SNMC oral liquid and preparation method thereof
Technical field:
The present invention relates to medical technical field, relate to particularly oral liquid of being made by glycyrrhizic glycoside, cysteine, glycine and pharmaceutic adjuvant and preparation method thereof.Be applied to the control of the diseases such as hepatopathy field, dermatosis field, tumor chemoradiotherapy protection field.
Background technology:
Compound glycyrrbizic acid glycosides formulation was produced and is appeared on the market in Japan in 1948 the earliest, at first for treating skin disease.1958, Japanese doctor helped Yamamoto husband and attempts with it, treating chronic hepatitis, result patient's liver function index BSP(bromine sulfonephthalein) value obtained obvious improvement.Within 1977, the grand professor of Japanese hepatopathy expert's Suzuki adopts strict randomized controlled method to verify the therapeutical effect of SNMC to chronic hepatitis, has confirmed that it is to chronic hepatitis determined curative effect; After this, SNMC has been subject to the attention of height as the medicine of hepatitis, and basis and clinical research are more deep, and range of application and clinical indication progressively expand.Bears Tian Boguang in 2002 has reported that again SNMC is to the challenging late result result of hepatitis C, and has obtained the pathological checking support of hepatopathy.Within 1985, start said preparation and introduce China's treatment chronic viral hepatitis, not only can significantly improve chronic hepatitis patient's liver function, reduce aminotransferase, and can control chronic hepatitis to the development process of liver cirrhosis, hepatocarcinoma.Therefore, SNMC obtains rapidly numerous medical personnel's approval with its unique efficacy and saferry.Over more than 20 years; a large amount of bases and clinical research data show; said preparation has antiinflammatory, immunomodulating, to the inhibition of experimental hepatocyte injury, virus replication with to viral deactivation, antiallergic action and the effect of parahormone sample etc.; be widely used in the control of the diseases such as hepatopathy field, dermatosis field, tumor chemoradiotherapy protection field; and untoward reaction is few, there are good compliance and safety.
Chronic hepatitis B, in one of the commonly encountered diseases of Chinese sickness rate Hen Gao,Shi China, frequently-occurring disease, is to threaten the maximum killer of national health.Chronic hepatitis B has an appointment 1/10th in crowd according to estimates, and 1.2 hundred million, the person that is hepatitis b surface antigen positive; Wherein approximately 1/4th, 3,000 ten thousand is Chronic Hepatitis B.According to relevant data statistics, show, suffer from the patient of chronic viral hepatitis B disease, teen-age ratio is many especially, more than 95% is to infect before 3 years old, and this allows a lot of hepatopathy experts and teenager all feel relatively to perplex.These patients due to infect viral hepatocellular removing not exclusively, not thorough, generation new life is repeatedly hepatocellular to be infected again, make hepatocyte repeatedly destroy and regenerate, there is the change of liver structure and the hypertrophy of fibrous tissue thereupon, after the hepatitis activity several years, approximately 1/3 patient there will be liver cirrhosis, ascites, and even hepatocarcinoma.
Glycyrrhizic glycoside, claim again glycyrrhizic acid (Glycyrrhizicacid, GA), glycyrrhizin (Glycyrrhizin, GL), chemistry 3-O-(2 '-beta d glucopyranosiduronic acid base)-beta d glucopyranosiduronic acid glycosides 3 beta-hydroxies-11-carbonyl oxygen-18 β oleanolic acid-12-alkene-30-carboxylic acid by name, English chemical name: 3-O-(2 '-β-D-glucuronopyranosyl)-β-D-glucuronopyranoside3 β-hydroxy-11-oxo-18-olean-12-en-30-oic acid is the effective ingredient of separation and Extraction from Radix Glycyrrhizae.At present, SNMC has been widely used in clinical as the standard care medicine of chronic hepatitis in Japan, thereby stop and delay hepatitis B diseases, proceed to liver cirrhosis, hepatocarcinoma.Yet, SNMC oral glycyrrhizic glycoside preparation in clinical practice only has tablet at present, the solid preparations such as capsule, for example CN200610045278.6 patent documentation discloses a kind of solid soft capsule being prepared from by glycyrrhizic glycoside and glycine and methionine and excipient substance, CN200710151969.9 discloses a kind of by glycyrrhizic glycoside and methionine, the glycyrrhizin dropping pills preparation that glycine and Basic compose are made, CN20111084341.5 discloses a kind of by glycyrrhizic glycoside and methionine or add glycine again, aqueous injection prepared by cysteine hydrochloride, injectable powder or infusion preparation.
