CN1899264A - Temperature sensitive type water gel medicine release system and its preparing method - Google Patents

Abstract

A temperature-sensitive hydrogel drug delivery system and a preparation method thereof belong to the technical field of medicines. The weight percent range of each component of the system of the invention is: 0.1-30% of the loaded drug, 20-90% of the temperature-sensitive hydrogel, and 5-50% of the polymer polysaccharide. The system of the present invention is prepared by three methods: polysaccharide polymer particle-temperature-sensitive hydrogel composite method, polysaccharide-temperature-sensitive hydrogel hydrophilic emulsification method, or polysaccharide-temperature-sensitive hydrogel emulsification method. When the solution-gel phase transition occurs, the kinetically "controlled release phase" overcomes the burst release phenomenon of traditional thermosensitive hydrogels by virtue of retardation and diffusion, and at the same time increases the drug loading and improves the stability of the drug in the process of preparation, storage and release. sex. This system provides a simple and feasible technical solution for the controllable delivery of biomacromolecular drugs or other therapeutic components (such as vaccines, antibodies, viruses, liposomes, etc.) and the improvement of the release kinetics of the load.

Description

Temperature-sensitive hydrogel drug delivery system and preparation method thereof

technical field

The invention relates to a composition in the field of pharmaceutical technology and a preparation method thereof, in particular to a temperature-sensitive hydrogel drug delivery system and a preparation method thereof.

Background technique

Temperature-sensitive hydrogel is a polymer hydrogel whose volume changes with temperature. The so-called temperature sensitivity means that the amount of water (or solvent) absorbed by the hydrogel changes suddenly at a certain temperature. That is, the swelling ratio (the ratio of the amount of water or solvent absorbed to the weight of the dry gel) will suddenly change at a certain temperature, and this temperature is called the sensitive temperature. Near the critical temperature, as the temperature increases, the hydrogel whose swelling rate will suddenly increase is called a "thermal expansion" hydrogel (with a high critical solution temperature UCST); on the contrary, the swelling rate increases as the temperature increases. Hydrogels that decrease abruptly are then referred to as "heat-shrinkable" hydrogels (with a low critical solution temperature LCST).

The block copolymer formed by polyethylene oxide (PEO) and polypropylene oxide (PPO) has been approved by the US FDA as a polymer for pharmaceutical excipients. The trade name of the three-block class is Pluronic (BASF) or Poloxamer (ICI), and the structure is: PEO-PPO-PEO; or PPO-PEO-PPO; the trade name of the multi-block copolymer is Tet tonic, and the structure is: ( R ₁ ) ₂ NCH ₂ CH ₂ N(R ₂ ) ₂ , wherein R ₁ and R ₂ can be -PEO-PPO, -PPO-PEO, respectively. The trade name of the graft copolymer PEO-PPO-PEO-g-PAA is: Smart Hydrogel ^TM . Because it can form a gel at a polymer concentration of 1% to 5% in the human body environment (37.5°C, pH=7.4), has viscoelasticity and bioadhesion, and is visually unobstructed and has no toxic or side effects. It works well as an ophthalmic drug and a slow-release carrier for hydrophobic drugs. However, since poloxamer cannot be degraded, although the release curve can be adjusted by adding methyl cellulose, hydroxypropyl methyl cellulose, and polycaprolactone to prolong the sustained release time appropriately, within the concentration range allowed by safety, at the injection site It will completely dissolve in less than a week and cannot be used as a long-term sustained release. If it exceeds the maximum allowable concentration of 16%, it will show obvious symptoms of toxicity. In 1997, MacroMed in Salt Lake City, USA invented ABA and BAB type biodegradable tri-block copolymers, which undergo solution-gel transformation near body temperature, where A represents hydrophobic polylactic acid polymers, and B represents hydrophilic poly-lactic acid polymers. Ethylene glycol, which can be degraded in 4-6 weeks by adjusting the ratio of A and B chain breaks, is trying to be applied to the parenteral drug delivery system for sustained-release drugs.

