CN113209042A - Dextromethorphan hydrobromide quinidine sulfate capsule and preparation method thereof - Google Patents
Dextromethorphan hydrobromide quinidine sulfate capsule and preparation method thereof Download PDFInfo
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- CN113209042A CN113209042A CN202110588176.3A CN202110588176A CN113209042A CN 113209042 A CN113209042 A CN 113209042A CN 202110588176 A CN202110588176 A CN 202110588176A CN 113209042 A CN113209042 A CN 113209042A
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- quinidine sulfate
- dextromethorphan hydrobromide
- dextromethorphan
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- 239000002775 capsule Substances 0.000 title claims abstract description 57
- 229960004482 quinidine sulfate Drugs 0.000 title claims abstract description 49
- GJHKWLSRHNWTAN-UHFFFAOYSA-N 1-ethoxy-4-(4-pentylcyclohexyl)benzene Chemical compound C1CC(CCCCC)CCC1C1=CC=C(OCC)C=C1 GJHKWLSRHNWTAN-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 title claims description 49
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 title claims description 49
- 239000008187 granular material Substances 0.000 claims abstract description 33
- MRUNQKQTAMUPRF-PUTLROBFSA-N nuedexta Chemical compound Br.OS(O)(=O)=O.C([C@@H]12)CCC[C@]11CCN(C)[C@H]2CC2=CC=C(OC)C=C21.C1C([C@H](C2)C=C)CCN2[C@H]1[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21.C1C([C@H](C2)C=C)CCN2[C@H]1[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 MRUNQKQTAMUPRF-PUTLROBFSA-N 0.000 claims abstract description 30
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 29
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- 238000002156 mixing Methods 0.000 claims abstract description 16
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- 239000000463 material Substances 0.000 claims abstract description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 14
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- 229960001985 dextromethorphan Drugs 0.000 claims abstract description 11
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 claims abstract description 10
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims abstract description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 19
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- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical group O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 14
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 14
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 12
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- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- UXQPRXPNOJXOQO-UHFFFAOYSA-N sulfuric acid;hydrobromide Chemical compound Br.OS(O)(=O)=O UXQPRXPNOJXOQO-UHFFFAOYSA-N 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
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- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- 206010011224 Cough Diseases 0.000 description 1
- 206010011469 Crying Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 101000896576 Homo sapiens Putative cytochrome P450 2D7 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
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- 239000003434 antitussive agent Substances 0.000 description 1
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- STTADZBLEUMJRG-IKNOHUQMSA-N dextromethorphan hydrobromide Chemical compound O.Br.C([C@@H]12)CCC[C@]11CCN(C)[C@H]2CC2=CC=C(OC)C=C21 STTADZBLEUMJRG-IKNOHUQMSA-N 0.000 description 1
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- 238000011068 loading method Methods 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 1
- 229960004963 mesalazine Drugs 0.000 description 1
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 208000008510 paroxysmal tachycardia Diseases 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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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
- A61K9/4833—Encapsulating processes; Filling of capsules
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- 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
- A61K9/485—Inorganic compounds
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- 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
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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
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- 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
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Abstract
The invention provides a dextromethorphan hydrobromide and quinidine sulfate capsule and a preparation method thereof, the dextromethorphan hydrobromide and quinidine sulfate capsule comprises dextromethorphan hydrobromide and quinidine sulfate granules, colloidal silicon dioxide and magnesium stearate, the preparation method of the dextromethorphan hydrobromide and quinidine sulfate capsule comprises the steps of preparing the dextromethorphan and quinidine sulfate granules containing the dextromethorphan and hydrobromide sulfate granules by adopting a one-step granulation process, mixing and filling the dextromethorphan and quinidine sulfate granules with other auxiliary materials, adding cross-linked sodium carboxymethylcellulose during the preparation of the dextromethorphan and quinidine sulfate granules containing the hydrobromic acid, effectively regulating the release rate of a medicament, enabling the in-vitro dissolution behavior of the medicament to be similar to that of a reference preparation NUEDEXTA in a multi-medium, and adopting the one-step granulation process to prepare the granules with stable quality among batches and in batches.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to dextromethorphan hydrobromide and quinidine sulfate capsules and a preparation method thereof.
