CN103784400A - Novel oral micelle preparation of pegylated phosphatide-entrapped insulin - Google Patents
Novel oral micelle preparation of pegylated phosphatide-entrapped insulin Download PDFInfo
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Abstract
本发明提供了一种可供口服的胰岛素纳米胶束制剂，其含有治疗有效量的胰岛素、聚乙二醇化磷脂、以及药学上可接受的辅剂。该胰岛素胶束制剂采用一步自组装方法制备，可形成粒径非常均一的粒子，对胰岛素的包封率可达99.0％以上。在该胶束制剂中，聚乙二醇长链可以分布于包载药物的疏水核的表面形成亲水性保护膜，有利于克服消化道系统中存在粘液层屏障、酶屏障及上皮屏障，保护胰岛素顺利进入血液循环系统发挥降血糖活性。
The invention provides an oral insulin nano-micelle preparation, which contains therapeutically effective doses of insulin, pegylated phospholipids, and pharmaceutically acceptable adjuvants. The insulin micelle preparation is prepared by a one-step self-assembly method, can form particles with a very uniform particle size, and has an encapsulation efficiency of more than 99.0% for insulin. In the micellar preparation, the long chains of polyethylene glycol can be distributed on the surface of the hydrophobic core loaded with drugs to form a hydrophilic protective film, which is beneficial to overcome the mucus layer barrier, enzyme barrier and epithelial barrier in the digestive tract system, and protect the Insulin smoothly enters the blood circulation system to exert hypoglycemic activity.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of for oral insulin micellar preparation and preparation method thereof.
Background technology
Insulin (Insulin, INS), due to its unique blood sugar lowering curative effect, is insulin-dependent diabetes patient's drug of first choice up to now.At present, nearly all insulin preparation all passes through drug administration by injection.This not only brings very large financial burden to patient, affected patient and family members' thereof quality of life, simultaneously frequent long-term injecting drug use also can produce many untoward reaction as insulin edema, hypoglycemic reaction, hypertrophy lipodystrophy and lipoatrophy etc.
Oral administration is prevailing a kind of administering mode, it is the one of the most easily being accepted by patient in numerous route of administration, for the patient who particularly needs long-term or frequent medication for those, this administering mode of drug oral is greatly better than other administration route aspect compliance.The oral administration route of insulin can be simulated physiological insulin secretion, rebuild portal vein insulin concentration and the peripheral circulation insulin concentration ratio of approximate 1: 5 under physiological status, therefore, oral delivery system is the optimal Non-parenteral Delivery Routes of insulin, avoided injection pain and inconvenience, patient's compliance is strong.The key issue that oral insulin induction system will solve is to improve its bioavailability, makes it reach effective blood drug level.
Medicine carrying system of polymer micelle receives increasing concern with advantages such as its stable in properties, biocompatibility and lyotropy, is a study hotspot of pharmaceutical field in recent years.At present, the research of polymer micelle preparation concentrates on drug administration by injection mostly.Micellar preparation particle diameter is little, stable in properties, preparation method are simple, and the medicine that its bag is carried has the advantages such as protective effect, people's its carrier as oral administration that begins one's study.Polymer micelle is developed as to oral administration system and contributes to reduce medicine to gastrointestinal zest, increase the drug level of absorption site, improve the stability of medicine in gastrointestinal tract, and then improve drug bioavailability.
Polymer micelle is the thermodynamic stable system of amphipathic nature polyalcohol spontaneous formation in aqueous solution.This process is to be reduced and promoted by the free energy that hydrophobic fragment is withdrawn from from aqueous solution and polymerization causes.Compared with low-molecular-weight surfactant, the CMC of amphipathic nature polyalcohol is low, and this makes polymer micelle more can resist to a certain extent the dilution of solution, meanwhile, the hydrophobic fragment of composition micelle core is in conjunction with tight, after being diluted by Dali body fluid in physiological environment, be not easy to dissociate, stability is better.Micelle has unique advantage as pharmaceutical carrier: be positioned at the hydrophobicity fragment of micelle nuclear location as the bank of fat-soluble medicine, can combine with medicine by effect chemistry, physics or electrostatic force, and then play and improve the dissolubility of fat-soluble medicine in body fluid, avoid its inactivation in biotic environment, change its absorption behavior in vivo.
