CN1242810C - Drug composition, its preparation method and use - Google Patents
Drug composition, its preparation method and use Download PDFInfo
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- CN1242810C CN1242810C CN 03135469 CN03135469A CN1242810C CN 1242810 C CN1242810 C CN 1242810C CN 03135469 CN03135469 CN 03135469 CN 03135469 A CN03135469 A CN 03135469A CN 1242810 C CN1242810 C CN 1242810C
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Abstract
The present invention provides a drug composition, and a preparation method and an application of the drug composition. The drug composition is a new formulation, is a slow release preparation containing mannon peptide, and is a slow release preparation prepared by mixing mannon peptide and pharmacologically acceptable adjuvant, wherein each unit preparation contains 5 to 30 mg of mannon peptide. Clinical tests prove that the present invention has the advantages of satisfactory therapeutic effect, high bioavailability, safety and reliability on treating disease symptoms of leukocytopenia, a poor immune function, etc. after radiotherapy and chemotherapy, and provides a new treatment selection for clinic.
Description
Technical field
The invention provides a kind of pharmaceutical composition, specifically, is slow releasing preparation that contains mannatide and its production and use.
Background technology
Along with the change of environment, the incidence rate of human tumor improves constantly, and the generation age also passes by to reduce, and seeking safe and effective antitumor drug is the target of human effort always.
Carry out oncotherapy by the human body defense mechanism, be to advocate by national cancer institute the latter stage seventies, worldwide carry out gradually the eighties, Japan is being on the forefront aspect the research and development of employing immunoactivator antineoplastic, the listing in 1975 of the Saphlin of the Hemolytic streptococcus (OK-432) of approved production listing, the listing in 1977 of Intracellular Polysaccharide of Poly-stictus Versicolor PS-K (PSK is Krestin) fungus polysaccharide preparation, the sales volume of two kinds of medicines reaches 1,000 hundred million yen every year, distribute all over the world, sales volume accounts for half of Japanese antitumor medicine, the lentinan injection that in December, 1985 is ratified again to go on the market, the glucosan injection that extracts the Sohizop-hyllan of confirmation request (SPG) series wrinkle Pseudomonas just, ruburatin Nocard's bacillus thalline injection and bestatin (benzene fourth isoleucine) oral agents also has ten kinds of similar immunoactivators just in clinical research.This class medicine can activate body's immunological function, by changing the respond of tumor host to tumor cell, changes tumor cell and host's relation, to reach the effect of treatment tumor illness.The Hemolytic streptococcus SU (OK-432) of Japan is that the Hemolytic streptococcus thalline of attenuation is suspended in a kind of biological preparation in the penicillin, and side reaction is heavier, and main side reaction is heating, and injection site pain and cell reduce and use limited.
Chinese patent 98121898 discloses " a kind of composite mannosans peptides oral liquor ", contain multiple composition in this oral liquid, its mannatide is respectively from basidiomycete, heterobasidium fungus, porous order fungus, umbrella section fungus, composition is comparatively complicated, and oral dose is big.
Summary of the invention
Technical scheme to be solved by this invention provides a kind of pharmaceutical composition, and it is a kind of new dosage form, and it is the slow releasing preparation that contains mannatide.
Another technical scheme of the present invention provides this preparation of drug combination process.
Another technical scheme of the present invention provides the purposes of this pharmaceutical composition.
The invention provides a kind of pharmaceutical composition, it is the slow releasing preparation that the adjuvant by mannatide and pharmaceutically acceptable slow releasing preparation is mixed and made into.Wherein, contain 5～30mg in the per unit preparation.
Mannatide of the present invention is to be prepared by following method:
A, (Streptococcus hemolyticus-α-Hemolysis) produces bacterium to ferment with alpha-Hemolytic streptococcus;
B, collection fermentation liquid extract the purification mannatide.
The pH value of the extraction overall process of step b remains 1.5 to 5.0, and employed solvent is the ethanol of 60%-99.9%.
