CN102357093B - Medicinal composition of methanesulfonic acid arbidol oral solid preparation - Google Patents
Medicinal composition of methanesulfonic acid arbidol oral solid preparation Download PDFInfo
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- CN102357093B CN102357093B CN 201110256396 CN201110256396A CN102357093B CN 102357093 B CN102357093 B CN 102357093B CN 201110256396 CN201110256396 CN 201110256396 CN 201110256396 A CN201110256396 A CN 201110256396A CN 102357093 B CN102357093 B CN 102357093B
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Abstract
The invention relates to the technical field of medicinal oral solid preparations, in particular to a medicinal composition of a methanesulfonic acid arbidol oral solid preparation serving as an anti-influenza virus medicament. The composition exists in the form of film-coated tablets, dispersible tablets, chewable tablets, capsules or particles; the film-coated tablets, dispersible tablets, chewable tablets, capsules or particles consist of an effective dosage of methanesulfonic acid arbidol and excipient; and the excipient contains organic acid for enhancing the stability of the medicinal composition, and contains more than three of a diluent, a bonding agent, a disintegrating agent, a flavoring agent and a lubricant. The medicinal composition has the advantages of stable mass, reasonable formula, application of nontoxic excipient, high safety, small using amount of auxiliary materials, capability of meeting the requirement of the oral solid preparation, quick dissolving of all dosage forms, medicament dissolving rate over 85 percent within 15 minutes, contribution to in-vivo absorption of the oral solid preparation and guarantee of better curative effect.
Description
Technical field
The present invention relates to the oral drug preparation technical field, be specifically related to a kind of pharmaceutical composition of anti-influenza virus medicament methanesulfonic acid arbidol oral solid preparation.
Background technology
The at present domestic antiviral chemicals that uses clinically mainly contains arbidol HCl, ribavirin, amantadine, rimantadine, Oseltamivir, zanamivir etc.Wherein, ribavirin all has activity to first type and Influenza B virus when heavy dose, but have nucleoside medicine teratogenesis, cause change toxicity, can cause anemia and immunosuppressant.Amantadine and rimantadine are only effective to influenza A, and are prone to drug resistance.Such medicine also can cause the central nervous system toxicity reaction, thereby has reduced clinical use value.Neuraminidase inhibitor Oseltamivir and zanamivir determined curative effect, but price is very expensive.
Arbidol HCl and oral solid formulation (sheet, capsule, dispersible tablet, granule) thereof at Russia and Discussion on Chinese Listed is non-nucleosides compound, its mechanism of action is by activating 2 ', 5 '-oligo-adenylate synthetase, specificity suppresses the fusion of viral lipid cyst membrane and host cell membrane, thus the copying of blocking virus.Arbidol HCl successfully goes on the market in Russia and China, is mainly used in preventing and treating the upper respiratory tract infection that first, Influenza B virus causes.It has following advantage and characteristics: 1, infected by influenza first type and B-mode all effective.2, existing therapeutical effect also has preventive effect.3, have the direct dual function that suppresses virus and induce endogenous interferon concurrently.Arbidol HCl toxicity is very low, foreign literature report rat and the oral 2000mg/kg of Cavia porcellus single dose, and well-tolerated shows that oral acute toxicity is very low, estimates LD
50＞3000mg/kg.The oral LD of mice
50=340mg/kg.Chronic toxicity test: rat 100-125mg/kg, Canis familiaris L. 25mg/kg, oral administration 6 months pathology all do not occur and changes.Also safer to rabbit and Cavia porcellus long-term prescription.
Arbidol HCl physicochemical property characteristics are its in water almost insoluble (1g this product can not be dissolved) in 10000mL water, the preparation stripping is slower, might affect in its body to absorb.
Russia has carried out again the research of arbidol mesylate after hydrochloric acid Ah Bill listing, studies show that arbidol mesylate has preferably resisiting influenza virus curative effect and toxicity low, is a kind of new product that DEVELOPMENT PROSPECT is arranged.
Summary of the invention
Liyi Medicine Science ﹠ Tech. Co., Ltd., Hubei has researched and developed methanesulfonic acid arbidol oral solid preparation.Arbidol mesylate is 6-bromo-4-(dimethyl aminomethyl)-5-hydroxyl-1-methyl-2-(benzene sulfidomethyl)-1H-indole-3-carboxylic acid second fat mesylate, English name Abidol Mesylate.This product dissolubility in water has had large increase (1g this product dissolves in the 27mL water), and In Vitro Anti influenza virus results of pharmacodynamic test shows that this product is to swine flu Influenza Virus H
1N
1Be better than arbidol HCl with its clinical separation strain effect, and cytotoxicity is lower.
Have no at present the report of domestic and international any methanesulfonic acid arbidol oral solid preparation listing.
The object of the present invention is to provide a kind of pharmaceutical composition of methanesulfonic acid arbidol oral solid preparation, this pharmaceutical composition is comprised of arbidol mesylate and the pharmaceutically acceptable excipient of effective dose, contain organic acid in the described excipient, the stability of energy Effective Raise pharmaceutical composition.
The step of the synthetic method of the used arbidol mesylate of the present invention is as follows:
1) amination: take ethyl acetoacetate as initiation material, under 20-50 ℃ of stirring, drip the methylamine water solution of 40wt%, drip and finish, continue reaction 3 hours, then standing demix, lower floor's organic layer wash rear dry intermediate (B) 3-methylamino-butenoic acid ethyl with water;
The mol ratio of the methylamine in described ethyl acetoacetate and the methylamine water solution is: 1: 1.1-1: 1.4;
2) condensation: at first in solvent acetone, add 1,4-benzoquinone, then under 25-60 ℃ of stirring, drip intermediate (B), drip and finish, continue reaction 2 hours, react complete, steam 2/3 solvent, filter to get solid after being cooled to 0-5 ℃, namely get intermediate (C) 1 after the drying, 2-dimethyl-5-OHi-3-carboxyl ethyl ester;
The mol ratio of described intermediate (B) and 1,4-benzoquinone is: 1: 1;
The consumption of described solvent acetone and the ratio of 1,4-benzoquinone are (8.0-10.0) mL: 1.0g;
3) bromination: in chloroform, add intermediate (C) and be stirred to molten clearly, be heated to and reflux and drip bromine, drip and finish, continued back flow reaction 3 hours, cooling, sucking filtration gets intermediate (D) 6-bromo-2 bromomethyls-5-OHi-3-carboxyl ethyl ester with solid drying;
Described intermediate (C) is 1.0g with the usage ratio of chloroform: (5.0-8.0) mL;
The mol ratio of described intermediate (C) and bromine is 1: 2.5;
4) replace: at first methanol and sodium hydroxide are stirred, add phenylmercaptan., stir after 2 hours, add again intermediate (D), stirred 3 hours, then use acetic acid neutralization reaction liquid to neutral, leave standstill sucking filtration, washing filter cake, drying gets intermediate (E) 6-bromo-5-hydroxyl-1-methyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester.