This temperature-dependent expansion-contraction process of thermosensitive hydrogels is reversible. Utilizing this property to control the release of drugs is the basis for the application of thermosensitive hydrogels in intelligent drug delivery systems. However, when the above-mentioned temperature-sensitive hydrogel system is heated/cooled to phase transition, the gel is rapidly dehydrated and solidified to release the drug by means of the change of hydrogen bonding, thereby causing a burst release phenomenon.

Found through literature search to prior art, Sibao Chen et al published article "Triblock copolymers: synthesis, characterization, and delivery of amodel" in International Journal of Pharmaceutics ("International Journal of Pharmaceutics") 2005 No. 288, No. 207-218 pages protein” (tri-block copolymer: synthesis, characterization, transport research of model protein), ABA-type tri-block copolymer was obtained by ring-opening polymerization of polyethylene glycol, glycolide, and lactide under anaerobic and water-free conditions , the triblock copolymer was formulated into a 23% aqueous solution at room temperature to obtain a temperature-sensitive hydrogel formulation. Lysozyme <Lysozyme> was selected as the model drug, released in vitro for 10 days, but there was a burst release phenomenon (>20%) within the first day, especially within a few hours after administration; currently, MacroMed Inc, Salt Lake City, USA is applying this ABA three Block copolymer (trade name ReGel) is used for clinical research on auxin, leukocyte growth factor and insulin. However, relying solely on the slow-release technology of ABA tri-block copolymers, due to the rapid phase transition and solidification of the gel, the hydrogen bond is weakened microscopically, and a large amount of water molecules are lost from the hydrogel macroscopically, and some loaded drugs, especially hydrophilic drugs, are short-lived. Rapid burst release within the time, release greater than 20% in the first day, can not achieve safe and effective stable sustained release.

MacroMed Inc uses zinc ions and auxin to cross-link and precipitate to form particles and then wrap them in Regel in an attempt to alleviate the burst release phenomenon caused by the weakening of hydrogen bonds. Reduced, but still higher than 20%, the effect of alleviating burst release is not ideal. Moreover, this method is only limited to auxin, because in the in vivo environment, after zinc ions are complexed with auxin, it can increase the ability to bind to the receptor, thereby improving the physiological activity of auxin in vivo, but this method is applied to other Proteins, such as erythropoietin EPO, cause aggregation of protein molecules.

Contents of the invention

The purpose of the present invention is to provide a solution to the sudden release of drugs caused by water loss caused by dehydration and solidification caused by dehydration and solidification caused by the solution-gel phase transition when the existing temperature-sensitive hydrogel is used as a therapeutic substance carrier. A temperature-sensitive hydrogel drug delivery system and its preparation method can improve the release curve, increase the drug loading capacity, and stably load the drug in the process of preparation, storage and release; at the same time, it can also realize the pulse of vaccine delivery Release medicine.

The present invention is achieved through the following technical solutions. The temperature-sensitive hydrogel intelligent drug delivery system of the present invention includes a temperature-sensitive continuous phase and a hydrophilic dispersed phase with hydrophilic/hydrophobic properties and volume changes with temperature. The temperature-sensitive continuous phase is composed of temperature-sensitive hydrogel, and the hydrophilic dispersed phase is composed of high-molecular polysaccharide and loaded drug; the weight percentage of each component is: temperature-sensitive hydrogel 20-90%, high-molecular polysaccharide 5-50%, loaded Drug 0.1-30%. Wherein, polyelectrolyte and small molecule sugar can be added to the hydrophilic dispersed phase, and the weight percentage is: polyelectrolyte 0-4.9%, and small molecule sugar 0-10%.

The preparation method of the temperature-sensitive hydrogel intelligent drug delivery system of the present invention is prepared by any one of the following three methods:

<1> Polysaccharide polymer particle-thermosensitive hydrogel composite method

a) Preparation of drug-loaded polysaccharide polymer particles

① Prepare two kinds of polymer aqueous solutions, which are used as continuous phase and dispersed phase respectively, and mix the two phases in the range of -4°C to 95°C to obtain a homogeneous solution or suspension; or add polyelectrolyte to any phase to stabilize the emulsion The agent is emulsified in the range of -4°C to 95°C to obtain an emulsion; the loaded drug is dissolved in the dispersed phase.