Mannatide of the present invention is from alpha-Hemolytic streptococcus (Streptococcushemolyticus-α-hemolysis) extract the refining a kind of mannan peptide matters with pharmacologically active that forms the tunning.The relevant expert is in the research of Keshan disease; adopt Hemolytic streptococcus thalline preparation (OK-432) as proposing to adopt Hemolytic streptococcus metabolite antineoplastic imagination on the basis of antineoplastic immune reinforcing agent according to Japan; through strain improvement and discriminating; the research of fermentation manufacturing technique; discovery separates the alpha-Hemolytic streptococcus obtain from human mouth, and (α-mannatide that contains in the tunning of Streptococcushemolyticus-α-Hemolysis) has can enhancing body's immunological function; antiinflammatory; leukocyte increasing, multiple physiologically actives such as protection and enhancing bone marrow stem cell.
Wherein, the adjuvant of described pharmaceutically acceptable slow releasing preparation is: the mixture of any one or a few in ethyl cellulose, ethylmethylcellulose, ethylhydroxyethylcellulose, polyethylene, polrvinyl chloride, polyvinylacetate, acrylic resin I, II, III, IV number, polymethacrylates, silicone rubber, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl starch, polyvinylpyrrolidone, the carboxylic polrvinyl.Particularly, the adjuvant of described pharmaceutically acceptable slow releasing preparation is: ethyl cellulose, acrylic resin II number, and wherein mixing the ratio range that uses is 1～15: 1～10, ratio range is 3: 2 particularly.
Said slow releasing preparation is slow releasing capsule, slow releasing tablet, sustained-release granular formulation, slow releasing pill.
The present invention also provides the preparation method of said composition, and it comprises following steps:
A, mannatide is mixed granulation, drying, granulate with the slow releasing preparation adjuvant of pharmaceutically accepting.
B, mannatide is mixed granulation, drying, granulate with the adjuvant of pharmaceutically accepting;
C, the adjuvant that a step and b step is required mix, and make slow releasing preparation pharmaceutically commonly used.
The present invention also provides the purposes of pharmaceutical composition, and it is the medicine that can strengthen the human immunologic function, and particularly, it is the medicine of treatment repetitive upper respiratory tract infection, leukopenia.
Medicine of the present invention, behind the treatment chemicotherapy aspect the diseases such as leukopenia and immunologic hypofunction, good effect, safe and reliable, the bioavailability height, effect is lasting, provides a kind of new treatment to select for clinical.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
The preparation method of thing combined according to the invention, it comprises following steps: a, mannatide is mixed granulation, drying, granulate with the slow releasing preparation adjuvant of pharmaceutically accepting.B, mannatide is mixed granulation, drying, granulate with the adjuvant of pharmaceutically accepting.C, the adjuvant that a step and b step is required mix, and make dosage form pharmaceutically commonly used.The specific embodiment is:
The preparation of example 1 mannatide:
The preparation of sweat: i, strain: selecting strain for use is alpha-Hemolytic streptococcus (Streptococcushemolyticus-α-hemolysis);
Culture medium: bacterium culture medium: glucose 0.4-0.8%, sodium chloride 0.4-0.8%, peptone 0.4-1%, Carnis Bovis seu Bubali cream 0.1-0.5%, sheep blood 10%, agar 1.5-2%, PH7.2-7.8 fermentation medium: glucose 0.1-0.5%, peptone 0.4-0.7%, yeast extract 0.4-0.6%, sodium chloride 0.4-0.8%, bubble enemy 0.01%
Extraction, the required raw and auxiliary material of subtractive process: ethanol, acetone, trichloroacetic acid, dehydrated alcohol
A, female bottle preparation: unpacking strain cryovial, with aseptic broth bouillon dilution, insert the blood inclined-plane under aseptic condition.18-45 ℃ of constant temperature culture 24h;
B, the preparation of son bottle: cultured blood slant strains is pressed the 1-8% inoculum concentration insert in the broth bouillon 18-45 ℃ of constant temperature culture 10-24h under aseptic condition;
C, bacterium culture medium sterilising temp are 120-124 ℃, sterilization time 30 minutes, sterilization steam pressure 0.12-0.14Mpa;
