WO2020143395A1 - 一种氟哌噻吨美利曲辛片剂及其制备方法 - Google Patents
一种氟哌噻吨美利曲辛片剂及其制备方法 Download PDFInfo
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- WO2020143395A1 WO2020143395A1 PCT/CN2019/125240 CN2019125240W WO2020143395A1 WO 2020143395 A1 WO2020143395 A1 WO 2020143395A1 CN 2019125240 W CN2019125240 W CN 2019125240W WO 2020143395 A1 WO2020143395 A1 WO 2020143395A1
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- Prior art keywords
- droperidol
- hydrochloride
- tablet
- granules
- melitrexine
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- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000007443 Neurasthenia Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- IOVDQEIIMOZNNA-MHKBYHAFSA-N cis-flupenthixol dihydrochloride Chemical compound Cl.Cl.C1CN(CCO)CCN1CC\C=C\1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C2/1 IOVDQEIIMOZNNA-MHKBYHAFSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940004199 droperidol injection Drugs 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940081762 haloperidol 0.5 mg Drugs 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- -1 melitrexine Chemical compound 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Definitions
- the invention relates to a droperidol melitricine tablet and a preparation method thereof, which belong to the technical field of pharmaceutical preparations.
- the stability of pharmaceutical preparations is a very important consideration during the design, production, and storage of pharmaceutical compositions. Drugs with poor stability may be degraded into certain degradation products to cause unnecessary side reactions or reduce the efficacy or bioavailability of the drug itself, making it difficult to achieve satisfactory results.
- Haloperidol hydrochloride is the hydrochloride form of the atypical antipsychotic haloperidol. It is a thioxanthene derivative and has a strong dopamine receptor blocking effect. It has anxiolytic and antidepressant effects in small doses. Its chemical name is: 2-[4-[3(EZ)-(2-trifluoromethylthioanthracene-9-ylidene)propyl]piperazin-1-yl]ethanol dihydrochloride, structural formula as follows:
- Melitrexine hydrochloride is a tricyclic biphasic antidepressant. It has exciting properties when used in low doses. Its chemical name is: 3-[10,10-dimethyl-9(10H)-anthracene]-N,N-dimethyl-1-propylamine hydrochloride, the structural formula is as follows:
- Haloperidol was marketed in 1966, and its formulations include flupentixol tablets (specification: 0.5 mg and 5 mg) and droperidol injection (specification: 1 mL: 20 mg). Melicin was marketed in 1968, and its preparation is a capsule. Haloperidol and melitrexine compound formulations have antidepressant, anxiolytic and excitatory properties. Denmark's Lingbei Pharmaceutical Co., Ltd.
- each tablet Contains 0.584mg of flupentixol dihydrochloride (0.5mg as flupenthixol) and 11.25mg of melitrexine hydrochloride (10mg as melitrexine), the product has mild to moderate depression and anxiety, neurasthenia Psychogenic depression, depressive neurosis have definite curative effect, fast onset, and small adverse reactions, and are one of the most used antidepressants in China.
- the patent with publication number CN101912397A discloses a droperidol melitrisine tablet containing cyclodextrin, hydrogenated vegetable oil, lactose, starch, hydroxypropyl cellulose, microcrystalline cellulose and other auxiliary materials, in one of which
- the premix of flupentixol is mixed with ⁇ -cyclodextrin, lactose monohydrate, corn starch, and hydroxypropylcellulose, and purified water is added to wet granulation, as the flupentixol granules, and then the United States Quxin, corn starch, lactose monohydrate, and hydroxypropylcellulose are mixed, and purified water is added for wet granulation.
- the droperidol and meltriptan granules are combined with microcrystalline cellulose, Mix croscarmellose sodium, talc, hydroxypropyl cellulose, hydrogenated vegetable oil, and magnesium stearate, and tablet.
- the process uses ⁇ -cyclodextrin as a stabilizer, the amount is large, and the tablet is easy to absorb moisture.
