CN111821425A - Gel compound sustained-release preparation for treating type 2 diabetes and preparation method thereof - Google Patents
Gel compound sustained-release preparation for treating type 2 diabetes and preparation method thereof Download PDFInfo
- Publication number
- CN111821425A CN111821425A CN201910309872.9A CN201910309872A CN111821425A CN 111821425 A CN111821425 A CN 111821425A CN 201910309872 A CN201910309872 A CN 201910309872A CN 111821425 A CN111821425 A CN 111821425A
- Authority
- CN
- China
- Prior art keywords
- gel
- block copolymer
- sustained
- release preparation
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- 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
- A61K38/26—Glucagons
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
Abstract
The invention discloses a gel compound sustained-release preparation for treating type 2 diabetes. The gel sustained-release preparation consists of an amphiphilic block copolymer, an effective amount of a drug and a solvent. The gel sustained-release preparation is in a flowing sol state at low temperature or room temperature, and can spontaneously form thermotropic hydrogel at body temperature along with the increase of temperature. Wherein the amphiphilic block copolymer is a block copolymer formed by polyethylene glycol (PEG) as a hydrophilic block and degradable polyester as a hydrophobic block; the gel sustained-release preparation at least comprises two block copolymers, and at least one block copolymer is negatively charged in a physiological environment; the drug loaded was lixisenatide. The drug and the block copolymer carrier can generate electrostatic interaction, and the release kinetics of the drug can be effectively regulated and controlled by regulating the composition and the charge quantity of the polymer and the mixing ratio of the drug and the block copolymer carrier.
Description
Technical Field
The invention belongs to the technical field of high polymer materials and medicines, and particularly relates to a gel compound sustained-release preparation for treating type 2 diabetes and a preparation method thereof.
Background
Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia due to insufficient insulin secretion and/or insulin resistance. Diabetes is mainly divided into type I and type 2, wherein the type 2 diabetes accounts for more than 90 percent. Long-term hyperglycemia causes pathological changes of large and small blood vessels, and tissues and organs such as cardiovascular and cerebrovascular diseases, peripheral nerves, retina and the like. A range of complications lead to higher morbidity and mortality in diabetes.
To effectively control blood glucose and slow down the occurrence of complications, a variety of new therapeutic formulations have been developed. Lixisenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that acts on pancreatic islet beta cells in a glucose concentration dependent manner, promotes the biosynthesis and secretion of insulin, and is effective in preventing hypoglycemia. However, only one injection of lixisenatide is injected once a day at present, and the administration mode of frequent injection greatly increases the burden of patients.
The long-acting sustained-release preparation has been deeply researched for decades, and has the advantages of reducing the administration frequency, reducing side effects, maintaining the blood level to be stable, improving the compliance of patients and the like. The PEG/polyester thermotropic hydrogel is a drug long-acting slow-release carrier with good biocompatibility and injection minimally invasive property. The drug is in a flowable sol state at low temperature, and the drug can be loaded through simple physical mixing, and sol-gel transformation occurs with the increase of temperature to form physical hydrogel. This convenient drug encapsulation process can achieve almost 100% drug loading.
Lixisenatide is a hydrophilic polypeptide, and if the Lixisenatide is simply mixed into a PEG/polyester hydrogel system, the early sudden release of the Lixisenatide can be caused by the rapid diffusion of the drug, so that the bioavailability of the drug is reduced, and the long-acting blood sugar reducing effect cannot be achieved. However, the 6 lysines at the tail end of the lixisenatide enable the lixisenatide to be positively charged in a physiological environment, and after a negatively charged terminal group is introduced into the PEG/polyester block copolymer carrier, the drug and the polymer carrier can form a compound through electrostatic interaction, so that the early burst release of the drug is effectively reduced, and the long-acting hypoglycemic effect is realized. Meanwhile, the release kinetics of the drug can be regulated and controlled by regulating the composition and the charge quantity of the polymer and the proportion of the drug and the block copolymer carrier, so that the slow release period of the drug can be designed according to requirements.
Disclosure of Invention
According to the invention, the end group with negative charge is introduced into the PEG/polyester block copolymer thermotropic hydrogel carrier, and the slow release of the drug in the gel carrier is realized by utilizing the electrostatic interaction between the drug and the polymer carrier, so that the long-acting blood sugar reducing effect is obtained. In order to realize the purpose of the invention, the concrete scheme is as follows:
a gel compound sustained-release preparation for treating type 2 diabetes is composed of a gel carrier and a solvent, wherein the gel carrier is a block copolymer composed of polyethylene glycol serving as a hydrophilic block and polyester serving as a hydrophobic block, the gel carrier is composed of a drug and the solvent, the gel carrier forms a compound by electrostatic interaction between a negatively charged drug and a positively charged drug, and the gel compound sustained-release preparation comprises the following components in percentage by weight:
10-40 wt%, preferably 15-30 wt% of polyethylene glycol-polyester block copolymer;
0.2-2 wt% of lixisenatide;
the balance being solvent;
the block copolymer composition of the present invention:
(1) the polyethylene glycol has an average molecular weight of 600 to 20000 and a content of 10 to 90 wt.%, preferably 25 to 50 wt.%, and is designated as polymer A block;
(2) the polyester content is from 10 to 90% by weight, preferably from 50 to 75% by weight, and is designated as B polymer block;
(3) the block copolymer is ABA type or BAB type triblock copolymer, AB type diblock copolymer, A-g-B or B-g-A type graft copolymer, and (AB) n type multiblock copolymer, wherein A is polyethylene glycol, B is polyester, and n is an integer of 2 to 10;
(4) the polyester is any one of poly-DL-lactide, poly-L-lactide, polyglycolide, polyorthoester, poly-caprolactone, poly-alkyl substituted caprolactone, poly-valerolactone, polyesteramide, polyacrylate, polycarbonate and polyetherester or any form of copolymer of the above aliphatic polyesters;
(5) the block copolymer is two or more than two block copolymers, and the tail end of at least one block copolymer is connected with a functional group which is negatively charged under the physiological environment, wherein the functional end group which is negatively charged is one or more of carboxyl, sulfinic acid group, sulfonic acid group, phosphoric acid diester group, phosphoric acid ester group or amino acid group.
