阅读说明：本技术 一种用于长效降血糖皮下埋植棒及其制备方法 (Subcutaneous implanted rod for long-acting blood sugar reduction and preparation method thereof ) 是由 吕鹏威 于 2021-07-18 设计创作，主要内容包括：本发明公开了一种用于长效降血糖皮下埋植棒及其制备方法,采用二嵌段共聚物为载体,配方包括以下重量份的物质：聚己内酯10-20份,聚乙二醇5-10份,聚乙烯吡咯烷酮1-5份,原料药5-20份；其中,所述原料药是由格列本脲和罗格列酮两种药物组合而成,所述原料药中,以质量比计为,格列本脲∶罗格列酮＝1-20∶1。本发明埋植棒植入皮下后是直接长期缓释给药长期治疗稳定血糖,采用二嵌段共聚物作为载体,解决了现有埋植棒载体作用时间短的问题,且其制备方法简单,物料易得,生产工艺简单,容易掌握。本发明制备的埋植棒,植入人体皮下,根据生物材料具有完全降解性,有很好的生物相容性和无毒性,植入人体皮下舒适度好。(The invention discloses a subcutaneous implanted rod for long-acting blood sugar reduction and a preparation method thereof, wherein a diblock copolymer is used as a carrier, and the formula comprises the following substances in parts by weight: 10-20 parts of polycaprolactone, 5-10 parts of polyethylene glycol, 1-5 parts of polyvinylpyrrolidone and 5-20 parts of bulk drug; the bulk drug is prepared by combining glibenclamide and rosiglitazone, wherein the mass ratio of the glibenclamide to the rosiglitazone in the bulk drug is 1-20: 1. The embedded bar is directly sustained-release administrated for a long time after being implanted under the skin to stabilize blood sugar, a diblock copolymer is used as a carrier, the problem of short action time of the existing embedded bar carrier is solved, and the embedded bar carrier is simple in preparation method, easy in material obtaining, simple in production process and easy to master. The embedded bar prepared by the invention is implanted into the subcutaneous part of a human body, has complete degradability according to biological materials, good biocompatibility and nontoxicity, and good subcutaneous comfort degree.)

1. A subcutaneous implanted rod for long-acting blood sugar reduction is characterized in that a diblock copolymer is adopted as a carrier, and comprises the following substances in parts by weight:

10-20 parts of Polycaprolactone (PCL),

5-10 parts of polyethylene glycol,

1-5 parts of polyvinylpyrrolidone, namely, polyvinylpyrrolidone,

5-20 parts of raw material medicine;

the bulk drug is prepared by combining glibenclamide and rosiglitazone, wherein the mass ratio of the glibenclamide to the rosiglitazone in the bulk drug is 1-20: 1.

2. The subcutaneous implant rod for long-acting blood sugar reduction according to claim 1,

the mass ratio of the glibenclamide to the rosiglitazone is 1-10: 1.

3. The subcutaneous implanted rod for long-acting blood sugar reduction according to claim 1, characterized by comprising the following materials in parts by weight:

10 parts of polycaprolactone;

5 parts of polyethylene glycol;

2 portions of polyvinylpyrrolidone

10 parts of raw material medicine;

the raw material medicine comprises the following components:

5 parts of glibenclamide;

and 5 parts of rosiglitazone.

4. The subcutaneous implant rod for long-acting blood sugar reduction according to claim 1, wherein the implant rod has a diameter of 1-3mm and a length of 25-50 mm.

5. The subcutaneous implant rod for long-acting blood sugar reduction according to claim 1, wherein the implant rod has a diameter of 3mm and a length of 50 mm.

