CN111110626A - Gel drug sustained-release preparation based on hydrophobic modified gemcitabine derivative and preparation method and application thereof - Google Patents

Gel drug sustained-release preparation based on hydrophobic modified gemcitabine derivative and preparation method and application thereof Download PDF

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CN111110626A
CN111110626A CN201911228075.4A CN201911228075A CN111110626A CN 111110626 A CN111110626 A CN 111110626A CN 201911228075 A CN201911228075 A CN 201911228075A CN 111110626 A CN111110626 A CN 111110626A
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gel
drug
polymer
gemcitabine
gemcitabine derivative
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俞麟
杨孝伟
丁建东
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Fudan University
Zhuhai Fudan Innovation Research Institute
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Zhuhai Fudan Innovation Research Institute
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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a gel medicine sustained-release preparation based on a hydrophobic modified gemcitabine derivative and application thereof in preparing a tumor medicine, wherein the gel medicine sustained-release preparation disclosed by the invention mainly comprises a gel carrier material, an effective amount of the hydrophobic modified gemcitabine derivative and a solvent; the gemcitabine molecules are modified by using long fatty acid chains, and then the PEG/polyester block copolymer thermotropic hydrogel carrier is used for entrapment, so that the slow release of the drugs in the gel carrier is realized by using the hydrophobic interaction of the drugs and the polymer carrier, the utilization rate of the drugs is improved, the long-acting chemotherapy effect is obtained, and simultaneously, the long-acting chemotherapy effect is combined with radiotherapy, and the aims of one-time injection, continuous chemotherapy and multiple radiotherapy sensitization can be realized.

Description

Gel drug sustained-release preparation based on hydrophobic modified gemcitabine derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a long-acting radiotherapy-sensitization gel medicine sustained-release preparation based on a hydrophobic modified gemcitabine prodrug, and a preparation method and application thereof.
Background
Cancer is the first disease in the world, endangers the life health of people in various countries, and the clinical treatment mode of cancer mainly comprises surgical resection, chemotherapy and radiotherapy. Clinical application proves that single chemotherapy or radiotherapy cannot achieve the best curative effect, but has larger toxic and side effects. The search for an efficient combination therapy has become a current research focus, because the combination therapy can not only improve the curative effect, but also reduce the dosage of drugs or radiation and reduce the toxic and side effects.
Gemcitabine is a deoxycytidine nucleoside analogue, a potent chemotherapeutic drug, and clinically has resistance to various solid tumors, such as pancreatic cancer, breast cancer, ovarian cancer, non-small cell lung cancer and the like, and is the "gold standard" for treating pancreatic cancer. The antitumor mechanism of gemcitabine depends on its series of phosphorylation processes in vivo, and gemcitabine triphosphate can be incorporated into the DNA chain of cells, terminating DNA synthesis, leading to apoptosis, thereby killing tumor cells. However, after entering cells, more than 90% of gemcitabine is rapidly deaminated by deoxycytidine deaminase and thus inactivated, and thus gemcitabine has a very short half-life in vivo, not more than 15 minutes. In order to ensure the efficacy, repeated high-dose injections (1000 mg/m) are often required clinically2Once weekly for 30 minutes for 7 weeks), thereby causing severe toxic side effects and also causing gemcitabine drug resistance. In addition, clinical application proves that gemcitabine is also a powerful radiotherapy sensitizer, the combined use of gemcitabine and radiotherapy can obviously improve the treatment effect of tumors, and the radiotherapy sensitization mechanism of gemcitabine and gemcitabine diphosphate inhibit the synthesis of deoxyadenosine triphosphate and gemcitabine guideResulting in a redistribution of cells into the early S phase. The hydrophobic chain modification of gemcitabine can obviously prolong the plasma half-life of gemcitabine, and meanwhile, micelle entrapment is utilized to change the endocytosis mode of gemcitabine, so that the endocytosis amount of gemcitabine is greatly increased, and the problem of drug resistance of gemcitabine is effectively solved.
