CN101862445A - Oral insulin containing protease inhibitor - Google Patents
Oral insulin containing protease inhibitor Download PDFInfo
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- CN101862445A CN101862445A CN200910071785A CN200910071785A CN101862445A CN 101862445 A CN101862445 A CN 101862445A CN 200910071785 A CN200910071785 A CN 200910071785A CN 200910071785 A CN200910071785 A CN 200910071785A CN 101862445 A CN101862445 A CN 101862445A
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Abstract
The invention discloses oral insulin, the preparation relates to a polymer chemistry technology, and the technology can be applied to the synthesis of polymersomes gel components in the oral medication approach of insulin. The invention provides a preparation method for forming polymersomes gel by polymerizing protease inhibitor- ovomucoid (glycoprotein extracted from duck eggs), acrylamide and the like, a preparation method of the preparation thereof and application thereof in reducing animal hyperglycemia. The ovomucoid is used for protecting oral insulin for the first time, and the preparation of the polymersomes gel can be used for curing diabetes. The bioavailability of the preparation reaches above 20 percent of the same dose of subcutaneous injection insulin, and the preparation has the advantage of convenient medication, prevents the defects of injection pain and poor tolerance, and has very high use value.
Description
Technical field
This invention relates to producing high-molecular and learns a skill, and more particularly, this technology can be applicable to the synthetic of polymer gel component in the oral administration of insulin.This compositions can be used for preparing the medicine for the treatment of diabetes.
Background technology
The biosphere achievement in research has enlarged the application of protein medicaments aspect disease treatment greatly.Yet,, make the application of protein medicaments be very restricted owing to lack a kind of drug administration approach easily and effectively.Oral administration is the most comfortable and method easily, but common this method can not be applied to protein medicaments.Because protein medicaments must overcome the intravital three road barriers of people: (1) is decomposed owing to strong acidic environment and followed by action of proteolytic enzymes in the stomach organ; (2) in small intestinal by trypsin degradation; (3) aminoacid more than three kinds is difficult for being absorbed in intestinal in the polypeptide fractions.How can in and the Degradation of proteolytic enzyme be the challenging problem of tool.This also is why proteolysis is the most important factor of limit protein class medicine through gastrointestinal administration.Therefore, albumen that can the by oral route administration or polypeptide drug arrive final destination (blood circulation), just must can tolerate the effect of chemical and enzyme, and can pass intestinal mucosa.The intravital insulin of people is synthetic by pancreas, be secreted into blood vessel that hepatic portal vein is connected in.Simultaneously the product that digests gained in the intestinal is sent to liver in this blood vessel.The effect of insulin is exactly to control the Absorption of liver for digestion product.Under normal circumstances, this digestion raw material and controlling agent produce simultaneously and are sent to histoorgan.Therefore, liver is controlled the amount that insulin passes through.Type i diabetes patient pancreas can not produce insulin, needs to give patient's subcutaneous injection insulin injection.In this case, liver obviously can not control volume in content of insulin, can cause a series of complication usually, arteriosclerosis for example, heart disease, brain function is limited etc.The main route of administration of insulin is subcutaneous and intramuscular injection.This method is after having repeated hundreds of time even thousands of times, and patient's physiology and psychology all can not feel well.Therefore, oral insulin has very big advantage.For many years, people are devoted to study always and a kind ofly can resist digestible protein, and can infiltrate through oral insulin medicament preparation in the blood by intestinal mucosa.
At this problem, several solutions have been proposed, comprise insulin molecule self is modified, for example C terminal amino acid residue is replaced with more stable glycine residue; The hydrophobization of insulin molecule; Preparation monosaccharide derivatives or insulin molecule and other albumen combined.Yet, but do not have to be applied to the insulin preparation of oral administration all the time.
