A gel sustained-release preparation using a sparingly soluble salt as a pH regulator, and its preparation method and application

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a gel sustained-release preparation with a sparingly soluble salt as a pH regulator, and a preparation method and application thereof. The gel sustained-release preparation with a sparingly soluble salt as a pH regulator is obtained by blending sparingly soluble salt crystalline powder, alkaline coatings and polymer solutions. This type of preparation is injectable and can be converted into a gel state after being injected into the body, so as to achieve the slow release of the coating at the injection site. The sparingly soluble salt reduces the solubility of the coating in the gel by adjusting the pH inside the gel, so that part of the coating is dispersed in the gel network in the form of crystals. In the early stage, the sudden release of the coating from the gel is prevented, and in the later stage, as the acidic degradation products of the gel accumulate, the sparingly soluble salt gradually dissolves, thereby achieving the sustained release of the coating. This technology can be applied to the fields of long-acting analgesia, medical cosmetology and anti-tumor.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a gel sustained-release preparation using a sparingly soluble salt as a pH regulator, and a preparation method and application thereof. Background Art

[0002] Gel sustained-release preparations have a wide range of uses, but they also face the problem that the pH or changes in the gel interior are not conducive to sustained-release of drugs or encapsulated substances due to factors such as the polymer itself or its degradation products, or the solubility of the drug itself is too high to be conducive to sustained-release.

[0003] For example, among the polymers that make up the gel, the hydrogel solution obtained by compounding polyester-polyether block copolymers with water has a place in the drug delivery system due to its good biocompatibility, degradability and unique temperature-sensitive properties. Among them, the triblock copolymer PLGA-PEG-PLGA composed of polyethylene glycol (PEG) and poly (lactic acid-glycolic acid) (PLGA) is particularly useful. The synthesis method of this type of polymer is simple, that is, PEG is used as an initiator, and under the catalysis of stannous octoate, lactide and glycolide undergo ring-opening polymerization, and a triblock copolymer with polyester blocks at both ends and polyethylene glycol in the middle can be obtained by one-step polymerization. Under the appropriate block ratio, composition and concentration, this type of polymer solution is in a flowable solution state at room temperature and is easy to blend with drugs; at body temperature, it can spontaneously transform into a gel state to achieve in situ sustained release of the loaded drug at the injection site. In the field of pharmacy, the solubility of alkaline poorly soluble drugs is often increased by preparing them into soluble salts, which is used to achieve the drugability and injectability of the drug. The polyester-polyether block copolymer aqueous solution has a natural acidic environment, and degradation is achieved by hydrolysis, and the final degradation products are lactic acid, PEG and glycolic acid. At room temperature, the pH value of this gel solution is usually around 3, and this acidic environment is easy to achieve the dissolution of poorly soluble alkaline drugs. However, in the gel state in vivo, for small molecule drugs, the increase in drug solubility is often accompanied by the sudden release of drugs and water in the early stage of the gel, which is unfavorable for the performance of the long-term drug effect of the drug. Therefore, it is of great significance to solve the problem of sudden release of drugs in the early stage of the gel and realize the long-term sustained release of drugs in the gel. Summary of the invention

[0004] In view of this, the first object of the present invention is to provide a gel sustained-release preparation with a sparingly soluble salt as a pH regulator to address the problems existing in the prior art. The gel sustained-release preparation utilizes the interaction between the dissolved products of the sparingly soluble salt and the alkaline coating or polymer and its degradation products, which can significantly improve the sustained-release effect of the loaded drug or coating.

[0005] In order to achieve the above object, the present invention adopts the following technical solution:

[0006] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator comprises a sparingly soluble salt, an alkaline coating and a polymer water system.

[0007] It is worth noting that there is interaction between the dissolved product of the sparingly soluble salt disclosed in the present invention and the alkaline inclusion or polymer and its degradation product, and the interaction is adsorption, electrostatic interaction or coordination.

[0008] Most of the prior art uses soluble ionic compounds (such as soluble phosphate buffer) to adjust the pH of the system, which makes the pH adjustment effect only effective in the initial stage. The present invention uses a sparingly soluble salt as a pH regulator, and provides a gel sustained-release preparation with a sparingly soluble salt as a pH regulator. This type of preparation is injectable and can be converted into a gel state after being injected into the body, thereby achieving a slow release of the inclusions at the injection site. The sparingly soluble salt reduces the solubility of the inclusions in the gel by adjusting the pH inside the gel, so that part of the inclusions are dispersed in the gel network in the form of crystals. In the early stage, the sudden release of the inclusions from the gel is prevented, and in the later stage, as the acidic degradation products of the gel accumulate, the sparingly soluble salt gradually dissolves, thereby achieving a sustained release of the inclusions.

[0009] Further considering that the sparingly soluble salt needs to be slightly soluble or insoluble in water and can be dissolved in an acidic environment, the sparingly soluble salt described in the present invention includes one or more complexes of other carbonates, phosphates, hydrogen phosphates, silicates or calcium sulfate, silver sulfate, magnesium ammonium phosphate, and sodium bismuthate other than potassium, sodium, and ammonium.

[0010] It is worth noting that there are many kinds of sparingly soluble salts, among which calcium carbonate, a mineral crystal, can not only be used as an effective active substance for calcium supplementation, but also can be added to pharmaceutical preparations as a drug excipient. Calcium carbonate is cheap, has good biocompatibility, degradability and acid responsiveness, and can be widely used as a good drug carrier in drug delivery systems. It is worth noting that the U.S. Food and Drug Administration (FDA) has approved the use of calcium carbonate in food and pharmaceutical preparations. There are studies on encapsulating enzymes, DNA or drugs in calcium carbonate for the delivery and release of the substances carried. Common methods for loading drug packages into calcium carbonate include: adsorption method, osmosis method and coprecipitation method. In particular, due to its unique pH sensitivity, it is often used for targeted delivery of anti-tumor drugs, that is, by responding to the acidic tumor microenvironment, thereby achieving targeted delivery and release of the anti-tumor drugs carried.