In addition, the long-acting sustained-release preparation has been intensively studied for decades, and has the advantages of reducing the administration frequency, reducing side effects, maintaining the blood level to be stable, improving the compliance of patients and the like. The PEG/polyester thermotropic hydrogel is a drug long-acting slow-release carrier with good biocompatibility and injection minimally invasive property. The drug is in a flowable sol state at low temperature, and the drug can be loaded through simple physical mixing, and sol-gel transformation occurs with the increase of temperature to form physical hydrogel. This convenient drug encapsulation process can achieve almost 100% drug loading.
Gemcitabine is a small hydrophilic molecule, and if it is simply mixed into a PEG/polyester hydrogel system, its initial burst release will be caused by rapid diffusion of the drug, which not only reduces the bioavailability of the drug, but also fails to achieve a long-lasting anti-tumor effect. However, the gemcitabine is subjected to fatty acid hydrophobic chain modification to obtain a gemcitabine fatty acid derivative, so that the hydrophobicity of the gemcitabine fatty acid derivative is greatly improved, and after the gemcitabine is encapsulated by the PEG/polyester hydrogel, the medicament and a polymer carrier have hydrophobic interaction, so that the early burst release of the medicament is effectively reduced, and the slow and sustained release effect is realized through slow diffusion and gel degradation of the medicament. The release kinetics of the drug can be regulated and controlled by regulating the composition of the polymer, the length of the hydrophobic chain modified by the drug, the drug loading rate and the like, so that the slow release period of the drug can be designed according to requirements. Furthermore, the gel drug sustained-release preparation is combined with radiotherapy, has the effect of long-term radiotherapy sensitization, can realize the effects of single injection, long-term chemotherapy and multiple times of radiotherapy sensitization, improves the anti-tumor curative effect, reduces the dosage of the radiotherapy, improves the drug utilization rate, reduces the toxic and side effects, and improves the medication compliance of patients.
Disclosure of Invention
The invention discloses a gel drug sustained-release preparation based on a hydrophobic modified gemcitabine derivative, and aims to solve the inherent problem that gemcitabine has short half-life in vivo, the hydrophobic modification is carried out on the gemcitabine, gemcitabine molecules are modified by using a long fatty acid chain, then a PEG/polyester block copolymer thermotropic hydrogel carrier is used for entrapment, the hydrophobic interaction between a drug and a polymer carrier is used for realizing the slow release of the drug in the gel carrier, the drug utilization rate is improved, the long-acting chemotherapy effect is obtained, and meanwhile, the gel drug sustained-release preparation is used together with radiotherapy to realize the purposes of one-time injection, continuous chemotherapy and multiple radiotherapy sensitization. In order to realize the purpose of the invention, the concrete scheme is as follows:
a gel drug sustained-release preparation based on a hydrophobic modified gemcitabine derivative is composed of a block copolymer which is composed of polyethylene glycol as a hydrophilic block and polyester as a hydrophobic block and is used as a gel carrier material, and gemcitabine saturated or unsaturated fatty acid derivative as a carried drug and a solvent, and comprises the following components in percentage by weight:
10-40 wt%, preferably 15-30 wt% of polyethylene glycol-polyester block copolymer;
gemcitabine fatty acid derivatives 0.3-30 μmol/L, preferably 1-10 μmol/L;
the balance being solvent;
the block copolymer composition of the present invention:
(1) the polyethylene glycol has an average molecular weight of 600 to 20000 and a content of 10 to 90 wt.%, preferably 25 to 50 wt.%, and is designated as polymer A block;
(2) the polyester content is from 10 to 90% by weight, preferably from 50 to 75% by weight, and is designated as B polymer block;
(3) the polyester is any one of poly DL-lactide, poly L-lactide, polyglycolide, polyorthoester, poly epsilon-caprolactone, poly epsilon-alkyl substituted caprolactone, poly delta-valerolactone, polyesteramide, polyacrylate, polycarbonate and polyether ester or any form of copolymer of the above aliphatic polyesters;
(4) the gel material is composed of two or more block copolymers as described above, and the polymer of a single component does not necessarily have a property of thermal gelation.
Illustratively, the block copolymer may be a triblock copolymer of ABA type or BAB type, a diblock copolymer of AB type, a graft copolymer of A-g-B or B-g-A type, and (AB)nA multi-block copolymer of type wherein n is an integer from 2 to 10.