One of solution to this problem is with insulin and can improves its intestinal walls penetration power and assist its complex that enters in the blood to unite use.The chemical compound that can be applied to this approach has soap, surfactant, bile salts and chelate compound.Strengthening the activated insulin content that just can make in the arrival blood flow for the intestinal walls permeability increases; if but just insulin is directly sent in the intestinal through the esophagus stomach function regulating; even take very big dosage; this insulin does not have curative effect yet; if insulin and protease are suppressed to mix use; when intestinal canal administration, just can protect insulin not destroyed so by protease.Utilization contains protease inhibitor, and insulin and the blending ingredients that can improve the compositions of intestinal penetration during the by oral route administration, can reach identical effect.
Recently, relatively more popular oral insulin preparation method is that insulin is wrapped up with shell.This shell can protect insulin to pass through digestive tract, decomposes in small intestinal then, discharges activated insulin.Liposome, hydrogel, microcapsule or can be used for making this capsid by the polymer material that organism is degraded.
In the article (U.S.Pat.No.5,049,545), insulin has been fixed in a kind of polymer hydrogel made mixture, can pass through injection administration.This polymer is by starch, glucosan, and polyoxyethylene, polyvinylpyrrolidone, the cross-linked rubber protoplasm, albumen and its derivant comprise that proteinase inhibitor forms.This patience enhancing that contains the complex of insulin to proteolytic enzyme, and make insulin prolong the action time in blood flow.Yet the synthetic polymer mixture that contains insulin but can not demonstrate enough stability in this work under the effect of digestive enzyme, therefore can't be applied to oral route.
Article (Saffran, M., Kumar, G.S., et al, Biochem.Soc.Trans.) in, a kind of polymer mixture that contains insulin has been described, this is a kind of gel capsule that contains insulin, is wrapped up by the copolymer of styrene and hydroxyethylmethyl-cellulose and the crosslinked gained of divinylbenzene nitrogen containing derivative.Behind the oral administration, after insulin is released, enter in the process of blood passing intestinal walls, cross-linked copolymer is degraded under the enteric microorganism effect.The shortcoming of this mixture is that stability can reduce under the effect of digestive enzyme, thereby the insulin active that infiltrates through in the blood flow reduces.After oral administration 3-4 hour, copolymer is 1 to 40mg/ rat (calculating with insulin) at the intravital content of rat, average blood sugar concentration maximum reduced by 25% (from 384mg./100ml. to 287mg./100ml).
Article (Damge, C., J.Controlled Release) in, synthesized a kind of spherical microcapsule, it is a kind of biodegradable polyisobutylene-2-cyanoacrylate, diameter is 250-350nm.Insulin distributes with liquid form within it.Yet this microcapsule formulation only under the very high situation of insulin dose (100U/kg), just can play obvious blood sugar decreasing effect (25%) after the oral administration administration, and only after administration six days, this medicine could begin to play a role.
With mentioned a kind of high molecular polymer in the related article (Greenley, R.Z., Broun, T.M., et al, Polymer Prepr.) of the present invention, this polymer is that insulin has been fixed on the cross-linked copolymer of being modified by proteinase inhibitor.This copolymer comes down to the cross-linking products of a kind of polyacrylic acid or polymethylacrylic acid and triethylene glycolipid class, and aprotinin-protease inhibitor is as inhibitor.The shortcoming of this mixture is that synthetic polyalcohol hydrogel is very low for the resistance of digestive enzyme, causes the blood penetrance of insulin to reduce.
The present invention's advantage compared with the prior art; adopt ovomucoid to do proteinase inhibitor; ovomucoid can with the combination of Proteolytic enzyme enzyme spcificity; a molecule ovomucoid can be in conjunction with two molecule protein enzymes; thereby avoid insulin to be destroyed by the Proteolytic enzyme enzymatic degradation; insulin can not destroyed by the trypsin in the digestive tract under the protection of ovomucoid, arrives small intestinal smoothly.After arriving small intestinal, glycosyl component on the ovomucoid and the lectin generation specificity combination on the intestinal walls, thus make the insulin-containing gelinite can accumulate on the intestinal walls, insulin is released, and infiltrates through blood.The bioavailability of its preparation reaches with dosage subcutaneous injection insulin more than 20%, and the preparation of this polymer gel can be used for treating diabetes.