Described methanol and sodium hydroxide concentration ratio are: (25-30) mL: 1g;
The mol ratio of described sodium hydroxide and phenylmercaptan. is: 2.4: 1;
The mol ratio of described phenylmercaptan. and intermediate (D) is: 1: 1;
5) methylate: under 0-5 ℃ of stirring condition, be added to successively 33wt% dimethylamine solution, 37wt% formalin and intermediate (E) in the glacial acetic acid, then be warmed up to 60-70 ℃ of insulation reaction 2 hours, then cool to room temperature, with the sodium hydroxide solution neutrality that neutralizes, with the precipitation washing and drying of separating out, get intermediate (F) 6-bromo-5-hydroxyl-4-dimethyl aminomethyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester.
Dimethylamine in the described 33wt% dimethylamine solution, the formaldehyde in the 37wt% formalin and intermediate (E) three's mol ratio is: 1.3: 1.3: 1;
The usage ratio of described glacial acetic acid and intermediate (E) is 2mL: 1g;
6) salify: add acetone in intermediate (F), temperature rising reflux adds methanesulfonic acid again, and 55 ℃ of lower stirrings after 1 hour are cooled off, sucking filtration, and with solid drying, getting white crystals is arbidol mesylate.
The mol ratio of described intermediate (F) and methanesulfonic acid is: 1: 1.3-1: 1.5.
In the described intermediate (F) and acetone be 1g with magnitude relation: (5-6) mL.
Its reaction equation is as follows:
Arbidol mesylate synthesis route of the present invention is simpler than prior art, the critical process step operation is easier, this route is take ethyl acetoacetate as initiation material, through amination, react through Nenitzescu with 1,4-benzoquinone again, bromination, condensation, Mannich reaction obtain target product with the methanesulfonic acid salify again.Concrete advantage is as follows:
1, when preparation arbidol mesylate base, do not adopt the mode that passes into methylamine gas to carry out aminating reaction, and adopt the method that directly drips methylamine water solution, insulation reaction, direct layering gets final product.
2, the reaction of preparation intermediate (C) avoids using a kind solvent 1, the 2-dichloroethanes, but use three lower kind solvent acetone of toxicity to substitute more environmental protection.
3, in condensation and bromination reaction, avoid simultaneously the use of two kind of one kind solvent dichloroethanes and carbon tetrachloride, more met the requirement of environmental protection.
4, the bromination preparation process of preparation intermediate 6-bromo-2-bromomethyl-5-OHi-3-carboxyl ethyl ester has avoided using a kind solvent carbon tetrachloride, but uses two lower kind solvent chloroform (chloroform) of toxicity to substitute more environmental protection.
5, deprotection reaction has been saved in the protection of removing active hydroxyl on the indole ring, directly carries out bromo-reaction, has reduced reactions steps, has shortened the technological reaction time, has reduced production cost.
Described organic acid is selected from one or more in citric acid, tartaric acid, adipic acid, the fumaric acid.
Also contain in the described excipient in diluent, binding agent, disintegrating agent, correctives and the lubricant more than three kinds.
The pharmaceutical composition of a kind of methanesulfonic acid arbidol oral solid preparation provided by the present invention exists with the form of Film coated tablets, dispersible tablet, chewable tablet, capsule or granule.
The organic acid that contains 0.94wt%-3.25wt% in the described Film coated tablets.
The organic acid that contains 1.48wt%-2.87wt% in the described dispersible tablet.
The organic acid that contains 1.12wt%-2.55wt% in the described chewable tablet.
The organic acid that contains 1.61wt%-3.08wt% in the described capsule.
The organic acid that contains 0.65wt%-1.09wt% in the described granule.
The above-mentioned pharmaceutical composition that contains the organic acid methanesulfonic acid arbidol oral solid preparation is investigated 10 days under 60 ℃ of hot conditionss, character and related substance have no significant change, and stability better; And when not containing organic acid, significant change all occurs in its character and related substance under the same terms, less stable.
Also contain diluent, binding agent, disintegrating agent and lubricant in the excipient of described Film coated tablets.
Wherein diluent is selected from one or more in starch, pregelatinized Starch, microcrystalline Cellulose and the lactose, preferably from microcrystalline Cellulose and pregelatinized Starch.
Wherein binding agent is selected from one or more among the hypromellose HPMC that polyvidone PVP k30, polyvidone PVP k90, viscosity are 15 or 50 centipoises.
Wherein disintegrating agent is selected from one or more in carboxymethylstach sodium CMS-Na, low-substituted hydroxypropyl cellulose L-HPC, cross-linking sodium carboxymethyl cellulose (crosslinked CMC), the polyvinylpolypyrrolidone.
Wherein lubricant is selected from one or more in magnesium stearate, stearic acid, silicon dioxide, the Pulvis Talci.
Also contain diluent, binding agent, disintegrating agent, correctives and lubricant in the excipient of described dispersible tablet.
Wherein diluent is pregelatinized Starch and/or microcrystalline Cellulose.
Wherein binding agent is selected from one or more among PVP k30, PVP k90, the HPMC ( viscosity 15 or 50 centipoises).
Wherein disintegrating agent is selected from one or more in carboxymethylstach sodium CMS-Na, cross-linking sodium carboxymethyl cellulose (crosslinked CMC) and the polyvinylpolypyrrolidone.
