CN1879610A - Method for preparing oral administered sustained-release peptide micro capsule - Google Patents
Method for preparing oral administered sustained-release peptide micro capsule Download PDFInfo
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- CN1879610A CN1879610A CN 200610009893 CN200610009893A CN1879610A CN 1879610 A CN1879610 A CN 1879610A CN 200610009893 CN200610009893 CN 200610009893 CN 200610009893 A CN200610009893 A CN 200610009893A CN 1879610 A CN1879610 A CN 1879610A
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Abstract
The invention relates to a method for using template nanometer self-assemble technique to prepare polypeptide oral microcapsule, which comprises: using polypeptide grain as template grain; using two biological compatible macromolecules with reversed charges as wall material; based on mutual attraction between different charges, combining the macromolecule materials from layer to layer, to form thin protective film on the surface of polypeptide grain, to obtain the polypeptide microcapsule. The invention is stable in acid medium, but releases polypeptide medicine in neutral medium, to keep the function of polypeptide grain in oral. And the polypeptide microcapsule can be dispersed into water or other liquid to form variable micro nanometer polypeptide oral liquid; or mixing the micrometer or sub-micron polypeptide microcapsule to form sheets, ejections, etc.
Description
Technical field:
The invention belongs to the new medicinal preparation field, relate to a kind of preparation method of oral administered sustained-release peptide micro capsule.
Background technology:
The high value biochemical drug of polypeptide class is compared with chemical synthetic drug, has advantages such as side effect is little, consumption is few, good effect, is subjected to doctor and patient's popular welcome.Along with the development of technique for gene engineering, a lot of polypeptide drugs such as insulin, interferon can effectively have been developed by gene recombination technology, therefore have vast potential for future development.
Current society, the overweight people increases, and because of people lack the aging trend of motion and population, the sickness rate of diabetes is sharply risen, and diabetes have become " No. three killer " who threatens the mankind continue cardiovascular and cerebrovascular disease and tumor after in the world.Show according to nearest Epidemiological study, the onset diabetes rate of China by 0.67% before 15 years rise in recent years 3.21%, wherein the type ii diabetes patient accounts for more than 95% of sum, China diabetes patient surpasses 4,000 ten thousand at present.According to another the prediction of WHO latest data, will have 2.4 hundred million diabeticss to the whole world in 2010.
Insulin be clinical practice for many years, one of determined curative effect, potent antidiabetic medicine.Yet, because insulin is polypeptide drugs, decomposed by pepsin easily and lose drug effect, so injection becomes unique route of administration of clinical practice.Because this class drug half-life is short, must long-term frequent injection, not only expense height, trouble are big, and the injection site can cause scleroma and lipoatrophy, cause great misery and stress to the patient.Therefore, the non-injection administration approach of polypeptide drugs such as development insulin is current the world of medicine Focal Point of Common Attention, and wherein, oral administration forms the developing direction of attaching most importance to because of convenient, safety.If insulin can be realized oralization, will be a quantum jump for the treatment of diabetes!
Though the non-injection administration research to polypeptide drugs has obtained some progress in recent years, the difficulty that faces is still a lot, and the mucosa transmission of nearly all polypeptide drugs all needs the very strong penetration enhancer of stimulation.Using microparticulate systems sustained release polypeptide drugs is one of directions in the present polypeptide slow release research.The main difficult point of this respect research has: (1) improves the microgranule preparation method, improves yield; (2) stability problem of polypeptide in the solution microgranule preparation process; (3) improve the medicine carrying capacity; (4) reduce initial burst release rate, obtain medicine and discharge continuously.Therefore, an urgent demand exploitation can either keep pharmaceutically active can realize the new drug carrier of its sustained release again.Simultaneously, it is serious that domestic pharmaceuticals industry is impacted by foreign products, and the novel form of therefore developing the ripe medicine with independent intellectual property right is imperative.
