CN116440254A - Insulin hydrogel patch for treating diabetes and preparation method thereof - Google Patents
Insulin hydrogel patch for treating diabetes and preparation method thereof Download PDFInfo
- Publication number
- CN116440254A CN116440254A CN202310489144.7A CN202310489144A CN116440254A CN 116440254 A CN116440254 A CN 116440254A CN 202310489144 A CN202310489144 A CN 202310489144A CN 116440254 A CN116440254 A CN 116440254A
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- Prior art keywords
- insulin
- hydrogel
- hydrogel patch
- stirring
- hydrogel matrix
- Prior art date
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 130
- 239000000017 hydrogel Substances 0.000 title claims abstract description 98
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- 108090001061 Insulin Proteins 0.000 title claims abstract description 65
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- 229940079593 drug Drugs 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
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- 239000003961 penetration enhancing agent Substances 0.000 claims description 9
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 8
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- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 claims description 6
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- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 5
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- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
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Abstract
The invention provides an insulin hydrogel patch for treating diabetes and a preparation method thereof, comprising the following steps: preparing a hydrogel matrix, adding 14.06-14.29% of humectant, 3.16-3.22% of framework material, 0.17-0.18% of cross-linking agent, 0.02-0.03% of complexing agent, 0.66-0.68% of excipient, 1.40-1.43% of adhesive and 73.79-78.86% of purified water into a beaker, putting the humectant into the beaker, adding the framework material, the cross-linking agent and the complexing agent, and fully stirring uniformly to obtain a phase; adding purified water into excipient and adhesive, stirring at 80deg.C, dispersing and swelling thoroughly, cooling, adding crosslinking regulator, and dissolving to obtain two phases; adding two phases into one phase, and stirring to obtain a hydrogel matrix; adding 1-5% mixed permeation promoter into hydrogel matrix, adding 0.5-1.2% active drug under continuous stirring, removing bubbles with centrifuge, drying, coating, and covering with white non-woven fabric backing. The insulin hydrogel patch is prepared by uniformly mixing insulin and the hydrogel patch, so that the medicine is uniformly dispersed, the medicine is more stable, and the curative effect of the medicine is improved.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to an insulin hydrogel patch for treating diabetes and a preparation method thereof.
Background
Insulin is a protein hormone secreted by islet beta cells within the pancreas by stimulation with endogenous or exogenous substances such as glucose, lactose, ribose, arginine, glucagon, and the like. Insulin is the only hormone in the body that reduces blood glucose while promoting glycogen, fat, protein synthesis. Exogenous insulin is mainly used for treating diabetes mellitus and is a main medicament for treating type I diabetes mellitus. Good effect, but harsh preservation conditions, easy inactivation and instability. The traditional blood sugar regulating and controlling mode of diabetics is mostly limited to subcutaneous insulin injection, pain can be caused by frequent injection and administration for a long time, inflammation is easy to occur at injection positions, and the infection risk of other diseases is increased. In recent years, the prevalence of diabetes mellitus worldwide has rapidly increased, and has become a major disease threatening the health of humans. Global diabetes prevalence was 9.3% (4.63 million) in 2019, with an estimated increase in 2030 to 10.2% (5.78 million) and 2045 to 10.9% (7 million). Discussion of efficient ways of regulating blood glucose has been a focus of medical community attention.
Compared with oral preparation, transdermal administration has the advantages of stable blood concentration, no first pass effect, small gastrointestinal tract irritation, small liver toxicity, long-acting, high safety, direct focus and the like. The most critical problem of topical transdermal formulations is to enhance the transdermal absorption of the drug, especially water-soluble drugs, with very poor transdermal properties.
Disclosure of Invention
A first object of the present invention is to provide a method for preparing an insulin hydrogel patch for treating diabetes, aiming at the problems of the prior art of oral preparation of insulin for treating diabetes.
