CN112206209A - Acetylcysteine granules and preparation method thereof - Google Patents
Acetylcysteine granules and preparation method thereof Download PDFInfo
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- CN112206209A CN112206209A CN202010924964.0A CN202010924964A CN112206209A CN 112206209 A CN112206209 A CN 112206209A CN 202010924964 A CN202010924964 A CN 202010924964A CN 112206209 A CN112206209 A CN 112206209A
- Authority
- CN
- China
- Prior art keywords
- acetylcysteine
- percent
- menthol
- essence
- granules
- Prior art date
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- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 title claims abstract description 125
- 229960004308 acetylcysteine Drugs 0.000 title claims abstract description 125
- 239000008187 granular material Substances 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title abstract description 38
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims abstract description 76
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims abstract description 72
- 229940041616 menthol Drugs 0.000 claims abstract description 72
- 238000000034 method Methods 0.000 claims abstract description 37
- 239000000463 material Substances 0.000 claims abstract description 29
- 238000005469 granulation Methods 0.000 claims abstract description 11
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- 239000000796 flavoring agent Substances 0.000 claims abstract description 10
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- 239000002994 raw material Substances 0.000 claims abstract description 8
- 229930006000 Sucrose Natural products 0.000 claims description 36
- 229960004793 sucrose Drugs 0.000 claims description 36
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 34
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- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 28
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- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 claims description 11
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
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- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 2
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- XINCECQTMHSORG-UHFFFAOYSA-N Isoamyl isovalerate Chemical group CC(C)CCOC(=O)CC(C)C XINCECQTMHSORG-UHFFFAOYSA-N 0.000 claims description 2
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- 235000010358 acesulfame potassium Nutrition 0.000 claims description 2
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
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- 238000012360 testing method Methods 0.000 description 5
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 4
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- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 3
- 239000004925 Acrylic resin Substances 0.000 description 3
- 229920000178 Acrylic resin Polymers 0.000 description 3
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- 238000002474 experimental method Methods 0.000 description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 210000003802 sputum Anatomy 0.000 description 3
- 208000024794 sputum Diseases 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
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- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
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- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
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- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
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- 235000009508 confectionery Nutrition 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
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- 229960003180 glutathione Drugs 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- DFEYYRMXOJXZRJ-UHFFFAOYSA-N sevoflurane Chemical compound FCOC(C(F)(F)F)C(F)(F)F DFEYYRMXOJXZRJ-UHFFFAOYSA-N 0.000 description 1
- 229960002078 sevoflurane Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
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Images
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to acetylcysteine granules and a preparation method thereof, wherein the acetylcysteine granules comprise raw materials of acetylcysteine and auxiliary materials, and the auxiliary materials comprise a filling agent, menthol, a flavoring agent and essence, wherein the weight percentage of the menthol is 0.8-1.5%. The acetylcysteine granules provided by the invention use menthol and adopt a fluidized bed one-step granulation process, so that the prepared acetylcysteine granules have better stability and higher bioavailability.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to acetylcysteine granules and a preparation method thereof.
Background
N-Acetylcysteine (NAC) is formed by adding acetyl to L-cysteine, is a precursor of reduced Glutathione (GSH), is white crystalline powder in appearance, and has odor and taste similar to garlic. It can directly scavenge free radicals in vivo, enhance the body's ability to resist oxidative stress, and reduce the production of inflammatory cytokines, chemokines and adhesion molecules. In addition, acetylcysteine also regulates the immune status of the body and the apoptotic program.
Acetylcysteine is a mucolytic agent, and a-SH group in the chemical structure of acetylcysteine can break a disulfide bond (-S-S-) in a mucin polypeptide chain in sputum, reduce the viscosity of the sputum, liquefy the sputum and be easy to expectorate. But at the same time, because the acetylcysteine has active-SH group, the group is easy to be oxidized and is sensitive to damp heat, so that the stability of the raw material medicine is poor, the storage process is very unstable, and the curative effect of the acetylcysteine is seriously reduced.
