CN115381791B - Flunarizine hydrochloride pharmaceutical composition - Google Patents
Flunarizine hydrochloride pharmaceutical composition Download PDFInfo
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- CN115381791B CN115381791B CN202211148393.1A CN202211148393A CN115381791B CN 115381791 B CN115381791 B CN 115381791B CN 202211148393 A CN202211148393 A CN 202211148393A CN 115381791 B CN115381791 B CN 115381791B
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- flunarizine hydrochloride
- polyethylene glycol
- lactose
- corn starch
- hydroxy toluene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4833—Encapsulating processes; Filling of capsules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to a flunarizine hydrochloride capsule composition, and belongs to the technical field of pharmaceutical preparations. The technical scheme of the invention is as follows: each 1000 capsules of the flunarizine hydrochloride capsule composition contain 5.9g of flunarizine hydrochloride, 2-6g of polyethylene glycol stearate, 0.03-0.07g of dibutyl hydroxy toluene, 114-126g of lactose, 24-32g of corn starch and 2g of magnesium stearate. The invention provides a flunarizine hydrochloride capsule composition with stable quality and suitable for industrial production.
Description
Technical Field
The invention relates to a flunarizine hydrochloride pharmaceutical composition, a preparation method thereof and application thereof in the field of imitation drug consistency evaluation.
Background
Flunarizine hydrochloride is a calcium channel blocker, and is developed successfully by Janssen (Yansen) in 1968, and is mainly used for preventing cell damage caused by pathological calcium overload in cells due to ischemia and the like.
Flunarizine hydrochloride has the chemical name of (E) -1- [ bis (4-fluorophenyl) methyl]-4-2 (2-propenyl-3-phenyl) -piperazine dihydrochloride of formula C 26 H 26 F 2 N 2 2HCl, structural formula:
flunarizine hydrochloride is marketed in Europe in capsules and tablets, the trade names of which are Sibelium, and the Flunarizine hydrochloride is not marketed in the Mei Ri market; there are about 56 culture marks in China, and the main dosage forms include capsules, tablets, dispersible tablets and the like, and are mainly used for the preventive treatment of typical (with aura) or atypical (without aura) migraine and the symptomatic treatment of dizziness caused by vestibular dysfunction.
The national food and drug administration issues an announcement of a simulated drug reference formulation catalog (eleventh lot) on 12 months 29 2017, wherein a reference formulation (serial number 11-5) of the flunarizine hydrochloride capsule is shown as a company of western ampelopsis pharmaceutical limited (original ground variety), the commodity is named as xibelin, and a plurality of simulated pharmaceutical manufacturers in China develop the consistency evaluation work of the variety.
The European pharmacopoeia is searched for the standard of the flunarizine hydrochloride bulk drug, and the limits of the impurity A, B, C, D are respectively regulated, but the standard of the preparation is not received. The Chinese pharmacopoeia 2020 edition receives the flunarizine hydrochloride bulk drug and the preparation standard, wherein the related substance item of the bulk drug standard only prescribes that the total impurity limit is not more than 1.0%, and the preparation standard does not receive the related substance item.
The actual research process shows that the unknown impurity with larger growth appears in the middle condition (30 ℃ +/-2 ℃/65%RH+/-5%RH) placing process of the reference preparation and the self-grinding preparation, and the unknown impurity is determined to be the impurity L by separating, purifying and positioning and analyzing the unknown impurity. The impurity L is 4, 4-difluorobenzophenone which is a synthesis starting material of flunarizine hydrochloride, has stable physicochemical properties and has the following structural formula:
considering the increasing impurity L in the preparation stability sample, the limit of the impurity L is set to be 0.5% according to the maximum daily dose (20 mg) of the variety by referring to the degradation product limit requirement of the ICH guiding principle Q3B new drug preparation.
Through spot inspection of the commercial preparation, the problem that the impurity L exceeds standard exists in the reference preparation and the imitation preparation of a part of factories, and the requirement of the latest guiding principle is not met. In view of the above, a large number of prescription processes are used for finding that the introduction of a proper amount of dibutyl hydroxy toluene can effectively inhibit the rapid increase of the impurity L in the preparation and meet the ICH guiding principle requirement, and a proper amount of polyethylene glycol stearate can solve the problem of sticking rods of the variety in the capsule filling process, so that dust pollution caused by a conventional glidant (such as colloidal silicon dioxide and the like) is avoided, the process is simple, and the preparation method is suitable for industrial production.
Disclosure of Invention
The invention aims to: provides a stable flunarizine hydrochloride pharmaceutical composition and a preparation process thereof.
Experiments show that the problem that relevant substances L exceed the standard in the storage process of the flunarizine hydrochloride capsule can be solved by adding a proper amount of dibutyl hydroxy toluene (also called as BHT).