For this purpose, the above object of the present invention is achieved by the following technical solutions:
a method for preparing an insulin hydrogel patch for treating diabetes, comprising the following steps:
s1, preparing a hydrogel matrix, adding a humectant, a framework material, a cross-linking agent, a complexing agent, an excipient, an adhesive and purified water into a beaker, wherein the weight ratio of the humectant to the framework material is 14.06-14.29%, the framework material is 3.16-3.22%, the cross-linking agent is 0.17-0.18%, the complexing agent is 0.02-0.03%, the excipient is 0.66-0.68%, the adhesive is 1.40-1.43% and the purified water is 73.79-78.86%,
putting the humectant into a beaker, adding a framework material, a cross-linking agent and a complexing agent, and fully and uniformly stirring to obtain a phase; adding excipient and binder into beaker, adding purified water, stirring at 80deg.C to fully disperse and swell, cooling, and adding crosslinking regulator to dissolve to obtain two phases; adding two phases into one phase, and continuously stirring at the speed of 300-400r/min for 30min until the two phases are uniform to obtain a hydrogel matrix;
s2, adding 1-5% of mixed permeation promoter into the hydrogel matrix, adding 0.5-1.2% of active drug under continuous stirring at the speed of 300-400r/min, removing bubbles by using a centrifuge (10 min,6000rpm,25 ℃), finally performing drying coating, and covering with a white non-woven fabric backing.
The invention can also adopt or combine the following technical proposal when adopting the technical proposal:
as a preferable technical scheme of the invention: the humectant is glycerin, the framework material is polyacrylic acid, the crosslinking agent is aluminum glycinate, the complexing agent is disodium ethylenediamine tetraacetate, the excipient is gelatin, the adhesive is polyvinylpyrrolidone K90, and the crosslinking regulator is tartaric acid.
As a preferable technical scheme of the invention: the active medicine is insulin with purity over 99%.
As a preferable technical scheme of the invention: the mixed penetration enhancer is one or more of menthol, glyceryl monolinoleate, water-soluble azone, oleoyl polyoxyethylene glyceride and propylene glycol.
A second object of the present invention is to provide an insulin hydrogel patch for treating diabetes, which addresses the problems in the prior art.
For this purpose, the above object of the present invention is achieved by the following technical solutions: an insulin hydrogel patch for treating diabetes, the hydrogel patch comprising, in weight percent: 0.5-1.2% active drug, 1-5% mixed penetration enhancer and 93.8-98.5% hydrogel matrix.
Compared with the prior art, the invention has the following beneficial effects: according to the insulin hydrogel patch for treating diabetes and the preparation method thereof, the permeation enhancer is utilized to increase the permeability of the skin, promote the drug to be delivered to the skin, and improve the targeting property and the local administration concentration of the drug, and insulin and gel are uniformly mixed to prepare the hydrogel patch, so that the drug is uniformly dispersed, the curative effect of the drug is improved well, and the compliance of patients is improved. According to the insulin hydrogel patch for treating diabetes, insulin is prepared into the carrier hydrogel patch, so that the problems of possible serious side effects caused by insulin injection, low patient compliance and the like can be effectively treated, and the local application targeting and the medication safety of the medicine are improved. Compared with injection, the invention has the advantages of more free administration position, more convenient use, more convenient preservation and the like; compared with the common gel, the gel is not easy to pollute, has uniform administration and avoids the touch and scratch of patients; compared with oral preparation, the preparation has the advantages of avoiding failure of gastrointestinal tract oral effect and less administration times. The hydrogel patch has no irritation to skin, and can be adhered to skin for a long time, so that the medicine can be slowly released for a long time, the administration time is prolonged, and the possible toxic and side effects caused by the medicine are reduced. The invention prepares the insulin hydrogel patch by uniformly mixing insulin and the hydrogel patch, so that the medicine is uniformly dispersed, the medicine is more stable, and the curative effect of the medicine is improved.
Drawings
Table 1 the cumulative permeation per unit area results of the insulin hydrogel patches of the present invention (n=4,)；
FIG. 1 is an insulin hydrogel patch of the present invention;
FIG. 2 tissue section: A. normal group; B. an insulin hydrogel patch set;
figure 3 rat blood glucose concentration change.
Detailed Description
The invention will be described in further detail with reference to the drawings and specific embodiments.