Summary of the invention
The present invention seeks to prevent protein medicaments by the Proteolytic enzyme enzyme hydrolysis, thereby make medicine to be absorbed by digestive system.This method is that medicine is fixed on the hydrogel polymer that carries glycoprotein (by separating the ovomucoid that obtains in the Ovum Anas domestica album).This glycoprotein can the Profilin hydrolytic enzyme effect and can be used as the biospecific ligands of lectin on the intestinal walls.Improve and comprise the resistance of the polymer hydrogel of insulin digestive enzyme.Thereby make this prepared product can be applied to oral administration.
This target can be by being modified by proteinase inhibitor, and the hydrogel that is fixed with insulin realizes that this proteinase inhibitor is by separating the ovomucoid that obtains in the Ovum Anas domestica album.Ovomucoid is a kind of glycoprotein, molecular weight about 31000.Ovomucoid molecule comprises 12.5% glycosamine and other saccharide of 7.8%.
Extract ovomucoid in the Ovum Anas domestica, with this as protease inhibitor and bio-absorbable promoter.Ovomucoid is connected with acrylamide after using the acryloyl chloride chloride, and again with acrylamide, methylene diacrylamide, Ammonium persulfate., tetramethylethylenediamine form copolymer, aggregate into the water gel of high molecular polymer then.With this water gel lyophilization, the insulin solutions molecule enters in the water gel mesh by absorbing swollen mode, adds a certain amount of excipient, can further be prepared into enteric coated capsule or enteric coated tablet.Behind the oral administration, insulin can not destroyed by the trypsin in the digestive tract under the protection of ovomucoid, arrives small intestinal smoothly.After arriving small intestinal, glycosyl component on the ovomucoid and the lectin generation specificity combination on the intestinal walls, thus make the insulin gelinite can accumulate on the intestinal walls, insulin is released, and infiltrates through blood.
The present invention's advantage compared with the prior art is that the bioavailability of its preparation reaches with dosage subcutaneous injection insulin more than 20%, and the preparation of this polymer gel can be used for treating diabetes.
Introduce technical process below by embodiment, but the present invention is not limited to content and the scope of embodiment.
The specific embodiment:
Embodiment 1
The separation of ovomucoid, extraction, purification
The separation of ovomucoid is at first put into bottle with the 100g Ovum Anas domestica album, and agitator is installed.In 2.7g trichloroacetic acid and 27.3g distilled water, make solution.Then 70g ethanol and 30g trichloroacetic acid solution (100g altogether) are added in the bottle that fills Ovum Anas domestica album, stir with the speed dropping of 3～5ml/min.After all mixed solutions all add, continue to stir 40min again.Temperature is controlled at 15～25 ℃, then with sedimentation and filtration, abandons.Filtrate is transferred in the bottle, adds 550g ethanol, precipitation is put into distilled water dialyse, and the solution lyophilization can obtain ovomucoid crude product 1.5g, through the ion exchange column purification, gets the about 0.9g of the pure product of ovomucoid.
Embodiment 2
Oral insulin polymer hydrogel preparation technology flow process
1. get ovomucoid 0.8g, be dissolved in the NaHCO of 100ml0.1M
3In pH8.0～8.4 solution, stir, slowly be added dropwise to 0.1ml acryloyl chloride (lucifuge, cryopreservation), observe pH simultaneously and change, add acryloyl chloride solution meeting souring, if meta-acid is just used solid NaHCO at the ice bath lower magnetic force
3Transfer in 8.0～8.4, ice bath stirs 90min, prevents the acryloyl chloride effusion.Form the immobilization trim of acrylamide ovomucoid.
2. in above-mentioned 100ml solution, add the 8g acrylamide, the 0.4g methylene diacrylamide, the 0.1g-0.15g Ammonium persulfate. fully dissolves in stirring at room, pour in the round-bottomed flask, add the 0.2ml tetramethylethylenediamine, mixing, evacuation 30min closes vacuum and places 60min, obtains water gel.