Amphipathic nature polyalcohol is at least that the hydrophilic fragment of this base polymer is mostly selected Polyethylene Glycol (polyethylene glycol, PEG) at present by hydrophilic and lipophilic high molecular polymer dimerous.PEG water solublity is good, has high degree of hydration characteristic, for micelle provides enough sterically hindered.In addition, its biocompatibility is good, and has authenticated by FDA, therefore extensively uses as pharmaceutic adjuvant.
Summary of the invention
Inventive concept of the present invention: the micelle administration system of preparing based on Pegylation phospholipid not only has advantages of general nanoparticle to wanting system: particle diameter is little, substantially between 10nm～1000nm, it is a kind of system of dynamic stabilization, on the one hand avoid such as liposome of other particulate delivery systems, be easy to assemble agglomerating shortcoming; More can improve on the other hand drug distribution, improve curative effect of medication.Adopt Pegylation phospholipid as carrier material, PEG chain can form hydrophilic protective layer on the surface of particle, can further bring into play the advantage of micelle administration system.At present, the micelle of preparing about Pegylation phospholipid all there is not yet report both at home and abroad as the oral delivery systematic research of insulin.On the one hand; micelle prepared by Pegylation phospholipid can improve the dissolubility of insulin medicament, and on the other hand, the water solublity fragment of micelle can protect medicine to avoid the destruction of enzyme in gastric acid and digestive tract; and then the oral administration biaavailability of raising insulin, be a kind of desirable oral administration carrier.
The object of the present invention is to provide a kind of for oral insulin micellar preparation.After oral administration, can protect insulin rapidly through intestinal rete malpighii, reduce the degraded of digestive tract proteolytic enzyme, overcome epithelium barrier, enter blood circulation, play hypoglycemic effect.
Therefore, the invention provides a kind of for oral insulin micellar preparation, it contains insulin, Pegylation phospholipid and the pharmaceutically acceptable adjuvant for the treatment of effective dose, is describedly preferably enteric coated preparation, more preferably enteric coated capsule preparation for oral insulin micellar preparation.
Another object of the present invention is to provide can be for the preparation method of oral insulin micellar preparation.
The Pegylation phospholipid that to the effect that utilizes of the present invention, as major auxiliary burden, adopts suitable preparation means to prepare oral insulin micellar preparation.
Pegylation phospholipid in insulin micellar preparation of the present invention; be conducive to insulin molecule rapidly through intestinal rete malpighii; minimizing insulin molecule contacts with proteolytic enzyme in digestive tract, and protection insulin molecule enters blood circulation smoothly, plays hypoglycemic activity.
Detailed Description Of The Invention
The invention provides a kind of oral insulin micellar preparation that supplies, it contains insulin, Pegylation phospholipid and the pharmaceutically acceptable adjuvant for the treatment of effective dose.
The insulin micelle the present invention relates to can be solution form as required, can be also lyophilized form.
According to the present invention, the mol ratio of described insulin and Pegylation phospholipid is 1: 2 to 1: 20, preferably 1: 4 to 1: 10.
Pegylation phospholipid of the present invention is that peg molecule is combined into by the nitrogenous base on covalent bond and phospholipid molecule.
For Pegylation phospholipid of the present invention, the carbon number that in its structure, the fatty acid of phospholipid moiety comprises is 10～24, preferably 12,14,16,18,20,22,24 carbon atoms, fatty acid chain can be saturated, also can be fractional saturation, fatty acid be of particular note lauric acid (12 carbon), myristic acid (14 carbon), Palmic acid (16 carbon), stearic acid or oleic acid or linoleic acid (18 carbon), twenty acid (20 carbon), mountain Yu's acid (22 carbon), lignoceric acid (24 carbon).
Pegylation phospholipid, its phospholipid moiety can be phosphatidyl ethanolamine (PE), phosphatidylcholine (PC), phosphatidylinositols (PI), phosphatidyl silk amino acid (PS) diphosphatidylglycerol, the sour phospholipid that contracts, lysophosphatidylcholine (LPC), haemolysis sphingomylin (LPE) etc.
Pegylation phospholipid, its molecular weight polyethylene glycol scope is 500～20000 dalton, preferably molecular weight polyethylene glycol scope is 1000～10000 dalton, preferred scope 1000～5000 dalton, and most preferred molecular weight polyethylene glycol is 2000 dalton.
