CN1110320C - Medicine preparation containing glucokinase and its preparation method - Google Patents
Medicine preparation containing glucokinase and its preparation method Download PDFInfo
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- CN1110320C CN1110320C CN00111628A CN00111628A CN1110320C CN 1110320 C CN1110320 C CN 1110320C CN 00111628 A CN00111628 A CN 00111628A CN 00111628 A CN00111628 A CN 00111628A CN 1110320 C CN1110320 C CN 1110320C
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- sbphylokinase
- preparation
- pharmaceutical preparation
- enteric
- sak
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention belongs to the technical field of medicines, particularly to a medical preparation containing staphylokinase and a preparation method thereof. The present invention prepares an oral staphylokinase preparation dissolved in the intestines by that a protease inhibitor, an absorption promoting agent and auxiliary materials are added in staphylokinase used as an active ingredient and are loaded in capsule shells or directly pressed into tablets, and the capsules or the tablets are coated with enteric coating materials. Animal experiments prove that partial Sak can be absorbed in an active form, and the present invention increases the fibrinolytic activity of the blood plasma and has good effect on preventing thrombopoiesis.
Description
The conventional dosage forms of protein and polypeptide drug is an injection, yet, for an a little long-time use or preventive medicine, injection system is not only painful, inconvenient, and the expense height.In recent years, the dosage form research of bioactive substance is more and more paid attention to, and comprises eye drop, inhalant, unguentum, oral agents, suppository etc., and wherein peroral dosage form is had potentiality very much.Mucous membrane of small intestine and lung mucosa, nasal mucosa, eye conjunctiva (and nasolacrimal duct mucosa) etc. are the specific area maximum mutually, has more advantage on absorbing.
Under the normal physiological situation, after polypeptide, protein enter small intestinal, under the effect of trypsin, chymase, elastoser, carboxypeptidase A, carboxypeptidase B etc., be hydrolyzed into single amino acids the most at last, dipeptides, tripeptides have only on a small quantity and are absorbed.If remove or reduce the influence of protease, polypeptide, proteinic bioavailability will obviously improve.Morishita (1992) studies show that the adding of protease inhibitor helps proteinic absorption, and, enzyme inhibitor to press down zymogram wide more, it is strong more to press down the enzyme effect, short Absorption is also strong more.Protease inhibitor commonly used has trypsin inhibitor, chymotrypsin inhibitor, EDTA, Bowman-Birk enzyme inhibitor, aprotinin etc., and back three belongs to the broad-spectrum protease inhibitor.The utilization of protease inhibitor significantly improves the protein adsorption effect.
After uniting the use protease inhibitor, the parcel of enteric coating makes protein avoid the destruction and the hydrolysis of gastric acid, intestinal protease, and albumen mass-energy exists in intestinal with complete form, has part to be absorbed.Think at present, the absorption pattern of digestive tract internal protein has three kinds: a. absorbs by complete intestinal mucosa, but, compare with conventional medicament, protein drug generally has larger molecular weight (the MW hundreds of is to hundreds of thousands), electrically charged or be strong polarity, therefore the mucosa penetrance is poor, and the albumen quality that absorbs by this approach seldom; B. pass through Peyer ' spatches and absorb, intestinal wall Peyer ' s Patches accounts for intestinal mucosa 25%, and pinocytosis is arranged, and can engulf macromolecular substances and granule, enters blood circulation again after making it to enter lymphatic vessel; C. absorb by intercellular substance, but under the physiological situation, have only molecule can pass through intercellular substance less than the material of 11 , as if being short absorbent with surfactant, suitably improve the permeability of iuntercellular tight structure, proteinic absorption will be promoted greatly.
Tissue plasminogen activator (t-PA), streptokinase (SK), urokinase thrombolytic drugs such as (UK) be widely used in clinical after, (staphylokinase Sak) is subjected to people with advantages such as its fibrin-specific strong, good thrombolytic ability, molecular weight are little and payes attention to Sbphylokinase day by day.Above-mentioned several drugs is all with the administration of intravenous drip mode, is used for the first aid of vessel embolism such as acute myocardial infarction, and the thromboembolism treatment Best Times is in the morbidity 6hr.But intravenous injection must be carried out in hospital, and thus, many patients have lost the chance of thromboembolism treatment.
