CN113662921A - A kind of obeticholic acid pharmaceutical composition and its preparation method and its application - Google Patents
A kind of obeticholic acid pharmaceutical composition and its preparation method and its application Download PDFInfo
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Abstract
本发明提供了包含奥贝胆酸或其衍生物的药物组合物，及其制备方法和其应用。所述奥贝胆酸或其衍生物的药物组合物的制备方法省去了多次分批多步混合微晶纤维素的操作步骤，并通过制备工艺的优化提高了药物组合物的溶出度和质量均一性，且所制得的药物组合物具有产品均一性高、不易裂片、溶出度高等优点，进而提高药物的有效性和安全性，并有效解决了制剂脆碎度等质量问题。The present invention provides a pharmaceutical composition comprising obeticholic acid or a derivative thereof, and a preparation method and application thereof. The preparation method of the pharmaceutical composition of the obeticholic acid or its derivative saves the operation steps of mixing microcrystalline cellulose in batches and multi-steps, and improves the dissolution rate and the dissolution rate of the pharmaceutical composition through the optimization of the preparation process. Quality uniformity, and the prepared pharmaceutical composition has the advantages of high product uniformity, not easy to split, and high dissolution rate, thereby improving the effectiveness and safety of the drug, and effectively solving the quality problems such as preparation friability.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an obeticholic acid medicinal composition, and a preparation method and application thereof.
Background
Obeticholic acid (obeticholic acid, 6 alpha-ethyl-3 alpha, 7 alpha-dihydroxy-5 beta-cholane-24-acid, structure shown in formula I) is an oral active analogue of natural human bile acid CDCA (chenodeoxycholic acid), and is clinically used for treating primary biliary cholangitis (PSC).
Obeticholic acid has the characteristics of low solubility and high permeability, and the dissolution and dissolution of a drug are rate-limiting steps of in vivo absorption. Therefore, increasing the dissolution rate of the drug is an important means for increasing the bioavailability of the drug. The existing research adopts the modes of reducing the particle size of the raw material medicine, changing the crystal form and the like to improve the dissolution, dissolution and bioavailability of obeticholic acid. However, the electrostatic effect between the drug particles will be increased when the particle size of the drug is too small, which causes the drug particles to agglomerate, thereby affecting the dispersibility of the active ingredients of the drug and the quality of the pharmaceutical preparation. Moreover, the percentage of pharmaceutically acceptable carriers (pharmaceutical excipients) in the pharmaceutical preparation reaches 95%, and the percentage and content of obeticholic acid are low, so that effective measures need to be taken to solve the problems of dispersibility of pharmaceutical particles in the preparation and uniform mixing between obeticholic acid and the pharmaceutically acceptable carriers, and further solve the problems of quality uniformity, drug dissolution, bioavailability, effectiveness, safety and the like of the pharmaceutical preparation, and the pharmaceutical preparation becomes a research hotspot in the field.
CN107531742A adopts a dry granulation method to prepare obeticholic acid tablets, and the method comprises the steps of screening, pre-blending, dry granulation, total mixing, compression, coating, packaging and the like, wherein the pre-blending comprises the following steps:
(1) weighing the drug obeticholic acid according to the prescription design, premixing the drug obeticholic acid and part of microcrystalline cellulose by using a mixer, and discharging to obtain a drug/microcrystalline cellulose premix;
(2) adding part of microcrystalline cellulose into the mixer in the step (1), mixing, cleaning residual drug obeticholic acid on the inner wall of the mixer to obtain a microcrystalline cellulose cleaning substance, and discharging;
(3) passing the drug/microcrystalline cellulose premix prepared in the step (1) and the microcrystalline cellulose cleaning substance prepared in the step (2) through a 1.0mm screen for later use;
(4) dividing the rest microcrystalline cellulose in the internal granulating material into 1/4 parts (by mass, the same below), 1/4 parts and 1/2 parts for later use;
1/4 microcrystalline cellulose, 1/2 medicament/microcrystalline cellulose premix in step (1), "microcrystalline cellulose cleaning product in step (2)," 1/2 medicament/microcrystalline cellulose premix in step (1) "and 1/4 microcrystalline cellulose are added into another mixer with larger volume in sequence for mixing;
(5) then adding sodium carboxymethyl starch and the rest 1/2 microcrystalline cellulose for mixing;
(6) sieving magnesium stearate with 0.5mm mesh sieve, adding into above materials, and mixing.
The preparation process of the method is very complex, the microcrystalline cellulose (MCC), the carboxymethyl starch sodium (CMS-Na) and the magnesium stearate which are used for premixing are required to be respectively screened in advance, and the microcrystalline cellulose is required to be mixed with obeticholic acid and other pharmaceutically acceptable carriers in batches for multiple times in the premixing step according to a specific sequence, so that the defects of complicated operation steps, complex working procedures, poor process stability, low production efficiency, high manufacturing cost, inconvenience for large-scale industrial production and the like exist.
CN109620812A adopts a wet granulation pot to premix obeticholic acid or pharmaceutically acceptable salts, esters or amino acid conjugates thereof and pharmaceutic adjuvants to prepare a premix thereof, and then dry granulation is carried out to prepare the required preparation. The method has the defects of unstable preparation process, low production efficiency, high preparation cost, no contribution to large-scale industrial production and the like.