The earliest formulation of acetylcysteine on the market is inhalation aerosol, and acetylcysteine spraying agent is collected in Chinese pharmacopoeia and acetylcysteine solution is collected in American pharmacopoeia. Initially, acetylcysteine was considered ineffective orally due to its low oral bioavailability, which was shown to be as effective as inhalation by years of clinical studies. Gradually, various formulations are developed, including granules, solutions, effervescent tablets, injections and the like. The acetylcysteine granules are widely applied in China, are suitable for people in all stages, can improve the medicine taking compliance of patients, and have high popularity.
In view of the specific physicochemical properties of acetylcysteine, when developing acetylcysteine granules, it is a key technology how to control the quality of the stability of the preparation to avoid reducing the efficacy of NAC, an active ingredient. In the prior art, the relevant patents relating to acetylcysteine granules for improving stability are as follows:
chinese patent application No. CN 102144978A discloses acetylcysteine granules and a preparation process thereof, the granules mainly comprise acetylcysteine, acrylic resin, mannitol, aspartame and orange essence, the technical scheme mainly improves the stability of the acetylcysteine granules through the preparation process, and the preparation method comprises the following steps: the acetylcysteine is coated by acrylic resin and then mixed with other auxiliary materials, but the technical defects are as follows: firstly, the preparation process is complex, and the acrylic resin is required to be dissolved in an organic reagent and then to coat the acetylcysteine, so that the use problem of the organic reagent is involved, the problems of organic reagent residue and the like are also required to be concerned in the later period, and the preparation process is more complex from the aspect of medicine quality control, so that the preparation process is not beneficial to the industrial development of acetylcysteine granules; ② the patent proposal can not know whether the bioavailability of acetylcysteine can be improved.
The patent discloses a pharmaceutical composition of acetylcysteine and a preparation method thereof, and the granular composition disclosed by the patent is acetylcysteine, sucrose, sweet orange essence, aspartame, sunset yellow and a flow aid, and the stability of acetylcysteine granules is improved by adding the flow aid (silicon dioxide or talcum powder) in a formula and a preparation process of mixing the auxiliary material with acetylcysteine and the flow aid after wet granulation. But the technical defects are as follows: firstly, the auxiliary materials in the preparation method are subjected to wet granulation independently, so that the difference between the granularity and the properties of the auxiliary materials and acetylcysteine is large, and the mixing uniformity is difficult to control in production; ② the patent proposal can not know whether to improve the bioavailability of acetylcysteine.
In conclusion, the current research literature is not many how to improve the prescription of acetylcysteine granules, improve the stability of acetylcysteine by selecting a proper stabilizing agent, and improve the bioavailability of acetylcysteine.
The menthol crystal has cool, fresh and pleasant mint characteristic aroma, gives people a cold feeling, has the advantages of through aroma and unique mouthfeel, is often used as a flavoring agent for medicines, perfumes, tobacco products and the like, and for example, Chinese patent with the publication number of CN 103191080A discloses an acetylcysteine effervescent tablet, and the flavoring agent in the formula can be selected from the menthol crystal; also, for example, chinese patent publication No. CN 102028657a discloses an acetylcysteine liposome solid preparation, wherein the aromatic agent in the formulation can be selected from menthol. However, there is no report on the application of menthol as a stabilizer to acetylcysteine granules.
For example, chinese patent publication No. CN 105380957a discloses an acetylcysteine gel, its preparation method and application, wherein the formula contains a stabilizer selected from one or more of sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium thiosulfate, ascorbic acid, thiourea, methionine, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, and sodium citrate, and the formula also contains menthol, but the menthol is still used as a flavoring agent.
For another example, chinese patent publication No. CN 1997360a discloses a stabilized pharmaceutical composition of a fluoroether compound for anesthetic use, wherein a stabilizer is used to prevent degradation of the fluoroether compound, and the stabilizer is selected from propylene glycol, polyethylene glycol, a polyol of 2-methyl-2, 4-pentanediol and 1, 3-butanediol, or menthol. However, the drugs aimed at in the patent are fluoroether compounds such as sevoflurane and difluorine, and the physicochemical properties of the fluoroether compounds are different from those of acetylcysteine, so that the stabilizer mentioned in the patent is not suitable for developing acetylcysteine granules, and uncertainty exists.
Therefore, it is a technical problem that those skilled in the art have not solved to select menthol as a stabilizer for developing acetylcysteine granules and to select an appropriate formula ratio of acetylcysteine granules, so as to improve the stability of acetylcysteine and simultaneously improve the bioavailability of acetylcysteine.