(6) The weight percentage of the block copolymer terminated with a negatively charged functional end group in the total block polymer is 2 to 40 wt%, preferably 10 to 25 wt%.
The gel sustained-release preparation of the present invention has injectability, is in a solution state at low temperature, can be converted into a gel state within 1 minute at 4 to 37 ℃, and preferably has a gel transition temperature of 25 to 37 ℃.
The block copolymer gel carrier of the invention is charged negatively under physiological environment.
The solvent of the gel compound sustained-release preparation is pure water, normal saline, buffer solution, tissue culture solution, cell culture solution, body fluid of animals, plants or human bodies, or other aqueous solution and medium without organic solvent as main body.
The gel compound sustained-release preparation can also be added with a regulator, and the weight percentage of the regulator in the sustained-release preparation is 0.01-15 wt%; the regulator is selected from one or more of sugar, salt, sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40, Tween 80, xylitol, oligosaccharide, chondroitin, chitin, chitosan, collagen, gelatin, protein gel, hyaluronic acid, and polyethylene glycol.
The preparation method of the gel compound sustained-release preparation for treating type 2 diabetes mellitus in the method is selected from one of the following methods:
preparing a block copolymer aqueous solution, adding a medicament, dissolving uniformly to form a gel compound sustained-release preparation, storing at the temperature of-20 ℃ or below for later use, and redissolving and injecting in vivo before use;
respectively preparing a block copolymer aqueous solution and a medicine injection, separately packaging and storing, and fully and uniformly mixing the block copolymer aqueous solution and the medicine injection before injection to prepare a gel compound sustained-release preparation;
firstly, preparing a medicine injection, then mixing the medicine injection with the block copolymer and dissolving the mixture evenly to form a gel compound sustained-release preparation, storing the gel compound sustained-release preparation at the temperature of minus 20 ℃ or below for standby, and re-dissolving and injecting in vivo before use;
mixing the block copolymer with the medicine, adding a solvent, and dissolving uniformly to obtain a gel compound sustained-release preparation; storing at-20 deg.C or below for use, and re-dissolving and injecting in vivo before use;
preparing block copolymer water solution with negative charge, adding medicine, dissolving, adding the rest block copolymer, dissolving to obtain gel compound sustained release preparation, storing at-20 deg.C or below, re-dissolving, and injecting into body.
Compared with the prior art, the gel compound sustained-release preparation for treating type 2 diabetes has the following treatment advantages: the prepared gel compound preparation can realize the slow release of the lixisenatide medicament, is in a solution state at room temperature or below and can be converted into a gel state at the temperature of a human body, and can be conveniently administrated in an injection mode; after the preparation is gelatinized in situ in vivo, the wrapped medicine can be slowly released, and the long-acting blood sugar reducing effect is achieved. Meanwhile, the release kinetics of the drug can be regulated and controlled by regulating the composition and the charge quantity of the polymer and the proportion of the drug and the block copolymer carrier, the regulation of the drug release period from days to months is achieved, and the matching of the drug release period and the degradation period of the carrier material can be realized.
Drawings
FIG. 1 is a temperature swing dynamic rheology curve for the mix-1 (25 wt%) solution of example 20.
FIG. 2 is a temperature swing dynamic rheology curve for the mix-2 (25 wt%) solution of example 21.
FIG. 3 is a temperature swing dynamic rheology curve for the mix-3 (25 wt%) solution of example 22.
FIG. 4 is a temperature swing dynamic rheology curve for the mix-4 (25 wt%) solution of example 23.
FIG. 5 release profile of a mix-1 (25 wt%) gel formulation with lixisenatide concentration of 4 mg/mL.
FIG. 6 release profile of a mix-2 (25 wt%) gel formulation with lixisenatide concentration of 4 mg/mL.
FIG. 7 release profile of a mix-3 (25 wt%) gel formulation with lixisenatide concentration of 8 mg/mL.
FIG. 8 release profile of a mix-4 (25 wt%) gel formulation with lixisenatide concentration of 8 mg/mL.
FIG. 9 is a plot of blood glucose levels in the blank, drug solution positive control, Lixisenatide mix-1 gel formulation group.
Detailed Description
The present invention is further illustrated by the following specific examples, which should not be construed as limiting the invention in any way.
Example 1
15g of bishydroxypolyethylene glycol (PEG1500) was added to a 250mL three-necked flask, and water was removed under vacuum at 130 ℃ for 3 hours. Argon GAs is introduced to cool the mixture to 80 ℃, 30g of Lactide (LA), 8g of Glycolide (GA) and 38mg of stannous octoate (containing a small amount of toluene) are added, and the mixture is vacuumized for 30 minutes at 120 ℃. Argon gas is introduced, and the temperature is raised to 150 ℃ for reaction for 12 hours. After the reaction is finished, unreacted monomers and low-boiling-point products in the system are removed by vacuum filtration for 2 hours. Pouring the product into deionized water at 80 ℃ while the product is hot, repeatedly washing for three times, and freeze-drying to obtain the BAB type triblock polymer PLGA-PEG-PLGA with the yield of about 80%. The number average and weight average molecular weights (M) of the above BAB type triblock polymers (PLGA-PEG-PLGA, Copolymer-1) were determined by gel permeation chromatography (GPC, polystyrene as a standard)n，Mw) 5100 and 5870, respectively, molecular weightCoefficient of distribution
1.15, the polymer water system has thermal gelation properties.
