CN113980254A - Series of polymers with acid-sensitive degradation and temperature-sensitive properties and drug-loaded composition thereof - Google Patents

Series of polymers with acid-sensitive degradation and temperature-sensitive properties and drug-loaded composition thereof Download PDF

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CN113980254A
CN113980254A CN202010650090.4A CN202010650090A CN113980254A CN 113980254 A CN113980254 A CN 113980254A CN 202010650090 A CN202010650090 A CN 202010650090A CN 113980254 A CN113980254 A CN 113980254A
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carbon
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何东升
涂家生
冯作勋
孙春萌
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NANJING FANTAI CHEMICAL MEDICAL RESEARCH INSTITUTE
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/002—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from unsaturated compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses a series of polymers with acid-sensitive degradation and temperature-sensitive properties and a drug-loaded composition thereof, wherein the polymers have a structure shown in a formula (1), and have the properties of degradation and temperature sensitivity in a physiological environment, namely, the polymers are solid below a phase transition temperature and liquid above the phase transition temperature, are in a stable state in a low-temperature environment of a storage condition and in a state with better fluidity in a use environment, maintain good drug release property and degradability, and simultaneously give consideration to the stability during storage and the needle penetration during injection.
Figure DDA0002579193730000011

Description

Series of polymers with acid-sensitive degradation and temperature-sensitive properties and drug-loaded composition thereof
Technical Field
The invention belongs to the technical field of biological medicines and high molecular medical materials, and particularly relates to a series of polymers with acid-sensitive degradation and positive temperature-sensitive properties, a preparation method thereof and a pharmaceutical composition.
Technical Field
In the field of controlled drug release research, the properties of sustained-release materials are one of the important factors determining the success or failure of the design of a preparation. An ideal sustained-release injection material should simultaneously have good biocompatibility, effective control of drug release, good injectability and other properties. In the field of drug delivery, commonly used in-situ gels include natural gel materials and synthetic gel materials, which are classified by sources, and these materials form gels in situ after injection by mechanisms such as reverse temperature sensitivity (sol at a certain temperature range, and gel is generated by crosslinking when the temperature is increased), high temperature forward temperature sensitivity (sol at a higher temperature, and gel is generated by reducing the temperature after injection), pH sensitivity, chemical crosslinking or solvent exchange, and the like, and serve as drug reservoirs to slowly release drugs, and the drug release mechanisms include diffusion, dissolution and the like. However, the above conventional in situ gel materials have more or less the following problems: poor biocompatibility, difficult metabolism; the chemical crosslinking monomer has certain toxic effect; the drug release property is unstable; high water content in the system increases the risk of deterioration; the traditional positive temperature-sensitive material has over-high injection temperature, which brings pain to patients and even causes local death and the like.
The polyorthoester is a high molecular substance rich in orthoester bonds, and the orthoester bonds in the structure can be hydrolyzed in a water-containing environment, so that the polyorthoester has good biodegradability. Due to its good biodegradation and surface corrosion properties, polyorthoesters have developed rapidly in the field of sustained and controlled release of drugs, and are now marketed preparations developed by Heron Therapeutics
Figure BDA0002579193710000011
The application is as follows.
Classical polyorthoesters can be presented in the form of semi-solids and related products are marketed in the form of pre-filled injections, however their rheological properties are still insufficient. The classical semisolid polyorthoester has higher viscosity and lower fluidity at the use environment temperature, so that the needle penetration is poor during injection administration, and the difficulty of injection administration when the classical semisolid polyorthoester is singly used as an in-situ slow release matrix is increased. Therefore, when the classical semisolid polyorthoester is used as a slow release carrier for injection administration, a certain proportion of viscosity regulators (such as organic solvents like dimethyl sulfoxide, N-methylpyrrolidone and the like) are required to be mixed to improve the needle penetration, but the introduction of the viscosity regulators can increase the risk of adverse reactions such as irritation, toxicity and the like. Furthermore, the rheological changes of classical semi-solid polyorthoesters are very limited by temperature and have some fluidity in the cold environment during storage. Therefore, aggregation of drug particles, crystallization and precipitation of the drug may occur during long-term storage of the prefilled injection, thereby adversely affecting the quality of the preparation.