Wherein correctives is selected from one or more in aspartame, steviosin, saccharin sodium, the acesulfame potassium.
Wherein lubricant is selected from one or more in magnesium stearate, stearic acid, silicon dioxide and the Pulvis Talci.
Also contain diluent, binding agent, lubricant and correctives in the excipient of described chewable tablet.
Wherein diluent is selected from one or more in lactose, mannitol, sorbitol and the erythrose, preferred mannitol.
Wherein binding agent is selected from one or more among PVP k30, PVP k90, the HPMC ( viscosity 15 or 50 centipoises).
Wherein lubricant is selected from one or more in magnesium stearate, stearic acid, silicon dioxide, the Pulvis Talci.
Wherein correctives is selected from one or more in aspartame, steviosin, saccharin sodium, the acesulfame potassium.
Also contain diluent, binding agent, disintegrating agent and lubricant in the excipient of described capsule.
Wherein diluent is pregelatinized Starch and/or microcrystalline Cellulose.
Wherein binding agent is selected from one or more among PVP k30, PVP k90, the HPMC (15 or 50 centipoise).
Wherein disintegrating agent is selected from one or more in CMS-Na, L-HPC, crosslinked CMC, the cross-linked pvp.
Wherein lubricant is selected from one or more in magnesium stearate, stearic acid, silicon dioxide, the Pulvis Talci.
Also contain diluent, binding agent and correctives in the excipient of described granule.
Wherein diluent is selected from one or more in microcrystalline Cellulose, pregelatinized Starch, lactose, mannitol, sorbitol and the sucrose, preferably from sucrose and microcrystalline Cellulose.
Wherein binding agent is selected from one or more among PVP k30, PVP k90, the HPMC (15 or 50 centipoise).
Wherein correctives is selected from one or more in aspartame, steviosin, saccharin sodium, the acesulfame potassium.
When described pharmaceutical composition existed with the form of Film coated tablets, the mass percent of each component was as follows:
Arbidol mesylate is 50.77%-70.00%,
Organic acid is 0.94%-3.25%,
Diluent is 9.30%-43.11%,
Binding agent is 1.41%-3.90%,
Disintegrating agent is 3.30%-10.40%,
Lubricant is 0.47%-3.15%.
When described pharmaceutical composition existed with the form of dispersible tablet, the mass percent of each component was as follows:
Arbidol mesylate is 39.88%-51.50%,
Organic acid is 1.48%-2.87%,
Diluent is 26.28%-52.54%,
Binding agent is 0.74%-2.39%,
Disintegrating agent is 3.70%-9.55%,
Correctives is 1.11%-2.87%,
Lubricant is 0.55%-4.54%.
When described pharmaceutical composition existed with the form of chewable tablet, the mass percent of each component was as follows:
Arbidol mesylate is 40.25%-45.90%,
Organic acid is 1.12%-2.55%,
Diluent is 41.75%-55.45%,
Binding agent is 1.50%-3.41%,
Correctives is 1.12%-3.41%,
Lubricant is 0.56%-2.98%.
When described pharmaceutical composition existed with the form of capsule, the mass percent of each component was as follows:
Arbidol mesylate is 57.77%-66.42%,
Organic acid is 1.61%-3.08%,
Diluent is 18.79%-35.53%,
Binding agent is 1.34%-3.70%,
Disintegrating agent is 3.21%-6.16%,
Lubricant is 0.54%-1.85%.
When described pharmaceutical composition existed with the form of granule, the mass percent of each component was as follows:
Arbidol mesylate is 11.59%-13.12%,
Organic acid is 0.65%-1.09%,
Diluent is 83.85%-87.44%,
Binding agent is 0%-1.21%,
Correctives is 0.32%-0.73%.
The preparation method of aforementioned pharmaceutical compositions is as follows:
1, the preparation method of Film coated tablets
At first with solid material crushing screening (60-100 order) all, with add in the arbidol mesylate behind the crushing screening and diluent, the disintegrating agent partially mixed after, organic acid joined make dissolving in the binder solution, then add this and contain organic acid binder solution soft material processed, the granulation of 18-30 order, 50-60 ℃ of drying, 18-30 mesh sieve granulate, add lubricant and disintegrating agent Extra Section and mix rear tabletting, use the Opadry stomach dissolution type thin film coating material film coating of Shanghai Ka Lekang packaging technique company limited, slice, thin piece increases weight and about 3% namely gets Film coated tablets again.
The compound method of binder solution wherein: with binding agent with the dissolve with ethanol solution of water or 30-70v/v% after mix homogeneously, for subsequent use.
2, the preparation method of dispersible tablet
At first with solid material crushing screening (60-100 order) all, with add in the arbidol mesylate behind the crushing screening and diluent, the disintegrating agent partially mixed after, organic acid joined make dissolving in the binder solution, then add this and contain organic acid binder solution soft material processed, the granulation of 18-30 order, 50-60 ℃ of drying, 18-30 mesh sieve granulate adds lubricant, correctives and the rear tabletting of disintegrating agent Extra Section mixing and namely gets dispersible tablet.
The compound method of binder solution wherein: with binding agent with the dissolve with ethanol solution of water or 30-70v/v% after mix homogeneously, for subsequent use.
3, the preparation method of chewable tablet
At first with solid material crushing screening (60-100 order) all, behind arbidol mesylate and mixing diluents behind the crushing screening, organic acid joined make dissolving in the binder solution, then add this and contain organic acid binder solution soft material processed, the granulation of 18-30 order, 50-60 ℃ of drying, 18-30 mesh sieve granulate adds the rear tabletting of lubricant and correctives mixing and namely gets chewable tablet.
The compound method of binder solution wherein: with binding agent with the dissolve with ethanol solution of water or 30-70v/v% after mix homogeneously, for subsequent use.
4, the preparation method of capsule
At first with solid material crushing screening (60-100 order) all, with the arbidol mesylate behind the crushing screening with after diluent, disintegrating agent mix, organic acid joined make dissolving in the binder solution, then add this and contain organic acid binder solution soft material processed, the granulation of 18-30 order, 50-60 ℃ of drying, 18-30 mesh sieve granulate adds and encapsulatedly behind the lubricant namely to get capsule of the present invention.