[0011] The present invention uses calcium carbonate and other substances with good pH responsiveness as pH regulators, and directly adds them in the form of crystalline powders with drug powders to an aqueous solution of a polyester-polyether block copolymer and other substances for blending. The introduction of calcium carbonate and other substances does not affect the thermal gelation behavior of the polymer solution, that is, the prepared preparation is still injectable and is in a solution state at room temperature. After being injected into the body, it can be converted into a physical gel state to achieve slow release of the drug at the injection site. The addition of calcium carbonate and other substances reduces the solubility of the drug in the polymer solution by adjusting the pH inside the gel, so that part of the drug is dispersed in the gel network in the form of crystals, and the completely dissolved drug can meet the performance of the early drug effect. The crystallization of some drugs can reduce the sudden release of the early drug to a certain extent. In the later stage, as the gel degrades, acidic degradation products accumulate, calcium carbonate and other substances gradually dissolve, and the solubility of alkaline drugs gradually increases, so that the drug sustained release behavior synchronized with the degradation of the gel can be achieved.

[0012] Furthermore, the alkaline coating includes one or more of procaine, tetracaine, proparacaine, oxybuprocaine, lidocaine, bupivacaine, mepivacaine, ropivacaine, imiquimod, nitrogen mustard, gemcitabine, vinblastine, vincristine, doxorubicin, daunorubicin, irinotecan, 10-hydroxycamptothecin, nicotinamide, and arginine.

[0013] It is worth noting that the alkaline inclusions are inclusions with low solubility in aqueous solution and high solubility in acidic environment, contain protonable groups, and are often used clinically or pharmaceutically after being made into soluble salts by adding acid.

[0014] Furthermore, the polymer is a polyester-polyether block copolymer, a polymer having a carboxylate, sulfate, sulfonate or phosphate group in the side chain, and a mixture thereof.

[0015] It is worth noting that the polymer can achieve gelation in vivo, and the polymer aqueous solution or the aqueous solution after degradation is acidic.

[0016] Furthermore, the polyester-polyether block copolymer is an ABA or BAB type triblock copolymer, an AB type diblock copolymer, an AgB or BgA type graft copolymer, or an (AB) n Copolymer, A(BA) n or B(AB) n One or more of the type copolymers, wherein A is polyethylene glycol and B is an aliphatic polyester.

[0017] Furthermore, the polyether block A is polyethylene glycol with a molecular weight of 400-6000, and the polyester block B is an aliphatic polyester with a molecular weight of 500-5000.

[0018] Furthermore, the polyester block B is any combination of one or more of poly D,L-lactide, poly L-lactide, polyglycolide, poly ε-caprolactone, poly δ-valerolactone, and polycarbonate.

[0019] Furthermore, the polymer having carboxylate, sulfate, sulfonate or phosphate in the side chain is a polymer containing one or more blocks of acrylic acid, tert-butyl acrylate-co-acrylic acid, sodium 4-styrenesulfonate, methacrylic acid-2-propanesulfonic acid, β-ethyl methacrylate sulfate, β-ethyl methacrylate phosphate, glutamic acid, and aspartic acid.

[0020] Furthermore, the preparation can be injected at room temperature and can spontaneously form a physical hydrogel at body temperature. The preparation can delay the release of the contained inclusions. The addition of insoluble salts can adjust the pH inside the gel, reduce the solubility of the inclusions in the polymer solution, and make part or all of the inclusions dispersed in the gel network in the form of crystals; the pH value of the gel preparation that achieves sustained release of the inclusions is 5 to 8.

[0021] It is worth noting that, unlike other technologies that rely on the form of insoluble salts of drugs to achieve sustained release of drugs, the present invention adjusts the pH value of the sustained / controlled release system by adding insoluble salts, thereby reducing the solubility of the drug and allowing the drug to exist in the form of crystals, thereby achieving slow release of the drug. Moreover, unlike other pH regulators that are only effective in the initial stage, the undissolved insoluble salts of the present invention can be dispersed in the system and continue to interact with gel degradation products, etc., to play a continuous pH regulating role, thereby achieving drug sustained release behavior synchronized with gel degradation.

[0022] The second object of the present invention is to provide a method for preparing the above-mentioned gel sustained-release preparation using a sparingly soluble salt as a pH regulator.

[0023] In order to achieve the above object, the present invention adopts the following technical solution:

[0024] A method for preparing a gel sustained-release preparation using a sparingly soluble salt as a pH regulator comprises the following steps: firstly preparing a polymer aqueous solution, and then directly blending and compounding the polymer aqueous solution with an alkaline coating and sparingly soluble salt crystalline powder.

[0025] Furthermore, the specific steps of the preparation method include:

[0026] (1) placing one or more copolymers in an aqueous solution, stirring magnetically at -10-40° C. to completely dissolve the polymers, thereby obtaining a polymer water system for later use;

[0027] (2) adding alkaline coating and insoluble salt crystalline powder, and stirring them by magnetic force at -10-40° C. to fully mix them, thereby obtaining the gel sustained-release preparation with insoluble salt as pH regulator.

[0028] The third object of the present invention is to provide the use of the above-mentioned gel sustained-release preparation.

[0029] In order to achieve the above object, the present invention adopts the following technical solution:

[0030] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator is used as a material for preparing sustained / controlled-release drugs.

[0031] Furthermore, the sustained / controlled release drugs include analgesics, anti-tumor drugs or active substances with medical cosmetic effects.

[0032] It is worth noting that the gel sustained-release preparation disclosed in the present invention is in a flowable injectable state at room temperature and can be converted into a gel state after being injected into the body. The sparingly soluble salt contained in the preparation adjusts the pH inside the gel, reduces the solubility of the inclusions in the polymer solution, and makes part or all of the inclusions dispersed in the gel network in the form of crystals, so as to delay the release of the inclusions, reduce the frequency of administration, and improve patient compliance.

[0033] Furthermore, the administration forms of the preparation disclosed in the present invention include but are not limited to local injections such as subcutaneous injection, intramuscular injection, perineural injection, joint cavity injection, intratissue injection, and peritumoral injection.

