CN106581646A - Oral insulin composition - Google Patents
Oral insulin composition Download PDFInfo
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- CN106581646A CN106581646A CN201610959225.9A CN201610959225A CN106581646A CN 106581646 A CN106581646 A CN 106581646A CN 201610959225 A CN201610959225 A CN 201610959225A CN 106581646 A CN106581646 A CN 106581646A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
The invention provides an oral insulin composition. The composition comprises the following components in parts by weight: 1 part of insulin, 0.01-0.05 part of sodium glycocholate, 10-50 parts of sodium taurocholate, 130-150 parts of lecithin, 0.5-5 parts of cholesterol, 1-1.5 parts of bilirubin, 0.01-0.1 part of chloroquine, 10-50 parts of microcrystalline cellulose, and 2-5 parts of gelatin. The invention also provides a preparation method of the oral insulin composition. The duration time of insulin reaches 3 days or above due to the oral insulin composition, and at the same time, compared with saled long-acting insulin, the composition has better hypoglycemic effects.
Description
Technical field
The present invention relates to pharmaceutical grade protein field, more particularly, to oral insulin composition.
Background technology
Insulin is used to treat the existing 88 years history of diabetes as hypoglycemic Biochemical Drugs, is still insulin dependency so far
The drug of first choice of patients with type Ⅰ DM (IDDM) patient, be also increasing non-insulin-dependent diabetes mellitus (NIDDM) patient must
Indispensable medicine.Clinical treatment is more likely to use insulin as early as possible to type ii diabetes (2DM) patient at present, can so make
Islet cellss are repaired, while preferably reducing the complication caused by diabetes.But as insulin is polypeptide drug,
Can do not absorbed by the proteolytic degradation of intestines and stomach, institute orally treatment be almost it is invalid, for this purpose, clinical
Conventional insulin injection treatment.Parenteral is generally needed to give, such as subcutaneous injection.Therefore, most of diabeticss are often
Want oneself secondary subcutaneous injection insulin more than a day.However, a variety of limitation of additional drawbacks are insulin treatments daily
Some shortcomings, such as pain, inconvenience, continually monitor blood-glucose, patient's poor compliance poor for applicability and pancreas after the meal
Island element utilizability is difficult to match with GLPP demand for control.If additionally, the insulin for giving is in long time, example
There is provided therapeutical effect to be likely to cause hypoglycemia after such as causing elevated glucose level to be lowered because of dining.These situations are led to
Often result in glycemic control insufficient, it is believed that this chronic complicating diseases (comorbidity) related to many diabetes is relevant.
Additionally, for example by giving insulin in the injection position (and mode) inconsistent with normal physiological route of delivery
Hyperinsulinemia (haemoconcentration of insulin is raised) can occur.Insulin is circulated in blood with free monomer form, its
Volume of distribution is close to the volume of extracellular fluid.In fasted condition, in normal healthy people, insulin is dense in door (vein) blood
Degree is, e.g., from about 2-4ng/mL, and whole body (periphery) insulin concentration is, e.g., from about 0.5ng/mL, is converted to such as 5:1 ratio
Example.In the diabeticss that subcutaneous injection receives insulin, it is for about 0.75 that portal vein is become with the ratio of periphery:1.Therefore, exist
In this diabeticss, liver could not be adequately controlled the insulin concentration needed for blood glucose, although islets of langerhans in peripheral circulation
The concentration of element is higher than finding in health objects.Whole body insulin level is raised may cause glucose uptake, Glycogen synthesis, sugar
Zymolysis, fatty acid synthesis, hydrocortisone synthesis and triacylglycerol synthesis increase, and cause the key that glucose utilization can be caused to increase
Gene expression.
Therefore, want to for a long time prepare and neither change insulins combinations of the physiology clinical activity again without the need for injection
Thing.For safety and convenient consideration, it is especially desirable route of administration orally to give insulin, because it reduces as far as possible
Or eliminate the Jing discomforts that often subcutaneous injection is caused repeatedly.