Therefore, the preparation method of obeticholic acid preparation, which is simple and convenient to operate, good in process stability, more excellent in cost and suitable for large-scale industrial production, is urgently needed to be developed, and the problems of quality uniformity, preparation dissolution rate and the like of obeticholic acid preparation are effectively solved.
Disclosure of Invention
One of the purposes of the invention is to provide a preparation method of a pharmaceutical composition of obeticholic acid or derivatives thereof, which comprises the following steps:
(1) micronizing obeticholic acid or derivatives thereof to obtain micronized particles of obeticholic acid or derivatives thereof;
(2) uniformly mixing micronized particles of obeticholic acid or derivatives thereof with intragranular pharmaceutical excipients and sieving to obtain a premix; then dry granulating the prepared premix to obtain an intra-granular part;
(3) mixing the granules prepared in the step (2) with the medicinal auxiliary materials outside the granules, directly tabletting the prepared total mixture, and coating to obtain the tablet.
In a preferred technical scheme of the present invention, obeticholic acid is selected from any one or a combination of crystal form 1 (amorphous), crystal form a, crystal form C, crystal form D, crystal form F, and crystal form G of obeticholic acid, and is preferably crystal form 1.
In a preferred technical scheme of the invention, the obeticholic acid derivative is selected from any one or combination of pharmaceutically acceptable salts, ethers, esters, amino acid conjugates, taurine obeticholic acid (the structure is shown as formula II) or derivatives thereof.
In a preferred embodiment of the present invention, the salt of obeticholic acid is selected from any one or a combination of aluminum salt, calcium salt, lithium salt, magnesium salt, potassium salt, sodium salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, choline salt, procaine salt, diethanolamine salt, ethylenediamine salt, and meglumine (N-methylglucamine) salt thereof.
In a preferred embodiment of the present invention, the amino acid constituting the amino acid conjugate is selected from any one of lysine, arginine, histidine, ornithine, 2, 3-diaminopropionic acid, 2, 4-diaminopropionic acid, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, or a combination thereof.
In a preferred embodiment of the present invention, the taurine obeticholic acid derivative is selected from any one of salts, esters, ethers, amides, and amino acid conjugates of taurine obeticholic acid, or a combination thereof.
In a preferred embodiment of the present invention, the salt of taurine obeticholic acid is selected from any one or a combination of aluminum salt, calcium salt, lithium salt, magnesium salt, potassium salt, sodium salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine (N-methylglucamine) salt, and procaine salt thereof.
In a preferred embodiment of the present invention, the amino acid in the amino acid conjugate comprising taurine obeticholic acid is selected from any one or a combination of lysine, arginine, histidine, ornithine, 2, 3-diaminopropionic acid, 2, 4-diaminopropionic acid, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, S-adenosyl-L-methionine.
In a preferred embodiment of the present invention, the micronization method in step (1) is selected from any one or a combination of a jet milling method, a fluid milling method, a colloid milling method, a jet milling method, a co-milling method, and a ball milling method, and is preferably a jet milling method.
In a preferred technical scheme of the invention, the particle size of micronized obeticholic acid or derivatives thereof is less than or equal to 10 microns, preferably less than or equal to 5 microns, and more preferably 1-5 microns.
In the preferred technical scheme of the invention, the jet milling pressure is 0.2-0.8Mpa, preferably 0.3-0.6 Mpa.
In a preferred technical scheme of the invention, the intragranular pharmaceutical excipients in the step (2) are selected from any one or a combination of a filling agent, a disintegrating agent and a lubricating agent.
In a preferred technical scheme of the invention, the intragranular filling agent is selected from any one or combination of powdered sugar, dextrin, lactose, microcrystalline cellulose, pregelatinized starch, calcium sulfate dihydrate and mannitol.
In a preferred technical scheme of the invention, the intra-granular disintegrating agent is selected from any one of corn starch, potato starch, sodium carboxymethyl starch, low-substituted cellulose, polyvinylpyrrolidone and croscarmellose sodium or a combination thereof.
In a preferred embodiment of the present invention, the intragranular lubricant is selected from any one of magnesium stearate, aerosil, talc powder and hydrogenated vegetable oil, or a combination thereof.
In the preferable technical scheme of the invention, in the medicinal auxiliary materials in the granules, the mass ratio of the filling agent to obeticholic acid is 8-20:1, and is preferably 10.6:1 or 17.6: 1.
In the preferable technical scheme of the invention, in the medicinal auxiliary materials in the granules, the mass ratio of the disintegrant to obeticholic acid is 0.5-1:1, and the preferable mass ratio is 0.8: 1.
In the preferable technical scheme of the invention, in the medicinal auxiliary materials in the granules, the mass ratio of the lubricant to obeticholic acid is 0.1-0.5:1, and preferably 0.1: 1.
In a preferred embodiment of the present invention, in the premixing method in step (2), the micronized obeticholic acid or derivatives thereof and the intragranular pharmaceutical excipients are mixed at least 2 times, preferably at least 3 times.
In a preferred embodiment of the present invention, the premixing method in step (2) comprises the following steps: uniformly mixing micronized particles of obeticholic acid or derivatives thereof, an intragranular filler and an intragranular disintegrant, passing the prepared uniform mixture through a granulating machine provided with a screen mesh, uniformly mixing the sieved materials, adding an intragranular lubricant, and uniformly mixing to obtain the compound obeticholic acid.