[0034] In some embodiments, pain, as an important vital sign, often occurs after clinical surgery. The application of local anesthetics around peripheral nerves can not only effectively control pain, but also reduce the use of opioids and has received widespread attention. Clinically, hydrochlorides, sulfonates and other forms of such drugs are often used to improve the solubility of the drug, so that it can be formulated into injectable solutions to exert the efficacy of pain control, but the molecular weight of such drugs is low, the half-life is short, and the efficacy in the body can only be maintained for a few hours, which is far from enough to maintain a relatively long-term analgesic effect. Frequent administration is required in clinical use, which is extremely inconvenient to use. Therefore, it is of great significance to develop a long-acting preparation that is easy to use, has a high safety factor and can exert analgesic efficacy.

[0035] For example, bupivacaine is an amide local anesthetic widely used in clinical practice. The drug has a tertiary amine group in its structural formula and is easily soluble in acidic media. Bupivacaine is added together with calcium carbonate crystalline powder to a polymer solution that can achieve in vivo gelation. With the help of the thermal gelation characteristics of the polymer solution, bupivacaine can not only be fixed around the nerves to avoid the problem of easy leakage of the solution through the intermuscular space, but also the pH inside the gel can be adjusted by adding calcium carbonate, reducing the solubility of bupivacaine in the gel, so that part of the bupivacaine is dispersed in the gel network in the form of crystals. In the early stage, the sudden release of bupivacaine from the gel is prevented. In the later stage, as the acidic degradation products of the gel accumulate, the calcium carbonate gradually dissolves, achieving the sustained release of bupivacaine and achieving a long-term analgesic effect in the body.

[0036] Based on the same inventive concept, in other embodiments, the introduction of calcium carbonate into the polymer solution can delay the release of the immune adjuvant imiquimod (R837), continuously promote the maturation of dendritic cells, thereby enhancing the cell-mediated immune response and achieving better anti-tumor efficacy.

[0037] Compared with the prior art that mostly uses soluble ionic compounds (such as soluble phosphate buffer) to adjust the pH of the system, which makes the pH adjustment effect only effective in the initial stage, the present invention uses insoluble salts as pH regulators, and provides a gel sustained-release preparation with insoluble salts as pH regulators and its application. This type of preparation is simple to prepare and has injectability. After being injected into the body, it can be converted into a gel state to achieve slow release of the inclusions at the injection site. The insoluble salt reduces the solubility of the inclusions in the gel by adjusting the pH inside the gel, so that part of the inclusions are dispersed in the gel network in the form of crystals. In the early stage, the sudden release of the inclusions from the gel is prevented. In the later stage, as the acidic degradation products of the gel accumulate, the insoluble salts gradually dissolve, achieving sustained release of the inclusions. This technology can be applied to the fields of long-acting analgesia, medical cosmetology and anti-tumor. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the prior art descriptions are briefly introduced below. The drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without creative work.

[0039] Figure 1 These are the appearance diagrams of the sustained-release preparation P1 described in Example 1 of the present invention at room temperature and body temperature respectively.

[0040] Figure 2 This is the in vivo in situ gel formed after the injection of the preparation P1 in Example 2 of the present invention around the sciatic nerve of rats for several hours.

[0041] Figure 3 The in vitro release curves of ropivacaine (ROP) thermosensitive gel in each preparation group in Example 3 of the present invention are shown.

[0042] Figure 4 It is the pH value of each preparation group in Example 4 of the present invention.

[0043] Figure 5 This is an in vivo analgesic effect evaluation of each preparation group in Example 5 of the present invention.

[0044] Figure 6 The in vitro release curves of each group of preparation R837 in Example 6 of the present invention. DETAILED DESCRIPTION

[0045] The technical solutions in the embodiments of the present invention are described clearly and completely below. The described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0046] The word "embodiment" used here as an "exemplary" does not necessarily mean that any embodiment described is superior to or better than other embodiments. Unless otherwise specified, the performance index tests in the embodiments of this application are performed using conventional test methods in the art. It should be understood that the terms described in this application are only used to describe specific implementation methods and are not used to limit the content disclosed in this application.

[0047] Unless otherwise specified, the technical and scientific terms used in this document have the same meanings as commonly understood by ordinary technicians in the technical field to which this application belongs; other experimental methods and technical means not specifically specified in this application refer to experimental methods and technical means commonly used by ordinary technicians in this field.

[0048] The terms "substantially" and "approximately" used herein are used to describe small fluctuations. For example, they can refer to less than or equal to ±5%, such as less than or equal to ±2%, such as less than or equal to ±1%, such as less than or equal to ±0.5%, such as less than or equal to ±0.2%, such as less than or equal to ±0.1%, such as less than or equal to ±0.05%. The numerical data represented or presented in the range format herein are used only for convenience and brevity, and should therefore be flexibly interpreted as including not only the values ​​clearly listed as the limits of the range, but also all independent values ​​or sub-ranges contained in the range. For example, the numerical range of "1-5%" should be interpreted as including not only the clearly listed values ​​of 1% to 5%, but also the independent values ​​and sub-ranges within the range shown. Therefore, independent values ​​such as 2%, 3.5% and 4% and sub-ranges such as 1%-3%, 2%-4% and 3%-5% are included in this numerical range. This principle also applies to the range of only one numerical value. In addition, such an interpretation applies regardless of the width of the range or the characteristics described.

[0049] In order to better illustrate the content of the present application, numerous specific details are provided in the specific examples below. It should be understood by those skilled in the art that the present application can also be implemented without certain specific details. In the embodiments, some methods, means, instruments, equipment, etc. well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present application.

[0050] Under the premise of no conflict, the technical features disclosed in the embodiments of the present application can be combined arbitrarily, and the resulting technical solutions belong to the contents disclosed in the embodiments of the present application.

[0051] Example 1

[0052] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0053] Thermo-induced hydrogel sustained-release analgesic preparation P1, which includes polyester-polyether block copolymer PLGA-PEG-PLGA triblock copolymer, PLGA-PEG-PLGA (LA / GA=2.5 / 1) 2g with a molecular weight of 1262-1500-1262, PLGA-PEG-PLGA (LA / GA=3 / 1) 2g with a molecular weight of 1429-1000-1429, ropivacaine 0.45g, and calcium carbonate 0.02g.

