Salt of aryl propionic acid compound and pharmaceutical application thereof
阅读说明：本技术 一种芳基丙酸类化合物的盐及其制药用途 (Salt of aryl propionic acid compound and pharmaceutical application thereof ) 是由 叶海 闵涛 姜水湜 徐烨 曹卫 陈晨 宿连征 胡情姣 于 2020-04-08 设计创作，主要内容包括：本发明提供了一种式Ⅰ化合物的碱加成盐、盐的晶型、制备方法,以及包含这些盐的药物组合物、制剂形式和制药用途。式Ⅰ化合物是一种属于芳基丙酸类的药学活性物质,以其为基础制备了新颖的盐型及其结晶形式,在水溶解性、溶出度、稳定性方面均好于式Ⅰ化合物。这些盐型及其结晶形式具有给药剂量小、药物起效快以及可以减小毒副作用和提高生物利用度等优点。含有式Ⅰ化合物的碱加成盐的药物组合物在制备镇痛、解热、消炎药物中具有广泛用途和广阔前景。(The invention provides a base addition salt of a compound shown in a formula I, a crystal form of the salt, a preparation method, a pharmaceutical composition containing the salt, a preparation form and pharmaceutical application. The compound of the formula I belongs to pharmaceutical active substances of aryl propionic acids, and novel salt forms and crystal forms thereof are prepared on the basis of the compound of the formula I, and the compound of the formula I is better than the compound of the formula I in water solubility, dissolution rate and stability. The salt form and the crystal form thereof have the advantages of small administration dosage, quick response, reduced toxic and side effects, improved bioavailability and the like. The pharmaceutical composition containing the base addition salt of the compound of the formula I has wide application and wide prospect in preparing analgesic, antipyretic and anti-inflammatory drugs.)
1. A salt of a compound of formula i, which is a base addition salt formed by reacting a compound of formula i with a base; wherein the chemical name of the compound in the formula I is (S) -2- (4- (((1R, 2S) -2-hydroxycyclopentyl) methyl) phenyl) propionic acid, the structure is shown as follows,
2. The salt of claim 1, selected from the following forms, the salt being in a crystalline form or amorphous:
a sodium salt of a compound of formula I represented by formula II;
a compound of formula I, diethylamine salt, of formula III;
tromethamine salt of a compound of formula I as shown in formula IV;
a compound of formula I, formula V, ethanolamine salt;
a compound of formula I, L-lysine salt, represented by formula VI;
a compound of formula I, L-arginine salt, represented by formula VII;
a triethanolamine salt of a compound of formula I represented by formula VIII;
a compound of formula i, formula IX, N-methylglucamine salt;
a compound of formula I1- (2-hydroxyethyl) -pyrrolidine salt of formula X;
a magnesium salt of a compound of formula I, represented by formula XI;
calcium salts of compounds of formula I as shown in formula XII;
a compound of formula I, represented by formula XIII;
a piperazine salt of a compound of formula I represented by formula XIV:
3. the salt of claim 2, comprising a crystalline form of:
a sodium salt crystal form A of a compound of formula I, which has characteristic diffraction peaks at 2 theta values of 8.1 DEG + -0.2 DEG, 9.4 + -0.2 DEG, 12.9 + -0.2 DEG, 16.3 + -0.2 DEG, 16.8 + -0.2 DEG, 17.5 DEG + -0.2 DEG, 18.8 DEG soil 0.2 DEG, 19.7 DEG soil 0.2 DEG, 21.7 DEG soil 0.2 DEG, 24.1 DEG soil 0.2 DEG, 24.8 DEG soil 0.2 DEG and 27.9 DEG soil 0.2 DEG using an X-ray powder diffraction pattern of Cu-Ka radiation, and has characteristics substantially represented by the X-ray powder diffraction pattern shown in figure 4; the DSC pattern has endothermic peaks at about 69.6 ℃ and 181.6 ℃.
4. The salt of claim 2, comprising a crystalline form of:
the compound diethylamine salt crystal form A of the formula I has characteristic diffraction peaks at the positions of 9.6 degrees plus or minus 0.2 degrees, 10.6 plus or minus 0.2 degrees, 11.6 plus or minus 0.2 degrees, 12.7 plus or minus 0.2 degrees, 14.1 plus or minus 0.2 degrees, 16.2 degrees plus or minus 0.2 degrees, 19.5 degrees soil 0.2 degrees, 20.0 plus or minus 0.2 degrees, 21.2 plus or minus 0.2 degrees, 22.1 plus or minus 0.2 degrees, 24.6 plus or minus 0.2 degrees and 25.7 plus or minus 0.2 degrees by using an X-ray powder diffraction pattern of Cu-Ka radiation; having features represented by an X-ray powder diffraction pattern substantially as shown in figure 6; the DSC pattern has endothermic peaks at about 61 ℃ and 87 ℃.
5. The salt of claim 2, comprising a crystalline form of:
the compound ethanolamine salt crystal form A of the formula I has characteristic diffraction peaks corresponding to positions with 2 theta values of 6.1 degrees +/-0.2 degrees, 7.9 +/-0.2 degrees, 9.8 +/-0.2 degrees, 14.4 +/-0.2 degrees, 16.4 +/-0.2 degrees, 17.1 degrees +/-0.2 degrees, 18.4 degrees of soil 0.2 degrees, 20.7 degrees of soil 0.2 degrees, 21.6 degrees of soil 0.2 degrees, 22.5 degrees of soil 0.2 degrees, 24.2 degrees of soil 0.2 degrees and 27.8 degrees of soil 0.2 degrees by using an X-ray powder diffraction pattern radiated by Cu-Ka; and having the characteristics represented by an X-ray powder diffraction pattern using Cu-Ka radiation substantially as shown in figure 8; the DSC spectrum has an endothermic peak at a position of about 111.3 ℃.
6. The salt of claim 2, comprising a crystalline form of:
the compound triethanolamine salt crystal form A of the formula I has characteristic diffraction peaks at 2 theta values of 7.9 degrees +/-0.2 degrees, 9.5 degrees +/-0.2 degrees, 11.2 degrees +/-0.2 degrees, 13.5 degrees +/-0.2 degrees, 16.1 degrees +/-0.2 degrees, 16.5 degrees +/-0.2 degrees, 18.4 degrees of soil 0.2 degrees, 20.0 degrees of soil 0.2 degrees, 20.6 degrees of soil 0.2 degrees and 23.7 degrees of soil 0.2 degrees by using an X-ray powder diffraction pattern radiated by Cu-Ka; having the features represented by the X-ray powder diffraction pattern substantially as shown in figure 10; the DSC spectrum has an endothermic peak at a position of about 134.7 ℃.
7. The salt of claim 2, comprising a crystalline form of:
a crystal form A of a compound N-methylglucamine salt of a formula I has characteristic diffraction peaks at the positions of 7.7 degrees +/-0.2 degrees, 13.6 degrees +/-0.2 degrees, 15.2 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 17.8 degrees +/-0.2 degrees, 21.5 degrees +/-0.2 degrees, 22.3 degrees, 0.2 degrees and 25.1 degrees of soil 0.2 degrees by using an X-ray powder diffraction pattern of Cu-Ka radiation; having features represented by an X-ray powder diffraction pattern substantially as shown in figure 12; the DSC spectrum has an endothermic peak at about 99.6 ℃.
