid material bulk drugs of the co-amorphous substance of mesalamine and arginine or the co-amorphous substance containing mesalamine and arginine in proper proportion 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 mesalamine and arginine co-amorphous substance raw material with several excipient auxiliary materials uniformly without granulating, sieving, and directly encapsulating.
Example 3
Dose 1: co-amorphous combination of mesalamine and arginine (tablet):
the medicine composition prepared by using the mesalamine and arginine co-amorphous substance sample as the medicine active ingredient, and the mesalamine and arginine co-amorphous substance as the medicine active ingredient, wherein the daily administration dosage is 300mg, and the mesalamine and arginine co-amorphous substance can be prepared into 100mg common tablets of 3 times per time or 1 time per day or 300mg tablets of 1 time per time.
Dose 2: co-amorphous combination of mesalamine and arginine (capsule):
the medicine composition prepared by taking the co-amorphous substance sample of mesalamine and arginine as the medicine active ingredient, and taking the co-amorphous substance of mesalamine and arginine as the medicine active ingredient, wherein the daily administration dosage is 300mg, and the medicine composition can be prepared into 150mg capsules for 2 times a day/1 capsule for 1 time a day or 500mg capsules for 1 capsule for 1 time a day.
EXAMPLE 4 absorption and blood concentration characteristics of Co-amorphous form of mesalamine and arginine in rats
Determining the metabolic characteristics of mesalamine and arginine co-amorphous in animals, comprising the following processes:
12 SD rats were randomly divided into 4 groups of 3 rats. No water was forbidden for 12 hours before dosing. Weighing rat, weighing 150 mg.kg -1 The mesalamine dosage calculation of (2) is carried out by loading mesalamine and arginine co-amorphous substance and mesalamine sample into a solid dosage device, and directly putting the medicinal powder into the rat stomach through the oral cavity. The post-orbital venous plexus blood is collected in heparinized tubes 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours and 12 hours after administration, centrifuged at 4000rpm for 10 minutes at 4 ℃, and frozen in a refrigerator at-40 ℃ for testing. Precisely sucking 100 μL of heparin anticoagulated blood plasma, placing in a 1.5mL centrifuge tube, adding internal standard para aminobenzoic acid working solution (5 μg/mL), 10% trifluoroacetic acid, shaking thoroughly for 3min, centrifuging (13400 rpm,10 min), adding 10 μL of propionic anhydride, shaking thoroughly for 15min, centrifuging (13400 rpm,10 min), adding 1mL of extractant (ethyl acetate), shaking thoroughly for 3min, centrifuging (13400 rpm,10 min), 1mL of the upper layer solution was taken in a centrifuge tube and dried by blowing nitrogen at normal temperature. 100. Mu.L of mobile phase (methanol: water=30:70, v/v) was added for reconstitution, shaking for 3min, centrifugation (13400 rpm,10 min), taking 100. Mu.L of the upper solution in the liner tube, and feeding 10. Mu.L. Quantitative analysis was performed as the ratio of drug to internal standard peak area.
Chromatographic and mass spectrometry conditions: chromatographic column: agilent Eclipse XDB-C18 (4.6X105 mm,5 μm, USA); the mobile phase was acetonitrile: water: methanol (20:50:30, v/v/v); the flow rate is 0.3mL/min; sample injection amount: 10. Mu.L; run time: 20min; mass spectrum signal: the pharmacokinetics data of different samples of the ion m/z=192 (p-aminobenzoic acid derivative) and m/z=208 (mesalamine derivative) for quantitative analysis in rats are shown in table 10, the blood concentration-time curve is shown in fig. 8, the peak speed of mesalamine and arginine co-amorphous is improved by more than 50% in rats, the blood concentration is improved by 4 times, and the method has obvious biological advantages.
Table 10 mesalamine and mesalamine-arginine co-amorphous pharmacokinetic parameter table
Experimental example 5 in vivo uric acid lowering effects of mesalamine and arginine 1:1 co-amorphous
Experimental materials: c57BL/6J mice were purchased from Fukang Biotechnology Co., ltd. Potassium oxazinate, benzbromarone, was purchased from Sigma Aldrich, germany. Mesalazine was purchased from Shanghai source leaf biotechnology limited. Sodium carboxymethyl cellulose was purchased from national pharmaceutical group chemical company, inc. Uric acid kits were purchased from north-control biotechnology Co.Ltd.