Example 2
15g of bishydroxypolyethylene glycol (PEG1500) was added to a 250mL three-necked flask, and water was removed under vacuum at 130 ℃ for 3 hours. Argon GAs is introduced to cool the mixture to 80 ℃, 34g of Caprolactone (CL), 3g of Glycolide (GA) and 74mg of stannous octoate (containing a small amount of toluene) are added, and the mixture is vacuumized for 30 minutes at 120 ℃. Argon gas is introduced, and the temperature is raised to 150 ℃ for reaction for 12 hours. After the reaction is finished, unreacted monomers and low-boiling-point products in the system are removed by vacuum filtration for 2 hours. Pouring the product into deionized water at 80 ℃ while the product is hot, repeatedly washing for three times, and freeze-drying to obtain the BAB type triblock polymer PCGA-PEG-PCGA with the yield of about 80%. The number average and weight average molecular weights (M) of the above BAB type triblock polymer (PCGA-PEG-PCGA, Copolymer-2) were determined by gel permeation chromatography (GPC, polystyrene as a standard)n，Mw) 8000 and 10400, respectively, molecular weight distribution coefficient
1.30, and the polymer water system has thermal gelation property.
Example 3
10g of bishydroxypolyethylene glycol (PEG1000) was added to a 250mL three-necked flask, and water was removed under vacuum at 130 ℃ for 3 hours. Argon is introduced to cool the mixture to 80 ℃, 25g of caprolactone and 50mg of stannous octoate (containing a small amount of toluene) are added, and the mixture is vacuumized for 30 minutes at 90 ℃. Argon gas was introduced, and the temperature was raised to 130 ℃ to react for 12 hours. After the reaction is finished, pouring the product into deionized water at 80 ℃ while the product is hot, repeatedly washing for three times, and freeze-drying to obtain the BAB type triblock polymer PCL-PEG-PCL with the yield of about 80%. The BAB type triblock polymer (PCL-PEG-PCL, Copoly) was measured by gel permeation chromatography (GPC, polystyrene as a standard)mer-3) number average and weight average molecular weight (M)n，Mw) 4600 and 6030, respectively, molecular weight distribution coefficients (M)n/Mw,DM) 1.31, the polymer water system has thermal gelation property.
Example 4
A250 mL three-necked flask was charged with 15g of monomethoxypolyethylene glycol (mPEG750) and water was removed under vacuum at 130 ℃ for 3 hours. Introducing argon gas, cooling to 80 ℃, adding 30g of lactide, 10g of glycolide and 38mg of stannous octoate (containing a small amount of toluene), and vacuumizing for 30 minutes at 120 ℃. Argon gas is introduced, and the temperature is raised to 150 ℃ for reaction for 12 hours. The crude product was dissolved in dichloromethane solution, precipitated with ether and dried under vacuum for 48 hours to give AB type diblock polymer, mPEG-PLGA, in about 75% yield. The number average and weight average molecular weights (M) of the AB type diblock polymers (mPEG-PLGA, Copolymer-4) were determined by gel permeation chromatography (GPC, polystyrene as a standard)n，Mw) 2600 and 3250, respectively, molecular weight distribution coefficient
1.25, the polymer water system has thermal gelation properties.
Example 5
15g of bishydroxypolyethylene glycol (PEG1500) was added to a 250mL three-necked flask, and water was removed under vacuum at 130 ℃ for 3 hours. Introducing argon gas, cooling to 80 ℃, adding 26g of lactide, 9g of caprolactone and 105mg of stannous octoate (containing a small amount of toluene), and vacuumizing for 30 minutes at 90 ℃. Argon gas was introduced, and the temperature was raised to 130 ℃ to react for 12 hours. After the reaction, the product was poured into 80 ℃ deionized water while hot, washed three times repeatedly, and freeze-dried to obtain BAB type triblock polymer PCLA-PEG-PCLA with a yield of about 75%, and the number average and weight average molecular weight (M) of the BAB type triblock polymer (PCLA-PEG-PCLA, Copolymer-5) were determined by gel permeation chromatography (GPC, polystyrene as standard)n，Mw) 6980 and 8730, respectively, molecular weight distribution coefficient
1.25, the polymer water system has thermal gelation properties.
Example 6
A250 mL three-necked flask was charged with 15g of monomethoxypolyethylene glycol (mPEG550) and water was removed in vacuo at 125 ℃ for 3 hours. Argon is introduced to cool the mixture to 80 ℃, 28g of caprolactone and 56mg of stannous octoate (containing a small amount of toluene) are added, and the mixture is vacuumized for 30 minutes at 90 ℃. Argon gas was introduced, and the temperature was raised to 130 ℃ to react for 12 hours. And then dissolving the two-block copolymer in anhydrous toluene, adding 1/2 equivalents of HDMI of mPEG, carrying out reflux reaction at 60 ℃ for 8 hours, carrying out rotary evaporation and concentration, settling in a large amount of glacial ethyl ether, and carrying out vacuum drying for 48 hours to obtain the ABA type triblock polymer mPEG-PCL-mPEG with the yield of about 65%. The number average and weight average molecular weights (M) of the ABA type triblock polymer (mPEG-PCL-mPEG, Copolymer-6) were determined by gel permeation chromatography (GPC, polystyrene as a standard)n，Mw) 3100 and 3780, respectively, molecular weight distribution coefficients
1.22, the polymer water system has thermal gelation property.
Example 7
After 15g of monomethoxypolyethylene glycol (mPEG550) was dissolved in 120mL of toluene, it was distilled to 50mL to remove residual water from the polymer. 60g of trimethylene cyclic carbonate and 150mg of stannous octoate (containing a small amount of toluene) were added and the reaction was refluxed at 120 ℃ for 24 hours. After the reaction is finished, dissolving the initial product in a dichloromethane solvent, and settling with ethyl acetate to obtain the AB type triblock polymer mPEG-PTMC with the yield of about 85%. The number average and weight average molecular weights (M) of the AB type triblock polymer (mPEG-PTMC, Copolymer-7) were determined by gel permeation chromatography (GPC, polystyrene as a standard)n，Mw) 4650 and 6320, respectively, molecular weight distribution coefficient
1.36, the polymer water system has thermal gelation properties.