8. The salt of claim 2, comprising a crystalline form of:
the compound of formula I, namely the tromethamine salt crystal form A, has characteristic diffraction peaks at 2 theta values of 4.7 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 9.8 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 17.3 degrees +/-0.2 degrees, 18.6 degrees soil 0.2 degrees, 19.6 degrees soil 0.2 degrees, 20.4 degrees soil 0.2 degrees, 21.1 degrees soil 0.2 degrees, 23.4 degrees soil 0.2 degrees and 23.7 degrees soil 0.2 degrees by using an X-ray powder diffraction pattern radiated by Cu-Ka; having the features represented by the X-ray powder diffraction pattern substantially as shown in figure 14; the DSC spectrum has an endothermic peak at a position of about 108.5 ℃.
9. The salt of claim 2, comprising a crystalline form of:
the compound tromethamine salt crystal form B of the formula I has characteristic diffraction peaks at the positions with 2 theta values of 6.25 +/-0.2, 8.77 +/-0.2, 17.24 +/-0.2, 17.97 +/-0.2, 19.57 +/-0.2 and 20.56 +/-0.2 by using an X-ray powder diffraction pattern of Cu-Ka radiation; having the features represented by the X-ray powder diffraction pattern substantially as shown in figure 17; the DSC spectrum has an endothermic peak at a position of about 112.6 ℃.
10. A pharmaceutical composition comprising a therapeutically effective amount of a salt of a compound of formula i as claimed in any one of claims 1 to 9, together with a pharmaceutically acceptable adjuvant; wherein the salt is selected from the group consisting of sodium, potassium, magnesium, calcium, diethylamine, ethylenediamine, piperazine, 1- (2-hydroxyethyl) -pyrrolidine, tromethamine, choline, ethanolamine, trimethylglycine, triethanolamine, meglumine, glucamine, tert-butylamine, L-lysine, L-arginine; the preparation form of the pharmaceutical composition comprises tablets, capsules, granules, powder, dry suspension, freeze-dried powder injection, suspension, injection emulsion, suspension drops, syrup, oral solution, eye drops, nose drops, ointment, cream, gel, patch, cataplasm, gel plaster, gel cream, suppository, spray, inhalant and implant.
11. The pharmaceutical composition according to claim 10, characterized in that said salt is selected from tromethamine salts, L-arginine salts, L-lysine salts, N-methylglucamine salts; the preparation form is selected from one of injection, freeze-dried powder injection, suspension and injection emulsion.
12. The pharmaceutical composition according to claim 11, wherein the formulation is in the form of an injection, wherein the injection comprises 0.02 to 6.79% by weight of the active ingredient compound of formula i.
13. Use of a salt of a compound of formula i as defined in any one of claims 1 to 9 or a pharmaceutical composition as defined in any one of claims 10 to 12 in the manufacture of a medicament for use in prophylaxis or treatment of analgesia, anti-inflammatory, antipyretic.
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a base addition salt of a compound (S) -2- (4- (((1R, 2S) -2-hydroxycyclopentyl) methyl) phenyl) propionic acid shown as a formula I, a crystal form and a preparation method of the salt, and application of a pharmaceutical composition of the salt in preparation of antipyretic, analgesic and anti-inflammatory drugs.
Background
Loxoprofen sodium with chemical name of 2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl]Sodium propionate dihydrate, the English name Loxoprofen Sodium, molecular formula C15H17O3Na·2H2O, molecular weight 304.32, CAS number 80382-23-6. Loxoprofen sodium is an aryl propionic acid non-steroidal anti-inflammatory drug, and inhibits synthesis of prostaglandin by inhibiting cyclooxygenase. When the loxoprofen sodium is orally taken, the loxoprofen sodium is absorbed by the digestive tract in a precursor form, has weak stimulation effect on gastric mucosa, is quickly converted into an active metabolite after entering blood, namely the compound of the formula I, has the following structure,has analgesic, antiinflammatory and antipyretic effects. The loxoprofen sodium has 20 times of indometacin analgesic effect and is smallRat paw carrageenin edema experiment shows that the anti-inflammatory effect is 2 times of that of indometacin. The loxoprofen sodium has strong and lasting analgesic, anti-inflammatory and antipyretic effects. Compared with the similar medicines in clinic, the medicine effect is characterized in that: stronger (good clinical effect), quicker (the peak value can be reached after the oral administration for 30 minutes), safer (little side effect). Loxoprofen sodium has wide adaptation diseases, and is widely used for anti-inflammatory and analgesic treatment of rheumatoid arthritis, lumbago, scapulohumeral periarthritis, neck, shoulder and wrist syndrome, analgesic and anti-inflammatory treatment after operation, trauma and tooth extraction, antipyretic and analgesic treatment of acute upper respiratory inflammation, and the like. The current clinically used preparation formulations comprise tablets, granules, capsules and external patches.
The original manufacturer of loxoprofen sodium is the first three-drug pharmaceutical in Japan, and is marketed in Japan in 7 months in 1986. The raw material medicine is loxoprofen sodium dihydrate. Journal literature J.Med.chem.1984,27,212-216 is published for loxoprofen sodium research in the first three co-pharmaceutical laboratories in 1984. The preparation method of the loxoprofen sodium dihydrate crystal form is firstly related to the preparation method of the loxoprofen sodium dihydrate crystal form, loxoprofen and sodium hydroxide solution are prepared into loxoprofen sodium in ethanol, a solid is obtained by removing a solvent, and the loxoprofen sodium dihydrate is obtained by ethyl acetate recrystallization, wherein the melting point is 194-198 ℃.
Regarding the synthesis of loxoprofen active metabolites, i.e. compounds of formula i, hypodo et al, in "organiclettes, 2009 (11): 1103-1106' report a method for constructing a chiral loxoprofen skeleton by using an active organic copper intermediate, the method is harsh in conditions and low in yield, the reaction time is as long as 92 hours when primary alcohol is oxidized into carboxyl, and the method is not suitable for industrial production requirements.
CN201610435178 is a route of Schiff base intermediate, which comprises resolving 2- [ p- (bromomethyl) phenyl ] propionic acid, methyl esterifying, condensing with Schiff base prepared from cyclohexanone and chiral auxiliary agent, and hydrolyzing to obtain the final product.
The route reported in the literature tetrahedron asymmetry,2011,22: 1125-1132 comprises condensation, reduction, column chromatography, enzymatic acetyl reaction, column chromatography and amide removal of chiral amine to obtain a target product.
A single chemical molecule may form various salts or crystal forms. Loxoprofen sodium crystal forms with different crystal forms are reported by original manufacturers and pharmaceutical imitation manufacturers of loxoprofen sodium. Different salts or different crystal forms of the same drug molecule have different physical properties due to different molecular space structures and interaction forces. Different crystal forms have different solubilities, and different dissolution rates in gastrointestinal body fluid indirectly influence blood concentration and drug effect. Thus, salts or crystalline forms of the drug that possess suitable solubility properties have better therapeutic efficacy than salts or crystalline forms that dissolve more slowly.
Disclosure of Invention
The first purpose of the invention is to provide a base addition salt of the compound shown in the formula I, which overcomes the defects of small water solubility, poor physicochemical stability, easy moisture absorption and stickiness, poor flowability and the like of the compound shown in the formula I in the prior art. The new salt form has good physicochemical properties, is convenient for smooth operation in the preparation process, so as to obtain a preparation form with excellent quality and enrich the application of loxoprofen active metabolites in preparing antipyretic, analgesic and anti-inflammatory drugs.