Background
Dextromethorphan hydrobromide, also known as dextromethorphan hydrobromide, mesalamine hydrobromide, has the structural formula:
the dextrorotatory morphinan derivative is obtained by modifying the structure of morphine by Swiss in 1950, has a certain inhibiting effect on cough generated by medulla oblongata center, has the advantages of safety, high efficiency, no drug resistance and the like, and is the first choice of a central antitussive drug.
Quinidine sulfate is an inhibitor of CYP 4502D 6, and has a structural formula:
is mainly used for paroxysmal tachycardia, atrial flutter and premature beat; preventing ventricular tachycardia and reentry tachycardia to atrioventricular node; it can also be used for preventing symptomatic supraventricular and ventricular premature beat.
Dextromethorphan hydrobromide and quinidine sulfate are both a compound medicine NUEDEXTA, the dextromethorphan hydrobromide in the compound capsule preparation is a sigma-1 receptor agonist and a noncompetitive NMDA receptor antagonist, and quinidine reduces the biotransformation of dextromethorphan by competitively inhibiting cytochrome P4502D 6, thereby increasing the plasma level of dextromethorphan and being used for treating Pseudobulbar emotion (PBA). PBA is often secondary to other neurological diseases and is characterized by involuntary, sudden, frequently developing crying and/or laughing, with no subjective experience for the patient at the onset of PBA.
The original research manufacturer of the dextromethorphan hydrobromide-quinidine sulfate capsules is Avanir Pharmaceuticals in the United states, the American approval for marketing is declared in the 10 th month in 2010 and the European Union approves for marketing in the 25 th 6 th month in 2013, and the dextromethorphan hydrobromide-quinidine sulfate capsules are provided and have the trade name of NUEDEXTA. The medicine is an oral capsule taken once a day, and comprises 20mg/10mg and 30mg/10mg of dextromethorphan hydrobromide-quinidine sulfate capsules of 2 specifications.
Disclosure of Invention
The invention provides a preparation method of dextromethorphan hydrobromide quinidine sulfate capsules, which have good batch stability, and stable quality, and the in-vitro dissolution behavior in a plurality of dissolution media is similar to that of a reference preparation NUEDEXTA.
The dextromethorphan hydrobromide and quinidine sulfate capsule comprises a dextromethorphan hydrobromide-containing raw material drug, a quinidine sulfate-containing raw material drug, a disintegrant, a filler, a lubricant and a glidant, wherein the disintegrant is selected from cross-linked sodium carboxymethyl cellulose, and the filler is selected from lactose monohydrate and microcrystalline cellulose.
Preferably, the lubricant is selected from magnesium stearate and the glidant is selected from colloidal silicon dioxide.
Preferably, the weight ratio of the lactose to the microcrystalline cellulose is (4-1): 1.
Preferably, the dextromethorphan hydrobromide quinidine sulfate capsule consists of the following components in parts by weight:
the preparation method of the dextromethorphan hydrobromide quinidine sulfate capsule is a one-step granulation method.
Preferably, the preparation method of the dextromethorphan hydrobromide quinidine sulfate capsule comprises the following steps:
(1) preparation of dextromethorphan hydrobromide quinidine sulfate granules: adding dextromethorphan hydrobromide monohydrate, quinidine sulfate dihydrate, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium into a fluidized bed according to the formula amount for one-step granulation to obtain dextromethorphan hydrobromide quinidine sulfate granules;
(2) mixing: putting the dextromethorphan hydrobromide quinidine sulfate granules obtained in the step (1), colloidal silica and magnesium stearate into a mixer for mixing;
(3) filling: filling the mixture in the step (2) by using a proper filling mold.
Further, the fan frequency of the fluidized bed equipment is set to be 5-30 Hz, the material temperature is 45 +/-5 ℃, the air inlet temperature is 50-70 ℃, the heating function is started, when the material temperature reaches 40 ℃, the atomization pressure is adjusted to be 1.5-3.0 bar, the wetting agent is sprayed, and the one-step granulation time is 30-90 minutes.
Further, the filling mold of the step (3) is a capsule No. 1.