Preferably, the gel drug sustained-release preparation of the present invention has injectability, is in a solution state at low temperature, can be converted into a gel state within 1 minute at 4 to 37 ℃, and has a preferred gel transition temperature of 25 to 37 ℃.
In addition, the polymer ratio constituting the gel material in the present invention can be adjusted to obtain desired mechanical strength of the gel, sol-gel transition temperature, degradation rate, and the like.
The polymer composing the gel material in the invention can be any type of copolymer of various aliphatic polyesters, and the proportion of the comonomer can be adjusted, thereby obtaining the required mechanical strength of gel, sol-gel transition temperature, degradation rate and the like.
Preferably, the drug carried by the gel drug sustained-release preparation is gemcitabine saturated or unsaturated fatty acid derivative, the fatty acid chain modification site is located at the amino position of gemcitabine molecule, and the length of fatty acid is 8-20 carbon chain length.
Preferably, the solvent is pure water, physiological saline, buffer solution, tissue culture solution, cell culture solution, body fluid of animals, plants or human bodies, or other aqueous solution or other solvent medium without organic solvent as main body.
Preferably, the gel drug sustained-release preparation also comprises a regulator, and the weight percentage of the regulator in the sustained-release preparation is 0.01-15 wt%; the regulator is selected from one or more of sugar, salt, sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40, Tween 80, xylitol, oligosaccharide, chondroitin, chitin, chitosan, collagen, gelatin, protein gel, hyaluronic acid, and polyethylene glycol.
In addition, the invention also discloses a preparation method of the gel drug sustained-release preparation based on the hydrophobic modified gemcitabine derivative, and the preparation method is selected from one of the following methods:
(1) firstly, mixing two or more than two polymers, and then dissolving the polymer mixture in a solvent at low temperature; finally adding the medicine, dissolving and mixing uniformly to obtain gel injection, and storing at-20 ℃ or below for later use; redissolving and injecting in vivo before use;
(2) firstly, respectively dissolving two or more than two polymers by using a solvent at low temperature, and then mixing respective solutions; finally adding the medicine, dissolving and mixing uniformly to obtain gel injection, and storing at-20 ℃ or below for later use; redissolving and injecting in vivo before use;
(3) dissolving a water-soluble polymer in a solvent at a low temperature, and then adding a polymer which does not have or does not have water solubility completely to solubilize, thereby preparing a hydrogel composition; finally adding the medicine, dissolving and mixing uniformly to obtain gel injection, and storing at-20 ℃ or below for later use; redissolving and injecting in vivo before use;
(4) respectively preparing a block copolymer composition aqueous solution and a medicinal preparation, separately subpackaging and storing, and fully and uniformly mixing the block copolymer composition aqueous solution and the medicinal preparation before injection to prepare a gel medicament sustained-release preparation;
(5) firstly, preparing a medicine injection, then mixing the medicine injection with the block copolymer composition to form a gel injection, and storing the gel injection at the temperature of minus 20 ℃ or below for later use; redissolving and injecting in vivo before use;
(6) mixing the block copolymer composition with the medicine, and then adding a solvent to prepare a gel sustained-release injection; storing at low temperature or in frozen state, and heating for re-dissolving before use.
It should be noted that the four preparation methods have no obvious difference in preparation effect.
Exemplarily, the preparation method of the gel drug sustained-release preparation disclosed by the invention specifically comprises the following steps:
dissolving the amphiphilic block copolymer mixture in the solvent at low temperature, storing at the temperature below-20 ℃ for later use, redissolving in a refrigerator at the temperature of 4 ℃ before use, adding the hydrophobic modified gemcitabine derivative, and uniformly mixing to obtain the gel drug sustained release preparation of the gemcitabine derivative; or mixing the gemcitabine derivative with the copolymer, and then adding a solvent to dissolve at low temperature to prepare the gel sustained-release injection.
Preferably, the low temperature is a temperature not higher than the sol-gel transition temperature of the amphiphilic block copolymer mixture.
The invention also provides application of the gel drug sustained-release preparation or the gel drug sustained-release preparation prepared by the preparation method in preparing tumor drugs.