Pegylation phospholipid of the present invention is PEG4000-DSPE (PEG2000-DSPE) preferably.
In insulin micellar preparation of the present invention, the particle size range of micelle is 5-100nm, preferably 10-50nm, most preferably 10-20nm.
Insulin micellar preparation of the present invention, is to adopt Pegylation phospholipid as carrier, by certain preparation means, the insulin of therapeutic dose is wrapped in formed micelle, does not add any short absorbent, enzyme inhibitor etc. in preparation.
The present invention also provides the preparation method of insulin micellar preparation, comprises insulin is wrapped in the micelle of Pegylation phospholipid formation, is prepared into and can supplies oral insulin micellar preparation.
Specifically comprise the following steps according to the preparation method of insulin micellar preparation of the present invention:
(1) by insulin suspendible or dissolving in pure water or dilute hydrochloric acid solution (pH3.0);
(2) Pegylation phospholipid is dissolved in pure water;
(3) (1) is mixed with (2), aquation 30-60min at 25-60 ℃, optimal conditions is the dynamic assembling process that 50 ℃ of aquation 30min complete insulin and micelle.
According to the present invention, the unit dose of insulin is 50-300IU, preferred unit dosage 100-200IU, and optimum unit dose is 150IU, dosage is adjusted the needs according to each special entity.
Content for a better understanding of the present invention, we are explained as follows some technical terms.
" micelle " refers to when the concentration of amphiphilic in aqueous solution exceedes critical micelle concentration (CMC), and spontaneously polymerization forms micelle.The structure of micelle is different from liposome, does not have the architectural feature of lipid bilayer.In general, the structure of micelle is that hydrophobic part is inside, forms hydrophobic core, and hydrophilic segment outwards forms water-wetted surface.Micelle particle diameter is little, and mean diameter is in 10～20nm left and right.Therefore, it is thermodynamic stable system still not, and is dynamic stabilization system.In addition, micelle granule is difficult for assembling layering, and it is high that bag carries capacity, in the time of low concentration, can wrap and carry higher dose.
" phospholipid ", the molecular structure of phospholipid is similar with fat, and different is on glycerol molecule, to be only connected with two fatty acids, and the 3rd hydroxyl and phosphoric acid are combined into fat.This structure of phospholipid makes it become a kind of amphiphilic, and its phosphoric acid or phosphate ester one end are polarity, and easy and water is inhaled, form the hydrophilic head of phospholipid molecule, and its fatty acid one end is nonpolar, do not inhale with water, form the hydrophobicity afterbody of phospholipid molecule.Phospholipid involved in the present invention is mainly polyglycol derivatization phospholipid.In the present invention, polyglycol derivatization phospholipid also can be used in conjunction with other phospholipid.
" treatment effective dose " refers to that insulin produces the consumption of therapeutic effect.
Advantage of the present invention is: in Pegylation phospholipid is prepared the process of micelle, do not introduce any organic solvent, avoid the deactivation of insulin.Lyophilization step on the biological activity of insulin without impact.The oral administration dosage of insulin micellar preparation is suitable, when normal rat oral administration dosage is 50IU/kg, hyperglycemia reduces percentage rate and reaches more than 20%, has potential applicability in clinical practice widely, the serial side effect that can avoid the long-term drug administration by injection of diabetics to produce.And the preparation method of insulin micelle is simple, without large-scale instrument and equipment, be suitable for commercial production.
Therefore, insulin micellar preparation of the present invention can be used for oral administration.
In conjunction with embodiment, other objects of the present invention and advantage are done to further detailed description, make it more clear.
Accompanying drawing summary
Fig. 1 is the transmission electron microscope photo of insulin micelle;
Fig. 2 is the release graphics of insulin micelle in the dilute hydrochloric acid solution of pH 2.5;
Fig. 3 is the release graphics of insulin micelle in the phosphate buffer of pH 7.4;
Fig. 4 is the form that insulin molecule exists in micellar preparation;
Fig. 5 is the blood sugar level variation diagram after normal rat duodenal administration.
The specific embodiment
Following examples are mainly used for further illustrating the present invention, rather than limit the scope of the invention.
The preparation of embodiment 1 INS-PEG2000-DSPE micellar preparation
Preparation prescription is in table 1.
