Series of polymers with acid-sensitive degradation and temperature-sensitive properties and drug-loading composition thereof

Abstract

The invention discloses a series of polymers with acid-sensitive degradation and temperature-sensitive properties and a drug-loading composition thereof, the polymers have a structure represented by a formula (1), and have degradation and temperature-sensitive properties in a physiological environment, i.e., the polymers are in a solid state below a phase-transition temperature, are in a liquid state above the phase-transition temperature, are in a stable state in a low-temperature environment of a storage condition, and are in an acid-sensitive degradation and temperature-sensitive state. The polymer has a good fluidity state in a use environment, good drug release property and degradability are maintained, stability during storage and needle passing performance during injection are taken into consideration, and the invention also discloses a preparation method of the polymer and a pharmaceutical composition containing the polymer. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine and polymer medical materials, and specifically relates to a series of polymers with acid-sensitive degradation and positive temperature-sensitive properties, a preparation method thereof, and a pharmaceutical composition. Technical Background

[0002] In the field of drug controlled release research, the properties of sustained-release materials are one of the important factors that determine the success or failure of formulation design. An ideal sustained-release injection material should take into account good biocompatibility, effective control of drug release, and good injectability. In the field of drug delivery, commonly used in-situ gels are classified by source into natural gel materials and synthetic gel materials. These materials form gels in situ after injection through reverse temperature sensitivity (sol at low temperature within a certain temperature range, cross-linking to form gel when the temperature rises), high temperature positive temperature sensitivity (sol at higher temperature, gel formed when the temperature drops after injection), pH sensitivity, chemical cross-linking or solvent exchange mechanisms, and slowly release drugs as a drug reservoir. The drug release mechanism includes diffusion and dissolution. However, the above-mentioned traditional in-situ gel materials have more or less the following problems: poor biocompatibility and difficulty in metabolism; chemical cross-linking monomers have certain toxic effects; unstable drug release properties; high water content in the system increases the risk of deterioration; the injection temperature of traditional positive temperature-sensitive materials is too high, which brings pain to patients and even causes local necrosis.

[0003] Polyorthoesters are a class of high molecular weight substances rich in orthoester bonds. The orthoester bonds in their structure can be hydrolyzed in an aqueous environment, making them biodegradable. Due to their good biodegradability and surface dissolution properties, polyorthoesters have developed rapidly in the field of drug sustained and controlled release. Currently, they have been developed in the marketed formulations of Heron Therapeutics. Application.

[0004] Classic polyorthoesters can be presented in a semi-solid form, and related products are marketed in the form of prefilled injections, but their rheological performance is still insufficient. Classic semi-solid polyorthoesters have high viscosity and low fluidity at ambient temperature, which makes the injection poor, and increases the difficulty of injection when used alone as an in-situ sustained-release matrix. Therefore, when using classic semi-solid polyorthoesters as sustained-release carriers for injection, it is necessary to mix with a certain proportion of viscosity regulators (such as dimethyl sulfoxide, N-methylpyrrolidone and other organic solvents) to improve the injection, but the introduction of these viscosity regulators will increase the risk of adverse reactions such as irritation and toxicity. In addition, the changes in the rheological properties of classic semi-solid polyorthoesters are very limited by temperature, and they still have a certain fluidity in a low temperature environment during storage. Therefore, during the long-term storage of prefilled injections, drug particles may aggregate, the drug crystallizes and precipitates, which will have an adverse effect on the quality of the preparation.