It should be noted that the gel drug sustained-release preparation is in a solution state at low temperature and is converted into a gel state at 4-37 ℃. The gel composition sustained-release preparation can be independently used as chemotherapy or combined with radiotherapy, can increase the sensitivity of cancer cells to X rays or gamma rays, has the radiation dose of 1-100Gy, and can perform single or multiple sectional irradiation.
The gel composition slow release injection of the invention is injected subcutaneously, intracavity, abdominal cavity, thoracic cavity, vertebral canal, intratumoral, peritumoral, arterial, lymph node and intramedulary.
The gel composition sustained-release preparation can be used for treating various solid tumors, such as primary or secondary tumors of brain tumor, liver cancer, oral cancer, gallbladder cancer, skin cancer, hemangioma, bone cancer, lymph cancer, lung cancer, esophageal cancer, gastric cancer, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, ovarian cancer, endometrial cancer, kidney cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, testicular cancer, head and neck cancer.
According to the technical scheme, compared with the prior art, the gel drug sustained-release preparation based on the hydrophobic modified gemcitabine derivative, the preparation method and the application thereof provided by the invention have the following excellent effects:
(1) the gel drug sustained-release preparation provided by the invention has reversible temperature sensitivity, is in a free-flowing solution state at low temperature or room temperature, and can be subjected to thermoreversible gelation under the physiological condition of a warm-blooded animal, so that the preparation process of the preparation is simple and practical, and the actual operation and application are very convenient.
(2) The gel drug sustained-release preparation provided by the invention is characterized in that the drug carried by the gel drug sustained-release preparation is a hydrophobic modified gemcitabine derivative, the increase of the hydrophobicity of the gemcitabine drug also improves the in-vivo stability of the drug, and the gemcitabine drug can generate hydrophobic interaction with a gel carrier to achieve the purpose of sustained release.
(3) The gel drug sustained release preparation provided by the invention carries a gemcitabine derivative, gemcitabine can be used as an independent chemotherapeutic drug and is also a powerful radio-therapy sensitizer, and the radio-therapy sensitizing property of the gemcitabine derivative is not influenced by hydrophobic modification. The gel composition sustained-release preparation can be independently used as chemotherapy or combined with radiotherapy, can increase the sensitivity of cancer cells to X rays or gamma rays, has a long-term radiotherapy sensitization effect while obtaining a long-acting sustained-release effect, can realize the effects of single injection, long-term chemotherapy and multiple radiotherapy sensitization, improves the anti-tumor curative effect, obviously reduces the dose of the chemotherapy, improves the medicament utilization rate, reduces the toxic and side effects, and improves the medication compliance of patients.
(4) The gel drug sustained release preparation provided by the invention can be administered by injection, after the preparation is gelated in situ in vivo, the encapsulated drug can be slowly released, higher drug concentration can be maintained, the sensitivity of the drug can be increased, and the drug release period can be regulated and controlled from hours to weeks. The injectable temperature-sensitive hydrogel preparation loaded with the gemcitabine derivative can be administrated in a postoperative tumor cavity, can effectively cover an irregular tumor cavity after tumor resection so as to effectively remove postoperative residual tumor cells, and has good prevention effects on postoperative hemostasis and tumor cell diffusion prevention; can also be injected in or around the tumor, has passive targeting function, can effectively reduce the systemic toxicity of the medicine, and can be used for treating tumors at different stages.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a temperature swing dynamic rheology curve for a 25 wt% Polymer-1 block copolymer solution of example 9 of this invention.
FIG. 2 is a temperature swing dynamic rheology profile for a 25 wt% mix-1 block copolymer solution of example 10 of the present invention.
FIG. 3 is a temperature swing dynamic rheology profile for a 25 wt% mix-2 block copolymer solution of example 11 of the present invention.
FIG. 4 is a temperature swing dynamic rheology profile for a 25 wt% mix-3 block copolymer solution of example 12 of the present invention.
FIG. 5 is a temperature-changing dynamic rheological curve of a 25 wt% mix-1 block copolymer solution of example 23 of the present invention mixed with an equimolar concentration of gemcitabine or a different chain length fatty acid derivative thereof.