[0054] Step (1): placing two block copolymers of different molecular weights in water and stirring them under magnetic force at 4° C. for 24 h to prepare a polymer micelle solution having a polymer concentration of 26 wt %;

[0055] Step (2): 0.45g of ropivacaine and 0.02g of calcium carbonate are added to the polymer micelle solution prepared in step (1), and an appropriate amount of water is added to dilute the solution to a formulation of 25wt% polymer, 4.5wt% ropivacaine, and 0.2wt% calcium carbonate, and the solution is stirred at 4°C for 12h to form an injectable suspension. The preparation can be injected around the sciatic nerve of rats to form an in situ gel around the sciatic nerve for long-term analgesia.

[0056] In the obtained preparation, the calcium produced by the partial dissolution of CaCO3 can coordinate with the lone pair of electrons of oxygen in the PEG block of PLGA-PEG-PLGA, and can also coordinate with the lone pair of electrons of carbonyl oxygen in the structure of ropivacaine; the undissolved CaCO3 can adsorb ropivacaine in the preparation by adsorption.

[0057] Example 2

[0058] Application of a gel sustained-release preparation using a sparingly soluble salt as a pH regulator:

[0059] The rats anesthetized with isoflurane were placed in lateral position with the femur perpendicular to the trunk. The greater trochanter and the sciatic tuberosity were found by palpation, and the drug preparation disclosed in Example 1 was inserted from the posterior medial side of the greater trochanter through the syringe needle and advanced to the anterior medial side. When the needle touched the sciatic surface, the needle was withdrawn by about 1 mm, and then the drug preparation disclosed in Example 1 was pushed into the vicinity of the rat's sciatic nerve. After several hours, the rats were dissected, and the formation of in situ gel was observed around the sciatic nerve. Figure 2 .

[0060] Example 3

[0061] Study on the performance of a gel sustained-release preparation using a sparingly soluble salt as a pH regulator:

[0062] The preparation P1 disclosed in Example 1 and its control preparation C1 (25wt% polymer, 4.5wt% ropivacaine) were placed in a dialysis card with a molecular weight cutoff of 3500 to form a gel, and a certain amount of release solution was taken out at a specific time point. The drug concentration in the release solution at each sampling time point was measured, and the in vitro release curve was calculated and drawn. The addition of calcium carbonate delayed the release of ropivacaine from the gel to a certain extent, such as Figure 3 .

[0063] Example 4

[0064] Study on the performance of a gel sustained-release preparation using a sparingly soluble salt as a pH regulator:

[0065] The pH values ​​of the polymer solution (25 wt % polymer), the formulation P1 disclosed in Example 1 and its control formulation C1 (25 wt % polymer, 4.5 wt % ropivacaine), and C2 (25 wt % polymer, 0.2 wt % calcium carbonate) were measured by a pH meter, respectively. Figure 4 .

[0066] Example 5

[0067] Study on the performance of a gel sustained-release preparation using a sparingly soluble salt as a pH regulator:

[0068] Twenty SD male rats, weighing about 350 g, were randomly divided into four groups: A polymer solution group (25 wt% polymer), B bupivacaine (BUP) hydrochloride solution group (0.5 wt%), C bupivacaine gel polymer group (25 wt% polymer, 8 wt% bupivacaine), D bupivacaine and calcium carbonate gel polymer group (25 wt% polymer, 8 wt% bupivacaine, 0.2 wt% calcium carbonate). 0.5 mL of each preparation group was injected around the sciatic nerve of the rats.

[0069] The in vivo analgesic effect was evaluated by the hot plate method, and the hot plate temperature was set at 56°C. The time required for the rat to lift its hind foot was the thermal latency value. Before the experiment began, the basal thermal latency value of each rat was examined in turn, and each rat was measured three times at the same time point, and the average value was taken as the basal thermal latency value. The maximum value allowed for the thermal latency period was controlled at 12s. If the rat still had no reaction after 12s, the rat's foot was lifted off the hot plate to avoid damage to the rat's foot tissue. Each preparation group was injected around the sciatic nerve of the rat, and each rat was tested three times at each time point. The time interval between two measurements was 30s, and the various measurements obtained were real-time thermal latency values. The results of the thermal latency period are expressed by the maximum proportional effect (MPE), and the calculation formula is as follows:

[0070]

[0071] Among them, B is the basic thermal latency of rats, P is the maximum thermal latency allowed, and C is the real-time thermal latency of rats at each detection time point. The effective sensory blockade time is the time from the injection of the preparation to the recovery of the MPE value to 50%.

[0072] The effective duration of sensory blockade in each preparation group was: 2.71±0.26h in group B, 29.91±1.41h in group C, and 50.63±1.08h in group D. Figure 5 shown.

[0073] Example 6

[0074] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0075] Thermohydrogel sustained-release antitumor preparation P2, wherein the polyester-polyether block copolymer PLGA-PEG-PLGA triblock copolymer, PLGA-PEG-PLGA (LA / GA=4 / 1) 1g with a molecular weight of 1250-1500-1250, PLGA-PEG-PLGA (LA / GA=4 / 1) 1g with a molecular weight of 1500-1000-1500, R8375 mg; thermo-induced hydrogel sustained-release anti-tumor preparation P3, wherein a polyester-polyether block copolymer PLGA-PEG-PLGA triblock copolymer, PLGA-PEG-PLGA (LA / GA=4 / 1) with a molecular weight of 1250-1500-1250 1g, PLGA-PEG-PLGA (LA / GA=4 / 1) with a molecular weight of 1500-1000-1500 1g, R8375 mg, and calcium carbonate 5 mg; thermo-induced hydrogel sustained-release anti-tumor preparation P4, wherein a polyester-polyether block copolymer PLGA-PEG-PLGA triblock copolymer, PLGA-PEG-PLGA (LA / GA=4 / 1) with a molecular weight of 1250-1500-1250 1g, PLGA-PEG-PLGA (LA / GA=4 / 1) with a molecular weight of 1500-1000-1500 1g, R8375 mg, and calcium carbonate 15 mg.