6. A preparation method of a subcutaneous implanted rod for long-acting blood reduction is characterized by comprising the following steps:

the first step is as follows: preparing a PCL-PEG-diblock copolymer micelle: polyethylene glycol (PEG) is used as a macroinitiator, Polycaprolactone (PCL) is used as a monomer, and a toxic metal catalyst is avoided, so that a PCL-PEG-diblock copolymer is prepared;

the second step is that: preparing a buried planting rod: heating and melting the diblock copolymer micelle prepared in the first step into paste, adding the polyvinyl pioglitazone PVP in parts for hygroscopicity, heating, rotating and stirring for sufficient mixing, adding the bulk drugs glibenclamide and rosiglitazone in parts, rotating and stirring for sufficient mixing, encapsulating the copolymer micelle with the bulk drugs to form a microsphere capsule, cooling to form a solid, crushing the mixture by a crusher in sequence, granulating in a granulator, extruding and molding by an extruder to extrude a cylindrical strip with the diameter of 1-3mm, placing and drying the extruded cylindrical strip, cutting the cylindrical strip according to the length of 25-50mm, vacuum packaging, and irradiating and sterilizing by cobalt 60 for later use.

7. The preparation method of the subcutaneous implanted rod for long-acting blood sugar reduction according to claim 6, wherein in the first step, the ring-opening polymerization reaction of PCL initiated by PEG comprises the following specific steps: adding polycaprolactone and polyethylene glycol into a reaction kettle, sealing the reaction kettle, vacuumizing, heating and stirring for 4-6 hours under the protection of nitrogen, opening a reaction kettle cover, adding polyvinylpyrrolidone PVP according to a certain proportion, continuing heating and stirring for 4-6 hours, stopping heating and stirring, opening the reaction kettle cover, naturally cooling, taking out, and drying to obtain the PCL-PEG-diblock copolymer.

8. The method as claimed in claim 7, wherein the heating and stirring temperature is 100-150 ℃.

9. The method for preparing subcutaneous implanted rod for long-acting blood sugar reduction according to claim 6, wherein the vacuum package is packed by 4-6 pieces per package.

Technical Field

The invention relates to a subcutaneous sustained-release drug administration embedded rod and a preparation method thereof, the embedded rod is used for treating and stabilizing corresponding diseases according to the pharmacological performance of drugs mixed in the embedded rod after being implanted under the skin, in particular to a subcutaneous embedded rod for long-term blood sugar reduction, which is used for stabilizing normal blood sugar for a long time.

Background

At present, most of the treatment of type II diabetes at home and abroad depends on oral hypoglycemic drugs to maintain the normal and balanced blood sugar. The drug has short action time, and the drug is orally taken three times or two times a day. A large amount of hypoglycemic drugs taken orally have great side effects, cause systemic and gastrointestinal reactions and great damage to liver and kidney functions.

There are also precedents of treating diabetes by adopting traditional Chinese medicine catgut embedding therapy, however, the catgut embedding treatment effect is not obvious, and the effect of stabilizing blood sugar for a long time cannot be achieved.

Disclosure of Invention

Aiming at the technical defects, the invention aims to provide a subcutaneous implanted rod for long-acting blood sugar reduction and a preparation method thereof, so as to solve the problems in the background technology.

In order to solve the technical problems, the invention adopts the following technical scheme:

the invention provides a subcutaneous implanted rod for long-acting blood sugar reduction, which adopts diblock copolymer as a carrier and comprises the following substances in parts by weight:

10-20 parts of Polycaprolactone (PCL),

5-10 parts of polyethylene glycol,

1-5 parts of polyvinylpyrrolidone, namely, polyvinylpyrrolidone,

5-20 parts of raw material medicine;

the bulk drug is prepared by combining glibenclamide and rosiglitazone, wherein the mass ratio of the glibenclamide to the rosiglitazone in the bulk drug is 1-20: 1.

Preferably, the mass ratio of the glibenclamide to the rosiglitazone is 1-10: 1.