The compound method of binder solution wherein: with binding agent with the dissolve with ethanol solution of water or 30-70v/v% after mix homogeneously, for subsequent use.
5, the preparation method of granule
At first with solid material crushing screening (60-100 order) all, with the arbidol mesylate behind the crushing screening with after diluent, correctives mix, organic acid joined make dissolving in the binder solution, then add this and contain organic acid binder solution soft material processed, the granulation of 18-40 order, 50-60 ℃ of drying, 18-40 mesh sieve granulate, then packing and get final product.
The compound method of binder solution wherein: with binding agent with the dissolve with ethanol solution of water or 30-70v/v% after mix homogeneously, for subsequent use.
Advantage of the present invention and beneficial effect are:
The pharmaceutical composition of methanesulfonic acid arbidol oral solid preparation of the present invention (60 ℃) under hot environment is more stable, and its character and related substance all do not have significant change.
The preparation stripping more corresponding than existing arbidol HCl of involved Film coated tablets, dispersible tablet, chewable tablet, capsule and the granule of the pharmaceutical composition of methanesulfonic acid arbidol oral solid preparation of the present invention is faster, and drug-eluting is all greater than 85% within 15 minutes.
The prescription of the pharmaceutical composition of methanesulfonic acid arbidol oral solid preparation of the present invention is reasonable, and used adjuvant is all nontoxic, and is safe, and consumption is less, can satisfy the requirement of oral solid formulation.And the Film coated tablets of gained, fast disintegrate of dispersible tablet, chewable tablet, granule have better taste and mouthfeel, various, capsule stripping are all very fast, drug-eluting is all greater than 85% within 15 minutes, the interior absorption of body that is conducive to this oral solid formulation body is for its better performance curative effect provides powerful guarantee.Simultaneously dispersible tablet is taken and more conveniently both can have been suck clothes, swallow flexibly, takes after can adding aqueous dispersion again, greatly convenient for children, old man and the solid person of having any problem that swallows.Greatly convenient for children medication of granule.
Dispersible tablet disintegration time of the present invention is short, in the water of room temperature (15～25 ℃ or 19～21 ℃), all disintegrates, dispersion within 3 minutes, granule can be by No. 2 sieves, this dispersible tablet good dispersing state, drug-eluting rapidly, taking convenience, not only can swallow, but also can add the dispersions such as water or fruit juice after take, and production technology is identical with common non-coated tablet, do not need special installation, production cost is lower.
Chewable tablet among the present invention is by adding some correctivess, and making has better mouthfeel when taking, be particularly suitable for children taking.
In the safe concentration scope, arbidol mesylate (embodiment 20 makes) and arbidol HCl are chosen respectively 6 Concentraton gradient, and each concentration repeats 3 holes, add pastille maintain base, 35 ℃, 5%CO
2Cultivate, establish simultaneously normal cell contrast and virus control.Every day, observation of cell under inverted microscope changed, and treated that virus control group CPE reaches more than 80%, and the cell matched group dyes to living cells with MTT when normal, read the A590 light absorption value.Calculate medicine to the suppression ratio of virus, according to suppression ratio and corresponding concentration relation, draw the probit regression curve, calculate medicine IC50.At last, calculate the therapeutic index TI (TC50/IC50) of medicine according to TC50 (median toxic concentration) and IC50 (medium effective concentration).It carries out three tests, and the result is as follows:
In Vitro Anti influenza virus results of pharmacodynamic test shows that arbidol mesylate is better than arbidol HCl to swine flu Influenza Virus H1N1 and its clinical separation strain effect, and cytotoxicity is lower.
Description of drawings
Fig. 1 is the mass-spectrogram of the arbidol mesylate that makes of embodiment 20;
Fig. 2 is the carbon atom nuclear magnetic resonance map of the arbidol mesylate that makes of embodiment 20;
Fig. 3 is the hydrogen atom nuclear magnetic resonance map of the arbidol mesylate that makes of embodiment 20;
Fig. 4 is the infared spectrum of the arbidol mesylate that makes of embodiment 20;
Fig. 5 is the stripping curve comparison diagram of a kind of methanesulfonic acid arbidol oral solid preparation and arbidol HCl preparation.
Stripping curve wherein is respectively: series 1: arbidol hydrochloride tablet, series 2: arbidol HCl capsule, series 3: arbidol HCl dispersible tablet, series 4: arbidol mesylate Film coated tablets sheet embodiment 1, series 5: arbidol mesylate dispersible tablet embodiment 5, series 6: arbidol mesylate capsule embodiment 10, series 7: arbidol mesylate chewable tablet embodiment 16.Series 8: arbidol mesylate granule embodiment 18.
Dissolution determination: according to dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2010 first method), take water 900ml as dissolution medium, rotating speed is that per minute 100 turns, 37 ± 0.5 ℃ of constant temperature, in accordance with the law operation.
The specific embodiment
Below in conjunction with specific embodiment the inventive method is described in further detail.
The raw material of arbidol mesylate Film coated tablets compositions is composed as follows: (unit: the % mass percent)
Get arbidol mesylate, diluent and the recipe quantity of recipe quantity behind the crushing screening (60-100 order) disintegrating agent in add part, mix homogeneously gets mixture.Then take by weighing organic acid and the binding agent of recipe quantity, with binding agent take water (embodiment 1) or 70v/v% alcoholic solution (embodiment 2) as solvent, be mixed with the binder solution of 15wt% or 5wt%, or take by weighing organic acid and the HPMC (15 centipoises and/or 50 centipoises) of recipe quantity, with binding agent take water (embodiment 3) or 30v/v% alcoholic solution (embodiment 4) as solvent, be mixed with the binder solution of 0.5wt% or 1.5wt%, then organic acid joined and make dissolving in the binder solution.Add in the aforementioned mixture and contain accordingly the organic acid binder solution, soft material processed, the 18-30 mesh sieve is granulated, 50-60 ℃ of drying, 18-30 mesh sieve granulate adds Extra Section and the lubricant of disintegrating agent, mix homogeneously again, tabletting makes sheet heavily increase weight about 3% and get final product with the Opadry stomach dissolution type thin film coating material of Shanghai Ka Lekang packaging technique company limited.
