CN102144976A - Method for preparing insulin dry powder for oral administration by using micro capsulation technology - Google Patents
Method for preparing insulin dry powder for oral administration by using micro capsulation technology Download PDFInfo
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Abstract
The invention relates to a method for preparing insulin dry powder for oral administration from insulin and derivatives thereof and an application thereof, and solves the problems that insulin is easy to oxidize, can not be orally administered and is inconvenient for carrying. The method comprises the following steps: heating insulin and derivatives thereof (any content), a propolis antioxidant or a colloidal matter, vitamin E, vitamin C or derivatives thereof, fatty acid and an emulsifier, emulsifying in a sealed condition, and performing spray-drying to obtain insulin dry powder for oral administration. The insulin dry powder for oral administration is administered with water at a proportion at half hour before meal, and can replace synthesized insulin and derivatives thereof or other antihyperglycemic agents for intramuscular injection. The method adopts the advanced 'micro capsulation' principle in bioengineering, and basically solves the problem of insulin oxidation through spray embedment of insulin. The insulin dry powder can gradually stimulate slow recovery of islet cells of patients by use of the active substances of a natural propolis antioxidant while supplementing external insulin and derivatives thereof. The insulin dry powder produced by using the method provided by the invention has good oxidation resistance and low production cost, and is easy for carrying and large-scale production. Compared with the prior art, the method conducts oxidation resistance treatment of insulin by using the principle of bioengineering. The method provided by the invention can be widely used in pharmaceutical industry, and brings in the most essential progress for the relief and recovery of diabetic patients.
Description
Technical field: the present invention relates to method and application thereof that a kind of insulin, synthetic para-insulin, insulin derivates are prepared into oral islets of langerhans dry powder composite.Background technology: according to studies show that, except can replenishing the various trace elements, the islet secretion function in can also human activin can be used as the ancillary drug of diabetes to natural propolis in human body; Insulin, para-insulin, insulin derivates, the main medication of curing diabetes especially.But insulin belongs to the material of easy oxidation, and survival rate is very low under its room temperature, can not be oral, adopt cryopreservation, intramuscular injection always.Its emulsion, physical stability is poor, easily by the gastric acid oxidation, time of staying weak point in health, and not portable.Because it is subjected to certain restriction in the use the official post of insulin stability, injection causes certain injury to patient body, is to have controlled a kind of disease to have a foreshadowing for another kind of disease again.
Application (patent) number: 02145554.6 open (announcement) number: 142546, the oral insulin patent application, it is a kind of disclosed for a long time abroad esters synthetic compound.Its greatest drawback is to encase insulin fully, cannot stand the effect of gastric acid and enzyme, causes the bioavailability of insulin to reduce.
Application (patent) number: 01107881.2 open (announcements) number: 1374097, the oral insulin patent application, it is a kind of method of directly extracting the para-insulin film-making from plant, is the tabletting that a kind of plant extraction liquid for the treatment of diabetes adds starch.It can not be used for the treatment of the diabetics that relies on insulin.
Application (patent) number: 02112513.9 open (announcement) number: 1372973, the patent application of insulin dry powder, it is a kind of prescription fine powder that adopts press atomization, yields poorly, production cost is higher; Be transported to blood through pulmonary's suction by the pneumonocyte absorption; Its greatest drawback have be smoking, pulmonary has environment disease, that wind is arranged all can not use.
Application (patent) number: 01115327.x open (announcement) number: 1318416, oral insulin liquid be a kind of oral latex emulsion that utilizes surfactant to make, its disadvantage also is not solve gastric acid and the enzyme problem of oxidation to insulin fully.What but it was commendable is not adopt synthetic ester type compound.
Application (patent) number: 01128323.8 open (announcements) number: 1335182, the oral insulin sheet be the mode that adopts sublingual administration, the preservation insulin, it makes that insulin oxidized situation under gastric acid environment is not solved at all.