The encapsulation efficiency of table 1 INS-PEG2000-DSPE micelle
| Lipid/medicine (mol/mol) | Medicine (mg/ml) | Envelop rate (%) |
| 2∶1 | 1 | 70.5 |
| 6∶1 | 1 | 99.2 |
| 10∶1 | 1 | 99.3 |
Preparation technology: by the medicine/fat ratio in above-mentioned prescription, taking insulin (INS) (purchased from Xuzhou Wanbang Jinqiao Pharmaceutical Co., Ltd.) is dissolved in or is suspended in (1mg/ml) in pure water or dilute hydrochloric acid solution, take PEG2000-DSPE (purchased from Lipoid) and be dissolved in (20mg/ml) in pure water, both mix, leave standstill 60min, then aquation 60min at 37 ℃, obtains and can supply oral insulin micellar preparation.Gained sample appearance is the solution of achromatism and clarity, mean diameter 15nm, particle size distribution 10nm-20nm.Above-mentioned micellar solution can be after lyophilization lyophilized powder, its Chinese medicine/fat (insulin/phospholipid) mol ratio is that the transmission electron microscope photo of the micelle prepared for 1: 6 o'clock is shown in Fig. 1.
The preparation of embodiment 2 INS-PEG5000-DSPE micellar preparations
Preparation prescription is in table 2.
The encapsulation efficiency of table 2 INS-PEG5000-DSPE micelle
| Lipid/medicine (mol/mol) | Medicine (mg/ml) | Envelop rate (%) |
| 1∶1 | 1 | 65.1 |
| 4∶1 | 1 | 99.4 |
| 8∶1 | 1 | 99.2 |
Preparation technology: by the medicine fat ratio in above-mentioned prescription, taking INS is dissolved in or is suspended in (1mg/ml) in pure water or dilute hydrochloric acid solution, take PEG5000-DSPE (purchased from Lipoid) and be dissolved in (20mg/ml) in pure water, both mix, leave standstill 40min, then aquation 50min at 45 ℃, obtains and can supply oral insulin micellar preparation.Gained sample appearance is the solution of achromatism and clarity, mean diameter 15nm, particle size distribution 10nm-20nm.Above-mentioned micellar solution can obtain lyophilized powder after lyophilization.
The preparation of embodiment 3INS-PEG10000-DSPE micellar preparation
Preparation prescription is in table 3.
The encapsulation efficiency of table 3INS-PEG10000-DSPE micelle
| Lipid/medicine (mol/mol) | Medicine (mg/ml) | Envelop rate (%) |
| 3∶1 | 1 | 78.1 |
| 8∶1 | 1 | 99.4 |
| 12∶1 | 1 | 99.2 |
Preparation technology: by the medicine fat ratio in above-mentioned prescription, taking INS is dissolved in or is suspended in (1mg/ml) in pure water or dilute hydrochloric acid solution, take PEG10000-DSPE (purchased from Lipoid) and be dissolved in (20mg/ml) in pure water, both mix, leave standstill 40min, then aquation 30min at 55 ℃, obtains and can supply oral insulin micellar preparation.Gained sample appearance is the solution of achromatism and clarity, mean diameter 15nm, particle size distribution 10nm-20nm.Above-mentioned micellar solution can obtain lyophilized powder after lyophilization.
The extracorporeal releasing test of embodiment 4INS-PEG2000-DSPE micelle
The speed that adopts Determination by Stripping INS to discharge from the PEG2000-DSPE micelle (medicine/fat was than 1: 4) of preparing according to the method for above embodiment, HPLC detects.The INS-PEG2000-DSPE micelle 1ml (1mg/ml) preparing is placed in to bag filter (Beijing Bioisystech Co., Ltd of Jing Ke HTC, molecular cut off 14, 000) in, the bag filter of fastening is placed in to medicament dissolution instrument (model ZRS-8G, Radio Factory of Tianjin Univ.) turn in basket, dissolution medium is respectively the dilute hydrochloric acid solution (pH 2.5) and PBS buffer (pH 7.6) of 150ml, each sample is parallel does three, in 37 ℃, 50rpm, respectively at 1, 2, 3, 4h sampling, get 0.2ml dissolution medium at every turn, mend the dissolution medium 0.2ml of fresh 37 ℃.Reference standard curve, tries to achieve release percentage rate.The stripping curve of insulin from micelle is shown in respectively Fig. 2 and Fig. 3.