Disclosure of Invention
The invention aims to solve the technical problem of providing a prescription and a process of acetylcysteine granules, wherein a proper amount of menthol is added as a stabilizer, and a fluidized bed one-step granulation method process is adopted, so that the degradation of-SH groups in acetylcysteine is reduced, the stability of the medicine is improved, and the bioavailability of the medicine is improved.
In order to solve the technical problems, the invention adopts the following technical scheme:
the acetylcysteine granule comprises raw material acetylcysteine and auxiliary materials, wherein the auxiliary materials comprise a filling agent, menthol, a flavoring agent and essence, and the weight percentage of the menthol is 0.8-1.5%.
Preferably, in the granule, the weight percentages of acetylcysteine and auxiliary materials are as follows: 3 to 6 percent of acetylcysteine, 90 to 95 percent of filler, 0.8 to 1.5 percent of menthol, 0.5 to 3 percent of flavoring agent and 0.5 to 2 percent of essence.
More preferably, the bulking agent is one or more of sucrose, sorbitol, mannitol, and xylitol, and even more preferably sucrose.
More preferably, the flavoring agent is one or more of aspartame, saccharin sodium, acesulfame potassium and stevioside, and further preferably stevioside.
More preferably, the essence is apple essence, sweet orange essence, pineapple essence and banana essence, and more preferably sweet orange essence.
An acetylcysteine granule, the preferable prescription comprises the following components by weight: 5% of acetylcysteine, 92.46% of cane sugar, 1.2% of menthol, 0.67% of steviosin and 0.67% of orange essence.
An acetylcysteine granule, the preferable prescription comprises the following components by weight: 3.33 percent of acetylcysteine, 93.17 percent of cane sugar, 1.5 percent of menthol, 1 percent of steviosin and 1 percent of orange essence.
An acetylcysteine granule, the preferable prescription comprises the following components by weight: 3.33 percent of acetylcysteine, 92.2 percent of cane sugar, 0.8 percent of menthol, 3 percent of steviosin and 0.67 percent of orange essence.
A method for preparing acetylcysteine granules as described above, wherein the method comprises the steps of:
(1) pulverizing the raw materials, filler, Mentholum, and correctant, and sieving with 80 mesh sieve;
(2) mixing the raw materials, filler, Mentholum, and correctant;
(3) adding the mixture obtained in the step (2) into a fluidized bed, setting the air inlet temperature to be 40-50 ℃, adding purified water, granulating and drying;
(4) and (4) taking the dry particles obtained in the step (3), and sieving the dry particles with a 18-mesh sieve for finishing the particles.
(5) And (4) adding essence into the granules obtained in the step (4), and uniformly mixing to obtain the acetylcysteine granules.
Preferably, in step 3 of the preparation method, the temperature of the materials is controlled to be 35 +/-5 ℃ for granulation, the temperature of the materials is controlled to be 45 +/-5 ℃ for drying, and the water content is controlled to be 0.5-1.5%.
The fluidized bed one-step granulation is to complete dry mixing, wet mixing, stirring, particle forming and drying of materials in the same fluidized bed device, the whole production is carried out in a sealed environment, the pollution of the outside to medicines can be prevented, a large number of operation links are reduced, the production time is saved, and the production efficiency is obviously improved. In the fluidized bed one-step granulation process, granulation and drying processes are carried out simultaneously, so that the time of the moisture-proof materials contacting the wet environment can be greatly reduced, and meanwhile, the dynamic drying efficiency is high, the requirement on the drying temperature is not high, and the method is also suitable for high-temperature sensitive medicines. In addition, the granules prepared by the fluidized bed granulation technology have uniform granularity, good mixing uniformity and fluidity and convenient subpackage.
Compared with the prior art, the acetylcysteine granules and the preparation method thereof provided by the invention have the following beneficial effects:
the formula of the invention adopts the added menthol as the stabilizer with the weight ratio of 0.8-1.5%, and the technique adopts the fluidized bed one-step granulation technique to prepare the medicineThe process has high efficiency and no pollution, the preparation stability is improved, and the maximum plasma concentration (C) is reached within 0.5-1 hour after the preparation is takenmax) The onset time is obviously accelerated, and the bioavailability is obviously improved.