Application (patent) number: 00102942.8 open (announcement) number: 1270060, the oral insulin capsule be the mode that adopts the soft capsule fill, discharge insulin at stomach and use for health, it does not still have well to solve the problem of insulin oxidation under gastric acid environment; And the working condition harshness that this mode of production requires is because insulin requires K cryogenic treatment.
And the present invention has avoided insulin being unfavorable for processing and carrying fully, gastric acid environment is decomposition, low, the unconspicuous shortcoming of the hypoglycemic effect aspect of oral bioavailability rate easily, and the present invention has adopted the Chinese and western medicine principle of combining to make treatment on prescription and repaired and carry out synchronously; Processing technique adopts spray-dired advanced technology, moment, high temperature reached exsiccant purpose, insulin and derivant embedding thereof are advanced in the macromolecular structure such as propolis, and form the capsule of a microcosmic: its kernel is that insulin, interlayer are that forced for vitamins breast, skin are gelatin substances such as natural propolis.This structure has been protected insulin fully, is difficult for when oral by gastric acid and oxydasis, and the interior time of staying of body is long, the bioavailability height.It can make insulin be deep into and enter the blood facilitating digestion in the intestinal.
Summary of the invention: the present invention seeks to solve the insulin of prior art production and the problem of derivant non-oxidizability difference thereof, a kind of methods and applications of producing oral insulin dry powder and oral insulin derivant dry powder thereof with physics " microcapsule " are provided.
The said method for preparing oral insulin dry powder with insulin and derivant thereof of the present invention is finished according to the following steps:
---weighing: will be with the insulin for preparing and derivant thereof (each content all can) n, propolis alcoholic solution, calcium gluconate n1, by weight taking by weighing n part insulin respectively, 97-n-n1-x part propolis, n1 part calcium gluconate, wherein n is any natural number of 1 to 30;
---the preparation (x) of forced for vitamins: be by weight respectively with vitamin e, vitamin c derivant: take by weighing at 1: 1, join in the fatty acid, fatty acid and insulin weight ratio are 1: 1; Adding emulsifying agent value such as monoglyceride again in fatty acid is 1≤HLB≤8, is 50% by the fatty acid wt ratio, is heated to thawing, mix homogeneously.
---drying: with propolis insulin ethanol mixed solution and forced for vitamins breast mix homogeneously, adopt spray drying method, inlet temperature be 140 degrees centigrade to 220 degrees centigrade, temperature of outgoing air be 30 degrees centigrade to 60 degrees centigrade, make dry powder.
---finished product: the oral dry powder (0≤n≤30) that generates the insulin that contains n%.
Use:
To make the actual injection situation of oral insulin dry powder, take the circumstances into consideration oral getting final product according to patient.Can progressively substitute insuline pro injection, reduce the unnecessary sore spot that brings to the patient because of the treatment diabetes.
The advantage and the effect of invention: because oral insulin dry powder efficiently solves the oral problem of insulin and derivant thereof and the easy problem of oxidation, can progressively substitute insuline pro injection in the future days, make contributions for extensive patients reduces slight illness.1, the present invention adopts the principle of " microcapsule " embedding, by natural bee gelatin substance and reasonable scientific formula the natural activity of propolis class antioxidant and insulin and derivant thereof are combined, not only organically in generation, make its high as far as possible playing a role in human body insulin, its repairing islet cells as much as possible is in vivo again gone back function in the dummy in treatment simultaneously; Reach the effect for the treatment of both the principal and secondary aspects of a disease.2, the present invention has adopted advanced and easy spray drying on production technology, makes production cost lower, more helps the patient; 3, the physically trapping method of the present invention's employing and former chemicals logos are distinct; The present invention makes insulin and the spray-dried embedding of derivant thereof under certain condition, and this is two kinds of solitary different approach, compared with prior art, is a kind of leap, is that the bionic principle of utilization is finished the improvement to pharmaceutical technology; 4, the present invention can be widely used in the drug development of the easy oxidation of pharmaceutical industry.