- the patent with the publication number CN105663062A discloses a kind of droperidol xanthometricin tablet and its preparation method.
- melitrixine is evenly divided into 2 to 5 batches and added to droperidol Mix evenly, add binder solution to granulate, dry, and adjust granules, mix evenly with disintegrant and lubricant, and tablet.
- the process adopts the countercurrent gas flow method to add melitrexine to flupentixol.
- the energy consumption of airflow crushing is large and the yield is unstable. It is difficult to ensure the controllability and reproducibility of the process. Litricin is highly irritating, the production process is dusty, and the operation is not feasible.
- the patent with the publication number CN104288153A discloses a droperidol xanthometricin tablet and its preparation method, characterized by the use of fine particle size droperidol (particle size distribution D90 less than 150 ⁇ m), melitrixine, filling Agents, disintegrants, binders, lubricants are prepared by direct powder tableting process.
- fine particle size droperidol particle size distribution D90 less than 150 ⁇ m
- melitrixine filling Agents
- disintegrants binders
- lubricants are prepared by direct powder tableting process.
- haloperidol is very sensitive to oxidation and light. Haloperidol is mainly degraded to Lu28-159 and trifluoromethyl thioxanthone, and melitrexine will also degrade under alkaline environment and oxidizing conditions The main degradation of melitrexin is 10,10-dimethylthioxanthone.
- the main degradation pathways and degradation products of droperidol are as follows:
- the purpose of the present invention is to overcome the above-mentioned shortcomings of the prior art and provide a droperidol xanthimetrisine tablet and a preparation method thereof. Good reproducibility and stability, with excellent dissolution characteristics, stability, lower content of related substances, and more guarantee of product safety and effectiveness.
- a droperidol xanthimetrisine tablet comprising the following components in mass percentage: droperidol hydrochloride 0.3% ⁇ 1.0%, melitrixine hydrochloride 5.78% to 19.26%, antioxidant 0.01% to 10%, filler 60% to 88%, disintegrant 0.5% to 6%, binder 2% to 6%, lubricant 0.2% to 3%.
- the droperixant melitrixine tablet contains the following components in mass percentage: droperidol hydrochloride 0.4%-0.8%, hydrochloric acid Meltrixine 7.71% to 15.41%, antioxidant 0.02% to 5%, filler 72% to 85%, disintegrant 0.5% to 4%, binder 3% to 5%, lubricant 0.5% to 2%.
- the antioxidant is tert-butyl p-hydroxyanisole, dibutylhydroxytoluene, propyl gallate, sodium thiosulfate, L-cysteine, vitamin C or its sodium salt, vitamin C palm At least one of acid ester, vitamin E, and water-soluble organic weak acid;
- the filler is at least one of microcrystalline cellulose, lactose, dibasic calcium phosphate, starch, mannitol, and calcium carbonate;
- the disintegrant is croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose, carboxymethyl cellulose calcium At least one of
- the binder is at least one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, sodium carboxymethyl cellulose, methyl cellulose, and gum arabic;
- the lubricant is at least one of silica, magnesium stearate, stearic acid, sodium stearyl fumarate, talc, and glyceryl behenate;
- the flupentixol melitrexine tablet further includes a coating material, the mass of the coating material is 2% to 10% of the mass of the tablet core, and the coating material is Opadry II. At least one of Opadry 200 and Opadry amb.
- the antioxidant is tert-butyl-p-hydroxyanisole, dibutylhydroxytoluene, propyl gallate, vitamin C, vitamin C At least one of palmitate and water-soluble organic weak acid.
- the antioxidant is at least one of t-butyl p-hydroxyanisole, dibutylhydroxytoluene, and propyl gallate.
- the antioxidant is dibutylhydroxytoluene
- the filler is at least one of microcrystalline cellulose, lactose, starch, and calcium hydrogen phosphate;
- the disintegrant is at least one of croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch;
- the binder is at least one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and povidone;
- the lubricant is at least one of silica, magnesium stearate, stearic acid, talc, and glyceryl behenate;
- the mass of the coating material is 3% to 6% of the mass of the tablet core.