② Freeze-dry the homogeneous solution, suspension, and emulsion obtained in step ①, and wash and remove the continuous phase with a solvent to obtain drug-loaded polysaccharide polymer particles with a particle size ranging from 10nm to 50um;

b) Prepare thermosensitive hydrogel matrix by physical mixing or chemical methods, or directly select natural polymers with thermosensitive characteristics, ready to use or freeze-dried for storage;

c) preparing a polysaccharide polymer particle-thermosensitive hydrogel complex;

The temperature-sensitive hydrogel matrix prepared in step b) is formulated into a solution at a temperature ranging from -4°C to 95°C, and the polysaccharide polymer particles obtained in step a) are added to the hydrogel solution at a temperature ranging from 4°C to 95°C Composite, ready-to-use or lyophilized and reconstituted before use.

<2> Polysaccharide-thermosensitive hydrogel hydrophilic emulsification method

a) Physical mixing or chemical methods to prepare temperature-sensitive hydrogels, or directly select natural polymers with temperature-sensitive characteristics, ready to use or freeze-dried for storage;

b) preparing a polysaccharide polymer solution, dissolving the loaded drug in the polymer solution, and adding a polyelectrolyte as an emulsion stabilizer;

c) In the range of -4°C-95°C, prepare a temperature-sensitive hydrogel solution;

d) Add b) to c), emulsify to obtain a drug-loaded polysaccharide-hydrogel emulsion, and the droplet size ranges from 10nm-50um, ready to use;

e) Or freeze-dried and stored before reconstitution.

<3> Polysaccharide-thermosensitive hydrogel emulsification method

a) Physical mixing or chemical methods to prepare temperature-sensitive hydrogels, or directly select natural polymers with temperature-sensitive characteristics, ready to use or freeze-dried for storage;

b) preparing a polysaccharide polymer solution, and dissolving the loaded drug in the polymer solution;

c) Prepare a temperature-sensitive hydrocoagulant solution under the condition of -4°C-95°C;

d) Add b) to c), mix evenly to obtain a drug-loaded polysaccharide-hydrogel solution/suspension, ready to use;

e) Or freeze-dried and stored before reconstitution.

The temperature-sensitive hydrogel intelligent drug delivery system of the present invention includes a temperature-sensitive continuous phase and a hydrophilic dispersed phase with hydrophilic/hydrophobic properties and volume changes with temperature.

The temperature-sensitive continuous phase of the present invention is composed of temperature-sensitive hydrogel, which can be selected from natural polymers with temperature-sensitive characteristics, N-isopropylacrylamide copolymer <NiPAAM>, polyoxyethylene/polyoxypropylene block copolymer and its derivatives <PEO/PPO>, polyethylene glycol/polylactic acid block copolymers and other temperature-sensitive hydrogels; the block copolymers can be AB-type diblocks, ABA, BAB, ABC-type triblocks Block copolymers such as segment, star block, multi-block, graft block, etc. The temperature-sensitive hydrogel can be a heat-expandable or heat-shrinkable temperature-sensitive hydrogel. The structure of the temperature-sensitive hydrogel can be cross-linked or non-cross-linked; it can be prepared by physical mixing or chemical methods. The temperature of the phase transition (that is, the phase change caused by hydrophilic/hydrophobic properties and volume changes) of the temperature-sensitive hydrogel can be at body temperature, or it can be higher or lower than body temperature;

The hydrophilic dispersed phase of the present invention is composed of polymer polysaccharides and loaded drugs. Polyelectrolytes and small molecule sugars can be added to the hydrophilic dispersed phase. Polyelectrolytes can improve the stability of the emulsion, and small molecule sugars can improve the appearance of the freeze-drying process and improve the stability of the loaded drug. Polymer polysaccharides in the hydrophilic dispersed phase can be selected from one or a mixture of dextran, soluble cellulose derivatives, and hyaluronic acid; A mixture of release polymers; small molecular sugars can be one or a mixture of small molecular sugars such as sucrose, lactose, mannose, glucose, and trehalose. The hydrophilic dispersed phase acts as a "controlled release phase" through viscous retardation, thereby adjusting the release profile and solving the problem of burst release.