The dextromethorphan hydrobromide quinidine sulfate capsule prepared according to the invention is subjected to influence factor tests with a reference preparation NUEDEXTA sold in the market, and the research on the dissolution rate of multiple dissolution media shows that the dextromethorphan hydrobromide quinidine sulfate capsule prepared by the invention has the same or better quality than the reference preparation NUEDEXTA sold in the market, multiple dissolution curves are similar or consistent with those of the reference preparation, the in-vitro dissolution behavior similar to that of the reference preparation is shown, the quality is stable, and the dissolution behaviors among batches are consistent.
The multi-dissolution medium comprises a hydrochloric acid solution with pH1.2, an acetate buffer solution with pH4.0, a phosphate buffer solution with pH6.8 and an aqueous solution, and the determination method of the dissolution rate of the multi-dissolution medium comprises the following steps: according to the determination method of dissolution rate and release rate of Chinese pharmacopoeia (2015 edition of the four-part general rule 0931, II), the dissolution rate of dextromethorphan hydrobromide quinidine sulfate capsules prepared according to the invention and a reference preparation NUEDEXTA is calculated at each set time point by taking a hydrochloric acid solution with pH of 1.2 as a dissolution medium and adopting a basket method at a rotating speed of 50 revolutions per minute.
According to the determination method of dissolution rate and release rate of Chinese pharmacopoeia (2015 edition of the four-part general rule 0931, II), a dissolution rate is calculated at each set time point by taking acetate buffer solution with pH4.0 as a dissolution medium and adopting a basket method at the rotating speed of 50 revolutions per minute for carrying out dissolution rate detection on dextromethorphan hydrobromide quinidine sulfate capsules prepared according to the invention and a reference preparation NUEDEXTA.
According to the determination method of dissolution rate and release rate of Chinese pharmacopoeia (2015 edition of the four-part general rule 0931, II), a dissolution rate is calculated at each set time point by using phosphate buffer solution with pH6.8 as a dissolution medium and adopting a basket method at a rotating speed of 50 revolutions per minute for carrying out dissolution rate detection on dextromethorphan hydrobromide quinidine sulfate capsules prepared according to the invention and a reference preparation NUEDEXTA.
According to the determination method of dissolution rate and release rate of Chinese pharmacopoeia (2015 edition of the four-part general rule 0931, II), the dissolution rate of dextromethorphan hydrobromide quinidine sulfate capsules prepared according to the invention is determined at each set time point by taking an aqueous solution as a dissolution medium and adopting a paddle method and a settling basket at the rotating speed of 50 revolutions per minute.
The dextromethorphan hydrobromide and quinidine sulfate capsules are stable in batch and batch, are prepared by adopting a one-step granulation process, have in-vitro dissolution behavior similar to that of a reference preparation NUEDEXTA in a plurality of dissolution media, are prepared by adopting a prescription in which powder is directly filled or is prepared by adopting a wet method, and have the worst flowability of the prescription directly filled with the powder and the second flowability effect of the mixing and granulating of the wet granulator relative to the granules prepared by one-step granulation, and have large batch-to-batch difference.
The preparation method provided by the invention is characterized in that dextromethorphan hydrobromide and quinidine sulfate granules are prepared by a fluidized bed one-step granulation process and then mixed and filled with other auxiliary materials, compared with common wet granulation, the preparation method can reduce the process steps of wet mixing granulation, wet granulation and dry granulation, better solves the problem of fluidity, is easy to fill, greatly improves the production efficiency, and has the advantages of simple operation, low energy consumption, stable product quality for a long time and the like.
The invention adopts a one-step granulation process, the granulation liquid is purified water, the preparation method is easy to obtain and simple to operate, the granulation can be finished in one step by fluidized bed equipment, the granules obtained by granulation are uniform in size, only unqualified products need to be sieved and screened, wet granulation and dry granulation are not needed, the production process steps are reduced, the preparation time is shortened, the controllability of process parameters in the production process is high, the artificial influence of a plurality of process step operations is reduced, and the quality stability of the medicine is effectively improved. Meanwhile, the in vitro multi-characteristic dissolution curves of the dextromethorphan hydrobromide quinidine sulfate capsule prepared by the invention are similar to those of a reference preparation, and the number and the limit of impurities are not higher than those of the reference preparation.
