CN115073330A - Metformin cinnamate, preparation method, composition and application thereof - Google Patents
Metformin cinnamate, preparation method, composition and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
- C07C279/265—X and Y being nitrogen atoms, i.e. biguanides containing two or more biguanide groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
- C07C57/42—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the rings
- C07C57/44—Cinnamic acid
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- 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
Abstract
The invention belongs to the technical field of medicines, and discloses metformin cinnamate, a preparation method, a composition and application thereof. Specifically, the invention discloses a new chemical entity taking metformin cinnamate as a pharmaceutical active ingredient; a preparation method of metformin cinnamate; application of metformin cinnamate as active component in preparing medicine for preventing and treating diabetes is provided.
Description
Technical Field
The invention discloses metformin cinnamate, a preparation method, a composition and application thereof. Specifically, the invention discloses a salt formed by cinnamic acid and metformin: metformin cinnamate; a preparation method of metformin cinnamate; application of metformin cinnamate as a medicinal active ingredient in preparing a medicament for treating diabetes belongs to the technical field of medicines.
Background
The salification of a drug refers to the process of forming a new chemical entity by combining the drug with another chemical substance (salt former) in a proton transfer manner, and is an important way for the development of new drugs. The traditional salt formation refers to the formation of salt by combining an acidic compound with metal ions, such as potassium, calcium, sodium, magnesium and the like, or the formation of salt by combining a basic drug with an inorganic acid or an organic acid, such as hydrochloric acid, sulfuric acid, maleic acid, fumaric acid and the like, so that the physicochemical properties, such as stability and solubility, are improved, and the aim of improving the drug potency is fulfilled. Often these introduced chemicals are not pharmacologically active.
The invention adopts metformin as an active substance, the chemical name of which is 1, 1-dimethylbiguanide and the molecular formula of which is C 4 H 11 N 5 The structural formula is shown as a. The invention adopts cinnamic acid as salifying ligand with chemical name of beta-phenyl acrylic acid and molecular formula of C 9 H 8 O 2 The structural formula is shown as b.
Metformin (Metformin) is a biguanide derivative, often applied clinically in the form of a solid preparation (mainly tablets or capsules) of Metformin hydrochloride, the latter being a type 1 drug for the treatment of type 2 diabetes. Physical and chemical properties record that metformin hydrochloride is a white powder, and is readily soluble in water.
The reported information on metformin salts is as follows.
There are academic literature reports on metformin salts: metformin glimepiride salt [1] Metformin acesulfame potassium salt [2] Metformin gliclazide salt [3] Metformin pamoate [4] Metformin acetylsalicylate and its hydrate [5] Metformin nitrate salt [6] Metformin acetate salt [7] Metformin oxalate hydrate, metformin sulfate hydrate [8] Metformin tolbutamide salt [9] Metformin dinitrate [10] Metformin cup [ 4]]Arenesulfonate hydrate, metformin [ 5]]Aromatic hydrocarbon sulfonate hydrate [11] Metformin ethyl N- (3-tossulfonyl) carbamate salt [12] Metformin rosiglitazone salt [13] 。
Chinese patents have reported about metformin salts: salt of mercaptopurine and metformin, preparation method and crystal structure thereof [14] Metformin crystal, medicinal composition of metformin crystal and saxagliptin and preparation method of medicinal composition [15] Salt formation of sulfonylurea compound and metformin, preparation method and application thereof [16] Novel metformin glycinate for glycemic control [17] Salt of 5-fluorouracil and metformin, process for producing the same and crystal structure thereof [18] New salt form of metformin-tolbutamide, preparation method and medical application thereof [19] Metformin-pioglitazone salt and preparation method and application thereof [20] Metformin salt of thiazolidinedione drug and preparation method and application thereof [21] Metformin crystal, medicinal composition of metformin crystal and pioglitazone and preparation method of medicinal composition [22] Metformin acidic double salt compound and preparation method thereof [23] Metformin salt of thiazolidinedione medicine, preparation method and application thereof [24] Metformin and fenofibric acid compound and preparation thereof [25] Novel metformin glycinate salt for glycemic control [26] Metformin folate and preparation method thereof [27] 。
Among the various salt forms of metformin, metformin hydrochloride is the best medicinal choice, so metformin hydrochloride is mainly used in clinical application at present. However, although metformin hydrochloride is widely used in clinical practice, there are many adverse reactions, such as intolerance to long-term medication, and gastric dysfunction of patients who use metformin hydrochloride for a long time due to the release of high-concentration chloride ions.