[0005] At present, the patents related to polyorthoester polymers as drug carriers mainly include: ① Composition of polyorthoester and aprotic solvent (application number: CN201480028192); ② Long-acting polymer delivery system (application number: CN201580033564); ③ A new type of polyorthoester pharmaceutical excipient and its new sustained-release drug preparation (application number: CN201210436124). Patents ① and ② are patents applied by Heron Therapeutics, USA, for the application of polyorthoester as a drug sustained-release carrier. The polyorthoester used is a traditional semi-solid polyorthoester. Although the semi-solid polyorthoester has a certain effect in drug release control, its rheological performance is a shortcoming that limits its use. The simple use of classic semi-solid polyorthoester has a higher viscosity and lower fluidity in the use environment, which is difficult to meet the injection requirements. The above patents provide a pharmaceutical composition including a "viscosity regulator" to solve the problem of difficulty in injecting the pharmaceutical composition. However, suitable viscosity regulators (including organic solvents such as dimethyl sulfoxide, N-methylpyrrolidone, dimethylacetamide, etc.) may increase the irritation and toxicity of the pharmaceutical composition while improving the fluidity of the composition, thereby increasing the risk of formulation application. Traditional polyorthoesters still exhibit a certain fluidity at storage temperature, which makes the drug subject to the risk of crystallization and precipitation from the composition. In addition, the contents of related US patents (such as US10398686, US10357570, US10213510, etc.) are similar to those of the above patents ① and ②.

[0006] Patent ③ provides a patent for a new type of polyorthoester and its related sustained-release preparations that are different from the traditional polyorthoester structure. This patent focuses on the synthesis method of a new type of polymer rich in orthoester structure. In addition to the traditional polyorthoester synthesis route, it provides a new type of polyorthoester structure and its synthesis route that also has biodegradable properties, and looks forward to the application of this polymer as a pharmaceutical excipient, especially a drug sustained-release carrier. However, the unique degradation pathway of this new type of polyorthoester makes it have a higher safety risk than traditional polyorthoesters. During its degradation process, one of the final degradation products of the orthoester five-membered ring is formic acid. This degradation product with optic neurotoxicity greatly limits its prospects in clinical application.

[0007] Compared with the above inventions, the novel polymer containing an orthoester structure provided by the present invention creatively introduces a positive temperature-sensitive property while maintaining the high safety and excellent drug sustained-release performance of traditional polyorthoesters, so that the drug composition prepared from the polymer maintains good drug release properties and degradability while also taking into account the stability of the composition during storage and the permeability during injection. In short, this type of polymer and its drug-carrying system have the advantages of stable storage, convenient administration, stable drug release, and controllable degradation, and have great application and research value in the field of medicine. Summary of the invention

[0008] One object of the present invention is to provide a series of polymers with acid-sensitive degradation and positive temperature-sensitive properties and a preparation method thereof. The series of polymers have the advantages of acid-sensitive degradation, positive temperature-sensitive, good biocompatibility, etc. The preparation method is simple in process and easy to control.

[0009] Another object of the present invention is to provide an oligomer monomer and a preparation method thereof. The oligomer monomer can be used to synthesize the above-mentioned series of polymers with acid-sensitive degradation and positive temperature-sensitive properties, and has the characteristics of simple synthesis, wide source of raw materials, and low cost.

[0010] Another object of the present invention is to provide a drug complex comprising the above series of polymers having acid-sensitive degradation and positive temperature-sensitive properties as a sustained-release matrix.

[0011] To this end, the present invention provides a polymer having a structure of formula (1) with temperature-sensitive properties,

[0012]

[0013] Wherein: x and y are independently integers greater than 1;

[0014] R1 is:

[0015]

[0016] in:

[0017] s is an integer from 0 to 30;

[0018] t is an integer from 0 to 30;

[0019] R4 is hydrogen or methyl;

[0020] R2 is C 1-4 alkyl;

[0021] R3 is:

[0022]

[0023] in:

[0024] R5 is C with or without functional groups 1-30 Alkyl, wherein the functional group is independently selected from a carbon-carbon double bond, a carbon-carbon triple bond, a carbonyl group, an aldehyde group, a carboxyl group, an ester bond, an amide bond, an ether bond, and an amino group;

[0025] R6 is hydrogen or C 1-4 alkyl;

[0026] n is an integer from 1 to 20.