Drawings
FIG. 1 is a graph showing the dissolution curves of a primary sample (quinidine) and a small sample in a hydrochloric acid solution at pH1.2
FIG. 2 is the dissolution curve of the original ground sample (dextromethorphan hydrobromide) and the small sample in hydrochloric acid solution with pH of 1.2
FIG. 3 is a graph showing the dissolution profiles of a primary sample (quinidine) and a small sample in acetate buffer at pH4.0
FIG. 4 is the dissolution curves of the original ground sample (dextromethorphan hydrobromide) and the small sample in acetate buffer at pH4.0
FIG. 5 is a graph showing the dissolution profiles of the primary sample (quinidine) and the small sample in a phosphate buffer solution at pH6.8
FIG. 6 is the dissolution curve of the original ground sample (dextromethorphan hydrobromide) and the small sample in the phosphate buffer solution with pH6.8
FIG. 7 is the dissolution curve in water of the original sample (quinidine) and the small sample
FIG. 8 is the dissolution curve of the original ground sample (dextromethorphan hydrobromide) and the small sample in water
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
The dextromethorphan hydrobromide quinidine sulfate capsule comprises raw material medicines, a disintegrating agent, a filling agent, a lubricant and a glidant, and is determined through a large number of experiments when a prescription screening experiment is carried out. The disintegrating agent is an auxiliary material for promoting the preparation to be rapidly disintegrated into fine particles in the gastrointestinal tract after oral administration, and the rapid disintegration of the particles in the capsule is beneficial to the dissolution of the medicine. Common disintegrants include croscarmellose sodium (CCMC-Na), crospovidone (PVPP), and carboxymethyl starch sodium (CMS-Na), and when crospovidone (PVPP) and carboxymethyl starch sodium (CMS-Na) are used as disintegrants, the dissolution of quinidine sulfate in medium with pH4.0 is slow, which is not similar to the original grinding, and croscarmellose sodium is selected as the disintegrant after screening. The common fillers comprise lactose, starch, microcrystalline cellulose and the like, and the lactose and the microcrystalline cellulose are adopted as the fillers in the formula. Further, the product is formulated with magnesium stearate and colloidal silicon dioxide in order to increase the flowability of the granules during filling.
According to the invention, through groping and adjustment of a plurality of experiments, the following 4 formulas are finally selected, the dissolution rates of dextromethorphan hydrobromide and quinidine sulfate in four dissolution media of the formulas 1-4, such as hydrochloric acid solution with pH1.2, acetate buffer solution with pH4.0, phosphate buffer solution with pH6.8, water and the like are respectively investigated, the results are compared with the original ground product, and the experimental results are shown in Table 1.
In formula 1, the ratio of lactose (monohydrate) to microcrystalline cellulose is 1: 1, the dosage of the croscarmellose sodium accounts for 4.0 percent of the weight of the capsule granules, and the total dosage of the magnesium stearate and the colloidal silicon dioxide in the prescription is 1.0 percent respectively. The indexes of capsule investigation all meet the requirements of the four parts of the 2015 version of Chinese pharmacopoeia on capsules. In the sample of the formula 1, the dissolution curves of dextromethorphan hydrobromide in different media are similar to those of the original product, and the dissolution of quinidine sulfate in an aqueous medium (f 2< 50) is not similar to that of the original product.
In formula 2, the ratio of lactose (monohydrate) to microcrystalline cellulose is 1:2, the dosage of the croscarmellose sodium accounts for 4.0 percent of the weight of the capsule granules, and the total dosage of the magnesium stearate and the colloidal silicon dioxide accounts for 1.0 percent of the total dosage of the prescription. The indexes of capsule investigation all meet the requirements of the four parts of the 2015 version of Chinese pharmacopoeia on capsules. In the sample of formula 2, the dissolution curves of dextromethorphan hydrobromide and quinidine sulfate in phosphate buffer solution with pH6.8, hydrochloric acid with pH1.2 and acetate buffer solution with pH4.0 are similar to those of the original ground product, and the dissolution curves of dextromethorphan hydrobromide and quinidine sulfate in water medium (f 2< 50) are not similar to those of the original ground product.
