CN111419825A - Intelligent response type sustained and controlled release microsphere and preparation method thereof - Google Patents
Intelligent response type sustained and controlled release microsphere and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an intelligent response type sustained and controlled release microsphere and a preparation method thereof, the novel microsphere preparation is mainly characterized in that the inside of the microsphere contains small-particle-size microspheres, the outer-layer microspheres use polylactic acid-glycolic acid copolymer (P L GA) as a carrier material, the small-particle-size microspheres mainly use polyketone or derivatives thereof as a framework, model drugs are embedded in the microspheres, and glucose oxidase and catalase trigger are dispersed outside the small-particle-size microspheres.
Description
Technical Field
The invention relates to an intelligent response type sustained and controlled release microsphere and a preparation method thereof, which regulates and controls drug release based on the acid sensitivity characteristic of a polyketal or derivative material thereof and a diffusion or corrosion mechanism of a high polymer material, in particular to a novel microsphere formed by the polyketal or derivative thereof-P L GA and a preparation method thereof, and belongs to the technical field of medicine production.
Background
Diabetes is a major health disease problem facing humans in modern life, and the prevalence of diabetes increases year by year both in developed and developing countries, with about 4.25 million adults suffering from diabetes worldwide as shown by the 2017 global diabetes map report published by the international diabetes union (IDF). Wherein, the situation is severe in China, the number of the sick people exceeds 1.14 hundred million, and one diabetic patient exists in every ten people on average. The number of patients is expected to increase to 1.5 million in 2045 years.
At present, the development of a plurality of drugs for treating the diabetes is infinite, and great progress has been made on the research of a plurality of new dosage forms, the main dosage forms comprise inhalant, oral preparation, transdermal preparation, long-acting sustained release preparation prepared by utilizing nanocapsule technology, implant and the like, although part of sustained release preparation solves the problem of long-term administration of patients, a plurality of technical problems still exist, such as uncontrollable drug release rate and the like. Insulin is a common medicine for treating diabetes, and when the common injection is used for treating diabetes, the blood sugar of a patient is frequently monitored, subcutaneous injection is performed according to the result, or insulin injection is performed when the patient is close to a meal, and even the dosage of insulin administration is required to be adjusted according to the blood sugar concentration, so that great pain is brought to the patient. Chinese patent 201910084891.6 reports that insulin is prepared into nanoparticles, and then the nanoparticles are grafted and reacted with polylactic acid to form so-called double-layer microspheres, the preparation delays the release of the drug to a certain extent, but the release behavior of the drug needs to be further researched after the blood sugar is stable in the later period; chinese patent 201510162510.3 discloses a polyketal microsphere, which is prepared by adding a trigger to the polyketal microsphere to form a sugar-sensitive response, and realizes the regulation of the release of insulin by virtue of the acid sensitivity of the polyketal material, but the release in vitro is only about 7 days, the release time is short, the burst release is obvious, and the drug loading rate after 24 hours is up to more than 30%.
Moreover, the problem to be solved is that the microspheres cannot completely realize self-regulated release of the drug along with the change of blood sugar in a patient, especially when the blood sugar concentration of the patient returns to normal, the preparation still continuously releases the drug, and the accumulation amount of the drug is easy to cause the occurrence of hypoglycemia phenomenon of the patient, thus harming the body health of the patient. Therefore, aiming at the problems, the novel sustained-release preparation which can intelligently adjust the release rate of the drug by utilizing the blood sugar concentration in vivo and can furthest inhibit the release of the drug in normal blood sugar has wide research prospect.
Disclosure of Invention
The invention provides an intelligent response type sustained and controlled release microsphere, which mainly solves the problem that the conventional microsphere has burst release effect and the continuous release of a sugar-sensitive conventional microsphere under normal blood sugar concentration causes hypoglycemia to a human body.