Summary of the invention:
The objective of the invention is at polypeptide drugs easily be destroyed when oral by pepsin, and the mucosa transmission need be used the strong shortcomings such as penetration enhancer of stimulation, provide a kind of polypeptide drugs such as insulin that can prevent to be destroyed, make it steady release, bioavailability height, can keep the oral polypeptide drugs microcapsule of its effect fully by digestive enzyme, thereby thoroughly remove the misery of patient, and provide convenience for patient's medication from injection injection.It is achieved in that with the polypeptide drugs microgranule be template particles; biocompatibility macromolecule with two kinds of oppositely chargeds is the wall material; the principle that attracts each other according to the xenogenesis electric charge; these two kinds of macromolecular material one decks are combined with being close to one deck; at the surface of polypeptide drugs microgranule formation protectiveness adventitia as thin as a wafer, thereby obtain the polypeptide drugs microcapsule.This microcapsule is very stable in acid medium, but can discharge polypeptide drugs gradually in neutral medium, thereby can intactly keep the effect of polypeptide drugs when oral.The polypeptide drugs microcapsule is scattered in constitutes polytype micro-nano polypeptide drugs oral liquid in aqueous or the non-aqueous liquid solution, micron order or submicron order polypeptide drugs microcapsule are mixed with adjuvant, can constitute polypeptide drugs capsule, tablet, spray etc.
Method of the present invention has the following advantages:
(1) absorption of intestinal location and intestinal location absorb;
(2) the high envelop rate of polypeptide drugs and high carrying drug ratio;
(3) drug releasing rate can be by the THICKNESS CONTROL of cyst wall;
(4) technology of the present invention is simple, and the reaction condition gentleness is easy to operate, favorable reproducibility, and environmental friendliness for the development of the peroral dosage form of pharmaceutical grade protein provides material base and technical guarantee, has a good application prospect.
Description of drawings:
Fig. 1 has coated the Laser Scanning Confocal Microscope transmission picture of 3 high molecular insulin microparticles of bilayer.
Laser Scanning Confocal Microscope transmission picture after Fig. 2 insulin discharges by 3 molecular hollow microcapsules of double-deck high score
Fig. 3 macromolecule number of plies and pH value are to the influence of insulin rate of release: a) insulin microparticles is in phosphate buffered solution (pH7.4), b) coated 1 high molecular insulin microparticles of bilayer in phosphate buffered solution (pH7.4), c) 2 high molecular insulin microparticles of bilayer have been coated in phosphate buffered solution (pH7.4), d) coat 3 high molecular insulin microparticles of bilayer in phosphate buffered solution (pH7.4), e) coated 2 high molecular insulin microparticles of bilayer (pH1.7) in HCl solution.
Blood glucose situation over time after the administration of table 1 diabetes model rat oral gavage: irritate the insulin PBS solution that stomach gives 100IU/kg for the 1st group, irritate insulin capsule [adopting 3 the double-deck macromolecules coating insulin microparticles] suspension that stomach gives 25IU/kg for the 2nd group.
The specific embodiment:
The specific embodiment one: present embodiment is achieved in that
(a) the polypeptide drugs microgranule is placed the saline solution (pH value is between 1～6) of the 0.01-10M of the polyanion that contains 0.01～100mg/ml adsorbed 0.1-100 minute;
(b) centrifugal or remove by filter the polyanion that is not adsorbed, with saline solution (pH value is between 1～6) repeated washing of 0.01-10M for several times, washed 0.1-100 minute at every turn;
(c) again the microgranule that makes is placed the saline solution (pH value is between 1～6) of the 0.01-10M of the polycation that contains 0.01-100mg/ml to adsorb 0.1-100 minute;
(d) centrifugal or remove by filter the polycation that is not adsorbed, with saline solution (pH value is between 1～6) repeated washing of 0.01-10M for several times, washed 0.1-100 minute at every turn;
(e) repeating step (a) promptly obtains having assembled the high molecular polypeptide drugs microcapsule of the different numbers of plies to (d) successively.
In the present embodiment, inorganic salt can be selected sodium chloride, ammonium chloride, ammonium sulfate, potassium sulfate, sodium sulfate, potassium chloride, sodium phosphate, potassium phosphate or other strong electrolyte for use.
In the present embodiment, organic solvent can be selected ethanol, methanol, acetone or other micromolecular polar organic solvent for use.
In the present embodiment, polyanion can be selected one or more the mixture in seaweeds sodium, dextran sulfate, heparin, heparin sulfate, polyglutamic acid, sodium carboxymethyl cellulose, polyanion cellulose, kayexalate, chondroitin sulfate, sodium polyacrylate, hyaluronic acid, polymethylacrylic acid or other the electronegative macromolecular material for use.