D, fermentation: good son bottle strain is inserted fermentation tank by 0.2% inoculum concentration under aseptic condition, overall process 18-45 ℃ of constant temperature culture, the filtrated air air inflow is advisable can stir culture fluid, and tank pressure is no more than 0.01Mpa, fermentation period 20-100 hour.The fermentation medium sterilising temp is 120-124 ℃, and steam pressure is 0.12-0.14Mpa, time 30min; Ferment to 20-100 hour, jar is put in deactivation, and deactivation is adopted to heat and made the fermentation liquid temperature reach 80 ℃, lowers the temperature after constant temperature 30-50 minute again and puts jar, concentrates, and the concentrated solution specific gravity control is got final product at 1.20-1.22;
Ii, extraction:
A, the concentrated solution of i step is added the ethanol of 1-5 times of volume, fully stir and leave standstill the centrifugal removal supernatant in back and promptly obtain precipitate;
B, with gained precipitate dissolved in distilled water, transfer PH, obtain lysate and lysate left standstill and control lysate pH value after leaving standstill;
C, the centrifugal removal impurity of lysate is obtained clear liquid, accurately measure the clear liquid volume, transfer pH value, calculate required ethanol amount, ethanol is slowly joined in the clear liquid, and fully stir, leave standstill the centrifugal removal supernatant in back and obtain precipitate by the clear liquid stereometer;
D, above extracting method by from b-c step repeatable operation to intermediate detection qualified till, the precipitate that promptly obtains is the mannatide semi-finished product;
Iii, refining: the ii step is extracted repeatedly the mannatide semi-finished product precipitate that obtains, after sampling detects and meets quality standard, carry out primary dewatering with dehydrated alcohol, fully grind to form powdery, obtain wet-milling one time, reuse acetone carries out second dehydration, fully stirs and obtains the secondary wet-milling, and the secondary wet-milling was promptly got mannatide in 4-10 hour 60-100 ℃ of baking.
The using method of active carbon in the leaching process of ii step wherein: use amount is the required active carbon 1-10g of 1L lysate, transfers the lysate pH value after adding active carbon, and this liquid is incubated 20-70min under 40-100 ℃ of temperature, and is centrifugal, and the control charcoal takes off the liquid pH value.
PH value in the said extracted overall process remains 1.5 to 5.0.
Concentration of alcohol in the leaching process of ii step is 60-99.9%.
The preparation of example 2 medicines of the present invention
A, get the fine powder mix homogeneously of ethyl cellulose and acrylic resin II number, behind 60% dissolve with ethanol, then mannatide is prepared into 50mg/ml medicinal liquid slurry and sprays into, be mixed with into fine grained with starch, drying, granulate.B, mannatide is prepared into 50mg/ml medicinal liquid slurry is mixed with into fine grained with starch, drying, granulate.C, tabletting are with rapid release and slow-released part granule and magnesium stearate, and mix homogeneously is pressed into 1000, promptly.Select the not content of the medicine slurry of consumption for use, can prepare the different medicine of the present invention of content.
Example 3 assays
The preparation of reference substance solution: the about 0.1g of D-mannose reference substance that learns from else's experience 105 ℃ and be dried to constant weight, accurate claim surely, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, shake up, precision is measured 2ml, puts in the 100ml measuring bottle, thin up shakes up to scale again, promptly.
The preparation of need testing solution: 20 of the medicinal tablets of the present invention for the treatment of excess syndrome example 1 preparation, porphyrize, the accurate title, decide, precision takes by weighing (being equivalent to mannatide 25mg approximately), put in the 25ml volumetric flask, add the water 20ml dissolving that is chilled to below 5 ℃, after the jolting 10 minutes, put to room temperature and add water to scale, shake up, got 10ml (3000r/min) immediately centrifugal 10 minutes, collect supernatant 2.5ml and put in the 100ml volumetric flask, thin up is mixed with the solution that contains mannatide 25ug among every 1ml and makes need testing solution to scale.
