CN1254274C - Recombinant hirudin oral enteric soluble slowly-releasing preparation - Google Patents
Recombinant hirudin oral enteric soluble slowly-releasing preparation Download PDFInfo
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- CN1254274C CN1254274C CN 01133773 CN01133773A CN1254274C CN 1254274 C CN1254274 C CN 1254274C CN 01133773 CN01133773 CN 01133773 CN 01133773 A CN01133773 A CN 01133773A CN 1254274 C CN1254274 C CN 1254274C
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- lepirudin
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- oral
- recombinant hirudin
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Abstract
The present invention relates to components, a preparation and an application range of a recombinant hirudin oral enteric soluble slowly-releasing preparation. Verified by an animal experiment, the oral preparation administration has obvious inhibiting effect on forming domestic rabbit jugular thrombus and obvious anticoagulation function for rat peripheral blood. The preparation can effectively prevent a degradation function of the recombinant hirudin by gastrointestinal proteinase, and the preparation is suitable for anticoagulant therapy of a patient with thrombophilia.
Description
From world wide, thrombosis is diseases related to remain high as apoplexy, coronary heart disease, pulmonary infarction, vasculitic sickness rate, has accounted for first of the cause of death in China and some developed country.Though existing at present numerous anticoagulant medicines such as heparin and aspirin etc., its anticoagulant mechanism all is not the activity of direct Trombin inhibiting.The object of the present invention is to provide a kind of oral anticoagulant, its effective ingredient is a hirudin, and it is the strongest direct inhibitor of finding up to now of thrombin of effectiveness.Hirudin extracts purification by medical Hirudo head salivary gland and gets, and contains 65-66 amino acid whose little peptide, the activity of Trombin inhibiting specifically.Hirudin can combine with the catalytic site and the Fibrinogen recognition site of thrombin, and Trombin inhibiting changes into Fibrinogen fibrin and reaches the anticoagulation function; In addition, also can make the platelet aggregation of thrombin induction be subjected to press down, the activation of fibroblast, endotheliocyte and vascular smooth muscle cell is suppressed, thus the performance spy's property led anticoagulant and thromboembolism preventing effect.Lepirudin 023 ludon all adopts the drug administration by injection mode clinically at present, proved that to have consumption little, a little less than the immunogenicity, no obvious toxic-side effects, be difficult for by blood brain barrier, great majority are drained from urine with original shape behind the drug administration by injection, and its blood drug level and coagulation function are index related good, be convenient to the advantage of detection, so the existing trend that replaces heparin in the anticoagulant therapy abroad.Because the source of natural hirudin is limited, the lepirudin 023 ludon of using gene engineering technique production has obtained great success.Lepirudin 023 ludon has identical biological activity with natural hirudin, lepirudin 023 ludon by the yeast expression preparation is developed listing respectively by Novartis Co.,Ltd and conspicuous Chester company, is used for the treatment of heparin thrombocytopenia that causes and the aftertreatment of accepting the joint replacement patient.
Natural hirudin is a family that is made up of multiple variant, and kind surplus the variant of having found reaches ten wherein mainly is HV1, HV2 and HV3 three types.Use protein engineering technology and technique for gene engineering to the transformation of hirudin, can obtain the mutant of hirudin such as the hybridization type of HV1-HV2, HV2-K47 saltant etc.More than the variant of various hirudins and mutant expression system not only the escherichia coli of prokaryotic system, in the yeast of eukaryotic system and insecticide, successfully report is arranged all.Lepirudin 023 ludon and natural hirudin maximum difference structurally is not have thioesterification on its 63 tyrosine residues, but related data is thought and had or not thioesterification that the antithrombase effect of hirudin is not had influence.
Discover behind the Hirudo salivary gland extract oral administration to have certain anticoagulant effect in early days, therefore, the extract oral capsule made from Hirudo is used for the treatment of blood stasis disease clinically.Follow-up study finds that hirudin is very responsive to pepsin, and trypsin is had certain resistance.Hirudin is unstable under acidic condition, but to thermally-stabilised.Prove in the animal model of duodenal administration that with the lepirudin 023 ludon aqueous solution hirudin can be absorbed into blood by intestinal mucosa, but bioavailability is low.Heavy dose of lepirudin 023 ludon solution (5mg/kg) the directly zoopery demonstration of gastric infusion can play certain blood coagulation resisting function.Foreign patent reports that the recombinant hirudin oral dosage form made from liposome in the 0.1-1.0mg/kg dosage range, has significant antithrombotic effect in animal experiment.Thereby the proof lepirudin 023 ludon can be absorbed by intestinal mucosa and enter blood, and plays certain anticoagulant efficacy.