The temperature-sensitive hydrogel intelligent drug delivery system of the present invention is suitable for water-soluble drugs and other therapeutic components (such as vaccines, antibodies, viruses, liposomes, etc.), especially polypeptides, proteins, vaccines, antibodies, cytokines, Sustained release or pulse release of therapeutic substances such as gene substances, protein drugs include auxin, interferon, erythropoietin, BMP, etc., and antibodies include antibody drugs such as antibodies to angiogenesis factors; the administration method can be subcutaneous, Administration by intramuscular, intravenous, local intralesional injection. Combined with specific treatment needs, one or several therapeutic substances can be loaded in the thermosensitive hydrogel matrix at the same time, and it can be applied to bone tissue engineering three-dimensional scaffolds, drug-eluting scaffolds, vaccine adjuvants, etc.

For biomacromolecular therapeutic substances with advanced spatial structure, the "hydrophilic dispersed phase" is used as the "controlled release phase" of the system, which effectively isolates the direct contact between the loaded therapeutic substance and the hydrogel, avoiding the hydrophobic chain of the hydrogel. The structural damage of the segment to the loaded drug can improve the stability of the therapeutic substance <such as erythropoietin EPO>; for some macromolecular therapeutic substances that are unstable at low temperature, the solubility of the hydrophobic domain increases due to the decrease in temperature during the freezing process. The aggregation instability factor <neutrophil colony-stimulating factor G-CSF> can be directly emulsified by polysaccharide-thermosensitive hydrogel to avoid freeze-drying operation and effectively stabilize the therapeutic substance; the "controlled release phase" of the "hydrophilic dispersed phase" "The effect is achieved through viscous blockade, which can effectively prevent the burst release effect caused by the loss of water molecules due to dehydration, thereby adjusting the release curve; in addition, it can also increase the loading capacity and reduce the dosage, and the patient complies with the treatment process. Sex is better.

For the sub-vaccine delivery system, due to the destruction of the natural conformation due to physical and chemical factors, the "controlled release phase" can effectively maintain its spatial structure; according to the needs of the immune response, sometimes slow release is required and sometimes timed pulse release is required. Presentation time, and the time point can be determined according to needs to achieve pulse release, and the traditional three immunizations can be simplified to one immunization.

At the same time, according to actual treatment needs, the present invention can also simultaneously load several therapeutic substances in the thermosensitive hydrogel matrix, for example: bone tissue engineering scaffolds usually require bone morphogenetic protein factors <BMPs>, insulin-like growth factor-1< Synergistic effect of IGF-1> and transforming growth factor <TGF-β>; during the delivery of subunit vaccines, slow-release cytokines can be used as immune adjuvants to build a microenvironment that is more conducive to antigen presentation and enhance the immune effect of T cells; drug elution Cardiac stents require synergistic effects of vascular endothelial growth factor <VEGF> and basic fibroblast growth factor <bFGF>.

The present invention provides three methods for preparing the temperature-sensitive hydrogel intelligent drug release system with the temperature-sensitive hydrogel as the matrix; wherein one or several mixed polymer polysaccharides are used as the "controlled release phase" to load the drug Dissolved in the "controlled release phase", and the "controlled release phase" is evenly dispersed in the temperature-sensitive hydrogel matrix. When the solution-gel phase transition occurs, a large amount of water molecules will be lost due to the weakening of hydrogen bonds. Polysaccharides overcome the burst release effect by means of retarded diffusion to release drugs slowly; water-soluble therapeutic substances can be encapsulated in polymer polysaccharide particles and directly added to the polysaccharide solution, and polyelectrolytes and small molecular sugars can be optionally added to the polysaccharide solution.

