CN103371973B - A kind of outer wrapping nanometer emulsion that promotes that oral insulin absorbs - Google Patents
A kind of outer wrapping nanometer emulsion that promotes that oral insulin absorbs Download PDFInfo
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- CN103371973B CN103371973B CN201210129636.7A CN201210129636A CN103371973B CN 103371973 B CN103371973 B CN 103371973B CN 201210129636 A CN201210129636 A CN 201210129636A CN 103371973 B CN103371973 B CN 103371973B
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Abstract
The invention belongs to field of pharmaceutical preparations, relate to a kind of outer wrapping nanometer emulsion that promotes that oral insulin absorbs, relate in particular to a kind of calcium alginate/shitosan outer wrapping nanometer emulsion that can promote oral insulin absorption and preparation method thereof. Nanometer emulsion of the present invention is made up of insulin and pharmaceutic adjuvant; Described insulin is wrapped in the interior water of emulsion, and emulsion surface is by the crosslinked method parcel of shell; In the present invention, insulin is wrapped in nanometer emulsion in water, then with adhesiveness acid-resistant material, nanometer emulsion is wrapped up, can protect the integrality of nanometer emulsion in gastric juice, make insulin can not reveal fast in gastric juice and be degraded by pepsin, and can in animal gastrointestinal tract, adhere to, increase the holdup time of preparation in intestines and stomach, thus the absorption that improves medicine; The outer wrapping nanometer emulsion preparation that promotion oral insulin of the present invention absorbs is simple, can improve oral insulin bioavilability.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of outer wrapping nanometer emulsion that promotes that oral insulin absorbs, especially relate toAnd a kind of calcium alginate/shitosan outer wrapping nanometer emulsion that can promote oral insulin absorption and preparation method thereof.
Background technology
Insulin is as the indispensable medicine of first-selection of type 1 diabetes treatment, clinical always with subcutaneous since nineteen twenty-two comes outInjection administration, general medication every day 3-4 time, long-term prescription often causes patient to suffer untold misery. Also normal appearance in applicationFollowing bad reaction: injection site inflammation, scleroma, allergy and resistance, insulin edema, hypoglycemic reaction, hypertrophyMalnutrition and lipoatrophy etc.; Therefore the insulin preparation of, developing non-injecting pathway is aobvious for the treatment of diabetesObtain extremely important.
Current oral administration is also the safest clinical application approach of most convenient, therefore insulin is developed as to oral administrationForm be current research problem comparatively widely; But studies show that, due to insulin existing problems, as: (1) stomachUnstable in liquid, easily by pepsin fast degradation; (2) be subject to the degraded of the protease in enteron aisle; (3) insulin isHigh molecular weight protein class medicine, permeability of cell membrane is poor, hinders and absorbs etc., causes oral administration biaavailability very low, nothingMethod obtains good result for the treatment of. Improve at present oral insulin absorption and mainly comprise following methods: (1) adopts infiltration shortInto improving to a certain extent its bioavilability with protease inhibitors, but because it exists comparatively serious poisonProperty, its development prospect is still unpredictable; (2) adopting transferrins (Tf), cell-penetrating peptide TAT etc. to modify improves carefullyBorn of the same parents' permeability; (3) oral administration biaavailability that adopts particulate delivery system to improve insulin is that research is at present the most popularAspect, particulate delivery system can protect medicine to avoid the degraded of enzyme to a certain extent, simultaneously can improve medicine at mucous membraneEpithelium see through efficiency, main have nanoparticle, liposome, micro emulsion and an emulsion etc. Wherein, W/O micro emulsion is not only demonstrate,provedThe bright oral administration biaavailability that improves insulin, and also have obvious facilitation for other protein and peptide drugs,But W/O micro emulsion oral enter stomach in after, can be caused the unstable of W/O micro emulsion by a large amount of hydrochloric acid in gastric juice dilutions, a large amount ofInsulin can reveal in outer water, then degraded by pepsin, can not reach and improve the object of bioavilability,Have research to adopt W/O micro emulsion all by duodenum drug administration by injection, in practical clinical, compliance is poor, and itsIn prescription, contain a certain amount of water, cannot address this problem by being packed into capsulae enterosolubilis.