At present, the related patents of the polymer of polyorthoesters as the drug carrier mainly include: a composition of a polyorthoester and an aprotic solvent (application No. CN 201480028192); ② long-lasting polymer delivery systems (application No.: CN 201580033564); ③ a novel polyorthoester pharmaceutic adjuvant and a novel sustained-release medicine preparation thereof (application number: CN 201210436124). Wherein, the patents (I) and (II) are related to the application of polyorthoesters as drug sustained-release carriers applied by Heron Therapeutics, Inc. in the United states. The used polyorthoester is traditional semisolid polyorthoester, although the semisolid polyorthoester has a certain effect on the aspect of drug release control, the performance in rheology is a short plate for limiting the use of the polyorthoester, and the traditional semisolid polyorthoester has higher viscosity and lower fluidity in the use environment and is difficult to meet the requirement of injection. The above patent provides a pharmaceutical composition containing "viscosity modifier" to solve the problem of difficulty in injection of the pharmaceutical composition, however, suitable viscosity modifiers (including organic solvents such as dimethyl sulfoxide, N-methyl pyrrolidone, and dimethylacetamide) may increase irritation and toxicity of the pharmaceutical composition and increase the risk of application of the preparation while improving the fluidity of the composition. The conventional polyorthoesters still exhibit certain fluidity at storage temperature, so that there is a risk of crystallization, precipitation, etc. of the drug from the composition. Furthermore, the contents of related U.S. patents (e.g., US10398686, US10357570, US10213510, etc.) are similar to those of the above patents (r) and (r).
The patent provides a new type of polyorthoester and its related slow release preparation with structure different from that of the traditional polyorthoester. The patent focuses on the synthesis method of a novel polymer rich in an orthoester structure, provides a novel polyorthoester structure with biodegradation property and a synthesis way thereof besides the traditional polyorthoester synthesis way, and discloses the application of the polymer as a pharmaceutic adjuvant, in particular a drug sustained release carrier. However, this novel polyorthoester has a unique degradation pathway that puts it at a higher safety risk than traditional polyorthoesters. In the degradation process, one of degradation final products of the orthoester five-membered ring is formic acid, and the degradation product with the optic neurotoxicity greatly limits the prospect of the degradation product in clinical application.
Compared with the invention, the novel polymer containing the orthoester structure provided by the invention creatively introduces the positive temperature-sensitive property on the basis of keeping the high safety and excellent drug slow-release performance of the traditional polyorthoester, so that the drug composition prepared from the polymer keeps good drug release property and degradability, and simultaneously also considers the stability of the composition during storage and the needle penetration during injection. In a word, the polymer and the drug-loading system thereof have the advantages of stable storage, convenient drug delivery, stable drug release, controllable degradation and the like, and have great values in application and research in the field of medicine.
Disclosure of Invention
The invention aims 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 sensitivity, good biocompatibility and the like. The preparation method has simple process and is easy to control. .
It is still another object of the present invention to provide an oligomer monomer and a method for preparing the same. The oligomer monomer can be used for synthesizing the acid-sensitive degradable forward temperature-sensitive series polymers, and has the characteristics of simple synthesis, wide raw material source, low cost and the like.
The invention also aims to provide a drug compound which contains the series of polymers with acid-sensitive degradation and positive temperature-sensitive properties as a sustained-release matrix.
Therefore, the invention provides a polymer with a temperature-sensitive property and a structure shown in a formula (1),
Figure BDA0002579193710000031
wherein: x and y are independently integers greater than 1;
R1comprises the following steps:
Figure BDA0002579193710000032
wherein:
s is an integer from 0 to 30;
t is an integer of 0 to 30;
R4is hydrogen or methyl;
R2is C1-4An alkyl group;
R3comprises the following steps:
Figure BDA0002579193710000033
wherein:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are 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, an amino group;
R6is hydrogen or C1-4An alkyl group;
n is an integer from 1 to 20.
