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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- CN103784400A CN103784400A CN201210427544.7A CN201210427544A CN103784400A CN 103784400 A CN103784400 A CN 103784400A CN 201210427544 A CN201210427544 A CN 201210427544A CN 103784400 A CN103784400 A CN 103784400A
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Abstract
The invention provides an oral nanometer insulin micelle preparation, comprising a therapeutically effective amount of insulin, pegylated phosphatide and pharmaceutically acceptable adjuvant. The insulin micelle preparation is prepared by using a one-step self-assembly method; particles with a uniform size can be formed, and the entrapment rate of insulin reaches more than 99.0%. In the micelle preparation, polyethylene glycol long chains can be distributed on the surface of a hydrophobic nucleus of an entrapment drug to form a hydrophilic protection film, which is favorable for overcoming a slime layer barrier, an enzyme barrier and an epidermal barrier in an alimentary canal system and protecting smooth entering of insulin into a blood circulation system for performance of 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.
Claims (10)
1. one kind can supply oral insulin micellar preparation, comprise insulin, Pegylation phospholipid, and pharmaceutically acceptable adjuvant, wherein, the mol ratio of described insulin and Pegylation phospholipid is 1: 2 to 1: 20, described Pegylation phospholipid is that peg molecule is combined into by the nitrogenous base on covalent bond and phospholipid molecule, and preferably wherein the mol ratio of insulin and Pegylation phospholipid is 1: 4 to 1: 10.
2. micellar preparation according to claim 1, in wherein said Pegylation phospholipid, the fatty acid of phospholipid moiety comprises 10-24 carbon atom, fatty acid chain is saturated or fractional saturation, preferably lauric acid, myristic acid, Palmic acid, stearic acid, oleic acid, linoleic acid, 20 acid, mountain Yu's acid or lignoceric acid.
3. micellar preparation according to claim 1, the phospholipid in wherein said Pegylation phospholipid is PHOSPHATIDYL ETHANOLAMINE, phosphatidylcholine, phosphatidylinositols, Phosphatidylserine, diphosphatidylglycerol, contracting acid phospholipid, haemolysis cholinphospholipide or haemolysis sphingomylin.
4. micellar preparation according to claim 3, the phospholipid in described Pegylation phospholipid is DSPE, two palmityl phospholipid ethanolamine, DOPE.
5. micellar preparation according to claim 1, the molecular weight polyethylene glycol scope in described Pegylation structure of phospholipid is 500-20000 dalton, is preferably 1000-10000 dalton, more preferably 1000-5000 dalton, most preferably is 2000 dalton.
6. micellar preparation according to claim 5, described Pegylation phospholipid is PEG4000-DSPE.
7. according to the micellar preparation described in claim 1-6 any one, described micellar preparation is solution form or lyophilized form, is preferably enteric coated preparation, more preferably enteric coated capsule preparation.
According to the micellar preparation described in claim 1-7 any one in the application of preparing in oral hypoglycemic thing.
9. a method of preparing micellar preparation described in claim 1-8 any one, comprising: insulin is wrapped in the micelle that Pegylation phospholipid forms, makes and can supply oral insulin micellar preparation.
10. method according to claim 9, comprises the following steps:
(1) by insulin suspendible or dissolving in water or diluted hydrochloric acid aqueous solution (pH 3.0);
(2) Pegylation phospholipid is dissolved in water;
(3) (1) is mixed with (2), aquation 30-60min at 25 ℃-60 ℃, obtains insulin micelle.
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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 |
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| CN101322681A (en) * | 2007-06-13 | 2008-12-17 | 中国科学院生物物理研究所 | Method for preparing nano micelle formulation of anthracene nucleus antineoplastic 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 |
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| CN101322681A (en) * | 2007-06-13 | 2008-12-17 | 中国科学院生物物理研究所 | Method for preparing nano micelle formulation of anthracene nucleus antineoplastic 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 |
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| 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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