The purpose of this invention is to provide a kind of non-vein instillation preventive medicine oral enteric preparation that longer-term uses that is suitable for, can suitably improve fibrinolytic or anticoagulating active in the human plasma, so that the generation of thrombotic disease such as prophylaxis of acute myocardial infarction and cerebral infarction.Oral formulations is convenient, easily is that doctor and patient receive.Sak molecular weight less (MW=1,5000), penetrance is strong, is the good raw material of the oral anti-bolt medicine of preparation.
The present invention has comprised the enteric coated capsule of Sak, the preparation of tablet, contains short absorbent and protease inhibitor in the preparation.
The Sbphylokinase that the present invention refers to comprises natural Sbphylokinase (existing open source literature report), recombinant glucokinase (the recombinant staphylokinase that extracts from staphylococcus, r-Sak, the patent No. is 94112105), the various mutants of Sbphylokinase that produce by gene mutation and the external trim of above-mentioned kind.
The present invention concentrates on the following aspects:
1. the selection of enteric material comprises that cellulose acetate-phthalate (CAP), Hydroxypropyl Methylcellulose Phathalate (HPMCP), phthalic acid polyvinyl alcohol ester (PVAP), styrene maleic acid copolymer (StyMA), acrylic resin are (as EudragitL100, Eudragit S100,2
#Or 3
#Resin etc.);
2. the selection of short absorbent comprises surfactant and Ca
2+Chelating agen.Selection toxicity is little, oral safe nonionic surfactant, as fatty glyceride, the PEG analog derivative is (as PEG 400 monoleates, PEG 400 monolaurates), polyoxyethylene aliphatic alcohol ether class (as the Brij class), polyoxyethylene sorbitan fatty acid ester (Tween class), sorbitol and sorbitan fatty acid ester (Span class), polyoxyethylene fatty acid ester class (Myrj class), Vitamin E derivatives class (as Vitamin E TPGS, EastamnFine Chemical Company), the whole copolymerization surfactant (Pluronic class) of polyoxy alkene; Natural surfactant is as lecithin, fabaceous lecithin, cholesterol and cholic acid class, sodium alginate etc.; The anionic part surfactant is as dioctylis sulfosuccinas natricus (Aerosol OT).
3. the selection of enzyme inhibitor comprises trypsin inhibitor, chymotrypsin inhibitor, EDTA, Bowman-Birk enzyme inhibitor, aprotinin etc.
4. prepare oral enteric capsule or enteric coatel tablets.Enteric comprises that little enteric and colon are molten.
The present invention adopts following technical proposal:
1.Sak the preparation of capsule or tablet: after crossing 80 mesh sieves earlier before various adjuvants and additive use, fully mix pack into glue shell or direct compression (the loading amount error is ± 5%) with the Sak lyophilized powder.Wherein adjuvant comprises filler such as starch, lactose, dextrin, inorganic salt (as calcium carbonate, calcium sulfate etc.), microcrystalline Cellulose, amylum pregelatinisatum etc., lubricant such as Pulvis Talci, magnesium stearate etc.; Additive is above-mentioned 2,3 listed short absorbent and enzyme inhibitors.
2.Sak capsule or tablet are enteric coated: the selection of coating material is seen above-mentioned 1, and coating material contains coating material 2-10% with ethanol, isopropyl alcohol, acetone and other organic solvent dissolving in the coating solution, can contain low amounts of water (as 3-5%).Capsule or tablet coating in coating pan.Coating solution can contain the plasticizer (as phthalate, glyceryl triacetate, Chinese holly salt acid esters, Oleum Ricini, silicone oil etc.) of coating material amount 10-25%, the lubricant (as Pulvis Talci, magnesium stearate etc.) of coating material amount 10-15% etc.