Preferably, the subcutaneous implanted rod for long-acting blood sugar reduction comprises the following substances in parts by weight:

10 parts of polycaprolactone;

5 parts of polyethylene glycol;

2 portions of polyvinylpyrrolidone

10 parts of raw material medicine;

the raw material medicine comprises the following components:

5 parts of glibenclamide;

5 parts of rosiglitazone;

preferably, the diameter of the embedded rod is 1-3mm, and the length of the embedded rod is 25-50 mm.

Preferably, the diameter of the embedded rod is 3mm, and the length of the embedded rod is 50 mm.

A preparation method of a subcutaneous implanted rod for long-acting blood reduction comprises the following steps:

the first step is as follows: preparing a PCL-PEG-diblock copolymer micelle: polyethylene glycol (PEG) is used as a macroinitiator, Polycaprolactone (PCL) is used as a monomer, and a toxic metal catalyst is avoided, so that a PCL-PEG-diblock copolymer is prepared;

the second step is that: preparing a buried planting rod: heating and melting the diblock copolymer micelle prepared in the first step into paste, adding the polyvinyl pioglitazone PVP in parts for hygroscopicity, heating, rotating and stirring for sufficient mixing, adding the bulk drugs glibenclamide and rosiglitazone in parts, rotating and stirring for sufficient mixing, encapsulating the copolymer micelle with the bulk drugs to form a microsphere capsule, cooling to form a solid, crushing the mixture by a crusher in sequence, granulating in a granulator, extruding and molding by an extruder to extrude a cylindrical strip with the diameter of 1-3mm, placing and drying the extruded cylindrical strip, cutting the cylindrical strip according to the length of 25-50mm, vacuum packaging, and irradiating and sterilizing by cobalt 60 for later use.

Preferably, in the first step, the specific steps of the ring-opening polymerization reaction of PCL initiated by PEG are: adding polycaprolactone and polyethylene glycol into a reaction kettle, sealing the reaction kettle, vacuumizing, heating and stirring for 4-6 hours under the protection of nitrogen, opening a reaction kettle cover, adding polyvinylpyrrolidone PVP according to a certain proportion, continuing heating and stirring for 4-6 hours, stopping heating and stirring, opening the reaction kettle cover, naturally cooling, taking out, and drying to obtain the PCL-PEG-diblock copolymer. The heating and stirring temperature is 100-150 ℃.

The use method of the embedded bar of the invention comprises the following steps:

1. the embedding rod is embedded under the skin of the upper abdomen and is used for treating the type II diabetes with stable normal blood sugar.

2. The dosage is as follows: burying 6-12 subcutaneous tissue at one time, wherein the weight of each burying rod is 0.1-0.3 g.

Maladaptive symptoms: the embedded rod of the invention is not suitable for patients with type I diabetes.

Compared with the prior art, the invention has the beneficial effects that:

1. the embedded bar is implanted under the skin, the sustained-release drug delivery is directly carried out for a long time to treat and stabilize the normal blood sugar, the diblock copolymer is used as a carrier, the problem of short action time of the existing embedded bar carrier is solved, and the embedded bar carrier is simple in preparation method, easy to obtain materials, simple in production process and easy to master.

2. The embedded bar prepared by the invention is implanted under the skin of a human body, and the material has complete degradability according to the biodegradation performance, good biocompatibility and nontoxicity, and good subcutaneous comfort level of the human body.

3. The polycaprolactone monomer is initiated to carry out ring-opening polymerization under the protection of nitrogen by heating polyethylene glycol and vacuumizing, and the graft is generated by in-situ compatibilization, so that the composite mechanical property and thermal property of the polyester base are improved, and the application range of the polyester base is expanded. Is suitable for being applied to biological tissue engineering. The ring-opening polymerization of polycaprolactone, and considering the safety and compatibility of the PCL-PEG copolymer as a biomedical material when acting on a human body, the PCL-PEG diblock copolymer is successfully prepared by directly using polyethylene glycol (PEG) as a macroinitiator and Polycaprolactone (PCL) as a monomer in a closed environment in the laboratory without using a toxic metal catalyst.