In a preferred embodiment of the present invention, in the premixing method in step (2), the rotational speed for mixing the micronized obeticholic acid or the derivative thereof with the intragranular filler and the intragranular disintegrant is 5 to 100rpm, and the mixing time is preferably 10 to 60 min.
In a preferred embodiment of the present invention, the granulator is selected from any one or a combination of a vertical granulator, a swing granulator, a rapid granulator, a multi-functional granulator, and a granule mill.
In a preferred technical scheme of the invention, in the premixing method in the step (2), the particle size of a screen of the granulator is 1-5 mm.
In a preferred embodiment of the present invention, in the premixing method in step (2), the granulator is equipped with a round-corner granule-sizing knife, and preferably, the rotation speed of the granule-sizing knife is 100-500 rpm.
In the preferable technical scheme of the invention, in the premixing method in the step (2), the mixing time after the lubricant in the particles is added is 5-60 min.
In the preferred technical scheme of the invention, the step (2) adopts a dry granulating machine for granulation.
In a preferred technical scheme of the invention, the extra-granular pharmaceutical excipients in the step (3) are selected from any one or a combination of a filling agent, a disintegrating agent and a lubricating agent.
In a preferred technical scheme of the invention, the filler of the pharmaceutical excipients outside the granules is selected from any one or the combination of powdered sugar, dextrin, lactose, microcrystalline cellulose, pregelatinized starch, calcium sulfate dihydrate and mannitol, and is preferably microcrystalline cellulose.
In a preferred technical scheme of the invention, the disintegrant of the pharmaceutical adjuvant outside the granules is selected from any one or the combination of corn starch, potato starch, sodium carboxymethyl starch, low-substituted cellulose, polyvinylpyrrolidone and croscarmellose sodium, and is preferably sodium carboxymethyl starch.
In a preferred technical scheme of the invention, the lubricant of the extragranular pharmaceutical excipients is selected from any one or combination of magnesium stearate, aerosil, talcum powder and hydrogenated vegetable oil, and is preferably magnesium stearate.
In the preferable technical scheme of the invention, in the externally-used pharmaceutical excipients, the mass ratio of the filler to obeticholic acid is 0-10:1, and is preferably 7:1 or no externally-used filler.
In the preferable technical scheme of the invention, in the externally-used medicinal auxiliary material for granules, the mass ratio of the disintegrant to obeticholic acid is 0.2-0.8:1, and preferably 0.4: 1.
In the preferable technical scheme of the invention, in the externally-used medicinal auxiliary material, the mass ratio of the lubricant to obeticholic acid is 0.1-0.5:1, and preferably 0.1: 1.
In a preferred embodiment of the present invention, the total mixing in step (3) comprises mixing the prepared granule interior with the pharmaceutical excipient outside the granule for at least 2 times, preferably at least 3 times.
In a preferred technical scheme of the invention, the total mixing method in the step (3) comprises the following steps: mixing the obtained granule internal part with the external filler and the external disintegrating agent, adding the external lubricant, and mixing.
In a preferred technical scheme of the invention, the total mixing method in the step (3) comprises the following steps: mixing the obtained granule internal part with the granule external disintegrating agent, adding the granule external lubricant, and mixing.
In the preferable technical scheme of the invention, the mixing rotating speed in the total mixing step in the step (3) is 5-200 rpm.
In the preferable technical scheme of the invention, the mixing time of the obeticholic acid or the derivative thereof with the extragranular filling agent and the extragranular disintegrating agent or with the extragranular disintegrating agent in the total mixing step in the step (3) is 10-60min, and the mixing time after the extragranular lubricant is added is 5-30 min.
In the preferable technical scheme of the invention, the pressure of the direct compression in the step (3) is 5-20 kN.
In a preferred embodiment of the present invention, the coating in step (3) comprises the following steps: coating the tablet core with coating solution with concentration of 10-25% (w/w), wherein the rotation speed of a coating pan is 4-15rpm, the air supply temperature is 40-70 deg.C, the air exhaust temperature is 30-60 deg.C, and the temperature of the tablet bed layer is 35-55 deg.C, reducing the rotation speed of the coating pan to 1-10rpm, and drying.
In a preferred embodiment of the present invention, the coating material used in step (3) does not contain a plasticizer, or contain any one of polyethylene glycol, triethyl citrate, lecithin, glycerol fatty acid esters (including glycerol monostearate), propylene glycol, glycerol triacetate, polyoxyethylene sorbitan fatty acid esters (including polyoxyethylene sorbitan monooleate), concentrated glycerol, sorbitan fatty acid esters (including sorbitan sesquioleate and sorbitan monolaurate), sorbitol, glycerol, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, acetylated monoglycerides, acetyl triethyl citrate, acetyl tributyl citrate, glycerol monostearate, dioctyl phthalate, butyl phthalate glycolate, medium chain fatty acid triglyceride plasticizers, or combinations thereof.
In a preferred embodiment of the present invention, the fatty acid glyceride is any one or a combination of glycerol monolaurate, glycerol monomyristate, glycerol monopalmitate, glycerol monostearate, and glycerol monooleate, and preferably glycerol monostearate.
In a preferred embodiment of the present invention, the polyoxyethylene sorbitan fatty acid ester is selected from any one of or a combination of polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monomyristate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, and polyoxyethylene sorbitan monooleate, and is preferably polyoxyethylene sorbitan monooleate (also referred to as polysorbate 80).
