CN115350268B - A preparation for treating diabetes, microneedle and preparation process thereof - Google Patents
A preparation for treating diabetes, microneedle and preparation process thereof Download PDFInfo
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- CN115350268B CN115350268B CN202211018327.2A CN202211018327A CN115350268B CN 115350268 B CN115350268 B CN 115350268B CN 202211018327 A CN202211018327 A CN 202211018327A CN 115350268 B CN115350268 B CN 115350268B
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- microneedle
- nanocellulose
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- based hydrogel
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Abstract
为克服现有微针无法实现血糖持续、可控调节和容易断裂造成皮肤内发炎、感染的问题，本发明提供了一种用于治疗糖尿病的制剂，包括纳米纤维素基水凝胶、二肽基肽酶‑4抑制剂、葡萄糖激酶。本发明还提供一种载有所述制剂的微针。同时，本发明还公开了上述微针的制备方法，包括以下步骤：先将所述形成内层的溶液导入成型模具上，通过刮板将溶液刮涂至所述成型模具的成型腔内，真空干燥后脱模，得到内层微针，重新向所述成型模具的成型腔内注入外层溶液，再将所述内层微针插入盛有外层溶液的成型腔内，真空干燥、脱模后得到所述微针。In order to overcome the problems that existing microneedles cannot achieve continuous and controllable regulation of blood sugar and are easy to break, causing inflammation and infection in the skin, the present invention provides a preparation for treating diabetes, including nanocellulose-based hydrogel, dipeptidyl peptidase-4 inhibitor, and glucokinase. The present invention also provides a microneedle loaded with the preparation. At the same time, the present invention also discloses a method for preparing the above-mentioned microneedles, comprising the following steps: first introducing the solution forming the inner layer into a molding mold, scraping the solution into the molding cavity of the molding mold by a scraper, demolding after vacuum drying, obtaining inner layer microneedles, re-injecting the outer layer solution into the molding cavity of the molding mold, and then inserting the inner layer microneedles into the molding cavity containing the outer layer solution, and obtaining the microneedles after vacuum drying and demolding.
Description
Technical Field
The invention belongs to the technical field of metabolic disease medicines, and in particular relates to a preparation for treating diabetes, a microneedle and a preparation process thereof.
Background
Diabetes is a metabolic disease characterized by chronic hyperglycemia due to defective or impaired insulin secretion, which has a serious impact on the physical health of patients, and it is required to prevent a series of functional disorders and damage caused by diabetes by timely controlling blood glucose levels. Currently, clinically common sulfonylurea drugs include gliquidone, glipizide, glibenclamide, gliclazide and the like. The main mechanism of the medicine for treating diabetes is to inhibit the closing of ATP sensitive potassium ion channel of cell membrane, reduce the outflow of potassium ion, raise the concentration of potassium ion in cell and start insulin release by beta cell of pancreas islet to further realize the function of lowering blood sugar. However, if the dosage of the medicine exceeds the actual requirement range, hypoglycemia may occur, and the life and health of the patient may be seriously endangered.
In the prior art, diabetes treatment medicines such as insulin are delivered to a human body by adopting a microneedle mode, but most of the prior art mainly comprises hollow microneedles or solid microneedles, and the purpose is mainly to control the quantity of the delivered medicines. However, in practical use, there are problems with either hollow or solid microneedles. Firstly, although the delivery amount of the micro-needles can be controlled, the glucose content in the patient cannot be accurately judged, so that the blood sugar level cannot be accurately controlled, and secondly, the hollow micro-needles and the solid micro-needles are made of hard materials such as metal, and the situation that the needles are broken in the skin easily occurs, so that skin inflammation and infection are caused.
Disclosure of Invention
Aiming at the problems that the existing micro-needle cannot realize continuous and controllable regulation of blood sugar and is easy to break to cause inflammation and infection in skin, the invention provides a medicine for treating diabetes, the micro-needle and a preparation method thereof.
The technical scheme adopted by the invention for solving the technical problems is as follows:
The invention provides a medicine for treating diabetes, which comprises nanocellulose-based hydrogel, a dipeptidyl peptidase-4 inhibitor and glucokinase.