In addition, because insulin is unstable in gastro-intestinal Fluid, be vulnerable to the degradation of various protease in intestines and stomach, andIts cross-film poor ability, so cause its bioavilability very low. And in micro emulsion due to contain a large amount of oily constituents withAnd surfactant, mentioned component all can increase cell membrane fluidity, opens cell tight junction, exists thereby improve medicineThe permeability on enterocyte surface, thereby the absorption that improves medicine; But micro emulsion is unstable in gastric juice, easily there is phase inversionOr breakdown of emulsion, water soluble drug is easy to be leaked in outer water, for insulin, can be degraded by pepsin very soon, because ofAfter this microemulsion oral, can not significantly improve the oral administration biaavailability of insulin. Still there is research to adopt duodenum to be administered toMedicine, this kind of administering mode patient compliance is very poor, and in micro emulsion, has a certain amount of water, also should not pack in capsulae enterosolubilis.
Therefore, at present clinical have good stability under one's belt in the urgent need to one, can bring into play grease constituents simultaneously and increaseAdd cell membrane fluidity, open cell tight junction, promote the approach such as lymph transhipment to increase the medicine of the absorption of medicine.
In the urgent need to a kind of, by the medicine that adopts acid-resistant material that emulsion is wrapped up, this medicine has under one's belt preferablyStability, can bring into play grease constituents simultaneously increases cell membrane fluidity, opens cell tight junction, promotes lymph transhipmentIncrease the absorption of medicine etc. approach.
Summary of the invention
The object of the present invention is to provide and relate to a kind of outer wrapping nanometer emulsion that promotes that oral insulin absorbs, relate in particular toA kind of calcium alginate/shitosan outer wrapping nanometer emulsion that can promote oral insulin absorption and preparation method thereof. This medicineOral administration biaavailability and the effect of wrapping up nanometer emulsion raising insulin by alginate/chitosan can maintain longTime, easy to use, favorable reproducibility, is also suitable for improving the oral absorption of other polypeptide protein class medicines.
The present invention carries out dressing by sodium alginate and shitosan to insulin emulsion, is prepared in vitro emulsion, and passes throughGentle processing condition reduces its particle diameter, after by acid-resistant material, emulsion directly being wrapped up, can make it keep under one's belt steadyFixed, improve the stability of emulsion in intestines and stomach, by entering enteron aisle after stomach, the oily constituents in emulsion and surfaceActivating agent can play the effect that promotes drug absorption, thereby improves the oral administration biaavailability of insulin.
Particularly, the outer wrapping nanometer emulsion that promotion oral insulin of the present invention absorbs, is characterized in that, by pancreas isletElement and pharmaceutic adjuvant composition, insulin is wrapped in the interior water of emulsion, and emulsion surface is by the crosslinked method parcel of shell;
Wherein, insulin is dissolved in emulsion as active component interior mutually in, described emulsion by oil phase, surfactant andWater composition.
In the present invention, described insulin is preferably 0.1-100mg/ml in interior concentration in mutually;
In the present invention, the crosslinked material of described shell comprises sodium alginate, calcium chloride and shitosan; Wherein, sodium alginateWith the ratio of calcium ion be 1: 0.1-5, the ratio of sodium alginate and shitosan is 1: 0.1-5;
In the present invention, described oil phase is the mixture of medium chain, long-chain fat acid glyceride or above-mentioned material, and it is sad to be selected fromOne in/Triglyceride DDD, caprylic/capric monoglyceride, peanut oil, soybean oil, olive oil, corn oil or severalKind.
In the present invention, described surfactant comprises hydrophily and lipophilic emulsifier, lipophilic emulsifier be phosphatide,One or more in Span80, Span60, Span20; Hydrophilic emulsifier is CremophorEL, CremophorOne or more in RH40, Tween80, SolutolHS15, poloxamer188, Poloxamer407.
The preparation method who the invention provides the outer wrapping nanometer emulsion of described promotion oral insulin absorption, it comprises bagDraw together step:
First by after oil phase and fat-soluble surfactant mixed dissolution, under stirring, drip insulin solution,Form colostrum, then this colostrum is joined in the solution that contains hydrophilic surfactant active and sodium alginate, stir systemBecome emulsion; Above-mentioned emulsion reduces its particle diameter by high-pressure homogeneous (60bar), then dropwise adds calcium chloride solution crosslinked,Finally add again chitosan solution further to form fine and close softgel shell, make the outer wrapping nanometer that promotes that oral insulin absorbsEmulsion.