An intelligent response type sustained and controlled release microsphere comprises medicine, glucose oxidase, catalase, polyketone or its derivatives, polylactic acid-glycolic acid copolymer (P L GA),
according to the parts by weight, the weight percentage of the raw materials,
1 part of the medicine is prepared into the dosage form of,
0.5 to 5 portions of glucose oxidase,
0.5 to 5 portions of catalase,
5-100 parts of polyketal or derivative thereof,
5-100 parts of polylactic acid-glycolic acid copolymer (P L GA),
wherein the structural formula of the polyketal is as follows:
wherein n is more than or equal to 1
The structural formula of the polyketal derivative is as follows:
wherein R represents hydrocarbyl or alkyl, X is more than or equal to 1, Y is more than or equal to 1, and the weight average molecular weight of the polyketal or the derivative thereof is 2000-100000;
the intelligent sustained and controlled release microsphere is a solid microsphere, the outer layer is a polylactic acid-glycolic acid copolymer (P L GA) shell, the interior of the intelligent sustained and controlled release microsphere contains a plurality of polyketal or derivatives thereof as small-particle-size microspheres for embedding medicaments, and glucose oxidase and catalase trigger are filled between the outer part of the small-particle-size microspheres and the outer layer of the intelligent sustained and controlled release microsphere.
Preferably, the drug is selected from one or more of insulin, liraglutide, pramlintide, exenatide, sulfonylurea drugs, biguanide drugs and thiazolidinedione drugs.
The preparation method of the intelligent sustained and controlled release microsphere comprises the following steps:
(1) preparation of oil phase A: dissolving the drug, the polyketal or the derivative thereof in dichloromethane or dropwise adding the active drug solution into dichloromethane containing the polyketal or the derivative thereof under the high-speed shearing condition of 3000-12000 rpm;
(2) preparing oil phase B by dissolving glucose oxidase, catalase and P L GA in organic solution, wherein the organic solvent is one or more of ethyl acetate, ethanol, acetone, tetrahydrofuran and diethyl ether;
(3) dropwise adding the oil phase A into the phase B under the high-speed shearing condition of 2000-4000rpm to form an S/O/O phase or a W/O/O phase, wherein the mass concentrations of the polyketal or the derivative thereof in the oil phase A and the P L GA in the oil phase B are respectively 10-25%;
(4) adding the S/O/O phase or the W/O/O phase obtained in the step (3) into the solution C under the conditions of high-speed shearing of 4000-;
the solution C is a polyvinyl alcohol (PVA) aqueous solution with the mass percentage concentration of 0.5-3%;
(5) stirring the emulsion obtained in the step (4) at a medium speed for 1-2h, and then stirring at a low speed for 1-2h until the organic solvent is completely volatilized, so as to obtain the solidified microspheres; and centrifuging, washing and freeze-drying the solidified microspheres to obtain the intelligent response type sustained and controlled release microspheres.
Preferably, the mass concentration of the polyketide or the derivative thereof in the oil phase A and the mass concentration of the P L GA in the oil phase B in the step (3) are 15-20%.
Preferably, the medium-speed stirring rotation speed in the step (5) is 1000-2000rpm, and the low-speed stirring rotation speed is 500-800 rpm.
The key point of the intelligent response type sustained-release microsphere is that the intelligent response type sustained-release microsphere with a special structure of the particle microsphere embedded with the polyketal or the derivative thereof is formed by dripping under the condition of high-speed shearing by utilizing the difference of the precipitation speed of the polyketal or the derivative thereof and the polylactic acid-glycolic acid copolymer (P L GA) in different organic solvents.