Example 8
Into a 250mL three-necked flask was charged 10g of bishydroxypolyEthylene glycol (PEG1000), vacuum dewatering at 130 deg.C for 3 hr. After cooling to 80 ℃ under argon, CL18g, 8g of trimethylene carbonate and 56mg of stannous octoate (containing a small amount of toluene) were added and a vacuum was applied at 90 ℃ for 30 minutes. Argon gas was introduced, and the temperature was raised to 130 ℃ to react for 24 hours. After the reaction, the initial product was dissolved in a dichloromethane solvent, and the mixture was precipitated with glacial ethyl ether to obtain BAB type triblock polymer PCTC-PEG-PCTC in a yield of about 80%, and the number average molecular weight (M) and the weight average molecular weight (M) of the BAB type triblock polymer PCTC-PEG-PCTC, Copolymer-8 were measured by gel permeation chromatography (GPC, polystyrene as a standard)n，Mw) 5100 and 7400, respectively, molecular weight distribution coefficients
1.45, and the polymer water system has thermal gelation property.
Example 9
Following the basic procedure set forth in examples 1-8, additional block copolymers were synthesized using different molecular weight PEGs or mPEG with different monomers, the properties of which are set forth in tables 1, 2 and 3:
TABLE 1
The block polymers in the above tables all have thermotropic gelling properties. The polymer is prepared into a water solution with a certain concentration, the water solution is in a solution state when the temperature is lower than the gel transition temperature, the water solution is transformed into semisolid gel along with the temperature rise, and the process is reversible.
TABLE 2
None of the block polymers in the above table have thermal gelation properties and are soluble only in water.
TABLE 3
None of the block polymers in the above table have thermotropic gelling properties, neither polymer is soluble or only partially soluble in water.
One or more block polymers in table 1 are mixed in a ratio, dissolved in water at a temperature below the gel transition temperature, and the solution of the polymer mixture forms a gel when the temperature is above the gel transition temperature; mixing one or more block polymers of Table 1 and/or one or more block polymers of Table 2 and/or one or more block polymers of Table 3 in a ratio that dissolves in water at a temperature below the gel transition temperature and forms a gel when the temperature is above the gel transition temperature; one or more of the block copolymers of Table 2 are mixed with one or more of the block copolymers of Table 3 in a ratio that dissolves in water at temperatures below the gel transition temperature and at temperatures above the gel transition temperature, a solution of the polymer mixture forms a gel.
Example 10
15g of the Copolymer-9 of Table 1 was taken, and 4g of succinic anhydride and 2mL of pyridine were added and dissolved in 100mL of dichloromethane, followed by refluxing for 48 hours. Removing most of dichloromethane and pyridine by suspension evaporation, washing with 80 deg.C hot water (adding a few drops of 1M hydrochloric acid) to remove pyridine and dichloromethane, and freeze drying to obtain polymer material HOOC-PLGA-PEG-PLGA-COOH (Copolymer-28) with carboxyl as terminal group.
Example 11
15g of the Copolymer-10 of Table 1 was taken, and 4g of succinic anhydride and 2mL of pyridine were added and dissolved in 100mL of dichloromethane, followed by refluxing for 48 hours. Removing most of dichloromethane and pyridine by suspension evaporation, washing with 80 deg.C hot water (adding a few drops of 1M hydrochloric acid) to remove pyridine and dichloromethane, and freeze drying to obtain polymer material HOOC-PCGA-PEG-PCGA-COOH (Copolymer-29) with carboxyl as terminal group.
Example 12
20g of the Copolymer-1 of example 1 was charged into a 250mL eggplant-shaped bottle, 100mL of toluene was added thereto for azeotropic removal of water, 50mL of methylene chloride was added, the system was placed in an ice-water bath, 1.4mL of triethylamine and 10mL of a methylene chloride solution of chlorosulfonic acid (containing 0.8mL of chlorosulfonic acid) were added dropwise, and after completion of the addition, the reaction was carried out at room temperature for 80 hours. 250mL of deionized water was added and extracted 4 times with 50mL of dichloromethane, and after combining the organic phases, the system was washed three times with 150mL of 1MHCl (50 mL each) and three times with 150mL of saturated brine (50 mL each) in that order. Subsequently, the organic phase was collected and dried over anhydrous sodium sulfate overnight. After the system is filtered, the mixture is concentrated by rotary evaporation, settled in 500mL of glacial ethyl ether, and dried for 24 hours in a vacuum oven at room temperature to obtain sulfonated PLGA-PEG-PLGA (Copolymer-30).
Example 13
20g of the Copolymer-12 shown in Table 1 was put into a 250mL eggplant-shaped bottle, 100mL of toluene was added for azeotropic dehydration, 50mL of methylene chloride was added, the system was placed in an ice-water bath, and then N-hydroxysuccinimide and dicyclohexylcarbodiimide were added in equimolar amounts to the system, reacted at room temperature for 24 hours, and the precipitated dicyclohexylurea was removed by filtration to obtain a filtrate M. 0.3mol of aminoethyl phosphoric acid was dissolved in 25mL of deionized water, followed by the addition of 0.6mol of NaHCO3Then, the reaction mixture was added to the filtrate M and reacted at room temperature for 12 hours. Then, the mixture was distilled under reduced pressure, washed with chloroform, and the resulting product was dissolved in water and then adjusted to pH 3. Then decompression evaporation is carried out again, chloroform is used for dissolving, sodium salt is removed by filtration, decompression evaporation is carried out, and PCLA-PEG-PCLA dihydrogen phosphate (Copolymer-31) is obtained.