The polymer of the present invention is preferably polymerized from the following three monomers:
monomer A: 3, 9-di (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane or a homolog thereof;
a monomer B: a dihydric alcohol;
a monomer C: an oligomer monomer of formula (2) or (3):
Figure BDA0002579193710000041
wherein:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are 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, an amino group;
R6is hydrogen or C1-4An alkyl group;
n is an integer from 1 to 20.
The polymer of the present invention is more preferably, wherein,
monomer A: 3, 9-di (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane; 3, 9-bis (propylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane;
a monomer B: glycols (triethylene glycol or tripropylene glycol);
in monomer C:
R5is C with or without functional groups1-30Alkyl, wherein the functional groups are independently selectedFrom carbon-carbon double bonds, carbon-carbon triple bonds, carbonyl groups, aldehyde groups, carboxyl groups, ester bonds;
R6is hydrogen or C1-2An alkyl group;
n is an integer from 1 to 15.
The polymer of the present invention is particularly preferred, wherein,
monomer A: 3, 9-di (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane;
in monomer C:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are independently selected from a carbon-carbon double bond, a carbon-carbon triple bond, a carbonyl group;
R6is hydrogen or C1-2An alkyl group;
n is an integer from 1 to 10.
The polymer of the present invention, most preferably the following polymers:
Figure BDA0002579193710000051
wherein: x and y are independently integers greater than 1.
The present invention further provides a process for the preparation of a polymer according to the invention, which process comprises reacting a monomer a: 3, 9-di (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane or a homolog thereof; a monomer B: glycols (triethylene glycol or tripropylene glycol); a monomer C: an oligomer monomer of formula (2) or (3):
Figure BDA0002579193710000052
wherein:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are 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, an amino group;
R6is hydrogen or C1-4An alkyl group;
n is an integer from 1 to 20;
the polymerization reaction is carried out in the presence of an organic solvent, and the reaction temperature is 0-300 ℃.
The molecular weight of the polymer of the invention is 1000-50000, preferably 1000-20000.
The polymer of the invention has the complex viscosity of not less than 10000 pas at the storage temperature and not more than 500 pas at the use temperature.
The polymer has temperature-sensitive property, and the temperature at which the energy storage modulus value and the loss modulus value are equal is between 4 and 40 ℃.
The preparation method of the polymer comprises the following step of independently accounting for 0.01-99.99% of the molar ratio of the monomer B to the monomer C (based on 100% of the monomer A).
The preparation method of the invention takes place in the presence of a reaction solvent, preferably a polar aprotic solvent, more preferably ethyl acetate, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or a mixture of a plurality of solvents thereof. The reaction temperature is 0 to 300 deg.C, preferably 20 to 80 deg.C.
The invention further includes compositions of the polymers of the invention.
The compositions contain one or more therapeutically active agents. Wherein the therapeutic active agent is a substance for preventing, treating, diagnosing human diseases, purposefully regulating human physiological functions and prescribing indications or functional indications, usage and dosage, including traditional Chinese medicines, chemical medicines and biological products;
wherein the therapeutically active agent is an anti-Parkinsonian drug selected from the group consisting of levodopa, carbidopa, nitecapone, bromocriptine, pramipexole, ropinirole, selegiline, trihexyphenidyl, benztropine, amantadine, rotigotine.
Wherein the therapeutically active agent is a emetic selected from the group consisting of diphenhydramine, meclizine, scopolamine, diphenhydramine, chlorpromazine, ondansetron, granisetron, metoclopramide, domperidone;
wherein the therapeutically active agent is a local anaesthetic selected from procaine, tetracaine, lidocaine, bupivacaine;
wherein the therapeutically active agent is a non-steroidal anti-inflammatory drug selected from the group consisting of aspirin, acetaminophen, indomethacin, ibuprofen, naproxen, meloxicam;
wherein the therapeutically active agent is a growth factor;
wherein the therapeutically active agent is a gene drug;
wherein the therapeutically active agent is a proteinaceous drug or a therapeutic polypeptide selected from the group consisting of insulin, glucagon-like peptides.
The preparation method of the pharmaceutical composition comprises the step of mixing, including, complexing or compounding the polymer and the therapeutic active agent, wherein the preparation temperature is 0-300 ℃, and preferably the preparation temperature is 20-120 ℃.