- the present invention provides a wet granulation preparation method of the droperidol xanthimetrisine tablet, which includes the following steps:
- the preferred preparation method of the droperisteine granules is to dissolve droperidol hydrochloride and an antioxidant in an organic solution Solvent/aqueous solution, after mixing part of the filler and part of the binder, add organic solvent/aqueous solution of droperidol hydrochloride and antioxidant, stirring granulation or fluidized spray granulation or extrusion granulation, drying, Obtained droperidol particles.
- the granulation process is agitation granulation.
- the coating material is dissolved or suspended in an appropriate amount of solvent, and the solvent is 20%-85% ethanol At least one of an aqueous solution and purified water.
- the organic solvent is at least one of isopropyl alcohol, ethanol, and acetone.
- the drying process uses fluidized bed drying, the temperature is controlled below 50°C, and the LOD% of the granules does not exceed 3%.
- the present invention provides a dry granulation preparation method of the droperidol xanthimetrisine tablet, which includes the following steps:
- the droperidol hydrochloride and the antioxidant are granulated after being micronized.
- the bulk density of the droperixant granules and the melitoxine particles is 0.4-0.8 g/mL.
- the coating material is dissolved or suspended in an appropriate amount of solvent, and the solvent is 20%-85% ethanol At least one of an aqueous solution and purified water.
- the beneficial effects of the present invention are as follows: the droperixantomelitrixine tablet of the present invention, by adding an antioxidant, can effectively enhance the stability of droperidol ximelitricin tablet , Can effectively control the degradation of droperidol to produce Lu28-159, trifluoromethyl thioxanthone and other impurities, reduce the level of impurities, and ensure product safety and effectiveness; the droperidol melitresin tablets prepared according to the present invention The agent has similar in vitro dissolution behavior and bioequivalence to the original tablet Deanxit.
- a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.48 %, 9.30%, 0.08%, 82.69%, 1.49%, 4.96%, 0.99%, the quality of each component is shown in Table 1.
- a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.48 %, 9.19%, 0.82%, 81.68%, 1.96%, 4.41%, 1.47%, the quality of each component is shown in Table 1.
- melitrexine hydrochloride anhydrous lactose, starch, and hydroxypropyl cellulose into a high-speed stirring granulator, add purified water, stir and shear granulation; fluidized bed drying, whole granulation, that is, melitrexine Particles
- a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.48 %, 9.20%, 0.65%, 81.81%, 1.96%, 4.42%, 1.47%, the quality of each component is shown in Table 1.
- a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.49 %, 9.38%, 8.38%, 73.40%, 3.00%, 4.50%, 0.83%, the quality of each component is shown in Table 1.
- melitrexine hydrochloride lactose and microcrystalline cellulose into the fluidized granulator, add the aqueous solution of povidone K30, fluidize the granules, dry and adjust the granules to obtain the melitrexine granules;
- a kind of droperidol melitrexine tablet wherein the mass percentages of droperidol hydrochloride, melitrexine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.47% , 9.12%, 0.61%, 81.05%, 2.92%, 4.86%, 0.97%, the quality of each component is shown in Table 1.
- a kind of droperidol xanthimelide tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.53 %, 10.16%, 0.09%, 81.28%, 3.25%, 3.25%, 1.44%, the quality of each component is shown in Table 1.
- melitrexine hydrochloride, anhydrous lactose, microcrystalline cellulose, and magnesium stearate uniformly, roll the tablets into a dry granulator, and then granulate to obtain melitrexine granules;
- a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 1.04, respectively %, 19.99%, 0.01%, 71.96%, 0.5%, 6.01%, 0.5%, the quality of each component is shown in Table 1.
- a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.26 %, 5%, 10%, 73.74%, 6%, 2%, 3%, the quality of each component is shown in Table 1.