The history in development existing more than 40 years of oral insulin.It is big about the research of insulin oral preparation both at home and abroad at present
It is centered around the stabilizer for finding insulin, absorption enhancer and using macromolecule as carrier more, and adds protease inhibitor
Microcapsule, microsphere, liposome or emulsion etc., but these preparation common problems are absorption differences, and bioavailability is low.From discovery
Since insulin, so far, people think, because the protein degradation enzyme in digestive tract inactivates can insulin, it is taken as that
In mammalian digestive tract, (being exactly intestinal) can not possibly there are the insulin of biological activity.Chinese patent application
201510445981.5 disclose a kind of oral insulin liposome, microsphere (capsule), the prescription of nanoparticle (capsule) sublingual lozenge and
Preparation method.Chinese patent application 201510403993.1 discloses a kind of preparation method of enteric insulin preparation.In
State's patent application 201210494656.4 discloses a kind of preparation method of the slow control-release microsphere of long-acting oral insulin.Thousand side of people
Hundred meters from anti-proteasome degradation, set out, and devises various non-injection insulin systems by the angle for avoiding the liver first pass effect
Agent.Though the Development Status report of oral insulin is more, application is difficult, and practical application is not yet seen in clinical report.It is right
There is not yet breakthrough, the bioavailability of oral insulin is low, no for the research of proteasome degradation inhibitor and absorption enhancers
And the 20% of injection dosage, the problem of Simultaneous Stabilization can not also solve.This for a long time oral insulin can not appear on the market
Main cause.
This area is there remains a need to oral insulin.
The content of the invention
The technical problem to be solved in the present invention
The bioavailability of the oral insulin of prior art is low, and not as good as the 20% of injection dosage, Simultaneous Stabilization is asked
Topic can not also be solved.About 24 hours current protamine zine insulin persistent period, while having the disadvantage that drug absorption is poor, drug effect is unstable
It is fixed.Protamine zine insulin is not general alone, often shares with short-acting insulin, can not make intravenous drip.
The technological means of the present invention
The invention provides oral insulin composition, which includes insulin, NaGC, sodium taurocholate, lecithin
Fat, cholesterol, bilirubin, chloroquine, Microcrystalline Cellulose and gelatin, the weight portion of each component is：1 weight portion of insulin, sweet ammonia gallbladder
Sour sodium 0.01-0.05 weight portions, 25 weight portion of sodium taurocholate, lecithin 130-150 weight portions, cholesterol 0.5-5 weight portions,
Bilirubin 0.01-0.1 weight portions, chloroquine 0.01-0.1 weight portions, Microcrystalline Cellulose 10-50 weight portion and gelatin 2-5 weight portions.
The technique effect that the present invention is realized
The present invention is found that by substantial amounts of experiment can be by insulin using the oral insulin composition of the present invention
More than 3 days persistent period, it is significantly higher than 24 hours of presently commercially available product or so.Meanwhile, the oral insulin combination of the present invention
Thing is compared with commercially available protamine zine insulin with more preferable hypoglycemic effect.
The invention provides herein below：
1. a kind of oral insulin composition, it is solid which includes insulin, NaGC, sodium taurocholate, lecithin, gallbladder
Alcohol, bilirubin, chloroquine, Microcrystalline Cellulose and gelatin, the weight portion of each component is：1 weight portion of insulin, NaGC
0.01-0.05 weight portions, sodium taurocholate 10-50 weight portions, lecithin 130-150 weight portions, cholesterol 0.5-5 weight portions,
Bilirubin 0.01-0.1 weight portions, chloroquine 0.01-0.1 weight portions, Microcrystalline Cellulose 10-50 weight portion and gelatin 2-5 weight portions.
2. the oral insulin composition according to item 1, the oral insulin composition further comprising biguanideses,
Study of Thiazolidinedione derivatives as Insulin Sensitizer, sulphanylureas, prandial glucose regulator, alpha-glucosidase inhibitor or non-islets of langerhans
Plain glucose-lowering hormonal agents for diabetes.