The existence form of embodiment 5 insulin molecules
The INS-PEG5000-DSPE micellar solution preparing according to the method for above embodiment and the each 1ml of PBS solution (1mg/ml) of insulin are put respectively in the high scheming of analytical type high speed, rotating speed 60000rpm, centrifugal 6h altogether, analysis result shows (Fig. 4): in insulin solutions, insulin molecule mainly exists with dimer and six aggressiveness forms, and insulin molecule mainly exists with single aggressiveness form in insulin micellar solution.
The pharmacological experiment of embodiment 6 insulin micellar preparations
Get 15 of healthy male SD rats (purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.), body weight 180-200g, be divided at random 3 groups, first group gives insulin PBS solution (200IUkg-1), second and third group gives respectively INS-PEG2000-DSPE micelle, and dosage is respectively 50IUkg
-1with 200IUkg
-1.Fasting 16h before experiment, can freely drink water.Lumbar injection pentobarbital sodium anesthetized rat, is fixed on rat abdomen dull and stereotypedly upper subsequently upward, opens abdominal cavity along rat ventrimeson, duodenal administration, and concrete operations are as follows: apart from the about 5cm of pylorus place drug administration by injection.Excessive for fear of solution, should adopt small size syringe needle as far as possible, and along the downward drug administration by injection of intestinal direction.Subsequently rat abdomen is carried out to operation stitching, get blood respectively at 0,1,2,3,4,5,6,7,8, after 10h at rat tail vein, measure blood glucose value (Fig. 5) by blood glucose meter (three promises are stable).As seen from the figure, basically identical before the change of blood sugar of insulin solutions group and administration, the blood sugar level of the insulin micellar preparation group of high and low dose is starkly lower than insulin solutions group, and blood sugar level maintains downward trend in 3-8h, 35% and 23% left and right that floor level is about respectively initial value falls in high and low dose group blood glucose, and blood glucose starts to rise subsequently.Result shows, normal rat duodenum gives, after insulin micellar preparation, have obvious hypoglycemic activity.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105194663A (en) * | 2015-10-19 | 2015-12-30 | 中国科学院生物物理研究所 | Micelle polypeptide vaccine with poly(ethylene glycol)-phosphatidylethanolamine as carrier |
| EP3210621A4 (en) * | 2014-10-22 | 2018-07-11 | The Institute of Biophysics Chinese Academy of Sciences | Micellar polypeptide vaccine having pegylated phospholipids as carrier |
| CN109091459A (en) * | 2018-09-10 | 2018-12-28 | 中国科学院生物物理研究所 | A kind of sorbefacient promoting the oral absorptions of macromolecular drugs such as insulin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101322681A (en) * | 2007-06-13 | 2008-12-17 | 中国科学院生物物理研究所 | A kind of method for preparing the nano micellar preparation of anthracycline antitumor antibiotic |
| CN102093489A (en) * | 2010-12-24 | 2011-06-15 | 中国药科大学 | Amphiphilic N-long chain alkyl-N-arginine chitosan derivative and preparation of derivative micelle |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101322681A (en) * | 2007-06-13 | 2008-12-17 | 中国科学院生物物理研究所 | A kind of method for preparing the nano micellar preparation of anthracycline antitumor antibiotic |
| CN102093489A (en) * | 2010-12-24 | 2011-06-15 | 中国药科大学 | Amphiphilic N-long chain alkyl-N-arginine chitosan derivative and preparation of derivative micelle |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3210621A4 (en) * | 2014-10-22 | 2018-07-11 | The Institute of Biophysics Chinese Academy of Sciences | Micellar polypeptide vaccine having pegylated phospholipids as carrier |
| US10525113B2 (en) | 2014-10-22 | 2020-01-07 | Shanghai Tianhui Chemical Pharmaceutical Co. Ltd | Micellar polypeptide vaccine having pegylated phospholipids as carrier |
| CN105194663A (en) * | 2015-10-19 | 2015-12-30 | 中国科学院生物物理研究所 | Micelle polypeptide vaccine with poly(ethylene glycol)-phosphatidylethanolamine as carrier |
| CN109091459A (en) * | 2018-09-10 | 2018-12-28 | 中国科学院生物物理研究所 | A kind of sorbefacient promoting the oral absorptions of macromolecular drugs such as insulin |
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