Drawings
FIG. 1 is a graph of the drug profiles of each group of samples in the bioavailability test experiments.
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
Example 1 formulation and Process of granules of acetylcysteine
The prescription is shown below, and the ratio of the dosage of each component to the (unit: mg) weight is as follows by taking the total amount as 3 g/bag:
| acetylcysteine | 100(3.33％) |
| Sucrose | 2766(92.2％) |
| Menthol crystal | 24(0.8％) |
| Stevia rebaudianum extract | 90(3.0％) |
| Sweet orange essence | 20(0.67％) |
The preparation method comprises the following steps:
(1) pulverizing acetylcysteine, sucrose, menthol and steviosin in prescribed amount, and sieving with 80 mesh sieve;
(2) evenly mixing acetylcysteine, cane sugar, menthol and stevioside according to the prescription amount;
(3) adding the mixture into a fluidized bed, setting the air inlet temperature to be 45 ℃, adding purified water, granulating and drying, wherein the process conditions are as follows: controlling the temperature of the materials to be 35 +/-5 ℃ in the granulating process, controlling the temperature of the materials to be 45 +/-5 ℃ in the drying process, and drying until the moisture of the dry granules is 0.5-1.5%;
(4) the dry particles are granulated by a sieve with 18 meshes;
(5) and adding sweet orange essence into the dry particles, and uniformly mixing to obtain the acetylcysteine particles.
Example 2 formulation and Process of acetylcysteine granules
The prescription is shown below, and the ratio of the dosage of each component to the (unit: mg) weight is as follows by taking the total amount as 3 g/bag:
| acetylcysteine | 180(6.0％) |
| Sucrose | 2700(90.0％) |
| Menthol crystal | 45(1.5％) |
| Stevia rebaudianum extract | 15(0.5％) |
| Sweet orangeEssence | 60(2.0％) |
The preparation method comprises the following steps:
(1) pulverizing acetylcysteine, sucrose, menthol and steviosin in prescribed amount, and sieving with 80 mesh sieve;
(2) evenly mixing acetylcysteine, cane sugar, menthol and stevioside according to the prescription amount;
(3) adding the mixture into a fluidized bed, setting the air inlet temperature to be 40 ℃, adding purified water, granulating and drying, wherein the process conditions are as follows: controlling the temperature of the materials to be 35 +/-5 ℃ in the granulating process, controlling the temperature of the materials to be 45 +/-5 ℃ in the drying process, and drying until the moisture of the dry granules is 0.5-1.5%;
(4) the dry particles are granulated by a sieve with 18 meshes;
(5) and adding sweet orange essence into the dry particles, and uniformly mixing to obtain the acetylcysteine particles.
Example 3 formulation and Process of granules of acetylcysteine
The prescription is shown below, and the ratio of the dosage of each component to the (unit: mg) weight is as follows by taking the total amount as 3 g/bag:
| acetylcysteine | 90(3.0％) |
| Sucrose | 2850(95.0％) |
| Menthol crystal | 27(0.9％) |
| Stevia rebaudianum extract | 18(0.6％) |
| Sweet orange essence | 15(0.5％) |
The preparation method comprises the following steps:
(1) pulverizing acetylcysteine, sucrose, menthol and steviosin in prescribed amount, and sieving with 80 mesh sieve;
(2) evenly mixing acetylcysteine, cane sugar, menthol and stevioside according to the prescription amount;
(3) adding the mixture into a fluidized bed, setting the air inlet temperature to be 50 ℃, adding purified water, granulating and drying, wherein the process conditions are as follows: controlling the temperature of the materials to be 35 +/-5 ℃ in the granulating process, controlling the temperature of the materials to be 45 +/-5 ℃ in the drying process, and drying until the moisture of the dry granules is 0.5-1.5%;
(4) the dry particles are granulated by a sieve with 18 meshes;
(5) and adding sweet orange essence into the dry particles, and uniformly mixing to obtain the acetylcysteine particles.