[0027] The polymer of the present invention is preferably polymerized from the following three monomers:

[0028] Monomer A: 3,9-di(ethylene)-2,4,8,10-tetraoxaspiro[5,5]undecane or its homologues;

[0029] Monomer B: diol;

[0030] Monomer C: oligomer monomer of formula (2) or (3):

[0031]

[0032] in:

[0033] R5 is C with or without functional groups 1-30 Alkyl, wherein the functional group is independently selected from a carbon-carbon double bond, a carbon-carbon triple bond, a carbonyl group, an aldehyde group, a carboxyl group, an ester bond, an amide bond, an ether bond, and an amino group;

[0034] R6 is hydrogen or C 1-4 alkyl;

[0035] n is an integer from 1 to 20.

[0036] The polymer of the present invention is more preferably, wherein

[0037] Monomer A: 3,9-di(ethylene)-2,4,8,10-tetraoxaspiro[5,5]undecane; 3,9-di(propylene)-2,4,8,10-tetraoxaspiro[5,5]undecane;

[0038] Monomer B: diol (triethylene glycol or tripropylene glycol);

[0039] In monomer C:

[0040] R5 is C with or without functional groups 1-30 Alkyl, wherein the functional groups are independently selected from carbon-carbon double bonds, carbon-carbon triple bonds, carbonyl groups, aldehyde groups, carboxyl groups, and ester bonds;

[0041] R6 is hydrogen or C 1-2 alkyl;

[0042] n is an integer from 1 to 15.

[0043] The polymer of the present invention is particularly preferably, wherein

[0044] Monomer A: 3,9-di(ethylene)-2,4,8,10-tetraoxaspiro[5,5]undecane;

[0045] In monomer C:

[0046] R5 is C with or without functional groups 1-30 Alkyl, wherein the functional group is independently selected from a carbon-carbon double bond, a carbon-carbon triple bond, and a carbonyl group;

[0047] R6 is hydrogen or C 1-2 alkyl;

[0048] n is an integer from 1 to 10.

[0049] The polymer described in the present invention is most preferably the following polymer:

[0050]

[0051] Wherein: x and y are independently integers greater than 1.

[0052] The present invention further provides a method for preparing the polymer of the present invention, the method comprising: monomer A: 3,9-di(ethylene)-2,4,8,10-tetraoxaspiro[5,5]undecane or its homologues; monomer B: diol (triethylene glycol or tripropylene glycol); monomer C: oligomer monomer of formula (2) or (3):

[0053]

[0054] in:

[0055] R5 is C with or without functional groups 1-30 Alkyl, wherein the functional group is independently selected from a carbon-carbon double bond, a carbon-carbon triple bond, a carbonyl group, an aldehyde group, a carboxyl group, an ester bond, an amide bond, an ether bond, and an amino group;

[0056] R6 is hydrogen or C 1-4 alkyl;

[0057] n is an integer from 1 to 20;

[0058] The polymerization reaction takes place in the presence of an organic solvent at a temperature of 0-300°C.

[0059] The polymer of the present invention has a molecular weight of 1000-50000, preferably 1000-20000.

[0060] The polymer of the present invention has a composite viscosity of not less than 10000 Pa·s at storage temperature and a composite viscosity of not more than 500 Pa·s at use temperature.

[0061] The polymer of the present invention has a temperature-sensitive property, and the temperature at which the storage modulus value and the loss modulus value are equal is between 4-40°C.

[0062] In the method for preparing the polymer of the present invention, the molar proportion of monomer B and monomer C (based on monomer A as 100%) is independently 0.01%-99.99%.

[0063] The preparation method of the present invention is carried out in the presence of a reaction solvent, preferably a polar aprotic solvent, more preferably ethyl acetate, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or a mixture of multiple solvents thereof. The reaction temperature is 0-300°C, preferably 20-80°C.

[0064] The present invention further comprises compositions of the polymers described herein.