3. the oral insulin composition according to any one of item 1-2, wherein the insulin is ultrashort effect islets of langerhans
Element, short-acting insulin, intermediate-acting insulinses, protamine zine insulin or Mixed insulin.
4. the oral insulin composition according to any one of item 1-3, wherein the NaGC is 0.02 weight
Amount part, sodium taurocholate is 25 weight portions, and lecithin is 145 weight portions, and cholesterol is 0.7 weight portion, and bilirubin is 0.2 weight
Part, chloroquine is 0.05 weight portion, and Microcrystalline Cellulose is 25 weight portions, and/or gelatin is 3 weight portions.
5. the preparation method of the oral insulin composition of any one of 1-4, which includes：
1) insulin adds hydrochloric acid solution dissolving, adjusts pH value as 4-5 with sodium hydroxide solution after dissolving；
2) gelatin, chloroquine and Microcrystalline Cellulose add distilled water to be dissolved into gelatin mixed solution；
3), in insulin solutions being added the gelatin mixed solution under agitation, mix homogeneously is molten with 10%w/vNaOH
Liquid adjusts pH5-8, complex to separate out, and forms insulin complex substance suspension；
4) Sodium glycyl-cholate, sodium taurocholate, lecithin, cholesterol, bilirubin and chloroquine add anhydrous alcohol solution Cheng Rong
Liquid, decompression is lower to reclaim ethanol, drains and prepares mixed solution；
5) above-mentioned mixed solution is added in insulin complex substance suspension, insulin complex substance liposome is formed；
6) insulin complex substance liposome adds Microcrystalline Cellulose, and dispersed with stirring is uniform, lyophilization；
7) dried cake is ground in mortar,
The weight portion of wherein each component is：1 weight portion of insulin, NaGC 0.01-0.05 weight portions, taurocholic acid
Sodium 10-50 weight portions, lecithin 130-150 weight portions, cholesterol 0.5-5 weight portions, bilirubin 0.01-0.1 weight portions, chloroquine
0.01-0.1 weight portions, Microcrystalline Cellulose 10-50 weight portion and gelatin 2-5 weight portions.
Specific embodiment
Following examples are intended to each embodiment for illustrating the present invention.Therefore, the specific embodiment of discussion should not be solved
It is interpreted as limiting the scope of the present invention.For those skilled in the art's meeting it is evident that can be in the model without departing from the present invention
Various equivalents are carried out on the premise of enclosing, is changed and modifications, and it should be understood that such equivalents are included in this
Wen Zhong.
Insulin
Insulin is by endogenouss or exogenous material such as glucose, Lactose, ribose, essence by the beta Cell of islet in pancreas
The stimulation of propylhomoserin, glucagon etc. and a kind of proteohormone for secreting.Insulin is uniquely to drop hypoglycemic sharp in body
Element, while promoting glycogen, fat, protein synthesis.Exogenous insulin is mainly used to treating diabetes.
The species of current insulin
Rapid-effect insulin
There are Humalog (insulin lispro) and novorapid (Insulin Aspart) etc..Work within 10～20 minutes after this product injection,
It is effect peak within 40 minutes, acting duration 3～5 hours can be injected before the meal.
Short-acting insulin
There are two kinds of pig and insulin human.Novolin R, HumR and Gan Shu continuous heavy rains R are insulin human.30 points after this product injection
Clock starts effect, continues 5～7 hours, can be used for subcutaneous, intramuscular injection and intravenous drip, typically in 30 minutes subcutaneous notes before the meal
Penetrate.
Intermediate-acting insulinses
There are Novolin N, Humulin R N and Gan Shu continuous heavy rain N.Work within 3 hours after this product injection, be effect peak within 6～8 hours, hold
The continuous time is 14～16 hours.The length of acting duration is relevant with the dosage of injection.Intermediate-acting insulinses can be with short-acting pancreas
Island element hybrid injection, can also be used alone.Injection once or twice, should be determined intermediate-acting insulinses according to the state of an illness daily.It is subcutaneous
Or intramuscular injection, but can not intravenous drip.Intermediate-acting insulinses are suspensions, should be shaken up before extraction.