Yet in existing above-mentioned preparation, there are the following problems for solid orally ingestible: (1) old man and children's are not easy to accept, the inconvenience of taking medicine, and pediatric pharmaceuticals should be by age or body weight within different minutes, measure administration, and solid preparation old man and child administration difficulty, the bad accurate grasp of medication metering; (2) some are swallowed the inconvenient patient of solid drugs (as elderly and infirm) medication and have any problem; (3) the oral rear dissolution time of solid drugs is longer, absorbs slowlyer, and drug effect effect not in time.That is, as the drop pill of peroral dosage form, capsule its to leach speed lower, onset is slow, bioavailability is low, especially for child patient, takes very inconveniently, and needs divided dose to cause over administration or by quantity not sufficient; Although and that injection leaches speed is fast, bioavailability is high, its medication very inconvenient (needing hospitalization) is low for the non-hospitalization compliance of especial patient, and particularly children chronic hepatitis is difficult to adhere to injecting drug use.It is the task of top priority that dosage form and the specification of applicable child, old man, patient bedridden in long term and its physiological characteristics of dysphagia patients are provided, and is also the important measures that guarantee such crowd's rational use of drug.But glycyrrhizic glycoside is unstable in solution, easily produce precipitation and effective ingredient and degraded occurs and lower drug effect, therefore, have not yet to see the report of glycyrrhizic glycoside liquid oral medicine.
Summary of the invention:
For solving the above-mentioned problems in the prior art, the inventor is through long-term deep research, be surprisingly found out that, with etc. glycyrrhizic glycoside, cysteine and the glycine of weight ratio can make stable glycyrrhizic glycoside liquid oral medicine, said preparation has good stability, meet clinical application requirement completely, thereby completed the present invention.Therefore, the present invention is directed to physiological characteristics and the clinical treatment demand of special population, a kind of SNMC oral liquid and preparation method thereof is provided.The present invention is to be main component by glycyrrhizic glycoside, cysteine, glycine, and three's weight ratio is 1:1:1, and adds the SNMC oral liquid that pharmaceutic adjuvant is made.Liquid preparation of the present invention refers to (but being not limited to) oral administration solution, syrup, Orally taken emulsion, or faces the used time and add the liquid preparation (dry syrup, granule etc.) that mixing in water for oral taking (dissolving) forms.Glycyrrhizic glycoside, cysteine and glycine in described preparation content all in 0.05~10% weight range (preferably 0.5%-5% weight), and glycyrrhizic glycoside: cysteine: glycine=1:1:1(weight).
According to SNMC oral liquid of the present invention, it is characterized in that, described pharmaceutic adjuvant is one or more in the sweeting agent that contains 1~80 % by weight or the correctives that contains 0.01~10 % by weight or the antiseptic that contains 0.01~10 % by weight or the pH adjusting agent that contains 0.01~10 % by weight or vegetable oil, emulsifying agent, diluent, disintegrating agent and binding agent.
Wherein pharmaceutic adjuvant comprises sweeting agent, correctives, antiseptic, pH adjusting agent, vegetable oil, emulsifying agent, diluent, disintegrating agent and binding agent etc.