[0065] The composition contains one or more therapeutic active agents. The therapeutic active agents are substances used to prevent, treat, and diagnose human diseases, purposefully regulate human physiological functions, and have prescribed indications or functional indications, usage, and dosage, including traditional Chinese medicine, chemical medicine, and biological products;

[0066] The therapeutically active agent is an anti-Parkinson's drug selected from levodopa, carbidopa, niticapine, bromocriptine, pramipexole, ropinirole, selegiline, trihexyphenidyl, benztropine, amantadine, and rotigotine.

[0067] wherein the therapeutically active agent is an antiemetic selected from the group consisting of diphenhydramine, meclizine, scopolamine, trihexyphenidyl, chlorpromazine, ondansetron, granisetron, metoclopramide, and domperidone;

[0068] wherein the therapeutically active agent is a local anesthetic selected from the group consisting of procaine, tetracaine, lidocaine, and bupivacaine;

[0069] wherein the therapeutically active agent is a nonsteroidal anti-inflammatory drug selected from aspirin, acetaminophen, indomethacin, ibuprofen, naproxen, meloxicam;

[0070] wherein the therapeutically active agent is a growth factor;

[0071] wherein the therapeutically active agent is a gene drug;

[0072] The therapeutic active agent is a protein drug or a therapeutic polypeptide selected from insulin and glucagon-like peptide.

[0073] The method for preparing the pharmaceutical composition of the present invention comprises the steps of mixing, including, complexing or compounding the polymer and the therapeutic active agent, wherein the preparation temperature is 0-300°C, preferably, the preparation temperature is 20-120°C.

[0074] On the basis of obtaining the polymer of the present invention, the present invention also invents an oligomer monomer of structural formula (2) or (3):

[0075]

[0076] in:

[0077] R5 is C with or without functional groups 1-30 Alkyl, wherein the functional group is independently selected from a carbon-carbon double bond, a carbon-carbon triple bond, a carbonyl group, an aldehyde group, a carboxyl group, an ester bond, an amide bond, an ether bond, and an amino group;

[0078] R6 is hydrogen or C 1-4 alkyl;

[0079] n is an integer from 1 to 20.

[0080] And a method for preparing the oligomer monomer, wherein the oligomer is prepared by polymerization reaction of monomer D having the structural formula (6) or (7) and monomer E (glycolide or lactide) under heating conditions.

[0081]

[0082] in:

[0083] R5 is C with or without functional groups 1-30 Alkyl, wherein the functional groups are independently selected from carbon-carbon double bonds, carbon-carbon triple bonds, carbonyl groups, aldehyde groups, carboxyl groups, ester bonds, amide bonds, ether bonds, and amino groups.

[0084] The molar ratio of components D and E is 2:1 to 1:5;

[0085] Preferably, the heating temperature is 80-260° C. and the reaction time is 0.5-120 h.

[0086] The specific preparation method of the polymer of the present invention comprises the following steps:

[0087] DETOSU, diol and oligomer monomer C of formula (2) or (3) are put into reaction in appropriate proportions. DETOSU is dissolved in a suitable reaction solvent and diol under strict anhydrous and oxygen-free conditions, and oligomer monomer C of formula (2) or (3) is dissolved in the reaction solvent. The solution of oligomer monomer C of formula (2) or (3) is added to the solution of DETOSU and diol to initiate the reaction. Within a few minutes, the reaction solution reaches boiling point. The solution is cooled to room temperature and then the solvent is removed by rotary evaporation at 50°C-80°C.

[0088] The specific method for preparing the oligomer monomer of the present invention comprises the following steps:

[0089] The molar ratio of glycerol monoester to glycolide (or lactide) is 2:1 to 1:5. Under the protection of inert gas, glycerol monoester and glycolide (or lactide) are added to a reaction vessel, and stirred at 80-260°C for 6-72 hours in a closed state without adding a catalyst or solvent.

[0090] The specific pharmaceutical composition of the present invention comprises:

[0091] (i) the polymer according to claim 1; and

[0092] (ii) one or more therapeutically active agents dispersed or dissolved in the polymer of claim 1;

[0093] The active agent is released from the composition over a specified period of time.

[0094] The following experimental data further illustrate the beneficial effects of the present invention.