Taking insulin as an example, when the blood glucose concentration of the organism rises, glucose can diffuse into the interior of the microsphere through the surface pores of the outer-layer P L GA microsphere, at the moment, glucose oxidase and catalase dispersed in the interior of the microsphere act together to oxidize the glucose entering the microsphere into gluconic acid, and the polyketal or a derivative thereof has acid sensitivity and can be degraded under an acidic condition, at the moment, the generated gluconic acid firstly degrades the polyketal surface of the polyketal or a derivative thereof particle microsphere at the outermost layer in the interior of the microsphere, so that the embedded insulin is released outwards through the surface pores of the outer-layer P L GA microsphere, and simultaneously, the release time of the polyketal or a derivative thereof particle close to the central position of the microsphere is further delayed along with the release of the insulin, so that the conversion reaction quantity of the glucose, the glucose and the catalase is reduced, thereby the glucose acidic condition is retarded from further permeating into the polyketal microsphere at the central position of the microsphere, the release time of the polyketal or a derivative thereof particle close to the central position of the microsphere is further delayed, namely, the release mechanism of the sustained release of the polyketal release drug is gradually released, and the glucose oxidase release microsphere releases the glucose oxidase-release copolymer, and the glucose oxidase-glucose-release rate is reduced, and the glucose-release rate is reduced when the glucose release rate of the organism glucose release microsphere reaches the organism until the organism physiological glucose release rate of the organism reaches the organism, and the organism, so that the glucose release rate of the organism glucose release rate of the glucose release microsphere release rate is reduced, and the organism reaches the organism, and the organism.
Advantageous effects
1) The intelligent response type sustained and controlled release microsphere prepared by the invention has a unique P L GA round structure, and the existence of a multilayer structure of the drug-embedded microsphere and the particle microsphere of the polyketal or the derivative thereof is beneficial to the maximum wrapping of the drug in the microsphere, namely compared with the prior art, the invention greatly improves the drug-loading rate and the encapsulation rate of the drug.
2) The invention provides an intelligent response type sustained and controlled release microsphere medicine with novel structural characteristics, wherein the novel microsphere additionally comprises a plurality of small-particle-size microspheres, the outer-layer microspheres use P L GA as a carrier material, the inner microspheres mainly use polyketal or derivatives thereof as a framework, model medicines are embedded in the microspheres, glucose oxidase and catalase trigger are dispersed outside the small-particle-size microspheres, when external glucose enters the outer-layer microspheres through pores, the small polyketal or derivatives thereof embedded in the novel microspheres gradually degrade and release the medicines to show the characteristic of gradual release, and the novel preparation can be used for greatly solving the burst release phenomenon of common microspheres and showing more long-acting and stable release characteristics while intelligently responding and releasing the medicines.
3) The novel microspheres prepared by the invention can realize intelligent regulation of the drug release rate by utilizing the blood sugar concentration in vivo, and particularly can control drug release to the maximum extent when normal blood sugar (1 mg/ml) is reached, so that the technical problem that drug release is influenced by the glucose concentration in the prior art is solved, and the condition that hypoglycemia is easily caused by overhigh linear release accumulation of general sustained-release drugs is overcome.
Drawings
FIG. 1 is a scanning electron microscope image of an insulin-loaded intelligent response type sustained/controlled release microsphere according to a first embodiment of the present invention;
FIG. 2 is a cross-sectional view of a scanning electron microscope of an intelligent response type sustained/controlled release microsphere loaded with insulin according to a first embodiment of the present invention;
FIG. 3 is an in vitro release curve of an insulin-loaded intelligent response type sustained/controlled release microsphere according to a first embodiment of the present invention;
FIG. 4 is the in vitro release curve of the exenatide-loaded intelligent response type sustained or controlled release microsphere in the second embodiment of the present invention;
FIG. 5 is an in vitro release curve of three intelligent response type sustained and controlled release microspheres loaded with glibenclamide in the embodiment of the invention;
FIG. 6 is a scanning electron microscope image of the sugar-sensitive polyketal microspheres loaded with insulin according to comparative example one of the present invention;
FIG. 7 is the in vitro release curve of the insulin-loaded sugar-sensitive polyketal microspheres of comparative example one of the present invention;
FIG. 8 is the in vitro release curve of exenatide-loaded sugar-sensitive polyketal microspheres of comparative example II of the present invention;
FIG. 9 is the in vitro release curve of glibenclamide loaded sugar sensitive polyketal microspheres of comparative example three of the present invention.