4. The invention relates to an embedded bar prepared according to the principle of subcutaneous slow-release administration, which is implanted into the subcutaneous part of a human body after being sterilized by cobalt 60 irradiation, and is slowly degraded by taking a diblock copolymer as a carrier, thereby playing the role of stabilizing blood sugar for long-term treatment, and the drug is released after the degradation of a degradation material is finished, and finally is converted into carbon dioxide and water in the body to be absorbed by human tissues and finally discharged out of the body without generating any by-product.

Detailed Description

The present invention will be described in further detail with reference to examples.

The invention discloses a subcutaneous implanted rod for long-acting blood sugar reduction, which is implanted subcutaneously for realizing the purpose of stabilizing blood sugar for a long time and comprises the following substances in parts by weight: 10-20 parts of polycaprolactone, 5-10 parts of polyethylene glycol, 1-5 parts of polyvinylpyrrolidone and 5-20 parts of bulk drug; the parts herein may be expressed in mg, g, kg, without limitation to the unit. Among them, the polyethylene glycol used preferably has a molecular weight of 400.

The bulk drug is prepared by combining glibenclamide, rosiglitazone and two drugs, wherein the mass ratio of the glibenclamide to the rosiglitazone in the bulk drug is 1: 1, and the ratio is the optimal ratio in the application of the embedded bar.

The specific composition of the embedded rod may be any value within the above range of raw materials, for example, it is preferable that: 10 parts of polycaprolactone, 5 parts of polyethylene glycol and 2 parts of polyvinylpyrrolidone, wherein the raw material medicines comprise 5 parts of glibenclamide and 5 parts of rosiglitazone. The above-mentioned ratio is merely a preferable example, but the embedded rod prepared by the present invention is not limited to this formulation.

The invention discloses a medicine carrier for preparing an embedded rod by using a micelle of a diblock copolymer, in particular to a preparation method of a subcutaneous embedded rod for long-acting blood sugar reduction, which comprises the following steps:

the first step is as follows: preparation of polycaprolactone diblock copolymer micelle: the ring-opening polymerization of polycaprolactone is initiated by polyethylene glycol. The ring-opening polymerization of polycaprolactone, and considering the safety and compatibility of the PCL-PEG copolymer as a biomedical material when acting on a human body, the polyethylene glycol PEG is directly used as a macroinitiator and the polycaprolactone PCL is used as a monomer in the laboratory, and the PCL-PEG-diblock copolymer is successfully prepared by avoiding using a toxic metal catalyst due to the application of the PCL-PEG copolymer to the human body. Preparing a PCL-PEG-diblock copolymer micelle: adding polycaprolactone and polyethylene glycol into a reaction kettle, sealing the reaction kettle, vacuumizing, heating and stirring for 4-6 hours under the protection of nitrogen, opening a reaction kettle cover, adding polyvinylpyrrolidone PVP (polyvinyl pyrrolidone) in a certain proportion for moisture absorption, continuously heating and stirring for 4-6 hours, stopping heating and stirring, opening the reaction kettle cover, naturally cooling, taking out, and drying to obtain the PCL-PEG-diblock copolymer.

The second step is that: preparing a buried planting rod: heating and melting the diblock copolymer micelle prepared in the first step into paste, adding the raw material medicines of glibenclamide and rosiglitazone according to the weight, carrying out rotary stirring and full mixing, encapsulating the copolymer micelle with the raw material medicines to form a microsphere capsule, cooling to form a solid, sequentially crushing the mixture by a crusher, granulating in a granulator, carrying out extrusion molding by an extruder, extruding cylindrical strips with the diameter of 1-3mm, placing and drying the extruded cylindrical strips, cutting the cylindrical strips according to the length of 25-50mm, carrying out vacuum packaging, and carrying out irradiation sterilization by cobalt 60 for later use.