Further, the mass ratio of the nanocellulose-based hydrogel to the dipeptidyl peptidase-4 inhibitor to the glucokinase is (3-8): 5-10): 1-2.
Further, the nanocellulose-based hydrogel is in a vesicle structure, and the dipeptidyl peptidase-4 inhibitor is wrapped in the nanocellulose-based hydrogel.
Further, the dipeptidyl peptidase-4 inhibitor includes one or more of saxagliptin, vildagliptin, alogliptin, and linagliptin.
The preparation method of the nanocellulose-based hydrogel comprises the steps of obtaining a lignocellulose skeleton in wood by a delignification method as a base material, softening the lignocellulose skeleton by alkali treatment, and compositing the lignocellulose skeleton with polyacrylamide gel to obtain the nanocellulose-based hydrogel.
The invention also provides a microneedle for treating diabetes, which is loaded with the medicament for treating diabetes.
Further, the microneedle is a layered microneedle, and comprises an outer layer and an inner layer, wherein the solution forming the outer layer comprises glucokinase, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose, sucrose, sodium chloride and tris (hydroxymethyl) aminomethane, and the solution forming the inner layer comprises nanocellulose-based hydrogel, dipeptidyl peptidase-4 inhibitor, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose, sucrose, sodium chloride and tris (hydroxymethyl) aminomethane.
Further, the mass ratio of the outer layer to the inner layer of the microneedle is (1-2): 5-8.
The invention also provides a process for preparing the micro-needle, which comprises the steps of firstly guiding the solution for forming the inner layer into a forming die, scraping the solution into a forming cavity of the forming die through a scraping plate, vacuum drying and demoulding to obtain the inner layer micro-needle, re-injecting the outer layer solution into the forming cavity of the forming die, inserting the inner layer micro-needle into the forming cavity containing the outer layer solution, and vacuum drying and demoulding to obtain the micro-needle.
The main drug effect substances are the dipeptidyl peptidase-4 inhibitor and the glucokinase, and the dipeptidyl peptidase-4 inhibitor can prevent the dipeptidyl peptidase-4 from degrading GLP-1, so that the original effect of the dipeptidyl peptidase-4 is inhibited, and the effect of increasing insulin secretion is achieved. The glucokinase can increase beta cell ATP to improve glucose-induced insulin synthesis and secretion, and can also rapidly metabolize glucose to inhibit liver glycogen storage, so that alpha cells can be inhibited from secreting glucagon, but the rapid reaction can not be stopped when the blood sugar is low, the risk of occurrence of the blood sugar is high, and the adverse reaction of the blood sugar can be effectively reduced when the glucokinase is combined with the dipeptidyl peptidase-4 inhibitor, so that the treatment safety of the medicine is improved. Meanwhile, the invention also adopts the nanocellulose-based hydrogel to prepare the vesicle structure, and the dipeptidyl peptidase-4 inhibitor is wrapped in the nanocellulose-based hydrogel, so that the nanocellulose-based hydrogel has good biocompatibility, can be biodegraded, is nontoxic and harmless, and simultaneously has good mechanical property and certain hydrophobicity due to the unique nanocrystallization network structure, and can not be dissolved quickly when meeting water. The glucokinase is used as one of hexokinase isozymes, can catalyze glucose into 6-phosphoglucose, and the 6-phosphoglucose has excellent hydrophilicity, and can endow the nanocellulose-based hydrogel with a hydrophilic surface through phosphate groups, so that the nanocellulose-based hydrogel is dissolved to release the dipeptidyl peptidase-4 inhibitor wrapped in the nanocellulose-based hydrogel, that is, the preparation can control the release rate of the dipeptidyl peptidase-4 inhibitor according to the actual content of glucose in a body, thereby controlling the blood sugar value in the body within a stable range, namely controlling the excessive blood sugar content and avoiding the occurrence of hypoglycemia.