The raw material of the compositions of arbidol mesylate dispersible tablet is composed as follows: (unit: the % mass percent)
Get and add partially mixed even mixture in the disintegrating agent of arbidol mesylate, diluent and the recipe quantity of recipe quantity behind the crushing screening (60-100 order), then take by weighing organic acid and the binding agent of recipe quantity, binding agent take water (embodiment 5) or 70v/v% alcoholic solution (embodiment 6) as solvent, is mixed with the binder solution of 10wt% or 5wt%; Or take by weighing organic acid and the HPMC (15 centipoises and 50 centipoises) of recipe quantity, with binding agent take water (embodiment 7) or 30v/v% alcoholic solution (embodiment 8) as solvent, be mixed with the binder solution of 0.5wt% or 2wt%, then organic acid joined and make dissolving in the binder solution.Add in the aforementioned mixture and contain accordingly the organic acid binder solution, soft material processed, the 18-30 mesh sieve is granulated, 50-60 ℃ of drying, 18-30 mesh sieve granulate, Extra Section, lubricant and the correctives of adding disintegrating agent, mix homogeneously, tabletting and get final product.
The raw material of the pharmaceutical composition of arbidol mesylate capsule is composed as follows: (unit: the % mass percent)
| Raw material | Embodiment 9 | |
|
Embodiment 12 |
| Arbidol mesylate | 60.63 | 60.63 | 66.42 | 57.77 |
| Microcrystalline Cellulose | 28.12 | 0 | 0 | 17.77 |
| |
0 | 28.12 | 9.40 | 17.76 |
| |
0 | 0 | 9.39 | 0 |
| L-HPC | 5.62 | 0 | 0 | 0 |
| CMS- |
0 | 5.62 | 0 | 0 |
| |
0 | 0 | 0 | 3.21 |
| |
0 | 0 | 6.16 | 0 |
| |
0 | 2.25 | 0 | 0.89 |
| PVP K90 | 1.69 | 0 | 0 | 0.45 |
| HPMC (15 centipoise) | 0 | 0 | 3.70 | 0 |
| |
0 | 1.69 | 0 | 0.80 |
| |
0 | 0 | 3.08 | 0.81 |
| Citric acid | 2.25 | 0 | 0 | 0 |
| |
0 | 1.69 | 0 | 0 |
| |
0 | 0 | 1.85 | 0.54 |
| Stearic acid | 1.69 | 0 | 0 | 0 |
The disintegrating agent mix homogeneously of getting arbidol mesylate, diluent and the recipe quantity of the recipe quantity behind the crushing screening (60-100 order) gets mixture.Take by weighing organic acid and the binding agent of recipe quantity, binding agent take water (embodiment 9), 30v/v% alcoholic solution (embodiment 10) or 70v/v% alcoholic solution (embodiment 12) as solvent, is mixed with the binder solution of 5wt%, 10wt% or 15wt%; Or take by weighing organic acid and the HPMC (15 centipoise) of recipe quantity, take water as solvent, be mixed with the binder solution (embodiment 11) of 2wt%, then organic acid is joined and make dissolving in the binder solution, add in the aforementioned mixture and contain accordingly the organic acid binder solution, soft material processed, the 18-30 mesh sieve is granulated, 50-60 ℃ of drying, 18-30 mesh sieve granulate, add lubricant, mix homogeneously, encapsulated and get final product.
The raw material of the pharmaceutical composition of arbidol mesylate chewable tablet is composed as follows: (unit: the % mass percent)
| Raw material | Embodiment 13 | Embodiment 14 | |
Embodiment 16 |
| Arbidol mesylate | 41.49 | 40.79 | 45.90 | 40.25 |
| |
0 | 0 | 41.75 | 0 |
| Mannitol | 38.51 | 0 | 0 | 34.12 |
| |
0 | 40.86 | 0 | 0 |
| Erythrose | 11.55 | 11.35 | 21.33 | |
| PVP K30 | 2.69 | 0 | 3.41 | 0 |
| |
0 | 0 | 0 | 1.50 |
| HPMC (50 centipoise) | 0.38 | 1.51 | 0 | 0 |
| |
0 | 1.89 | 0 | 0 |
| |
0 | 0 | 2.12 | 1.12 |
| Tartaric acid | 2.31 | 0 | 0.43 | 0 |
| Aspartame | 1.92 | 0 | 0 | 0 |
| |
0 | 3.03 | 2.27 | 0 |
| Saccharin |
0 | 0 | 0 | 1.12 |
| Acesulfame potassium | 0.38 | 0 | 1.14 | 0 |
| Magnesium stearate | 0.77 | 0.57 | 0 | 0 |
| |
0 | 0 | 2.98 | 0.56 |
Get the arbidol mesylate of the recipe quantity behind the crushing screening (60-100 order) and mixing diluents even mixture.Then take by weighing organic acid and the binding agent of recipe quantity, binding agent take water (embodiment 13), 50v/v% alcoholic solution (embodiment 15) or 70v/v% alcoholic solution (embodiment 16) as solvent, is mixed with the binder solution that concentration is 5wt% or 10wt%; Or take by weighing organic acid and the HPMC (50 centipoise) of recipe quantity, binding agent HPMC take the 50v/v% alcoholic solution as solvent, is mixed with the binder solution (embodiment 14) of 2wt%, then organic acid is joined and make dissolving in the binder solution, add in the aforementioned mixture and contain accordingly the organic acid binder solution, soft material processed, the 18-30 mesh sieve is granulated, 50-60 ℃ of drying, 18-30 mesh sieve granulate, add lubricant and correctives, mix homogeneously, tabletting and get final product.