The invention provides a salt of a compound shown in formula I, which is a base addition salt formed by reacting the compound shown in formula I with a base; wherein the chemical name of the compound in the formula I is (S) -2- (4- (((1R, 2S) -2-hydroxycyclopentyl) methyl) phenyl) propionic acid, the structure is shown as follows,
Preferably, in the present invention, the salt is selected from salts represented by the following structural formula, which may be in a crystalline form or an amorphous form, including:
a sodium salt of a compound of formula I represented by formula II;
a compound of formula I, diethylamine salt, of formula III;
tromethamine salt of a compound of formula I as shown in formula IV;
a compound of formula I, formula V, ethanolamine salt;
a compound of formula I, L-lysine salt, represented by formula VI;
a compound of formula I, L-arginine salt, represented by formula VII;
a triethanolamine salt of a compound of formula I represented by formula VIII;
a compound of formula i, formula IX, N-methylglucamine salt;
a compound of formula I1- (2-hydroxyethyl) -pyrrolidine salt of formula X;
a magnesium salt of a compound of formula I, represented by formula XI;
calcium salts of compounds of formula I as shown in formula XII;
a compound of formula I, represented by formula XIII;
a piperazine salt of a compound of formula I represented by formula XIV:
preferably, the salt is an ethanolamine salt of the compound of formula I, represented by formula V.
Preferably, the salt is a compound of formula I tromethamine salt shown in formula IV.
Preferably, the salt is the diethylamine salt of the compound of formula i shown in formula III.
The second object of the present invention is to provide a crystalline form of the salt of the compound of formula i obtained in the present invention.
The invention obtains a sodium salt crystal form A of a compound shown in a formula I, which has characteristic diffraction peaks at positions with 2 theta values of 8.1 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 12.9 +/-0.2 degrees, 16.3 +/-0.2 degrees, 16.8 +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 18.8 degrees of soil 0.2 degrees, 19.7 degrees of soil 0.2 degrees, 21.7 degrees of soil 0.2 degrees, 24.1 degrees of soil 0.2 degrees, 24.8 degrees of soil 0.2 degrees and 27.9 degrees of soil 0.2 degrees by using an X-ray powder diffraction pattern radiated by Cu-Ka, and has characteristics represented by the X-ray powder diffraction pattern shown in figure 4 basically; the DSC spectrum has endothermic peaks at about 69.6 ℃ and 181.6 ℃ as shown in FIG. 5.
The invention obtains a crystal form A of diethylamine salt of a compound shown in a formula I, which has characteristic diffraction peaks at the positions of 9.6 degrees +/-0.2 degrees, 10.6 +/-0.2 degrees, 11.6 +/-0.2 degrees, 12.7 +/-0.2 degrees, 14.1 +/-0.2 degrees, 16.2 degrees +/-0.2 degrees, 19.5 degrees of soil 0.2 degrees, 20.0 +/-0.2 degrees, 21.2 +/-0.2 degrees, 22.1 +/-0.2 degrees, 24.6 +/-0.2 degrees and 25.7 +/-0.2 degrees by using an X-ray powder diffraction pattern radiated by Cu-Ka; having features represented by an X-ray powder diffraction pattern substantially as shown in figure 6; the DSC spectrum has endothermic peaks at about 61 ℃ and 87 ℃ as shown in FIG. 7.
The invention obtains a crystal form A of ethanolamine salt of a compound shown as a formula I, which uses an X-ray powder diffraction pattern of Cu-Ka radiation and has characteristic diffraction peaks at the positions of 6.1 degrees +/-0.2 degrees, 7.9 +/-0.2 degrees, 9.8 +/-0.2 degrees, 14.4 +/-0.2 degrees, 16.4 +/-0.2 degrees, 17.1 degrees +/-0.2 degrees, 18.4 degrees of soil 0.2 degrees, 20.7 degrees of soil 0.2 degrees, 21.6 degrees of soil 0.2 degrees, 22.5 degrees of soil 0.2 degrees, 24.2 degrees of soil 0.2 degrees and 27.8 degrees of soil 0.2 degrees of the 2 degrees; and having the characteristics represented by an X-ray powder diffraction pattern using Cu-Ka radiation substantially as shown in figure 8; the DSC spectrum has an endothermic peak at about 111.3 ℃ as shown in FIG. 9.
The invention obtains a crystal form A of triethanolamine salt of a compound shown in a formula I, which has characteristic diffraction peaks at the positions of 7.9 degrees +/-0.2 degrees, 9.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.5 +/-0.2 degrees, 16.1 +/-0.2 degrees, 16.5 +/-0.2 degrees, 18.4 degrees of soil 0.2 degrees, 20.0 degrees of soil 0.2 degrees, 20.6 degrees of soil 0.2 degrees and 23.7 degrees of soil 0.2 degrees by using an X-ray powder diffraction pattern radiated by Cu-Ka; having the features represented by the X-ray powder diffraction pattern substantially as shown in figure 10; the DSC spectrum has an endothermic peak at about 134.7 ℃ as shown in FIG. 11.
The invention obtains a crystal form A of N-methylglucamine salt of a compound shown as a formula I, which has characteristic diffraction peaks at the positions of 2 theta values of 7.7 degrees +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.2 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.8 +/-0.2 degrees, 21.5 degrees +/-0.2 degrees, 22.3 degrees soil 0.2 degrees and 25.1 degrees soil 0.2 degrees by using an X-ray powder diffraction pattern radiated by Cu-Ka; having features represented by an X-ray powder diffraction pattern substantially as shown in figure 12; the DSC spectrum has an endothermic peak at about 99.6 ℃ as shown in FIG. 13.
The invention obtains a tromethamine salt crystal form A, and an X-ray powder diffraction pattern radiated by Cu-Ka has characteristic diffraction peaks at the positions of 4.7 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 9.8 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 17.3 degrees +/-0.2 degrees, 18.6 degrees soil 0.2 degrees, 19.6 degrees soil 0.2 degrees, 20.4 degrees soil 0.2 degrees, 21.1 degrees soil 0.2 degrees, 23.4 degrees soil 0.2 degrees and 23.7 degrees soil 0.2 degrees of 2 degrees; having the features represented by the X-ray powder diffraction pattern substantially as shown in figure 14; a DSC profile having an endothermic peak at about 108.5 ℃ as shown in FIG. 15; also has an IR spectrum substantially as shown in FIG. 16.
The invention obtains the tromethamine salt crystal form B, and the X-ray powder diffraction pattern using Cu-Ka radiation has characteristic diffraction peaks at the positions with 2 theta values of 6.25 +/-0.2, 8.77 +/-0.2, 17.24 +/-0.2, 17.97 +/-0.2, 19.57 +/-0.2 and 20.56 +/-0.2.
Further, tromethamine salt form B, having the characteristics represented by the X-ray powder diffraction pattern substantially as shown in figure 17; a DSC profile having an endothermic peak at about 112.6 ℃ as shown in FIG. 18; also has an IR spectrum substantially as shown in FIG. 19.
It is a third object of the present invention to provide a process for the preparation of various base addition salts (including crystalline and amorphous forms) of the compounds of formula I. The overall process description, including the steps of:
(a) mixing a compound of formula I with a base in the presence of a good solvent;
(b) dissolving the mixture at normal temperature or under heating;
(c) the operation is selected from one of the following three modes:
cooling the mixture obtained in the step b to precipitate the salt;
or, directly or after partial solvent is removed, mixing the mixture obtained in the step b with a poor solvent, and precipitating the salt at normal temperature or under cooling;
or, removing the solvent from the mixture obtained in the step b, mixing the mixture with a poor solvent, and precipitating the salt at normal temperature or under cooling;
(d) separating the obtained precipitate or solid, and drying by conventional method.