Detailed Description
The present invention is described below with reference to specific examples, but the specific steps of the present invention are not limited to the examples. In addition, the drug loading rate, the encapsulation efficiency and the in vitro cumulative release degree of the active substances are calculated by adopting a reversed-phase high performance liquid chromatography in the experimental process.
Example one intelligent response type slow/controlled release microsphere loaded with insulin
(1) Preparing two separate oil phases, namely oil phase A, precisely weighing 20mg of insulin to be dissolved in 0.1ml of dimethyl sulfoxide (DMSO), dropwise adding the solution into 0.9ml of dichloromethane containing 150mg of polyketide (weight-average molecular weight 4250) under the high-speed shearing condition of 5000rpm, and oil phase B, precisely weighing 10mg of glucose oxidase, 10mg of catalase and 300mg of P L GA to be dissolved in 2ml of ethyl acetate together;
(2) quickly dripping the oil phase A into the phase B under the high-speed shearing condition of 2000rpm to form an S/O/O phase; rapidly dripping the S/O/O phase into 200ml of PVA aqueous solution with the mass concentration of 1% under the condition of high-speed shearing 4000rpm to form an S/O/O/W phase;
(3) stirring the obtained emulsion at 1000rpm for 1h, then stirring at 500rpm for 2h, centrifuging the solidified microspheres, washing with deionized water, and freeze-drying to obtain the product.
The scanning electron microscope image of the novel microsphere is shown in figure 1, and the novel microsphere is round and smooth in shape, uniform in particle size and not adhered, and the particle size is 50-100 mu m; from the section electron micrograph of the novel microsphere in FIG. 2, it can be seen that the novel microsphere contains a plurality of small microspheres and has a round and round shape; the drug loading of the novel microsphere is 3.66 percent, and the encapsulation rate is 74.8 percent; the in vitro release profiles in glucose release media of different concentrations are shown in FIG. 3.
EXAMPLE two Exenatide-loaded intelligent response type sustained-release microspheres
(1) Preparing two separate oil phases, oil phase A, precisely weighing exenatide 20mg dissolved in 1ml dichloromethane containing 200mg polyketide (weight average molecular weight 7250), oil phase B, precisely weighing glucose oxidase 15mg, catalase 15mg and 200mg P L GA together dissolved in 1ml acetone;
(2) quickly dripping the oil phase A into the phase B under the high-speed shearing condition of 3000rpm to form an O/O phase; quickly dripping the O/O phase into 200ml of PVA water solution with the mass concentration of 1% under the condition of high-speed shearing at 5000rpm to form an O/O/W phase;
(3) stirring the obtained emulsion at 1200rpm for 1h, then quickly stirring at 600rpm for 2h, centrifuging the solidified microspheres, washing with deionized water, and freeze-drying to obtain the product.
Through detection, the particle size of the novel microsphere is 50-100 μm; the drug loading rate is 3.41 percent, the encapsulation rate is 89.7 percent, and the in vitro release conditions of the drug in glucose release media with different concentrations are shown in figure 4.
Example III Intelligent response type sustained and controlled release microsphere loaded with glibenclamide
(1) Preparing two separate oil phases, namely oil phase A which is precisely weighed that 30mg of glibenclamide is dissolved in 1.5ml of dichloromethane containing 300mg of polyketide (weight average molecular weight 6500), and oil phase B which is precisely weighed that 20mg of glucose oxidase, 20mg of catalase and 300mg of P L GA are dissolved in 1.5ml of tetrahydrofuran together;
(2) quickly dripping the oil phase A into the phase B under the high-speed shearing condition of 4000rpm to form an O/O phase; quickly dripping the O/O phase into 300ml of PVA water solution with the mass concentration of 1% under the condition of high-speed shearing 6000rpm to form an O/O/W phase;
(3) stirring the obtained emulsion at 1500rpm for 1h, then rapidly stirring at 700rpm for 2h, centrifuging the solidified microspheres, washing with deionized water, and freeze-drying to obtain the product.