In the present embodiment, polycation can be selected one or more the mixture in chitosan, protamine, poly arginine, polyene propyl ammonium hydrochlorate, polydiene propyl group diformazan quaternary ammonium salt, collagen, poly-D-lysine, cation dextran, diphenylamines-4-diazo resin, substituted diphenylamine diazo resin or other the positively charged macromolecular material for use.
In the present embodiment, polypeptide drugs can be glucoseoxidase, blood coagulation factor VIII, Neurohypophysin, oxytocin, vasopressin, melanotropin, thymosin, thymosin, thymopoietin, thyroliberin, trypsin inhibitor, gonadotrophin chorionic, protamine, human gamma globulin (HGG), albumin, gastric Mucin, epidermal growth factor, erythropoietin, interleukin II and various cytokine class medicines etc. such as insulin, interferon, hirudin, calcitonin, growth hormone, ring spore bacterium (cyclic peptide), erythropoietin.
In the present embodiment, the polymer number of plies can be 1～50 layer.
The specific embodiment two: present embodiment is achieved in that
(a) insulin microparticles is placed the kayexalate solution (0.001～100mM hydrochloric acid solution contains the inorganic salt of 0.01-10M) that contains 0.01-100mg/ml adsorbed 0.1-100 minute;
(b) the centrifugal kayexalate that is not adsorbed of removing, the 0.001～100mM hydrochloric acid solution repeated washing several with the inorganic salt that contains 0.01-10M washed 0.1-100 minute at every turn;
(c) again the microgranule that makes is placed the polyene propyl ammonium hydrochlorate solution (0.001～100mM hydrochloric acid solution contains the inorganic salt of 0.01-10M) that contains 0.01-100mg/ml to adsorb 0.1-100 minute;
(d) the centrifugal polyene propyl ammonium hydrochlorate that is not adsorbed of removing, the 0.001～100mM hydrochloric acid solution repeated washing several with the inorganic salt that contains 0.01-10M washed 0.1-100 minute at every turn;
(e) repeating step (a) obtains to have assembled the high molecular insulin capsule of the different numbers of plies to (d) successively.
In the present embodiment step a), the concentration concentration of kayexalate solution is preferably 1mg/ml.
In the present embodiment step b), cleaning mixture is preferably the hydrochloric acid solution of sodium chloride-containing.
In the present embodiment step c), the concentration concentration of polyene propyl ammonium hydrochlorate solution is preferably 1mg/ml.
In the present embodiment step d), cleaning mixture is preferably the hydrochloric acid solution of sodium chloride-containing.
Studies show that the insulin microparticles in the microcapsule of sd so is very stable in the scope of pH value from 1.7 to 5, sees Fig. 1 and Fig. 3.Insulin begins slow release when pH value surpasses 5, and the speed that insulin discharges when pH value is increased to 8 is accelerated greatly.This be because, when pH value was higher than 5, insulin had negative electricity, getting in touch of the electronegative kayexalate polymer of it and capsule ground floor is destroyed.This just high molecule microcapsule provides probability to the dependence of pH value for development oral insulin capsule medicament.When insulin discharges totally, stay the macromolecule ghost, see Fig. 2, illustrated that effectively insulin microparticles can adopt the nanometer layer-by-layer to coat with the polyelectrolyte of oppositely charged.
By the macromolecule number of plies (wall thickness) regulating medicine rate of release easily, along with the macromolecule number of plies increases, drug releasing rate reduces, and sees Fig. 3.This microcapsule biggest advantage is: cyst wall is extremely thin, less than 20 nanometers, only accounts for about 5% of microcapsule gross mass.Therefore, struck capacity is quite big.
The foundation of diabetes rat model, get the SD rat, after the fasting 12 hours, subcutaneous injection alloxan solution 160mg/kg, the normal raising after 3 days from eyeground vein clump blood sampling 0.1ml, centrifugal, get serum, press the determination of glucose oxidase blood glucose value, blood glucose value reaches the above person of 16.65mmol/L and is the diabetes model rat.
With the fasting of diabetes model rat after 12 hours, be divided into 2 groups at random, every group of 6 rats, irritate the insulin phosphate buffered solution that stomach gives 100IU/kg for the 1st group, irritate insulin capsule [adopting 3 double-deck macromolecules the to coat insulin microparticles] suspension that stomach gives 25IU/kg for the 2nd group, carried out eyeground vein clump blood sampling 0.1ml respectively at 0,0.5,1,2,4,8,12,16,20,24 hour, centrifugal, get 20 μ l serum, adopt the determination of glucose oxidase blood glucose value, be 100% with zero the time, calculate the percentage rate of each time point blood glucose.