The technical scheme of the invention is as follows:
each 1000 capsules of the flunarizine hydrochloride capsule composition contain 5.9g of flunarizine hydrochloride, 2-6g of polyethylene glycol stearate, 0.03-0.07g of dibutyl hydroxy toluene, 114-126g of lactose, 24-32g of corn starch and 2g of magnesium stearate.
Preferably, each 1000 granules of the flunarizine hydrochloride capsule composition contain 5.9g of flunarizine hydrochloride, 3-5g of polyethylene glycol stearate, 0.04-0.06g of dibutyl hydroxy toluene, 117-123g of lactose, 26-30g of corn starch and 2g of magnesium stearate.
Preferably, each 1000 granules of the flunarizine hydrochloride capsule composition contain 5.9g of flunarizine hydrochloride, 4g of polyethylene glycol stearate, 0.05g of dibutyl hydroxy toluene, 120g of lactose, 28g of corn starch and 2g of magnesium stearate.
According to the technical scheme, the polyethylene glycol stearate is added, so that the problem of sticking of the rod in the capsule filling process is solved. In every 1000 capsules, the dosage of polyethylene glycol stearate is lower than 2g, the problem of sticking the rod exists in the capsule filling process, and the filled capsule is unqualified in the filling quantity difference; in every 1000 capsules, the dosage of polyethylene glycol stearate is higher than 6g, which affects the dissolution behavior of the capsules.
According to the technical scheme, the problem that relevant substances in the process of storing the flunarizine hydrochloride capsules exceed standards is solved by adding the dibutyl hydroxyl toluene. The use of dibutylhydroxytoluene in an amount of more than 0.07g or less than 0.03g affects the stability during storage.
The preparation method of the flunarizine hydrochloride capsule composition comprises the following steps:
step 1, dissolving polyethylene glycol stearate and dibutyl hydroxy toluene with a prescription amount in 95% ethanol for later use;
step 2, sequentially adding lactose, flunarizine hydrochloride and corn starch into a wet granulation pot, performing wet granulation by using the wetting agent obtained in the step 1, drying at 50 ℃, and performing granulation by using a screen with a 1.0mm aperture;
step 3, putting the granules obtained in the step 2 into a total mixer, adding the prescription amount of magnesium stearate, and mixing for 5min;
step 4 the total mixture from step 3 is added to a capsule filling machine and filled with 4# capsules.
According to the preparation method of the flunarizine hydrochloride capsule composition, polyethylene glycol stearate and dibutyl hydroxy toluene are sprayed in the form of a solution, otherwise, the filling effect of the capsule and the stability in the storage process are affected.
Advantageous effects
The flunarizine hydrochloride capsule composition solves the problem of sticking rods in the capsule filling process and the problem of exceeding standard of related substances in the storage process through reasonable auxiliary material compatibility, and provides a medicine with stable quality for clinic.
Example 1 Flunarizine hydrochloride 5.9g, polyethylene glycol stearate 4g, dibutyl hydroxy toluene 0.05g, lactose 120g, corn starch 28g, magnesium stearate 2g, 1000 granules are prepared according to the preparation method described in the technical scheme of the specification.
Example 2 Flunarizine hydrochloride 5.9g, polyethylene glycol stearate 6g, dibutyl hydroxy toluene 0.03g, lactose 114g, corn starch 32g, magnesium stearate 2g, 1000 granules were prepared according to the preparation method described in the technical scheme of the specification.
Example 3 Flunarizine hydrochloride 5.9g, polyethylene glycol stearate 2g, dibutyl hydroxy toluene 0.07g, lactose 126g, corn starch 24g, magnesium stearate 2g, 1000 granules were prepared according to the preparation method described in the technical scheme of the specification.
Comparative example 1 with reference to the example 1 formulation, no dibutylhydroxytoluene was added
5.9g of flunarizine hydrochloride, 4g of polyethylene glycol stearate, 120g of lactose, 28g of corn starch and 2g of magnesium stearate, and 1000 granules are prepared according to the preparation method of the technical scheme of the specification.
Comparative example 2 with reference to the formulation of example 1, polyethylene glycol stearate was not added
5.9g of flunarizine hydrochloride, 0.05g of dibutyl hydroxy toluene, 122g of lactose, 30g of corn starch and 2g of magnesium stearate, wherein 1000 capsules are prepared by the preparation method according to the technical scheme of the specification, stick is stuck in the process of filling capsules, and part of the capsules are unqualified in filling quantity.
Comparative example 3 with reference to the formulation of example 1, the amount of dibutylhydroxytoluene exceeds the upper limit
5.9g of flunarizine hydrochloride, 4g of polyethylene glycol stearate, 0.08g of dibutyl hydroxy toluene, 120g of lactose, 28g of corn starch and 2g of magnesium stearate, and 1000 granules are prepared according to the preparation method of the technical scheme of the specification.