The invention also discloses an oligomer monomer with structural formula (2) or (3) on the basis of obtaining the polymer of the invention:
Figure BDA0002579193710000071
wherein:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are 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, an amino group;
R6is hydrogen or C1-4An alkyl group;
n is an integer from 1 to 20.
The oligomer is prepared by polymerizing a monomer D with a structural formula shown in the specification (6) or (7) and a monomer E (glycolide or lactide) under a heating condition.
Figure BDA0002579193710000072
Wherein:
R5is C with or without functional groups1-30Alkyl radicalWherein the functional groups are independently selected from the group consisting of carbon-carbon double bonds, carbon-carbon triple bonds, carbonyl groups, aldehyde groups, carboxyl groups, ester bonds, amide bonds, ether bonds, amino groups.
The molar ratio of the two components D and E is 2:1 to 1: 5;
preferably, the heating temperature is 80-260 ℃. The reaction time is 0.5-120 h.
The preparation method of the polymer comprises the following steps:
DETOSU, dihydric alcohol and oligomer monomer C shown as formula (2) or (3) are put into reaction according to a proper proportion. DETOSU is dissolved in a suitable reaction solvent and glycol under strictly anhydrous and oxygen-free conditions, and the oligomer monomer C of formula (2) or (3) is dissolved in the reaction solvent. The solution of oligomer monomer C as shown in formula (2) or (3) is added to the solution of DETOSU and glycol to initiate the reaction. Within a few minutes, the reaction liquid reached boiling point. The solution was allowed to cool to room temperature and then the solvent was removed by rotary evaporation at 50-80 ℃.
The preparation method of the oligomer monomer comprises the following steps:
the molar ratio of the monoester of glycerol to glycolide (or lactide) is from 2:1 to 1: 5. Under the protection of inert gas, adding the monoester of glycerol and glycolide (or lactide) into a reaction vessel, and stirring under sealed condition at 80-260 ℃ for 6-72h without adding catalyst and solvent.
The pharmaceutical composition of the invention comprises:
(i) the polymer of claim 1; and
(ii) one or more therapeutically active agents dispersed or dissolved in the polymer of claim 1;
wherein the active agent is released from the composition over a defined period of time.
The beneficial effects of the invention are further illustrated by experimental data below
TABLE 1 rheological Properties Change of the novel polymers provided by the invention at temperatures ranging from 0 to 40 ℃
Figure BDA0002579193710000081
We have studied and surprisingly found that a new class of polymers containing orthoester structure, as shown in table 1 (the above experiment using the polymer of example 2), has positive temperature sensitive properties. By adjusting the proportion of the block units in the polymer molecules, the storage modulus and the loss modulus of the polymer can be flexibly adjusted to be equal at a certain specific temperature within the range of 20-40 ℃, and simultaneously, when the ambient temperature is gradually increased to be higher than the specific temperature, as shown in figure 10, the complex viscosity of the polymer is also sharply reduced, so that the fluidity of the polymer is greatly improved. The rheological property of the polymer sensitively changing along with the temperature can adapt to different requirements of long-term storage and application, so that the polymer is represented as a more stable solid state under the storage environment and is represented as a liquid state with better fluidity under the use environment. Compared with the traditional positive temperature-sensitive high molecular material, the novel polymer has lower conversion temperature, is applied as a drug slow-release carrier, has the injection temperature close to or lower than the body temperature of a human body, can simplify the injection operation, and can reduce the local stimulation and reduce the pain of a patient. The medicine compound prepared from the novel polymer and a proper active therapeutic agent has stable medicine release behavior in an in-vitro release experiment, and the medicine release rate can be flexibly controlled by adjusting the proportion of related structural units in the polymer.
The pharmaceutical composition prepared from the polymer maintains good drug release property and degradability, and simultaneously has stability during storage and needle penetration during injection. In a word, the polymer and the drug-loading system thereof have the advantages of stable storage, convenient drug delivery, stable drug release, controllable degradation and the like, and have great values in application and research in the field of medicine.
Drawings
FIG. 1 shows that the molar ratio of two components selected from Glycerol Monostearate (GMS) and Glycolide (GA) in example 1 of the present invention is 1:1 one of the possible structures for the synthesis of oligomer monomers.