3. water gel is pulverized, 20 eye mesh screens are crossed in extruding, and the abundant magnetic agitation Xian Di of the water for injection that the water gel volume is tens of times removes acrylamide, and ovomucoid etc. change water for injection 3 times in one day, water Xian Di 4 days, and filtrate is monitored A with ultraviolet method
230 ± 2≤ 0.003. (this is the ultraviolet absorption value of acrylamide), monitoring A
280 ± 2≤ 0.003 (this is the ultraviolet absorption value of ovomucoid), reach requirement after, place the freeze dryer lyophilization, vacuum 60mbar, evacuation 48h is frozen into powder crystal, weighing, about 8 grams of the polyacrylamide contain ovomucoid are modified in immobilization.
4. the ovomucoid binding ability detects in the water gel
Preparation respectively: 0.1M NaHCO
3PH8.4; 0.2M KCI-HCI pH 1.87; 0.05M Tris-HCI pH8.0,0.1M NaCI solution.
Remarks: trypsin can form the conformation that combines of similar part and donor with ovomucoid, under the condition of pH8.0, the two can form the aglucon combination, the 1mol ovomucoid can be in conjunction with 2mol trypsin molecule, under the condition of pH1.87, destroy the combination of the two, the two separation is with this evaluating characteristics ovomucoid binding capacity and adding amount of insulin.
Take by weighing the freeze dried water-setting rubber powder of above-mentioned 0.1g, add the NaHCO of 3ml 0.1M pH8.4
3Solution, swelling is more than 3 hours.
Pour swollen water gel into G that the lower end is connected to hose clip
3In the incipient fusion filter, use 0.1M NaHCO respectively successively
3PH8.4 solution; 0.2M KCI-HCI pH 1.87 solution; 0.05M Tris-HCI pH8.0,0.1M NaCI solution, the Xian Di water gel, wash filtrate is to A
230 ± 2≤ 0.003; A
280 ± 2≤ 0.003.
Get the 30mg trypsin and be dissolved in the 5ml 0.005N HCI solution, fully dissolving adds 15ml 0.05M Tris-HCI pH8.0, and 0.1MNaCI solution is settled to 20ml, and the 30mg trypsin is so far arranged in 20ml solution.
Above-mentioned solution is added above-mentioned G
3In the incipient fusion filter, clamp the flexible pipe of lower end, after 1.5 hours, open clip with the Glass rod stirring, collect effluent with the container of 500ml, with 0.05M Tris-HCI pH8.0,0.1M NaCI is towards Xian, and wash filtrate is to A
230 ± 2≤ 0.003; A
280 ± 2≤ 0.003.Continue to collect effluent, and (collect in fact be not with the bonded trypsin of ovomucoid), accurately measure the volume V that collects liquid in the 500ml container
1, measure A
280Value is calculated unconjugated tryptic concentration: C
1(unconjugated trypsinase concentration)=A
280 ± 2* 0.7 (k=0.7 is specific absorbance), X
1(unconjugated trypsin amount)=V
1* C
1
Clamp flexible pipe, add the solution of 0.2M KCI-HCI pH1.87, towards Xian G
3Water gel in the incipient fusion filter is collected effluent with the container of another 500ml, and wash filtrate is to A
230 ± 2≤ 0.003; A
280 ± 2≤ 0.003, (this part is that ovomucoid is in conjunction with the trypsin amount), accurately the volume V of effluent is collected in weighing
2, measure A
280 ± 2Value, then C
2(bonded trypsinase concentration)=A
280 ± 2* 0.7, X
2(bonded Trypsin amount)=C
2* V
2, 30mg-X1 ≈ X2 (X2 is more accurate than X1) passes judgment on 0.1g water gel dry powder can in conjunction with what milligram trypsin with this result, and infers to calculate 1g hydrogel dry powder can in conjunction with what milligram trypsin with this.(this index also is evidence ovomucoid amount controlling index in water gel, and is most important to the control product quality).Counting ovomucoid according to 1mol can be in conjunction with the trypsin of 2mol number; can tentatively calculate; what milligram ovomucoids 1g hydrogel dry powder combines, and according to drug effect situation in animal body, confirms that tentatively 1g hydrogel dry powder can protect the insulin of how many units.