In formula 3, the ratio of lactose (monohydrate) to microcrystalline cellulose is 3: 1, the dosage of the croscarmellose sodium accounts for 4.0 percent of the weight of the capsule granules, and the total dosage of the magnesium stearate and the colloidal silicon dioxide in the prescription is 1.0 percent respectively. The indexes of capsule investigation all meet the requirements of the four parts of the 2015 version of Chinese pharmacopoeia on capsules. In the sample of the formula 3, the dissolution curves of dextromethorphan hydrobromide and quinidine sulfate in different media are similar to those of the original product.
In formula 4, the ratio of lactose (monohydrate) to microcrystalline cellulose is 2: 1, the dosage of the croscarmellose sodium accounts for 2.0 percent of the weight of the capsule granules, and the total dosage of the magnesium stearate and the colloidal silicon dioxide accounts for 1.0 percent of the total dosage of the prescription. The indexes of capsule investigation all meet the requirements of the four parts of the 2015 version of Chinese pharmacopoeia on capsules. In the sample of formula 4, the dissolution curves of dextromethorphan hydrobromide and quinidine sulfate in the phosphate buffer solution with pH6.8, the hydrochloric acid with pH1.2 and the acetate buffer solution with pH4.0 are similar to those of the original ground product, wherein the dissolution curves of dextromethorphan hydrobromide and quinidine sulfate in an aqueous medium (f 2< 50) are not similar to those of the original ground product.
Based on the groping and analysis, the prescription 3 is determined to be selected as the basic prescription for screening the prescription of the dextromethorphan hydrobromide quinidine sulfate capsule, namely the ratio of lactose (monohydrate) to microcrystalline cellulose is 3: 1, 4.0 percent of croscarmellose sodium and 1.0 percent of lubricant and glidant.
Three formulas are designed on the basis of the original ground product formula, and the dosage of the croscarmellose sodium is 5 mg/granule, 15 mg/granule and 25 mg/granule respectively, and respectively accounts for 2.0%, 6.0% and 10.0% of the weight of the granules. The comparative study was conducted using various factors such as the difference in loading, bulk density, angle of repose, dissolution rate, etc. as the investigation indices, and the disintegrant was preferred, and the results are shown in Table 2.
The formula 5 shows that the dissolution curves of dextromethorphan hydrobromide in phosphate buffer solution with pH6.8, hydrochloric acid solution with pH1.2 and acetate buffer solution with pH4.0 are similar to those of the original ground product, and the medium in water is not similar to the original ground product. The dissolution curves of the quinidine sulfate in hydrochloric acid solution with pH1.2 and phosphate buffer solution with pH6.8 are similar to those of the original ground product, and the dissolution of acetate buffer solution with pH4.0 in aqueous medium (f 2< 50) is not similar to that of the original ground product.
The formula 6 shows that the dissolution curves of dextromethorphan hydrobromide in phosphate buffer solution with pH6.8, hydrochloric acid solution with pH1.2 and acetate buffer solution with pH4.0 are similar to those of the original ground product, and the medium in water is not similar to the original ground product. The dissolution curves of the quinidine sulfate in hydrochloric acid solution with pH1.2, acetate buffer solution with pH4.0 and phosphate buffer solution with pH6.8 are similar to those of the original ground product, and the dissolution in an aqueous medium (f 2< 50) is not similar to that of the original ground product.
In the sample of the formula 7, dissolution curves of dextromethorphan hydrobromide and quinidine sulfate in different media are similar to those of the original ground product, and the investigation indexes of the samples of the formula 5-7 all meet the requirements of the four parts of the national pharmacopoeia 2015 edition on capsules.
The research results show that the dissolution curves of dextromethorphan hydrobromide and quinidine sulfate in the samples of the prescription 5 and the prescription 6 in acetate and water with pH of 4.0 are greatly different from those of the original product, and the dissolution curves are dissimilar when f2 is less than 50. Based on the above groping and analysis, the amount of disintegrant in dextromethorphan hydrobromide quinidine sulfate capsule in formula 7 is finally selected, and thus the amount of disintegrant croscarmellose sodium is selected to be 2.0%.