FIG. 2 shows that the molar ratio of the three components 3, 9-di (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane (DETOSU), triethylene glycol (TEG) and glyceryl monostearate bisglycolide (GMS-digL) in example 2 of the present invention (DETOSU: TEG: GMS-digL) is 90:80:20 synthesizing one of the possible structures of the polymer with acid-sensitive degradation and positive temperature-sensitive property.
FIG. 3 is a mass spectrum of an oligomer synthesized in example 1 of the present invention from GMS and GA in a molar ratio of 1: 1.
FIG. 4 is a graph of the infrared spectrum of an oligomer monomer synthesized from GMS and GA in a molar ratio of 1:1 in example 1 of the present invention.
FIG. 5 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 mole ratio of 90:80:20 in example 2 of the present invention (DETOSU: TEG: GMS-diGL).
FIG. 6 shows the change of rheological properties of a polymer with acid sensitive degradation and positive temperature sensitive properties (GMS-POE) synthesized from DETOSU, TEG and GMS-diGL at a molar ratio of 90:80:20 in example 2 of the present invention (DETOSU: TEG: GMS-diGL) at a temperature of 0-40 ℃.
FIG. 7 shows the gel state of polymers synthesized from DETOSU, TEG and GMS-diGL at a molar ratio of 90:80:20 with acid sensitive degradation and forward temperature sensitive properties at 37 deg.C (left) and 4 deg.C (right) in example 2 of the present invention.
FIG. 8 is the in vitro release profile of the drug complex containing 1.25% pramipexole prepared with the above acid-labile degradable, positive temperature-sensitive polymer at pH7.40 at 37 ℃ in example 7 of the present invention.
FIG. 9 is an in vitro release profile of a drug complex containing 3.3% granisetron prepared with the above acid-labile degradable, positive temperature-sensitive polymer at 37 deg.C and pH7.40 in example 8 of the present invention.
FIG. 10 is the complex viscosity change curve of the series of novel polymers (GMS-POEs) provided by the invention in the range of 0-40 DEG C
Detailed Description
The invention is further illustrated by the following examples. The invention is not limited to the following examples, but various modifications and equivalents may be made within the scope of the invention as set forth in the claims.
EXAMPLE 1 preparation of an oligomer monomer
The oligomer monomers of this example were prepared from Glycerol Monostearate (GMS) and Glycolide (GA). The molar ratio of the two components was 1: 1.
As shown in the attached figure 1, Glycerin Monostearate (GMS) (17.928g, 0.05mol) and Glycolide (GA) (5.8035g, 0.05mol) are weighed into a pressure-resistant reaction tube, and are hermetically heated and stirred for 24 hours at 180 ℃ under the protection of inert GAs, so that the obtained product is glycerin monostearate bis-glycolide (GMS-digL).
Example 2 preparation of a Polymer with acid sensitive degradation and Positive temperature sensitive Properties
The polymer with acid-sensitive degradation and positive temperature-sensitive properties of this example was prepared from 3, 9-bis (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane (DETOSU), triethylene glycol (TEG) and glyceryl monostearate bisglycolide (GMS-digL). The molar ratio of the three components (DETOSU: TEG: GMS-diGL) was 90:80: 20.
As shown in FIG. 2, DETOSU (1.910g, 0.009mol) was dissolved in 15ml of anhydrous Tetrahydrofuran (THF) and TEG (1.2014g, 0.008mol) in a 50ml flask under strictly anhydrous conditions, and GMS-digL (0.9493g, 0.002mol) was dissolved in 5ml of anhydrous THF. GMS-digL solution was added to the DETOSU and TEG solution to initiate polymerization. Within a few minutes, the solution reaches boiling point. The solution was allowed to cool to room temperature and then concentrated by rotary evaporation at 50 ℃ followed by rotary evaporation at 80 ℃.
Example 3 preparation of a Polymer with acid sensitive degradation and Positive temperature sensitive Properties
The polymer with acid-sensitive degradation, positive temperature-sensitive properties of this example was prepared from 3, 9-bis (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane (DETOSU), triethylene glycol (TEG), and glyceryl monolaurate bisglycolide (GML-digL). The molar ratio of the three components (DETOSU: TEG: GML-diGL) was 95:80: 20.