Example 1
The invention provides a preparation method of a hydrogel patch of an insulin hydrogel patch for treating diabetes, which specifically comprises the following steps:
s1, weighing 14.06mg of glycerin in a beaker, adding 3.16mg of sodium polyacrylate, 0.17mg of aluminum glycinate and 0.02mg of disodium ethylenediamine tetraacetate, and fully and uniformly stirring to obtain a phase; adding gelatin 0.66mg and polyvinylpyrrolidone K90 1.40mg into beaker, adding purified water 78.86mg, stirring at 80deg.C (600 rpm,30 min) to make the mixture fully disperse and swell, cooling, and adding tartaric acid 0.17mg to dissolve to obtain two phases; adding two phases into one phase, and continuously stirring at 300-400r/min for 30min to obtain hydrogel matrix.
S2, adding 1mg of menthol into the hydrogel matrix, adding 0.5mg of insulin under continuous stirring at a speed of 300-400r/min, removing bubbles by using a centrifugal machine (10 min,6000rpm,25 ℃), finally performing drying coating, and covering a white non-woven fabric backing, thereby obtaining the insulin hydrogel patch.
Where all values in S1 and S2 add up to 100%, this ratio is calculated as the mass ratio of the hydrogel patch.
Comparative examples 1 to 1
The hydrogel matrix was prepared as in example 1 without the addition of permeation enhancers. Adding 0.5mg of insulin into the hydrogel matrix under continuous stirring at 300-400r/min, removing bubbles (10 min,6000rpm,25 deg.C) with a centrifuge, drying, coating, and covering with white non-woven fabric backing to obtain insulin hydrogel patch.
Comparative examples 1 to 2
The hydrogel matrix was prepared as in example 1, varying the menthol ratio of the permeation enhancer. Adding 0.1mg menthol into hydrogel matrix, adding 0.5mg insulin under continuous stirring at 300-400r/min, removing bubbles (10 min,6000rpm, 25deg.C) with centrifuge, drying, coating, and covering with white non-woven fabric backing to obtain insulin hydrogel patch.
Comparative examples 1 to 3
The hydrogel matrix was prepared as in example 1, with varying types of permeation enhancers. 1mg of isopropyl myristate was added to the hydrogel matrix, and 0.5mg of insulin was added with continuous stirring at a speed of 300-400r/min, and the air bubbles were removed by using a centrifuge (10 min,6000rpm,25 ℃), and finally, the coating was dried, and a white nonwoven fabric backing was capped to obtain an insulin hydrogel patch.
Example 2
The invention provides a preparation method of a hydrogel patch of an insulin hydrogel patch for treating diabetes, which specifically comprises the following steps:
(1) 14.29mg of glycerin is weighed into a beaker, 3.22mg of sodium polyacrylate, 0.18mg of aluminum glycinate and 0.03mg of disodium ethylenediamine tetraacetate are added, and the mixture is fully and uniformly stirred to obtain a phase; adding gelatin 0.68mg and polyvinylpyrrolidone K90 1.43mg into beaker, adding purified water 73.79mg, stirring at 80deg.C (600 rpm,30 min) to make the mixture fully disperse and swell, cooling, and adding tartaric acid 0.18mg to dissolve to obtain two phases; adding two phases into one phase, and continuously stirring at 300-400r/min for 30min to obtain hydrogel matrix.
(2) 5mg of water-soluble azone and propylene glycol were added to the hydrogel matrix in a ratio of 1:1, and 1.2mg of insulin was added with continuous stirring at a rate of 300-400r/min, the air bubbles were removed using a centrifuge (10 min,6000rpm,25 ℃), finally, the coating was dried, and a white nonwoven backing was capped.
Comparative example 2-1
(1) Preparation of hydrogel matrix A preparation of the same example 2, 5.68mg of gelatin, 6.43mg of polyvinylpyrrolidone K90 were added to a beaker, 63.79mg of purified water was stirred at 80℃under heating (600 rpm,30 min) to allow swelling to be fully dispersed, and after cooling, 0.18mg of tartaric acid was added to dissolve to give a two-phase; adding two phases into one phase, and continuously stirring at 300-400r/min for 30min to obtain hydrogel matrix.