Example 4 formulation and Process of acetylcysteine granules
The prescription is shown below, and the ratio of the dosage of each component to the (unit: mg) weight is as follows by taking the total amount as 3 g/bag:
| acetylcysteine | 120(4.0％) |
| Sucrose | 2781(92.7％) |
| Menthol crystal | 30(1.0％) |
| Stevia rebaudianum extract | 24(0.8％) |
| Sweet orange essence | 45(1.5％) |
The preparation method comprises the following steps:
(1) pulverizing acetylcysteine, sucrose, menthol and steviosin in prescribed amount, and sieving with 80 mesh sieve;
(2) evenly mixing acetylcysteine, cane sugar, menthol and stevioside according to the prescription amount;
(3) adding the mixture into a fluidized bed, setting the air inlet temperature to be 50 ℃, adding purified water, granulating and drying, wherein the process conditions are as follows: controlling the temperature of the materials to be 35 +/-5 ℃ in the granulating process, controlling the temperature of the materials to be 45 +/-5 ℃ in the drying process, and drying until the moisture of the dry granules is 0.5-1.5%;
(4) the dry particles are granulated by a sieve with 18 meshes;
(5) and adding sweet orange essence into the dry particles, and uniformly mixing to obtain the acetylcysteine particles.
Example 5 formulation and Process of granules of acetylcysteine
The prescription is shown below, and the ratio of the dosage of each component to the (unit: mg) weight is as follows by taking the total amount as 3 g/bag:
| acetylcysteine | 150(5.0％) |
| Sucrose | 2774(92.46％) |
| Menthol crystal | 36(1.2％) |
| Stevia rebaudianum extract | 20(0.67％) |
| Sweet orange essence | 20(0.67％) |
The preparation method comprises the following steps:
(1) pulverizing acetylcysteine, sucrose, menthol and steviosin in prescribed amount, and sieving with 80 mesh sieve;
(2) evenly mixing acetylcysteine, cane sugar, menthol and stevioside according to the prescription amount;
(3) adding the mixture into a fluidized bed, setting the air inlet temperature to be 50 ℃, adding purified water, granulating and drying, wherein the process conditions are as follows: controlling the temperature of the materials to be 35 +/-5 ℃ in the granulating process, controlling the temperature of the materials to be 45 +/-5 ℃ in the drying process, and drying until the moisture of the dry granules is 0.5-1.5%;
(4) the dry particles are granulated by a sieve with 18 meshes;
(5) and adding sweet orange essence into the dry particles, and uniformly mixing to obtain the acetylcysteine particles.
Example 6 formulation and Process of granules of acetylcysteine
The prescription is shown below, and the ratio of the dosage of each component to the (unit: mg) weight is as follows by taking the total amount as 3 g/bag:
| acetylcysteine | 100(3.33％) |
| Sucrose | 2795(93.17％) |
| Menthol crystal | 45(1.5％) |
| Stevia rebaudianum extract | 30(1.0％) |
| Sweet orange essence | 30(1.0％) |
The preparation method comprises the following steps:
(1) pulverizing acetylcysteine, sucrose, menthol and steviosin in prescribed amount, and sieving with 80 mesh sieve;
(2) evenly mixing acetylcysteine, cane sugar, menthol and stevioside according to the prescription amount;
(3) adding the mixture into a fluidized bed, setting the air inlet temperature to be 50 ℃, adding purified water, granulating and drying, wherein the process conditions are as follows: controlling the temperature of the materials to be 35 +/-5 ℃ in the granulating process, controlling the temperature of the materials to be 45 +/-5 ℃ in the drying process, and drying until the moisture of the dry granules is 0.5-1.5%;
(4) the dry particles are granulated by a sieve with 18 meshes;
(5) and adding sweet orange essence into the dry particles, and uniformly mixing to obtain the acetylcysteine particles.
Example 7 Effect of selection of stabilizer types on formulation Properties
In this example, only the type of stabilizer is changed, the components and the amounts of the other formulations are not changed, the preparation method is not changed, and the influence of the selection of the type of stabilizer on the stability of the preparation is examined.
The stabilizer is selected from: propylene glycol, sodium thiosulfate and menthol.