DETOSU (2.0164g, 0.0095mol) was dissolved in 15ml of anhydrous (tetrahydrofuran) THF and TEG (1.2014g, 0.008mol) in a 50ml flask under strictly anhydrous conditions, and GML-digL (0.7807g, 0.002mol) was dissolved in 5ml of anhydrous THF. The GML-digL solution was added to a solution of DETOSU and TEG to initiate polymerization. Within a few minutes, the solution reaches boiling point. The solution was allowed to cool to room temperature and then concentrated by rotary evaporation at 50 ℃ followed by rotary evaporation at 80 ℃.
Example 4 preparation of a Polymer with acid sensitive degradation and Positive temperature sensitive Properties
The polymer with acid-sensitive degradation and positive temperature-sensitive properties of this example was prepared from 3, 9-di (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane (DETOSU), triethylene glycol (TEG) and glyceryl monooleate bisglycolide (GMO-digL). The molar ratio of the three components (DETOSU: TEG: GMO-diGL) was 100:85: 15.
DETOSU (2.1225g, 0.0100mol) was dissolved in 15ml of anhydrous ethyl acetate and TEG (1.2750g, 0.0085mol) in a 50ml flask under strictly anhydrous conditions, and GMO-digL (0.7088g, 0.0015mol) was dissolved in 5ml of anhydrous ethyl acetate. The GMO-digL solution was added to a solution of DETOSU and TEG to initiate polymerization. Within a few minutes, the solution reaches boiling point. The solution was allowed to cool to room temperature and then concentrated by rotary evaporation at 50 ℃ followed by rotary evaporation at 80 ℃.
EXAMPLE 5A method for preparing a semi-solid drug Compound
A semi-solid pharmaceutical composition comprising pramipexole (PPX) as an active agent is prepared by the following process:
pramipexole, 1.25 w.t%, and a polymer, 98.75 w.t%, were stirred for 3h under inert gas with heating at 40 ℃ and cooled to room temperature to obtain a semi-solid with a uniform texture.
EXAMPLE 6 preparation of a semi-solid drug Complex
A semi-solid pharmaceutical composition comprising Granisetron (GRA) as an active agent is prepared by the following method:
stirring 3.0 w.t% granisetron and 97.0 w.t% polymer under inert gas atmosphere at 40 deg.C for 3h, and cooling to room temperature to obtain a semi-solid with uniform texture.
EXAMPLE 7 in vitro Release Properties of pharmaceutical compositions
The pharmaceutical composition of example 5 was weighed into a dialysis bag and placed in a screw-capped test tube to which 15ml of 0.2N PBS (pH7.4) was added at 37 ℃. The tube was sealed and allowed to stand at a constant temperature of 37 ℃. At different time points, the tube was inverted several times and then 5ml of release solution was removed and an equal volume of 37 ℃ release medium was replenished. The pramipexole content in the release solution was measured by HPLC, the release was calculated, and the release curve was plotted (fig. 8).
EXAMPLE 8 in vitro Release Properties of pharmaceutical compositions
The pharmaceutical composition of example 6 was weighed into a dialysis bag and placed in a screw-capped test tube to which 15ml of 0.2N PBS (pH7.4) was added at 37 ℃. The tube was sealed and allowed to stand at a constant temperature of 37 ℃. At different time points, the tube was inverted several times and then 5ml of release solution was removed and an equal volume of 37 ℃ release medium was replenished. The release was calculated by measuring the granisetron content of the release by HPLC and the release was plotted (fig. 9).

Claims (10)

1. A polymer with a temperature-sensitive property and a structure shown in a formula (1),
Figure FDA0002579193700000011
wherein: x and y are independently integers greater than 1;
R1comprises the following steps:
Figure FDA0002579193700000012
wherein:
s is an integer from 0 to 30;
t is an integer of 0 to 30;
R4is hydrogen or methyl;
R2is C1-4An alkyl group;
R3comprises the following steps:
Figure FDA0002579193700000013
wherein:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are 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, an amino group;
R6is hydrogen or C1-4An alkyl group;
n is an integer from 1 to 20.