The specific method is described below according to the different bases of various salt forms:
a) the preparation method of the sodium salt crystal form A of the compound shown in the formula I comprises the following steps: (1) dissolving a compound shown in a formula I and an alkaline sodium compound in an alcohol solvent, adding an ester solvent or a ketone solvent after the reaction is finished, slowly cooling, and separating out; (2) separating the obtained product; (3) optionally, drying the resulting product;
alternatively, the first and second electrodes may be,
b) the preparation method of the crystal form A of the diethylamine salt of the compound shown in the formula I comprises the following steps: (1) dissolving a compound shown in a formula I and diethylamine in an alcohol solvent, adding an ester solvent or a ketone solvent after the reaction is finished, slowly cooling, and separating out; (2) separating the obtained product; (3) optionally, drying the resulting product;
alternatively, the first and second electrodes may be,
c) the preparation method of the compound of the formula I, L-lysine salt amorphous alpha, comprises the following steps: (1) dissolving a compound shown in a formula I and L-lysine in an alcohol solvent, removing the solvent under reduced pressure after the reaction is finished, adding an ester solvent, rapidly cooling to-20-10 ℃, and precipitating; (2) separating the obtained product; (3) optionally, drying the resulting product;
alternatively, the first and second electrodes may be,
d) the preparation method of the compound L-arginine salt amorphous alpha of the formula I comprises the following steps: (1) dissolving a compound shown in a formula I and L-arginine in an alcohol solvent, decompressing and removing the solvent after the reaction is finished, adding an ester solvent, quickly cooling to-20-10 ℃, and precipitating; (2) separating the obtained product; (3) optionally, drying the resulting product;
alternatively, the first and second electrodes may be,
e) the preparation method of the compound of the formula I, namely the triethanolamine salt crystal form A, comprises the following steps: (1) dissolving a compound shown in a formula I and triethanolamine in an alcohol solvent, adding an ether solvent after the reaction is finished, slowly cooling and precipitating; (2) separating the obtained product; (3) optionally, drying the resulting product;
alternatively, the first and second electrodes may be,
f) the preparation method of the N-methylglucamine salt crystal form A of the compound shown in the formula I comprises the following steps: (1) dissolving a compound shown in a formula I and N-methylglucamine salt in an alcohol solvent, removing the solvent under reduced pressure after the reaction is finished, adding an ether solvent, slowly cooling and precipitating; (2) separating the obtained product; (3) optionally, drying the resulting product;
alternatively, the first and second electrodes may be,
g) the preparation method of the compound 1- (2-hydroxyethyl) -pyrrolidine salt amorphous alpha of the formula I comprises the following steps: (1) dissolving a compound shown in a formula I and 1- (2-hydroxyethyl) -pyrrolidine salt in an alcohol solvent, removing the solvent under reduced pressure after the reaction is finished, adding an alkane solvent, quickly cooling to-20-10 ℃, and separating out; (2) separating the obtained product; (3) optionally, drying the resulting product;
alternatively, the first and second electrodes may be,
h) the preparation method of the amorphous alpha of the magnesium salt of the compound shown in the formula I comprises the following steps: (1) dissolving a sodium salt of a compound shown in a formula I in water, and adding a water-soluble magnesium salt to separate out; (2) separating the obtained product; (3) optionally, drying the resulting product;
alternatively, the first and second electrodes may be,
i) the preparation method of the amorphous alpha of the calcium salt of the compound shown in the formula I comprises the following steps: (1) dissolving a compound of formula I in an alcohol solvent; (2) dissolving calcium acetate in water; (3) adding a calcium acetate aqueous solution into an alcoholic solution of the compound shown in the formula I, and separating out; (4) separating the obtained product; (5) optionally, drying the resulting product;
wherein, in the above steps, the "alkaline sodium compound" is selected from sodium hydroxide, sodium methoxide and sodium ethoxide, preferably sodium hydroxide; the ketone solvent is selected from one or more of acetone, butanone, pentanone and methyl isopropyl ketone, and acetone is preferred; the alcohol solvent is selected from one or more of ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol; preferably ethanol; the ester solvent is selected from one or more of ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate, and ethyl acetate is preferred; the ether solvent is selected from one or more of isopropyl ether, n-butyl ether and methyl tert-butyl ether, preferably methyl tert-butyl ether; the alkane solvent is selected from one or more of petroleum ether, n-hexane, cyclohexane, methylcyclohexane, n-heptane and isooctane, preferably n-hexane; the water-soluble magnesium salt is selected from one or more of magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, magnesium phosphate, magnesium formate and magnesium acetate, and preferably is magnesium chloride.
Further, the preparation method of the compound tromethamine salt crystal form A of the formula I comprises the following steps: reacting the compound shown in the formula I with an equivalent amount of tromethamine in methanol or ethanol at 30-60 ℃, concentrating under reduced pressure to remove a solvent after the reaction is finished, adding ethyl acetate, keeping the temperature and stirring at 45-60 ℃, cooling to-20-10 ℃ under stirring after all the materials are solidified, filtering, collecting the obtained product, and drying under reduced pressure at 30-50 ℃ to obtain the compound shown in the formula I, namely the tromethamine salt crystal form A.
Further, the preparation method of the compound tromethamine salt amorphous alpha of the formula I comprises the following steps: reacting a compound shown in the formula I and an equivalent amount of tromethamine in methanol or ethanol at 30-60 ℃, after the reaction is finished, adding ethyl acetate under heat preservation, quickly placing the mixture in a cooling bath at-20 to-10 ℃, stirring, carrying out suction filtration, adding a filter cake into n-hexane, stirring, filtering, collecting the obtained product, and drying under reduced pressure at 30-50 ℃ to obtain the compound shown in the formula I, namely tromethamine salt amorphous alpha.
Further, the preparation method of the compound tromethamine salt crystal form B of the formula I comprises the following steps: reacting a compound shown in the formula I and an equivalent amount of tromethamine in methanol or ethanol at 30-60 ℃, adding ethyl acetate and active carbon after the reaction is finished, preserving heat and stirring at 45-60 ℃, filtering, adding ethyl acetate into filtrate, gradually cooling to 0-5 ℃, preserving heat and stirring, filtering, pulping a filter cake at 0-10 ℃ by using normal hexane, performing suction filtration, and drying the filter cake at 30-50 ℃ under reduced pressure to obtain the compound tromethamine salt crystal form B shown in the formula I.
Further, the method for preparing the ethanolamine salt crystal form A of the compound shown in the formula I comprises the steps of reacting the compound shown in the formula I with ethanolamine with an equivalent weight in methanol or ethanol at 30-60 ℃, adding ethyl acetate after the reaction is finished, gradually cooling to 0-5 ℃, stirring at a constant temperature, filtering, and drying a filter cake at 30-50 ℃ under reduced pressure to obtain the ethanolamine salt crystal form A of the compound shown in the formula I.
The above-described production method can be appropriately adjusted, changed and optimized by a person skilled in the art by a conventional means. For example, in preparing the amorphous form of the salt of the compound of formula I, the product is obtained by vacuum freeze-drying an aqueous solution of the salt using a freeze-vacuum dryer.
A fourth object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a salt of a compound of formula i and a pharmaceutically acceptable adjuvant, wherein the salt is selected from: sodium salt, potassium salt, magnesium salt, calcium salt, diethylamine salt, ethylenediamine salt, piperazine salt, 1- (2-hydroxyethyl) -pyrrolidine salt, tromethamine salt, choline salt, ethanolamine salt, trimethylglycine salt, triethanolamine salt, meglumine salt, glucamine salt, tert-butylamine salt, L-lysine salt, and L-arginine salt.