Algoscopy: precision is measured reference substance and each 2ml of need testing solution, put respectively in the tool plug test tube, respectively add 2.5% phenol solution 0.5ml, shake up, put and slowly drip sulphuric acid 5.0ml in the ice bath, shake up, put and boil 3 minutes in the boiling water, take out, put cooling (about 3-5 minute) in the ice bath, take out, in 10-40 minute, measure trap according to beam split light method (two appendix IV of Chinese Pharmacopoeia version in 2000 A) respectively at 490nm wavelength place, calculate, that is result: contain mannatide 5～30mg in the per unit preparation.
The test of example 4 release in vitro degree
The medicinal tablet of the present invention for the treatment of excess syndrome example 1 preparation according to drug release determination method (appendix XD first method), is a solvent with water, and rotating speed is that per minute 150 changes, and solution 10ml was got in operation respectively at 2,4,6 hours in accordance with the law, filter, and timely supplementing water 10ml in process container.Collect filtrate 6.3ml and put in the 50ml volumetric flask, thin up is mixed with the solution that contains mannatide 25ug among every 1ml and makes need testing solution to scale.Measuring according to the method under the assay item. other gets 10 of this product, porphyrize, the accurate title, decide, precision takes by weighing (being equivalent to mannatide 25mg approximately), put in the 25ml volumetric flask, add the water 20ml dissolving that is chilled to below 5 ℃, jolting is after 10 minutes, put to room temperature and add water to scale, shake up, got 10ml (3000r/min) immediately centrifugal 10 minutes, collect supernatant 2.5ml and put in the 100ml volumetric flask, thin up is mixed with the solution that contains mannatide 25ug among every 1ml and makes need testing solution to scale.Measure according to the method under the assay item.Calculate every burst size respectively by separately the content and the content ratio of comparative solution at different time.Medicine product of the present invention are respectively 40～60% 2 hours, 4 hours, 6 hours burst size limit, and 55%～80%, more than 75%, should be up to specification.
By the test of release in vitro degree, prove that medicine of the present invention has tangible slow release effect.
Below by pharmacodynamics, pharmacology test specifies beneficial effect of the present invention.
The slow releasing tablet of test example 1 medicine of the present invention is at the intravital pharmacokinetic study of dog
1, material and reagent
1.1 instrument: UV-2102 PCS type ultraviolet spectrophotometer
1.2 reagent: the slow releasing tablet of medicine of the present invention (by example 1 preparation, 30mg/ sheet)
1.3 laboratory animal: the hybrid dog, 6, body weight 8～12kg, male and female are not limit, and are provided by laboratory animal quality-monitoring center, Sichuan Province.
2, method and result
2.1 detection method
The preparation precision of mannatide reference substance solution is measured the D-mannose reference substance 0.1g that is dried to constant weight through 105 ℃, puts in the 100ml measuring bottle, is dissolved in water and is diluted to scale, shakes up; Precision is measured 5ml, puts in the measuring bottle of 100ml, adds water to scale, shakes up.Contain mannose 50 μ g among every 1ml.
It is an amount of that the preparation precision of test sample is measured this product, adds water and make the solution that contains 40 μ g among every 1mL.
The preparation precision of standard curve is measured reference substance solution 0,0.2,0.4,0.6,0.8,1.0ml, put respectively in the tool plug test tube, respectively add water to 1.0ml, add 3% phenol solution 1.0ml again, shake up, pour sulphuric acid 4.5ml, shake up, putting to room temperature, is blank with 0 pipe, measures trap according to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2000 A) at the wavelength place of 490nm.To corresponding trap, calculate regression equation with mannose μ g number.
The algoscopy precision is measured need testing solution 1.0ml, and from " adding 3% phenol solution 1.0ml again ", operation is in accordance with the law measured trap, by the content of regression equation calculation mannose under the sighting target directrix curve preparation.