This patent hangs down on the ph factors of instability basis in the intestinal mucosa absorption characteristic of taking all factors into consideration lepirudin 023 ludon with to responsive the reaching of gastrointestinal protein; invented and added protection stabilizing agent such as human albumin and mannitol, a kind of novel lepirudin 023 ludon enteric slow release oral formulations of adding gastrointestinal protein inhibitor such as aprotinin.Interrelated data shows that aprotinin can extensively suppress the proteolysis of multiple pipe intestinal digesting enzyme, thereby improves the bioavailability of oral protein, has now become enzyme inhibitor the most frequently used in the protein peroral dosage form.The great advantage of said preparation is that lepirudin 023 ludon is not released in gastric solubleness liquid in addition, therefore can avoid the Degradation of pepsin and gastric acid.Add proteinic stabilizing agent and enzyme inhibitor, make lepirudin 023 ludon in intestinal juice, resist the Degradation of digestive tract protease behind the slow release, thereby improve the bioavailability of its intestinal absorption effectively, play anticoagulative function.Because the heat stability of lepirudin 023 ludon, the enteric slow release dosage form that its method in by example is prepared into has good stability.Therefore, recombinant hirudin oral intestinal absorption slow releasing preparation of the present invention has stable in properties, and convenient oral, bioavailability is good and anticoagulation, antithrombotic effect.The present invention is characterized as in its component and contains: lepirudin 023 ludon 1 mass parts, human albumin 2-5 mass parts, aprotinin 0.2-1.0 mass parts.
The drug oral preparation has multiple, and wherein enteric and intestinal absorption preparation are that mainly the principal agent composition should discharge and absorb in intestinal.Comprise forming agent, binding agent, skeleton agent etc. by adding various corresponding dosage forms adjuvants, make tablet or capsule commonly used clinically.Along with the development of dosage form, common delivery formulations has developed into slow release, the controlled release preparation stage.The technology of this respect is quite ripe, and has obtained clinical extensive use.Recombinant hirudin oral enteric soluble slowly-releasing preparation of the present invention mainly refers to the tablet or the capsule that are prepared into by release method, through the zoopery proof good anticoagulation and antithrombotic effect is arranged.
The invention example:
One, the preparation of lepirudin 023 ludon
65 amino acid sequences of lepirudin 023 ludon HV1 variant are ValValTyrThrAspCysThrGluSerGlyGlnAsnLeuCysLeuCysGluGlySe rAsnValCysGlyGlnGlyAsnLysCysIleLeuGlySerAspGlyGluLysAsnG lnCysValThrGlyGluGlyThrProLysProGlnSerHisAsnAspGlyAspPhe GluGluIleProGluGluTyrLeuGln, and 65 amino acid sequences of lepirudin 023 ludon HV2-K47 mutant (variation of HV2 type mutant 47 amino acids is lysine) are IleThrTyrThrAspCysThrGluSerGlyGlnAsnLeuCysLeuCysGlySerAs nValCysGlyLysGlyAsnLysCysIleLeuGlySerAsnGlyLysGlyAsnGlnC ysValThrGlyGluGlyThrProLysProGluSerHisAsnAsnGlyAspPheGlu GluIleProGluGluTyrLeuGln
Two kinds of corresponding CDNA sequences of lepirudin 023 ludon are embedded among the XhoI and EcoR1 of Bijie yeast secretion type expression plasmid PIC9k by synthetic, and recombiant plasmid screening back is called after PIC-HV1 and PIC-K47 respectively.Transform Bijie yeast host bacterium GS115, expression screening corresponding engineering bacterium is denoted as GS-HV1 and GS-K47.The Chromozym T method that expression screening is measured with the antithrombin activity of standard.Two kinds of express recombinant hirudin HV1 and HV2-K47 engineering bacteria are through fermentation, and purification obtains purity greater than 95%, and the N-terminal amino acid sequence analysis is worth in full accord with Design Theory.Wherein lepirudin 023 ludon HV1 specific activity is 14000ATU/mg, and lepirudin 023 ludon HV2-K47 specific activity is 15500ATU/mg.