3.r-Sak enteric coated preparation disintegrate condition detection: enteric coated preparation places 0.1N HCl, 37 ℃ are stirred 2hr, move into pH6.8 buffer (3.4g KH then
2PO
4With 500ml H
2The O dissolving, 0.1N NaOH transfers) in, capsule or tablet situation are observed in 37 ℃ of stirrings in the 1hr.
4. the blood plasma fibrinolytic is measured before and after the oral r-Sak enteric coated preparation of rabbit: 12 of new zealand rabbits, divide 2 groups, and 6 every group, oral capsule or the tablet that contains 2mg Sak.Group 1: matched group, the oral enteric coated preparation that does not contain Sak; Group 2: oral pastille preparation (more than the fasting 10hr, only supplying water before the rabbit administration), get blood 1ml every 1hr after (0hr), the administration before the administration, the sodium citrate anticoagulant, directly the chromophoric substrate method is surveyed blood plasma fibrinolytic situation of change, represents with A405.
Capsule of the present invention or tablet coating rear surface are level and smooth, uniform and smooth.Capsule or tablet are got four at random, and the 1000ml beaker that is placed in is a simulated gastric fluid with 0.1N HCl, and 37 ℃ are stirred 2hr down, and capsule, tablet are all intact; Then, be simulated intestinal fluid with the pH6.8 buffer, 37 ℃ are stirred down, all damaged, the disintegration of tablet of capsule in the 1hr, its Chinese medicine dissolves fully.Measure the fibrinolytic of this solution with the chromophoric substrate method, the result shows before and after the coating active no significant difference in the preparation.
Blood sample chromophoric substrate method is surveyed fibrinolytic before and after the administration, and the 2nd group of fibrinolytic obviously improves; The 1st group of fibrinolytic there was no significant difference in whole process.
After accompanying drawing was the oral pharmaceutical preparation of the present invention of rabbit, the blood plasma fibrinolytic (surveyed, with A by the chromophoric substrate method
405Expression) situation of change.Group 1 is a matched group, and the blood plasma fibrinolytic does not have significant change; Group 2 obviously rises after administration for administration group, blood plasma fibrinolytic, and 4hr reaches peak after the administration.Explanation is under the combined effect of enteric coating, short absorbent, protease inhibitor, and Sak can enter blood circulation, suitably improves the blood plasma fibrinolytic, thereby reaches the thrombotic purpose of prevention.
Embodiment one:
Pharmaceutical formulation
Sak lyophilized powder 60mg
Lactose 6g
Pulvis Talci 1.5%
Magnesium stearate 0.5%
Pluronic?F68 1％
Protease inhibitor 100mg
(Complete?TM，Boehriger?Mannheim)
Coating solution components
Eudragit?L100 5％
Pulvis Talci 0.8%
Magnesium stearate 0.2%
Oleum Ricini 0.01%
Water 0.4%
Alcohol solvent
After lactose, Pluronic F68 crossed 80 mesh sieves, mix, add Sak lyophilized powder and protease inhibitor at last, abundant mixing in the mortar, the 0.2 ± 0.01g/ grain glue shell of packing into Pulvis Talci, magnesium stearate.
Under agitation, in ethanol, slowly add Eudragit L100, make fine dispersion and be dissolved into clear solution; Drip entry and Oleum Ricini, add Pulvis Talci and magnesium stearate at last, make to be uniformly dispersed.
Capsule is put into coating pan, successively spray into coating solution under 30-37 ℃, each capsule spends coating solution 1.7ml at last.
Embodiment two:
Pharmaceutical formulation
Sak lyophilized powder 65mg
Starch 3.5g
Calcium carbonate 3g
Pulvis Talci 1.5%
Magnesium stearate 0.5%
Myvaple?600 2％
(Eastman?Fine?Chemical?Company)
Soybean trypsin 500mg
Coating solution components
2
#Resin 4%
Pulvis Talci 2%
Magnesium stearate 1%
Silicone oil 0.04%
Diethyl phthalate 0.01%
90% alcohol solvent
After starch, calcium carbonate and Myvaple 600 crossed 80 mesh sieves, mixes, add Sak lyophilized powder and soybean trypsin at last, abundant mixing in the mortar, the 0.2 ± 0.01g/ grain glue shell of packing into Pulvis Talci, magnesium stearate.