Above-mentioned sweeting agent is one or more in sucrose, cyclamate, stevioside, fructose, glucose, simple syrup, aspartame, protein sugar, saccharin sodium, maltose alcohol, sorbitol;
Above-mentioned correctives is one or more in Mentholum, flavoring banana essence, Fructus Citri tangerinae essence, flavoring pineapple essence, Fructus Citri Limoniae essence, strawberry essence, rose essence, cherry essence, Oleum Cinnamomi, orange peel oil, milk-taste essence, chocolate essence, powder cocoanut flavour;
Foregoing preservatives is one or more in nipagin, aethyl parabenum, propylparaben, oxybenzene butyl formate, sorbic acid, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate;
Above-mentioned pH adjusting agent is one or more in dilute hydrochloric acid, lactic acid, malic acid, citric acid, phosphoric acid, acetic acid, succinic acid, propanoic acid;
Above-mentioned vegetable oil is one or more in soybean oil, Oleum Arachidis hypogaeae semen, olive oil;
Mentioned emulsifier is one or more in non-ionic surface emulsifying agent, the agent of anion ratio surfactant emulsion, or the compound emulsifying agent forming in proportion, as female in phospholipid-pool Lip river sand etc.;
Above-mentioned diluent is one or more in starch, lactose, cane sugar powder etc.;
Above-mentioned disintegrating agent and binding agent are starch, cellulose derivative, hypromellose (HPMC), ethyl cellulose (EC), IV acrylic resin (Eudragit IV), polyvinyl alcohol (PVA), pluronic gram F
68(Pluronic F
68), polyethylene glycol 6000 (PEG
6000), one or more in low-substituted hydroxypropyl methylcellulose (L-HPC).
As follows according to the concrete preparation method of SNMC oral liquid of the present invention:
1. oral administration solution glycyrrhizic glycoside, cysteine, glycine are main component, add pharmaceutic adjuvant and make.Wherein pharmaceutic adjuvant comprises sweeting agent, correctives, pH adjusting agent and antiseptic etc.According to oral solution preparation rules, prepare and get final product.
2. syrup glycyrrhizic glycoside, cysteine, glycine are main component, add pharmaceutic adjuvant and make.Wherein pharmaceutic adjuvant comprises sucrose, sweeting agent, correctives, pH adjusting agent and antiseptic etc.According to syrup preparation rules, prepare and get final product.
3. Orally taken emulsion glycyrrhizic glycoside, cysteine, glycine are main component, add pharmaceutic adjuvant and make stable oil/water type emulsion for oral liquid preparation.Conventional solvent is water and vegetable oil, and after emulsifying agent emulsifying, the drop that particle diameter is mostly more than 0.1 μ m is dispersed in the liquid preparation that forms the oral oil/water type emulsion of confession in liquid dispersion medium.In Orally taken emulsion, can add suitable emulsifying agent, coemulsifier, suspending agent.Also add suitable antiseptic, correctives, antioxidant etc., mainly by dispersion method, prepare.Can adopt dispersing emulsification machine, colloid mill, the preparation of ultrasonic emulsification device.
4. dry syrup glycyrrhizic glycoside, cysteine, glycine are main component, add pharmaceutic adjuvant and make.In dry syrup, adjuvant used comprises hypromellose (HPMC), ethyl cellulose (EC), IV acrylic resin (Eudragit IV), polyvinyl alcohol (PVA), pluronic gram F
68(Pluronic F
68), polyethylene glycol 6000 (PEG
6000), low-substituted hydroxypropyl methylcellulose (L-HPC), sucrose, mannitol, glucose, ethyl hydroxybenzoate, powder cocoanut flavour.PEG
6000as binding agent, and in prescription, add cellulose family and the less water-soluble saccharides adjuvant of hygroscopicity with HPMC.
5. granule glycyrrhizic glycoside, cysteine, glycine are main component, add pharmaceutic adjuvant and make.Icing Sugar, dextrin are as major auxiliary burden.By medicine and diluent (as starch, lactose, sucrose etc.), also can add if desired disintegrating agent (as starch, cellulose derivative etc.), correctives, fully mix, add appropriate water or other binding agents to mix soft material processed, mix available various types of mixer and carry out.Granulate (can adopt dry granulation, wet granulation, sulfuration spray granulation, spray-drying process), dry, granulate, packing, obtains.