[0095] Table 1. Changes in rheological properties of the novel polymer provided by the present invention in the range of 0-40°C

[0096]

[0097] After research, we surprisingly found a new type of polymer containing orthoester structure, as shown in Table 1 (the above experiment uses the polymer of Example 2), which has positive temperature-sensitive properties. By adjusting the ratio of block units inside the polymer molecule, the storage modulus and loss modulus of the polymer can be flexibly adjusted so that the values ​​of the two are equal at a certain specific temperature in the range of 20-40°C. At the same time, when the ambient temperature gradually rises to above the specific temperature, Fig.10As shown, the composite viscosity of the polymer also drops sharply, and the fluidity of the polymer is greatly improved. The rheological property of the polymer that changes sensitively with temperature can adapt to the different needs of long-term storage and application, so that it behaves as a more stable solid state in the storage environment and a liquid state with good fluidity in the use environment. Compared with traditional positive temperature-sensitive polymer materials, its conversion temperature is lower. The new polymer is used as a drug sustained-release carrier, and its injection temperature is close to or lower than human body temperature, which can simplify the injection operation, reduce local irritation, and reduce patient pain. The drug complex prepared by this type of new polymer and a suitable active therapeutic agent has been shown to have a stable drug release behavior in in vitro release experiments, and the drug release rate can also be flexibly controlled by adjusting the proportion of relevant structural units in the polymer.

[0098] The pharmaceutical composition prepared from the polymer maintains good drug release properties and degradability while taking into account stability during storage and injection. In short, the polymer and its drug delivery system have the advantages of stable storage, convenient administration, smooth drug release, and controllable degradation, and have great application and research value in the medical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0099] Figure 1 This is one of the possible structures of the oligomer monomer synthesized from glyceryl monostearate (GMS) and glycolide (GA) in a molar ratio of 1:1 in Example 1 of the present invention.

[0100] Figure 2 One of the possible structures of the polymer with acid-sensitive degradation and positive thermosensitive properties synthesized from 3,9-di(ethylene)-2,4,8,10-tetraoxaspiro[5,5]undecane (DETOSU), triethylene glycol (TEG) and glyceryl monostearate diglycolide (GMS-diGL) in Example 2 of the present invention with a molar ratio of 90:80:20 (DETOSU:TEG:GMS-diGL).

[0101] Figure 3 This is the mass spectrum of the oligomer synthesized from GMS and GA in a molar ratio of 1:1 in Example 1 of the present invention.

[0102] Figure 4 This is an infrared spectrum of the oligomer monomer synthesized from GMS and GA in a molar ratio of 1:1 in Example 1 of the present invention.

[0103] Figure 5 This is an infrared spectrum of a polymer having acid-sensitive degradation and positive temperature-sensitive properties synthesized from DETOSU, TEG and GMS-diGL at a molar ratio of 90:80:20 (DETOSU:TEG:GMS-diGL) in Example 2 of the present invention.

[0104] Figure 6 The rheological properties of the polymer (GMS-POE) with acid-sensitive degradation and positive thermosensitive properties synthesized from DETOSU, TEG and GMS-diGL in Example 2 of the present invention at a molar ratio of 90:80:20 at a temperature of 0-40°C.

[0105] Figure 7 The gel state of the polymer with acid-sensitive degradation and positive thermosensitive properties at 37°C (left) and 4°C (right) synthesized from DETOSU, TEG and GMS-diGL in Example 2 of the present invention with a molar ratio of 90:80:20 (DETOSU:TEG:GMS-diGL).

[0106] Figure 8 This is the in vitro release curve of the drug complex containing 1.25% pramipexole prepared by the above acid-sensitive degradation and positive temperature-sensitive polymer in Example 7 of the present invention at 37° C. and pH 7.40.

[0107] Fig. 9 This is the in vitro release curve of the drug complex containing 3.3% granisetron prepared by the above acid-sensitive degradation and positive temperature-sensitive polymer in Example 8 of the present invention at 37° C. and pH 7.40.