Compared with the prior art, the present invention can effectively alleviate the initial burst release problem of traditional temperature-sensitive hydrogels, increase the loading capacity, and improve the stability of therapeutic substances in the process of preparation, storage and release. For biomacromolecular protein drugs, it has good biocompatibility with the selected polymer polysaccharides and polyelectrolytes, and the viscosity retardation effect effectively isolates the protein from the hydrophobic domain of the thermosensitive hydrogel, which can be effectively released while slowing down. Protect the high-order spatial structure of macromolecules from changes, and improve the stability of protein drugs in the process of preparation, storage and release.

Description of drawings

Fig. 1 is the in vitro release figure of the novel thermosensitive hydrogel drug delivery system prepared by different methods of the present invention

Detailed ways

As shown in Figure 1, the in vitro release diagram of the novel thermosensitive hydrogel drug delivery system prepared by different methods of the present invention. The specific prescription and method are shown in Table 1.

Table 1. Preparation method and proportioning factors of the new thermosensitive hydrogel drug delivery system sample group method Proportion A Polysaccharide-thermosensitive hydrogel emulsification method <lyophilization> Thermosensitive Hydrogel 90%, Dextran 5.77%, Sodium Alginate 2.16%, BSA 2.07 B Polysaccharide-thermosensitive hydrogel composite method <lyophilization> Thermosensitive Hydrogel 90%, Dextran 7.58%, BSA 2.42% C Regel method Thermosensitive Hydrogel 97.93%, BSA 2.07% D. Polysaccharide-thermosensitive hydrogel direct emulsification method <ready to use> Thermosensitive Hydrogel 90%, Dextran 5.77%, Sodium Alginate 2.16%, BSA 2.07 E. Polysaccharide-thermosensitive hydrogel composite method <ready-to-use> Thermosensitive Hydrogel 90%, Dextran 7.58%, BSA 2.42%

The following examples are intended to help those skilled in the art better understand and implement the technology disclosed in the present invention, but do not represent the scope of application of the present invention, and should not be taken as limitations on the scope of application of the present invention.

Example 1

Preparation of novel thermosensitive hydrogel loaded with BSA by polysaccharide polymer particle-thermosensitive hydrogel composite method

Select BSA as a model drug, prepare a mixed solution of dextran, BSA and a mixed solution of polyethylene glycol and sodium alginate; mix and homogenize the two to obtain a stable emulsion; freeze for 12 hours, dry in vacuum for 24 hours, and use the solid sample obtained Washing with dichloromethane, centrifuging, pouring to remove the supernatant, washing away the polyethylene glycol, and evaporating the organic solvent to obtain dextran-sodium alginate polysaccharide polymer particles. Before use, the temperature-sensitive hydrogel matrix is made into a 25% solution, and the polymer polysaccharide particles are added for compounding. In the composition, BSA (0.1%, w/w), dextran (5%, w/w), thermosensitive hydrogel matrix (90%, w/w), sodium alginate (4.9%, w/w) . The composition is released in vitro in HEPEs buffer at 37°C for 10 days, without burst release and incomplete release, and achieves an ideal stable and sustained release effect.

Example 2.

Preparation of novel thermosensitive hydrogel loaded with BSA by polysaccharide-thermosensitive hydrogel emulsification method

A mixed solution of dextran, BSA, sodium alginate and trehalose is prepared, and a temperature-sensitive hydrogel matrix is prepared as a 25% solution. After mixing the two phases, homogenate to obtain a stable emulsion; freeze for 12 hours, vacuum dry for 24 hours, and reconstitute the obtained solid sample before use. In the composition, BSA (30%, w/w), thermosensitive hydrogel (29.55%, w/w), dextran (27.5%, w/w), sodium alginate (2.95%, w/w), Trehalose (10%, w/w). The composition is released in vitro in HEPEs buffer at 37°C for 10 days, without burst release and incomplete release, and achieves an ideal stable and sustained release effect.

Example 3.