In a preferred embodiment of the present invention, the sorbitan fatty acid ester is selected from any one of or a combination of sorbitan sesquioleate, sorbitan monolaurate, sorbitan monomyristate, sorbitan monopalmitate, sorbitan monostearate, and sorbitan monooleate, and is preferably any one of or a combination of sorbitan sesquioleate and sorbitan monolaurate.
In a preferred embodiment of the present invention, the plasticizer content in the coating material containing plasticizer in step (3) is 0.1-30% (w/w), preferably 1-25% (w/w), and more preferably 1-15% (w/w).
In a preferred embodiment of the present invention, the weight increase of the coating in step (3) is 1% -5% (w/w), and preferably the weight increase of the coating is 2% -4% (w/w).
The invention also aims to provide a pharmaceutical composition of obeticholic acid or derivatives thereof prepared by the preparation method.
In a preferred technical scheme of the invention, the pharmaceutical composition comprises the following components:
in a preferred technical scheme of the invention, the pharmaceutical composition comprises the following components:
in a preferred technical scheme of the invention, the pharmaceutical composition comprises the following components:
another object of the present invention is to provide a pharmaceutical composition comprising obeticholic acid or a derivative thereof and a fatty acid or a derivative thereof.
In a preferred embodiment of the present invention, the fatty acid derivative is selected from any one of pharmaceutically acceptable esters, derivatives, salts, or conjugates thereof, or combinations thereof.
In a preferred embodiment of the present invention, the fatty acid is any one or a combination of Linoleic Acid (LA), Arachidonic Acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linolenic acid (ALA), stearic acid (STA), eicosatrienoic acid (ETA), and docosapentaenoic acid (DPA).
In a preferred embodiment of the present invention, the pharmaceutically acceptable ester of eicosapentaenoic acid (EPA) is selected from any one of esters of eicosapentaenoic acid, alkyl esters of eicosapentaenoic acid from C1 to C5, ethyl esters of eicosapentaenoic acid, methyl esters of eicosapentaenoic acid, propyl esters of eicosapentaenoic acid, butyl esters of eicosapentaenoic acid, or combinations thereof.
In a preferred embodiment of the present invention, the derivative of eicosapentaenoic acid (EPA), the conjugate or the salt thereof is selected from one of all-cis eicosapentaenoic acid-5, 8, 11, 14, 17-pentaenoic acid, all-cis eicosapentaenoic acid-5, 8, 11, 14, 17-pentaenoic acid ethyl ester, ethyl-eicosapentaenoic acid, lithium eicosapentaenoic acid, monoglyceride, diglyceride or triglyceride eicosapentaenoic acid or eicosapentaenoic acid, free acid of eicosapentaenoic acid, 2-substituted eicosapentaenoic acid or a combination thereof.
Another object of the present invention is to provide the use of pharmaceutical compositions of obeticholic acid or derivatives thereof for the treatment of FXR related diseases.
In a preferred embodiment of the present invention, the FXR-related disease is selected from any one of liver disease, lung disease, gastrointestinal disease, metabolic disease, osteoporosis, cancer, cardiovascular disease, or a complication thereof.
In a preferred embodiment of the present invention, the liver disease is selected from any one of primary biliary cirrhosis (PBS), nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, Primary Sclerosing Cholangitis (PSC), and complications thereof.
In a preferred embodiment of the present invention, the pulmonary disease is selected from any one of obstructive pulmonary disease (COPD), emphysema, asthma, idiopathic pulmonary fibrosis, pneumonia, tuberculosis, cystic fibrosis, bronchitis, pulmonary hypertension, interstitial lung disease, and lung cancer or a complication thereof, and preferably, the pulmonary hypertension is selected from any one of Idiopathic Pulmonary Arterial Hypertension (IPAH), Secondary Pulmonary Hypertension (SPH), or a complication thereof.
In a preferred embodiment of the invention, the gastrointestinal disease is selected from any one of Inflammatory Bowel Disease (IBD), Irritable Bowel Syndrome (IBS), bacterial overgrowth, malabsorption, colorectal cancer, post-radiation colitis, microscopic colitis, or a complication thereof.
In a preferred embodiment of the present invention, the metabolic disease is selected from any one of hyperglycemia, diabetes, obesity, and insulin resistance, or a complication thereof.
In a preferred embodiment of the present invention, the cancer is any one or a complication selected from liver cancer, pancreatic cancer, kidney cancer, prostate cancer, esophageal cancer, breast cancer, stomach cancer, salivary gland cancer, ovarian cancer, uterine body cancer, bladder cancer, and lung cancer.
In a preferred embodiment of the present invention, the cardiovascular related diseases are selected from any one of hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction, other cardiovascular diseases or complications thereof.
Another object of the present invention is to provide a pharmaceutical composition of obeticholic acid or a derivative thereof for use in combination with other drugs.
In a preferred embodiment of the present invention, the other drug is selected from any one of PPAR- α agonists, PPAR- δ agonists, PPAR- α and δ dual agonists, hypoglycemic drugs, angiotensin II receptor blockers (ARBs), or a combination thereof.