[0076] Step (1): placing two block copolymers of different molecular weights in water and stirring them under magnetic force at 4° C. for 24 h to prepare a polymer micelle solution with a polymer concentration of 20 wt %;

[0077] Step (2): Add the above amount of R837 and calcium carbonate to the polymer micelle solution prepared in step (1), place at 4°C and stir for 12 hours to form an injectable suspension. The preparation can be injected around the tumor of mice to form an in situ gel around the tumor to achieve long-term anti-tumor effect.

[0078] In the obtained preparation, the calcium generated by the partial dissolution of CaCO3 mainly coordinates with the lone pair of oxygen electrons in the PEG block of PLGA-PEG-PLGA; the undissolved CaCO3 can adsorb R837 in the preparation by adsorption.

[0079] Example 7

[0080] Study on the performance of a gel sustained-release preparation using a sparingly soluble salt as a pH regulator:

[0081] According to the preparation method in Example 6, the compound preparations P2, P3, and P4 were prepared. A 10 mL cylindrical glass bottle was placed in a 37°C water bath shaker, and 0.5 g of the P2, P3, and P4 preparations were added to the bottom of the glass bottle, respectively, and kept at a constant temperature for 10 minutes to make them gel. 50 mL of PBS buffer was added to each glass bottle. 5 mL of liquid in the cylindrical glass bottle was extracted at a fixed time point and replaced with an equal amount of fresh deionized water. The R837 concentration of the sample was measured with a UV spectrophotometer and converted into the cumulative release rate of the drug. The cumulative release curve was plotted, as shown in FIG. Figure 6 .

[0082] Example 8

[0083] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0084] Thermohydrogel sustained-release antitumor preparation P5, wherein the polyester-polyether block copolymer is a mPEG-PLGA diblock copolymer, the molecular weight is 600-1000, the polymer mass is 2g, irinotecan 0.05g, and calcium sulfate 0.05g.

[0085] Step (1): 2 g of the block copolymer was placed in physiological saline and magnetically stirred at -5°C for 24 h to prepare a polymer micelle solution with a polymer concentration of 25 wt%;

[0086] Step (2): 0.05g of irinotecan and 0.05g of calcium sulfate are added to the polymer micelle solution prepared in step (1), and an appropriate amount of water is added to dilute the solution to a formulation of 20wt% polymer, 0.5wt% irinotecan, and 0.5wt% calcium sulfate, and the solution is stirred at 25°C for 12h to form an injectable sustained-release preparation. The preparation can be injected around the tumor of a mouse to form an in situ gel around the tumor, thereby achieving long-term anti-tumor effect.

[0087] In the obtained preparation, the calcium generated by the partial dissolution of CaSO4 can coordinate with the lone pair of oxygen electrons in the PEG block of mPEG-PLGA, and can also coordinate with the lone pair of carbonyl oxygen electrons in the irinotecan structure; the undissolved CaSO4 can adsorb irinotecan in the preparation by adsorption.

[0088] Example 9

[0089] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0090] Thermohydrogel-filled anti-aging preparation P6, in which the polyester-polyether block copolymer is a PLGA-PEG-PLGA triblock copolymer, with a molecular weight of 1850-1500-1850 (LA / GA=4 / 1), a polymer mass of 2g, arginine 0.03g, and calcium hydrogen phosphate 0.02g.

[0091] Step (1): 2 g of the triblock copolymer was placed in deionized water and magnetically stirred at 40° C. to completely dissolve the polymer to prepare a polymer micelle solution with a polymer concentration of 20 wt %;

[0092] Step (2): Add 0.03g arginine and 0.02g calcium hydrogen phosphate to the polymer micelle solution prepared in step (1), and add appropriate amount of water to dilute the preparation to 15wt% polymer, 0.3wt% arginine, 0.2wt% calcium hydrogen phosphate, and stir at 5°C to form an injectable sustained-release preparation. The preparation can be injected into the skin around aging tissue by intramuscular injection, forming an in-situ gel at the part to be filled, and is used to achieve tissue filling and long-term anti-aging.

[0093] In the obtained preparation, the calcium generated by the partial dissolution of CaHPO4 can coordinate with the lone pair of oxygen electrons in the PEG block of PLGA-PEG-PLGA, and can also coordinate with the lone pair of carbonyl oxygen electrons in the arginine structure; the undissolved CaHPO4 can adsorb the arginine in the preparation by adsorption.

[0094] Example 10

[0095] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0096] Thermohydrogel sustained-release anti-tumor preparation P7, with methylcellulose (MC) and γ-polyglutamic acid (γ-PGA) as raw materials, prepared methylcellulose stearate / γ-polyglutamic acid composite thermosensitive hydrogel by esterification reaction. First, take 0.15g stearic acid and an appropriate amount of DMF, stir and dissolve, then add 0.2g dicyclohexylcarbodiimide (DCC) and 0.005g dimethylaminopyridine (DMAP), react in an ice bath for 20min, add 0.3g MC and react at room temperature for 24h. After the reaction, the reaction solution was slowly added to 250mL of anhydrous ethanol for precipitation, purified, filtered and vacuum dried to obtain methylcellulose stearate (MCS). Then, take 0.2g MCS and 0.2g γ-PGA in deionized water, stir under ice bath conditions until the system becomes viscous and bubbles are generated, and refrigerate to completely dissolve and eliminate bubbles. 0.1g of vinblastine and 0.02g of magnesium silicate powder were directly added to the above polymer solution, placed at -10°C and stirred to mix evenly to form an injectable sustained-release preparation. The preparation can be injected around the tumor of mice to form an in situ gel around the tumor to achieve long-term anti-tumor effect.

[0097] In the obtained preparation, the magnesium produced by the partial dissolution of MgSiO3 can coordinate with the lone pair of electrons of the carbonyl oxygen in methylcellulose stearate / γ-polyglutamic acid, and can also coordinate with the lone pair of electrons of the carbonyl oxygen in the structure of vinblastine; the undissolved MgSiO3 can absorb vinblastine in the preparation by adsorption.