The experimental method comprises the following steps: acetylcysteine granules are prepared by taking acetylcysteine, cane sugar, a stabilizer, steviosin and orange essence with the same dosage as a prescription, the acetylcysteine granules are placed for six months under the conditions of 0 day and accelerated post-packaging of a paper/aluminum composite film bag (the temperature is 40 ℃ plus or minus 2 ℃ and the relative humidity is 75 percent plus or minus 5 percent), and the stability test results are shown in table 1:
TABLE 1 stability comparison after 0 days of standing and six months accelerated
Criteria for judging significant differences in stability: according to the ICH three-party coordination guidance principle: stability test of new crude drug and preparation "2.2.7.1 general case" on page 15 of Q1A (R2) specifies: typically, a "significant difference" in a formulation is defined as a 5% difference in content from the initial value.
As can be seen from Table 1, after accelerated 6 months, the stabilizer is acetylcysteine granules of menthol, and the content, single impurity and total impurity of related substances of the granules are not changed obviously, which shows that the stability is good. The stabilizer is acetylcysteine granules of propylene glycol and sodium thiosulfate, the content of related substances of the granules is reduced by more than 8 percent, and the granules have obvious change and do not accord with the stability quality control regulation of the preparation.
In conclusion, the invention determines to select the menthol crystal as the stabilizer in the prescription of the acetylcysteine granules.
EXAMPLE 8 examination of the influence of selection of the amount of stabilizer and Process on the stability of the preparation
On the basis of selecting the menthol as the stabilizing agent, the applicant further examines the influence of the dosage change and the process change of the stabilizing agent on the stability of the preparation.
Comparative examples 6-1, 6-2, 6-3, 6-4 of example 6 were designed as follows:
comparative example 6-1 was prepared in the same manner as in example 6, except that menthol was not added to the formulation, the amount of menthol was replaced with sucrose as a filler, and acetylcysteine, steviosin and orange essence were used in the same amounts as in example 6.
The comparative example 6-2 was prepared in the same manner as in example 6, except that the amount of menthol used in the formulation was set to 0.7%, the amounts of acetylcysteine, steviosin and orange flavor were set to the same amounts as in example 6, and the amount of sucrose was adjusted to make the total amount of the whole formulation 100%.
Comparative examples 6 to 3 were prepared in the same manner as in example 6, except that the amount of menthol in the formulation was 1.6%, the amounts of acetylcysteine, steviosin and orange flavor were the same as in example 6, and the amount of sucrose was adjusted to make the total amount of sucrose in the formulation 100%.
The formulation of comparative examples 6-4 was the same as example 6, and the preparation method was changed to a high shear wet granulation process (see step 3 for differences), and the specific steps were as follows:
(1) pulverizing acetylcysteine, sucrose, menthol and steviosin in prescribed amount, and sieving with 80 mesh sieve;
(2) evenly mixing acetylcysteine, cane sugar, menthol and stevioside according to the prescription amount;
(3) adding the mixture into a high shear wet granulator, and adding purified water for granulation;
(4) adding the wet particles into a fluidized bed, and setting the air inlet temperature to be 50 ℃ for drying;
(5) the dry particles are granulated by a sieve with 18 meshes;
(6) and adding sweet orange essence into the dry particles, and uniformly mixing to obtain the acetylcysteine particles.
Meanwhile, a commercial acetylcysteine granule product (A) is selected
Prescription in accordance with the original study) as a control, and examples 1 to 6 and comparative examples 6-1 to 6-4 were left for six months under accelerated conditions (temperature 40 ℃ ± 2 ℃, relative humidity 75% ± 5%) after being packed in a paper/aluminum composite film bag, and the results of the stability test are shown in table 2:
TABLE 2 stability comparison after 0 days of standing and six months accelerated
Criteria for judging significant differences in stability: according to the ICH three-party coordination guidance principle: stability test of new crude drug and preparation "2.2.7.1 general case" on page 15 of Q1A (R2) specifies: typically, a "significant difference" in a formulation is defined as a 5% difference in content from the initial value.
As can be seen from table 2, it is,
1) after the acceleration of 6 months, the related substances of the samples of the examples 1 to 6 prepared by the invention are not increased, but the impurities of the commercial reference substances are obviously increased and have larger differences, which shows that the stability of the samples of the examples 1 to 6 prepared by the invention is better than that of the original research.