The pharmaceutical compositions of the present invention may be prepared according to the state of the art. When necessary, the active ingredient can be combined with the medicine by selecting proper auxiliary materials, and then the medicine is prepared into a proper administration form or dosage form which can be used for human medicine.
The pharmaceutical compositions of the present invention may be administered in unit dosage form, either enterally or parenterally, for example orally, intramuscularly, subcutaneously, nasally, oromucosally, dermally, peritoneally or rectally, and the like. The pharmaceutical composition can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems. The pharmaceutical composition is any clinically or pharmaceutically acceptable dosage form.
The route of administration of the pharmaceutical composition of the present invention may be administration by injection. The injection route comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection and the like.
When used for parenteral administration, it can be prepared into injections. The injection is a sterile preparation of solution, emulsion or suspension for injection into the body and powder or concentrated solution for preparation or dilution into solution or suspension before use, and can be divided into injection, sterile powder for injection and concentrated solution for injection. The injection is sterile solution type injection, emulsion type injection or suspension type injection prepared from the medicine for injection into human body, and can be used for intramuscular injection, intravenous drip, etc. The sterile powder for injection is sterile powder or sterile block which is prepared by proper sterile solution to be prepared into clear solution or uniform suspension before use, can be prepared by proper solvent for injection and then injected, and can also be prepared by intravenous infusion and then is subjected to intravenous drip; the sterile powder is prepared by solvent crystallization, spray drying or freeze drying. Concentrated solution for injection refers to sterile concentrated solution of the drug for dilution before use for intravenous drip. In order to prepare the administration unit into the composition of the present invention into an injectable preparation, such as a solution, a suspension solution, an emulsion, a lyophilized powder injection, the preparation may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants.
The injection can be prepared by conventional method in pharmaceutical field, and can be aqueous solvent or non-aqueous solvent. The most commonly used aqueous solvent is water for injection, and 0.9% sodium chloride solution or other suitable aqueous solution can also be used; the common non-aqueous solvent is vegetable oil, which is mainly soybean oil for injection, and other aqueous solutions of ethanol, propylene glycol, polyethylene glycol and the like. When preparing the injection, the additive can be not added, and the proper additives can be added according to the property of the medicine, such as osmotic pressure regulator, pH value regulator, solubilizer, filler, antioxidant, bacteriostatic agent, emulsifier, suspending agent and the like. Commonly used osmo-regulators include sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol, etc., preferably sodium chloride or glucose; common pH regulator includes acetic acid-sodium acetate, lactic acid, citric acid-sodium citrate, sodium bicarbonate-sodium carbonate, etc.; commonly used solubilizers include
When used for oral administration, the composition can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. The tablet is a round or special-shaped tablet solid preparation prepared by uniformly mixing and pressing the medicament and proper auxiliary materials, mainly takes an oral common tablet as a main part, and also comprises a buccal tablet, a sublingual tablet, an oral patch, a chewable tablet, a dispersible tablet, a soluble tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet, an enteric-coated tablet 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. The capsule refers to a solid preparation prepared by filling a drug or an adjuvant into an empty capsule or sealing in a soft capsule material, and can be divided into hard capsules (generally called capsules), soft capsules (capsules), sustained-release capsules, controlled-release capsules, enteric capsules and the like according to the dissolution and release characteristics of the solid preparation. The pill refers to a spherical or spheroidal solid preparation prepared by mixing the medicine and proper materials uniformly and preparing the mixture by a proper method, and comprises a dropping pill, a sugar pill, a pellet and the like. The granules refer to dry granular preparations with certain granularity prepared by the medicines and proper auxiliary materials, and can be divided into soluble granules (generally called granules), suspension granules, effervescent granules, enteric granules, sustained-release granules, controlled-release granules and the like. Oral solution means that the drug is dissolved in a suitable solvent to make into a clear liquid preparation for oral administration. Oral suspensions refer to poorly soluble solid drugs dispersed in a liquid medium to form a suspension formulation for oral administration, including dry suspensions or concentrated suspensions. Syrup refers to a concentrated aqueous solution of sucrose containing the drug.
When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. Common fillers include starch, calcium phosphate, calcium sulfate dihydrate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, lactose, mannitol, sucrose, sodium chloride, glucose, calcium carbonate, microcrystalline cellulose, aluminum silicate, and the like; common binders include sodium carboxymethylcellulose, povidone K30, hydroxypropyl cellulose, starch slurry, methyl cellulose, ethyl cellulose, hypromellose, gelatinized starch, acacia slurry, gelatin slurry, polyvinylpyrrolidone, polyethylene glycol, etc.; common disintegrating agents include dry starch, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, alginates, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.; common lubricants include talc, sodium lauryl sulfate, colloidal silica, silica dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. In addition, according to the formulation requirements, a disintegration inhibitor such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil, etc. may be optionally added; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like.
For making the administration units into pills, a wide variety of carriers well known in the art can be used. Examples of vectors are as follows: diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, and the like; binding agents, such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc.
For making the administration unit into a suppository, various carriers well known in the art can be widely used. Examples of vectors are as follows: such as polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, and the like.
To encapsulate the administration units, the active ingredient is mixed with the various carriers described above, and the mixture thus obtained is placed in hard gelatin capsules or soft gelatin capsules. Or making into microcapsule, suspending in aqueous medium to form suspension, or making into hard capsule or injection.
In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparations, if desired.
The pharmaceutical composition provided by the invention comprises the following preparation forms: tablet, capsule, granule, powder, dry suspension, lyophilized powder for injection, suspension, drop suspension, syrup, oral solution, eye drop, nasal drop, ointment, cream, gel, patch, cataplasma, suppository, spray, inhalant or implant.
Wherein, the tablet comprises a slow release tablet, a double release tablet and an enteric-coated tablet besides the common tablet; the capsule includes hard capsule, soft capsule, delayed release capsule, and enteric capsule.
Preferably, the pharmaceutical composition comprises a therapeutically effective amount of salt of the compound of formula i and pharmaceutical excipients, wherein the salt is selected from sodium salt, potassium salt, magnesium salt, calcium salt, diethylamine salt, ethylenediamine salt, piperazine salt, 1- (2-hydroxyethyl) -pyrrolidine salt, tromethamine salt, choline salt, ethanolamine salt, trimethylglycine salt, triethanolamine salt, meglumine salt, glucosamine salt, tert-butylamine salt, L-lysine salt, L-arginine salt; the preparation form of the pharmaceutical composition comprises tablets, capsules, granules, powder, dry suspension, freeze-dried powder injection, suspension, injection emulsion, suspension drops, syrup, oral solution, eye drops, nose drops, ointment, cream, gel, patch, cataplasm, gel plaster, gel cream, suppository, spray, inhalant or implant.
Preferably, the salt of the pharmaceutical composition of the present invention is selected from sodium salt, diethylamine salt, tromethamine salt, L-arginine salt, L-lysine salt, N-methylglucamine salt, and 1- (2-hydroxyethyl) -pyrrolidine salt, and the preparation form thereof is solid preparation selected from one of tablet, capsule, granule, and dry suspension.
Preferably, the pharmaceutical composition of the present invention, the salt is selected from tromethamine salt, L-arginine salt, L-lysine salt, N-methylglucamine salt; the preparation form is selected from one of injection, freeze-dried powder injection, suspension and injection emulsion.
Preferably, the pharmaceutical composition of the invention is prepared from tromethamine salt, L-arginine salt and lysine salt in an injection form, wherein the weight percentage of the active ingredient compound shown in the formula I in the injection is 0.02-6.79%.