Preparation of novel thermosensitive hydrogel loaded with BSA by polysaccharide-thermosensitive hydrogel composite method

A mixed solution of dextran, BSA and trehalose is prepared, and a temperature-sensitive hydrogel matrix is prepared as a 25% solution. The two phases are mixed and homogenized to obtain a suspension, which is ready to use. In the composition, BSA (25%, w/w), thermosensitive hydrogel (20%, w/w), dextran (50%, w/w), trehalose (5%, w/w) (poly electrolyte). The composition is released in vitro in HEPEs buffer at 37°C for 10 days, without burst release and incomplete release, and achieves an ideal stable and sustained release effect.

Example 4.

Preparation of novel thermosensitive hydrogel loaded with BSA by polysaccharide-thermosensitive hydrogel composite method

A mixed solution of dextran, BSA and trehalose is prepared, and a temperature-sensitive hydrogel matrix is prepared as a 25% solution. The two phases were mixed and homogenized to obtain a suspension, which was frozen for 12 hours and vacuum-dried for 24 hours. The obtained solid sample was stored and redissolved immediately before use. In the composition, BSA (25%, w/w), thermosensitive hydrogel (20%, w/w), dextran (50%, w/w), trehalose (5%, w/w) (poly electrolyte). The composition is released in vitro in HEPEs buffer at 37°C for 10 days, without burst release and incomplete release, and achieves an ideal stable and sustained release effect.

Example 5.

Preparation of novel thermosensitive hydrogel loaded with BSA by polysaccharide-thermosensitive hydrogel emulsification method

A mixed solution of dextran, BSA and sodium alginate was prepared, and a temperature-sensitive hydrogel matrix was made into a 25% solution; the two were mixed and homogenized to obtain a stable emulsion; frozen for 12 hours, and vacuum-dried for 24 hours to obtain a solid sample. Before use, reconstitute. In the composition, BSA (14.95%, w/w), dextran (27.5%, w/w), thermosensitive hydrogel matrix (55%, w/w), sodium alginate (1.05%, w/w) . Trehalose (1.5%, w/w). The composition is released in vitro in HEPEs buffer at 37°C for 10 days, without burst release and incomplete release, and achieves an ideal stable and sustained release effect.

Example 6.

Preparation of novel thermosensitive hydrogel loaded with BSA by polysaccharide-thermosensitive hydrogel emulsification method

A mixed solution of dextran, BSA and sodium alginate is prepared; a thermosensitive hydrogel matrix is prepared as a 25% solution. Two-phase mixing homogenizer emulsification to obtain a stable emulsion, ready to use. In the composition, BSA (14.95%, w/w), dextran (27.5%, w/w), thermosensitive hydrogel matrix (55%, w/w), sodium alginate (1.05%, w/w) . Trehalose (1.5%, w/w). The composition is released in vitro in HEPEs buffer at 37°C for 10 days, without burst release and incomplete release, and achieves an ideal stable and sustained release effect.

Claims (10)