SNMC oral liquid of the present invention, has increased the peroral dosage form of SNMC, has realized again SNMC and has directly entered in body with liquid form, taking convenience, absorbs soon, and onset is rapid, the object that bioavailability is high; Compare with injection and overcome injection and use and carry inconvenient shortcoming.In addition safe, patient compliance good, the patient who is particularly suitable for child, old people and dysphagia takes, this is that other dosage forms are incomparable.While preparation method of the present invention, technique is simple, is suitable for suitability for industrialized production.、
The specific embodiment:
By embodiment, enter a cloth and illustrate the present invention, but embodiment does not constitute any limitation the present invention.All technology realizing based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1. SNMC oral administration solutions
Prescription forms: glycyrrhizic glycoside 5g, cysteine hydrochloride 5g, glycine 5g, stevioside 0.5g, essence 1g, benzoic acid 2g, citric acid are appropriate, and water adds to 1000ml.
Preparation method:
Glycyrrhizic glycoside, cysteine hydrochloride, glycine, stevioside are added in suitable quantity of water and dissolved respectively; After separately benzoic acid and essence being dissolved respectively, join in medicinal liquid, stir evenly; With citric acid soln, regulate pH value, add purified water to enough, stir evenly, filter, subpackage, sterilizing, obtains.
Embodiment 2. SNMC syrup
Prescription forms: glycyrrhizic glycoside 10g, cysteine hydrochloride 10g, glycine 10g, sucrose 450g, Fructus Citri tangerinae essence 2g, aethyl parabenum 1g, malic acid are appropriate, water adds to 1000ml.
Preparation method: glycyrrhizic glycoside, cysteine hydrochloride, glycine, sucrose are added in suitable quantity of water and dissolved respectively; Separately aethyl parabenum is added to dissolve with ethanol, after Fructus Citri tangerinae essence is dissolved in water, join respectively in medicinal liquid, stir evenly; Malic acid is added after suitable quantity of water is dissolved and regulates pH value, add purified water to enough, stir evenly, filter, subpackage, sterilizing, obtains.
Embodiment 3. SNMC Orally taken emulsions
Prescription forms: glycyrrhizic glycoside 25g, cysteine hydrochloride 25g, glycine 25g, soybean oil 440g, stevioside 0.3g, emulsifying agent [phospholipid-pool Lip river husky female (1:6)] 7.0g, benzoic acid 1.5g, citric acid are in right amount, water adds to 1000ml.
Preparation method: adopt Mechanical Method preparation.Glycyrrhizic glycoside, cysteine hydrochloride, glycine, stevioside, benzoic acid, citric acid etc. are added after appropriate amount of purified water dissolving, add soybean oil, emulsifying agent (phospholipid-pool Lip river is husky female), through high speed dispersing emulsification machine machine, stir (10000 r/ min) 1 5min, add water to enough, stir again, subpackage, sterilizing, obtains.
Embodiment 4. SNMC dry syrups
Prescription forms: glycyrrhizic glycoside 15g, cysteine 15g, glycine 15g, HPMC 60g, binding agent (PEG
6000, HPMC) appropriate, sucrose is appropriate, ethyl hydroxybenzoate is appropriate, powder cocoanut flavour is appropriate, makes altogether 1000g.
Preparation method: take each component by recipe quantity, cross respectively 100 mesh sieves, ethyl hydroxybenzoate is adsorbed in carbohydrate admixture after with a little anhydrous alcohol solution, and principal agent, hypromellose and essence fully mix, by equivalent incremental method and saccharide adjuvant, fully mix, add by PEG
6000granulate with the binding agent that HPMC forms.Dry, granulate, subpackage, obtains.
Embodiment 5. SNMC granules
Prescription forms: glycyrrhizic glycoside 20g, Cys2 0g, glycine 20g, cane sugar powder 80g, starch is appropriate, dextrin is appropriate, powder cocoanut flavour appropriate, disintegrating agent (cellulose derivative etc.) in right amount, benzoic acid 2g, make altogether 1000g.
Preparation method: take each component by recipe quantity, cross respectively 100 mesh sieves, soft material processed, granulates (can adopt dry granulation, wet granulation, sulfuration spray granulation, spray-drying process), dry, granulate, packing, obtains.