Preparing a solution: dissolving 0.5% sodium carboxymethyl cellulose, boiling, cooling, and respectively dissolving mesalamine, potassium oxazinate and benzbromarone to obtain suspension.
Experimental grouping: 18g of mice were randomly assigned to normal control groups,model group, benzbromarone group (20mg.kg) -1 Positive control), mesalamine low, medium, and high dose groups (10, 30, 100mg kg) -1 ) Mesalamine and arginine 1:1 co-amorphous low, medium, and high dose groups (10, 30, 100mg kg -1 ) Each group had 10.
300mg/kg of Potassium Oxazinate was intraperitoneally injected daily except for the control group -1 Normal control groups were injected daily with an equivalent of 0.5% sodium carboxymethylcellulose solution, continuously molded for 7 days, then administered in groups, and after 7 days of administration, mice were sacrificed, blood was collected from the retroorbital venous plexus, left standing for 2h, centrifuged at 4500rpm for 15min at 4 ℃ to collect serum, and serum uric acid levels were determined using a uric acid kit.
TABLE 11 influence of mesalamine on serum uric acid levels in hyperuricemia model micen=10)
Results: after the model animals take mesalamine (10, 30, 100 mg/kg), serum uric acid levels can be reduced by 46%, 63% and 46% respectively, and the total amorphous substances can be reduced by 56%, 68% and 79% respectively, and other results are shown in table 11 and fig. 9, which show that mesalamine produces better uric acid reducing effect compared with the total amorphous substance of arginine.
Reference to the literature
[1]Z,/>B,/>I.Hydrogen bonds in the crystal packings of mesalazine and mesalazine hydrochloride[J].Journal of molecular structure,1997,416(1-3):209- 220.
[2]Montis R,Hursthouse M B.Surprisingly complex supramolecular behaviour in the crystal structures of a family of mono-substituted salicylic acids[J].CrystEngComm,2012,14(16):5242- 5254.
[3]Cherukuvada S,Bolla G,Sikligar K,et al.4-Aminosalicylic acid adducts[J].Crystal growth&design,2013,13(4):1551-1557.
[4]Suresh S,Padmanabhan S,Vijayan M.X-ray studies on crystalline complexes involving amino acids and peptides.XXVII.Effect of chirality,specific interactions and characteristic aggregation patterns in the structures of arginine and its complexes with formic acid[J].Journal of Biomolecular Structure and Dynamics,1994,11(6):1425-1435.
[5]Karle I L,Karle J.An application of the symbolic addition method to the structure of L- arginine dihydrate[J].Acta Crystallographica,1964,17(7):835-841.
[6]Lehmann M S,Verbist J J,Hamilton W C,et al.Precision neutron diffraction structure determination of protein and nucleic acid components.Part V.Crystal and molecular structure of the amino-acid L-arginine dihydrate[J].Journal of the Chemical Society,Perkin Transactions 2, 1973(2):133-137.
[7]Monaco S B,Davis L E,Velsko S P,et al.Synthesis and characterization of chemical analogs of L-arginine phosphate[J].Journal of Crystal Growth,1987,85(1-2):252-255.
[8]Hughes C E,Boughdiri I,Bouakkaz C,et al.Elucidating the crystal structure of dl-arginine by combined powder X-ray diffraction data analysis and periodic DFT-D calculations[J].Crystal Growth&Design,2018,18(1):42-46.
[9]Courvoisier E,Williams P A,Lim G K,et al.The crystal structure of l-arginine[J]. Chemical Communications,2012,48(22):2761-2763.
Claims (12)
1. A co-amorphous form of mesalamine and arginine or a pharmaceutically acceptable salt thereof, wherein mesalamine and arginine are non-covalently bound to form the co-amorphous form, the co-amorphous form is in a solid state, and the molar ratio of mesalamine to arginine is 1:5 to 5:1, or 1:3 to 3:1, 1:2 to 2:1, or 1:2, 1:1, preferably 2:1.