In described preparation method, lipophilic surfactant is selected from one in phosphatide, Span80, Span60, Span20Kind or several, wherein preferred phosphatide and Span80;
In described preparation method, hydrophilic surfactant active be selected from CremophorEL, CremophorRH40,One in Tween80, Tween80, SolutolHS15, poloxamer188, poloxamer407 and several, itsIn preferred CremophorEL.
The present invention has carried out hypoglycemic contrast experiment in vitro stability and body, and experimental result shows, promotion pancreas islet of the present inventionThe outer wrapping nanometer emulsion of element oral absorption, keeps stable, under one's belt by entering enteron aisle after stomach, the grease in emulsionProperty composition and surfactant can play the effect that promotes drug absorption, thereby improve the oral administration biaavailability of insulin.
The outer wrapping nanometer emulsion tool that promotion oral insulin of the present invention absorbs has the following advantages:
Insulin is wrapped in nanometer emulsion in water, then with adhesiveness acid-resistant material by nanometer emulsion parcel, protectionThe integrality of nanometer emulsion in gastric juice, makes insulin can not reveal fast in gastric juice and be degraded by pepsin, and energyIn animal gastrointestinal tract, adhere to, increase the holdup time of preparation in intestines and stomach, thus the absorption that improves medicine; This is oralInsulin medicament composition preparation simple, can improve oral insulin bioavilability.
Brief description of the drawings
Fig. 1 has shown insulin emulsion and the stability of parcel emulsion of the present invention in simulated gastric fluid.
Fig. 2 has shown insulin emulsion and the hypoglycemic effect of parcel emulsion of the present invention in normal rat body.
Fig. 3 has shown insulin emulsion and the hypoglycemic effect of parcel emulsion of the present invention in diabetes rat body.
Detailed description of the invention
Embodiment 1
First prepare colostrum, take 150mg insulin, be settled to 10ml with pH2HCl solution, after dissolving completelyAs interior water; LabrafacCC (caprylic/capric triglyceride) is as oil phase, Span80 and phosphatide 4: 1 in mass ratioMix as emulsifying agent; LabrafacCC is mixed in mass ratio with emulsifying agent at 7: 3, accurately weigh 8gBe placed on magnetic stirring apparatus water 800 μ l in dripping while stirring. Mixing speed is 800rpm, and the time is 15min,Make w/o colostrum; Then take sodium alginate 0.2g, CremophorEL1.8g, add 55ml deionized water,Mix rear as outer water; Take the outer water of 18g and be placed on magnetic stirring apparatus, drip while stirring make at the beginning ofBreast, makes w/o/w emulsion; Adding colostrum amount is 8g, and mixing speed is 600rpm, and the time is 10min. To makeStandby emulsion 80bar pressure, high-pressure homogeneous 40s, obtains nanometer emulsion; Shitosan is molten with 1% acetumSolution is spent the night, for subsequent use after filtering; Get w/o/w emulsion prepared by 12g, under stirring with 600rpm rotating speed, slowly drip0.5ml concentration is 0.1% calcium chloride solution. Continue to stir after 30min, slowly drip concentration and be 0.06% shell poly-Sugar juice, addition is 2ml, continues to stir 1h, must wrap up nanometer emulsion.
Embodiment 2
First prepare colostrum, take 150mg insulin, be settled to 10ml with pH2HCl solution, after dissolving completelyAs interior water; Peanut oil is as oil phase, and Span80 mixes as emulsifying agent in mass ratio with Span20 at 3: 1.Peanut oil is mixed in mass ratio with emulsifying agent at 7: 3, accurately weigh 8g and be placed on magnetic stirring apparatus, while stirringWater 800 μ l in dripping. Mixing speed is 800rpm, and the time is 15min, makes w/o colostrum. Then take marine algaAcid sodium 0.2g, CremophorEL1.8g, add 55ml deionized water, mixes rear as outer water; TakeThe outer water of 18g is placed on magnetic stirring apparatus, drips while stirring the colostrum making, and makes w/o/w emulsion; At the beginning of addingBreast amount is 8g, and mixing speed is 600rpm, and the time is 10min. By the emulsion 80bar pressure of preparation, high pressure is equalMatter 40s, obtains nanometer emulsion. Shitosan is dissolved and spent the night with 1% acetum, for subsequent use after filtering; Get 12g systemStandby w/o/w emulsion, under stirring, slowly drips 0.5ml concentration and is 0.1% calcium chloride solution with 600rpm rotating speed.Continue to stir after 30min, slowly drip concentration and be 0.06% chitosan solution, addition is 2ml, continues to stir 1H, must wrap up nanometer emulsion.