Example 14
15g of the Copolymer of example 4 was taken, 2g of succinic anhydride and 1mL of pyridine were added, and the mixture was dissolved in 100mL of dichloromethane and refluxed for 48 hours. Suspending and steaming to remove most of dichloromethane and pyridine, washing with 80 deg.C hot water (adding a few drops of 1M hydrochloric acid) to remove pyridine and dichloromethane, and freeze drying to obtain polymer material mPEG-PLGA-COOH (Copolymer-32) with carboxyl as terminal group.
Example 15
20g of the Copolymer-14 shown in Table 1 was put into a 250mL eggplant-shaped bottle, 150mL of toluene was added thereto for azeotropic dehydration, 50mL of methylene chloride was added, the system was placed in an ice-water bath, 0.8mL of triethylamine and 5mL of a methylene chloride solution of chlorosulfonic acid (containing 0.4mL of chlorosulfonic acid) were added dropwise, and after completion of the addition, the reaction was carried out at room temperature for 80 hours. 250mL of deionized water was added and extracted 4 times with 50mL of dichloromethane, and after combining the organic phases, the system was washed three times with 150mL of 1MHCl (50 mL each) and three times with 150mL of saturated brine (50 mL each) in that order. Subsequently, the organic phase was collected and dried over anhydrous sodium sulfate overnight. After the system is filtered by suction, the solution is concentrated by rotary evaporation, then is settled in 500mL of glacial ethyl ether, and is dried for 24 hours in a vacuum oven at room temperature to obtain sulfonated mPEG-PLA (Copolymer-33).
Example 16
Polymer Copolymer-1 obtained in example 1 was blended with Copolymer-2 obtained in example 2 at a ratio of 1:1 to prepare a mixed polymer phosphate solution mix-1 of 25 wt%.
Example 17
Polymer CoPolymer-1 obtained in example 1 was blended with CoPolymer-2 obtained in example 2 at a ratio of 2:1 to prepare a 25 wt% mixed polymer phosphate solution mix-2.
Example 18
The polymers Copolymer-18 and Copolymer-23 obtained in example 9 were mixed with the three block polymers Copolymer-29 obtained in example 11 to prepare a 25 wt% mixed polymer phosphate solution mix-3, in which the concentrations of Copolymer-18 and Copolymer-23 were 12 wt% and 8 wt%, respectively, and the concentration of Copolymer-29 was 5 wt%.
Example 19
The polymer Copolymer-10 obtained in example 9 was mixed with two block polymers of Copolymer-28 obtained in example 10 to prepare a 25 wt% mixed polymer phosphate solution mix-4 in which the concentration of Copolymer-10 was 20 wt% and the concentration of Copolymer-28 was 5 wt%.
Example 20
An appropriate amount of the block copolymer mixed solution mix-1 prepared in example 16 was taken, and the change of the rheological properties such as modulus, viscosity and the like of the aqueous polymer system with temperature was measured by a rotational rheometer. Temperature sweeps were performed at a fixed shear frequency (w ═ 10rad/s) at a ramp rate of 0.5 ℃/min. The results are recorded in FIG. 1. As shown in FIG. 1, the 25 wt% solution of the texture-1 polymer has a small storage modulus at room temperature and a good fluidity, while the storage modulus sharply increases around 32 ℃ and the phase transition point of the solution-gel is 34 ℃.
Example 21
An appropriate amount of the mixed solution of the block copolymer prepared in example 17, mix-2, was taken and the change of the rheological properties such as modulus, viscosity and the like of the aqueous polymer system with temperature was measured by a rotational rheometer. Temperature sweeps were performed at a fixed shear frequency (w ═ 10rad/s) at a ramp rate of 0.5 ℃/min. The results are recorded in figure 2. As shown in FIG. 2, the 25 wt% solution of the Mixture-2 polymer has a small storage modulus at room temperature and a good fluidity, while the storage modulus sharply increases around 32 ℃ and the phase transition point of the solution-gel is 34 ℃.
Example 22
An appropriate amount of the mixed solution of the block copolymer prepared in example 18, Mixture-3, was used to measure the change of the rheological properties such as modulus, viscosity and the like of the aqueous polymer system with temperature by using a rotational rheometer. Temperature sweeps were performed at a fixed shear frequency (w ═ 10rad/s) at a ramp rate of 0.5 ℃/min. The results are recorded in figure 3. As shown in FIG. 3, the 25 wt% solution of the Mixture-3 polymer has a small storage modulus at room temperature and a good fluidity, while the storage modulus sharply increases around 24 ℃ and the phase transition point of the solution-gel is 27 ℃.
Example 23
An appropriate amount of the mixed solution of the block copolymer prepared in example 19, mix-4, was taken and the change of the rheological properties such as modulus, viscosity and the like of the aqueous polymer system with temperature was measured by a rotational rheometer. Temperature sweeps were performed at a fixed shear frequency (w ═ 10rad/s) at a ramp rate of 0.5 ℃/min. The results are recorded in FIG. 4. As shown in FIG. 4, the 25 wt% solution of the Mixture-4 polymer has a small storage modulus at room temperature and a good fluidity, while the storage modulus sharply increases around 32 ℃ and the phase transition point of the solution-gel is 34 ℃.
Example 24
4mg of lixisenatide was added to 1g (25 wt%) of the mix-1 polymer solution described in example 16 and mixed well. Adding 0.5g of the drug-loaded polymer solution into a test tube, placing the test tube in a water bath shaker at 37 ℃ for 15min, adding 5mL of phosphate buffer solution (pH7.4) after gelling, periodically taking a point to measure absorbance, and measuring a drug release curve at 227nm by using a UV-vis spectrophotometer, wherein the measured drug release curve is shown in figure 5, and the drug can be continuously released for about 10 days.