Protamine zine insulin (includes protamine zinc insulin)
(insulin Glargine), Levemir (Insulin Detemir) if the time comes, this product is generally daily to inject at dusk, during action
Between be 1.5 hours, effect steadily can keep 22 hours or so, and be not susceptible to Nocturnal hypoglycemia, the untoward reaction of increased weight
Also it is less；Domestic protamine zine insulin is protamine zinc porcine insulin, already in Clinical practice.Start within 4 hours after this product injection
Work, be effect peak within 8～12 hours, about 24 hours persistent period, which has the disadvantage that drug absorption is poor, and drug effect is unstable.It is long-acting
Insulin is not general alone, often shares with short-acting insulin, can not make intravenous drip.
Mixed insulin
It is by the short-acting insulin system being pre-mixed by different proportion (30/70/, 50/50,70/30) with intermediate-acting insulinses
Agent, such as Novolin 30R are the insulin that 30% Novolin R is pre-mixed with 70% Novolin N.Select 30/70 or 50/50,70/
30 is early after the meal and noon level of postprandial blood sugar is determining a dose subcutaneous injection before breakfast according to patient；After patient's dinner
And morning next day blood sugar level is determining subcutaneous doses before dinner.
The component of compositionss
Microcrystalline Cellulose is a kind of purification, the cellulose of part depolymerization, white, odorless, tasteless, is made up of small porous particle
Crystalline powder.In pharmaceuticals industry, Microcrystalline Cellulose is commonly used for adsorbent, suspending agent, diluent, disintegrating agent.Microcrystalline cellulose
Element is widely used in pharmaceutical preparation, is mainly used as diluent and binding agent in oral tablet and capsule, cannot be only used for wet method
Granulation can also be used for dry method direct compression.Also certain lubrication and disintegration, it is highly useful in prepared by tablet.Crystallite is fine
Dimension element also is used as the slow releasing agent of medicine.Slow release process is the loose structure that carrier is entered by active substance.Active substance is divided
Between son, hydrogen bond is included, and after being dried, active substance is fixed.As water is in the capillary piping of polymer support when active substance discharges
System internal diffusion causes swollen, carrier and is destroyed by the chemical combination key between fixed active substance, and active substance lentamente discharges
Out.
Chloroquine is initially used to treat malaria, and purposes gradually expands later.Chloroquine can delay the degraded of insulin, the pancreas in blood
Island element concentration is raised so as to strengthen its hypoglycemic activity.
Sodium glycyl-cholate, is also called NaGC.It is reported that, islets of langerhans is sucked from nasal spray when patient has dinner and just starts
Element, is put into 15u insulins in 1% glycocholic acid sodium solution every time with the deficiency for making up firm Meal-time insulin secretion；Fat
Sour NaGC Emulsion promotes oral insulin to absorb, used as absorption enhancer.In addition, Liu Hui et al. (several enzyme inhibitors
Impact to insulin intestinal absorption,《Acta Pharmaceutica Sinica》,2004,39(2):140-143) report enzyme inhibitor and improve insulin
The order of hypoglycemic effect is:Leupeptin>NaGC>Bacitracin>Bestatin>Guang albumen；Wherein NaGC
Also there is infiltration facilitation with bacitracin.
Sodium taurocholate purposes includes lipase accelerator, anion remover, for the dissolving of protein.It was reported that, cattle
Sulphur sodium cholate can be used as absorption enhancer in insulin preparation.
The biolvgical name of lecithin is phosphatidylcholine, is content highest phospholipid in tissue, is to constitute neural group
The important component knitted, belongs to higher nerve nutrient.Liposome is mainly made up of phospholipid and cholesterol, and wherein cholesterol is to lipid
The physicochemical properties of body have large effect.