In a preferred embodiment of the present invention, the PPAR- α agonist is selected from any one of bezafibrate, ciprofibrate, clofibrate, fenofibrate, gemfibrozil, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirfibrate, pramipexole, clinofibrate, clofibrate, tolofibrine, and tocofibrate, or a pharmaceutically acceptable salt or ester thereof.
In a preferred embodiment of the invention, the PPAR-alpha agonist is a derivative of 2-phenoxy-2-methylpropionic acid, preferably the phenoxy moiety in said derivative is substituted by an optionally substituted piperidine, 4-hydroxypiperidine, piperidin-3-ene or piperazine.
In a preferred embodiment of the invention, the PPAR-delta agonist is selected from {4- [ ({ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -1, 3-thiazol-5-yl } methyl) sulfanyl ] -2-methylphenoxy } acetic acid, { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -2H- [1,2,3] triazol-4-ylmethylsulfanyl ] -phenoxy } -acetic acid, any one of [4- [ [ [2- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -4-methyl-5-thiazolyl ] methyl ] thio ] -2-methylphenoxy ] -acetic acid or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the invention, the PPAR-alpha and delta dual agonist is selected from the group consisting of 2- [2,6 dimethyl-4- [3- [4- (methylthio) phenyl ] -3-oxo-1 (E) -propenyl ] phenoxy ] -2-methylpropionic acid, (2S) -2-methoxy-3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy ] -7-benzothiophenyl ] propionic acid, N- [ (4-methoxyphenoxy) carbonyl ] -N- {4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy ] benzyl } glycine, and mixtures thereof, Any one of (2S) -2-ethoxy-3- [4- [2- (4-methylsulfonyloxyphenyl) ethoxy ] phenyl ] propanoic acid, or (2S) -2-ethoxy-3- [4- (2- { 2-methyl-5- [4- (methylsulfanyl) phenyl ] -1H-pyrrol-1-yl } ethoxy) phenyl ] propanoic acid, or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the hypoglycemic drug is selected from the group consisting of insulin lispro, insulin aspart, gelucin, rapid acting insulin, zinc glargine, insulin detemir, insulin arrestin, insulin zinc long acting insulin, zinc degluin, tolbutamide, acetohexamide, tolazamide, chlorpropamide, amicarbazide, metahexylamide, glipizide, euglycemic, glyburide, glipiride, gliquidone (Glurenorm), gliclazide (Uni diamacrron), glibornuride, glimeperide, glimepiride, j253, exenatide/exendin-4, liraglutide, lixide, albiglutelin, dolaride, soglutanmide, BRX-0585 (Pfizer/bioreexis), and CJC-1134-PC (exendin-4 conjugated to human serum albumin) Vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, sitagliptin, alagliptin, giagliptin, treliptin, canagliptin, goligliptin, dulagliptin, berberine, lupeol, rosiglitazone, troglitazone, pioglitazone, englitazone, balaglitazone, ciglitazone, lobeglitazone, and nateglinide, as well as nateglinide, metformin, buformin, phenformin, canagliflozin, engliptin, regagliflozin, sjogrezin, trogliflozin, eggliflozin, miglitol acarbose, voglibose, dextrin or dextrin analogues, pramlintide, imipramipexole, indoglitazole, glidolidago, idago, efavirenz, fluxofenaminoxidin, berroside, glycitein, glycitin, glycitein, any one or combination of carbenoxolone, abietic acid, flavonoid naringenin (naringenin), anthraquinone emodin, adamantyl [1,2,4] triazolo [4,3-a ] azepine, BVT-2733, BVT-116429, BVT-3498/AMG-311, AMG-221, PF-915275, HSD-016, INCB-13739, INCB-20817, MK-0916, MK-0736, AZD-4017, AZD-8329, RG-4929, RG-7234, BMS-816336 and JTT-654.
In a preferred embodiment of the present invention, the angiotensin II receptor blocker
(ARB) is selected from any one of losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan, azilsartan or combinations thereof.
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the preparation method of the pharmaceutical composition of obeticholic acid or the derivative thereof provided by the invention omits the operation step of mixing microcrystalline cellulose in batches and in multiple steps, improves the dissolution rate and quality uniformity of the pharmaceutical composition through optimization of the preparation process, and the prepared pharmaceutical composition has the advantages of high product uniformity, difficulty in cracking, high dissolution rate and the like, so that the effectiveness and safety of the medicine are improved, and the quality problems of friability and the like of the preparation are effectively solved.
2. The preparation method of the invention has the advantages of simple operation, obviously shortened production period, further obviously reduced production cost and suitability for large-scale industrial production.
Drawings
Figure 1 dissolution curve of obeticholic acid pharmaceutical composition.
FIG. 2 shows the compatibility test results of obeticholic acid and coating powder.
Figure 3 accelerated stability test results of obeticholic acid pharmaceutical compositions at 40 ℃ and 75 Relative Humidity (RH).
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention. Based on the embodiments of the present invention, those skilled in the art can change or modify the present invention without any inventive changes or modifications.
The pharmaceutical compositions of examples 1-4 are exemplified by a 10mg standard tablet, and obeticholic acid used is obeticholic acid crystalline form 1 (amorphous). The specific composition of the pharmaceutical composition is shown in table 1.