Example 25
4mg of lixisenatide was added to 1g (25 wt%) of the Mixture-2 polymer solution described in example 17 and mixed well. Adding 0.5g of the drug-loaded polymer solution into a test tube, placing for 15min in a water bath shaker at 37 ℃, adding 5mL of phosphate buffer solution (pH7.4) after gelling, periodically taking a point to measure absorbance, and measuring a drug release curve at 227nm by using a UV-vis spectrophotometer, wherein the measured drug release curve is shown in figure 6, and the drug can be released continuously for more than two weeks.
Example 26
8mg of lixisenatide was added to 1g (25 wt%) of the Mixture-3 polymer solution described in example 18 and mixed well. Adding 0.5g of the drug-loaded polymer solution into a test tube, placing the test tube in a water bath shaker at 37 ℃ for 15min, adding 5mL of phosphate buffer solution (pH7.4) after gelling, periodically taking a point to measure absorbance, and measuring a drug release curve at 227nm by using a UV-vis spectrophotometer, wherein the measured drug release curve is shown in figure 7, and the drug can be released continuously for about two weeks.
Example 27
8mg of lixisenatide was added to 1g (25 wt%) of the mix-4 polymer solution described in example 19 and mixed well. Adding 0.5g of the drug-loaded polymer solution into a test tube, placing for 15min in a water bath shaker at 37 ℃, adding 5mL of phosphate buffer solution (pH7.4) after gelling, periodically taking a point to measure absorbance, and measuring a drug release curve at 227nm by using a UV-vis spectrophotometer, wherein the measured drug release curve is shown in figure 8, and the drug can be released continuously for more than two weeks.
Example 28
Preparing a mixed aqueous solution (23 wt%) of block polymers of 15 wt% of Copolymer-3, 5 wt% of Copolymer-12 and 3 wt% of Copolymer-28, adding 2mg/mL of lixisenatide medicine, dissolving uniformly to obtain a gel compound sustained-release preparation, storing at-20 ℃ or below for later use, and re-dissolving and injecting in vivo before use.
Example 29
Preparing a mixed physiological saline solution (30 wt%) of block polymers of 20 wt% of Copolymer-4, 3 wt% of Copolymer-23 and 7 wt% of Copolymer-29, adding 10mg/mL of lixisenatide medicine, uniformly dissolving to obtain a gel compound sustained release preparation, storing at the temperature of-20 ℃ or below for later use, and redissolving and injecting in vivo before use.
Example 30
Preparing a mixed normal saline solution (36 wt%) of 26 wt% Coplolymer-11 and 10 wt% Copolymer-28 block Copolymer and a lixisenatide drug injection of 20mg/mL, separately subpackaging and storing, fully and uniformly mixing the block Copolymer aqueous solution and the drug injection before injection to prepare a gel compound sustained release preparation, storing at the temperature of-20 ℃ or below for later use, and re-dissolving and injecting in vivo before use.
Example 31
Firstly, preparing 20mg/mL lixisenatide phosphate buffer solution, then mixing with 25 wt% of Copolymer-14 and 10 wt% of Copolymer-28 block Copolymer (35 wt%), uniformly blending to obtain a gel compound sustained-release preparation, storing at the temperature of-20 ℃ or below for later use, and redissolving and injecting in vivo before use.
Example 32
Block Copolymer Copolymer-2 was blended with Copolymer-30 (8:2), mixed with lixisenatide drug, and cell culture was added to give a final polymer concentration of 30 wt% and drug concentration of 6 mg/mL. Dissolving uniformly to obtain a gel compound sustained-release preparation; storing at-20 deg.C or below for use, and re-dissolving and injecting in vivo before use.
Example 33
Preparing 3 wt% of water solution of negatively charged block Copolymer Copolymer-31, adding 5mg/mL of medicine, uniformly dissolving, and adding 22 wt% of residual block Copolymer Copolymer-5 to make the final polymer concentration be 25 wt% and medicine concentration be 5 mg/mL. Dissolving uniformly to obtain gel compound sustained release preparation, storing at-20 deg.C or below, and re-dissolving and injecting in vivo before use.
Example 34
The Copolymer-1 of example 1, the Copolymer-17 of example 9 and the Copolymer-32 of example 14 were prepared as a 30 wt% aqueous polymer mixture (1:1:1), and then dissolved uniformly by adding 7mg/mL lixisenatide to prepare a gel complex sustained release preparation. Storing at-20 deg.C or below for use, and re-dissolving and injecting in vivo before use.
Example 35
The Copolymer-3 of example 3, the Copolymer-15 of example 9 and the Copolymer-33 of example 15 were prepared as a 24 wt% polymer mixed physiological saline solution at (3:2:1), and 3mg/mL lixisenatide was added and dissolved uniformly to prepare a gel complex sustained release preparation. Storing at-20 deg.C or below for use, and re-dissolving and injecting in vivo before use.
Example 36
The Copolymer-19 and Copolymer-23 in example 9 and the Copolymer-30 in example 12 were prepared as a 25 wt% aqueous polymer mixture (3:1:1), and 10mg/mL lixisenatide was added and dissolved uniformly to form a gel complex sustained release preparation. Storing at-20 deg.C or below for use, and re-dissolving and injecting in vivo before use.
Example 37
The Copolymer-16 in example 9, the Copolymer-30 in example 12 and the Copolymer-31 in example 13 were prepared into 30 wt% polymer mixed phosphate buffer solution in (8:1:1), and 12mg/mL lixisenatide was added and dissolved uniformly to form a gel complex sustained release preparation. Storing at-20 deg.C or below for use, and re-dissolving and injecting in vivo before use.
Example 38
The Copolymer-8 in example 8, the Copolymer-27 in example 9 and the Copolymer-33 in example 15 were prepared as a 24 wt% polymer mixed aqueous solution at (6:1:1), and 3mg/mL lixisenatide aqueous solution was added and dissolved uniformly to obtain a gel complex sustained release preparation. Storing at-20 deg.C or below for use, and re-dissolving and injecting in vivo before use.