The result shows that after the administration of diabetes model rat oral gavage, the insulin capsule suspension has hypoglycemic activity preferably.Behind diabetes model rat oral administration, maximum blood glucose decline percentage rate is 39.22%, and blood glucose decline percentage rate is kept and reached 24h more than 28.17%.Then do not have the obvious functions of blood sugar effect for insulin solutions for the diabetes model rat oral gavage, see Table 1.In gastric juice, when the pH value of solution is an acid-base value when being 1.7 to 5, this high molecule microcapsule can protect insulin can not destroyed by low pH value and digestive enzyme.And when insulin capsule process stomach, when arriving small intestinal and ileum, pH value herein is between 6 to 8, chemical reaction and breaking gradually can take place in capsule wall, and insulin here is released, and the goldbeater's skin by as thin as a wafer enters blood, absorbed by health, begin to regulate the carbohydrate metabolism of body.Because selected polymer composite has bioadhesive, the energy prolong drug is in the holdup time of absorption site, can also increase the permeability of hydrophilic macromole cell bypass by interacting simultaneously with electronegative cell membrane, therefore can promote the absorption of hydrophilic macromolecular drug, improve the oral drugs bioavailability.Thisly wrapped up the microcapsule that polypeptide drugs make with macromolecule and make the polypeptide drugs not to be absorbed by the body at once, can only wait slowly dissolved in human body, the degraded of macromolecule, the macromolecule cyst membrane slowly breaks, and medicine slowly is released, thereby reaches the purpose of slow release.Being used to make capsular two kinds of natural polymers can both be decomposed by enzyme after the task of finishing the transportation insulin and excrete, to health without any side effect.Therefore, replacing penetration enhancer with microcapsule is very promising oral administration method.
Table 1
| Time (hour) | The 1st group | The 2nd group |
| 0 0.5 1 2 4 8 12 16 20 24 | 100 101.41±6.24 100.15±4.18 99.94±10.37 103.89±9.29 104.63±8.25 100.48±5.21 102.51±3.44 103.81±4.20 101.36±1.94 | 100 61.42±6.24 60.78±7.33 68.64±16.88 65.44±6.78 64.76±13.65 69.68±9.55 69.23±10.46 70.10±6.29 71.83±6.29 |
Claims (7)
1, the preparation method of oral administered sustained-release peptide micro capsule is characterized in that it is achieved in that
1) polypeptide particle is placed the saliniferous acid solution of 0.01-10M (pH value is between 1～6) of the polyanion that contains 0.01-100mg/ml adsorbed 0.1-100 minute;
2) centrifugal or remove by filter the polyanion that is not adsorbed, with saline solution (pH value is between 1～6) repeated washing of 0.01-10M for several times, washed 0.1-100 minute at every turn;
3) polypeptide particle is placed the saliniferous acid solution of 0.01-10M (pH value is between 1～6) of the polycation that contains 0.01-100mg/ml adsorbed 0.1-100 minute;
4) centrifugal or remove by filter the polycation that is not adsorbed, with the saliniferous acid solution of 0.01-10M (pH value is between 1～6) repeated washing for several times, washed 0.1-100 minute at every turn;
5) repeating step 1 successively) to 4), obtain to have assembled the polypeptide drugs microcapsule of the different macromolecule numbers of plies.
2, the preparation method of oral administered sustained-release peptide micro capsule according to claim 1 is characterized in that described inorganic salt is sodium chloride, ammonium chloride, ammonium sulfate, potassium chloride, sodium phosphate, potassium phosphate, potassium sulfate, sodium sulfate or other strong electrolyte.
3, the preparation method of oral administered sustained-release peptide micro capsule according to claim 1 is characterized in that described organic solvent is ethanol, methanol, acetone or other micromolecular polar organic solvent.
4, the preparation method of oral administered sustained-release peptide micro capsule according to claim 1 is characterized in that described polyanion is one or more the mixture in kayexalate, sodium polyacrylate, heparin, seaweeds sodium, dextran sulfate, heparin sulfate, polyglutamic acid, sodium carboxymethyl cellulose, polyanion cellulose, chondroitin sulfate, hyaluronic acid, polymethylacrylic acid or other polyanion electrolyte.