Example 1

The diameter of the embedded bar produced by the formula of the embodiment is 3mm, the length of the embedded bar is 50mm, the weight of each embedded bar is 300mg, and each embedded bar contains 100mg of raw material medicines.

Specifically, the subcutaneous implanted rod for long-acting blood sugar reduction comprises the following components in percentage by weight: 10g of polycaprolactone, 5g of polyethylene glycol, 2g of polyvinylpyrrolidone, 5g of glibenclamide and 5g of rosiglitazone, wherein the total weight is 27g, and each piece is 300mg and is prepared into about 90 pieces.

The preparation process of the embedded bar comprises the following steps:

the first step is as follows: preparation of polycaprolactone diblock copolymer micelle: the ring-opening polymerization of polycaprolactone is initiated by polyethylene glycol. The ring-opening polymerization of polycaprolactone, and considering the safety and compatibility of the PCL-PEG copolymer as a biomedical material when acting on a human body, the polyethylene glycol PEG is directly used as a macroinitiator and the polycaprolactone PCL is used as a monomer in the laboratory, and the PCL-PEG-diblock copolymer is successfully prepared by avoiding using a toxic metal catalyst due to the application of the PCL-PEG copolymer to the human body. Preparing a PCL-PEG-diblock copolymer micelle: adding polycaprolactone and polyethylene glycol into a reaction kettle, sealing the reaction kettle, vacuumizing, heating and stirring for 4-6 hours under the protection of nitrogen, wherein the heating and stirring temperature is 100-150 ℃, opening the cover of the reaction kettle, adding polyvinylpyrrolidone (PVP) according to a certain proportion, continuously heating and stirring for 4-6 hours, stopping heating and stirring, opening the cover of the reaction kettle, naturally cooling, taking out, and drying to obtain the PCL-PEG-diblock copolymer.

The second step is that: preparing a buried planting rod: heating and melting the diblock copolymer micelle prepared in the first step into paste, adding the raw material medicines of glibenclamide and rosiglitazone according to the weight, carrying out rotary stirring and full mixing, encapsulating the copolymer micelle with the raw material medicines to form a microsphere capsule, cooling to form a solid, sequentially crushing the mixture by a crusher, granulating in a granulator, carrying out extrusion molding by an extruder, extruding cylindrical strips with the diameter of 1-3mm, placing and drying the extruded cylindrical strips, cutting the cylindrical strips according to the length of 25-50mm, carrying out vacuum packaging, and carrying out irradiation sterilization by cobalt 60 for later use.

Example 2

The diameter of the embedded bar is 3mm, the length of the embedded bar is 25mm, the weight of each embedded bar is 15mg, and the content of the raw material medicines in each embedded bar is 50 mg.

The specific formula of the embodiment is as follows: 15g of polycaprolactone, 7g of polyethylene glycol, 1g of polyvinylpyrrolidone, 15g of glibenclamide and 2g of rosiglitazone, wherein the total weight is 40g, and each piece is 300mg and is prepared into about 133 pieces.

The preparation method of this example is the same as example 1.

Example 3

The diameter of the embedded bar is 3mm, the length of the embedded bar is 50mm, the weight of each embedded bar is 300mg, and the content of the raw material medicines in each embedded bar is 100 mg.

The specific formula of the embodiment is as follows: 20g of polycaprolactone, 10g of polyethylene glycol, 2g of polyvinylpyrrolidone, 20g of glibenclamide and 2g of rosiglitazone, wherein the total weight is 54g, and each piece is 300mg, and about 180 pieces are prepared.

The preparation method of this example is the same as example 1.

The implementation steps of the embedded rod prepared in the above embodiment are as follows:

1) the patient takes the seat, and is positioned on the upper abdomen for local conventional disinfection and local subcutaneous anesthesia.