The injection contains at least one of the following injection grade auxiliary materials except the main medicine: osmotic pressure regulator, pH regulator, stabilizer; wherein the osmotic pressure regulator is selected from sodium chloride or glucose, and the pH regulator is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, dilute hydrochloric acid solution, tromethamine, L-arginine, phosphate buffer solution and citrate buffer solution.
Further preferably, the salt of the pharmaceutical composition of the present invention is tromethamine salt, the preparation form is injection, and the injection contains sodium chloride as an osmotic pressure regulator and tromethamine as a pH regulator in addition to the main drug.
Further preferably, the salt of the pharmaceutical composition is L-arginine salt, the preparation form is injection, and the injection contains sodium chloride as an osmotic pressure regulator and L-arginine as a pH regulator besides main drugs.
Further preferably, the salt of the pharmaceutical composition is L-lysine salt, the preparation form is injection, the injection contains sodium chloride as an osmotic pressure regulator besides main drugs, and the pH regulator is one or more selected from L-arginine, sodium hydroxide and dilute hydrochloric acid solution.
Preferably, the pharmaceutical composition of the present invention, which can be used in external preparations, is, for example, selected from tromethamine salt, ethanolamine salt, diethylamine salt, triethanolamine salt, 1- (2-hydroxyethyl) -pyrrolidine salt; the preparation can be in the form of patch, cataplasma, gel plaster, cream, and ointment.
Preferably, the pharmaceutical composition of the present invention, the salt is selected from tromethamine salt, ethanolamine salt, diethylamine salt; the preparation form is ointment; the ointment comprises: main medicine, white vaseline and one or more of the following auxiliary materials: liquid paraffin, hardened oil, lanolin, glyceryl monostearate, stearic acid, antiseptic, skin penetration enhancer, and aromatic; among them, the hardened oil is preferably hydrogenated peanut oil or hydrogenated castor oil; the preservative is selected from one or more of methyl hydroxybenzoate, ethyl hydroxybenzoate and propyl hydroxybenzoate; the skin penetration enhancer is one or more selected from N-methyl-2-pyrrolidone, L-menthol, isopropyl myristate, azone, urea, and Borneolum Syntheticum; and the types and the dosage of the auxiliary materials are in the conventional range of ointment preparation and pharmaceutically acceptable.
Preferably, the pharmaceutical composition of the present invention, the salt is selected from tromethamine salt, ethanolamine salt, diethylamine salt; the preparation form is cream; the cream comprises main drug, oil phase matrix, water, emulsifier and one or more of the following auxiliary materials: humectant, penetration enhancer, antiseptic, thickener; wherein the oil phase matrix is selected from one or more of white vaseline, liquid paraffin, hardened oil, lanolin, glyceryl monostearate, stearic acid, cetyl alcohol, and stearyl alcohol; the emulsifier is preferably one or more of tween, span, sodium dodecyl sulfate, polyoxyethylene alkyl ether, polyoxyethylene nonyl phenyl ether, cetostearyl alcohol and macrogol glyceride; the humectant is selected from one or more of propylene glycol, glycerol, sorbitol, and polyethylene glycol; the penetration enhancer is one or more selected from N-methyl-2-pyrrolidone, L-menthol, isopropyl myristate, azone, diisopropyl adipate, laurocapram, and cocoyl caprylocaprate; the preservative is selected from one or more of methyl hydroxybenzoate, ethyl hydroxybenzoate and propyl hydroxybenzoate; the thickener is one or more of xanthan gum, carbomer and sodium carboxymethylcellulose; and the types and the dosage of the auxiliary materials are in the conventional range of cream preparation and pharmaceutically acceptable.
Preferably, the salt of the pharmaceutical composition is selected from sodium salt, tromethamine salt, L-arginine salt, L-lysine salt and N-methylglucamine salt, and the preparation form of the pharmaceutical composition is a spray, and the spray contains hydroxypropyl methylcellulose, 1, 3-butanediol, citric acid hydrate, methyl p-hydroxybenzoate, L-menthol and ethanol besides main medicines; and the types and the dosage of the auxiliary materials are in the conventional range of the preparation of the spray and the pharmaceutical acceptance.
Preferably, the salt of the pharmaceutical composition is selected from sodium salt, tromethamine salt, L-arginine salt, L-lysine salt and N-methylglucamine salt, and the preparation form of the pharmaceutical composition is granules, and the granules comprise one or more of the following auxiliary materials besides main drugs: lactose, hydroxypropyl cellulose, magnesium stearate, iron oxide, flavoring agents, adhesion inhibitors; wherein the flavoring agent is preferably fumaric acid, D-mannitol; the adhesion inhibitor is one or more selected from pulvis Talci, hydrous silicon dioxide, and light anhydrous silicic acid; and the types and the dosage of the auxiliary materials are in the conventional range of granule preparation and pharmaceutically acceptable.
Preferably, the salt of the pharmaceutical composition is selected from sodium salt, tromethamine salt, L-arginine salt, L-lysine salt and N-methylglucamine salt, the preparation form of the pharmaceutical composition is tablets, and the granules comprise one or more of the following auxiliary materials besides main drugs: lactose hydrate, hydroxypropyl cellulose, corn starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, iron oxide, povidone, pregelatinized starch, sodium carboxymethyl starch, crospovidone, light anhydrous silicic acid, magnesium aluminum silicate, talc, light anhydrous silicon dioxide, and polysorbate; and the types and the dosage of the auxiliary materials are in the conventional range of tablet preparation and pharmaceutically acceptable.
Preferably, the salt of the pharmaceutical composition is selected from sodium salt, tromethamine salt, L-arginine salt, L-lysine salt and N-methylglucamine salt, and the preparation form of the pharmaceutical composition is an inhalant, and the inhalant comprises one or more of the following auxiliary materials besides the main drug: lactose, hydroxypropyl cellulose, corn starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, iron oxide, povidone, pregelatinized starch, sodium carboxymethyl starch, crospovidone, light anhydrous silicic acid, magnesium aluminum silicate, talc, light anhydrous silicon dioxide, and polysorbate; and the types and the dosage of the auxiliary materials are in the conventional acceptable range of the preparation of the inhalant and the pharmacy, and the main medicine and the auxiliary materials are subjected to spray freeze drying to obtain the dry powder inhalant.
Preferably, the pharmaceutical composition of the present invention, the salt is selected from sodium salt, tromethamine salt, L-arginine salt, L-lysine salt, N-methylglucamine salt, and the preparation form thereof is an implant, the implant is prepared by encapsulating the pharmaceutical active ingredient into a biodegradable and biocompatible polymer material carrier composed of a certain proportion, the polymer material carrier is selected from one or a mixture of Polylactide (PLA), Polyglycolide (PGA), polylactide-glycolide (PLGA), Polycaprolactone (PCL), Polyhydroxybutyrate (PHB), polyhydroxybutyrate valerate (PHBV), polydecanoic acid (PDA), polylactic acid-polyethylene glycol, preferably one or a mixture of Polylactide (PLA), Polyglycolide (PGA), polylactide-glycolide (PLGA), Polycaprolactone (PCL), the types and the dosage of the auxiliary materials are in the conventional range of the preparation of the inhalant and the pharmaceutical acceptance.