According to the microneedle provided by the invention, the outer layer contains glucokinase in the form of a layered needle, and can firstly diffuse in the body after the microneedle is inserted into the body to catalyze the conversion of glucose in the body into glucose-6-phosphate, and the inner layer of the microneedle begins to dissolve and release the nanocellulose-based hydrogel capsule coated with the dipeptidyl peptidase-4 inhibitor after the outer layer is dissolved, so that the glucose-6-phosphate generated in the body is endowed with hydrophilic dissolution, and the effect of reducing blood sugar is achieved. Meanwhile, the microneedle provided by the invention is a soluble microneedle, can be rapidly dissolved after being inserted into skin, and is free from the situations of broken needle and repeated use infection.
Drawings
FIG. 1 is a schematic diagram of a layered microneedle provided by the present invention;
Fig. 2 is a schematic diagram of a vesicle structure provided by the present invention.
Reference numerals in the drawings of the specification are as follows:
1. The preparation comprises a microneedle outer layer, a vesicle, a microneedle inner layer, a microneedle substrate, a dipeptidyl peptidase-4 inhibitor and a nanocellulose-based hydrogel.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects solved by the invention more clear, the invention is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The present invention discloses a formulation for treating diabetes, which can be used to treat complications resulting from diabetes, including but not limited to diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, glaucoma and diabetic ketoacidosis, or glucose metabolism disorders leading to hyperglycemia, in addition to diabetes, and in some embodiments, can be used to treat endocrine metabolic diseases other than diabetes, such as obesity, osteoporosis, hyperuricemia, and the like.
In some embodiments, the formulation comprises a dipeptidyl peptidase-4 inhibitor, glucokinase, nanocellulose-based hydrogel. Among them, the dipeptidyl peptidase-4 inhibitor has a main function of preventing in vivo protein from being decomposed by dipeptidyl peptidase-4. One of the proteins decomposed by dipeptidyl peptidase-4 is called GLP-1, which is a hormone secreted by intestinal cells, and GLP-1 can lower blood sugar in a manner of stimulating insulin, inhibiting glucagon, inhibiting gastric emptying and regenerating islet cells, so that dipeptidyl peptidase-4 does not decompose GLP-1, thereby achieving the effect of lowering blood sugar. The dipeptidyl peptidase-4 inhibitor may be one or more of Sitagliptin (SITAGLIPTIN), vildagliptin (VILDAGLIPTIN), saxagliptin (Saxagliptin), alogliptin (Alogliptin), linagliptin (linagliptin), and the like.
The glucokinase is used as one kind of hypoglycemic matter and has the action mechanism that when insulin beta cell senses blood sugar concentration higher than 5mmol/L, glucokinase is activated to start insulin secretion and gradually raised insulin acts on liver cell to promote the gene expression of glucokinase in liver cell. When the blood glucose concentration increased to 8mmol/L, hepatic glucokinase was activated, and hepatic glycogen synthesis was started. The gene expression of liver glucokinase depends on insulin, when the blood sugar is reduced below 4mmol/L, the glucokinase activity is rapidly reduced, a glucagon releasing mechanism of islet alpha cells is started, glucagon acts on a receptor of liver cells, a hepatic glycogenolysis and gluconeogenesis mechanism is started, glucose is delivered to an organism, and the blood sugar steady state is maintained. Through the action of glucokinase, the most important glucose sensing cells and glucose disposal cells of the organism coordinate with each other to maintain the blood sugar steady state. Meanwhile, the glucokinase is also one of hexokinase isozymes, plays a catalytic role in the phosphorylation process of converting glucose into glucose-6-phosphate, and the enzyme activity of the glucokinase can also be changed along with the concentration of glucose in the environment, when the concentration of glucose is lower, the enzyme activity is slowly increased, and after the concentration of glucose is increased to a certain degree, the enzyme activity is obviously increased and finally the maximum activity is increased.