The raw material of the pharmaceutical composition of arbidol mesylate granule is composed as follows: (unit: the % mass percent)
| Raw material | Embodiment 17 | Embodiment 18 | Embodiment 19 | The comparative example 1 |
| Arbidol mesylate | 11.68 | 11.59 | 13.12 | 11.80 |
| Microcrystalline Cellulose | 9.84 | 0 | 5.99 | 9.95 |
| |
0 | 10.80 | 5.99 | 0 |
| Sucrose | 75.86 | 76.64 | 71.87 | 76.60 |
| PVP K30 | 1.00 | 0 | 0 | 0.99 |
| HPMC (50 centipoise) | 0 | 0 | 1.21 | 0 |
| |
0 | 0.65 | 0 | 0 |
| Tartaric acid | 0.97 | 0 | 0 | 0 |
| |
0 | 0 | 1.09 | 0 |
| Aspartame | 0.43 | 0 | 0 | 0.44 |
| Steviosin | 0 | 0.32 | 0 | 0 |
| |
0 | 0 | 0.49 | 0 |
| Acesulfame potassium | 0.22 | 0 | 0.24 | 0.22 |
Arbidol mesylate, diluent and the correctives mix homogeneously of getting the recipe quantity behind the crushing screening (60-100 order) get mixture, then take by weighing organic acid and the PVP K30 of recipe quantity, PVP K30 is mixed with concentration as the binder solution of 10wt% or 0% take 70v/v% alcoholic solution (embodiment 17) or water (embodiment 18) as solvent; Or take by weighing organic acid and the HPMC (50 centipoise) of recipe quantity, with HPMC take 50v/v% alcoholic solution (embodiment 19) as solvent, be mixed with the binder solution of 1wt%, then organic acid is joined and make dissolving in the binder solution, add in the aforementioned mixture and contain accordingly organic acid binder solution, soft material processed, the 18-40 mesh sieve is granulated, 50-60 ℃ of drying, 18-40 mesh sieve granulate, packing and get final product.
Get arbidol mesylate, microcrystalline Cellulose, sucrose and the correctives of the recipe quantity behind the crushing screening (60-100 order), mix homogeneously gets mixture.Take by weighing the PVP K30 of recipe quantity, take 70v/v% alcoholic solution (comparative example 1) as solvent, be mixed with the binder solution that concentration is 10wt%, then in aforementioned mixture, add binder solution, soft material processed, the 18-40 mesh sieve is granulated, 50-60 ℃ of drying, 18-40 mesh sieve granulate, packing and get final product.
The Preparation Example of arbidol mesylate:
A kind of synthetic method of arbidol mesylate, its step is as follows:
1) preparation of 3-methylamino-butenoic acid ethyl
In reaction bulb, drop into ethyl acetoacetate 150.0g, under 25 ℃ of stirrings, drip the methylamine water solution 160mL of 40wt%, drip and finish, under this temperature, continued stirring reaction 3 hours, standing demix, lower floor's organic layer washes with water, dry intermediate (B) 157.6g, the yield: 95.5% of getting.
2) 1, the preparation of 2-dimethyl-5-OHi-3-carboxyl ethyl ester
In reaction bulb, the 124.0g 1,4-benzoquinone is dissolved in the 1200mL acetone, stir, under agitation drip intermediate (B) 150.0g after being heated to 30 ℃, drip and finish, continue reaction 2 hours, react complete, steam 2/3 solvent, filter to get solid after being cooled to 0-5 ℃, dry intermediate (C) 90.1g, the yield: 36.9% of getting.
3) preparation of 6-bromo-2-bromomethyl-5-OHi-3-carboxyl ethyl ester
80.0g intermediate (C) is joined in the 400mL chloroform, be stirred to molten clearly, reflux drips the 44.0mL bromine, drips and finishes, and continues back flow reaction 3 hours, cooling, and sucking filtration with solid drying, gets intermediate (D) 107.4g, yield: 80.0%.
4) preparation of 6-bromo-5-hydroxyl-1-methyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester
In 650mL methanol, add the 24.5g sodium hydroxide, stir, get clear liquor, add the 28.2g phenylmercaptan., stir after 2 hours, add again 100.0g intermediate (D), stirred 3 hours, and then used acetic acid neutralization reaction liquid to neutral, have a large amount of solids to separate out, leave standstill, sucking filtration, washing filter cake, drying, get intermediate (E) 91.2g, yield: 85.0%.
5) preparation of 6-bromo-5-hydroxyl-4-dimethyl aminomethyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester
Under 0-5 ℃ of stirring condition, with 33wt% dimethylamine solution 20mL, 37wt% formalin 11mL and intermediate (E) 48.0g, be added to successively in the 98mL glacial acetic acid, then be warmed up to 65 ℃ of insulation reaction 2 hours, after being cooled to room temperature, the hydro-oxidation sodium solution neutrality that neutralizes is with the precipitation washing and drying of separating out, get intermediate (F) 43.4g, yield: 79.6%.
6) preparation of arbidol mesylate
In flask, drop into 40g intermediate (F), add 200mL acetone, temperature rising reflux adds methanesulfonic acid 10.5g, 55 ℃ of lower stirrings 1 hour, be cooled to 0-5 ℃, sucking filtration with solid drying, gets white crystals (G) arbidol mesylate 40.8g, yield 85.0% detects to such an extent that product purity is 99.2% by HPLC.
What the arbidol mesylate in the aforementioned pharmaceutical composition all used is the product of embodiment 20.
Embodiment 21
A kind of synthetic method of arbidol mesylate, its step is as follows:
1) preparation of 3-methylamino-butenoic acid ethyl
In reaction bulb, drop into ethyl acetoacetate 100g, under 30 ℃ of stirrings, drip the methylamine water solution 120mL of 40wt%, drip and finish, under this temperature, continued stirring reaction 3 hours, standing demix, lower floor's organic layer washes with water, dry intermediate (B) 99.0g, the yield: 90.0% of getting.
2) 1, the preparation of 2-dimethyl-5-OHi-3-carboxyl ethyl ester
In reaction bulb, the 74.7g 1,4-benzoquinone is dissolved in the 700mL acetone, stir, under agitation drip intermediate (B) 90.0g after being heated to 40 ℃, drip and finish, continue reaction 2 hours, react complete, steam 2/3 solvent, filter to get solid after being cooled to 0-5 ℃, dry intermediate (C) 52.3g, the yield: 37.7% of getting.