Cinnamic acid (Cinnamic acid), a beta-phenyl acrylic compound, has a variety of biological activities such as antitumor, antibacterial, and diabetes treatment, but because of its poor solubility, it is not used clinically.
The invention creatively selects an organic acid-cinnamic acid which has poor solubility and is not commonly used in pharmacy as a salifying ligand to form a new chemical entity with metformin, and the obtained metformin cinnamate can have water solubility equivalent to that of metformin hydrochloride and more advantageous dissolution rate, and effectively improves the hypoglycemic activity, which are unexpected by the technical personnel in the field. In addition, the metformin cinnamate provided by the invention can also effectively solve the problem of side effect of metformin hydrochloride in the prior art.
Disclosure of Invention
The technical problems to be solved by the invention are as follows:
the invention aims to solve one of the technical problems that: provides a salt type substance existing state and a characterization mode of cinnamic acid and metformin.
The second technical problem to be solved by the present invention is: provides a preparation method of a novel, crystalline and stable metformin cinnamate.
The invention aims to solve the third technical problem: provides a pure product containing the metformin cinnamate or a mixed solid substance containing the metformin cinnamate with any non-zero proportion and a pharmaceutical composition thereof.
The fourth technical problem to be solved by the invention is: provides a pharmaceutical composition using metformin cinnamate as a pharmaceutically active ingredient, wherein the daily dosage of metformin cinnamate is within the range of 200-4000 mg. The pharmaceutical composition comprises tablets, capsules, pills, injection preparations, granules, powder, pellets, dripping pills, suppositories, films, patches, aerosols, sprays, sustained-release preparations or controlled-release preparations.
The invention aims to solve the technical problems that: is to provide metformin cinnamate, which has better solubility advantage in aqueous isopropanol solution than metformin hydrochloride.
The technical problems to be solved by the invention are as follows: application of metformin cinnamate as effective component in preparing medicine for preventing type 2 diabetes.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. morphological characteristics of the metformin cinnamate sample:
1.1 metformin cinnamate according to the present invention is characterized in that metformin forms a salt with cinnamic acid in a molar ratio of 1:1.
1.2 metformin cinnamate of the present invention, when analyzed by powder X-ray diffraction using CuK α Diffraction peak position under irradiation test conditions: 2-Theta value (°) or d value
Diffraction peak relative intensity: the peak Height (Height%) or peak Area (Area%) had the following characteristics (table 1, fig. 1). The X-ray diffraction pattern and data of the physical mixed powder of the metformin hydrochloride and the cinnamic acid are shown in the table 2 and the figure 2. The X-ray diffraction patterns of the physical mixed powder of the metformin cinnamate, the metformin hydrochloride and the cinnamic acid have obvious differences in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topological graph and the like, and the results show that the physical mixture of the metformin cinnamate, the metformin hydrochloride and the cinnamic acid is different or identical.
TABLE 1 powder X-ray diffraction peaks of metformin cinnamate
TABLE 2 powder X-ray diffraction peaks of physical mixtures of metformin hydrochloride and cinnamic acid
1.3 the metformin cinnamate according to the present invention is characterized in that when analyzed by attenuated total reflection fourier infrared spectroscopy, it is 3500, 3400, 3344, 3119, 1693, 1637, 1562, 1538, 1493, 1448, 1416, 1404, 1371, 1286, 1246, 1176, 1109, 1050, 1028, 972, 932, 873, 847, 808, 770, 724, 685cm -1 Has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm -1 . (FIG. 3).
1.4 metformin cinnamate according to the present invention is characterized in that when analyzed by differential scanning calorimetry, it shows that 1 endothermic peak at 178 + -3 deg.C and 1 exothermic peak at 224 + -5 deg.C exist in DSC chart when the temperature rising rate is 10 deg.C per minute (FIG. 4). The DSC fold patterns of metformin hydrochloride, cinnamic acid and metformin cinnamate are shown in figure 5. The DSC spectra of metformin hydrochloride, cinnamic acid and metformin cinnamate have obvious difference in the number, position and the like of endothermic/exothermic peaks, and metformin cinnamate has only 1 melting endothermic peak, which shows that the metformin cinnamate forms a new substance in the form of salt.