The nano cellulose-based hydrogel has a unique nano entanglement network structure, excellent mechanical property, high specific surface, biodegradation and biocompatibility, and a space network structure near pi bond of cellulose molecules of the nano cellulose-based hydrogel has good hydrophobicity. Besides the preparation method, the nanocellulose-based hydrogel can also be prepared by taking cotton linter cellulose (sheared into fragments, performing vacuum drying at 80 ℃ for 24 hours) with certain mass, adding into NaOH/urea/H 2 O (mass ratio is 7:12:8:1) solution for dispersion, freezing at-18 ℃ for 12 hours after uniform dispersion, rapidly and vigorously stirring at normal temperature for 10 minutes after taking out, performing centrifugal defoaming for 5 minutes at 5-10 ℃ and 8000r/min to obtain a transparent cellulose solution, pouring the mixed solution into a mold, taking HCL (mass fraction) as a coagulation bath, neutralizing NaOH, washing with deionized water to remove impurities for 2 hours, and replacing deionized water for 1 time until the replacement liquid is neutral, thereby obtaining the nanocellulose-based hydrogel at room temperature.
In some embodiments, as shown in fig. 2, having nanocellulose-based hydrogels as vesicles 2, encapsulating dipeptidyl peptidase-4 inhibitor 5, the term "vesicles" may refer to artificially created particles (in some embodiments, nanoparticles) comprising a fluid surrounded by concentric layers or molecular or polymer layers (e.g., amphiphilic polymers). The preparation process of the nano-cellulose-based hydrogel bubble comprises the steps of taking a dipeptidyl peptidase-4 inhibitor with the concentration of 25g/L in a round-bottom flask, slowly drying the raw materials for 4-6 hours by nitrogen flow, adding HEPES buffer solution, magnetically stirring the raw materials for 30 minutes to obtain a suspension of the dipeptidyl peptidase-4 inhibitor, adding the suspension into an extruder filled with nano-cellulose-based hydrogel, and passing the suspension through the pore diameter of a nano-cellulose-based hydrogel film to obtain the nano-cellulose-based hydrogel bubble wrapped with the dipeptidyl peptidase-4 inhibitor.
In some embodiments, the nanocellulose-based hydrogel capsule may also be encapsulated with other pharmacodynamic substances, including, but not limited to, one or more of insulin, metformin, sodium-glucose symporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, alpha-glucosidase inhibitors, rosiglitazone, pioglitazone, and the like.
The invention also discloses a microneedle for treating diabetes, and the length of the microneedle can be between about 50 mu m and 2 mm. In most cases they are between about 200 μm and 1200 μm, and desirably between about 500 μm and 1000 μm.
In some embodiments, as shown in fig. 1, the microneedle is a layered microneedle, and includes an outer layer 1 and an inner layer 3, the outer layer 1 is a surface layer that contacts the internal environment first after the microneedle is inserted into the body, and the inner layer 3 is covered in the outer layer 1 and contacts the internal environment only after the outer layer 1 is dissolved or detached.
In some embodiments, the solution forming the outer layer comprises the glucokinase, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxyethyl cellulose, sucrose, sodium chloride, tris. Meanwhile, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyvinyl alcohol, protein (e.g., gelatin, etc.) may be included in the solution. Hyaluronic acid, sodium hyaluronate, pullulan, dextran, dextrin, sodium chondroitin sulfate, cellulose derivatives (e.g., water-soluble cellulose derivatives in which cellulose is locally modified such as carboxymethyl cellulose, hydroxypropyl methylcellulose, etc.), hydroxyethyl starch, gum arabic, maltose, lactose, fructose, phosphoric acid, tris-hydroxymethyl-aminomethane, acetic acid.
When the microneedle is inserted into a human body, the outer layer is contacted with body fluid to start dissolving, and the glucokinase in the microneedle is diffused into the in-vivo environment, is activated by glucose in the body and starts to play a role in regulating the glucose, and can also serve as a catalyst to convert the glucose into glucose-6-phosphate.
In some embodiments, the solution forming the inner layer comprises nanocellulose-based hydrogel, dipeptidyl peptidase-4 inhibitor, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxyethyl cellulose, sucrose, sodium chloride, tris. Meanwhile, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyvinyl alcohol, protein (e.g., gelatin, etc.) may be included in the solution. Hyaluronic acid, sodium hyaluronate, pullulan, dextran, dextrin, sodium chondroitin sulfate, cellulose derivatives (e.g., water-soluble cellulose derivatives in which cellulose is locally modified such as carboxymethyl cellulose, hydroxypropyl methylcellulose, etc.), hydroxyethyl starch, gum arabic, maltose, lactose, fructose, phosphoric acid, tris-hydroxymethyl-aminomethane, acetic acid.