1. A temperature-sensitive hydrogel drug delivery system, characterized in that: it includes a temperature-sensitive continuous phase and a hydrophilic dispersed phase whose hydrophilic/hydrophobic properties and volume change with temperature, and the temperature-sensitive continuous phase is composed of a temperature-sensitive hydrogel The hydrophilic dispersed phase is composed of polymer polysaccharides and loaded water-soluble drugs. The weight percentage ranges of each component are: loaded drugs 0.1-30%, temperature-sensitive hydrogel 20-90%, polymer polysaccharides 5% -50%. 2. The temperature-sensitive hydrogel drug delivery system according to claim 1, wherein the polymer polysaccharides are dextran, soluble cellulose derivatives, hyaluronic acid, starch and modified derivatives one or a mixture of several. 3. The temperature-sensitive hydrogel drug delivery system according to claim 1, characterized in that the temperature-sensitive hydrogel comprises natural polymers, N-polyisopropylacrylamide polymers, polyoxyethylene- One or a mixture of polyoxypropylene copolymers and their derivatives, polyethylene glycol/polylactic acid block copolymers. 4. The temperature-sensitive hydrogel intelligent drug delivery system according to claim 3, characterized in that the block copolymer includes AB type diblocks, ABA, BAB, ABC type triblocks, star type One or a mixture of blocks, multi-blocks, and grafted blocks. 5. The temperature-sensitive hydrogel intelligent drug delivery system according to claim 1 or 3, characterized in that, the temperature-sensitive hydrogel is thermal expansion type or thermal shrinkage type; the temperature-sensitive hydrogel structure is cross-linked type Or non-crosslinked type; the phase transition temperature of thermosensitive hydrogel is from 10°C to 80°C. 6. The temperature-sensitive hydrogel drug delivery system according to claim 1, characterized in that polyelectrolytes and small molecular sugars are added to the hydrophilic dispersed phase, and the weight percentages are 0-4.9% of polyelectrolytes, Small molecule sugar 0-10%. 7. The temperature-sensitive hydrogel drug delivery system according to claim 6, characterized in that, the polydielectric medium comprises a mixture of one or several alginate-dissociable polymers, and the small molecular sugars include One or a mixture of trehalose, mannose, sucrose, lactose, and glucose. 8. A method for preparing a temperature-sensitive hydrogel intelligent drug delivery system according to claim 1, characterized in that: polysaccharide polymer particles-temperature-sensitive hydrogel composite method is adopted, and the steps are as follows: a) Preparation of drug-loaded polysaccharide polymer particles ① Prepare two kinds of polymer aqueous solutions, which are used as continuous phase and dispersed phase respectively, and mix the two phases in the range of -4°C to 95°C to obtain a homogeneous solution or suspension; or add polyelectrolyte to any phase to stabilize the emulsion The agent is emulsified in the range of -4°C to 95°C to obtain an emulsion; the loaded drug is dissolved in the dispersed phase. ② Freeze-dry the homogeneous solution, suspension, and emulsion obtained in step ①, and wash and remove the continuous phase with a solvent to obtain drug-loaded polysaccharide polymer particles with a particle size ranging from 10nm to 50um; b) Prepare thermosensitive hydrogel matrix by physical mixing or chemical methods, or directly select natural polymers with thermosensitive characteristics, ready to use or freeze-dried for storage; c) preparing a polysaccharide polymer particle-thermosensitive hydrogel complex; The temperature-sensitive hydrogel matrix prepared in step b) is formulated into a solution at a temperature ranging from -4°C to 95°C, and the polysaccharide polymer particles obtained in step a) are added to the hydrogel solution at a temperature ranging from 4°C to 95°C Composite, ready-to-use or lyophilized and reconstituted before use. 9. A method for preparing a temperature-sensitive hydrogel intelligent drug delivery system according to claim 1, characterized in that: a polysaccharide-temperature-sensitive hydrogel hydrophilic emulsification method is adopted, and the steps are as follows: a) Physical mixing or chemical methods to prepare temperature-sensitive hydrogels, or directly select natural polymers with temperature-sensitive characteristics, ready to use or freeze-dried for storage; b) preparing a polysaccharide polymer solution, dissolving the loaded drug in the polymer solution, and adding a polyelectrolyte as an emulsion stabilizer; c) In the range of -4°C-95°C, prepare a temperature-sensitive hydrogel solution; d) Add b) to c), emulsify to obtain a drug-loaded polysaccharide-hydrogel emulsion, and the droplet size ranges from 10nm-50um, ready to use; e) Or freeze-dried and stored before reconstitution. 10. A method for preparing a temperature-sensitive hydrogel intelligent drug delivery system according to claim 1, characterized in that: polysaccharide temperature-sensitive hydrogel emulsification method is adopted, and the steps are as follows: a) Physical mixing or chemical methods to prepare temperature-sensitive hydrogels, or directly select natural polymers with temperature-sensitive characteristics, ready to use or freeze-dried for storage; b) preparing a polysaccharide polymer solution, and dissolving the loaded drug in the polymer solution; c) Prepare a temperature-sensitive hydrocoagulant solution under the condition of -4°C-95°C; d) Add b) to c), mix well to obtain a drug-loaded polysaccharide-hydrogel solution/suspension, ready to use; e) Or freeze-dried and stored before reconstitution.

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