- melitrexine hydrochloride, anhydrous lactose, microcrystalline cellulose, and magnesium stearate uniformly, roll the tablets into a dry granulator, and then granulate to obtain melitrexine granules;
- a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, filler, disintegrant, binder, lubricant are 0.48% and 9.31%, respectively , 82.76%, 1.49%, 4.97%, 0.99%, the quality of each component is shown in Table 2.
- the preparation method of the tablet of the comparative example is as follows:
- a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, filler, disintegrant, binder, lubricant are 0.53% and 10.17% respectively , 81.35%, 3.25%, 3.25%, 1.45%, the quality of each component is shown in Table 2.
- the preparation method of the tablet of the comparative example is as follows:
- melitrexine hydrochloride, lactose, and microcrystalline cellulose evenly, and roll-press the tablet with a dry granulator to form granules to obtain melitrexine granules;
- dissolution determination method Choinese Pharmacopoeia 2015 edition four parts 0931 general rules second method
- the dissolution of Examples 1 to 8 and Comparative Examples 1 to 2 were tested.
- the rotation speed is 75 revolutions per minute, and samples are taken after 30 minutes, and the continuous filtrate is taken as the solution for the test product; according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512) Determination.
- phenylsilane-bonded silica gel as a filler (XBridge TM Phenyl 3.5 ⁇ m, 4.6 ⁇ 100mm chromatographic column is applicable), using 0.02mol/L ammonium acetate buffer-methanol (35:65) as the mobile phase, the detection wavelength is 270nm, Flow rate 1.0mL/min, column temperature 40°C.
- the theoretical plate number should be no less than 1400 based on the melitrexine peak, and the resolution of the melitrexine peak and the droperidol peak should be greater than 2.0.
- Examples 1 to 8 of the present invention and Comparative Examples 1 to 2 were placed under accelerated test conditions (40°C/75% RH) for 6 months, and the changes in content, dissolution and related substances were investigated.
- the test results are shown in Table 4.
- Determination of content take 20 tablets of this product, weigh accurately, grind them into powder, take appropriate amount of sample powder (equivalent to 20mg of melitrexine and 1mg of droperidol), weigh accurately, place in 50ml measuring bottle, add flow Phase 40ml, shake to completely disperse and wet the sample, sonicate for 20min, let cool to room temperature, dilute to the mark with mobile phase, shake and filter, discard the initial filtrate and collect the subsequent filtrate to obtain the test solution .
- melitrexine hydrochloride reference substance (the conversion coefficient of melitrexine and melitrexine hydrochloride is 0.8887) about 22.6mg, accurately weigh it, put it in a 50ml measuring bottle, and accurately remove the droperidol hydrochloride reference substance reserve Dissolve 2ml into the same volumetric flask, dissolve with mobile phase and dilute to the mark, shake well to obtain a control solution containing haloperidol 0.02mg/ml and melitrexine 0.4mg/ml. According to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512) determination.
- Phenylsilane-bonded silica gel as filler (XBridge TM Phenyl 3.5 ⁇ m, 4.6 ⁇ 100mm), with 0.02mol/L ammonium acetate buffer-methanol (35:65) as mobile phase, detection wavelength of 270nm, flow rate 1.0mL /min, column temperature 40°C.
- the number of theoretical plates calculated according to the peak of Melitrexine should not be less than 3000, and the resolution of the peaks of Melitrexine and droperidol should be greater than 4.0. Precisely measure 10 ⁇ L each of the test solution and the reference solution, and inject it into a high-performance liquid chromatograph. Calculate the content of melitrexin and droperidol in each tablet according to the peak area according to the external standard method.
- Dissolution test the same as the dissolution test method in Effect Example 1.
- the chromatographic conditions were tested under the same content.
- the control solution and the test solution were each 20 ⁇ L and injected into high performance liquid chromatography.
- Relative to the marked amount of melitrexine a single unknown impurity shall not exceed 0.2%, and the total amount of impurities shall not exceed 4.0%.