Example 39
The drug-loaded gel sustained-release preparation in example 25 was added with 1% sucrose regulator to achieve in vitro two-week release of the drug.
Example 40
The drug-loaded gel sustained-release preparation in example 25 was added with 5% of sucrose regulator, and the release of the drug in vitro for one week was achieved.
EXAMPLE 41
The drug-loaded gel sustained-release preparation in example 27 was added with 5% of polyethylene glycol 400 regulator, and the in vitro release of the drug was achieved for two weeks.
Example 42
The drug-loaded gel sustained-release preparation in example 27 was added with 11% of a polyethylene glycol 200 modulator, and the release of the drug in vitro for one week was achieved.
Example 43
The drug-loaded gel sustained-release preparation in example 26 was added with 2% sorbitol regulator, and the release of the drug in vitro for 10 days was achieved.
Example 44
The drug-loaded gel sustained-release preparation in example 26 was added with 5% mannitol regulator, and the release of the drug in vitro for one week was achieved.
Example 45
The drug-loaded gel sustained-release preparation in example 27 was added with 8% xylitol regulator, and the release of the drug in vitro for one week was achieved.
Example 46
The drug-loaded gel obtained in example 24 was injected subcutaneously into db/db diabetic mice (experimental group, once injection), the blank group was injected subcutaneously twice daily with phosphate buffer solution, and the positive control group was injected subcutaneously twice daily with lixisenatide solution at 0.4 mg/mL. The subcutaneous dose per mouse was 0.2 mL. The control blood glucose levels of the blank, experimental and positive control groups are shown in fig. 9. The blank group was injected with phosphate buffer solution only and db/db diabetic mice maintained high blood glucose levels all the time, while the drug loaded gel of example 24 was injected once to maintain blood glucose to normal levels for 9 days, with similar control blood glucose levels as the positive control group injected with lixisenatide drug solution only.
Claims (6)
1. A gel compound sustained-release preparation for treating type 2 diabetes is characterized by comprising a block copolymer which is composed of polyethylene glycol as a hydrophilic block and polyester as a hydrophobic block and is used as a gel carrier, lixisenatide as a carried drug and a solvent, the gel carrier is formed into a compound by electrostatic interaction of the negative charge of the gel carrier and the positive charge of the lixisenatide drug, and the gel compound sustained-release preparation comprises the following components in percentage by weight:
the content of the polyethylene glycol-polyester block copolymer is 10 to 40 wt%, preferably 15 to 30 wt%;
the content of lixisenatide is 0.2-2 wt%;
the balance being solvent;
wherein, in the block copolymer:
(1) the polyethylene glycol has an average molecular weight of 600 to 20000, a content of 10 to 90 wt%, preferably 25 to 50 wt%, and is marked as an A polymer block;
(2) the polyester content is 10 to 90 wt.%, preferably 50 to 75 wt.%, denoted as B polymer block;
(3) the block copolymer is selected from the group consisting of ABA or BAB type triblock copolymers, AB type diblock copolymers, A-g-B or B-g-A type graft copolymers, and (AB)nA multi-block copolymer of the type wherein a is polyethylene glycol and B is a polyester, wherein n is an integer from 2 to 10;
(4) the polyester is selected from one of poly-DL-lactide, poly-L-lactide, polyglycolide, polyorthoester, poly-caprolactone, poly-alkyl substituted caprolactone, poly-valerolactone, polyesteramide, polyacrylate, polycarbonate and polyether ester or any form of copolymer of the above aliphatic polyesters;
(5) the block copolymer comprises two or more block copolymers, and the tail end of at least one block copolymer is connected with a functional group which is negatively charged under physiological environment, wherein the functional terminal group which is negatively charged is one or more of carboxyl, sulfinic acid group, sulfonic acid group, phosphoric acid diester group, phosphoric acid ester group or amino acid group, and the weight percentage of the block copolymer which is connected with the functional terminal group which is negatively charged in the tail end in the total block polymer is 2-40 wt%, preferably 10-25 wt%.
2. The gel composition sustained-release preparation for treating type 2 diabetes according to claim 1, wherein the prepared gel sustained-release preparation has injectability, is in a solution state at a low temperature, and can be transformed into a gel state within 1 minute at 4-37 ℃, and the preferred gel transition temperature is 25-37 ℃.
3. The sustained-release gel complex formulation for the treatment of type 2 diabetes mellitus as claimed in claim 1, wherein said block copolymer as a gel carrier is negatively charged under physiological environment.
4. The sustained-release preparation of gel complex for treating type 2 diabetes according to claim 1, wherein the solvent of the sustained-release preparation of gel complex is pure water, physiological saline, buffer solution, tissue culture solution, cell culture solution, body fluid of animals, plants or human body, or other aqueous solution and medium without organic solvent as main body.
5. The sustained-release gel complex preparation for treating type 2 diabetes as claimed in claim 1, wherein the sustained-release gel complex preparation further comprises a regulator, wherein the regulator is contained in the sustained-release preparation in an amount of 0.01 to 15 wt%; the regulator is selected from one or more of sugar, salt, sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40, Tween 80, xylitol, oligosaccharide, chondroitin, chitin, chitosan, collagen, gelatin, protein gel, hyaluronic acid, and polyethylene glycol.