(2) 5mg of water-soluble azone and propylene glycol were added to the hydrogel matrix in a ratio of 1:1, and 1.2mg of insulin was added with continuous stirring at a rate of 300-400r/min, the air bubbles were removed using a centrifuge (10 min,6000rpm,25 ℃), finally, the coating was dried, and a white nonwoven backing was capped.
Comparative examples 2 to 2
(1) Preparation of hydrogel matrix A preparation of the same example 2, 5.68mg of gelatin, 1.43mg of polyvinylpyrrolidone K90 were added to a beaker, 68.79mg of purified water was stirred at 80℃under heating (600 rpm,30 min) to allow swelling to be fully dispersed, and after cooling, 0.18mg of tartaric acid was added to dissolve to give a two-phase; adding two phases into one phase, and continuously stirring at 300-400r/min for 30min to obtain hydrogel matrix.
(2) 5mg of water-soluble azone and propylene glycol were added to the hydrogel matrix in a ratio of 1:1, and 1mg of insulin was added with continuous stirring at a rate of 300-400r/min, the air bubbles were removed using a centrifuge (10 min,6000rpm,25 ℃), and finally, the coating was dried, capped with a white nonwoven backing.
Comparative examples 2 to 3
(1) Preparation of hydrogel matrix A preparation of the same example 2, 0.68mg of gelatin, 6.43mg of polyvinylpyrrolidone K90 were added to a beaker, 68.79mg of purified water was stirred at 80℃under heating (600 rpm,30 min) to allow full dispersion and swelling, and after cooling, 0.18mg of tartaric acid was added to dissolve to give a two-phase; adding two phases into one phase, and continuously stirring at 300-400r/min for 30min to obtain hydrogel matrix.
(2) 5mg of water-soluble azone and propylene glycol were added to the hydrogel matrix in a ratio of 1:1, and 1.2mg of insulin was added with continuous stirring at a rate of 300-400r/min, the air bubbles were removed using a centrifuge (10 min,6000rpm,25 ℃), finally, the coating was dried, and a white nonwoven backing was capped.
Example 3
The invention provides a preparation method of a hydrogel patch of an insulin hydrogel patch for treating diabetes, which specifically comprises the following steps:
(1) 14.29mg of glycerin is weighed into a beaker, 3.22mg of sodium polyacrylate, 0.18mg of aluminum glycinate and 0.03mg of disodium ethylenediamine tetraacetate are added, and the mixture is fully and uniformly stirred to obtain a phase; adding gelatin 0.68mg and polyvinylpyrrolidone K90 1.43mg into beaker, adding purified water 73.79mg, stirring at 80deg.C (600 rpm,30 min) to make the mixture fully disperse and swell, cooling, and adding tartaric acid 0.18mg to dissolve to obtain two phases; adding two phases into one phase, and continuously stirring at 300-400r/min for 30min to obtain hydrogel matrix.
(2) 5mg of glyceryl monolinoleate and oleoyl polyoxyethylene glyceride were added to the hydrogel matrix in a ratio of 3:1, 1.2mg of insulin was added with continuous stirring at a rate of 300-400r/min, air bubbles were removed using a centrifuge (10 min,6000rpm,25 ℃), and finally, the coating was dried, and a white nonwoven backing was capped.
Comparative example 3-1
(1) Preparation of hydrogel matrix two same example 3 10.29mg of glycerol was weighed into a beaker, 5.22mg of sodium polyacrylate, 2.18mg of aluminum glycinate, 0.03mg of disodium edetate were added and thoroughly stirred to obtain a phase; adding two phases into one phase, and continuously stirring at 300-400r/min for 30min to obtain hydrogel matrix.
(2) 5mg of glyceryl monolinoleate and oleoyl polyoxyethylene glyceride were added to the hydrogel matrix in a ratio of 3:1, 1.2mg of insulin was added with continuous stirring at a rate of 300-400r/min, air bubbles were removed using a centrifuge (10 min,6000rpm,25 ℃), and finally, the coating was dried, and a white nonwoven backing was capped.