Through detection, the particle size of the novel microsphere is 50-100 μm; the drug loading rate is 4.16 percent, the encapsulation rate is 92.8 percent, and the in vitro release conditions of the drug in glucose release media with different concentrations are shown in figure 5.
Comparative example an insulin-loaded sugar-sensitive polyketal microsphere
Precisely weighing 10mg of insulin, dissolving in 0.1ml of DMSO, dropwise adding the solution into 0.9ml of dichloromethane dissolved with 20mg of glucose oxidase, 20mg of catalase and 125mg of polyketide (weight-average molecular weight 4250) under the high-speed shearing condition of 7500rpm, and preparing into uniform oil phase; dripping the oil phase into 100ml of PVA water solution with the mass concentration of 1% at 1500rpm to form an S/O/W phase, continuously stirring for 8 hours, volatilizing the organic solvent, and solidifying the microspheres; washing the microspheres for 3 times by using deionized water, transferring the microspheres to a culture dish, and freeze-drying to obtain the insulin sugar sensitive polyketal microspheres.
Through detection, a scanning electron microscope image of the microsphere is shown in fig. 6, and it can be seen that the microsphere has a rough and non-smooth surface, a particle size of 10-50 μm, a drug loading rate of 3.02%, and an encapsulation rate of 60.7%; the in vitro release profiles in glucose release media of different concentrations are shown in FIG. 7.
Comparative example II Exenatide-loaded sugar-sensitive polyketide microspheres
Precisely weighing 10mg of exenatide, 15mg of glucose oxidase and 15mg of catalase, and dissolving in 0.5ml of water solution to form an internal water phase; 200mg of polyketal (weight average molecular weight 7250) was dissolved in 2ml of dichloromethane to form an oil phase; dropwise adding the inner water phase into the oil phase under the condition of high-speed shearing of 7500rpm to form W/O type primary emulsion; adding the primary emulsion into 100ml of PVA water solution with the mass concentration of 1% under the stirring condition of 1500rpm to form a W/O/W phase; continuously stirring for 8h, volatilizing the organic solvent, and solidifying the microspheres; washing the microsphere for 3 times by deionized water, transferring the microsphere to a culture dish, and freeze-drying to obtain the exenatide sugar-sensitive polyketide microsphere.
Through detection, the particle size of the microsphere is 10-50 μm, the drug-loading rate is 3.16%, and the encapsulation rate is 68.5%; the in vitro release profiles in glucose release media of different concentrations are shown in FIG. 8.
Comparative example sugar-sensitive polyketal microspheres loaded with glibenclamide
Precisely weighing 15mg of glucose oxidase and 15mg of catalase, and dissolving in 0.5ml of water solution to form an internal water phase; dissolving glibenclamide 15mg and polyketal (weight average molecular weight 6500) 300mg in dichloromethane 2ml to prepare oil phase; dropwise adding the internal water phase into the oil phase under the condition of high-speed shearing 25000rpm to form a W/O phase; adding the primary emulsion into 100ml of PVA water solution with the mass concentration of 1% under the stirring condition of 1500rpm to form a W/O/W phase; continuously stirring for 8h, volatilizing the organic solvent, and solidifying the microspheres; washing the microspheres for 3 times by using deionized water, transferring the microspheres into a culture dish, and freeze-drying to obtain the glibenclamide sugar-sensitive polyketal microspheres.
The detection shows that the particle size of the microsphere is 10-50 μm, the drug loading rate is 3.22%, the encapsulation rate is 65.4%, and the in vitro release condition of the microsphere in glucose release media with different concentrations is shown in figure 9.
The intelligent response type sustained and controlled release microsphere prepared by the invention has a unique round P L GA structure as shown in figure 1, the surface compactness degree of the novel microsphere is obviously superior to that of the sugar sensitive polyketal microsphere of the comparative example, meanwhile, as shown in figure 2, the existence of the multilayer structure of the novel microsphere is beneficial to the maximum wrapping of the drug into the microsphere (the drug embedding and the particle microsphere of the polyketal or the derivative thereof in the microsphere), as shown in figure 6, the comparative example adopts a single microsphere with loose and porous surface, and the water-soluble drug is easy to leak out to the aqueous solution.