5. the preparation of insulin hydrogel
In 100ml pH2.2 purified water, add 40mg (the suitable 25U of 1mg insulin) insulin, fully dissolving.Get 10g water gel lyophilized powder, add the above-mentioned insulin solution of 100ml, fully swelling absorbs, place the freeze dryer lyophilization, vacuum 60mbar, evacuation 48 hours, be frozen into powder crystal, get the about 10g of insulin hydrogel dry powder, the suitable 100U of every gram water gel lyophilized powder insulin-containing.
Embodiment 3
1. get ovomucoid 0.1g, be dissolved in the NaHCO of 100ml 0.1M
3In pH8.0～8.4 solution, stir, slowly be added dropwise to 0.01ml acryloyl chloride (lucifuge, cryopreservation), observe pH simultaneously and change, add acryloyl chloride solution meeting souring, if meta-acid is just used solid NaHCO at the ice bath lower magnetic force
3Transfer PH in 8.0～8.4, ice bath stirs 90min, prevents the acryloyl chloride effusion.Form the immobilization trim of acrylamide ovomucoid.
2. in above-mentioned 100ml solution, add the 5g acrylamide, the 0.5g methylene diacrylamide, the 0.05g-0.1g Ammonium persulfate. fully dissolves in stirring at room, pour in the round-bottomed flask, add 0.05 tetramethylethylenediamine, mixing, evacuation 30min closes vacuum and places 60min, obtains water gel.
3. water gel is pulverized, 20 eye mesh screens are crossed in extruding, and the abundant magnetic agitation Xian Di of the water for injection that the water gel volume is tens of times removes acrylamide, and ovomucoid etc. change water for injection 3 times in one day, water Xian Di 4 days, and filtrate is monitored A with ultraviolet method
230 ± 2≤ 0.003. (this is the ultraviolet absorption value of acrylamide), monitoring A
280 ± 2≤ 0.003 (this is the ultraviolet absorption value of ovomucoid), reach requirement after, place the freeze dryer lyophilization, vacuum 60mbar, evacuation 48h is frozen into powder crystal, weighing, about 5 grams of the polyacrylamide contain ovomucoid are modified in immobilization.
4. the ovomucoid binding ability detects in the water gel:
With embodiment 2-4.
5. the preparation of insulin hydrogel
In 100ml pH2.2 purified water, add 1mg (the suitable 25U of 1mg insulin) insulin, fully dissolving.Get 5g water gel lyophilized powder, add the above-mentioned insulin solution of 50ml, fully swelling absorbs, place the freeze dryer lyophilization, vacuum 60mbar, evacuation 48 hours, be frozen into powder crystal, get the about 5g of insulin hydrogel dry powder, the suitable 5U of every gram water gel lyophilized powder insulin-containing.
Embodiment 4
1. get ovomucoid 10g, be dissolved in the NaHCO of 100m 0.1lM
3In pH8.0～8.4 solution, stir, slowly be added dropwise to 1.0ml acryloyl chloride (lucifuge, cryopreservation), observe pH simultaneously and change, add acryloyl chloride solution meeting souring, if meta-acid is just used solid NaHCO at the ice bath lower magnetic force
3Transfer in pH 8.0～8.4, ice bath stirs 90min, prevents the acryloyl chloride effusion.Form the immobilization trim of acrylamide ovomucoid.
2. in above-mentioned 100ml solution, add the 15g acrylamide, 0.75 methylene diacrylamide, the 1g Ammonium persulfate. fully dissolves in stirring at room, pour in the round-bottomed flask, add the 5g tetramethylethylenediamine, mixing, evacuation 30min closes vacuum and places 60min, obtains water gel.
3. water gel is pulverized, 20 eye mesh screens are crossed in extruding, and the abundant magnetic agitation Xian Di of the water for injection that the water gel volume is tens of times removes acrylamide, and ovomucoid etc. change water for injection 2 times in one day, water Xian Di 4 days, and filtrate is monitored A with ultraviolet method
230 ± 2≤ 0.003. (this is the ultraviolet absorption value of acrylamide), monitoring A
280 ± 2≤ 0.003 (this is the ultraviolet absorption value of ovomucoid), reach requirement after, place the freeze dryer lyophilization, vacuum 60mbar, evacuation 48h is frozen into powder crystal, weighing, about 15 grams of the polyacrylamide contain ovomucoid are modified in immobilization.