Preferably, the pharmaceutical composition of the present invention, the salt is selected from tromethamine salt, ethanolamine salt, diethylamine salt; the preparation form is a water-based gel, and comprises a main drug, a gel matrix, a solvent and one or more of the following auxiliary materials: neutralizer, perfume, penetration enhancer, antiseptic, antioxidant, cross-linking agent, and humectant;
alternatively, the salt is selected from tromethamine salts, ethanolamine salts, diethylamine salts; the preparation form is latex type gel (emulsion), which comprises main drug, gel matrix, oily matrix, emulsifier, solvent, and one or more of the following auxiliary materials: neutralizer, perfume, penetration enhancer, antiseptic, antioxidant, cross-linking agent, and humectant;
wherein, in the aqueous gel or latex type gel, the gel matrix is selected from one or more of carboxyvinyl polymer, preferably carbomer, hydroxypropyl methylcellulose, sodium hyaluronate, hydroxyethyl cellulose and hydroxypropyl cellulose; the solvent is one or more selected from water, ethanol, isopropanol and propylene carbonate; the neutralizer is one or more selected from triethanolamine, diisopropanolamine, concentrated ammonia solution, diethylamine and sodium hydroxide; the humectant is one or more selected from glycerol, 1, 3-butanediol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, and sorbitol; the perfume is selected from one or more of neroli oil, orange essence, banana essence, peppermint oil and lavender oil; the penetration enhancer is one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, polyethylene glycol monoethyl ether, cocoyl caprylocaprate, water-soluble azone, L-menthol, laurocapram, octyl decyl myristate and isopropyl myristate; the antiseptic is selected from one or more of sodium benzoate, benzyl alcohol, butyl p-hydroxybenzoate, methyl hydroxybenzoate, ethyl hydroxybenzoate, and propyl hydroxybenzoate; the antioxidant is one or more selected from dibutyl hydroxy toluene, sodium bisulfite, sodium metabisulfite, propyl gallate and DL-alpha-tocopherol; the emulsifier is selected from one or more of polyoxyethylene (35) castor oil, polyoxyethylene (20) hexadecyl octadecyl ether, hexadecyl octadecyl alcohol, oleyl alcohol, tween, span, polyoxyethylene polyoxypropylene hexadecyl ether and polyethylene glycol glyceride; the cross-linking agent is one or more selected from edetate disodium, lactic acid, citric acid, and tartaric acid; the oily matrix is selected from one or more of liquid paraffin, mineral oil, castor oil and coconut oil; and the types and the dosage of the auxiliary materials are in the conventional range of gel preparation and pharmaceutically acceptable.
Preferably, the pharmaceutical composition of the present invention, the salt is selected from sodium salt, tromethamine salt, ethanolamine salt, diethylamine salt; the preparation form is patch; the patch is a pressure-sensitive adhesive type patch, and comprises a backing, a patch-containing layer and an anti-adhesion film; the material of the pressure-sensitive adhesive is selected from ethylene/acrylate copolymer, polyisobutylene, polypentadiene, polyacrylate, silicone copolymer, styrene-isoprene-styrene triblock copolymer (SIS), ethylene-butadiene-styrene triblock copolymer (SBS), hydrogenated SBS (SEBS), polyurethane; the plaster comprises a backing, a plaster-containing layer and an anti-sticking film, wherein the plaster-containing layer contains a styrene-isoprene-styrene segmented copolymer, tackifying resin, a plasticizer and a main drug; wherein, the types and the dosages of the auxiliary materials are matched with each other, and the basic requirements of preparing the patch can be met. In addition, in the patch, a dissolving penetration enhancer, an antioxidant, a filling agent, a tackifier and other pharmaceutically acceptable excipients can be added into the patch-containing layer; wherein the tackifying resin is selected from one or more of saturated cyclic hydrocarbon resin, hydrogenated rosin glyceride and terpene resin; the plasticizer is selected from one or more of liquid paraffin and hardened oil; the tackifier is selected from one or more of polybutylene and polyisobutylene; the dissolution penetration enhancer is selected from one or more of L-menthol, isostearic acid, polyethylene glycol, N-methyl-2-pyrrolidone, medium chain fatty acid triglyceride, isopropyl myristate, laurocapram and azone; the antioxidant is selected from one or more of butyl hydroxy miaquilon, dibutyl hydroxy toluene, propyl gallate and tert-butyl hydroquinone, preferably dibutyl hydroxy toluene; the filler is selected from one or more of titanium dioxide, silicon dioxide and kaolin; the backing is a non-woven fabric or a woven fabric, and is preferably a non-woven fabric; the substrate material of the backing is selected from one or more of polyester, cotton, polyamide, polyolefin, polyurethane, silk and hemp, and is preferably polyolefin or polyester; the polyolefin is selected from one or more of polyethylene, polypropylene and polyvinyl chloride, and is more preferably polypropylene; the polyester is selected from polyethylene terephthalate or polybutylene terephthalate, and is preferably polyethylene terephthalate; the anti-sticking film material is selected from one or more of polyethylene, polypropylene, vinyl acetate, ethylene polymer and polyvinyl chloride, and more preferably, the surface layer of the anti-sticking film is treated by silica gel and the like; and the types and the dosage of the auxiliary materials are in the conventional range of patch preparation and pharmaceutically acceptable.
Preferably, the pharmaceutical composition of the present invention, the salt is selected from sodium salt, tromethamine salt, ethanolamine salt, diethylamine salt; the preparation form is cataplasm, also called gel plaster; the cataplasm comprises a backing, a plaster-containing layer and an anti-sticking film; wherein, the ointment-containing layer comprises a humectant, a hydrophilic framework material, a cross-linking agent, a pH regulator, a surfactant, a filling agent, a tackifier, a dissolution penetration enhancer, a preservative and purified water; the humectant is one or more selected from glycerol, propylene glycol, D-sorbitol solution, and polyethylene glycol 300; the hydrophilic skeleton material is selected from one or more of partially neutralized sodium polyacrylate, polyacrylic acid, sodium carboxymethylcellulose, polyvinyl alcohol (partially saponified), carboxyvinyl polymer (carbomer), and methylcellulose; the cross-linking agent is selected from one or more of aluminum hydroxide dry gel and sodium ethylene diamine tetracetate hydrate; the pH regulator is selected from one of tartaric acid, citric acid and malic acid, more preferably tartaric acid; the surfactant is selected from one or more of polyoxyethylene hydrogenated castor oil, polysorbate 80, sorbitan sesquioleate, polyoxyethylene nonyl phenyl ether, sodium dodecyl sulfate, polyoxyethylene alkyl ether, cetostearyl alcohol and polyethylene glycol glyceride; one or more of titanium dioxide as filler, light anhydrous silicic acid, talcum powder and kaolin; tackifier methyl acrylate/acrylic acid-2-ethylhexyl copolymer emulsion, and/or gelatin; the dissolution penetration enhancer is selected from one or more of L-menthol, isopropyl myristate, isostearic acid, polyethylene glycol, N-methyl-2-pyrrolidone, medium chain fatty acid triglyceride, laurocapram and azone; the preservative is selected from one or more of methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and ethyl p-hydroxybenzoate; and the types and the dosage of the auxiliary materials are in the conventional range of patch preparation and pharmaceutically acceptable.
The salt of the compound shown in the formula I belongs to a non-steroidal anti-inflammatory drug, and plays roles of relieving fever, easing pain and resisting inflammation by inhibiting the biosynthesis of prostaglandin. Therefore, the fifth object of the present invention is to provide a use of the salt of the compound of formula i, or the pharmaceutical composition of the present invention in the preparation of drugs for preventing or treating pain, inflammation and fever.