2.2 the interference measurement of adjuvant
Precision takes by weighing the adjuvant of the slow releasing tablet 10mg that is equivalent to medicine of the present invention in the tablet formulation, with an amount of water stirring and dissolving and be settled to 10ml, get subsequent filtrate direct injected under these conditions, and contrast with the chromatogram of the slow releasing tablet standard solution of medicine of the present invention, visible adjuvant content to the slow releasing tablet of medicine of the present invention under this condition does not disturb.
2.3 extraction recovery
Get blank plasma 0.5mL and put difference in vitro, the slow releasing tablet standard solution that adds not commensurability medicine of the present invention respectively, and compare with the slow releasing tablet standard solution of the medicine of the present invention of same concentrations, press the blood plasma quadrat method and handle and measure, calculate recovery rate the results are shown in Table 1.
Table 1
| The pipe number | Contrast amount (ug) | The amount of recording (ug) | The response rate (%) | Average |
| 1 | 100 | 101.3 | 101.3 | 100.73±1.72 |
| 2 | 100 | 98.4 | 98.4 | |
| 3 | 100 | 102.5 | 102.5 | |
| 4 | 100 | 100.7 | 100.7 |
2.4 precision
Get the slow releasing tablet plasma sample of the medicine of the present invention of variable concentrations, after handling as stated above, in different time on the same day, replication is 5 times respectively, calculates relative standard deviation in a few days; In same date not, the same concentrations plasma sample used with method handle and measure, repeat 5, calculate relative standard deviation in the daytime, the results are shown in Table 2.
Table 2
| Absolute sample size | Average | |||
| 100 | 300 | 600 | ||
| The amount of recording (ng) in a few days | 88.5±2.74 | 301.7±3.69 | 594.9±6.61 | 1.70 |
| RSD (%) in a few days | 2.78 | 1.22 | 1.11 | |
| In the daytime the amount of recording (ng) | 97.44±3.04 | 298.4±5.82 | 592.3±9.75 | 2.24 |
| In the daytime RSD (%) | 3.12 | 1.95 | 1.65 | |
2.5 average recovery
Get the dog plasma 0.5mL of concentration known, adding concentration respectively is the slow releasing tablet standard solution of an amount of medicine of the present invention of 20ug/mL, is equivalent to 6 respectively, 12, the slow releasing tablet of the medicine of the present invention of 20ug is handled by above-mentioned blood sample preprocess method, and measure with the HPLC method, average recovery sees Table 3.
Table 3
| Blood plasma Chinese medicine amount (ug) | Addition (ug) | The amount of recording (ug) | The response rate (%) | Average recovery rate (%) | RSD％ |
| 8.5 | 4 | 12.7 | 105 | 101.3 | 3.63 |
| 8.5 | 4 | 12.4 | 97.5 | ||
| 8.5 | 5 | 13.3 | 96 | ||
| 8.5 | 5 | 13.7 | 104 | ||
| 8.5 | 6 | 14.6 | 101.7 | ||
| 8.5 | 6 | 14.7 | 103.3 |
2.6 pharmacokinetics in the slow releasing tablet of medicine of the present invention and ordinary tablet animal (dog) body
2.6.1 animal subject
Select the more approaching dog of digestive system and people as study subject.
2.6.2 medication
Adopt self intersection single oral dose administration, directly tablet is sent into dog throat, 50mL simultaneously feeds water; Dosage 1.75 grams/only, respectively at timing is from the about 2.5mL of hind leg venous blood collection before the administration and after the administration, separated plasma is standby immediately; Fasting 12h before the administration, and fasting to sampling finishes; Dosing interval: 1 week; Plasma sample is used with method and is handled and measure.
Adopt the 3P87 program (Liang Wenquan. Biopharmaceutics and Pharmacokinetics. People's Health Publisher .2000 June) pharmacokinetic parameter and the statistical result of two kinds of preparations calculating sees Table 4.