[0098] Embodiment 11

[0099] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0100] Thermosensitive hydrogel sustained-release antitumor preparation P8, by using N-acryloylethyl chloride polyaspartimide (NAE-PAI) as a crosslinker, synthesizes polyaspartic acid crosslinked poly (N-isopropylacrylamide / acrylic acid) (P (NIPAAm / AAc)) thermosensitive hydrogel. First, NIPAAm, AAc (NIPAAm / AAc=97.5 / 2.5) and crosslinker NAE-PAI (0.5%) were added to 50mL phosphate buffer solution to completely dissolve the monomers. Nitrogen was passed to remove dissolved oxygen in the solution, and a certain amount of ammonium persulfate and N, N, N, N-tetramethylethylenediamine were added as initiators and promoters. After strong stirring for 1 hour, the nitrogen was stopped, and the reaction was carried out at room temperature for 24 hours. After the reaction was completed, it was washed with distilled water to remove the unreacted monomers. The polymer was obtained after freeze-drying. Take 2g of polymer and dissolve it in water to prepare a polymer solution, then add 0.3g of doxorubicin and 0.03g of barium phosphate powder directly to the polymer solution, stir and mix evenly at 40°C to form an injectable sustained-release preparation. The preparation can be injected around the tumor of mice to form an in situ gel around the tumor to achieve long-term anti-tumor effect.

[0101] In the obtained preparation, the barium produced by the partial dissolution of Ba3(PO4)2 can coordinate with the lone pair of electrons of the carbonyl oxygen in polyaspartic acid cross-linked poly(N-isopropylacrylamide / acrylic acid), and can also coordinate with the lone pair of electrons of the carbonyl oxygen in the doxorubicin structure; the undissolved Ba3(PO4)2 can adsorb doxorubicin in the preparation by adsorption.

[0102] Example 12

[0103] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0104] Thermo-induced hydrogel sustained-release analgesic preparation P9, take 2.28g N-isopropylacrylamide, add appropriate amount of acetone and distilled water, stir to completely dissolve N-isopropylacrylamide, freeze with liquid nitrogen, evacuate and then pass high-purity argon, add 20mg cuprous chloride and tris(2-methylaminoethyl)amine, after freezing-evacuating-argon cycle, add 0.1mmol bis[2-(2'-bromoisobutyryloxy)ethyl] disulfide, react at 0℃ for 12h to prepare poly N-isopropylacrylamide. Add 0.02mol oxygen-free tert-butyl acrylate to the system, react for 24h and transfer the product, and obtain poly tert-butyl acrylate-b-poly N-isopropylacrylamide-b-poly tert-butyl acrylate after filtration, dialysis and freeze drying. The product was precipitated with ether and redissolved in chloroform, and then vacuum dried to obtain a triblock polymer of poly(tert-butyl acrylate)-b-poly(N-isopropylacrylamide)-b-poly(tert-butyl acrylate). 2 g of the polymer was dissolved in water and stirred at 40°C to completely dissolve the polymer; 0.05 g of lidocaine and 0.02 g of calcium sulfate powder were added and stirred at 15°C to form an injectable sustained-release preparation. The preparation can be injected into the joint cavity of rats to form an in situ gel in the joint cavity for long-term analgesia.

[0105] In the obtained preparation, the calcium produced by the partial dissolution of CaSO4 can coordinate with the lone pair of electrons of the carbonyl oxygen in polytert-butyl acrylate-b-poly N-isopropylacrylamide-b-polytert-butyl acrylate, and can also coordinate with the lone pair of electrons of the carbonyl oxygen in the lidocaine structure; the undissolved CaSO4 can absorb the lidocaine in the preparation by adsorption.

[0106] Embodiment 13

[0107] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0108] Thermo-induced hydrogel sustained-release analgesic preparation P10, take 2.28g N-isopropylacrylamide, add appropriate amount of acetone and distilled water, stir to completely dissolve N-isopropylacrylamide, freeze with liquid nitrogen, evacuate and pass high-purity argon, add 20mg cuprous chloride and tris(2-methylaminoethyl)amine, after freezing-vacuuming-argon passing cycle, add 0.1mmol bis[2-(2'-bromoisobutyryloxy)ethyl] disulfide, react at 0℃ for 12h to prepare poly N-isopropylacrylamide. Take 0.3g of poly N-isopropylacrylamide and dissolve it in an appropriate amount of methylpyrrolidone. Add 0.3mmol / mL dimethyl sulfoxide solution of methacrylic acid-2-propanesulfonic acid under argon protection, then add cuprous bromide and 1,1,4,7,10,10-hexamethyltriethylenetetramine, react at 80℃ for 10h, and the product is separated, purified and vacuum dried to obtain polymethacrylic acid-2-propanesulfonic acid-poly-N-isopropylacrylamide-b-polymethacrylic acid-2-propanesulfonic acid triblock polymer. Take 1g of polymer and dissolve it in water, stir it at 25℃ to completely dissolve the polymer; add 0.02g of tetracaine and 0.015g of aluminum phosphate powder and stir it at 30℃ for 12h to form an injectable sustained-release preparation. The preparation can be injected into the rat joint cavity to form an in situ gel in the joint cavity for long-term analgesia.

[0109] In the obtained preparation, aluminum produced by partial dissolution of AlPO4 can coordinate with the lone pair of electrons of carbonyl oxygen in polymethacrylate-2-propanesulfonic acid-poly-N-isopropylacrylamide-b-polymethacrylate-2-propanesulfonic acid, and can also coordinate with the lone pair of electrons of carbonyl oxygen in the structure of tetracaine; undissolved AlPO4 can adsorb tetracaine in the preparation by adsorption.

[0110] Embodiment 14

[0111] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0112] Thermohydrogel sustained-release antitumor preparation P11, with ethyl 2-bromopropionate as the macromolecular initiator, triethylene glycol methyl ether methacrylate, cuprous bromide, 2-2'-bipyridine were reacted at 60°C for 5 hours, diluted with tetrahydrofuran and the catalyst cuprous bromide was removed with an alumina column, and the product was vacuum dried to obtain poly(ethylene glycol) methyl ether methacrylate. 0.3g of poly(ethylene glycol) methyl ether methacrylate was dissolved in an appropriate amount of methyl pyrrolidone, and a 0.3mmol / mL dimethyl sulfoxide solution of sodium 4-styrene sulfonate was added under argon protection, followed by the addition of cuprous bromide and 1,1,4,7,10,10-hexamethyltriethylenetetramine, and the reaction was carried out at 120°C for 24 hours. After post-treatment, a poly(4-styrene sulfonate)-b-poly(ethylene glycol) methyl ether methacrylate diblock polymer was obtained. After dissolving 1.5g of polymer in water, stir at -2°C to completely dissolve the polymer; add 0.015g of 10-hydroxycamptothecin and 0.01g of iron phosphate powder and stir at 0°C for 12h to form an injectable sustained-release preparation. The preparation can be injected around the tumor of mice to form an in situ gel around the tumor to achieve long-term anti-tumor effect.