3) preparation of 6-bromo-2-bromomethyl-5-OHi-3-carboxyl ethyl ester
40.0g intermediate (C) is joined in the 300mL chloroform, be stirred to molten clearly, reflux is dripped the 22.0mL bromine, drips and finishes, and continues back flow reaction 3 hours, cooling, and sucking filtration with solid drying, gets intermediate (D) 56.9g, yield: 85.0%.
4) preparation of 6-bromo-5-hydroxyl-1-methyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester
This step reaction is with embodiment 20.
5) preparation of 6-bromo-5-hydroxyl-4-dimethyl aminomethyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester
This step reaction is with embodiment 20.
6) preparation of arbidol mesylate
In flask, drop into 10g intermediate (F), add 50mL acetone, temperature rising reflux adds methanesulfonic acid 2.7g, 55 ℃ of lower stirrings 1 hour, be cooled to 0-5 ℃, sucking filtration with solid drying, gets white crystals (G) arbidol mesylate 10.0g, yield 83.3% detects to such an extent that product purity is 98.8% by HPLC.
Embodiment 22
A kind of synthetic method of arbidol mesylate, its step is as follows:
1) preparation of 3-methylamino-butenoic acid ethyl
In reaction bulb, drop into ethyl acetoacetate 153.2g, under 35 ℃ of stirrings, drip the methylamine water solution 180mL of 40wt%, drip and finish, under this temperature, continued stirring reaction 3 hours, standing demix, lower floor's organic layer washes with water, dry intermediate (B) 161.9g, the yield: 96.14% of getting.
2) 1, the preparation of 2-dimethyl-5-OHi-3-carboxyl ethyl ester
In reaction bulb, the 132.9g 1,4-benzoquinone is dissolved in the 1300mL acetone, stirs, under agitation drip intermediate (B) 160.0g after being heated to 45 ℃, drip and finish, continue reaction 2 hours, react complete, steam 2/3 solvent.Filter to get solid after being cooled to 0-5 ℃, dry intermediate (C) 91.2g, the yield: 35.0% of getting.
3) preparation of 6-bromo-2-bromomethyl-5-OHi-3-carboxyl ethyl ester
90.0g intermediate (C) is joined in the 600mL chloroform, be stirred to molten clearly, reflux drips the 49.6mL bromine, drips and finishes, and continues back flow reaction 3 hours, cooling, and sucking filtration with solid drying, gets intermediate (D) 117.8g, yield: 78.0%.
4) preparation of 6-bromo-5-hydroxyl-1-methyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester
This step reaction is with embodiment 20.
5) preparation of 6-bromo-5-hydroxyl-4-dimethyl aminomethyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester
This step reaction is with embodiment 20.
6) preparation of arbidol mesylate
In flask, drop into 35.0g intermediate (F), add 210mL acetone, temperature rising reflux adds methanesulfonic acid 12.1g, 55 ℃ of lower stirrings 1 hour, be cooled to 0-5 ℃, sucking filtration with solid drying, gets white crystals (G) arbidol mesylate 34.7g, yield 82.5% detects to such an extent that product purity is 98.6% by HPLC.
Embodiment 23
A kind of synthetic method of arbidol mesylate, its step is as follows:
1) preparation of 3-methylamino-butenoic acid ethyl
In reaction bulb, drop into ethyl acetoacetate 100g, under 40 ℃ of stirrings, drip the methylamine water solution 120mL of 40wt%, drip and finish, under this temperature, continued stirring reaction 3 hours, standing demix, lower floor's organic layer washes with water, dry intermediate (B) 104.1g, the yield: 94.6% of getting.
2) 1, the preparation of 2-dimethyl-5-OHi-3-carboxyl ethyl ester
In reaction bulb, the 83.0g 1,4-benzoquinone is dissolved in the 800mL acetone, stir, under agitation drip intermediate (B) 100g after being heated to 50 ℃, drip and finish, continue reaction 2 hours, react complete, steam 2/3 solvent, filter to get solid after being cooled to 0-5 ℃, dry intermediate (C) 55.4g, the yield: 34.0% of getting.
3) preparation of 6-bromo-2-bromomethyl-5-OHi-3-carboxyl ethyl ester
50.0g intermediate (C) is joined in the 400mL chloroform, be stirred to molten clearly, reflux drips the 27.5mL bromine, drips and finishes, and continues back flow reaction 3 hours, cooling, and sucking filtration with solid drying, gets intermediate (D) 116.7g, yield: 82.0%.
4) preparation of 6-bromo-5-hydroxyl-1-methyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester
This step reaction is with embodiment 20.
5) preparation of 6-bromo-5-hydroxyl-4-dimethyl aminomethyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester
This step reaction is with embodiment 20.
6) preparation of arbidol mesylate
In flask, drop into 18.3g intermediate (F), add 91mL acetone, temperature rising reflux adds methanesulfonic acid 4.8g, 55 ℃ of lower stirrings 1 hour, be cooled to 0-5 ℃, sucking filtration with solid drying, gets white crystals (G) arbidol mesylate 17.5g, yield 79.5% detects to such an extent that product purity is 98.9% by HPLC.
Embodiment 24
A kind of synthetic method of arbidol mesylate, its step is as follows:
1) preparation of 3-methylamino-butenoic acid ethyl
In reaction bulb, drop into ethyl acetoacetate 200g, under 45 ℃ of stirrings, drip the methylamine water solution 235mL of 40wt%, drip and finish, under this temperature, continued stirring reaction 3 hours, standing demix, lower floor's organic layer washes with water, dry intermediate (B) 205.1g, the yield: 93.3% of getting.
2) 1, the preparation of 2-dimethyl-5-OHi-3-carboxyl ethyl ester
In reaction bulb, the 132.8g 1,4-benzoquinone is dissolved in the 1500mL acetone, stir, under agitation drip intermediate (B) 160g after being heated to 50 ℃, drip and finish, continue reaction 2 hours, react complete, steam 2/3 solvent, filter to get solid after being cooled to 0-5 ℃, dry intermediate (C) 92.7g, the yield: 35.6% of getting.