- Table 5 shows the AUC 0- ⁇ and C max of droperidol and melitrexine .
- Table 6 compares the BE of the test formulation (T) and the reference formulation (R).
- the inventors conducted a bioequivalence test on the tablets of the present invention with different ratios.
- the test results show that the tablets prepared with the components and the ratio of the present invention are bioequivalent to Deanxit.
- the test process and data are in This will not be repeated here.
- the type of antioxidant of the present invention affects the stability of droperidol xanthimetrisine tablets.
- the applicant prepared a test In the group, the dissolution rate and stability of the dropofixantomelitrixine tablets were tested according to the test methods of effect example 1 and effect example 2 according to the test methods of effect example 1 and effect example 2.
- the types of antioxidants are different, and the rest are the same.
- the types of antioxidants are shown in Table 7.
- the mass of droperidol hydrochloride was 0.584 mg/tablet
- the antioxidant mass was 0.4 mg/tablet
- the filler was lactose and microcrystalline cellulose (1:2).
- the mass is 58mg/tablet
- the binder is hydroxypropylcellulose, and the mass is 1.8mg/tablet
- the mass of melitrexine hydrochloride is 11.25mg/tablet
- the filler is lactose and microcrystalline fibers Element (1:3)
- the mass is 28mg/tablet
- the binder is hydroxypropyl cellulose
- the mass is 1.2mg/tablet
- the disintegrant is croscarmellose sodium
- the quality is 1.8mg Per tablet
- the filler is microcrystalline cellulose with a mass of 14 mg per tablet
- the binder is hydroxypropyl cellulose with a mass of 3 mg per tablet
- the lubricant is stearic acid with a mass of 1.2 mg per tablet.
- the type of antioxidant of the present invention affects the stability of droperidol melitricine tablets.
- the antioxidant is tert-butyl p-hydroxyanisole, dibutylhydroxytoluene, propyl gallate , Vitamin C, vitamin C palmitate
- the stability of droperidol melitrisine tablets is better; when the antioxidant is tert-butyl p-hydroxyanisole, dibutylhydroxytoluene, propyl gallate
- the stability of droperidol melitricine tablets is better; when the antioxidant is dibutylhydroxytoluene, the stability of droperidol melitricine tablets is the best.
- the mass percentage of the antioxidant of the present invention affects the stability of droperidol melitricine tablets.
- the test group and the control group of droperioxant melitrixine tablets were tested, and according to the test methods of effect example 1 and effect example 2, the effect group test group and control group of droperioxant melitrixine tablets were tested Dissolution and stability.
- the mass percentages of antioxidants are different. Except for the mass percentage of fillers, the mass percentages of the other auxiliary materials are the same.
- the mass percentages of droperidol hydrochloride, melitrexine hydrochloride, and antioxidants are shown in Table 8. Shown.
- the antioxidant was dibutylhydroxytoluene
- the filler was lactose and microcrystalline cellulose (1:2)
- the mass was 58 mg/tablet
- the binder was hydroxy Propylcellulose, mass: 1.8 mg/tablet
- the mass is 28 mg/tablet
- the binder is hydroxypropylcellulose
- the mass is 1.2mg/tablet
- the disintegrant is croscarmellose sodium
- the quality is 1.8mg/tablet
- the binder is hydroxypropyl cellulose
- the quality is 3mg/tablet
- the lubricant is stearic acid
- the mass is 1.2mg/tablet
- the rest are fillers
- the filler is microcrystalline cellulose.
- the mass percentage of the antioxidant of the present invention affects the stability of droperidol melitricine tablets.
- the mass ratio of the antioxidant in the control group 1 is 0.006%
- the stability of the related substances is slightly worse
- the mass ratio of the antioxidant 2 in the control group is 12%
- the stability is better, but it is not better than the mass ratio of 10%, so it is preferred that the mass percentage of the antioxidant is 0.01% to 10%.
- the stability of thioxanthene and melitoxine tablets is better; when it is further preferred that the mass percentage of the antioxidant is 0.02% to 5%, the stability of flupentixol and melitoxine tablets is the best.