2) The needle point of the stainless steel sleeve needle obliquely penetrates into the subcutaneous part at an angle of 25 degrees, the penetration depth is equal to the length of the embedded rod, the needle core in the steel sleeve needle is pulled out, then the embedded rod is placed along the needle cylinder from the tail part of the needle cylinder of the sleeve needle, and the needle core is used for pushing the embedded rod to the subcutaneous part. Completing an embedding process, implanting 6-12 embedding rods under the skin according to the method, pressing the needle hole with an alcohol cotton ball, and fixing with a band-aid.

Clinical verification of the invention is demonstrated by typical cases, the invention is embedded in subcutaneous tissues of acupuncture points of human bodies, and long-term pharmacological action is achieved by slowly degrading modified polycaprolactone. The invention achieves the purpose of treating diabetes for a long time, and has no discomfort, no toxic or side effect, safety and reliability after being implanted under the skin. The clinical verification proves that the effective rate of the traditional Chinese medicine is more than 90%.

Typical cases

Case 1: a certain king, male, 61 years old, people in Zhou Kou City of Henan province, suffer from hyperglycemia for 7 years, have fasting blood sugar 14, have postprandial blood sugar 18, take medicines such as sitagliptin, metformin and glimepiride, etc., blood sugar is maintained at about 8 o 'clock after taking the medicine, after the subcutaneous implantation, the fasting blood sugar is about 6 o' clock now, the patient feels very good.

Case 2: yan A certain person, male, Han, aged 51 years old, Zhou kou city, Henan province, suffers from hyperglycemia for 8 years, rarely takes medicine at ordinary times, and has blood sugar of about 9.5 at ordinary times. After the implant is implanted, the fasting blood sugar is about 5.3, and the patient feels good.

Case 3: one of Wang, man, Han, 40 years old, Zhou Kou City, Henan province, suffered from hyperglycemia for 6 years, and had blood glucose at 12 o' clock in peacetime. About 8.5 days after taking the medicine. After being buried, the patient feels good because the fasting blood sugar is about 6.1.

The invention relates to an embedded bar prepared according to the principle of subcutaneous slow-release administration, which is implanted into the subcutaneous part of a human body after being sterilized by cobalt 60 irradiation, and is slowly degraded by taking a diblock copolymer as a carrier, thereby playing the role of stabilizing blood sugar for long-term treatment, and the drug is released after the degradation of a degradation material is finished, and finally is converted into carbon dioxide and water in the body to be absorbed by human tissues and finally discharged out of the body without generating any by-product.

The embedded rod prepared by the invention is detected to have no cytotoxicity and good biocompatibility, and is an ideal human subcutaneous administration carrier implantation material.

The embedded bar prepared by the invention is detected by rats, 20 diabetic rats in a research group and 20 diabetic rats in a control group are set, the diabetic rats in the research group are subjected to drug intervention, the diabetic rats in the control group are not subjected to drug intervention, and the average value of the specific results is as follows:

1. comparison of blood glucose and glycated hemoglobin levels of rats in each group before and after intervention

The results are shown in table 1, the fasting blood glucose and the postprandial blood glucose levels of the rats in the study group and the control group are not greatly different before intervention, the fasting blood glucose and the postprandial blood glucose levels of the rats in the study group after one month of intervention are obviously lower than those in the control group, and the glycosylated hemoglobin level is also reduced. The results show that the drug intervention can obviously reduce the fasting blood sugar and the postprandial blood sugar of the rats and also can reduce the glycosylated hemoglobin of the diabetic rats, and has good blood sugar reducing effect.

TABLE 1 comparison of blood glucose and glycated hemoglobin levels in groups of rats before and after intervention

2. Comparison of liver and kidney function of rats in each group before and after intervention

The results are shown in Table 2, and there was no significant difference in serum ALT, AST and creatinine levels between the study and control rats before and after intervention. It shows that the medicine intervention has no obvious most influence on the liver and kidney functions of the diabetic rats.

TABLE 2 comparison of liver and kidney function of rats in each group before and after intervention

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.