Compared with the comparative example in which the release of the drug is triggered by the stimulation of gluconic acid in the single-layer microsphere, the novel microsphere prepared by the invention additionally contains the polyketone or derivative particle microsphere, and the release mechanism with controllable slow release is characterized in that the polyketone or derivative particle thereof in the external gluconic acid stimulated microsphere degrades and releases the drug layer by layer in a gradient manner, so that the novel microsphere shows a better slow release effect compared with the comparative example. In order to verify the beneficial effect of the drug of the invention with controllable slow release, examples 1-3 and comparative examples 1-3 respectively examine the release conditions of microspheres in glucose solution simulated human body normal blood sugar (1 mg/ml), hyperglycemia (2 mg/ml), hyperglycemia (5 mg/ml) and phosphate buffer (PBS, pH = 7.4), and it can be seen from the in vitro release curves of the examples and comparative examples that when the novel microspheres are in PBS, the release rate is slower due to the existence of sugar-free, the release rate of the microspheres is gradually accelerated along with the increase of glucose concentration, mainly due to the fact that the generated gluconic acid causes the polyketide to accelerate degradation; meanwhile, the novel microspheres solve the sudden release phenomenon of the drug in the comparative example to a great extent, the cumulative release percentage of the drug at several glucose concentrations on the 1 st day is not more than 20%, the cumulative release percentage of the novel microspheres in several release mediums on the 6 th day is not more than 60%, compared with the sugar sensitive polyketal microspheres in the comparative example, the release time of the drug is obviously prolonged, a better slow release effect is shown, and the compliance of a diabetic patient is further improved.
Further analysis shows that, because the P L GA shell of the novel microsphere is round and uniform in pores, and the polyketal or derivative particle microsphere thereof is embedded inside the novel microsphere, when glucose is uniformly diffused into the microsphere through the pores on the surface of the outer P L GA microsphere, the polyketal or derivative particle microsphere thereof on the outermost layer inside the microsphere is firstly degraded to release the drug, and simultaneously the glucose content around the polyketal particle microsphere on the outer layer is reduced along with the release of the drug, so that the further permeation of the glucose acidic condition into the polyketal microsphere at the central position of the microsphere is retarded, and the release time of the polyketal or derivative particle microsphere thereof closer to the central position of the microsphere is further delayed, i.e. a better sustained release effect is shown, compared with the novel microsphere of the present invention, the microsphere is embedded with the drug, glucose and catalase by using the polyketal as the microsphere shell, the outer surface of the microsphere formed by the polyketal material ketal is loose and porous and has larger pores (as shown in fig. 6), so that the release of the glucose oxidase directly enters the glucose oxidase and the catalase in the microsphere, and the release mechanism of the polyketal is further degraded, thereby expanding the release of the glucose is a great amount of the glucose controlled release of the glucose and the glucose is short single drug.
It should be noted that the test of the examples shows that when the novel microspheres are under normal blood glucose concentration (1 mg/ml), the release rate is close to that of the microspheres in PBS, and the stability of blood glucose value can be maintained, the analysis reason is that the outer layer of the polylactic acid-glycolic acid copolymer (P L GA) of the invention can effectively delay the glucose entering the inner layer to trigger the release of the drug, because the glucose molecule needs to enter the novel microspheres through the shell layer of the P L GA microsphere for a certain time and is converted into the glucose acid to cause the degradation of the inner polyketal microspheres to release the drug, and the drug is released gradually, i.e. the inner microspheres break down one by one to release the drug, the release amount of the drug in unit time is small, meanwhile, the released drug from the inner microspheres to the body also needs to pass through the outer layer of P L GA, the inner microspheres degrade and release gradually, and the existence of the outer layer of the P L GA material, the drug release is retarded, the amount of the drug in the body is low, so that the stability of the blood glucose value is maintained, compared with the novel microspheres of the comparative example, compared with the comparative example, when the glucose sensitive polyketal microspheres recover normal blood glucose concentration is recovered, the surface is very easily recovered, and the case of the glucose level is very low, the case of the glucose release is very low, the first glucose release rate is very low, the case of the invention, the case of the glucose release is very low, the glucose release is very easily reduced, and the initial glucose release of the novel microspheres, the initial glucose release microsphere, the initial glucose release is very low glucose release, and.
Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the embodiments, and various equivalent modifications can be made within the technical spirit of the present invention, and the scope of the present invention is also within the scope of the present invention. It should be noted that the various features described in the above embodiments may be combined in any suitable manner without departing from the scope of the invention. The invention is not described in detail in order to avoid unnecessary repetition. In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (5)
1. An intelligent response type sustained and controlled release microsphere comprises a medicament, glucose oxidase, catalase, polyketide or derivatives thereof, and is characterized by also comprising polylactic acid-glycolic acid copolymer (P L GA),
according to the parts by weight, the weight percentage of the raw materials,
1 part of the medicine is prepared into the dosage form of,
0.5 to 5 portions of glucose oxidase,
0.5 to 5 portions of catalase,
5-100 parts of polyketal or derivative thereof,
5-100 parts of polylactic acid-glycolic acid copolymer (P L GA),
wherein the structural formula of the polyketal is as follows:
wherein n is more than or equal to 1
The structural formula of the polyketal derivative is as follows:
wherein R represents hydrocarbyl or alkyl, X is more than or equal to 1, Y is more than or equal to 1, and the weight average molecular weight of the polyketal or the derivative thereof is 2000-100000;
the intelligent sustained and controlled release microsphere is a solid microsphere, the outer layer is a polylactic acid-glycolic acid copolymer (P L GA) shell, the interior of the intelligent sustained and controlled release microsphere contains a plurality of polyketal or derivatives thereof as small-particle-size microspheres for embedding medicaments, and glucose oxidase and catalase trigger are filled between the outer part of the small-particle-size microspheres and the outer layer of the intelligent sustained and controlled release microsphere.
2. The microsphere of claim 1, wherein the drug is selected from one or more of insulin, liraglutide, pramlintide, exenatide, sulfonylurea drugs, biguanide drugs, thiazolidinedione drugs.
3. A method for preparing microspheres as claimed in claim 1 or 2, characterized by the steps of:
(1) preparation of oil phase A: dissolving the drug, the polyketal or the derivative thereof in dichloromethane or dropwise adding the active drug solution into dichloromethane containing the polyketal or the derivative thereof under the high-speed shearing condition of 3000-12000 rpm;
(2) preparing oil phase B by dissolving glucose oxidase, catalase and P L GA in organic solution, wherein the organic solvent is one or more of ethyl acetate, ethanol, acetone, tetrahydrofuran and diethyl ether;
(3) dropwise adding the oil phase A into the phase B under the high-speed shearing condition of 2000-4000rpm to form an S/O/O phase or a W/O/O phase, wherein the mass concentrations of the polyketal or the derivative thereof in the oil phase A and the P L GA in the oil phase B are respectively 10-25%;
(4) adding the S/O/O phase or the W/O/O phase obtained in the step (3) into the solution C under the conditions of high-speed shearing of 4000-;
the solution C is a polyvinyl alcohol (PVA) aqueous solution with the mass percentage concentration of 0.5-3%;
(5) stirring the emulsion obtained in the step (4) at a medium speed for 1-2h, and then stirring at a low speed for 1-2h until the organic solvent is completely volatilized, so as to obtain the solidified microspheres; and centrifuging, washing and freeze-drying the solidified microspheres to obtain the intelligent response type sustained and controlled release microspheres.
4. The method according to claim 3, wherein the mass concentration of the polyketal or a derivative thereof in oil phase A and P L GA in oil phase B in step (3) is 15-20%.
5. The preparation method according to claim 3, wherein the medium-speed stirring rotation speed in the step (5) is 2000rpm and the low-speed stirring rotation speed is 800rpm and 1000 rpm.
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