2. The preparation method of the metformin cinnamate and the mixed solid substance is characterized in that:
2.1 the process for the preparation of metformin cinnamate according to the present invention comprises the steps of:
(1) dissolving cinnamic acid and a metformin raw material in a solvent according to a molar ratio of 1: 0.9-1: 1.1 to obtain a mixture;
(2) reacting and crystallizing the mixture obtained in the step (1) at the temperature of 10-50 ℃ for 12-48 hours;
(3) and (3) carrying out solid-liquid phase separation on the product obtained in the step (2), and drying to obtain a solid product formed by the cinnamic acid and the metformin salt.
2.2 the organic solvent in the preparation method of metformin cinnamate according to the present invention is preferably a mixed solvent prepared by combining any one or more of acetone, acetonitrile, ethyl acetate, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, methanol, dioxane, and tetrahydrofuran in different proportions.
2.3 the metformin cinnamate-containing mixed solid material of the present invention is obtained by mixing the metformin cinnamate ingredient obtained by the above-mentioned method with other chemical substances in any non-zero ratio and by a conventional method.
3. Pharmaceutical formulation composition containing metformin cinnamate ingredient, dosing profile and pharmaceutical use:
3.1 the pharmaceutical composition of the present invention comprises metformin cinnamate and a pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition of the present invention comprises a mixed solid of metformin cinnamate and a pharmaceutically acceptable carrier.
3.3 in the pharmaceutical composition, the daily dosage of the metformin cinnamate is 200-4000 mg.
3.4 the invention relates to a pharmaceutical composition, which is characterized in that the pharmaceutical composition is various tablets, capsules, pills, injection preparations, granules, powder, pellets, dropping pills, suppositories, film agents, patches, aerosols, sprays, sustained-release preparations or controlled-release preparations.
3.5 the invention relates to the use of metformin cinnamate, mixed solid materials or pharmaceutical compositions containing metformin cinnamate in the preparation of medicaments for the prevention and treatment of diabetes.
The invention relates to a pharmaceutical composition with metformin cinnamate of the invention as an active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The metformin cinnamate ingredient of the present invention may be formulated into any dosage form suitable for human or animal use by combining it with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the metformin cinnamate in the pharmaceutical composition is within the range of 10 to 90 percent by weight.
The metformin cinnamate of the present invention can be administered in unit dosage form, either enterally or parenterally, primarily orally.
The administration form according to the invention is preferably a solid form. The solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.
The metformin cinnamate can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
In order to formulate the metformin cinnamate of the present invention into tablets, a wide variety of excipients known in the art can be 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 humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, 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 double-layer and multi-layer tablets.
In order to make the administration unit into a capsule, the active ingredient metformin cinnamate of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed into a hard capsule or a soft capsule. Or the effective component of the metformin cinnamate of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the metformin cinnamate tablet of the present invention may also be used to prepare the metformin cinnamate capsule of the present invention.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug of the present invention can be administered by any known administration method.
The dosage of the metformin cinnamate pharmaceutical composition of the present invention to be administered 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, and the like. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The metformin cinnamate or the composition of the present invention can be taken alone or in combination with other therapeutic agents or symptomatic agents. When the metformin cinnamate of the present invention has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual situation.
4. The invention has the beneficial technical effects that: the advantageous features of safety, solubility and biological activity of metformin cinnamate.
4.1 the metformin cinnamate of the present invention has no endothermic peak of any crystallization solvent or crystallization water on the DSC chart (fig. 4), and no weight loss peak exists before decomposition weight loss in the thermogravimetric analysis chart (fig. 6), indicating that the metformin cinnamate does not contain any crystallization solvent, and has good safety and pharmaceutical advantages.
4.2 the solubility of the metformin cinnamate of the invention in water system is equivalent to that of metformin hydrochloride, and both are easy to dissolve, and the solubility advantage superior to that of metformin hydrochloride is shown in 90% isopropanol, especially the dissolution rate is obviously improved, which shows that the fat solubility of the metformin cinnamate is superior to that of metformin hydrochloride (figure 7).