FIG. 6 is a release profile of a gel formulation of Mixture-1(25 wt%) with gemcitabine (Gem) concentration of 3. mu. mol/L according to the present invention.
FIG. 7 is a release profile of a Mixture-1(25 wt%) gel formulation of the present invention with a concentration of gemcitabine caprylic acid derivative (GemC8) of 3. mu. mol/L.
FIG. 8 is a release profile of a Mixture-1(25 wt%) gel formulation of the present invention with a concentration of gemcitabine palmitic acid derivative (GemC16) of 3. mu. mol/L.
FIG. 9 is a graph showing the change in tumor volume of 4T1 tumor-bearing mice in different treatment groups and a blank control group in example 38 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Bishydroxypolyethylene glycol (PEG1500) was added to a 250mL three-necked flask and water was removed under vacuum at 120 ℃ for 3 hours. Introducing argon GAs, cooling to 80 ℃, adding Lactide (LA), Glycolide (GA) and stannous octoate (containing a small amount of toluene), and vacuumizing at 120 ℃ for 30 minutes. Argon gas is introduced, and the temperature is raised to 150 ℃ for reaction for 12 hours. After the reaction is finished, unreacted monomers and low-boiling-point products in the system are removed by vacuum filtration for 2 hours. Pouring the product into deionized water at 80 ℃ while the product is hot, repeatedly washing for three times, and freeze-drying to obtain the BAB type triblock polymer PLGA-PEG-PLGA with the yield of about 81%. The number average and weight average molecular weights (M) of the above BAB type triblock polymers (PLGA-PEG-PLGA, Copolymer-1) were determined by gel permeation chromatography (GPC, polystyrene as a standard)n，Mw) 5280 and 6340, respectively, molecular weight distribution coefficient (M)n/Mw，
Figure BDA0002302787510000081
) 1.20, the polymer water system thereof had no thermal gelation property.
Example 2
Bishydroxypolyethylene glycol (PEG1000) was added to a 250mL three-necked flask and water was removed under vacuum at 120 ℃ for 3 hours. Introducing argon GAs, cooling to 80 ℃, adding Lactide (LA), Glycolide (GA) and stannous octoate (containing a small amount of toluene), and vacuumizing at 120 ℃ for 30 minutes. Argon gas is introduced, and the temperature is raised to 150 ℃ for reaction for 12 hours. After the reaction is finished, unreacted monomers and low-boiling-point products in the system are removed by vacuum filtration for 2 hours. Pouring the product into deionized water at 80 ℃ while the product is hot, repeatedly washing for three times, and freeze-drying to obtain the BAB type triblock polymer PLGA-PEG-PLGA with the yield of about 87%. The number average and weight average molecular weights (M) of the above BAB type triblock polymers (PLGA-PEG-PLGA, Copolymer-9) were determined by gel permeation chromatography (GPC, polystyrene as a standard)n，Mw) 5210 and 6760, respectively, molecular weight distribution coefficient (M)n/Mw，
Figure BDA0002302787510000082
) 1.30, the polymer water system thereof had no thermal gelation property.
Example 3
Monomethoxypolyethylene glycol (mPEG550) was added to a 250mL three-necked flask and water was removed in vacuo at 120 ℃ for 3 hours. Introducing argon gas, cooling to 80 ℃, adding lactide, glycolide and stannous octoate (containing a small amount of toluene), and vacuumizing for 30 minutes at 120 ℃. Argon gas is introduced, and the temperature is raised to 150 ℃ for reaction for 12 hours. After the reaction is finished, the initial product is dissolved in dichloromethane solution, ether is precipitated, and the AB type diblock polymer mPEG-PLGA is obtained after vacuum drying for 48 hours, wherein the yield is about 80%. The number average and weight average molecular weights (M) of the AB type diblock polymers (mPEG-PLGA, Copolymer-11) were determined by gel permeation chromatography (GPC, polystyrene as a standard)n，Mw) 4680 and 6100, respectively, molecular weight distribution coefficient (M)n/Mw，
Figure BDA0002302787510000083
) 1.30, the polymer water system thereof had no thermal gelation property.