2) Similarly, after the samples of comparative examples 6-1 to 6-4 are accelerated for 6 months, the content of the samples deviates more than 5% relative to 0 day, and the impurities are also obviously increased, which shows that the stability of the preparation is obviously different when the process adopts a high-shear wet granulation process without adding menthol and the dosage of the menthol is less than 0.8 or more than 1.5.
EXAMPLE 9 Effect of selection of the amount of stabilizer on the bioavailability of the formulations
On the basis of selecting comparative examples 6-1 to 6-4 of example 8 and a commercially available reference substance, the stabilizer is selected to be menthol, and the applicant further examines the influence of the dosage change of the stabilizer on the bioavailability of the preparation.
Examples 1, 5, 6, and comparative examples 6-1 to 6-3 and commercial controls were subjected to pharmacokinetic tests to compare bioavailability. The specific test method is as follows:
42 healthy Beagle dogs with half male and female bodies and a body weight of (10 +/-1.0) kg are selected. No drug was used for the first 14d of the experiment, which was compared to the first 1d 20: 00 fasting was started, with the test at 7: 00 taking the preparation with specified dosage on empty stomach, and taking food 4h after taking the preparation.
The dosing regimen was designed using a single-site, randomized, parallel, control trial. 42 test dogs were randomly numbered and randomly divided into A, B, C, D, E, F, G groups of 6 dogs each. Example 1, example 5, example 6, comparative example 6-1-6-3 and the commercially available drugs were taken at random. The random grouping and dosing schedule is shown in table 3 below. The 7 formulations were all administered orally. 3.0ml of blood is taken from forelimb veins and placed in an anticoagulation tube for drug concentration analysis at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0 and 8.0h before (0h) and after administration, and the time curve of the experimental result is shown in figure 1.
TABLE 3 dosing regimen
| Randomized grouping of test dogs | Taking medicine |
| A(7,12,18,25,27,31) | Example 1 |
| B(5,6,13,22,30,37) | Example 5 |
| C(1,4,19,23,26,34,) | Example 6 |
| D(2,11,15,21,33,38) | Comparative example 6-1 |
| E(8,10,20,28,32,40) | Comparative examples 6 to 2 |
| F(14,16,24,29,35,41) | Comparative examples 6 to 3 |
| G(3,9,17,36,39,42) | Commercial control |
As can be seen from the figure 1 of the drawings,
1) example 1 (menthol to 0.8%), example 5 (menthol to 1.2%) and example 6 (menthol to 1.5%) of the present invention peaked in Beagle canine plasma levels within 1 hour after dosing, and comparative example 6-1 (no menthol added), comparative example 6-2 (menthol to 0.7%), comparative example 6-3 (menthol to 1.6%), and commercial products peaked in Beagle canine plasma levels 2 hours after dosing. The invention shows that the menthol granule with the weight ratio of 0.8-1.5% is easier to absorb and has the characteristic of quick effect.
2) The bioavailability of each group of samples relative to the commercial control was calculated as follows, taking the bioavailability of the commercial control as a baseline of 100%:
the bioavailability of the present invention is 131.40% for example 1 (menthol to 0.8%), 139.14% for example 5 (menthol to 1.2%) and 132.45% for example 6 (menthol to 1.5%);
the bioavailability was 97.01% for comparative example 6-1 (without menthol), 90.56% for comparative example 6-2 (menthol to 0.7%) and 87.65% for comparative example 6-3 (menthol to 1.6%).
Therefore, when the dose of the menthol is less than 0.8 or more than 1.5 without adding the menthol, the bioavailability cannot be obviously improved, and the effect is inferior to that of the original research; the dosage of the menthol is only within the range of 0.8-1.5, so that the bioavailability can be obviously improved, and the effect is better than that of the original research.
Claims (10)
1. The acetylcysteine granules comprise raw materials of acetylcysteine and auxiliary materials, and are characterized in that the auxiliary materials comprise a filling agent, menthol, a flavoring agent and essence, wherein the weight percentage of the menthol is 0.8-1.5%.
2. The acetylcysteine granule according to claim 1, wherein the weight percentage of acetylcysteine and adjuvant in the granule is: 3 to 6 percent of acetylcysteine, 90 to 95 percent of filler, 0.8 to 1.5 percent of menthol, 0.5 to 3 percent of flavoring agent and 0.5 to 2 percent of essence.