Comparative example 4 with reference to the recipe of example 1, the amount of dibutylhydroxytoluene exceeds the lower limit
5.9g of flunarizine hydrochloride, 4g of polyethylene glycol stearate, 0.02g of dibutyl hydroxy toluene, 120g of lactose, 28g of corn starch and 2g of magnesium stearate, and 1000 granules are prepared according to the preparation method of the technical scheme of the specification.
Comparative example 5 with reference to the formulation of example 1, the amount of polyethylene glycol stearate exceeds the upper limit
5.9g of flunarizine hydrochloride, 7g of polyethylene glycol stearate, 0.05g of dibutyl hydroxy toluene, 118g of lactose, 27g of corn starch and 2g of magnesium stearate, and 1000 granules are prepared according to the preparation method of the technical scheme of the specification.
Comparative example 6 with reference to the formulation of example 1, the amount of polyethylene glycol stearate exceeds the lower limit
5.9g of flunarizine hydrochloride, 1g of polyethylene glycol stearate, 0.05g of dibutyl hydroxy toluene, 122g of lactose, 29g of corn starch and 2g of magnesium stearate, wherein 1000 capsules are prepared by the preparation method according to the technical scheme of the specification, stick is stuck in the process of filling capsules, and part of the capsules are unqualified in filling quantity.
Test example 1 investigation of substances
The reference (lot number JKJOXAN), examples 1-3 and comparative examples 1-3-5 were each measured by high performance liquid chromatography (rule 0512 in the fourth edition of Chinese pharmacopoeia 2020) and the data are recorded in Table 1 under intermediate conditions (30 ℃ + -2 ℃ C./65%RH+ -5%RH) for 12 months. Since comparative examples 2 and 6 had a stick problem during the capsule filling process, the partial capsule contents were not acceptable, and thus the subsequent index tests were not performed.
Chromatographic conditions: octadecylsilane chemically bonded silica (BDS-HYPERIL-C18, 4.6mm.times.100mm, 3 μm) is used as filler; taking a solution containing 23.8g of tetrabutylammonium bisulfate and 7.0g of ethanolamine in every 1000mL of water as a mobile phase A and acetonitrile as a mobile phase B, and performing gradient elution according to the following table, wherein the flow rate is 1.5mL per minute; the column temperature is 25 ℃; the detection wavelength is 230nm; the sample volume was 10. Mu.L.
Limit: in the chromatogram of the sample solution, the peak areas (correction factors are 1.5 and 1.4 respectively) of the impurity A and the impurity L after correction are not more than 2 times (0.5%) of the main peak area of the control solution, the peak areas of other single impurities are not more than 0.8 times (0.2%) of the main peak area of the control solution, and the total amount of the impurities is not more than 1.5%. Impurity B, impurity C and peaks less than 0.04 times the main peak area of the control solution were ignored.
Table 1 results of investigation of related substances for each sample of flunarizine hydrochloride capsule under intermediate condition for 12 months
Table 1 data illustrates: the individual impurities and the total impurity content of examples 1 to 3 and comparative example 5 meet the requirements concerning the limitation of substances.
Test example 2 dissolution profile investigation
The dissolution similarity factor f2 with the reference formulation was calculated by measuring the release rates of the samples of examples 1 to 3 and comparative examples 1 to 3 to 5 in pH4.5 medium for 5min, 10min and 45min, respectively, according to the dissolution rate and release rate measurement method (first method of the fourth edition of the Chinese pharmacopoeia 2020 edition, rule 0931), and the data are recorded in Table 2.
Table 2 data illustrates: examples 1-3 and comparative examples 1-3 have dissolution similarity factors greater than 50, similar to the dissolution of the reference formulation; comparative example 5 had a dissolution similarity factor below 50 and was dissimilar to the reference formulation.
In conclusion, the technical scheme of the invention obtains the flunarizine hydrochloride pharmaceutical composition with stable process and stable product quality.
Claims (4)
1. The flunarizine hydrochloride capsule composition is characterized by comprising 5.9g of flunarizine hydrochloride, 2-6g of polyethylene glycol stearate, 0.03-0.07g of dibutyl hydroxy toluene, 114-126g of lactose, 24-32g of corn starch and 2g of magnesium stearate in each 1000 granules.
2. The flunarizine hydrochloride capsule composition as claimed in claim 1, wherein each 1000 capsules contains 5.9g of flunarizine hydrochloride, 3-5g of polyethylene glycol stearate, 0.04-0.06g of dibutyl hydroxy toluene, 117-123g of lactose, 26-30g of corn starch and 2g of magnesium stearate.