- the mass percentage of flupentixol hydrochloride and melitrexine hydrochloride in the present invention affects the stability of flupentixol hydrochloride and melitrexine tablets.
- the applicant prepared the test group and the control group of droperithione melitoxine tablets, and tested this effect according to the test methods of effect example 1 and effect example 2. Dissolution and stability of dropperidoxantimemeltrixine tablets in experimental group and control group.
- the mass percentages of droperidol hydrochloride and melitrexine hydrochloride are different. Except for the mass percentage of fillers, the mass percentages of other auxiliary materials are the same. The mass percentage of octene and the mass of filler are shown in Table 9.
- the antioxidant was dibutylhydroxytoluene with a mass percentage of 0.08%, and the binder was hydroxypropylcellulose with a mass percentage of 1.49%; melitroxine granules Medium, the mass of melitrexine hydrochloride is 11.25mg/tablet, the binder is hydroxypropyl cellulose, the mass percentage is 0.99%; in the auxiliary materials, the disintegrant is croscarmellose sodium, the mass percentage is 1.49 %, the binder is hydroxypropyl cellulose, the mass percentage is 2.48%, the lubricant is magnesium stearate, the mass percentage is 0.99%, and the rest are fillers.
- the mass percentage of droperidol hydrochloride and melitrexine hydrochloride of the present invention affects the stability of droperidol xenolide melitrexine tablets.
- the mass percentage of droperisen hydrochloride is 0.3% to 1.0 %
- the mass percentage of melitrexine hydrochloride is 5.78% to 19.26%
- the stability of droperidol melitrexine tablets is better
- the mass percentage of droperisen hydrochloride is 0.4% to 0.8%
- the mass percentage of melitrexine hydrochloride is 7.71% to 15.41%
- the stability of flupentixol mexterine tablets is the best.
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Abstract
Description
Claims (10)
- 一种氟哌噻吨美利曲辛片剂,其特征在于,包含如下质量百分比的组分:盐酸氟哌噻吨0.3%~1.0%、盐酸美利曲辛5.78%~19.26%、抗氧剂0.01%~10%、填充剂60%~88%、崩解剂0.5%~6%、粘合剂2%~6%、润滑剂0.2%~3%。
- 如权利要求1所述的氟哌噻吨美利曲辛片剂,其特征在于,包含如下质量百分比的组分:盐酸氟哌噻吨0.4%~0.8%、盐酸美利曲辛7.71%~15.41%、抗氧剂0.02%~5%、填充剂72%~85%、崩解剂0.5%~4%、粘合剂3%~5%、润滑剂0.5%~2%。