TABLE 1 Obeticholic acid pharmaceutical composition formulation
EXAMPLE 1 preparation of obeticholic acid pharmaceutical compositions of the invention
The preparation method of the obeticholic acid pharmaceutical composition comprises the following steps:
(1) micronizing the obeticholic acid raw material drug in a super-high-speed jet mill under the pressure of 0.3 Mpa;
(2) putting micronized obeticholic acid particles, microcrystalline cellulose in the particles and sodium carboxymethyl starch in the particles into a self-sealing bag, mixing for 5min, passing through a vertical granulating machine with a 1.0mm screen, transferring into the self-sealing bag, mixing for 8min, adding magnesium stearate in the particles, and mixing for 5min to obtain a premix;
the prepared premix was fed into a dry granulator, setting the feed rate: 20rpm, nip pressure: 25bar, press roll speed: 8rpm, shear rate: 100rpm, finishing rotation speed: 100rpm, screen mesh size: 1.0mm, operating according to the parameters, and collecting the granulated material at a material receiving port to obtain the intra-granular part, wherein the distance between compression rollers is 1.2-1.3mm in a steady state;
(3) mixing the inside part of the granules obtained in the step (2) with the outside-granule microcrystalline cellulose and the outside-granule carboxymethyl starch sodium in a self-sealing bag for 10min, and then mixing with the outside-granule magnesium stearate for 10min to obtain a total mixture;
tabletting the obtained total mixture in a tabletting machine, wherein the tabletting pressure is 5 kN; coating the tablet core with 20% w/w coating solution, coating powder 85A620004-CN (purchased from Calycor corporation), coating pan rotating speed of 5rpm, air supply temperature of 45 deg.C, air exhaust temperature of 35 deg.C, tablet bed layer temperature of 35 deg.C, coating weight increment of 3%, reducing the rotating speed of the coating pan to 2rpm, and drying.
EXAMPLE 2 preparation of obeticholic acid pharmaceutical compositions of the invention
The preparation method of the obeticholic acid pharmaceutical composition comprises the following steps:
(1) delivering the obeticholic acid raw material medicine into a jet mill for micronization, wherein the pressure is 0.5 Mpa;
(2) putting micronized obeticholic acid particles, microcrystalline cellulose in the particles and sodium carboxymethyl starch in the particles into a 5L mixing hopper, mixing at the rotating speed of 30rpm for 25min, passing through a vertical granulating machine provided with a 1.2mm screen, transferring into the mixing hopper, mixing at the same rotating speed for 10min, adding magnesium stearate in the particles, and mixing for 8min to obtain a premix;
the prepared premix is put into a dry-process granulator, and the feeding speed is set as follows: 20rpm, nip pressure: 40bar, press roll speed: 8rpm, shear rate: 100rpm, finishing rotation speed: 100rpm, screen mesh size: 1.5mm, operating according to the parameters, and collecting the granulated material at a material receiving port to obtain the intra-granular part, wherein the distance between compression rollers is 1.2-1.3mm in a steady state;
(3) mixing the inside of the granules obtained in the step (2) with the outside-granule microcrystalline cellulose and the outside-granule carboxymethyl starch sodium in a hopper at the rotating speed of 100rpm for 10min, and then mixing the inside of the granules with the outside-granule magnesium stearate at the same rotating speed for 15min to obtain a total mixture;
tabletting the obtained total mixture in a tabletting machine, wherein the tabletting pressure is 8 kN; coating the tablet core with 25% w/w coating solution, coating powder 85A620004-CN (purchased from Calycor corporation), coating pan rotating speed of 10rpm, air supply temperature of 48 ℃, air exhaust temperature of 30 ℃, tablet bed layer temperature of 50 ℃, coating weight gain of 2.8%, reducing the coating pan rotating speed to 4rpm, and drying.
EXAMPLE 3 preparation of obeticholic acid pharmaceutical compositions of the invention
The preparation method of the obeticholic acid pharmaceutical composition comprises the following steps:
(1) delivering the obeticholic acid raw material medicine into a jet mill for micronization, wherein the pressure is 0.6 Mpa;
(2) putting micronized obeticholic acid particles, microcrystalline cellulose in the particles and sodium carboxymethyl starch in the particles into a 50L mixing hopper, mixing at the rotating speed of 25rpm for 60min, then passing through a vertical granulator provided with a 1.5mm screen, wherein the granulator is also provided with a fillet granulating knife, the rotating speed is set to 300rpm, transferring undersize materials into the 50L mixing hopper, and mixing at the rotating speed of 45 rpm; adding magnesium stearate into the granules after 30min, and mixing for 20min to obtain a premix;
the prepared premix is put into a dry-process granulator, and the feeding speed is set as follows: 60rpm, nip pressure: 50bar, roller speed 15rpm, shear speed: 200rpm, finishing rotation speed: 200rpm, screen mesh size: 1.5mm, operating according to the parameters, and collecting the granulated material at a material receiving port to obtain the intra-granular part, wherein the distance between compression rollers is 1.2-1.3mm in a steady state;
(3) mixing the inside of the granules obtained in the step (2) with the outside-granule microcrystalline cellulose and the outside-granule carboxymethyl starch sodium in a hopper at the rotating speed of 160rpm for 35min, and then mixing the inside of the granules with the outside-granule magnesium stearate at the same rotating speed for 25min to obtain a total mixture;
tabletting the obtained total mixture in a tabletting machine, wherein the tabletting pressure is 10 kN; coating the tablet core with coating solution with concentration of 15% w/w, coating powder of 85A620004-CN (purchased from Calycor corporation), coating pan rotating speed of 15rpm, air supply temperature of 40 deg.C, air exhaust temperature of 30 deg.C, tablet bed layer temperature of 35 deg.C, coating weight increasing 3.1%, reducing the rotating speed of the coating pan to 5rpm, and drying.