Bilirubin is one kind of bile pigments, and it is the primary pigments in human bile, in orange-yellow.It is internal iron porphyrin
The main metabolites of compound, it is toxic, irreversible infringement can be caused to brain and nervous system, but also have antioxidant work(
Can, the oxidation of linoleic acid and phospholipid can be suppressed.But, the bilirubin of low concentration but can effectively be removed and either be existed in vitro
Spoke free radical excessively produced by chemical reaction in simple solution or in multiphasic liposomeses.
Embodiment
Embodiment 1：The preparation of analgesic composition
1) insulin 1g adds hydrochloric acid solution (pH1-2) 10ml dissolvings, with sodium hydroxide solution (10%-20%) after dissolving
PH value is adjusted to be 4；
2) gelatin 3g adds distilled water 150ml to be dissolved into gelatin solution；
3) insulin solutions are added in gelatin solution under agitation, mix homogeneously, pH5-8 are adjusted with 10%NaOH solution,
Complex is separated out, and forms the gelatin-compounded thing suspension of insulin；
4) glycocholic acid 0.02g, sodium taurocholate 25g, lecithin 145g, cholesterol 0.7g, bilirubin 0.2g and chloroquine
0.05g adds anhydrous alcohol solution into solution, and decompression is lower to reclaim ethanol, drains and prepares mixed solution；
5) above-mentioned mixed solution is added in the gelatin-compounded thing suspension of insulin, insulin complex substance liposome is formed；
6) insulin complex substance liposome adds 25g Microcrystalline Cellulose, and dispersed with stirring is uniform, lyophilization；
7) dried cake is ground in mortar, addition blots agent micropowder silica gel into microgranule, crosses 32 mesh sieves, obtains final product pancreas
Island element microgranule.Sealing, freezer storage.
Embodiment 2：Analgesic composition is compared with the vivo efficacy of commercially available protamine zine insulin
Experimental design：
Animal：Animal pure lines SD rats (Nanjing Jun Ke biological engineering company limited), 30, male and female half and half, age in days (60 ±
10) day, body weight 180-220 gram；Standard particle feedstuff；Packet is fed, and after experimental day, after next day medicine feed, every group of animal is fixed on an equal basis
Amount feeding (every animal daily feeding 25-30g), free water.
Laboratory temperature：18-25 DEG C, relative humidity：40%-70%.
Reagent：Streptozocin, Merck Products.
Experimental technique：
The preparation of type i diabetes model：After rat is fed 7 days, fasting 36h, before experiment by 0.1M citric acid solns and
Three sodium solution of 0.1M citric acid is made into the buffer solution of PH=4.5, and experiment is molten when the streptozocin that daily buffer solution is made into 1%
Liquid, is injected by 10mg/200g single is.Glucose Liquid is fed afterwards.Tail is cut after 36h and takes blood, blood is determined with micro blood glucose meter
Sugar, is arranged as diabetes model with preprandial glucose >=7mMol/L.Blood glucose intact animal is randomly divided into into 1 group；Diabetic animal is random
It is divided into 4 groups；Per group of 10 animals.
Each group dosage：
(1) blood glucose normal group：Chow diet is fed, is not administered；
(2) hyperglycemia model group：Chow diet is fed, is not administered；
(3) oral insulin group：Chow diet is fed, every rat is treated with oral insulin gavage, and total acceptable dose is
0.1mg/kg/ days insulins；
(4) injection of insulin agent matched group：The commercially available protamine zine insulin of every animal lumbar injection, total acceptable dose is
0.1mg/kg/ days insulins (LANTUS, Aventis Pharma Deutschland GmbH)；
(5) blood-sampling method：With tail blood taking method is cut, administration measured preprandial glucose in same time point in continuous three days after one day.
Testing index：Blood glucose is measured using blood glucose meter.Every group of blood glucose measurement meansigma methodss are following (n=10).
Experimental result：
The inventors discovered that the oral insulin of the present invention can realize than commercially available protamine zine insulin it is longer effective
Property, and possess more preferable hypoglycemic effect.