Under agitation, 2
#Resin becomes clear solution with 90% dissolve with ethanol; Be added dropwise to silicone oil and diethyl phthalate, add Pulvis Talci and magnesium stearate at last, make to be uniformly dispersed.Capsule is put into coating pan, successively spray into coating solution under 30-37 ℃, each capsule spends coating solution 1.5ml at last.
Claims (9)
1, a kind of Sbphylokinase pharmaceutical preparation is characterized in that with Sbphylokinase as active component, add protease inhibitor, short absorbent and adjuvant after, outsourcing is made Sbphylokinase oral enteric preparation with enteric-coating material.
2. by the described Sbphylokinase pharmaceutical preparation of claim 1, it is characterized in that described Sbphylokinase comprises: natural Sbphylokinase, recombinant glucokinase, the glucokinase mutant that produces by gene mutation.
3. according to claim 1 or 2 described Sbphylokinase pharmaceutical preparatioies, it is characterized in that described Sbphylokinase is a recombinant glucokinase.
4,, it is characterized in that described protease inhibitor is trypsin inhibitor, chymotrypsin inhibitor, EDTA, Bowman-Birk enzyme inhibitor, aprotinin according to the described Sbphylokinase pharmaceutical preparation of claim 1.
5,, it is characterized in that described short absorbent is surfactant and Ca according to the described Sbphylokinase pharmaceutical preparation of claim 1
2+Chelating agen.
6,, it is characterized in that described surfactant comprises nonionic surfactant, natural surfactant and anionic part surfactant according to the described Sbphylokinase pharmaceutical preparation of claim 5.
7,, it is characterized in that described enteric-coating material is cellulose acetate-phthalate (CAP), Hydroxypropyl Methylcellulose Phathalate (HPMCP), phthalic acid polyvinyl alcohol ester (PVAP), styrene maleic acid copolymer (StyMA), acrylic resin (as Eudragit L100, Eudragit S100,2# or 3# resin etc.) according to the described Sbphylokinase pharmaceutical preparation of claim 1.
8,, it is characterized in that described enteric-coating material is Eudragit L100, Eudragit S100,2 according to the described Sbphylokinase pharmaceutical preparation of claim 1
#Or 3
#Resin.
9, a kind of preparation method that contains Sbphylokinase pharmaceutical preparation is characterized in that adopting the following step:
(1). preparation Sak capsule or tablet: add filler, lubricant, short absorbent and enzyme inhibitor in the Sak lyophilized powder, pack into glue shell or direct compression;
(2). Sak capsule or tablet is enteric coated: coating material adds plasticizer and lubricant, capsule or tablet coating in coating pan with organic solvent dissolution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN00111628A CN1110320C (en) | 2000-01-28 | 2000-01-28 | Medicine preparation containing glucokinase and its preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN00111628A CN1110320C (en) | 2000-01-28 | 2000-01-28 | Medicine preparation containing glucokinase and its preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1268376A CN1268376A (en) | 2000-10-04 |
| CN1110320C true CN1110320C (en) | 2003-06-04 |
Family
ID=4581537
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00111628A Expired - Fee Related CN1110320C (en) | 2000-01-28 | 2000-01-28 | Medicine preparation containing glucokinase and its preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1110320C (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1109508A (en) * | 1995-01-23 | 1995-10-04 | 成都世新药物技术开发中心 | Full DNA sequence of recombinative glucokinase |
-
2000
- 2000-01-28 CN CN00111628A patent/CN1110320C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1109508A (en) * | 1995-01-23 | 1995-10-04 | 成都世新药物技术开发中心 | Full DNA sequence of recombinative glucokinase |
Non-Patent Citations (1)
| Title |
|---|
| 高技术通讯 1999-04-01 宋钢等 用计算机模型研究葡激酶与人微小纤溶酶原的相互作用 * |
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| Publication number | Publication date |
|---|---|
| CN1268376A (en) | 2000-10-04 |
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