The statistical result of the main pharmacokinetic parameter of two kinds of preparations of table 4
| Cmax (ug/mL) slow releasing tablet ordinary tablet | Tmax (min) slow releasing tablet ordinary tablet | AUC[ug/ (mL min) slow releasing tablet ordinary tablet |
| 31.75 28.36 P value P＞0.05 | 7.83 2.25 P＜0.01 | 8143.8 5072.5 P＜0.05 |
Cmax: maximum plasma concentration; Tmax: the time when blood drug level is maximum.
3, conclusion and discussion
Pharmacokinetic parameters statistical result shows: there is significant differences in the peak time of two kinds of preparations, and the slow releasing tablet peak time significantly improves, and the indication slow releasing tablet can be brought into play drug effect soon; The difference of the peak value blood drug level of two kinds of preparations does not have significance, but the area under the drug-time curve (AUC of the two, can reflect the medicine cumulative release amount in a period of time in vivo) there is a significant difference, illustrate that slow releasing tablet can keep higher blood drug level for more time than ordinary tablet, this is very important to keeping of the performance of drug effect and drug effect; AUC with ordinary tablet is a reference, and the relative bioavailability of slow releasing tablet is 152%, illustrates that slow releasing tablet absorbs fully than ordinary tablet.
Below by clinical trial, prove that medicament slow release preparation of the present invention compares with conventional tablet, brought into play identical effect, and taking convenience.
Test example 2 medicament sustained-release tablets of the present invention to chemicotherapy after leukopenia and the clinical trial of immunologic hypofunction therapeutical effect
Show from this observed result: 1, two groups of mannatides are to leukopenia behind the chemicotherapy, satisfactory effect.Slow releasing tablet dosage form group and tablet group, total effective rate reaches 97.2% and 97.4% respectively.Two groups all can obviously be improved patient's leukocyte count level behind the chemicotherapy, before and after its treatment patient's leukocyte average relatively, there is significant differences in P＜0.01.Simultaneously, the result shows there was no significant difference existence on the curative effect between two kinds of dosage forms of mannatide, controls between the group of back and compares P＞0.05.2, Immunoglobulin IgM, IgA, IgG value change: behind two groups of patient treatments, IgM, IgA, IgG all have obvious rising, compare before and after each individual event value treatment, all there is significant differences, Immunoglobulin IgM, IgA, IgG value change relatively between the group of treatment back, then there was no significant difference exists, P＞0.05.According to The above results explanation, medicament sustained-release tablets of the present invention for leukopenia behind the chemicotherapy and immunologic hypofunction, has curative effect preferably clinically, shows effectively to improve quantity of leucocyte behind the chemicotherapy rapidly, improves immunologic function.Its curative effect and tablet matched group compare, and there was no significant difference exists between the two.
In clinical observation on the therapeutic effect, the patient has been carried out the observation of detection such as livers before and after the treatment, kidney merit and clinical symptoms respectively, do not see that toxic and side effects exists.
By clinical trial, prove drug sustained-release tablet of the present invention, behind the treatment chemicotherapy aspect the diseases such as leukopenia and immunologic hypofunction, satisfactory effect, safe and reliable.Observe demonstration from this, the utilization of this medicine slow releasing tablet dosage form is the treatment of leukopenia and immunologic hypofunction behind the clinical chemicotherapy, provides a kind of new treatment to select.
Mode by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
The preparation technology of embodiment 1 slow releasing capsule
A, get the fine powder mix homogeneously of ethyl cellulose and acrylic resin II number, behind 60% dissolve with ethanol, then mannatide is prepared into 50mg/ml medicinal liquid slurry and sprays into, be mixed with into fine grained with starch, drying, granulate.B, mannatide is prepared into 50mg/ml medicinal liquid slurry and starch through being mixed with into fine grained, drying, granulate.C, the granule of a, b two step gained is mixed, encapsulated 1000, promptly.
Embodiment 2 slow releasing tablet preparation technologies:
A, get the fine powder mix homogeneously of ethyl cellulose and acrylic resin II number, behind 60% dissolve with ethanol, then mannatide is prepared into 50mg/ml medicinal liquid slurry and sprays into, be mixed with into fine grained with starch, drying, granulate.B, mannatide is prepared into 50mg/ml medicinal liquid slurry is mixed with into fine grained with starch, drying, granulate.C, tabletting are with rapid release and slow-released part granule and magnesium stearate, and mix homogeneously is pressed into 1000, promptly.