2. The polymer of claim 1, polymerized from three monomers:
monomer A: 3, 9-di (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane or a homolog thereof;
a monomer B: a dihydric alcohol:
a monomer C: an oligomer monomer of formula (2) or (3):
Figure FDA0002579193700000021
wherein:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are 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, an amino group;
R6is hydrogen or C1-4An alkyl group;
n is an integer from 1 to 20.
3. The polymer of claim 2, wherein,
monomer A: 3, 9-di (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane; 3, 9-bis (propylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane;
a monomer B: a diol of the formula (4) or (5):
Figure FDA0002579193700000022
wherein:
s is an integer from 0 to 30;
t is an integer of 0 to 30;
R4is hydrogen or methyl;
in monomer C:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are 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;
R6is hydrogen or C1-2An alkyl group;
n is an integer from 1 to 15.
4. The polymer of claim 3, wherein,
monomer A: 3, 9-di (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane;
in monomer C:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are independently selected from a carbon-carbon double bond, a carbon-carbon triple bond, a carbonyl group;
R6is hydrogen or C1-2An alkyl group;
n is an integer from 1 to 10.
5. The polymer of claim 1, wherein the polymer is selected from the group consisting of,
Figure FDA0002579193700000031
wherein: x and y are independently integers greater than 1.
6. The method for preparing the polymer according to claim 1, wherein the molar ratio of the monomer A: 3, 9-di (ethylene) -2,4,8, 10-tetraoxaspiro [5,5] undecane or a homolog thereof;
a monomer B: a diol of the formula (4) or (5):
Figure FDA0002579193700000032
wherein:
s is an integer from 0 to 30;
t is an integer of 0 to 30;
R4is hydrogen or methyl;
a monomer C: an oligomer monomer of formula (2) or (3):
Figure FDA0002579193700000033
wherein:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are 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, an amino group;
R6is hydrogen or C1-4An alkyl group;
n is an integer from 1 to 20;
the polymerization reaction is carried out in the presence of an organic solvent, and the reaction temperature is 0-300 ℃.
7. A composition comprising a polymer as claimed in any one of claims 1 to 5.
8. The composition according to claim 7, further comprising one or more therapeutically active agents and pharmaceutically acceptable excipients, wherein the therapeutically active agent is a substance for preventing, treating, diagnosing human diseases, purposefully regulating human physiological functions and prescribing indications or functional indications, usage and dosage, including traditional Chinese medicines, chemical medicines and biological products;
wherein the therapeutically active agent is an anti-Parkinsonian drug selected from the group consisting of levodopa, carbidopa, nitecapone, bromocriptine, pramipexole, ropinirole, selegiline, trihexyphenidyl, benztropine, amantadine, rotigotine.
Wherein the therapeutically active agent is a emetic selected from the group consisting of diphenhydramine, meclizine, scopolamine, diphenhydramine, chlorpromazine, ondansetron, granisetron, metoclopramide, domperidone;
wherein the therapeutically active agent is a local anaesthetic selected from procaine, tetracaine, lidocaine, bupivacaine;
wherein the therapeutically active agent is a non-steroidal anti-inflammatory drug selected from the group consisting of aspirin, acetaminophen, indomethacin, ibuprofen, naproxen, meloxicam;
wherein the therapeutically active agent is a growth factor;
wherein the therapeutically active agent is a gene drug;
wherein the therapeutically active agent is a proteinaceous drug or a therapeutic polypeptide selected from the group consisting of insulin, glucagon-like peptides.
9. An oligomeric monomer of structural formula (2) or (3):
Figure FDA0002579193700000041
wherein:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are 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, an amino group;
R6is hydrogen or C1-4An alkyl group;
n is an integer from 1 to 20.
10. The method for preparing the oligomer monomer according to claim 9, wherein the oligomer is prepared by polymerizing a monomer D having a structural formula (6) or (7) with a monomer E (glycolide or lactide) under heating.
Figure FDA0002579193700000051
Wherein:
R5is C with or without functional groups1-30An alkyl group, wherein the functional groups are 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, an amino group.
The molar ratio of the two components D and E is 2:1 to 1: 5.
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