Two, the preparation of recombinant hirudin oral enteric soluble coated slow release sheet
After lepirudin 023 ludon HV1 solution was measured protein concentration with the Lowry method, by adding 20 gram mannitol in 1 gram, 2.5 restrained human serum albumins, and 0.5 gram aprotinin after-filtration is lyophilized into white dry powder.By the following component amount of getting:
By the following component amount of getting:
Lepirudin 023 ludon HVl 1g principal agent
Human serum albumin 2.5g protective agent
Aprotinin 0.5g stabilizing agent
Mannitol 20g protective agent
Microcrystalline Cellulose 150g binding agent
Hydroxypropyl emthylcellulose 125g sustained-release matrix material
A-lactose 150g diluent
Magnesium stearate 5g lubricant
With lepirudin 023 ludon, human serum albumin, aprotinin, mannitol, a-lactose, microcrystalline Cellulose and hydroxypropyl emthylcellulose dry method mixing, with water-wet system soft material, cross 16 mesh sieves and granulate, after the vacuum decompression drying, cross 14 mesh sieve granulate, add the magnesium stearate tabletting again and get the sheet heart.Sheet heart weight 280mg contains lepirudin 023 ludon HV1 0.5mg, totally 2000.
Enteric coating
By the following component amount of getting:
Polyacrylic acid II resin 17.2g
III resin 17.2g
85% ethanol 26.6ml
Titanium dioxide 8.6g
Tween 80 4.3ml
Oleum Ricini 13ml
Lemon yellow 0.5g
Pulvis Talci 8.6g
II, III resin are placed container, add 95% ethanol and stir, make it moistening fully, place and it was dissolved fully in 12-24 hour, add other composition again and make suspension, the sheet heart is heated to about 35 ℃, spray the coating after drying.Every coating tablets film weight is 4mg.
Can prepare enteric coating equally by this law and release slow lepirudin 023 ludon HV2-K47 tablet.
Three, the capsular preparation of recombinant hirudin oral enteric soluble slowly-releasing
After lepirudin 023 ludon HV2-k47 solution is measured protein concentration with the Lowry method, by adding 20g mannitol among the 1g, the 2.5g human serum albumin, 0.5g aprotinin after-filtration is lyophilized into white dry powder.By the following component amount of getting:
Lepirudin 023 ludon HV2-k47 1g principal agent
Human serum albumin 25g protective agent
Aprotinin 0.5g stabilizing agent
Mannitol 20g protective agent
Sucrose 115g ball core
Starch 115g ball core
Polyvinylpyrrolidone 10g binding agent
Ethyl cellulose 24.9g coating material
Hydroxypropyl cellulose 8.3g coating material
Propanol 3.3ml solvent
Ethanol 660ml solvent
Get 30-40 order celphere 240g (sucrose 115g, starch 115g, polyvinylpyrrolidone 10g) puts in the rotation coating pan, lepirudin 023 ludon, mannitol, aprotinin, albumin lyophilized powder is water-soluble, be sprayed on the celphere dry, until making lepirudin 023 ludon content is 3% piller, reuse ethyl cellulose and hydroxypropyl cellulose and the alcoholic solution spray coating that contains propanol be to increasing weight 10%, gets 20-30 order piller after the drying and screening and pack in the opaque No. 2 enteric blank capsules promptly.Every capsules loading amount is 250mg, contains lepirudin 023 ludon HV2-k47 0.5mg, totally 2000.
Can prepare enteric slow release lepirudin 023 ludon HV1 capsule equally by this law.
Four. recombinant hirudin oral enteric soluble slowly-releasing capsule prevention administration is to the thrombotic inhibitory action of new zealand rabbit jugular vein
45 of new zealand rabbits about body weight 2.5kg, are divided into 7 groups at random: matched group is not for containing the identical enteric-soluble controlled-release capsule of lepirudin 023 ludon.Oral sustained release capsule HV1 and HV2-K47 are respectively 100,250,3 dosage groups of 500ATU/kg.