5, the preparation method of oral administered sustained-release peptide micro capsule according to claim 1 is characterized in that described polycation is a kind of several mixture in polyene propyl ammonium hydrochlorate, polydiene propyl group diformazan quaternary ammonium salt, chitosan, protamine, poly arginine, collagen, poly-D-lysine, cation dextran, diphenylamines-4-diazo resin, substituted diphenylamine diazo resin or other polycation electrolyte.
6, the preparation method of oral administered sustained-release peptide micro capsule according to claim 1 is characterized in that described polypeptide drugs are insulins, interferon, hirudin, calcitonin, growth hormone, ring spore bacterium (cyclic peptide), glucoseoxidases such as erythropoietin, blood coagulation factor VIII, Neurohypophysin, official's element contracts, vasopressin, melanotropin, thymosin, thymosin, thymopoietin, thyroliberin, trypsin inhibitor, gonadotrophin chorionic, protamine, human gamma globulin (HGG), albumin, gastric Mucin, epidermal growth factor, erythropoietin, interleukin II and various cytokine class medicines etc.
7, the preparation method of oral administered sustained-release peptide micro capsule according to claim 1 is characterized in that the described polymer number of plies is 1～50 layer.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102813937A (en) * | 2012-06-12 | 2012-12-12 | 天津大学 | Hydrophobic drug containing polyelectrolyte complex, its preparation method and application thereof |
| CN103006714A (en) * | 2013-01-06 | 2013-04-03 | 福建广生堂药业股份有限公司 | Red nocardia rubra cell wall skeleton (N-CWS) sustained release preparation and preparation method of same |
| CN103656623A (en) * | 2013-12-06 | 2014-03-26 | 南通大学 | Nanoparticles loaded with neurotrophic factors, and preparation and applications thereof |
| CN105032309A (en) * | 2015-07-08 | 2015-11-11 | 北京理工大学 | Microcapsule and preparation method therefor |
| CN105617362A (en) * | 2014-10-27 | 2016-06-01 | 中国医学科学院药物研究所 | Novel insulin-phospholipid-chitosan self-assembled microparticle carrier and preparation thereof |
| CN105727260A (en) * | 2016-02-03 | 2016-07-06 | 华侨大学 | Long-acting preparation of follicle-stimulating hormone |
| WO2016159267A1 (en) * | 2015-03-31 | 2016-10-06 | アステラス製薬株式会社 | Medicinal composition containing mirabegron |
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2006
- 2006-04-03 CN CN 200610009893 patent/CN1879610A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813937A (en) * | 2012-06-12 | 2012-12-12 | 天津大学 | Hydrophobic drug containing polyelectrolyte complex, its preparation method and application thereof |
| CN103006714A (en) * | 2013-01-06 | 2013-04-03 | 福建广生堂药业股份有限公司 | Red nocardia rubra cell wall skeleton (N-CWS) sustained release preparation and preparation method of same |
| CN103656623A (en) * | 2013-12-06 | 2014-03-26 | 南通大学 | Nanoparticles loaded with neurotrophic factors, and preparation and applications thereof |
| CN103656623B (en) * | 2013-12-06 | 2015-04-15 | 南通大学 | Nanoparticles loaded with neurotrophic factors, and preparation and applications thereof |
| CN105617362A (en) * | 2014-10-27 | 2016-06-01 | 中国医学科学院药物研究所 | Novel insulin-phospholipid-chitosan self-assembled microparticle carrier and preparation thereof |
| CN105617362B (en) * | 2014-10-27 | 2021-05-11 | 中国医学科学院药物研究所 | Novel insulin-phospholipid-chitosan self-assembled particle carrier and preparation thereof |
| WO2016159267A1 (en) * | 2015-03-31 | 2016-10-06 | アステラス製薬株式会社 | Medicinal composition containing mirabegron |
| US10058536B2 (en) | 2015-03-31 | 2018-08-28 | Astellas Pharma Inc. | Pharmaceutical composition containing mirabegron |
| CN105032309A (en) * | 2015-07-08 | 2015-11-11 | 北京理工大学 | Microcapsule and preparation method therefor |
| CN105727260A (en) * | 2016-02-03 | 2016-07-06 | 华侨大学 | Long-acting preparation of follicle-stimulating hormone |
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