- 如权利要求1或2所述的氟哌噻吨美利曲辛片剂,其特征在于:(a)所述抗氧剂为叔丁基对羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯、硫代硫酸钠、L-半胱氨酸、维生素C或其钠盐、维生素C棕榈酸酯、维生素E、水溶性有机弱酸中的至少一种;(b)所述填充剂为微晶纤维素、乳糖、磷酸氢钙、淀粉、甘露醇、碳酸钙中的至少一种;(c)所述崩解剂为交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素、羧甲基淀粉钠、羧甲基纤维素、羧甲基纤维素钙中的至少一种;(d)所述粘合剂为羟丙基纤维素、羟丙甲基纤维素、聚维酮、羧甲基纤维素钠、甲基纤维素、阿拉伯胶中的至少一种;(e)所述润滑剂为二氧化硅、硬脂酸镁、硬脂酸、硬脂酰富马酸钠、滑石粉、山嵛酸甘油酯中的至少一种;(f)所述氟哌噻吨美利曲辛片剂还包括包衣材料,所述包衣材料的质量为片剂片芯质量的2%~10%,所述包衣材料为欧巴代II、欧巴代200、欧巴代amb中的至少一种。
- 如权利要求3所述的氟哌噻吨美利曲辛片剂,其特征在于:(a)所述抗氧剂为二丁基羟基甲苯;(b)所述填充剂为微晶纤维素、乳糖、淀粉、磷酸氢钙中的至少一种;(c)所述崩解剂为交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素、羧甲基淀粉钠中的至少一种;(d)所述粘合剂为羟丙基纤维素、羟丙甲基纤维素、聚维酮中的至少一种;(e)所述润滑剂为二氧化硅、硬脂酸镁、硬脂酸、滑石粉、山嵛酸甘油酯中的至少一种;(f)所述包衣材料的质量为片剂片芯质量的3%~6%。
- 如权利要求1~4任一项所述的氟哌噻吨美利曲辛片剂的制备方法,其特征在于,包括 如下步骤:(1)将盐酸氟哌噻吨与5%~30%填充剂进行等量递加混合,再与30%~70%填充剂、10%~50%粘合剂混合,加入抗氧剂的有机溶剂/水溶液,进行搅拌制粒或流化喷雾制粒或挤压制粒,干燥,得氟哌噻吨颗粒;或将盐酸氟哌噻吨与抗氧剂溶于有机溶剂/水溶液,将30%~70%填充剂、10%~50%粘合剂混合后,加入盐酸氟哌噻吨与抗氧剂的有机溶剂/水溶液,进行搅拌制粒或流化喷雾制粒或挤压制粒,干燥,得氟哌噻吨颗粒;(2)将盐酸美利曲辛与20%~50%填充剂、10%~40%粘合剂混合,进行搅拌制粒或流化喷雾制粒或挤压制粒,干燥,得美利曲辛颗粒;(3)将氟哌噻吨颗粒与美利曲辛颗粒、5%~30%填充剂、崩解剂、10%~60%粘合剂、润滑剂混合,压片,包衣。
- 如权利要求5所述的氟哌噻吨美利曲辛片剂的制备方法,其特征在于,所述有机溶剂为异丙醇、乙醇、丙酮中的至少一种。
- 如权利要求5所述的氟哌噻吨美利曲辛片剂的制备方法,其特征在于,所述干燥过程采用流化床干燥,温度控制在50℃以下,干燥至颗粒LOD%不超过3%。
- 如权利要求1~4任一项所述的氟哌噻吨美利曲辛片剂的制备方法,其特征在于,包括如下步骤:(1)将盐酸氟哌噻吨与抗氧剂、10%~70%填充剂、20%~60%润滑剂进行等量递加混合均匀,通过辊压法进行干法制粒,得氟哌噻吨颗粒;(2)将美利曲辛与10%~50%填充剂、20%~50%润滑剂混合混合均匀,通过辊压法进行干法制粒,得美利曲辛颗粒;(3)将氟哌噻吨颗粒与美利曲辛颗粒、崩解剂、粘合剂、20%~40%润滑剂混合,压片,包衣。
- 如权利要求8所述的氟哌噻吨美利曲辛片剂的制备方法,其特征在于,所述盐酸氟哌噻吨、抗氧剂经过微粉化处理后进行制粒。
- 如权利要求8所述的氟哌噻吨美利曲辛片剂的制备方法,其特征在于,所述氟哌噻吨颗粒与美利曲辛颗粒的松密度为0.4~0.8g/mL。
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CN109771386A (zh) * | 2019-01-10 | 2019-05-21 | 广东赛烽医药科技有限公司 | 一种氟哌噻吨美利曲辛片剂及其制备方法 |
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EP2374450A1 (en) * | 2010-04-06 | 2011-10-12 | H. Lundbeck A/S | Flupentixol compositions |
CN104288153A (zh) * | 2014-09-19 | 2015-01-21 | 四川海思科制药有限公司 | 一种氟哌噻吨美利曲辛药物组合物及其制备方法 |
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CN109771386A (zh) * | 2019-01-10 | 2019-05-21 | 广东赛烽医药科技有限公司 | 一种氟哌噻吨美利曲辛片剂及其制备方法 |
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