When the microneedle outer layer is dissolved, the inner layer is contacted with an in-vivo environment, wherein the nanocellulose-based hydrogel capsule wrapped with the dipeptidyl peptidase-4 inhibitor is released into the in-vivo environment, when the content of glucose in the in-vivo environment is low, the converted 6-phosphoglucose is relatively less, and the nanocellulose-based hydrogel is hydrophobic and is not easy to dissolve in the body, so that the internally wrapped dipeptidyl peptidase-4 inhibitor is not released, namely the condition that the blood sugar is not continuously reduced to cause hypoglycemia is avoided, and when the content of glucose in the body is high, the converted 6-phosphoglucose is relatively more, and the phosphate groups on the 6-phosphoglucose can endow the nanocellulose-based hydrogel capsule with the surface hydrophilicity, so that the nanocellulose-based hydrogel capsule can rapidly and quickly interpret the internally wrapped dipeptidyl peptidase-4 inhibitor, thereby rapidly reducing the content of glucose in the in-vivo environment and preventing hyperglycemia.
The invention also discloses a preparation process of the microneedle, which comprises the following steps of firstly introducing the solution for forming the inner layer into a forming die, scraping the solution into a forming cavity of the forming die through a scraping plate, and vacuum pumping the forming cavity to fill the whole forming cavity with the solution due to the fact that the forming cavity is made of breathable liquid-proof materials. And (3) demolding after vacuum drying to obtain an inner layer microneedle, re-injecting an outer layer solution into a molding cavity of the molding die, inserting the inner layer microneedle into the molding cavity containing the outer layer solution, and vacuum drying and demolding to obtain the microneedle.
The invention is further illustrated by the following examples.
Example 1
A process for preparing microneedle for treating diabetes is provided.
1. 3.25G of glucokinase, 5.21g of polyvinyl alcohol 03CP, 4.35g of polyvinyl alcohol 30CP, 6.84g of polyvinylpyrrolidone K, 9.62g of hydroxyethyl cellulose, 2.56g of sucrose, 3.92g of sodium chloride and 4.43g of tris (hydroxymethyl) aminomethane are weighed, 400ml of purified water is added, and the mixture is uniformly mixed to obtain a microneedle outer layer solution.
2. 18.47G of nanocellulose-based hydrogel, 8.43g of dipeptidyl peptidase-4 inhibitor, 15.34g of polyvinyl alcohol 03CP, 20.82g of polyvinyl alcohol 30CP, 17. 17 32.41g of polyvinylpyrrolidone, 39.73g of hydroxyethyl cellulose, 12.58g of sucrose, 18.32g of sodium chloride and 22.38g of tris (hydroxymethyl) aminomethane are weighed, 300ml of purified water is added, and the solution is uniformly mixed to obtain a microneedle inner layer solution, wherein the dipeptidyl peptidase-4 inhibitor is wrapped by the nanocellulose-based hydrogel to form vesicles.
3. Placing the outer layer solution of the micro-needle into a forming cavity of a forming die, carrying out vacuum suction for 15min, then carrying out air drying in a vacuum drying oven for 3h, demolding to obtain the inner layer micro-needle, re-injecting the outer layer solution into the forming cavity of the forming die, inserting the inner layer micro-needle into the forming cavity containing the outer layer solution, and carrying out vacuum drying and demolding to obtain the micro-needle.
Example 2
A process for preparing microneedle for treating diabetes is provided.
1. 4.38G of glucokinase, 5.21g of polyvinyl alcohol 03CP, 4.35g of polyvinyl alcohol 30CP, 6.84g of polyvinylpyrrolidone K, 9.62g of hydroxyethyl cellulose, 2.56g of sucrose, 3.92g of sodium chloride and 4.43g of tris (hydroxymethyl) aminomethane are weighed, 400ml of purified water is added, and the mixture is uniformly mixed to obtain a microneedle outer layer solution.