Comparative example 3-2
(1) Preparation of hydrogel matrix two same example 3 12.29mg of glycerol was weighed into a beaker, 5.22mg of sodium polyacrylate, 0.18mg of aluminum glycinate, 0.03mg of disodium edetate were added and thoroughly stirred to obtain a phase; adding two phases into one phase, and continuously stirring at 300-400r/min for 30min to obtain hydrogel matrix.
(2) 5mg of glyceryl monolinoleate and oleoyl polyoxyethylene glyceride were added to the hydrogel matrix in a ratio of 3:1, 1.2mg of insulin was added with continuous stirring at a rate of 300-400r/min, air bubbles were removed using a centrifuge (10 min,6000rpm,25 ℃), and finally, the coating was dried, and a white nonwoven backing was capped.
Comparative examples 3 to 3
(1) Preparation of hydrogel matrix two same example 3 12.29mg of glycerol was weighed into a beaker, 3.22mg of sodium polyacrylate, 2.18mg of aluminum glycinate, 0.03mg of disodium edetate were added and thoroughly stirred to obtain a phase; adding two phases into one phase, and continuously stirring at 300-400r/min for 30min to obtain hydrogel matrix.
(2) 5mg of glyceryl monolinoleate and oleoyl polyoxyethylene glyceride were added to the hydrogel matrix in a ratio of 3:1, 1.2mg of insulin was added with continuous stirring at a rate of 300-400r/min, air bubbles were removed using a centrifuge (10 min,6000rpm,25 ℃), and finally, the coating was dried, and a white nonwoven backing was capped.
Appearance inspection of insulin hydrogel patch
As can be seen from FIG. 1, the finished hydrogel patches prepared in examples 1-3 have uniform thickness, smooth and clean substrate, white semitransparent shape and good formability. The whole meets the preparation requirement. The comparative examples 1-1 to 3 only changed the ratio and types of permeation enhancers, and did not significantly affect the appearance of the prepared hydrogel patch. Comparative examples 2-1 to 3 changed the ratio of two phases, and comparative examples 3-1 to 3 changed the ratio of one phase, and the prepared hydrogel patch plaster had a large number of lumps and bubbles, and the plaster surface was uneven with obvious fluctuation.
Insulin hydrogel patch irritation investigation
3 guinea pigs which are qualified in quarantine and have no skin injury are taken, a test area of 4cm multiplied by 4cm is respectively shaved on the left side and the right side of the back spine of each guinea pig by an electric shaver 24 hours before administration, the administration area is on the left side, and the blank control area is on the right side. According to the above section, a 3cm×3cm insulin hydrogel patch (example 2) was applied to the left side, no treatment was done to the right side, and the hydrogel patch was withdrawn after 24h of fixation. The skin of the application part is taken down, put into tissue fixing liquid, dehydrated and embedded, the wax block embedded with skin tissue is fixed on a slicing machine, cut into slices with the diameter of 10 mu m, and the slices are sealed and observed under an optical microscope after dyeing. Skin irritation caused by permeation enhancers is considered to be a major limitation of transdermal administration. Tissue sections showed no histopathological changes in both epidermal and dermal cells after 24h of application in the insulin hydrogel patch treated experimental group compared to the control group (fig. 2). These results indicate that the insulin hydrogel patch formulation is not skin irritant and has skin tolerance.
In vitro drug permeation study of insulin hydrogel patch
In vitro skin permeation studies were performed using a Valia-Chien double-chamber diffusion cell with a receptor chamber capacity of 5.0mL and an effective diffusion area of 0.77cm2. Fresh SD rat dorsal skin was mounted between donor and acceptor compartments of the diffusion cell with stratum corneum facing the donor compartment. Placing the cut patch on skin, overlapping the patch with the cell opening, covering with a fixed cover, fixing with a clip to avoid liquid leakage, discharging excessive bubbles in the diffusion cell, and filling 20% polyethylene glycol 400-normal saline (20% PEG-NS) in the diffusion cell receptor chamber. The whole assembly was fixed on a magnetic stirrer and stirred continuously and constantly with magnetic beads at 600rpm, and its temperature was maintained at 32.+ -. 0.5 ℃ by a circulating water bath. Samples containing 1.0mL of solution were sampled at predetermined time intervals (4, 6, 8, 10, 24, 48 h) and immediately replenished with an equal amount of fresh 20% peg-NS. Drug permeation was analyzed by HPLC at each time point, and all measurements were performed in duplicate on 3 samples. The cumulative permeation quantity (Q) was evaluated according to the following formula.