2. The co-amorphous material or a pharmaceutically acceptable salt thereof according to claim 1, wherein the co-amorphous material does not contain a crystallization solvent or a crystallization water component.
3. The co-amorphous or pharmaceutically acceptable salt thereof according to claim 1, wherein pi-pi stacking and/or van der waals forces are present between the mesalamine and arginine.
4. The co-amorphous material or pharmaceutically acceptable salt thereof according to claim 1, wherein the co-amorphous material is used in the form of CuK α Powder X-ray diffraction analysis as a radiation source, the powder X-ray diffraction pattern exhibiting a diffuse diffraction peak; expressed by a 2 theta angle, the peak value of the dispersion diffraction peak is positioned at 21+/-0.3-24+/-0.3 degrees; preferably, the powder X-ray diffraction pattern does not exhibit sharp diffraction peaks; preferably, the powder X-ray diffraction patterns of the co-amorphous of mesalamine and arginine in a molar ratio of mesalamine to arginine of 1:1, 1:2 or 2:1 are shown in fig. 1, fig. 2 or fig. 3, respectively.
5. The co-amorphous form or pharmaceutically acceptable salt thereof according to claim 1, wherein the analysis is performed using attenuated total reflectance fourier infrared spectroscopy at 3333±2, 3062±2, 2956±2, 2869±2, 2575±2, 1984±2, 1621±2, 1573±2, 1488±2, 1451±2, 1407±2, 1376±2, 1352±2, 1309±2, 1267±2, 1242±2, 1192±2, 1136±2, 929±2, 900±2, 824±2, 816±2, 809±2, 773±2, 703±2, 683±2cm -1 There is an infrared spectrum characteristic peak.
6. The process for preparing a co-amorphous of mesalamine and arginine of any one of claims 1-5, comprising mixing mesalamine and arginine in a molar ratio of 1:5 to 5:1, 1:3 to 3:1, or 1:2 to 2:1, or 1:2, 2:1, or 1:1, and preparing the co-amorphous by mechanochemical method or co-solvent drying; preferably, both mesalamine and arginine are in crystalline forms.
7. The production method according to claim 6, wherein the mechanochemical method is a mechanical ball milling method; preferably, the ball-to-material ratio is 1:1-10:1, preferably 6:1-10:1; ball milling rotation speed is 20 r/min-400 r/min; grinding time is 0.1-70 hours; drying mesalamine and arginine in an oven at 50-70 ℃, preferably 60 ℃ for 12-72 hours before grinding; the ambient humidity during grinding was less than 30%.
8. The production method according to claim 6, wherein in the co-solvent drying method, the suspension is performed with a solvent selected from methanol, ethanol, acetonitrile, n-propanol, isopropanol, n-butanol, ethyl acetate, and/or acetone; preferably, the solvent is selected from methanol, ethanol, n-propanol and/or isopropanol; the obtained suspension is heated and dried in vacuum for 12 to 72 hours at a temperature of between 30 and 80 ℃, preferably between 40 and 60 ℃ to obtain solid powder.
9. A solid mixture comprising the co-amorphous form of mesalamine and arginine, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein the amount of the co-amorphous form of mesalamine and arginine is 1-99.9 wt%, preferably 10-99.9 wt%, more preferably 50-99.9 wt%, most preferably 90-99.9 wt% of the solid mixture.
10. A pharmaceutical composition comprising the co-amorphous form of mesalamine and arginine of any one of claims 1-5 or a pharmaceutically acceptable salt thereof or the solid mixture of claim 9, and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition according to claim 10, wherein the dosage form of the pharmaceutical composition is a tablet, capsule, pill, powder injection, sustained release formulation or controlled release formulation.
12. Use of a co-amorphous form of mesalamine and arginine, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5, a solid mixture according to claim 9, or a pharmaceutical composition according to claim 10 or 11, in the manufacture of a medicament for the prevention or treatment of enteritis, spinal arthritis, hyperuricemia or gout diseases, and complications thereof.
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