[0108] Fig.10 The composite viscosity change curve of the series of novel polymers (GMS-POEs) provided by the present invention in the range of 0-40°C DETAILED DESCRIPTION

[0109] The present invention is further described below by way of examples. The present invention is not limited to the following examples, and various changes and equivalent substitutions may be made to the present invention within the scope of the claims of the present invention.

[0110] Example 1 A method for preparing an oligomer monomer

[0111] The oligomer monomer of this example is prepared from glyceryl monostearate (GMS) and glycolide (GA), and the molar ratio of the two components is 1:1.

[0112] As attached Figure 1 As shown, glyceryl monostearate (GMS) (17.928 g, 0.05 mol) and glycolide (GA) (5.8035 g, 0.05 mol) were weighed into a pressure-resistant reaction tube, and heated and stirred at 180° C. for 24 h under the protection of inert gas. The obtained product was glyceryl monostearate diglycolide (GMS-diGL).

[0113] Example 2 Preparation method of a polymer with acid-sensitive degradation and positive temperature-sensitive properties

[0114] The polymer with acid-sensitive degradation and positive temperature-sensitive properties of this embodiment is prepared from 3,9-di(ethylene)-2,4,8,10-tetraoxaspiro[5,5]undecane (DETOSU), triethylene glycol (TEG) and glyceryl monostearate diglycolide (GMS-diGL). The molar ratio of the three components (DETOSU:TEG:GMS-diGL) is 90:80:20.

[0115] As attached Figure 2 As shown, under strict anhydrous conditions, DETOSU (1.910 g, 0.009 mol) was dissolved in 15 ml of anhydrous tetrahydrofuran (THF) and TEG (1.2014 g, 0.008 mol) in a 50 ml flask, and GMS-diGL (0.9493 g, 0.002 mol) was dissolved in 5 ml of anhydrous THF. The GMS-diGL solution was added to the solution of DETOSU and TEG to initiate polymerization. Within a few minutes, the solution reached boiling point. The solution was cooled to room temperature and then concentrated by rotary evaporation at 50° C. and then rotary evaporated at 80° C.

[0116] Example 3 Preparation method of a polymer with acid-sensitive degradation and positive temperature-sensitive properties

[0117] The polymer with acid-sensitive degradation and positive temperature-sensitive properties of this embodiment is prepared from 3,9-di(ethylene)-2,4,8,10-tetraoxaspiro[5,5]undecane (DETOSU), triethylene glycol (TEG) and glyceryl monolaurate diglycolide (GML-diGL). The molar ratio of the three components (DETOSU:TEG:GML-diGL) is 95:80:20.

[0118] Under strict anhydrous conditions, DETOSU (2.0164 g, 0.0095 mol) was dissolved in 15 ml of anhydrous (tetrahydrofuran) THF and TEG (1.2014 g, 0.008 mol) in a 50 ml flask, and GML-diGL (0.7807 g, 0.002 mol) was dissolved in 5 ml of anhydrous THF. The GML-diGL solution was added to the solution of DETOSU and TEG to initiate polymerization. Within a few minutes, the solution reached boiling point. The solution was cooled to room temperature and then concentrated by rotary evaporation at 50° C. and then rotary evaporated at 80° C.

[0119] Example 4 Preparation method of a polymer with acid-sensitive degradation and positive temperature-sensitive properties

[0120] The polymer with acid-sensitive degradation and positive temperature-sensitive properties of this embodiment is prepared from 3,9-di(ethylene)-2,4,8,10-tetraoxaspiro[5,5]undecane (DETOSU), triethylene glycol (TEG) and glyceryl monooleate diglycolide (GMO-diGL). The molar ratio of the three components (DETOSU:TEG:GMO-diGL) is 100:85:15.