Description of drawings:
Fig. 1 is: the dose-effect of oral insulin dry powder and time relation figure
Fig. 2 is: through the oral insulin dry powder microcapsule of ultramicroscope shooting
Fig. 3 is: forint-phenol law is measured oral insulin dry powder ultraviolet absorption peak
Fig. 4 is: the high-performance liquid chromatogram determination insulin content
Fig. 5 is: oral insulin dry powder ultramicroscope particle diameter
The specific embodiment:
Embodiment 1
A kind ofly prepare the method for oral dry powder with insulin and derivant thereof, this method is finished according to the following steps:
---weighing: take by weighing the insulin (this example adopt be that the bovine insulin of Jiangsu ten thousand nations also can adopt insulin derivates) of 5 gram synthetic respectively, 75% propolis alcoholic solution 100 grams, calcium gluconate 5 grams, mix homogeneously is to dissolving fully.
---the preparation of forced for vitamins breast: vitamin e, vitamin c derivant respectively claim 3 grams, add fatty acid 5 grams, and monoglyceride 5 grams are heated to dissolving fully, make it mix homogeneously;
---drying: the solution mix homogeneously that will prepare, 180 ℃ on 140 ℃ of islands of inlet temperature, temperature of outgoing air carries out drying for 30 ℃ to 60 ℃, obtains finished product content and be 3.5% oral insulin dry powder; The forming agents such as afterwards adding cellulose that converts in proportion stirs, and high performance liquid chromatography records insulin content and is about 11.5 iu/grams (seeing accompanying drawing).
Embodiment 2
Take by weighing: 7 gram insulins (Jiangsu ten thousand nations " insulin human "), 75% propolis alcoholic solution 98 grams; Vitamin e, the vitamin c derivant is 3 grams respectively, can prepare by the step among the embodiment 1 and contain 4.9% oral insulin dry powder; The forming agents such as afterwards adding maltodextrin that converts in proportion stirs, and records content and is about 11.4 iu/grams.
The oral insulin dry powder that obtains different content can be implemented down (1-21%) by that analogy and get final product.
Embodiment no longer continues to tell about, but does not represent embodiment to limit to.Embodiment can directly become the insulin content proportioning emulsion of certain content, and spray drying can become oral insulin dry powder then.
Application example
A kind of application of oral insulin dry powder:
---with the dry powder of making in the foregoing description 1 rat of feeding, matched group is oral insulin suspension and oral insulin dry powder, and is specific as follows:
Choosing of animal: 40 of adult SD rats, every body weight 175g--220g, Lanzhou University's Experimental Animal Center provides, the animal quality certification number: moving word 14-006 number of doctor; Occupancy permit SCXK (sweet) 2003-1
Experiment purpose: the hypoglycemic effect and the pharmacokinetics of check oral insulin dry powder, investigate oral insulin microcapsule dry powder with pepsin, trypsin, gastrointestinal content test, to the protective effect of insulin.Measure the rat blood sugar value with enzyme-phenol, use the serum measured by radioimmunoassay insulin content.
The method of inspection: the external release insulin assay of microcapsule forint-phenol law.
Experimental facilities: blood glucose meter, ultraviolet spectrophotometer, liquid item chromatograph, centrifuge, culture dish, calorstat etc.
Experimental rat: alloxan diabetes rats is all adopted in whole experiments, and (alloxan is available from Sigma, and rat gives 150 respectively, 180mgkg
-1, ip.) blood glucose＞16.7mmolL
-1At least 3d.Blood sugar detection adopts rapid blood sugar analyzer (Onc touch II, the U.S.).
35 of alloxan diabetes rats, under the non-empty stomach state with 2% pentobarbital sodium 36mgkg
-1Ip, jugular vein keep somewhere the heparinization conduit in advance in order to blood drawing.Respectively behind the tube feed oral administration 10,30min and after per hour survey jugular vein blood blood glucose, level before blood glucose returns to administration naturally mends the equivalent normal saline after each blood drawing immediately in conduit.As blood glucose＜2.0mmolL
-1The time immediately iv give 25%GS 5ml.Repeatedly survey the influence of blood glucose to the normal feed of rat for getting rid of, we have also carried out not having the hunger experiment (can drink water) that not administration of abdomen is not opened in anesthesia the same period to 5 diabetes rats (contrasting 2), and the same method is observed change of blood sugar.Randomly draw 5 normal rats, as reference group. oral insulin suspension combination oral insulin dry powder group, 5 in every cage, every group 2 cage.