EXAMPLE 4 preparation of obeticholic acid pharmaceutical compositions of the invention
The preparation method of the obeticholic acid pharmaceutical composition comprises the following steps:
(1) micronizing the obeticholic acid raw material drug in a super-high-speed jet mill under the pressure of 0.3 Mpa;
(2) putting micronized obeticholic acid particles, microcrystalline cellulose in the particles and sodium carboxymethyl starch in the particles into a self-sealing bag, mixing for 5min, passing through a vertical granulating machine with a 1.0mm screen, transferring into the self-sealing bag, mixing for 8min, adding magnesium stearate in the particles, and mixing for 5min to obtain a premix;
the prepared premix was fed into a dry granulator, setting the feed rate: 20rpm, nip pressure: 25bar, press roll speed: 8rpm, shear rate: 100rpm, finishing rotation speed: 100rpm, screen mesh size: 1.0mm, operating according to the parameters, and collecting the granulated material at a material receiving port to obtain the intra-granular part, wherein the distance between compression rollers is 1.2-1.3mm in a steady state;
(3) mixing the inside of the granules obtained in the step (2) with the sodium carboxymethyl starch outside the granules in a self-sealing bag for 10min, and then mixing with the magnesium stearate outside the granules for 10min to obtain a total mixture;
tabletting the obtained total mixture in a tabletting machine, wherein the tabletting pressure is 5 kN; coating the tablet core with 20% w/w coating solution, coating powder 85A620004-CN (purchased from Calycor corporation), coating pan rotating speed of 5rpm, air supply temperature of 45 deg.C, air exhaust temperature of 35 deg.C, tablet bed layer temperature of 35 deg.C, coating weight increment of 3%, reducing the rotating speed of the coating pan to 2rpm, and drying.
Test example 1 Obeticholic acid particle size distribution
And detecting the particle size distribution of obeticholic acid by using a Malvern laser particle size analyzer laser diffraction method. The dispersion principle is as follows: dry process, pressure: 3.0bar, feed rate: 20%, feed height: 2mm, at least 3 measurements were made and the average was taken. The results are as follows:
| D90/μm | |
| example 1 | 3.8 |
| Example 2 | 4.0 |
| Example 3 | 4.7 |
| Example 4 | 4.1 |
Test example 2 content and mixing uniformity of obeticholic acid pharmaceutical composition
10 tablets of each of the coated prodrug tablets prepared in examples 1 to 4 were dissolved in 80% methanol, and the relative content of the drug was measured by HPLC. Meanwhile, the method in the 'Chinese pharmacopoeia' 2015 edition (fourth part) '9041' is adopted to detect the content uniformity of the medicine, and the result is as follows:
| content average (%) | RSD(％) | A+2.2S | |
| Example 1 | 99.41 | 0.8 | 2.45 |
| Example 2 | 100.08 | 1.44 | 3.24 |
| Example 3 | 99.95 | 2.04 | 4.53 |
| Example 4 | 99.70 | 0.53 | 1.46 |
Test example 3 friability test of obeticholic acid pharmaceutical composition
The hardness of the tablet before coating was measured by a hardness measuring instrument, and the friability and disintegration time were measured by the methods in "chinese pharmacopoeia" 2015 edition (fourth part) "0923" and "0921", with the following results:
| average single tablet weight (mg) | Hardness (kg) | Degree of friability | Disintegration time(s) | |
| Example 1 | 202.23 | 10 | ＜0.3％ | ＜30 |
| Example 2 | 201.90 | 11 | ＜0.3％ | ＜30 |
| Example 3 | 200.85 | 12 | ＜0.3％ | ＜30 |
| Example 4 | 201.11 | 12 | ＜0.3％ | ＜30 |
Test example 4 dissolution test of obeticholic acid pharmaceutical composition
As Obeticholic acid tablets from Intetocept pharmaceutical, USA
(10mg) As a control, the coated pharmaceutical compositions prepared in examples 1-3 were tested for dissolution by the United states Pharmacopeia (USP II) method. The dissolution medium is pH4.5 acetate buffer solution + 0.08% Tween, the dissolution volume is 900ml, the rotation speed is 75rpm, the temperature is 37 + -0.5 ℃, the sampling time is 5/15/20/30/45/60/90min, and the analysis method is HPLC/Corona CAD. Dissolution results are shown in figure 1.
Test example 5 stability study of obeticholic acid pharmaceutical composition
Compatibility research is carried out on raw materials and auxiliary materials, and the raw material of obeticholic acid and two coating powders 85A620004-CN (coating powder 1, purchased from Calycor company),
II (coating powder 2) was mixed at a ratio of 1:5, and the occurrence of impurities was measured by HPLC/Corona method after mixing for 0 day and standing at 60 ℃ for 5 days, as shown in FIG. 2. The results show thatThe polyethylene glycol coating powder 85A620004-CN (coating powder 1) has good compatibility with the main component obeticholic acid, and new impurities are not generated basically.