Example 4
Monomethoxypolyethylene glycol (mPEG550) was added to a 250mL three-necked flask and water was removed in vacuo at 120 ℃ for 3 hours. Introducing argon gas, cooling to 80 ℃, adding lactide, glycolide and stannous octoate (containing a small amount of toluene), and vacuumizing for 30 minutes at 120 ℃. Argon gas is introduced, and the temperature is raised to 150 ℃ for reaction for 12 hours. And then dissolving the two-block copolymer in anhydrous toluene, adding 1/2 equivalents of HDMI of mPEG, carrying out reflux reaction at 60 ℃ for 8 hours, carrying out rotary evaporation and concentration, settling in a large amount of glacial ethyl ether, and carrying out vacuum drying for 48 hours to obtain the ABA type triblock polymer mPEG-PLGA-mPEG with the yield of about 70%. The number average and weight average molecular weights (M) of the ABA type triblock polymer (mPEG-PLGA-mPEG, Copolymer-4) were determined by gel permeation chromatography (GPC, polystyrene as a standard)n，Mw) 3150 and 3800, respectively, molecular weight distribution coefficient (M)n/Mw,
Figure BDA0002302787510000092
) 1.21, the polymer in water system has thermal gelationAnd (4) performance.
Example 5
Following the basic procedure given in examples 1-4, other block copolymers were synthesized using different molecular weight PEGs or mPEG with different monomers, the properties of which are shown in tables 1, 2 and 3:
TABLE 1
Figure BDA0002302787510000091
Figure BDA0002302787510000101
The above-mentioned polymer aqueous system has no thermogelation property, and can be dissolved in water at 0-50 deg.C to form stable solution, but can not produce sol-gel transition.
TABLE 2
Figure BDA0002302787510000102
Figure BDA0002302787510000111
The polymers in the above tables are not or only partially soluble in water at the respective temperatures and therefore also do not have thermogelling properties.
TABLE 3
Figure BDA0002302787510000112
The block polymers in the above table are not only soluble in water, but also capable of undergoing a reversible sol-gel transition with increasing temperature, i.e., have thermotropic gelation properties.
In accordance with the basic fact of the present invention, one or more block copolymers selected from Table 1 are physically mixed with one or more block copolymers of Table 2 in a ratio such that the mixture is soluble in water at low temperature to form a homogeneous solution and at elevated temperature to form a physical gel having the reversible sol-gel phase transition properties of the present invention as described above. Similarly, one or more block copolymers selected from table 1 and/or table 2 can be physically mixed with one or more block copolymers in table 3 according to a certain ratio, and the mixture also has reversible sol-gel phase transition property, and can be used for encapsulating gemcitabine fatty acid derivatives to achieve long-acting sustained release effect of the series of drugs.
Example 6
Dissolving 1mmol of gemcitabine base in 4mL of deionized water in a 100mL round bottom flask, adding 2mmol of caprylic anhydride dissolved in 16mL of 1, 4-dioxane in advance after complete dissolution, refluxing for 48h, removing the solvent by rotary evaporation after the reaction is finished, eluting the residual liquid with a silica gel column (eluent: dichloromethane/ethanol ═ 96/4), collecting the filtrate, and obtaining pure gemcitabine caprylic acid derivative (GemC8) by rotary evaporation and vacuum drying with the yield of 78%.
Example 7
1mmol gemcitabine base was dissolved in 4mL deionized water in a 100mL round bottom flask, after complete dissolution, 2mmol palmitic anhydride dissolved in 16mL 1, 4-dioxane in advance was added, the mixture was refluxed for 48 hours, after the reaction was completed, the solvent was removed by rotary evaporation, the residue was rinsed with silica gel column (eluent: dichloromethane/ethanol ═ 96/4), the filtrate was collected, and pure gemcitabine palmitic acid derivative (GemC16) was obtained by rotary evaporation and vacuum drying, with a yield of 83%.