Experiment content:
At first: measure the insulin content in the microcapsule
According to containing the principle that phenyl ring aminoacid can generate blue chemical compound with the complexation of Folin-phenol in the protein, can measure protein content with spectrophotometer.And have only insulin molecule to contain phenyl ring aminoacid in the microcapsule, so adopt the external release of Folin-phenol method research microcapsule.Measure at wavelength 500nm with 751G type spectrophotometer (Shanghai analytical tool factory), see Figure of description 3.This method sensitivity is 1u/ml.The insulin content of this oral insulin dry powder is 11.5 ± 1.0IU after testing.
Oral insulin is tested in the gastric acid percent of pass of powder: adopt the external analog gastric acid environment to test detection.Hydrochloric acid (99% chemical pure) is diluted respectively, be diluted to pH value and be 2 A solution; Be diluted to pH value and be 2.5 B solution; Add respectively again protease at A solution and trypsin at B solution.The oral insulin dry powder (insulin content is 11.5IU) of above-mentioned production is put into successively the gastric acid of these two pH values respectively and simulated solution, carry out the insulin gastric acid environment and preserve test, result such as following table
Secondly: the oral insulin dry powder that use is measured behind the content experimentizes to rat, the effectiveness of checking oral insulin dry powder.
Insulin active is determined as understanding microcapsule preparation process and whether can destroys insulin active in the microcapsule, at room temperature with microcapsule natural release 24h soluble in water, centrifugal, get supernatant and measure insulin content with Folin-phenol method, observe change of blood sugar for this supernatant of 4 diabetes rats, and to contain equivalent insulin (pharmacy of Jiangsu ten thousand nations) medicinal liquid to 2 diabetes rat intramuscular injection, the relatively variation of insulin active.
The result: external release experiment demonstration begins release from 30min, and 6～10h has discharged 65%～80%, and lasting release reaches 108h.Supernatant after the release is injected diabetes rat, and insulin wherein still keeps hypoglycemic biological activity.
20 non-empty stomaches of diabetes rat of the rat experiment of oral insulin dry powder, nothing are anaesthetized in tube feed microcapsule suspension 2～3ml in early morning., take medicine back 30min preceding, per hour survey tail vein blood glucose to 18h in taking medicine, until blood sugar recovery to control level.Be not increased to control level yet as 18h blood glucose, then per 2～4h surveys blood glucose until 48h.As blood glucose＜2.0mmolL
-1Stop to give 25% heparin 5ml.But animal ad lib, water in the experimentation.
By feeding diabetes rat to oral insulin dry powder blood sugar reducing function test, scale of feeding is by 11.5IU/kg, result of the test is as follows: A organizes to being used for hypodermic insulin fluid; The B group is oral insulin dry powder
10 rats of first group of test are the oral insulin suspension, and concrete data are as follows: being blood glucose value before the meal before the meal in the instruction card, is postprandial plasma glucose level after the meal, and unit is: u/mol
First cage:
Second cage:
10 rats of second group of test are oral insulin dry powder, medication test in 1 month blood glucose, and concrete data are as follows:
First cage:
Second cage:
The 3rd group is matched group 2, and concrete data are as follows:
Normal group:
2) be the analysis of oral insulin dry powder experiment the class value.
The test of diabetes rat is shown, give insulin to reducing and to keep blood sugar level effective by oral insulin dry powder.