Embodiment 3
First prepare colostrum, take 300mg insulin, be settled to 10ml with pH2HCl solution, after dissolving completelyAs interior water; Soybean oil is as oil phase, and Span80 mixes as emulsifying agent in mass ratio with Span60 at 5: 1;Soybean oil is mixed in mass ratio with emulsifying agent at 7: 3, accurately weigh 8g and be placed on magnetic stirring apparatus, while stirringWater 800 μ l in dripping. Mixing speed is 800rpm, and the time is 15min, makes w/o colostrum; Then take marine algaAcid sodium 0.2g, CremophorRH401.5g, add 55ml deionized water, mixes rear as outer water; ClaimGet the outer water of 18g and be placed on magnetic stirring apparatus, drip while stirring the colostrum making, make w/o/w emulsion; AddEntering colostrum amount is 8g, and mixing speed is 600rpm, and the time is 10min. By the emulsion 80bar pressure of preparation, heightPress homogeneous 40s, obtain nanometer emulsion. Shitosan is dissolved and spent the night with 1% acetum, for subsequent use after filtering; Get 12gThe w/o/w emulsion of preparation, under stirring, slowly drips 0.5ml concentration and is 0.1% calcium chloride molten with 600rpm rotating speedLiquid; Continue to stir after 30min, slowly drip concentration and be 0.06% chitosan solution, addition is 2ml, continues to stirMix 1h, must wrap up nanometer emulsion.
Embodiment 4
First prepare colostrum, take 100mg insulin, be settled to 10ml with pH2HCl solution, after dissolving completelyAs interior water; Corn oil is as oil phase, and Span60 mixes as emulsifying agent in mass ratio with phosphatide at 2: 1; By jadeRice bran oil mixes in mass ratio with emulsifying agent at 7: 3, accurately weighs 8g and is placed on magnetic stirring apparatus, drips while stirringInterior water 800 μ l; Mixing speed is 800rpm, and the time is 15min, makes w/o colostrum; Then take sodium alginate0.2g, Tween802g, add 55ml deionized water, mixes rear as outer water; Take the outer water of 18gBe placed on magnetic stirring apparatus, drip while stirring the colostrum making, make w/o/w emulsion; Adding colostrum amount is 8g,Mixing speed is 600rpm, and the time is 10min. By the emulsion 80bar pressure of preparation, high-pressure homogeneous 40s, to obtain final productNanometer emulsion; Shitosan is dissolved and spent the night with 1% acetum, for subsequent use after filtering; Get w/o/w prepared by 12g multipleBreast, under stirring, slowly drips 0.5ml concentration and is 0.1% calcium chloride solution with 600rpm rotating speed; Continue to stir 30After min, slowly drip concentration and be 0.06% chitosan solution, addition is 2ml, continues to stir 1h, obtains parcelNanometer emulsion.
Embodiment 5
First prepare colostrum, take 150mg insulin, be settled to 10ml with pH2HCl solution, after dissolving completelyAs interior water; Olive oil is as oil phase, and Span20 mixes as emulsifying agent in mass ratio with phosphatide at 2: 1; Will be largeSoya-bean oil mixes in mass ratio with emulsifying agent at 7: 3, accurately weighs 8g and is placed on magnetic stirring apparatus, drips while stirringInterior water 800 μ l; Mixing speed is 800rpm, and the time is 15min, makes w/o colostrum. Then take sodium alginate0.2g, Solutol1.5g, add 55ml deionized water, mixes rear as outer water; Take the outer water of 18gBe placed on magnetic stirring apparatus, drip while stirring the colostrum making, make w/o/w emulsion; Adding colostrum amount is 8g,Mixing speed is 600rpm, and the time is 10min; By the emulsion 80bar pressure of preparation, high-pressure homogeneous 40s, to obtain final productNanometer emulsion; Shitosan is dissolved and spent the night with 1% acetum, for subsequent use after filtering; Get w/o/w prepared by 12g multipleBreast, under stirring, slowly drips 0.5ml concentration and is 0.1% calcium chloride solution with 600rpm rotating speed; Continue to stir 30After min, slowly drip concentration and be 0.06% chitosan solution, addition is 2ml, continues to stir 1h, obtains parcelNanometer emulsion.