2. 27.32G of nanocellulose-based hydrogel, 12.57g of dipeptidyl peptidase-4 inhibitor, 15.34g of polyvinyl alcohol 03CP, 20.82g of polyvinyl alcohol 30CP, 17. 17 32.41g of polyvinylpyrrolidone, 39.73g of hydroxyethyl cellulose, 12.58g of sucrose, 18.32g of sodium chloride and 22.38g of tris (hydroxymethyl) aminomethane are weighed, 300ml of purified water is added, and the solution is uniformly mixed to obtain a microneedle inner layer solution, wherein the dipeptidyl peptidase-4 inhibitor is wrapped by the nanocellulose-based hydrogel to form vesicles.
3. Placing the outer layer solution of the micro-needle into a forming cavity of a forming die, carrying out vacuum suction for 16min, then carrying out air drying for 3.5h in a vacuum drying box, demolding to obtain the inner layer micro-needle, re-injecting the outer layer solution into the forming cavity of the forming die, then inserting the inner layer micro-needle into the forming cavity containing the outer layer solution, and carrying out vacuum drying and demolding to obtain the micro-needle.
Example 3
A process for preparing microneedle for treating diabetes is provided.
1. 5.31G of glucokinase, 5.21g of polyvinyl alcohol 03CP, 4.35g of polyvinyl alcohol 30CP, 6.84g of polyvinylpyrrolidone K, 9.62g of hydroxyethyl cellulose, 2.56g of sucrose, 3.92g of sodium chloride and 4.43g of tris (hydroxymethyl) aminomethane are weighed, 400ml of purified water is added, and the mixture is uniformly mixed to obtain a microneedle outer layer solution.
2. 36.42G of nanocellulose-based hydrogel, 11.72g of dipeptidyl peptidase-4 inhibitor, 15.34g of polyvinyl alcohol 03CP, 20.82g of polyvinyl alcohol 30CP, 17. 17 32.41g of polyvinylpyrrolidone, 39.73g of hydroxyethyl cellulose, 12.58g of sucrose, 18.32g of sodium chloride and 22.38g of tris (hydroxymethyl) aminomethane are weighed, 300ml of purified water is added, and the solution is uniformly mixed to obtain a microneedle inner layer solution, wherein the dipeptidyl peptidase-4 inhibitor is wrapped by the nanocellulose-based hydrogel to form vesicles.
3. Placing the outer layer solution of the micro-needle into a forming cavity of a forming die, carrying out vacuum suction for 17min, then carrying out air drying for 3.5h in a vacuum drying box, demolding to obtain the inner layer micro-needle, re-injecting the outer layer solution into the forming cavity of the forming die, then inserting the inner layer micro-needle into the forming cavity containing the outer layer solution, and carrying out vacuum drying and demolding to obtain the micro-needle.
Example 4
A process for preparing microneedle for treating diabetes is provided.
1. 6.42G of glucokinase, 5.21g of polyvinyl alcohol 03CP, 4.35g of polyvinyl alcohol 30CP, 6.84g of polyvinylpyrrolidone K, 9.62g of hydroxyethyl cellulose, 2.56g of sucrose, 3.92g of sodium chloride and 4.43g of tris (hydroxymethyl) aminomethane are weighed, 400ml of purified water is added, and the mixture is uniformly mixed to obtain a microneedle outer layer solution.
2. Weighing 43.28g of nanocellulose-based hydrogel, 14.25g of dipeptidyl peptidase-4 inhibitor, 15.34g of polyvinyl alcohol 03CP, 20.82g of polyvinyl alcohol 30CP, 17. 17 32.41g of polyvinylpyrrolidone, 39.73g of hydroxyethyl cellulose, 12.58g of sucrose, 18.32g of sodium chloride and 22.38g of tris (hydroxymethyl) aminomethane, adding 300ml of purified water, and uniformly mixing to obtain a microneedle inner layer solution, wherein the dipeptidyl peptidase-4 inhibitor is wrapped by the nanocellulose-based hydrogel to form vesicles.
3. Placing the outer layer solution of the micro-needle into a forming cavity of a forming die, carrying out vacuum suction for 19min, then carrying out air drying in a vacuum drying oven for 4h, demolding to obtain the inner layer micro-needle, re-injecting the outer layer solution into the forming cavity of the forming die, inserting the inner layer micro-needle into the forming cavity containing the outer layer solution, and carrying out vacuum drying and demolding to obtain the micro-needle.