On the basis of formula 7, the ratio of lactose (monohydrate) and microcrystalline cellulose was adjusted to 4: 1. 1: 1 and 1:2, preparing a soft material, and sieving with a 24-mesh sieve. Drying the sieved granules in a 45 +/-5 ℃ oven until the water content is 1.0-3.0%, mixing the granules with magnesium stearate and colloidal silicon dioxide, and filling the mixture into capsules, wherein the filling amount of the capsules is 250 mg. Based on this, the amount of the filler was selected with emphasis, and the results are shown in Table 3.
The dissolution curves of dextromethorphan hydrobromide and quinidine sulfate in different dissolution media of the prescription 8 and the prescription 9 are similar to those of the original research product, but the dissolution curves of dextromethorphan hydrobromide in a water dissolution medium of the prescription 10 are not similar to those of the original research product, so that the dosage ratio of lactose (monohydrate) to microcrystalline cellulose is adjusted from 1:2 to 3: 1. 4: 1 or 1: 1, the characteristic dissolution curve of the sample is similar to that of the original product. According to the experimental results, the ratio of lactose (monohydrate) to microcrystalline cellulose is preferably 3: 1.
the similarity of the characteristic dissolution curves of the prescriptions and the original research products is comprehensively compared, and the screening results are summarized as follows:
the results show that the characteristic dissolution profiles of formulas 3, 7, 8, and 9 are similar to those of the original study.
Note:
1. by constant search and trial, the optimal prescription amount is finally determined, preferably 7 compared to prescriptions 3, 8, 9.
2. CCMC-Na-croscarmellose sodium; SiO2 — colloidal silica; MS-magnesium stearate; MCC-microcrystalline cellulose; LAC-lactose (monohydrate).
Example 1
Prescription:
the preparation method comprises the following steps: powder direct filling
(1) Preparing dextromethorphan hydrobromide quinidine sulfate capsules: mixing dextromethorphan hydrobromide (monohydrate), quinidine sulfate (dihydrate), anhydrous lactose, silicified microcrystalline cellulose, croscarmellose sodium, and magnesium stearate in a mixer for 15 minutes;
(2) filling: and (3) filling the mixture in the step (1) by using a No. 1 capsule mold.
Example 2
Prescription:
the preparation method comprises the following steps: wet granulation
(1) Preparation of dextromethorphan hydrobromide quinidine sulfate granules: sequentially adding microcrystalline cellulose, croscarmellose sodium, quinidine sulfate (dihydrate), dextromethorphan hydrobromide (monohydrate), and lactose (monohydrate) into a wet mixing granulator, premixing for 10min, adding purified water according to a prescription amount under stirring, granulating, and sieving with a 30-mesh sieve to obtain soft material.
(2) And (3) drying: and setting the air inlet temperature to be 60-70 ℃ and the material temperature to be 45 ℃, drying the materials by a fluidized bed, and stopping heating until the moisture is less than 3.0%.
(3) Sieving, grading, and mixing, manually sieving the dried material with 24 mesh sieve, grading larger than 24 mesh, sequentially adding the graded material, magnesium stearate and colloidal silicon dioxide into a total mixer, mixing for 15min, and sampling for inspection.
(4) Filling according to the standard filling amount converted from the sample content, and filling capsules according to the filling amount range (100% +/-8%). Filling with 1# gelatin empty capsule.
Example 3
Prescription:
the preparation method comprises the following steps: one-step granulation
(1) Preparation of dextromethorphan hydrobromide quinidine sulfate granules: putting microcrystalline cellulose, croscarmellose sodium, quinidine sulfate (dihydrate), dextromethorphan hydrobromide (monohydrate), and lactose (monohydrate) into a fluidized bed for one-step granulation, and weighing purified water according to the prescription amount for later use.
(2) Setting the frequency of a fan to be 5-30 Hz, the temperature of the material to be 45 +/-5 ℃ and the temperature of inlet air to be 50-70 ℃, starting a heating function, adjusting the atomization pressure to be 1.5-3.0 bar when the temperature of the material reaches 40 ℃, starting spraying purified water until spraying is finished, starting drying, setting the drying temperature to be 45 ℃ and stopping heating when the moisture is less than 3.0%.
(3) Sieving and total mixing, namely manually sieving the dried material by a 24-mesh sieve, sequentially putting the material smaller than 24 meshes, magnesium stearate and colloidal silicon dioxide in the formula amount into a total mixer for mixing for 15min, and sampling and inspecting.