Embodiment 3 sustained-release granular formulation preparation technologies:
A, get the fine powder mix homogeneously of ethyl cellulose and acrylic resin II number, behind 60% dissolve with ethanol, then mannatide is prepared into 50mg/ml medicinal liquid slurry and sprays into, be mixed with into fine grained with starch, drying, granulate.B, mannatide is prepared into 50mg/ml medicinal liquid slurry is mixed with into fine grained with starch, drying, granulate.C, the granule of a, b two step gained is mixed, promptly.
The preparation of embodiment 4 slow release honeyed pill:
A, get the fine powder mix homogeneously of ethyl cellulose and acrylic resin II number, behind 60% dissolve with ethanol, then mannatide is prepared into 50mg/ml medicinal liquid slurry and sprays into, be mixed with into fine grained with starch, drying, granulate.B, mannatide is prepared into 50mg/ml medicinal liquid slurry is mixed with into fine grained with starch, drying, granulate.C, the granule of a, b two step gained is mixed, add the abundant mixing of an amount of refined honey, the pill piece uses automatic pellet processing machine pill bar, gradation, round, the pill grain, and 80 ℃ of dryings, promptly.
Claims (11)
1, a kind of pharmaceutical composition is characterized in that it is the slow releasing preparation that the adjuvant by mannatide and pharmaceutically acceptable slow releasing preparation is mixed and made into.
2, pharmaceutical composition according to claim 1 is characterized in that: described mannatide is to be prepared by following method:
A, (Streptococcus hemolyticus-α-hemolysis) produces bacterium to ferment with alpha-Hemolytic streptococcus;
B, collection fermentation liquid extract the purification mannatide.
3, pharmaceutical composition according to claim 1 is characterized in that, contains mannatide 5～30mg in the per unit preparation.
4, pharmaceutical composition according to claim 1 is characterized in that the adjuvant of described pharmaceutically acceptable slow releasing preparation is: the mixture of any one or a few in ethyl cellulose, ethylmethylcellulose, ethylhydroxyethylcellulose, polyethylene, polrvinyl chloride, polyvinylacetate, acrylic resin I, II, III, IV number, polymethacrylates, silicone rubber, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl starch, polyvinylpyrrolidone, the carboxylic polrvinyl.
5, pharmaceutical composition according to claim 4 is characterized in that the adjuvant of described pharmaceutically acceptable slow releasing preparation is: ethyl cellulose, acrylic resin II number, wherein mixing the ratio range that uses is 1～15: 1～10.
6, pharmaceutical composition according to claim 5 is characterized in that the adjuvant of described pharmaceutically acceptable slow releasing preparation is: ethyl cellulose, acrylic resin II number, wherein mixing the ratio range that uses is 3: 2.
7, pharmaceutical composition according to claim 1 is characterized in that said slow releasing preparation is slow releasing capsule, slow releasing tablet, sustained-release granular formulation, slow releasing pill.
8, the described preparation of drug combination method of claim 1～7, it comprises following steps:
A, mannatide is mixed granulation, drying, granulate with the slow releasing preparation adjuvant of pharmaceutically accepting;
B, mannatide is mixed granulation, drying, granulate with the adjuvant of pharmaceutically accepting;
C, the granule of a step and b step preparation is mixed, make the slow releasing preparation of pharmaceutically using always.
9, the described pharmaceutical composition of claim 1 is characterized in that: it is the medicine that can strengthen the human immunologic function.
10, pharmaceutical composition according to claim 9 is characterized in that, it is the medicine of treatment repetitive upper respiratory tract infection.
11, pharmaceutical composition according to claim 9 is characterized in that, it is the medicine of treatment leukopenia.
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| CN1242810C true CN1242810C (en) | 2006-02-22 |
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