3. The flunarizine hydrochloride capsule composition as claimed in claim 1, wherein each 1000 capsules contains 5.9g of flunarizine hydrochloride, 4g of polyethylene glycol stearate, 0.05g of dibutyl hydroxy toluene, 120g of lactose, 28g of corn starch and 2g of magnesium stearate.
4. A method for preparing a flunarizine hydrochloride capsule composition as claimed in claim 1, comprising the steps of:
step 1, dissolving polyethylene glycol stearate and dibutyl hydroxy toluene with a prescription amount in 95% ethanol for later use;
step 2, sequentially adding lactose, flunarizine hydrochloride and corn starch into a wet granulation pot, performing wet granulation by using the wetting agent obtained in the step 1, drying at 50 ℃, and performing granulation by using a screen with a 1.0mm aperture;
step 3, putting the granules obtained in the step 2 into a total mixer, adding the prescription amount of magnesium stearate, and mixing for 5min;
step 4 the total mixture from step 3 is added to a capsule filling machine and filled with 4# capsules.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0292050A1 (en) * | 1987-05-18 | 1988-11-23 | Janssen Pharmaceutica N.V. | Improved flunarizine-containing compositions |
| WO2007105229A1 (en) * | 2006-03-14 | 2007-09-20 | Panacea Biotec Ltd. | Controlled release pharmaceutical composition and process thereof |
| WO2010008203A2 (en) * | 2008-07-15 | 2010-01-21 | 한올제약주식회사 | Pharmaceutical formulation containing a calcium channel blocker |
| CN104382878A (en) * | 2014-12-02 | 2015-03-04 | 石家庄市华新药业有限责任公司 | Flunarizine hydrochloride capsules and preparation method thereof |
| CN105395504A (en) * | 2015-11-26 | 2016-03-16 | 郑州瑞启生物技术有限公司 | Flunarizine hydrochloride matrix sustained-release tablets and preparing method thereof |
| CN105998024A (en) * | 2016-06-15 | 2016-10-12 | 迪沙药业集团有限公司 | Flunarizine-hydrochloride pharmaceutical composition |
| WO2017148361A1 (en) * | 2016-03-01 | 2017-09-08 | 江苏恒瑞医药股份有限公司 | Method for preparing pharmaceutical composition comprising pyrrolo-fused six-membered heterocyclic compound |
| CN112190558A (en) * | 2020-10-20 | 2021-01-08 | 迪沙药业集团有限公司 | Levofloxacin composition |
| WO2022060309A1 (en) * | 2020-09-18 | 2022-03-24 | İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş. | Long-term stable anagrelid capsule composition |
-
2022
- 2022-09-21 CN CN202211148393.1A patent/CN115381791B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0292050A1 (en) * | 1987-05-18 | 1988-11-23 | Janssen Pharmaceutica N.V. | Improved flunarizine-containing compositions |
| WO2007105229A1 (en) * | 2006-03-14 | 2007-09-20 | Panacea Biotec Ltd. | Controlled release pharmaceutical composition and process thereof |
| WO2010008203A2 (en) * | 2008-07-15 | 2010-01-21 | 한올제약주식회사 | Pharmaceutical formulation containing a calcium channel blocker |
| CN104382878A (en) * | 2014-12-02 | 2015-03-04 | 石家庄市华新药业有限责任公司 | Flunarizine hydrochloride capsules and preparation method thereof |
| CN105395504A (en) * | 2015-11-26 | 2016-03-16 | 郑州瑞启生物技术有限公司 | Flunarizine hydrochloride matrix sustained-release tablets and preparing method thereof |
| WO2017148361A1 (en) * | 2016-03-01 | 2017-09-08 | 江苏恒瑞医药股份有限公司 | Method for preparing pharmaceutical composition comprising pyrrolo-fused six-membered heterocyclic compound |
| CN105998024A (en) * | 2016-06-15 | 2016-10-12 | 迪沙药业集团有限公司 | Flunarizine-hydrochloride pharmaceutical composition |
| WO2022060309A1 (en) * | 2020-09-18 | 2022-03-24 | İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş. | Long-term stable anagrelid capsule composition |
| CN112190558A (en) * | 2020-10-20 | 2021-01-08 | 迪沙药业集团有限公司 | Levofloxacin composition |
Non-Patent Citations (2)
| Title |
|---|
| Hybridization of antioxidant and calcium uptake inhibitory pharmacophores;Gere, A;MEDICINAL CHEMISTRY RESEARCH;第7卷;第192-198页 * |
| 不同干预措施对老年 ２ 型糖尿病患者脑血管储备能力的影响;刘小利;中华老年病研究电子杂志;第1卷;第27-29页 * |
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