Fasting is 12 hours before the rabbit experiment, can't help water.By 1 hour anesthesia rabbit behind the above dosed administration, separate local jugular vein, to insert the long cotton thread of 3cm, and close with vascular clamp folder with well at this section venous distal end and proximal part, the vascular clamp of removing two ends after 30 minutes is to recover blood flow.Take out the cotton thread of having thrombosis from intravenous after 90 minutes, 80 ℃ of heating oven dry in 1 hour is also weighed.Calculate the thrombosis suppression ratio, the result is as follows:
The recombinant hirudin oral enteric soluble slowly-releasing capsule is to the thrombotic influence of new zealand rabbit jugular vein
| Group | Dosage (ATU/kg) | Thrombus weight (mg) | Thrombosis suppression ratio (%) |
| Matched group slow releasing capsule HV1 HV2-K47 | 0 100 250 500 100 250 500 | 34.5 28.4 17.7 7.8 27.5 15.9 8.5 | - 17.7 48.7 77.4 20.3 44.0 75.4 |
Five. the recombinant hirudin oral enteric soluble slowly-releasing capsule is to the anticoagulation of rat.
50 of rats, body weight 150-200 gram is divided into 8 groups at random, and matched group is not for containing the same enteric-soluble controlled-release capsule of lepirudin 023 ludon, and experimental group is that lepirudin 023 ludon HV1 and each three dosage group of HV2-K47 are distinguished 100ATU/kg, 250ATU/kg, 500ATU/kg.Oral administration gavage secondary every day, successive administration three days.Before administration, measured ATPP value in the serum after the administration after 3 days and the drug withdrawal in 1 day.
The recombinant hirudin oral enteric soluble slowly-releasing capsule is to the influence of rat coagulation function
| The APTT value | ||||||
| Group | Dosage (ATU/kg) | 0 day | After the administration 3 days | Increase (%) | After the drug withdrawal 1 day | Increase (%) |
| Matched group slow releasing capsule HV1 HV2-K47 | 0 100 250 500 100 250 500 | 18.7 | 17.8 24.1 31.8 38.2 24.9 35.2 41.3 | 35.4 78.6 114.6 39.9 97.2 132.0 | 18.2 20.1 25.3 30.1 20.9 26.2 30.9 | 10.4 39.0 65.3 14.8 43.9 69.8 |
Above experimental result proves to behind the rat oral enteric soluble slowly-releasing lepirudin 023 ludon capsule coagulation function being significantly improved.Wherein lepirudin 023 ludon HV1 is consistent to the prolongation effect of APTT with HV2-K47.
Claims (3)
1, a kind of oral enteric soluble slowly-releasing preparation that contains lepirudin 023 ludon is characterized by wherein and contains:
Lepirudin 023 ludon 1 mass parts, human albumin 2-5 mass parts, aprotinin 0.2-1.0 mass parts.
2, recombinant hirudin oral enteric soluble slowly-releasing preparation as claimed in claim 1 is characterized by wherein and contains:
Lepirudin 023 ludon 1 mass parts, human albumin's 2.5 mass parts, aprotinin 0.5 mass parts, mannitol 20 mass parts.
3, recombinant hirudin oral enteric soluble slowly-releasing preparation as claimed in claim 1 or 2 is characterized by the medicinal dosage form adjuvant of adding and makes enteric soluble coating slow releasing sheet or capsule.
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| CN100502941C (en) * | 2005-12-02 | 2009-06-24 | 南京中医药大学 | Hirudin dry powder inhalant and preparing method |
| CN102283818A (en) * | 2010-06-20 | 2011-12-21 | 段明华 | Orally-administrated enteric capsule with polypeptide and protein medicaments and preparation method thereof |
| WO2013175494A2 (en) * | 2012-04-10 | 2013-11-28 | Rubicon Research Private Limited | Controlled release pharmaceutical formulations of direct thrombin inhibitors |
| CN107098964A (en) * | 2017-05-19 | 2017-08-29 | 何向锋 | A kind of tumour-specific lepirudin 023 ludon and its production and use |
| CN108815514B (en) * | 2018-07-11 | 2022-07-08 | 浙江工业大学 | A hirudin tannate tablet and its preparation method |
| CN110639003A (en) * | 2019-09-30 | 2020-01-03 | 张继光 | Sublingual thrombolytic peptide and processing method thereof |
| CN112915106A (en) * | 2021-02-05 | 2021-06-08 | 张虎山 | Preparation and application of tumor immune microenvironment regulator |
| CN113817048B (en) * | 2021-08-16 | 2023-06-16 | 华南理工大学 | Anticoagulation titanium-based material and construction method thereof |
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