Example 5
A process for preparing microneedle for treating diabetes is provided.
1. 7.23G of glucokinase, 5.21g of polyvinyl alcohol 03CP, 4.35g of polyvinyl alcohol 30CP, 6.84g of polyvinylpyrrolidone K, 9.62g of hydroxyethyl cellulose, 2.56g of sucrose, 3.92g of sodium chloride and 4.43g of tris (hydroxymethyl) aminomethane are weighed, 400ml of purified water is added, and the mixture is uniformly mixed to obtain a microneedle outer layer solution.
2. 55.68G of nanocellulose-based hydrogel, 16.83g of dipeptidyl peptidase-4 inhibitor, 15.34g of polyvinyl alcohol 03CP, 20.82g of polyvinyl alcohol 30CP, 17. 17 32.41g of polyvinylpyrrolidone, 39.73g of hydroxyethyl cellulose, 12.58g of sucrose, 18.32g of sodium chloride and 22.38g of tris (hydroxymethyl) aminomethane are weighed, 300ml of purified water is added, and the solution is uniformly mixed to obtain a microneedle inner layer solution, wherein the dipeptidyl peptidase-4 inhibitor is wrapped by the nanocellulose-based hydrogel to form vesicles.
3. Placing the outer layer solution of the micro-needle into a forming cavity of a forming die, carrying out vacuum suction for 20min, then carrying out air drying in a vacuum drying oven for 5h, demolding to obtain the inner layer micro-needle, re-injecting the outer layer solution into the forming cavity of the forming die, then inserting the inner layer micro-needle into the forming cavity containing the outer layer solution, and carrying out vacuum drying and demolding to obtain the micro-needle.
Comparative example 1
This comparative example substantially corresponds to the experimental procedure and experimental parameters of example 1, except that no nanocellulose-based hydrogel vesicles were provided outside of the dipeptidyl peptidase-4 inhibitor in the microneedle inner layer solution of this comparative example 1.
Comparative example 2
This comparative example substantially corresponds to the experimental procedure and experimental parameters of example 1, except that this comparative example 2 is insulin encapsulated in nanocellulose-based hydrogel vesicles.
Comparative example 3
This comparative example substantially corresponds to the experimental procedure and experimental parameters of example 1, except that the microneedle outer layer solution of this comparative example 3 does not contain glucokinase.
The prepared microneedle was tested:
The test method comprises preparing 40 rats with weight of (160+ -20) g, randomly dividing into 8 groups, feeding with high-fat high-sugar fodder continuously for 4 weeks, applying the prepared microneedles to rats with different components, during administration, each group does not limit feeding or drinking water, collecting blood 4ml with 4 deg.C inner canthus intravenous sinus every 30min, centrifuging at 3000rpm for 15min, sucking serum, preserving at low temperature refrigerator, testing blood sugar and free fatty acid concentration, recording corresponding data, and testing for 6 times. The average value of the data of each group of rats and the difference between the maximum value and the minimum value of the blood sugar data were taken.
The test results obtained are filled in Table 1.
TABLE 1
Conclusion from the test results of table 1, it can be seen that the application of the micro-scale of examples 1 to 5 and comparative examples 1 to 3 to rats significantly reduced the blood glucose level of the rats, and that comparative examples 1 and 2, although having a good hypoglycemic effect, had a large blood glucose excursion and failed to exert a good stabilizing effect. Therefore, the nanocellulose-based hydrogel capsule can effectively and stably control blood sugar within a certain range under the action of glucokinase, and meanwhile, the synergistic blood sugar reducing effect of the dipeptidyl peptidase-4 inhibitor and the glucokinase is better than that of the cooperation of the glucokinase and insulin. It can also be seen from comparative example 3 that the lack of glucokinase reduces the synergistic hypoglycemic effect of the drug on the one hand and fails to catalyze the conversion of glucose into glucose-6-phosphate on the other hand, thus leading to slow dissolution of nanocellulose-based hydrogel vesicles and further reducing the hypoglycemic effect.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (7)
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