Note that: q is the accumulated permeation quantity per unit area after a plurality of hours; drug concentration; v: the volume of the receiving liquid at each time point; and A is effective penetration area. In this experiment, v0=5.0 mL, a=0.77 cm2, v=1.0 mL.
In vitro drug permeation studies were performed on optimized transporter formulations in 20% PEG-NS through rat skin using Valia-Chien double chamber diffusion cells. The cumulative permeation per unit area (Qn) at each time (t) is shown in Table 1, and it is clear from the results of the tables that the cumulative permeation per unit area per 48 hours of the insulin hydrogel patches prepared in examples 1 to 3 is 80. Mu.g.cm-2 or more. The hydrogel patches of comparative examples 1-1 to 3 were modified in the proportion and type of penetrant, and the cumulative permeation amount at 48 hours was only 25. Mu.g.cm-2 or less, and the gel patches of comparative examples 2-1 to 3 and comparative examples 3-1 to 3 were not completely adhered to the skin due to the presence of the air bubble patch mass and air bubbles, and the cumulative permeation amount at 48 hours was only 30. Mu.g.cm-2 or less.
Pharmacodynamic experiments on diabetes mellitus in rats
1. Experimental method
12 male SD rats were prepared, ranging in weight from 200 to 250kg, and divided into 4 groups, i.e., insulin solution injection group, insulin hydrogel patch group, model group and control group. Prior to formal experiments, a model of type i diabetes rats was established with Streptozotocin (STZ) induction. Feeding in SPF environment for 10 days, using 2.1% citric acid solution and 2.94% sodium citrate solution according to 1: 1.32% of the buffer solution obtained by mixing to dissolve STZ, preparing a STZ solution with the concentration of 2%, filtering and sterilizing by a 0.22 mu m filter head, and preserving at the temperature of 4 ℃ in a dark place for preparation. Each rat was intraperitoneally injected with a 2% STZ solution in an amount of 55mg/kg, and after 72 hours, the blood glucose concentration of tail vein blood was measured with a blood glucose meter, and rats having blood glucose higher than 16.7mmol/L were selected for inclusion in the experiment.
The insulin solution group was administered by intraperitoneal injection at a dose of 0.5mg, and the insulin hydrogel group was administered to the back of the dehaired rats (example 2), further fixed with a medical tape, and administered at a dose of 1mg at an area of 3cm×3 cm. After administration, the rats were allowed to freely move and drink water, blood was collected at the rat tail for 15min,30min,60min,120min,240min,300min, and blood glucose was measured with a blood glucose meter. The average value of each group of rats was recorded.
2. Experimental results
As shown in the experimental result in figure 3, the random blood sugar of the rat measured after 72 hours is larger than 16.7mmol/L, and meanwhile, the polydipsia, polyphagia and diuresis states of the rat are observed, so that the success of the modeling of the diabetes model of the rat is proved. From the experimental results of fig. 1, it can be seen that: in the positive group with intraperitoneally injected insulin, blood glucose rapidly decreased after administration, reached a minimum of 5.5mmol/L at 30min, and then gradually increased to the initial value. The administration result of the insulin hydrogel group shows that the blood sugar is respectively reduced to 50-70% after 30min and 120min after administration, the minimum value of the blood sugar can reach 7.5mmol/L, and then the initial value is slowly recovered, and the result is similar to that of the intraperitoneal injection group.