4.3 biological absorption of the drug developed with metformin cinnamate of the present invention as an active ingredient and the pharmaceutical composition thereof by oral administration, characterized by using a pharmaceutical composition containing metformin cinnamate as described in claim 1 as an active ingredient. In the experiment of measuring glucose consumption by hepatocytes, metformin cinnamate can significantly increase glucose consumption in a concentration-dependent manner (fig. 8). The metformin cinnamate solid substance has better hypoglycemic effect than metformin hydrochloride, and eliminates the intake of a large amount of chloride ions, thereby reducing the toxic and side effect.
Drawings
FIG. 1 powder X-ray diffraction Pattern of metformin cinnamate
FIG. 2X-ray diffraction pattern of physical mixed powder of metformin hydrochloride and cinnamic acid
FIG. 3 Infrared absorption Spectroscopy of metformin cinnamate
FIG. 4 differential scanning calorimetry thermogram of metformin cinnamate
Figure 5 differential scanning calorimetry thermograms of metformin hydrochloride, cinnamic acid and metformin cinnamate
FIG. 6 thermogravimetric mapping of metformin cinnamate
FIG. 7 dissolution Rate Profile of metformin cinnamate
FIG. 8 cellular evaluation of metformin cinnamate in vitro-glucose consumption
Detailed Description
The following examples are given to better illustrate the technical aspects of the present invention, but the present invention is not limited thereto.
Example 1
Preparation method of metformin cinnamate 1:
putting a proper amount of metformin and cinnamic acid into a clean container according to a molar ratio of 1:1, adding a proper amount of methanol, stirring for 12 hours at the temperature of 40 ℃, filtering the obtained suspension solvent, drying in vacuum, filtering, and naturally drying or evaporating to dry. Powder X-ray diffraction analysis is carried out on the sodium-containing composite, the diffraction pattern of the sodium-containing composite is consistent with that of figure 1, and the obtained sample is metformin cinnamate.
putting metformin hydrochloride and sodium hydroxide or sodium carbonate or other appropriate alkali into a clean container according to the molar ratio of 1:1, adding an appropriate amount of ethanol, stirring for an appropriate time of 8 hours at the temperature of 30 ℃, filtering, collecting all filtrate, adding equimolar cinnamic acid, stirring for an appropriate time of 8 hours at the temperature of 30 ℃, filtering, drying the obtained suspension solvent in vacuum, filtering, and naturally drying or evaporating to dry. Powder X-ray diffraction analysis is carried out on the sodium-containing composite, the diffraction pattern of the sodium-containing composite is consistent with that of figure 1, and the obtained sample is metformin cinnamate.
Preparation method of metformin cinnamate 3:
putting metformin hydrochloride and sodium hydroxide or sodium carbonate or other appropriate alkali into a clean container according to the molar ratio of 1:1, adding an appropriate amount of organic solvent, stirring for an appropriate time (2-48 h) at an appropriate temperature (10-50 ℃), filtering, and evaporating the filtrate at an appropriate temperature to obtain metformin solid powder. Putting the solid powder and an appropriate amount of cinnamic acid into a clean container according to a molar ratio of 1:1, adding an appropriate amount of organic solvent, stirring for an appropriate time (2-48 h) at an appropriate temperature (10-50 ℃), filtering the obtained suspension solvent, and drying in vacuum, filtering and naturally drying or evaporating. Powder X-ray diffraction analysis is carried out on the sodium-containing composite, the diffraction pattern of the sodium-containing composite is consistent with that of figure 1, and the obtained sample is metformin cinnamate.
Example 2
Stability characteristics of metformin cinnamate:
and (3) illumination test: taking 50mg of metformin cinnamate, placing for 5 days and 10 days under the illumination condition, and carrying out powder X-ray diffraction analysis on the metformin cinnamate, wherein the diffraction pattern of the metformin cinnamate is consistent with that of a figure 1, which shows that the sample is the metformin cinnamate and is stable under the illumination condition.
High-temperature test: 50mg of metformin cinnamate is placed under a high-temperature condition for 5 days and 10 days, powder X-ray diffraction analysis is carried out on the metformin cinnamate, and the diffraction pattern is consistent with that of a figure 1, which shows that the sample is the metformin cinnamate and is stable under the high-temperature condition.
High humidity test: 50mg of metformin cinnamate is taken to be placed under the high-humidity condition for 5 days and 10 days, powder X-ray diffraction analysis is carried out on the metformin cinnamate, the diffraction pattern is consistent with that shown in a figure 1, and the sample is the metformin cinnamate and is stable under the high-humidity condition.