Further, the pharmaceutical use can also be described as follows: the use of a sodium salt of a compound of formula I, a diethylamine salt of a compound of formula I, a tromethamine salt of a compound of formula I, a L-arginine salt of a compound of formula I, a L-lysine salt of a compound of formula I, and a 1- (2-hydroxyethyl) -pyrrolidine salt of a compound of formula I for the preparation of a solid preparation for preventing or treating analgesia, inflammation diminishing and fever relieving, wherein the solid preparation is selected from tablets, capsules, granules and dry suspensions.
Further, the pharmaceutical use can also be described as follows: the compound of formula I is tromethamine salt, the compound of formula I is L-arginine salt, the compound of formula I is L-lysine salt, and the compound of formula I is N-methyl glucosamine salt, and the compound of formula I is used for preparing the injection for preventing or treating pain easing, inflammation diminishing and fever relieving, wherein the injection is selected from one of injection, freeze-dried powder injection, suspension and injection emulsion.
Further, the pharmaceutical use can also be described as follows: the use of the sodium salt of the compound of formula i, the tromethamine salt of the compound of formula i, the ethanolamine salt of the compound of formula i, the diethylamine salt of the compound of formula i, the triethanolamine salt of the compound of formula i and the 1- (2-hydroxyethyl) -pyrrolidine salt of the compound of formula i for the preparation of an external semisolid preparation for preventing or treating pain, inflammation and fever, wherein the external semisolid preparation is selected from one of ointment, cream, gel plaster, patch and cataplasm.
The salt of the compound shown in the formula I can be used for diminishing inflammation, and the inflammation which can be used for treating the inflammation is non-infectious inflammation including trauma, inflammation after operation or tooth extraction, chronic rheumatoid arthritis, osteoarthritis, lumbago, scapulohumeral periarthritis, neck-shoulder-wrist syndrome, periodontitis and ocular inflammation diseases.
The salts of the compounds of formula I provided by the invention are useful for antipyretic purposes.
The salt of the compound of formula I provided by the invention can be used for analgesia and can be used for symptomatic treatment of mild to moderate acute pain, such as musculoskeletal pain, dysmenorrhea and toothache; can be used for treating moderate pain, and can be used as adjuvant of opioid analgesic for treating moderate to severe pain.
The invention achieves the following beneficial technical effects and progresses:
the invention reports the salt and the crystal form of the compound shown in the formula I for the first time, the solid form has good physicochemical characteristics, is easy to prepare into corresponding preparations, and has important application in preparing antipyretic, analgesic and anti-inflammatory drugs.
1) The water solubility is greatly improved: the free acid of the compound shown in the formula I has low water solubility, the solubility after salification is greatly improved to about 60-100 times, and the compound is very convenient to prepare uniform liquid preparations such as injection, and meanwhile, the dissolution rate and the dissolution rate of the medicine are improved when the compound is prepared into solid preparations, so that the absorption and the bioavailability are improved.
2) The free acid of the compound shown in the formula I has poor physical and chemical properties, and tends to become sticky and yellow under the conditions of high temperature, high humidity, cold white fluorescent lamps and ultraviolet lamps, so that solids are easy to absorb moisture and adhere, and the preparation of solid preparations is difficult. However, most of the salts of the compound of the formula I have stable physicochemical properties under high temperature, high humidity and strong light irradiation, and the color is always white or quasi-white without discoloration. DVS results indicate that most of the new salt forms have reduced hygroscopicity and improved stability under high humidity conditions.
3) The solid form of the free acid of the compound shown in the formula I is often flocculent, is difficult to crush, is difficult to meet the content uniformity of a solid preparation, and cannot meet the requirement of large-scale production of the preparation. After salification, the beneficial preparation processing characteristics are obtained, the fluidity is improved, and the preparation of the solid preparation is convenient.
4) The salt of the compound of the formula I is prepared into a solid preparation, so that the dissolution rate and the dissolution rate are greatly improved compared with those of free acid, and the bioavailability is increased. Animal pharmacodynamic tests show that the salt of the invention has improved efficacy compared with free acid.
5) A series of pharmaceutically acceptable salts are prepared, the preparation method is simple to operate, the crystallization process is easy to control, the reproducibility is good, each salt type has improved physical and chemical properties including but not limited to solubility, dissolution rate, light stability, low hygroscopicity, high-temperature high-humidity stability, improved fluidity and anti-stickiness, uniform and stable preparations are conveniently prepared in large-scale production, and meanwhile, the material storage and quality control cost is indirectly reduced, so that the preparation method has economic value.
6) The salt is suitable for preparing injections, oral solid preparations and external semi-solid preparations. Particularly, the salt of the compound shown in the formula I can directly and quickly take effect, does not need to be absorbed by the liver through oral administration and then is converted into active metabolites to take effect, avoids the first-pass effect, and is suitable for injection preparations including injection and freeze-dried powder. In addition, the new salt form of the product is suitable for preparing external preparations, including ointment or cream, patch, cataplasm or emplastrum. The salt type has excellent physicochemical stability, good animal drug effect and preclinical safety test evaluation result.
Drawings
FIG. 1 is a hydrogen spectrum of a compound of formula I.
FIG. 2 is a mass spectrum of a compound of formula I.
FIG. 3 is a two-dimensional NOESY spectrum of a compound of formula I.
FIG. 4 is a PXRD pattern of form A of the sodium salt of the compound of formula I.
Figure 5 is a DSC profile of the sodium salt form a of the compound of formula i.
FIG. 6 is a PXRD pattern of diethylamine salt form A of the compound of formula I.
Figure 7 is a DSC profile of the compound of formula i diethylamine salt form a.
FIG. 8 is a PXRD pattern of the ethanolamine salt form A of the compound of formula I.
FIG. 9 is a DSC of the ethanolamine salt form A of the compound of formula I.
FIG. 10 is a PXRD pattern of the triethanolamine salt form A of the compound of formula I.
FIG. 11 is a DSC of the triethanolamine salt of the compound of formula I in crystalline form A.
FIG. 12 is a PXRD pattern of N-methylglucamine salt form A of the compound of formula I.
FIG. 13 is a DSC of N-methylglucamine salt form A of the compound of formula I.
FIG. 14 is a PXRD pattern of compound tromethamine salt form A of formula I.
FIG. 15 is a DSC of tromethamine salt of the compound of formula I, crystalline form A.
FIG. 16 is an IR spectrum of the compound of formula I tromethamine salt form A.
FIG. 17 is a PXRD pattern of compound tromethamine salt form B of formula I.
FIG. 18 is a DSC of the compound of formula I tromethamine salt form B.
FIG. 19 is an IR spectrum of compound tromethamine salt form B of formula I.
FIG. 20 is a PXRD pattern of the compound of formula I tromethamine salt amorphous form α.
FIG. 21 is a PXRD pattern measured after 6 months of prolonged testing of form B of the compound tromethamine salt of formula I.
FIG. 22 is a PXRD pattern measured after 6 months of accelerated testing of the compound of formula I tromethamine salt form B.
Remarking: PXRD refers to powder X-ray diffraction. DSC refers to differential scanning calorimetry. IR refers to infrared spectroscopy.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present disclosure more comprehensible, embodiments accompanying the present disclosure are described in detail below with reference to the accompanying drawings and specific examples.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure, but the present disclosure may be practiced in other ways than those described herein, and it will be apparent to those of ordinary skill in the art that the present disclosure may be practiced without departing from the spirit or scope of the present disclosure, and therefore the present disclosure is not limited to the specific embodiments disclosed below.
- 上一篇：一种医用注射器针头装配设备
- 下一篇：一种含有芳基丙酸类化合物的药物组合物