Pharmacokinetic analysis shows that dry powder obviously prolongs the half-life and the average resistance time of insulin.In addition, the interior elimination of the body of insulin significantly is slower than the interior insulin of solution in the dry powder formulation.Single dose dry powder is directly sent into fasting diabetic mice gastric, and monitoring blood sugar level 72 hours is to estimate its hypoglycemic activity after the administration.Use this administering mode, blood sugar level has promptly descended 80% rapidly in treatment first hour, and hypoglycemic activity keeps 73 hours (blood glucose value is to keep between 3.1 to 6.6 to reach more than 72 hours) always, removes in 5 days.On the contrary, the insulin solutions blood glucose in first hour that gives equal number separately only reduces in 20%, 5 hour and reduces by 35%, and blood glucose gos up to baseline value rapidly afterwards.
Zooperal oral insulin dry powder among the embodiment 1 is respectively applied for the patient's experiment that substitutes metformin and injection of insulin:
Sufferer 1: clinical trial example 1
Patient name: week so-and-so sex: man's age: 69 Han nationality occupation: the land-reclaimable retired veteran cadre of group in Gansu
Diagnosis: type i diabetes
Medical history: diabetes 15 years, sooner or later respectively inject the 20IU novolin every day, takes before the trial drug before the meal that blood (mMol/L) is about about 6, and postprandial plasma glucose level (mMol/L) is about about 8
It is as follows to take oral insulin dry powder gram (every gram contains insulin 11.5IU) blood glucose value in mornings 2:
Sufferer 2: clinical trial example 2
Patient name: so-and-so sex of Liu: man's age: 45 Han nationality occupation: Jinchang, Gansu chemical industry cadre
Diagnosis: type ii diabetes
Medical history: diabetes 15 years, sooner or later respectively inject the 30IU novolin every day, takes before the trial drug before the meal that blood glucose value (mMol/L) is about about 6.2, and postprandial plasma glucose level (mMol/L) is about about 7.8
It is as follows to take oral insulin dry powder gram (every gram contains insulin 11.5IU) blood glucose value in mornings 3:
Sufferer 3: clinical trial example 3
Patient name: so-and-so sex of land: man's age: 50 Han nationality occupation: salt pan gorge, Gansu chemical industry cadre
Diagnosis: type ii diabetes
Medical history: diabetes 10 years, sooner or later respectively inject the 10IU novolin every day, takes before the trial drug before the meal that blood glucose value (mMol/L) is about about 5.5, and postprandial plasma glucose level (mMol/L) is about about 7.9
Take oral insulin dry powder 1 gram morning, it is as follows that content is that 11.5IU/g records data:
Sufferer 4: clinical trial example 4
Patient name: so-and-so sex of Gong: man's age: 55 Han nationality occupation: Inner Mongol Alxa cadre
Diagnosis: type ii diabetes
Medical history: diabetes 20 years, every day is 2 of each oral administration of metformin sooner or later, take before the trial drug before the meal that blood glucose value (mMol/L) is about about 4.5, and postprandial plasma glucose level (mMol/L) is about about 7.5
Take oral insulin dry powder 0.5 gram morning, it is as follows that content is that 11.5IU/g records blood glucose value:
Sufferer 5: clinical trial example 5
Patient name: Bao's sex: man's age: 50 Meng ethnic group occupation: Inner Mongol Alxa driver
Diagnosis: type i diabetes
Medical history: diabetes 10 years, sooner or later respectively inject the 10IU novolin every day, takes before the trial drug before the meal that blood glucose value (mMl/L) is about about 4.5, and postprandial plasma glucose level (mMol/L) is about about 7.9
Take oral insulin dry powder 1 gram morning, it is as follows that content is that 11.5IU/g records data:
Sufferer 6: clinical trial example 6
Patient name: Zhang's sex: woman's age: 55 Han nationality occupation: huge port, Tianjin petrochemical industry retired worker
Diagnosis: type ii diabetes
Medical history: diabetes 20 years, 2 of each oral administration of metformin of morning and evening every day are injected the 10IU novolin simultaneously.