Example 3
The solubility of the metformin cinnamate and the solubility of the metformin hydrochloride are equivalent, and the metformin cinnamate and the metformin hydrochloride are both easy to dissolve; in order to further examine the solubility difference of the two in a fat-soluble system, a 90% isopropanol water solvent system is selected to examine the dissolution rates of the two.
The content is measured at the wavelength of 233nm by using the dissolving percentage of the metformin as an evaluation index and adopting a high performance liquid chromatography, and the dissolving percentage is calculated by an external standard method. Dissolution rate curves were plotted with time as the abscissa and percent dissolution as the ordinate, respectively (fig. 7). The data are shown in the following table:
TABLE 3 dissolution Profile data for metformin cinnamate and metformin hydrochloride in 90% isopropyl alcohol water
The experimental data show that the dissolution rate of the metformin cinnamate is obviously superior to that of metformin hydrochloride in 90% isopropanol water, and the metformin cinnamate has a faster dissolution rate and is easy to be rapidly absorbed to achieve effective blood concentration; the solubility in 90% isopropanol water also reflects that the compound is better in lipid solubility than metformin hydrochloride.
Example 4
In vitro biological characteristics of metformin cinnamate: in a test for detecting glucose consumption by using liver cells, the metformin cinnamate can obviously increase the consumption of glucose, the glucose consumption is improved by 0.34-13.36% under different concentrations, the concentration dependence is shown (figure 8), the blood sugar reducing effect is better than that of metformin hydrochloride, and the intake of a large amount of chloride ions is eliminated, so that the toxic and side effects are reduced.
Example 5
Method for the preparation of a combined pharmaceutical preparation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that metformin cinnamate and a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, tablet samples containing 50-500 mg of eutectic crystal are prepared according to a certain proportion, and the formula proportion of the tablet is given in table 4:
TABLE 4 formulation for the preparation of metformin cinnamate combination pharmaceutical tablets
The method for preparing the tablet preparation by taking the metformin cinnamate as the raw material medicament comprises the following steps: mixing several excipients with the raw materials, and directly tabletting; or mixing the auxiliary materials, granulating by a dry method, uniformly mixing with the raw material medicines, and tabletting to obtain the traditional Chinese medicine.
Method for the preparation of a combined pharmaceutical preparation 2 (tablet):
a preparation method of a combined medicine tablet is characterized in that metformin cinnamate and a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, tablet samples containing 50-500 mg of eutectic crystal are prepared according to a certain proportion, and the formula proportion of the tablet is given in table 5:
TABLE 5 formulation for the preparation of metformin cinnamate combination pharmaceutical tablets
The method for preparing the tablet preparation by taking the metformin cinnamate as the raw material medicine comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into soft material, sieving, granulating, oven drying, sieving, grading, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Method for preparing a combined pharmaceutical preparation 3 (capsule):
a preparation method of a combined medicine capsule is characterized in that metformin cinnamate is used as a raw material medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine capsule, a capsule sample with the medicine content of 50-500 mg is prepared according to a certain proportion, and the formula proportion of the capsule is given in a table 6:
TABLE 6 formula of raw material and auxiliary materials for metformin cinnamate combination pharmaceutical capsule formulation
The method for preparing the capsule by taking the metformin cinnamate as the raw material medicine comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into wet granules, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing the metformin cinnamate bulk drug with a plurality of excipient auxiliary materials without using a granulation step, sieving and directly encapsulating to obtain the metformin cinnamate capsule.
Example 6
Dosage 1 (tablet) of metformin cinnamate combination drug administered:
the pharmaceutical composition prepared and developed by using the metformin cinnamate as the active ingredient of the medicine is characterized in that the metformin cinnamate is used as the active ingredient of the medicine, the daily administration dosage is 200mg, and the metformin cinnamate can be respectively prepared into 1 100mg common tablet which is taken 2 times a day each time or 1 tablet which is taken 1 time a day and 200mg tablet.
Dosage of metformin cinnamate combination 2 (capsule):
the pharmaceutical composition prepared and developed by using the metformin cinnamate as the active ingredient of the medicine is characterized in that the metformin cinnamate is used as the active ingredient of the medicine, the daily administration dosage is 500mg, and the metformin cinnamate can be respectively prepared into 1 capsule of 250mg 2 times a day or 1 capsule of 500mg 1 time a day.