The tablets prepared in example 3 were subjected to an accelerated stability test at 40 ℃ and 75 Relative Humidity (RH) for 6 months. The crystal form was measured by an X-ray powder diffractometer, and the results are shown in fig. 3, and after 6 months of accelerated conditions, the crystal form did not change.
Claims (10)
1. A method for preparing a pharmaceutical composition comprising obeticholic acid or a derivative thereof, comprising the steps of:
(1) micronizing obeticholic acid or derivatives thereof to obtain micronized particles of obeticholic acid or derivatives thereof;
(2) uniformly mixing micronized particles of obeticholic acid or derivatives thereof with intragranular pharmaceutical excipients and sieving to obtain a premix; then dry granulating the prepared premix to obtain an intra-granular part;
(3) mixing the granules prepared in the step (2) with the medicinal auxiliary materials outside the granules, directly tabletting the prepared total mixture, and coating to obtain the tablet.
2. The method according to claim 1, wherein the obeticholic acid derivative is selected from any one or a combination of a pharmaceutically acceptable salt, ether, ester, amino acid conjugate, taurine obeticholic acid or a derivative thereof.
3. The method according to any one of claims 1 to 2, wherein the pulverization method of step (1) is selected from any one of a jet milling method, a fluid milling method, a colloid milling method, a jet milling method, a co-milling method, a ball milling method, or a combination thereof; preferably, the particle diameter of the crushed obeticholic acid or derivative thereof is less than or equal to 10 microns.
4. The method according to any one of claims 1 to 3, wherein the intragranular pharmaceutical excipients in step (2) are selected from any one or more of fillers, disintegrants, lubricants; preferably, the mass ratio of the filler to the obeticholic acid is 8-20: 1; preferably, the mass ratio of the disintegrant to obeticholic acid is 0.5-1: 1; preferably, the mass ratio of the lubricant to obeticholic acid is 0.1-0.5: 1.
5. The process according to any one of claims 1 to 4, wherein in the pre-mixing process of step (2) the micronized particles of obeticholic acid or derivatives thereof are homogeneously mixed with the intragranular pharmaceutical excipients at least 2 times.
6. The method according to any one of claims 1 to 5, wherein the extra-granular pharmaceutical excipients in step (3) are selected from any one of a filler, a disintegrant, a lubricant, or a combination thereof; preferably, the mass ratio of the filler to the obeticholic acid is 0-10: 1; preferably, the mass ratio of the disintegrant to obeticholic acid is 0.2-0.8: 1; preferably, the mass ratio of the lubricant to obeticholic acid is 0.1-0.5: 1.
7. The method according to any one of claims 1 to 6, wherein the total mixing in step (3) is performed by uniformly mixing the intra-granular part obtained in step (3) with the extra-granular pharmaceutical excipients at least 2 times.
8. The method according to any one of claims 1 to 7, wherein the coating material used in step (3) does not contain a plasticizer or contains polyethylene glycol, triethyl citrate, lecithin, glycerol fatty acid esters (including glycerol monostearate), propylene glycol, glycerol triacetate, polyoxyethylene sorbitan fatty acid esters (including polyoxyethylene sorbitan monooleate), condensed glycerol, sorbitan fatty acid esters (including sorbitan sesquioleate and sorbitan monolaurate), sorbitol, glycerol, diethyl phthalate, dibutyl sebacate, tributyl citrate, diethyl sebacate, acetylated monoglycerides, acetyl triethyl citrate, acetyl tributyl citrate, glycerol monostearate, dioctyl phthalate, butyl phthalyl butyl glycolate, butyl glycolate, Any one or combination of medium chain fatty acid triglyceride plasticizers.
9. A pharmaceutical composition prepared by the process according to any one of claims 1 to 8.
10. Use of a pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of FXR related diseases.
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| CN115598267A (en) * | 2022-12-13 | 2023-01-13 | 山东省食品药品检验研究院（Cn） | Analysis method of potential genotoxic impurities in gliclazide |
| CN117838706A (en) * | 2024-01-11 | 2024-04-09 | 中国人民解放军空军军医大学 | Application of obeticholic acid in the preparation of drugs for preventing and/or treating radiation-induced intestinal injury |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109620812A (en) * | 2019-01-16 | 2019-04-16 | 浙江华海药业股份有限公司 | A kind of preparation method of Austria's shellfish cholic acid composition |
| WO2019106043A1 (en) * | 2017-11-29 | 2019-06-06 | Hexal Ag | Pharmaceutical composition comprising obeticholic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019106043A1 (en) * | 2017-11-29 | 2019-06-06 | Hexal Ag | Pharmaceutical composition comprising obeticholic acid |
| CN109620812A (en) * | 2019-01-16 | 2019-04-16 | 浙江华海药业股份有限公司 | A kind of preparation method of Austria's shellfish cholic acid composition |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115598267A (en) * | 2022-12-13 | 2023-01-13 | 山东省食品药品检验研究院（Cn） | Analysis method of potential genotoxic impurities in gliclazide |
| CN115598267B (en) * | 2022-12-13 | 2023-05-09 | 山东省食品药品检验研究院 | A method for analyzing potential genotoxic impurities in gliclazide |
| CN117838706A (en) * | 2024-01-11 | 2024-04-09 | 中国人民解放军空军军医大学 | Application of obeticholic acid in the preparation of drugs for preventing and/or treating radiation-induced intestinal injury |
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