4. the ovomucoid binding ability detects in the water gel
With above-mentioned embodiment 2-4.
5. the preparation of insulin hydrogel
In 100ml pH2.2 purified water, add 160mg (the suitable 25U of 1mg insulin) insulin, fully dissolving.Get 20g water gel lyophilized powder, add the above-mentioned insulin solution of 200ml, fully swelling absorbs, place the freeze dryer lyophilization, vacuum 60mbar, evacuation 48 hours, be frozen into powder crystal, get the about 20g of insulin hydrogel dry powder, the suitable 400U of every gram water gel lyophilized powder insulin-containing.
Embodiment 5
Enteric insulin sheet or enteric coated capsule preparation technology
1. 1000 or capsules prescription
The composition consumption
The dried hydrogel 100g of insulin-containing (200U insulin/hydrogel body lyophilized powder g)
Microcrystalline Cellulose 180g
Pregelatinized starch 20g
Carboxymethyl starch sodium 12.5g
Magnesium stearate 1.25g
Polyvinylpyrrolidone (0.2% aqueous solution) is an amount of
2. preparation technology
Microcrystalline Cellulose and pregelatinized starch elder generation mix homogeneously with recipe quantity; add an amount of 0.2% polyvinylpyrrolidone aqueous solution; the system soft material; cross 20 mesh sieves; 50～60 degree decompression or constant pressure and dries; to the granule bone dry, cross 20 mesh sieve granulate, with the dried hydrogel granule and the above-mentioned granule mix homogeneously of insulin-containing; add carboxymethyl starch sodium, magnesium stearate mix homogeneously once more; granulate mixture, the enteric coated capsule of packing into, about 310 milligrams of every nt wt net weight; or tabletting; about 310 milligrams of every weight, slice, thin piece pressure, hardness are moderate, and the plain sheet of insulin is enteric coated.
Embodiment 6
The application aspect the experimental hyperglycemia animal of enteric insulin sheet or enteric coated capsule
1. the experimental hyperglycemia SD rat test of pesticide effectiveness: get 36 hyperglycemia SD rats
*, fasting before the experiment, test divides 4 groups, and 9 every group, blank group, 2 test group--enteric coated capsule group, positive drug group--regular iletin group; Animal environment peace and quiet, comfortable, enteric coated capsule group gastric infusion, blank group is given blank preparation.Positive drug group subcutaneous injection, the tail vein is got blood, surveys blood glucose value with superior blood glucose meter, the blood glucose value of each animal before the record administration, and 30,60,90,120,150,180,210 minutes blood glucose value after the administration.
The result is as follows for the hyperglycemia SD rat test of pesticide effectiveness:
The variation that blood sugar concentration is produced with insulin prepared product type and dosage difference (every group of 9 rat blood sugar meansigma methodss)
* SD rat skin lower injection dosage is that the streptozotocin of 60mg/kg the weight of animals brings out it and produces artificial diabetes
2. the livid purple blue rabbit test of pesticide effectiveness of experimental hyperglycemia: get 24 livid purple blue rabbit * of hyperglycemia, fasting before the experiment, test divides 4 groups, and 6 every group, blank group, 2 test group--enteric coated capsule group, positive drug group--insulin solutions group; Animal environment peace and quiet, comfortable, enteric coated capsule group gastric infusion, blank group is given blank preparation.Positive drug group subcutaneous injection, auricular vein is got blood, surveys blood glucose value with superior blood glucose meter, the blood glucose value of each animal before the record administration, and 30,60,90,120,150,180,210 minutes blood glucose value after the administration.