[0113] In the obtained preparation, the iron produced by the partial dissolution of FePO4 can coordinate with the lone pair of electrons of polyethylene glycol oxygen in poly (sodium 4-styrene sulfonate)-b-poly (ethylene glycol methyl ether methacrylate), and can also coordinate with the lone pair of electrons of carbonyl oxygen in the structure of 10-hydroxycamptothecin; the undissolved FePO4 can adsorb 10-hydroxycamptothecin in the preparation through electrostatic and adsorption effects.

[0114] Embodiment 15

[0115] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0116] Thermohydrogel sustained-release anti-tumor preparation P12, 1.5g PCLA-PEG-PCLA, whose molecular weight is 1800-1500-1800, is dissolved in water and magnetically stirred at -5℃ for 48h to prepare a polymer solution; 0.2g 10-hydroxycamptothecin and 0.01g zinc silicate powder are added and stirred at -5℃ to form an injectable sustained-release preparation. The preparation can be injected around the tumor of mice to form an in situ gel around the tumor to achieve long-term anti-tumor effect.

[0117] In the obtained preparation, the zinc produced by the partial dissolution of Zn2SiO4 can coordinate with the lone pair of oxygen electrons in the PEG block of PCLA-PEG-PCLA, and can also coordinate with the lone pair of carbonyl oxygen electrons in the structure of 10-hydroxycamptothecin; the undissolved Zn2SiO4 can adsorb 10-hydroxycamptothecin in the preparation by adsorption.

[0118] Example 16

[0119] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0120] Thermohydrogel sustained-release analgesic preparation P13, take PEG-PLGA-PEG 2g with a molecular weight of 550-2780-550, oxybuprocaine 0.5g, and aluminum carbonate 0.1g.

[0121] Step (1): 2 g of the triblock copolymer was placed in water and magnetically stirred at -10°C to completely dissolve the polymer to prepare a polymer micelle solution with a polymer concentration of 20 wt%;

[0122] Step (2): 0.5 g of oxybuprocaine and 0.1 g of Al2(CO3)3 are added to the polymer micelle solution prepared in step (1), and an appropriate amount of water is added to dilute the solution to a formulation of 15 wt% polymer, 5 wt% oxybuprocaine, and 1 wt% Al2(CO3)3, and the solution is stirred at 30°C for 12 hours to form an injectable sustained-release preparation. The preparation can be injected around the sciatic nerve of rats to form an in situ gel around the sciatic nerve for long-term analgesia.

[0123] In the obtained preparation, the aluminum produced by the partial dissolution of Al2(CO3)3 can coordinate with the lone pair of electrons of oxygen in the PEG block of PEG-PLGA-PEG, and can also coordinate with the lone pair of electrons of carbonyl oxygen in the structure of oxybuprocaine; the undissolved Al2(CO3)3 can adsorb oxybuprocaine in the preparation by adsorption.

[0124] Embodiment 17

[0125] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0126] The thermo-induced hydrogel sustained-release analgesic preparation P14 was prepared by multi-step reactions including esterification, cyclization, ring-opening polymerization, etherification, and 1,3-dipolar cycloaddition to prepare poly(γ-propyl-L-glutamate-graft-oligoethylene glycol) (PPLG n -g-OEG m ). Take PPLG with a molecular weight of 32500 88 After 22 g of -g-OEG was dissolved in water, it was placed at 30°C and stirred to completely dissolve the polymer; 0.01 g of proparacaine and 0.01 g of silver sulfate powder were added and stirred at -2°C for 5 hours to form an injectable sustained-release preparation. The preparation can be injected around the sciatic nerve of rats to form an in situ gel around the sciatic nerve for long-term analgesia.

[0127] In the obtained preparation, the silver produced by the partial dissolution of Ag2SO4 can coordinate with the lone pair of oxygen electrons in the polyethylene glycol block in the poly(γ-propyl-L-glutamate-graft-oligoethylene glycol), with the lone pair of carbonyl oxygen electrons in the structure, and can also coordinate with the lone pair of carbonyl oxygen electrons in the structure of proparacaine.

[0128] Embodiment 18

[0129] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0130] Thermohydrogel sustained-release analgesic preparation P15, take 0.5g of diamino PEG 2000 Add 50 ml of toluene to azeotropically remove water, add 3.99 g of γ-benzyl-L-glutamic acid-N-carboxyl cyclic anhydride (BGL-NCA) monomer to the CHCl3 / DMF mixed solvent, and stir and mix at room temperature. Under argon protection, transfer the mixed monomer solution to the dry NH2-PEG 2000 -NH2, the system temperature was raised to 37 ° C, after 3 days of reaction, the system was cooled to room temperature, 22 ml of CHCl3 was added, after the product was completely dissolved, it was slowly added dropwise to a mixed solvent of acetic acid and methanol for precipitation to obtain a white solid. After vacuum drying, the triblock polymer PBGL-PEG was obtained 2000 -PBGL. The benzyl protecting group was then removed by catalytic hydrogenation to obtain the final product PGL-PEG 2000 -PGL. Take PGL-PEG with a molecular weight of 5500 2000 -PGL 2g was dissolved in normal saline, and stirred at 20℃ to completely dissolve the polymer; 0.01g procaine and 0.008g magnesium hydrogen phosphate powder were added and stirred at 8℃ for 12h to form an injectable sustained-release preparation. The preparation can be injected around the sciatic nerve of rats to form an in situ gel around the sciatic nerve for long-term analgesia.