Embodiment 6
First prepare colostrum, take 150mg insulin, be settled to 10ml with pH2HCl solution, after dissolving completelyAs interior water; Migyol812 (caprylic/capric triglyceride) is as oil phase, Span80 and phosphatide 5: 1 in mass ratioMix as emulsifying agent; Migyol812 is mixed in mass ratio with emulsifying agent at 7: 3, accurately weigh 8g and putOn magnetic stirring apparatus, water 800 μ l in dripping while stirring; Mixing speed is 800rpm, and the time is 15min, systemObtain w/o colostrum; Then take sodium alginate 0.2g, Poloxamer1881.0g, add 55ml deionized water, mixedAfter closing evenly as outer water; Take the outer water of 18g and be placed on magnetic stirring apparatus, drip while stirring the colostrum making,Make w/o/w emulsion; Adding colostrum amount is 8g, and mixing speed is 600rpm, and the time is 10min; By what prepareEmulsion 80bar pressure, high-pressure homogeneous 40s, obtains nanometer emulsion; Shitosan was dissolved with 1% acetumNight, for subsequent use after filtering; Get w/o/w emulsion prepared by 12g, under stirring with 600rpm rotating speed, slowly drip 0.5mlConcentration is 0.1% calcium chloride solution; Continue to stir after 30min, slowly drip concentration and be 0.06% chitosan solution,Addition is 2ml, continues to stir 1h, must wrap up nanometer emulsion.
Embodiment 7
First prepare colostrum, take 500mg insulin, be settled to 10ml with pH2HCl solution, after dissolving completelyAs interior water; MCM (caprylic/capric glycerine list dibasic acid esters) is as oil phase, and Span80 and phosphatide mix in mass ratio at 5: 1Close evenly as emulsifying agent; MCM is mixed in mass ratio with emulsifying agent at 7: 3, accurately weigh 8g and be placed in magnetic forceOn agitator, water 800 μ l in dripping while stirring. Mixing speed is 800rpm, and the time is 15min, makes w/oColostrum; Then take sodium alginate 0.2g, Poloxamer4071.0g, add 55ml deionized water, mixAfterwards as outer water; Take the outer water of 18g and be placed on magnetic stirring apparatus, drip while stirring the colostrum making, i.e. systemObtain w/o/w emulsion; Adding colostrum amount is 8g, and mixing speed is 600rpm, and the time is 10min; By the emulsion of preparationUse 80bar pressure, high-pressure homogeneous 40s, obtains nanometer emulsion; Shitosan is dissolved and is spent the night with 1% acetum,For subsequent use after filtering; Get w/o/w emulsion prepared by 12g, under stirring with 600rpm rotating speed, slowly drip 0.5ml denseDegree is 0.1% calcium chloride solution; Continue to stir after 30min, slowly drip concentration and be 0.06% chitosan solution,Addition is 2ml, continues to stir 1h, must wrap up nanometer emulsion.
Hypoglycemic contrast experiment in embodiment 8 vitro stability and body
(1) emulsion and the stability of parcel emulsion in SGF
Respectively get respectively 1ml nanometer emulsion and parcel nanometer emulsion, as for 9mlpH2.5 aqueous hydrochloric acid solution, (simulation is artificialGastric juice) in, in 37 DEG C of water-baths, hatch with 100rpm speed oscillation; In 15min, 30min, 1h, 2h timePoint takes out 200 μ l sample suspensions, and supplements equivalent hydrochloric acid solution in former suspension; To the 200 μ l suspensions that take outIn add 200 μ l methyl alcohol and 400 μ l hydrochloric acid solutions, vortex, after 3 minutes, after the centrifugal 10min of 15000g, is got supernatantLiquid is measured free insulin content by HPLC, and emulsion and the stability result of parcel emulsion in SGF are as Fig. 1Shown in;
(2) emulsion and the hypoglycemic effect of parcel emulsion in rat body
Using wistar rat as normal rat model, GK rat is as diabetes rat model,
Get 36 of rats, be divided into six groups, 6 every group, be respectively four groups of experimental group, one group of positive controls and one groupBlank group; Test and carry out fasting processing in first 12 hours, but can freely drink water; Test and give a small amount of food after 6 hoursThing, freely drinks water in experimentation; Test two groups of oral administration gavage 50IU/Kg, 25IU/Kg and 12.5IU/Kg bags respectivelyWrap up in nanometer emulsion, 50IU/Kg nanometer emulsion; Positive controls adopts hypodermic injection 1IU/Kg insulin solutions; BlankControl group is the blank emulsion (not insulin-containing) that gives equivalent; Before administration, take out 0.2ml blood by tail vein and stayMake assay standard blood glucose value; After administration, experimental group and blank group are by 0.5,1,2,3,4,6,8,12,24hTime point tail venous blood sampling 0.2ml; Control group is in 0.25,0.5,1,2,3,4,5,6,8h time point tail veinGet blood 0.2ml; Blood sample is used the centrifugal 10min of rotating speed of 4000rpm immediately after taking out, take out supernatant blood plasma; Pass through grapeCarbohydrate oxidase method is measured glucose content in blood plasma; Taking benchmark blood glucose value as 100%, other moment blood sugar and a reference value ratioValue is drawn hypoglycemic curve in body with the time, in normal rat body blood sugar-time graph as shown in Figure 2, diabetes rat asShown in Fig. 3.