Therefore, the medicine can be delivered transdermally and distributed in skin tissues, can permeate into the skin for a long time, and can exert the curative effect for a long time, so that the medicine acts on the whole body to exert the efficacy. Wherein the penetration enhancer increases penetration into the stratum corneum, softens the intercellular matrix of the stratum corneum, and penetrates into the targeted site, releasing the drug depot. The results of the study revealed that the permeation enhancer may exert efficacy in delivering the drug into the skin. The invention provides an insulin hydrogel patch for transdermal drug delivery and a preparation method thereof. Compared with an oral dosage form, the absorption of the medicine is not influenced by gastrointestinal tract factors during transdermal administration, the peak-valley phenomenon of blood concentration caused by oral administration is avoided, the first pass effect is avoided, the constant and effective blood concentration or physiological effect can be maintained, and patients can take medicine autonomously or withdraw the medicine. Common gel and other smearing agents easily cause medicine pollution in the long-term and repeated medicine taking process, so that bacteria exceed standard, the medicine taking safety of patients is affected, and the medicine is easy to touch and scratch. The penetration enhancer in the formula influences the mobility of lipid in the stratum corneum, increases the penetration of the stratum corneum, distributes to the stratum corneum and other deeper skins more quickly, releases a drug reservoir, improves the penetration of the deep skin layers, realizes safe and effective drug delivery, and meanwhile, the hydrogel patch has a simple preparation method and strong operability.
Table 1. Cumulative permeation per unit area results for insulin hydrogel patches (n=4,)
the above detailed description is intended to illustrate the present invention by way of example only and not to limit the invention to the particular embodiments disclosed, but to limit the invention to the precise embodiments disclosed, and any modifications, equivalents, improvements, etc. that fall within the spirit and scope of the invention as defined by the appended claims.
Claims (5)
1. A method for preparing an insulin hydrogel patch for treating diabetes, comprising the following steps:
s1, preparing a hydrogel matrix, adding a humectant, a framework material, a cross-linking agent, a complexing agent, an excipient, an adhesive and purified water into a beaker, wherein the weight ratio of the humectant to the framework material is 14.06-14.29%, the framework material is 3.16-3.22%, the cross-linking agent is 0.17-0.18%, the complexing agent is 0.02-0.03%, the excipient is 0.66-0.68%, the adhesive is 1.40-1.43% and the purified water is 73.79-78.86%,
putting the humectant into a beaker, adding a framework material, a cross-linking agent and a complexing agent, and fully and uniformly stirring to obtain a phase; adding excipient and binder into beaker, adding purified water, stirring at 80deg.C to fully disperse and swell, cooling, and adding crosslinking regulator to dissolve to obtain two phases; adding two phases into one phase, and continuously stirring at the speed of 300-400r/min for 30min until the two phases are uniform to obtain a hydrogel matrix;
s2, adding 1-5% of mixed permeation promoter into the hydrogel matrix, adding 0.5-1.2% of active drug into the hydrogel matrix under continuous stirring at the speed of 300-400r/min, removing bubbles by using a centrifuge, centrifugally separating at the speed of 6000rpm for 30min at 25 ℃, finally drying and coating, and covering with a white non-woven fabric backing.
2. The method for preparing an insulin hydrogel patch for treating diabetes as claimed in claim 1, wherein: the humectant is glycerin, the framework material is polyacrylic acid, the crosslinking agent is aluminum glycinate, the complexing agent is disodium ethylenediamine tetraacetate, the excipient is gelatin, the adhesive is polyvinylpyrrolidone K90, and the crosslinking regulator is tartaric acid.
3. The method for preparing an insulin hydrogel patch for treating diabetes as claimed in claim 1, wherein: the active medicine is insulin with purity over 99%.
4. The method for preparing an insulin hydrogel patch for treating diabetes as claimed in claim 1, wherein: the mixed penetration enhancer is one or more of menthol, glyceryl monolinoleate, water-soluble azone, oleoyl polyoxyethylene glyceride and propylene glycol.
5. A hydrogel patch prepared by the method of any one of claims 1-4, characterized in that: the hydrogel patch comprises the following components in percentage by weight: 0.5-1.2% active drug, 1-5% mixed penetration enhancer and 93.8-98.5% hydrogel matrix.
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