[0131] In the obtained preparation, the magnesium produced by partial dissolution of MgHPO4 can react with PGL-PEG 2000 -PGL can coordinate with the lone pair of oxygen electrons in the polyethylene glycol block, and can also coordinate with the lone pair of carbonyl oxygen electrons in the procaine structure; undissolved MgHPO4 can adsorb procaine in the preparation by adsorption.

[0132] Embodiment 19

[0133] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0134] Thermohydrogel sustained-release anti-tumor preparation P16, take 1.5g of polymethacrylate β-phosphoethyl ester-poly N-vinyl n-butyramide and dissolve it in normal saline, place it at 2℃ and stir it to completely dissolve the polymer; add 0.01g of nitrogen mustard, 0.05g of imiquimod and 0.005g of calcium silicate powder and place it at 8℃ and stir it for 12h to form an injectable sustained-release preparation. This preparation can be injected around the tumor of mice to form an in situ gel around the tumor, which is used to achieve long-term anti-tumor effect.

[0135] In the obtained preparation, the calcium produced by the partial dissolution of CaSiO3 can coordinate with the lone pair of electrons of the carbonyl oxygen in poly β-ethyl phosphate methacrylate-poly N-vinyl n-butyramide, and can also coordinate with the lone pair of electrons of nitrogen in the nitrogen mustard structure; the undissolved CaSiO3 can adsorb the nitrogen mustard and imiquimod in the preparation through electrostatic and adsorption effects.

[0136] Embodiment 20

[0137] A gel sustained-release preparation using a sparingly soluble salt as a pH regulator and its preparation method and application:

[0138] Thermohydrogel sustained-release anti-tumor preparation P17, take 1.5g of polymethacrylate β-ethyl sulfate-poly N-vinyl pyrrolidone and dissolve it in normal saline, place it at 12℃ and stir it to completely dissolve the polymer; add 0.008g of gemcitabine and 0.005g of magnesium ammonium phosphate powder and place it at 2℃ and stir it for 12h to form an injectable sustained-release preparation. This preparation can be injected around the tumor of mice to form an in situ gel around the tumor, which is used to achieve long-term anti-tumor effect.

[0139] In the obtained preparation, the magnesium produced by the partial dissolution of MgNH4PO4 can coordinate with the lone pair of electrons of the carbonyl oxygen in the poly N-vinyl pyrrolidone block in poly β-ethyl sulfate methacrylate-poly N-vinyl pyrrolidone, and can also coordinate with the lone pair of electrons of the carbonyl oxygen in the gemcitabine structure; the undissolved MgNH4PO4 can adsorb gemcitabine in the preparation by adsorption.

[0140] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A gel sustained-release preparation using a sparingly soluble salt as a pH regulator, characterized in that: A solid form comprising a sparingly soluble salt, an alkaline inclusion and a polymer water system, and containing the sparingly soluble salt; The sparingly soluble salt is slightly soluble or insoluble in water, but soluble in an acidic environment, and is selected from one or more complexes of other carbonates, phosphates, hydrogen phosphates, silicates, or calcium sulfate, silver sulfate, magnesium ammonium phosphate, and sodium bismuthate other than potassium, sodium, and ammonium; The alkaline coating is selected from one or more of procaine, tetracaine, proparacaine, oxybuprocaine, lidocaine, bupivacaine, mepivacaine, ropivacaine, imiquimod, nitrogen mustard, gemcitabine, vinblastine, vincristine, doxorubicin, daunorubicin, irinotecan, 10-hydroxycamptothecin, nicotinamide, and arginine; The polymer is a polyester-polyether block copolymer, a polymer having carboxylate, sulfate, sulfonate or phosphate in the side chain, and a mixture thereof; the polyester-polyether block copolymer is an ABA or BAB type triblock copolymer, an AB type diblock copolymer, an AgB or BgA type graft copolymer, or an (AB) n Copolymer, A(BA) n or B(AB) n One or more of the copolymers of the type, wherein A is polyethylene glycol, and B is an aliphatic polyester; the polyester block B is a combination of one or more of poly D,L-lactide, poly L-lactide, polyglycolide, poly ε-caprolactone, poly δ-valerolactone, and polycarbonate in any form; The preparation can be injected at room temperature and can spontaneously form a physical hydrogel at body temperature. The preparation can delay the release of the contained inclusions. The addition of the insoluble salt can adjust the pH inside the gel, reduce the solubility of the inclusions in the polymer solution, and make part or all of the inclusions dispersed in the gel network in the form of crystals. The pH value of the gel preparation for achieving sustained release of the inclusions is 5-8.

2. The gel sustained-release preparation using a sparingly soluble salt as a pH regulator according to claim 1, characterized in that: The polyether block A is polyethylene glycol with a molecular weight of 400-6000, and the polyester block B is an aliphatic polyester with a molecular weight of 500-5000.

3. The gel sustained-release preparation using a sparingly soluble salt as a pH regulator according to claim 1, characterized in that: The polymer having carboxylate, sulfate, sulfonate or phosphate in the side chain is a polymer containing one or more blocks of acrylic acid, tert-butyl acrylate-co-acrylic acid, sodium 4-styrenesulfonate, methacrylic acid-2-propanesulfonic acid, β-ethyl methacrylate sulfate, β-ethyl methacrylate phosphate, glutamic acid and aspartic acid.

4. A method for preparing a gel sustained-release preparation according to any one of claims 1 to 3, characterized in that: The polymer is firstly prepared into a polymer aqueous solution, and then directly blended with the alkaline coating and the insoluble salt crystalline powder.

5. The preparation method according to claim 4, characterized in that: The specific steps include: (1) placing one or more copolymers in an aqueous solution, stirring magnetically at -10-40° C. to completely dissolve the polymers, thereby obtaining a polymer water system for later use; (2) adding alkaline coating and insoluble salt crystalline powder, and stirring them magnetically at -10-40° C. to fully mix them, thereby obtaining the gel sustained-release preparation with insoluble salt as pH regulator.

6. Use of the gel sustained-release preparation according to any one of claims 1 to 3, characterized in that: As a material for preparing sustained / controlled release drugs.

7. The use of a gel sustained-release preparation according to claim 6, characterized in that: The sustained / controlled release drugs include analgesics, anti-tumor drugs or active substances with medical cosmetic effects.

Images