(4) Filling according to the standard filling amount converted from the sample content, and filling capsules according to the filling amount range (100% +/-8%). Filling with 1# gelatin empty capsule.
Example 4
And (4) conclusion: the flowability of the granules prepared by adopting the powder direct filling process is the worst, the flowability of the granules prepared by adopting the one-step granulation process is the second best, and the flowability of the granules prepared by adopting the powder direct filling process meets the production requirement.
Example 5 blend uniformity
And (4) conclusion: from the mixing uniformity data, it is shown that the granules prepared by the one-step granulation process are most effective in mixing.
Example 6
Content uniformity results
And (4) conclusion: the content uniformity A +2.2S of the three batches of small test repetitive particles is less than 15, and the content uniformity accords with the specification.
Example 7
Dissolution curve
In the same way as the NUEDEXTA of the original study, we plotted the multiple characteristic dissolution curves of the three process-verified samples 1, 2, 3 and compared them for study. As shown in the drawings.
The results show that: the process verifies that the in vitro dissolution behavior of dextromethorphan hydrobromide quinidine sulfate in three samples in the dissolution medium of pH1.2 hydrochloric acid solution, water, pH4.0 acetate buffer solution and pH6.8 phosphate buffer solution is similar to that of the original ground product.
In conclusion, the invention adopts a one-step granulation process, the granulation liquid is purified water, the obtainment is easy, the operation is simple, the granulation can be finished in one step by fluidized bed equipment, the size of the granules obtained by granulation is uniform, only screening is needed, unqualified products are screened, wet granulation and dry granulation are not needed, the production process steps are reduced, the preparation time is shortened, the controllability of the process parameters in the production process is high, the artificial influence of a plurality of process step operations is reduced, and the quality stability of the medicine is effectively improved. Meanwhile, the in vitro multi-characteristic dissolution curves of the dextromethorphan hydrobromide quinidine sulfate capsule prepared by the invention are similar to those of a reference preparation, and the number and the limit of impurities are not higher than those of the reference preparation.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (7)
1. The dextromethorphan hydrobromide and quinidine sulfate capsule is characterized by comprising a dextromethorphan hydrobromide-containing raw material drug, a quinidine sulfate-containing raw material drug, a disintegrant, a filler, a lubricant and a glidant, wherein the disintegrant is selected from cross-linked sodium carboxymethyl cellulose, and the filler is selected from lactose monohydrate and microcrystalline cellulose.
2. A dextromethorphan hydrobromide quinidine sulfate capsule according to claim 1, wherein said lubricant is selected from magnesium stearate and said glidant is selected from colloidal silicon dioxide.
3. The dextromethorphan hydrobromide quinidine sulfate capsule according to claim 1, wherein the weight ratio of lactose to microcrystalline cellulose is (4-1): 1.
4. The dextromethorphan hydrobromide quinidine sulfate capsule according to any one of claims 1 to 3, wherein the dextromethorphan hydrobromide quinidine sulfate capsule is composed of the following components in parts by weight:
5. a method for preparing the dextromethorphan hydrobromide quinidine sulfate capsules according to claims 1 to 4, wherein the method for preparing the dextromethorphan hydrobromide quinidine sulfate capsules is a one-step granulation method.
6. A method for preparing according to claim 5, characterized in that it comprises the following steps:
(1) preparation of dextromethorphan hydrobromide quinidine sulfate granules: adding dextromethorphan hydrobromide monohydrate, quinidine sulfate dihydrate, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium into a fluidized bed according to the formula amount for one-step granulation to obtain dextromethorphan hydrobromide quinidine sulfate granules;
(2) mixing: putting the dextromethorphan hydrobromide quinidine sulfate granules obtained in the step (1), colloidal silica and magnesium stearate into a mixer for mixing;
(3) filling: filling the mixture in the step (2) by using a proper filling mold.
7. The preparation method according to claim 6, wherein the blower frequency of the fluidized bed equipment is set to be 5-30 Hz, the material temperature is 45 +/-5 ℃, the air inlet temperature is 50-70 ℃, the heating function is started, the atomizing pressure is adjusted to be 1.5-3.0 bar when the material temperature reaches 40 ℃, the wetting agent is sprayed, and the one-step granulation time is 30-90 minutes.
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