3) preparation of 6-bromo-2-bromomethyl-5-OHi-3-carboxyl ethyl ester
85g intermediate (C) is joined in the 650mL chloroform, be stirred to molten clearly, reflux drips the 46.8mL bromine, drips and finishes, and continues back flow reaction 3 hours, cooling, and sucking filtration with solid drying, gets intermediate (D) 122.7g, yield: 86.0%.
4) preparation of 6-bromo-5-hydroxyl-1-methyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester
This step reaction is with embodiment 20.
5) preparation of 6-bromo-5-hydroxyl-4-dimethyl aminomethyl-2-benzene sulfidomethyl indole-3-carboxyl ethyl ester
This step reaction is with embodiment 20.
6) preparation of arbidol mesylate
In flask, drop into intermediate (F) 15.6g, add 78mL acetone, temperature rising reflux adds methanesulfonic acid 4.0g, 55 ℃ of lower stirrings 1 hour, be cooled to 0-5 ℃, sucking filtration with solid drying, gets white crystals (G) arbidol mesylate 15.2g, yield 81.5% detects to such an extent that product purity is 98.8% by HPLC.
With above-described embodiment 1,5,9,13,17 and comparative example 1 compositions be placed in 60 ℃ the calorstat and investigate, in the time of the 10th day, take a sample to check, and have unchanged with 0 o'clock (before the test) sample comparison character and related substance.
The results of stability of table 1 compositions
Table 2 dispersible tablet disintegration time mensuration result
| The prescription sequence number | Disintegration | Can granule pass through 24 mesh sieves | Outward appearance after the disintegrate |
| Embodiment 5 | 55 seconds | Energy | Even |
| Embodiment | |||
| 6 | 1 |
Energy | Even suspension |
| Embodiment 7 | 59 seconds | Energy | Even |
| Embodiment | |||
| 8 | 1 |
Energy | Even suspension |
Annotate: the disintegration time mensuration method: get this dispersible tablet 2 or 6, join 100mL, in 15～25 ℃ of water, jolting, the record complete disintegrate powdered of slice, thin piece or granule required time.
Claims (1)
1. the pharmaceutical composition of a methanesulfonic acid arbidol oral solid preparation, it is characterized in that: this pharmaceutical composition is comprised of arbidol mesylate and the pharmaceutically acceptable excipient of effective dose;
Described pharmaceutical composition exists with the form of Film coated tablets, dispersible tablet or capsule;
The excipient of described Film coated tablets is comprised of adipic acid, microcrystalline Cellulose, cross-linked pvp, PVP k30 and magnesium stearate;
The mass percent of each component is as follows in the described Film coated tablets:
Arbidol mesylate is 53.16%,
Adipic acid is 0.99%,
Microcrystalline Cellulose is 34.50%,
PVP k30 is 2.96%,
Cross-linked pvp is 7.40%, and adding part in wherein is 4.93%, and Extra Section is 2.47%,
Magnesium stearate is 0.99%;
The excipient of described dispersible tablet is comprised of tartaric acid, microcrystalline Cellulose, PVP k30, cross-linked pvp, magnesium stearate, silicon dioxide, aspartame and acesulfame potassium;
The mass percent of each component is as follows in the described dispersible tablet:
Arbidol mesylate is 40.25%,
Tartaric acid is 1.87%,
Microcrystalline Cellulose is 44.8%,
PVP k30 is 1.87%,
Cross-linked pvp is 7.47%, and adding part in wherein is 3.74%, and Extra Section is 3.73%,
Magnesium stearate is 0.75%,
Silicon dioxide 0.37%,
Aspartame 1.87%,
Acesulfame potassium 0.75%;
The excipient of described capsule is comprised of adipic acid, pregelatinized Starch, PVP k30, CMS-Na and silicon dioxide;
The mass percent of each component is as follows in the described capsule:
Arbidol mesylate is 60.63%,
Adipic acid is 1.69%,
Pregelatinized Starch is 28.12%,
PVP k30 is 2.25%,
CMS-Na is 5.62%,
Silica 1 .69%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030710A (en) * | 2015-09-08 | 2015-11-11 | 湖北生物医药产业技术研究院有限公司 | Arbidol tablet |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106366029A (en) * | 2016-08-19 | 2017-02-01 | 江苏吴中医药集团有限公司苏州制药厂 | Arbidol mesylate monohydrate crystal C and its preparation method and use |
| CN112933061B (en) * | 2021-02-22 | 2022-08-09 | 石家庄四药有限公司 | Arbidol hydrochloride capsule and preparation method thereof |
| CN115463098A (en) * | 2022-06-28 | 2022-12-13 | 则正(上海)生物科技有限公司 | Arbidol-containing particles, preparation method and application thereof, and arbidol dry suspension |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1535680A (en) * | 2003-04-08 | 2004-10-13 | 中奇制药技术（石家庄）有限公司 | Abidor inclusion compound |
| CN1589790A (en) * | 2003-09-04 | 2005-03-09 | 中奇制药技术（石家庄）有限公司 | Abedol slow release tablet and its preparation method |
| CN1839829A (en) * | 2006-02-08 | 2006-10-04 | 沈阳中海生物技术开发有限公司 | Antiviral cold compound formulation containing arbidol and taurine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1535680A (en) * | 2003-04-08 | 2004-10-13 | 中奇制药技术（石家庄）有限公司 | Abidor inclusion compound |
| CN1589790A (en) * | 2003-09-04 | 2005-03-09 | 中奇制药技术（石家庄）有限公司 | Abedol slow release tablet and its preparation method |
| CN1839829A (en) * | 2006-02-08 | 2006-10-04 | 沈阳中海生物技术开发有限公司 | Antiviral cold compound formulation containing arbidol and taurine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030710A (en) * | 2015-09-08 | 2015-11-11 | 湖北生物医药产业技术研究院有限公司 | Arbidol tablet |
| CN105030710B (en) * | 2015-09-08 | 2021-07-30 | 湖北生物医药产业技术研究院有限公司 | Arbidol tablet |
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