Take before the trial drug before the meal that blood glucose value (mMol/L) is about about 4.5, postprandial plasma glucose level (mMol/L) is about takes oral insulin dry powder 1.5 grams 7.5 mornings, and it is as follows that content is that 11.5IU/g records blood glucose value:
Sufferer 7: clinical trial example 7
Patient name: so-and-so sex of Lee: woman's age: 65 Han nationality occupation: huge port, Tianjin petrochemical industry retired worker
Diagnosis: type ii diabetes
Medical history: diabetes 20 years, respectively inject the 20IU novolin every day sooner or later.
Before taking trial drug, blood glucose value (mMol/L) is about about 4.5 before the meal, postprandial plasma glucose level (mMol/L) is about 7.5 left sides
Right: take trial target 2 grams, insulin content 11.5IU/ gram blood glucose value is as follows:
Embodiment also has, and no longer describes in detail.Do not represent and implement limitation.
Claims (4)
1. use the method that microcapsule technology prepares oral insulin dry powder for one kind, its feature is as follows:
---the dry powder that adopts natural macromolecular material, antioxidant and insulin medicament spray drying to generate, antioxidant derives from the extraction of substance of natural plants or microorganism in this dry powder.
2. the method described in the claim 1, its feature:
---this new medicine is made up of three layer components;
---ground floor: emulsifying agent uniform dissolution in aqueous solution of water-soluble layer, starch based, monosaccharide and gelatin class macromolecular substances and HLB 〉=8;
---the second layer: the preparation of forced for vitamins breast (x): be by weight respectively with vitamin e, vitamin c or derivatives thereof: take by weighing at 0.3: 1, join in the fatty acid, fatty acid and natural carotenoid weight ratio are 0.5: 1; The emulsifying agent that adds 1≤HLB≤8 again in fatty acid is 50% by the fatty acid wt ratio, is heated to thawing, mix homogeneously.
---the 3rd layer (medicine layer): the capsule psychological treatment thing solution that antioxidant such as natural carotenoid and trypsin class medicine and gelatin substance are formed, solution mixes in solvent distillation.
3. after the mixed solution described in the claim 2 mixes in solvent distillation, under aseptic condition directly with the mixed solution drying: adopt the heating spray drying method, inlet temperature is that 140 degrees centigrade to 220 degrees centigrade, temperature of outgoing air are 30 degrees centigrade to 60 degrees centigrade, makes oral insulin dry powder.
---finished product: generate the oral insulin dry powder that contains n%, color is yellow or red (n is 0 to 30 numeral).
---with above-mentioned solution heat, heating, airtight mixing, distillation sterilization filling;
---the above-mentioned solution that mixes is adopted heating spray drying method drying;
---with the Natural antioxidant and insulin mixing such as natural carotenoids;
---the adding of forced for vitamins breast, the more effective insulin of having protected
---the mode of production of the product process using heating high temperature spray-drying method large-scale low-cost of preparation.
4. claim, the oral insulin dry powder of preparation adopt oral or add sterilized water after inject dual mode, the treatment diabetes.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111417387A (en) * | 2017-07-12 | 2020-07-14 | 罗盖特兄弟公司 | Cross-linked maltodextrin for oral delivery of biologically active substances |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030125237A1 (en) * | 2000-06-27 | 2003-07-03 | Chan-Hwa Kim | Controlled release preparation of insulin and its method |
| CN1660416A (en) * | 2004-02-27 | 2005-08-31 | 谢庆 | Method and application of preparing oral powder of insulin through microcapsule technique |
-
2011
- 2011-01-19 CN CN2011100208788A patent/CN102144976A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030125237A1 (en) * | 2000-06-27 | 2003-07-03 | Chan-Hwa Kim | Controlled release preparation of insulin and its method |
| CN1660416A (en) * | 2004-02-27 | 2005-08-31 | 谢庆 | Method and application of preparing oral powder of insulin through microcapsule technique |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111417387A (en) * | 2017-07-12 | 2020-07-14 | 罗盖特兄弟公司 | Cross-linked maltodextrin for oral delivery of biologically active substances |
| CN111417387B (en) * | 2017-07-12 | 2022-12-23 | 罗盖特兄弟公司 | Cross-linked maltodextrin for oral delivery of biologically active substances |
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