3. Acetylcysteine granules according to claim 1 or 2, wherein the bulking agent is one or more of sucrose, sorbitol, mannitol, xylitol, preferably sucrose.
4. Acetylcysteine granules according to claim 1 or 2, wherein the flavoring agent is one or more of aspartame, saccharin sodium, acesulfame potassium, stevioside, preferably stevioside.
5. Acetylcysteine granules according to claim 1 or 2, wherein the essence is apple essence, sweet orange essence, pineapple essence, banana essence, preferably sweet orange essence.
6. The acetylcysteine granule according to any one of claims 1-5, wherein the formulation comprises the following components by weight: 5% of acetylcysteine, 92.46% of cane sugar, 1.2% of menthol, 0.67% of steviosin and 0.67% of orange essence.
7. The acetylcysteine granule according to any one of claims 1-5, wherein the formulation comprises the following components by weight: 3.33 percent of acetylcysteine, 93.17 percent of cane sugar, 1.5 percent of menthol, 1 percent of steviosin and 1 percent of orange essence.
8. The acetylcysteine granule according to any one of claims 1-5, wherein the formulation comprises the following components by weight: 3.33 percent of acetylcysteine, 92.2 percent of cane sugar, 0.8 percent of menthol, 3 percent of steviosin and 0.67 percent of orange essence.
9. A process for preparing acetylcysteine granules according to claim 1, wherein a fluid bed one-step granulation process is selected, comprising the steps of:
(1) pulverizing the raw materials, filler, Mentholum, and correctant, and sieving with 80 mesh sieve;
(2) mixing the raw materials, filler, Mentholum, and correctant;
(3) adding the mixture obtained in the step (2) into a fluidized bed, setting the air inlet temperature to be 40-50 ℃, adding purified water, granulating and drying;
(4) and (4) taking the dry particles obtained in the step (3), and sieving the dry particles with a 18-mesh sieve for finishing the particles.
(5) And (4) adding essence into the granules obtained in the step (4), and uniformly mixing to obtain the acetylcysteine granules.
10. The method for preparing acetylcysteine granules according to claim 9, wherein in step 3, the temperature of the material is controlled at 35 ± 5 ℃ for granulation, the temperature of the material is controlled at 45 ± 5 ℃ for drying, and the moisture is controlled at 0.5% -1.5%.
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| WO2010090611A2 (en) * | 2009-02-05 | 2010-08-12 | Bilgic Mahmut | Taste and odor masked pharmaceutical compositions with high bioavailability |
| CN103142505A (en) * | 2013-03-29 | 2013-06-12 | 山东罗欣药业股份有限公司 | Acetylcysteine composition granules and preparation method thereof |
| CN103191080A (en) * | 2013-04-24 | 2013-07-10 | 程刚 | Acetylcysteine effervescent tablet |
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| CN110507618A (en) * | 2019-09-05 | 2019-11-29 | 杭州百诚医药科技股份有限公司 | A kind of Acetylcysteine granules agent and preparation method thereof |
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2019
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2020
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| WO2010090611A2 (en) * | 2009-02-05 | 2010-08-12 | Bilgic Mahmut | Taste and odor masked pharmaceutical compositions with high bioavailability |
| CN103142505A (en) * | 2013-03-29 | 2013-06-12 | 山东罗欣药业股份有限公司 | Acetylcysteine composition granules and preparation method thereof |
| CN103191080A (en) * | 2013-04-24 | 2013-07-10 | 程刚 | Acetylcysteine effervescent tablet |
| CN107847493A (en) * | 2015-07-31 | 2018-03-27 | 阿提努公司 | Antibechic drug composition and method |
| CN110507618A (en) * | 2019-09-05 | 2019-11-29 | 杭州百诚医药科技股份有限公司 | A kind of Acetylcysteine granules agent and preparation method thereof |
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| CN114010605A (en) * | 2021-11-26 | 2022-02-08 | 广东百澳药业有限公司 | Acetylcysteine granules and preparation method thereof |
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| CN110507618A (en) | 2019-11-29 |
| CN112206209B (en) | 2022-08-23 |
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