Livid purple blue rabbit test of pesticide effectiveness result is as follows for experimental hyperglycemia:
* giving livid purple blue rabbit auricular vein injected dose is its generation artificial diabetes of model induced by alloxan of 150mg/kg (dividing the secondary administration) the weight of animals
Claims (9)
1. Macrulin, it contains polymer hydrogel, protease inhibitor, insulin, filler.
2. according to claim 1, the polymer hydrogel be a kind of can be in water expansible polymer, this polymer hydrogel, be that protease inhibitor is after the acryloyl chloride chloride, the formation immobilization is modified, again with acrylamide, the copolymer that methylene-bisacrylamide, Ammonium persulfate., tetramethylethylenediamine form.
3. according to claim 1, protease inhibitor is selected from from duck and poultry eggs such as turkey and separates the ovomucoid that obtains.
4. according to claim 1, insulin can be selected from biochemical extract or the engineered insulin of animal.
5. according to claim 2, a kind of composition of polymer hydrogel, the consumption of each component are ovomucoid 0.05～20%; Acryloyl chloride 0.005%～10%; Acrylamide 5～20%; Methylene-bisacrylamide 0.1%～1%; Ammonium persulfate. 0.05%～1%; Tetramethylethylenediamine 0.01%～10%.
6. according to claim 1, the polymer hydrogel preparation method of insulin-containing, after the polymer hydrogel forms, through pulverizing, washing, through the freeze drying process lyophilizing, after adding insulin solutions absorption swelling again, lyophilizing again, content of insulin can be 0.1～200 milligram in every gram dried hydrogel.
7. according to claim 1, filler in the Macrulin is selected from microcrystalline Cellulose, lactose, mannitol, extra large bath sugar, sucrose etc., and consumption can be 10～80%.
8. according to claim 1, oral insulin adopts tablet or capsule, and tablet adopts enteric coated, and capsule adopts enteric coated capsule.
9. according to Claim 8, to contain insulin active be 0.1～500U for every or every preparation.
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| CN200910071785A CN101862445A (en) | 2009-04-16 | 2009-04-16 | Oral insulin containing protease inhibitor |
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| CN200910071785A CN101862445A (en) | 2009-04-16 | 2009-04-16 | Oral insulin containing protease inhibitor |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5698515A (en) * | 1994-03-23 | 1997-12-16 | Institut Neftekhimicheskogo Sinteza Imeni A.V.Topchieva Rossiiskoi Akademii Nauk | Insulin-containing polymer composition for oral administration |
| CN1726044A (en) * | 2002-12-17 | 2006-01-25 | 纳斯泰克制药公司 | Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity |
| WO2007029238A2 (en) * | 2005-09-06 | 2007-03-15 | Oramed Pharmaceuticals, Inc. | Methods and compositions for oral administration of proteins |
| CN101084016A (en) * | 2004-04-15 | 2007-12-05 | 克艾思马有限公司 | Compositions capable of facilitating penetration across a biological barrier |
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2009
- 2009-04-16 CN CN200910071785A patent/CN101862445A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5698515A (en) * | 1994-03-23 | 1997-12-16 | Institut Neftekhimicheskogo Sinteza Imeni A.V.Topchieva Rossiiskoi Akademii Nauk | Insulin-containing polymer composition for oral administration |
| CN1726044A (en) * | 2002-12-17 | 2006-01-25 | 纳斯泰克制药公司 | Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity |
| CN101084016A (en) * | 2004-04-15 | 2007-12-05 | 克艾思马有限公司 | Compositions capable of facilitating penetration across a biological barrier |
| WO2007029238A2 (en) * | 2005-09-06 | 2007-03-15 | Oramed Pharmaceuticals, Inc. | Methods and compositions for oral administration of proteins |
Non-Patent Citations (2)
| Title |
|---|
| VIKAS AGARWAL ET AL: "Transport studies of insulin across rat jejunum in the presence of chicken and duck ovomucoids", 《JOURNAL OF PHARMACY AND PHARMACOLOGY》 * |
| 徐晖等: "一种PH敏感水凝胶的性质及用于胰岛素口服给药的研究", 《沈阳药科大学学报》 * |
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Application publication date: 20101020 |