Result shows, the outer wrapping nanometer emulsion making keeps stable under one's belt, by entering enteron aisle after stomach, in emulsionOily constituents and surfactant can play and promote the effect of drug absorption, thereby improve the oral biological profit of insulinExpenditure.
Claims (5)
1. promote the outer wrapping nanometer emulsion that oral insulin absorbs, it is characterized in that, by insulin and medicinal auxiliaryMaterial is made; Described insulin is wrapped in the interior water of emulsion, and emulsion surface is by the crosslinked method parcel of shell;
Wherein, insulin is dissolved in emulsion as active component interior mutually in, described emulsion by oil phase, surfactant andWater composition, wherein, surfactant comprises hydrophily and lipophilic emulsifier;
Described insulin is 0.1-100mg/ml in interior concentration in mutually;
The crosslinked material of described shell comprises sodium alginate, calcium chloride and shitosan; Wherein, the ratio of sodium alginate and calcium ionExample is 1:0.1-5, and the ratio of sodium alginate and shitosan is 1:0.1-5;
Described outer wrapping nanometer emulsion is prepared by following method:
First by after oil phase and lipophilic surfactant mixed dissolution, under stirring, drip insulin solution,Form colostrum, then this colostrum is joined in the solution that contains hydrophilic surfactant active and sodium alginate, stir systemBecome emulsion; Above-mentioned emulsion reduces its particle diameter by high-pressure homogeneous 60bar, then dropwise adds calcium chloride solution crosslinked,Finally add again chitosan solution to form fine and close softgel shell, make the outer wrapping nanometer emulsion that promotes that oral insulin absorbs.
2. the outer wrapping nanometer emulsion absorbing by promotion oral insulin claimed in claim 1, is characterized in that instituteThe oil phase of stating is selected from caprylic/capric triglyceride, caprylic/capric monoglyceride, peanut oil, soybean oil, olive oil, jadeOne or more in rice bran oil.
3. the outer wrapping nanometer emulsion absorbing by promotion oral insulin claimed in claim 1, is characterized in that instituteThe surfactant of stating comprises hydrophily and lipophilic emulsifier; Described lipophilic emulsifier be selected from phosphatide, Span80,One or more in Span60, Span20, described hydrophilic emulsifier is selected from CremophorEL, CremophorOne or more in RH40, Tween80, SolutolHS15, poloxamer188, Poloxamer407.
4. the outer wrapping nanometer emulsion absorbing by promotion oral insulin claimed in claim 1, is characterized in that instituteState lipophilic surfactant and be selected from phosphatide or Span80.
5. the outer wrapping nanometer emulsion absorbing by promotion oral insulin claimed in claim 1, is characterized in that instituteStating hydrophilic surfactant active is CremophorEL.
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| CN107233298B (en) * | 2016-03-28 | 2021-01-22 | 复旦大学 | Yeast cell wall particle preparation for promoting oral absorption of protein polypeptide medicine |
| CN106075403A (en) * | 2016-06-12 | 2016-11-09 | 暨南大学 | A kind of oral insulin selenium nanometer formulation and preparation method thereof |
| CN107753934A (en) * | 2016-08-18 | 2018-03-06 | 温州医科大学 | Contain the preparation of SA mGM CSF or/and SA hTNF α biotin chitosan calcium alginate microsphere |
| CN106334185B (en) * | 2016-08-25 | 2020-01-10 | 广东省人民医院 | Oral preparation containing polypeptide drug self-nanoemulsion and preparation method thereof |
| CN108904789A (en) * | 2018-07-25 | 2018-11-30 | 中国医学科学院生物医学工程研究所 | Alginic acid treats the new application that itself property is immunized in diabetes medicament in preparation |
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