Problems to be explained: the metformin cinnamate pharmaceutical composition of the present invention has many factors affecting the administration dosage of the active ingredient, for example: the age and the body surface area of patients are different, and the administration route, the administration frequency and the treatment purpose are different, so that the dosage of each administration is different; the differences in absorption and blood concentration among samples also result in the use of metformin cinnamate in a dosage range of 3-66 mg/kg body weight, preferably 8-35 mg/kg body weight, per appropriate dose of the present invention. When in use, different total dosage schemes of the metformin cinnamate active ingredients are made according to different actual requirements of treatment, and the administration can be completed in a multi-time or one-time mode.
Reference to the literature
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[14] Salt of mercaptopurine and metformin, preparation method and crystal structure-201810870846.9 thereof
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[16] Salt formation of sulfonylurea compound and metformin, preparation method and application-201911050807.5
[17] Novel metformin glycinate salt-200880130084.3 for use in glycemic control
[18] Salt of 5-fluorouracil and metformin, preparation method and crystal structure-201810983887.9 thereof
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[22] A metformin crystal and a medicinal composition of the metformin crystal and pioglitazone and a preparation method-201110214411.7; 102349905B
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[24] Metformin salt of thiazolidinedione medicine, preparation method and application thereof-200910103662.0
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Claims (12)
1. Metformin cinnamate characterized in that metformin forms a salt with cinnamic acid in a molar ratio of 1:1.
2. The metformin cinnamate according to claim 1, wherein CuK is used when powder X-ray diffraction analysis is used α Diffraction peak position under irradiation test conditions: 2-Theta value (°) or d value
Diffraction peak relative intensity: the peak Height value (Height%) or peak Area value (Area%) has the following characteristics:
3. metformin cinnamate according to claim 1, wherein the concentration of the compound is 3500, 3400, 3344, 3234, 3119, 3055, 2869, 2809, 1693, 1637, 1562, 1538, 1493, 1448, 1416, 1404, 1371, 1286, 1246, 1236, 1176, 1109, 1050, 1028, 972, 932, 873, 847, 808, 770, 724, 685cm when analyzed using attenuated total reflectance fourier infrared spectroscopy -1 Has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm -1 。
4. Metformin cinnamate according to claim 1, characterized in that, when analyzed using differential scanning calorimetry, it shows a DSC profile with 1 endothermic peak at 178 ± 3 ℃ and 1 exothermic peak at 224 ± 5 ℃ at a temperature rise rate of 10 ℃ per minute.
5. The process for the preparation of metformin cinnamate according to any one of claims 1 to 4, comprising the steps of:
(1) dissolving cinnamic acid and a metformin raw material in a solvent according to a molar ratio of 1: 0.9-1: 1.1 to obtain a mixture;
(2) reacting and crystallizing the mixture obtained in the step (1) at the temperature of 10-50 ℃ for 2-48 hours;
(3) and (3) carrying out solid-liquid phase separation on the product obtained in the step (2), and drying to obtain a solid product formed by the cinnamic acid and the metformin salt.
6. The method according to claim 5, wherein the organic solvent is a mixed solvent prepared by combining any one or more of acetone, acetonitrile, ethyl acetate, ethanol, n-propanol, isopropanol, methanol and tetrahydrofuran in different proportions.
7. Mixed solid matter containing metformin cinnamate in an amount of 1 to 99.9%, preferably 10 to 99.9%, more preferably 50 to 99.9%, most preferably 85 to 99.9% in the range of any one of claims 1 to 4.
8. A pharmaceutical composition comprising an effective amount of the metformin cinnamate of any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition comprising an effective amount of the mixed solid substance containing metformin cinnamate of claim 7 and a pharmaceutically acceptable carrier.
10. Pharmaceutical composition according to any of claims 8 or 9, characterized in that the daily dose of metformin cinnamate is in the range of 200 to 4000 mg.
11. The pharmaceutical composition according to any one of claims 8 or 9, wherein the pharmaceutical composition is in the form of a tablet, capsule, pill, injection, granule, powder, pellet, drop pill, suppository, film, patch, aerosol, spray, sustained release formulation or controlled release formulation.
12. Use of metformin cinnamate as claimed in any one of claims 1 to 4 or mixed solid substance containing metformin cinnamate as claimed in claim 7 or pharmaceutical composition as claimed in any one of claims 8 to 11 for the preparation of a medicament for the prophylaxis and treatment of diabetes.
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