Although preferred embodiment has been described above, for those skilled in the art's meeting is it is evident that can
So that modification is made on the premise of without departing from the displosure.Think that such modification is the possible modification included in scope of disclosure.
Claims (5)
1. a kind of oral insulin composition, its include insulin, NaGC, sodium taurocholate, lecithin, cholesterol,
Bilirubin, chloroquine, Microcrystalline Cellulose and gelatin, the weight portion of each component is：1 weight portion of insulin, NaGC 0.01-
0.05 weight portion, sodium taurocholate 10-50 weight portions, lecithin 130-150 weight portions, cholesterol 0.5-5 weight portions, bilirubin
0.01-0.1 weight portions, chloroquine 0.01-0.1 weight portions, Microcrystalline Cellulose 10-50 weight portion and gelatin 2-5 weight portions.
2. oral insulin composition according to claim 1, the oral insulin composition further include biguanide
Class, Study of Thiazolidinedione derivatives as Insulin Sensitizer, sulphanylureas, prandial glucose regulator, alpha-glucosidase inhibitor or non-pancreas
Island element glucose-lowering hormonal agents for diabetes.
3. oral insulin composition according to claim 1, wherein the insulin is Rapid-effect insulin, short-acting pancreas
Island element, intermediate-acting insulinses, protamine zine insulin or Mixed insulin.
4. oral insulin composition according to claim 1, wherein the NaGC is 0.02 weight portion, cattle sulphur
Sodium cholate is 25 weight portions, and lecithin is 145 weight portions, and cholesterol is 0.7 weight portion, and bilirubin is 0.2 weight portion, and chloroquine is
0.05 weight portion, Microcrystalline Cellulose is 25 weight portions, and/or gelatin is 3 weight portions.
5. the preparation method of the oral insulin composition of any one of claim 1-4, which includes：
1) insulin adds hydrochloric acid solution dissolving, adjusts pH value as 4-5 with sodium hydroxide solution after dissolving；
2) gelatin, chloroquine and Microcrystalline Cellulose add distilled water to be dissolved into gelatin mixed solution；
3), in insulin solutions being added the gelatin mixed solution under agitation, mix homogeneously is adjusted with 10%w/vNaOH solution
PH5-8, complex are separated out, and form insulin complex substance suspension；
4) Sodium glycyl-cholate, sodium taurocholate, lecithin, cholesterol, bilirubin and chloroquine add anhydrous alcohol solution into solution, subtract
Ethanol is reclaimed in pressure, is drained and is prepared mixed solution；
5) above-mentioned mixed solution is added in insulin complex substance suspension, insulin complex substance liposome is formed；
6) insulin complex substance liposome adds Microcrystalline Cellulose, and dispersed with stirring is uniform, lyophilization；
7) dried cake is ground in mortar,
The weight portion of wherein each component is：1 weight portion of insulin, NaGC 0.01-0.05 weight portions, sodium taurocholate 25
Weight portion, lecithin 130-150 weight portions, cholesterol 0.5-5 weight portions, bilirubin 0.01-0.1 weight portions, chloroquine 0.01-
0.1 weight portion, Microcrystalline Cellulose 10-50 weight portion and gelatin 2-5 weight portions.
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| CN109395088A (en) * | 2017-08-15 | 2019-03-01 | 江苏平衡生物医药科技有限公司 | A kind of ligand being used in combination with protein-based medicinal active ingredient and oral protein class pharmaceutical preparation |
| CN109620832A (en) * | 2019-01-14 | 2019-04-16 | 大连大学 | Glycocholic acid is preparing the application in resisting hyperplasia of mammary glands drug |
| CN109620832B (en) * | 2019-01-14 | 2021-01-01 | 大连大学 | Application of glycocholic acid in preparation of anti-hyperplasia of mammary glands medicine |
| CN114099645A (en) * | 2021-11-15 | 2022-03-01 | 重庆医科大学附属第二医院 | Pharmaceutical composition for repairing corneal tissue by using insulin nano system and application thereof |
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