[0121] Under strict anhydrous conditions, DETOSU (2.1225 g, 0.0100 mol) was dissolved in 15 ml of anhydrous ethyl acetate and TEG (1.2750 g, 0.0085 mol) in a 50 ml flask, and GMO-diGL (0.7088 g, 0.0015 mol) was dissolved in 5 ml of anhydrous ethyl acetate. The GMO-diGL solution was added to the solution of DETOSU and TEG to initiate polymerization. Within a few minutes, the solution reached boiling point. The solution was cooled to room temperature and then concentrated by rotary evaporation at 50°C and then rotary evaporated at 80°C.

[0122] Example 5 A method for preparing a semisolid drug complex

[0123] A semisolid pharmaceutical composition with pramipexole (PPX) as an active agent is prepared by the following method:

[0124] 1.25 wt% of pramipexole and 98.75 wt% of polymer were stirred for 3 h under the protection of inert gas and heated at 40°C, and then cooled to room temperature to obtain a semi-solid with uniform texture.

[0125] Example 6 A method for preparing a semisolid drug complex

[0126] A semisolid pharmaceutical composition with granisetron (GRA) as an active agent is prepared by the following method:

[0127] 3.0 wt% of granisetron and 97.0 wt% of polymer were stirred for 3 h under the protection of inert gas and heated at 40° C., and then cooled to room temperature to obtain a semi-solid with uniform texture.

[0128] Example 7 In vitro release properties of the pharmaceutical composition

[0129] The pharmaceutical composition of Example 5 was weighed into a dialysis bag and placed in a test tube with a screw cap and 15 ml of 37°C 0.2N PBS (pH 7.4). The test tube was sealed and kept at 37°C. At different time points, the test tube was inverted several times, and then 5 ml of the release solution was removed and an equal volume of 37°C release medium was added. The pramipexole content in the release solution was determined by HPLC, the release rate was calculated, and the release curve was plotted (see Appendix). Figure 8 ).

[0130] Example 8 In vitro release properties of the pharmaceutical composition

[0131] The pharmaceutical composition of Example 6 was weighed into a dialysis bag and placed in a test tube with a screw cap and 15 ml of 37°C 0.2N PBS (pH 7.4). The test tube was sealed and kept at 37°C. At different time points, the test tube was inverted several times, and then 5 ml of the release solution was removed and an equal volume of 37°C release medium was added. The granisetron content in the release solution was determined by HPLC, the release rate was calculated, and the release curve was drawn (see Appendix). Fig. 9 ).

Claims

1. A polymer having a structure of formula (1) and having a thermosensitive property, in: x and y are independently integers greater than 1; n is an integer from 1 to 20; m has a carbon number of 14 to 16 and can be selected from one of the carbon numbers of 14 to 16 or a mixture thereof.

2. The polymer and a composition according to claim 1, wherein the composition further contains one or more therapeutically active agents and pharmaceutically acceptable excipients, wherein the therapeutically active agent is a substance used to prevent, treat, and diagnose human diseases, purposefully regulate human physiological functions, and has prescribed indications or functional indications, usage, and dosage, including traditional Chinese medicine, chemical medicine, and biological products. wherein the therapeutically active agent is an antiemetic selected from diphenhydramine, meclizine, scopolamine, trihexyphenidyl, chlorpromazine, ondansetron, granisetron, tropisetron, metoclopramide, domperidone, etc.; wherein the therapeutically active agent is a psychotropic drug selected from paliperidone, risperidone, lurasidone, aripiprazole, haloperidol, etc.; The therapeutically active agent is an anti-Parkinson's drug, such as rotigotine, pramipexole, levodopa, carbidopa, niticapine, bromocriptine, ropinirole, selegiline, trihexyphenidyl, benztropine, amantadine, etc.; The therapeutic active agent is a rheumatoid arthritis drug, such as celecoxib, diclofenac, ibuprofen, meloxicam, prednisone, methotrexate, cyclosporine, etc. The progestogen drug is selected from progesterone, dydrogesterone, megestrol acetate, medroxyprogesterone acetate and the like. The therapeutically active agents are polypeptides and enzyme drugs, such as bromelain and the like.

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