6. A method of preparing the sustained release formulation of gel complex for the treatment of type 2 diabetes mellitus according to any one of claims 1 to 5, wherein the method of preparation is selected from one of the following:
preparing a block copolymer aqueous solution, adding a medicament, dissolving uniformly to form a gel compound sustained-release preparation, storing at the temperature of-20 ℃ or below for later use, and redissolving and injecting in vivo before use;
respectively preparing a block copolymer aqueous solution and a medicine injection, separately packaging and storing, and fully and uniformly mixing the block copolymer aqueous solution and the medicine injection before injection to prepare a gel compound sustained-release preparation;
firstly, preparing a medicine injection, then mixing the medicine injection with the block copolymer and dissolving the mixture evenly to form a gel compound sustained-release preparation, storing the gel compound sustained-release preparation at the temperature of minus 20 ℃ or below for standby, and re-dissolving and injecting in vivo before use;
mixing the block copolymer with the medicine, adding a solvent, and dissolving uniformly to obtain a gel compound sustained-release preparation; storing at-20 deg.C or below for use, and re-dissolving and injecting in vivo before use;
preparing block copolymer water solution with negative charge, adding medicine, dissolving, adding the rest block copolymer, dissolving to obtain gel compound sustained release preparation, storing at-20 deg.C or below, re-dissolving, and injecting into body.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910309872.9A CN111821425A (en) | 2019-04-17 | 2019-04-17 | Gel compound sustained-release preparation for treating type 2 diabetes and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910309872.9A CN111821425A (en) | 2019-04-17 | 2019-04-17 | Gel compound sustained-release preparation for treating type 2 diabetes and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111821425A true CN111821425A (en) | 2020-10-27 |
Family
ID=72914301
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910309872.9A Pending CN111821425A (en) | 2019-04-17 | 2019-04-17 | Gel compound sustained-release preparation for treating type 2 diabetes and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111821425A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113214462A (en) * | 2021-05-10 | 2021-08-06 | 复旦大学 | Polyethylene glycol/polyester block copolymer containing alkyl side chain, thermotropic hydrogel preparation containing polyethylene glycol/polyester block copolymer and application of thermotropic hydrogel preparation |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090203602A1 (en) * | 2006-09-01 | 2009-08-13 | Cohava Gelber | Compositions and methods for diagnosis and treatment of type 2 diabetes |
| CN104248628A (en) * | 2013-06-25 | 2014-12-31 | 深圳翰宇药业股份有限公司 | Lixisenatide controlled-release microspheres and preparation method thereof |
| CN105764491A (en) * | 2013-12-09 | 2016-07-13 | 度瑞公司 | Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same |
| CN107837229A (en) * | 2017-11-07 | 2018-03-27 | 中国药科大学 | A kind of temperature-sensitive hydrogel preparation and preparation method for being sustained Evacet |
-
2019
- 2019-04-17 CN CN201910309872.9A patent/CN111821425A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090203602A1 (en) * | 2006-09-01 | 2009-08-13 | Cohava Gelber | Compositions and methods for diagnosis and treatment of type 2 diabetes |
| CN104248628A (en) * | 2013-06-25 | 2014-12-31 | 深圳翰宇药业股份有限公司 | Lixisenatide controlled-release microspheres and preparation method thereof |
| CN105764491A (en) * | 2013-12-09 | 2016-07-13 | 度瑞公司 | Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same |
| CN107837229A (en) * | 2017-11-07 | 2018-03-27 | 中国药科大学 | A kind of temperature-sensitive hydrogel preparation and preparation method for being sustained Evacet |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113214462A (en) * | 2021-05-10 | 2021-08-06 | 复旦大学 | Polyethylene glycol/polyester block copolymer containing alkyl side chain, thermotropic hydrogel preparation containing polyethylene glycol/polyester block copolymer and application of thermotropic hydrogel preparation |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Shi et al. | PEG-based thermosensitive and biodegradable hydrogels | |
| Wu et al. | Engineering bioresponsive hydrogels toward healthcare applications | |
| KR102099981B1 (en) | Hydrogel based on a hyaluronic acid derivative modified with a galol group and use thereof | |
| KR100933580B1 (en) | Biodegradable block copolymeric compositions for drug delivery | |
| DK2521534T3 (en) | FUNCTIONALIZED TRIBLE COPOLYMERS AND COMPOSITIONS CONTAINING SUCH POLYMERS | |
| US20120164100A1 (en) | Temperature sensitive hydrogel and block copolymers | |
| US20060233857A1 (en) | Degradable elastomeric network | |
| CN1899264A (en) | Temperature sensitive type water gel medicine release system and its preparing method | |
| CN1965802B (en) | Injectable hydrogel preparation of pegylated medicament and preparing method thereof | |
| CN111346047B (en) | Thermotropic hydrogel metformin sustained-release preparation and preparation method and application thereof | |
| Guo et al. | Thermosensitive polymer hydrogel as a physical shield on colonic mucosa for colitis treatment | |
| CN111150702B (en) | Gel drug sustained release preparation and preparation method and application thereof | |
| US20160058698A1 (en) | Composition for controlled delivery of bioactive agents | |
| Wu et al. | Decisive influence of hydrophobic side chains of polyesters on thermoinduced gelation of triblock copolymer aqueous solutions | |
| CN105982845A (en) | Thermotropic hydrogel hypoglycemic drug preparation and preparing method thereof | |
| JP5653441B2 (en) | Reconfigurable reverse heat gelling polymer | |
| US7781400B2 (en) | Pharmaceutical compositions comprising dextran with a molecular weight of 1.0-100 KDA and processes for their preparation | |
| CN1916050B (en) | Injectable temperature sensitive hydrogel of poly (lactide - glycolide - p-dioxane ketone) - polyethyleneglycol block copolymer | |
| CN111821425A (en) | Gel compound sustained-release preparation for treating type 2 diabetes and preparation method thereof | |
| CN107405307B (en) | Exenatide microsphere preparation and preparation method thereof | |
| Zhang et al. | Chitosan-based injectable hydrogels with dual glucose sensors for precise control of insulin release and diabetes mellitus therapy | |
| CN111110626A (en) | Gel drug sustained-release preparation based on hydrophobic modified gemcitabine derivative and preparation method and application thereof | |
| KR101815780B1 (en) | Temperature and pH-sensitive hydrogel and the preparing method thereof | |
| WO2012059820A1 (en) | Temperature sensitive hydrogel and block copolymers | |
| CN116687868A (en) | Recombinant III type humanized collagen freeze-dried powder and preparation of redissolved solution |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20201027 |