Example 8
Dissolving 1mmol of gemcitabine base in 4mL of deionized water in a 100mL round bottom flask, adding 2mmol of eicosanoic anhydride dissolved in 16mL of 1, 4-dioxane in advance after complete dissolution, refluxing for 48h, removing the solvent by rotary evaporation after the reaction is finished, eluting the residual liquid with a silica gel column (eluent: dichloromethane/ethanol ═ 96/4), collecting the filtrate, and obtaining pure gemcitabine eicosanoic acid derivative (GemC20) by rotary evaporation and vacuum drying with the yield of 87%.
Example 9
Physiological saline is used as a solvent to prepare a 25 wt% Polymer-1 block copolymer solution, and a rotational rheometer is adopted to measure the change of rheological properties such as storage modulus, loss modulus and the like of a Polymer water system along with the temperature. The temperature sweep was performed at a fixed shear frequency (f: 1.592Hz) with a heating rate of 0.5 ℃/min and the results are reported in fig. 1. As shown in FIG. 1, a 25 wt% Polymer-1 Polymer solution has no intersection point of storage modulus and loss modulus at the test temperature, cannot undergo sol-gel phase transition, and thus has no thermogelation property.
Example 10
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 1:2, and a mixed Polymer physiological saline solution mix-1 was prepared at a concentration of 25 wt% using physiological saline as a vehicle. The rheological properties such as storage modulus and loss modulus of the polymer aqueous system were measured as a function of temperature using a rotational rheometer according to example 9, and the results are shown in FIG. 2. As shown in FIG. 2, the intersection point of the storage modulus and the loss modulus of a 25 wt% Mixture-1 polymer solution at the test temperature shows that the polymer solution can generate sol-gel phase transition and has the property of thermal gelation, and the phase transition temperature is the intersection point temperature of the storage modulus and the loss modulus, namely 28 ℃.
Example 11
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 1:1, and a mixed Polymer physiological saline solution mix-2 was prepared at a concentration of 25 wt% using physiological saline as a vehicle. The rheological properties such as storage modulus and loss modulus of the polymer aqueous system were measured as a function of temperature using a rotational rheometer according to example 9, and the results are recorded in FIG. 3. As shown in FIG. 3, the intersection point of the storage modulus and the loss modulus at the test temperature of the 25 wt% Mixture-2 polymer solution shows that the polymer solution can generate sol-gel phase transition and has the property of thermal gelation, and the phase transition temperature is 32 ℃.
Example 12
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 2:1, and a mixed Polymer physiological saline solution mix-3 of 25 wt% was prepared using physiological saline as a vehicle. The rheological properties such as storage modulus and loss modulus of the polymer aqueous system were measured as a function of temperature using a rotational rheometer according to example 9, and the results are recorded in FIG. 4. As shown in FIG. 4, the intersection point of the storage modulus and the loss modulus at the test temperature of the 25 wt% Mixture-3 polymer solution shows that the polymer solution can generate sol-gel phase transition and has the property of thermal gelation, and the phase transition temperature is 37 ℃.
Example 13
Polymer-2 of Table 1 of example 5 and Polymer-16 of Table 3 were blended at a ratio of 1:1, and a mixed Polymer physiological saline solution mix-4 of 25 wt% was prepared using physiological saline as a vehicle. The change of rheological properties such as storage modulus and loss modulus of the polymer aqueous system with temperature was measured by a rotational rheometer according to example 9. The results show that the intersection point of the storage modulus and the loss modulus of the 25 wt% Mixture-4 polymer solution at the test temperature shows that the polymer solution can generate sol-gel phase transition and has the property of thermal gelation, and the phase transition temperature is 34 ℃.
Example 14
Polymer-13 of Table 2 of example 5 and Polymer-21 of Table 3 were blended at a ratio of 1:1, and mixed Polymer physiological saline solution mix-5 was prepared at a concentration of 25 wt% using physiological saline as a vehicle. The change of rheological properties such as storage modulus and loss modulus of the polymer aqueous system with temperature was measured by a rotational rheometer according to example 9. The results show that the intersection point of the storage modulus and the loss modulus of the 25 wt% Mixture-5 polymer solution at the test temperature shows that the polymer solution can generate sol-gel phase transition and has the property of thermal gelation, and the phase transition temperature is 31 ℃.
Example 15
Polymer-4 of Table 1 of example 5 and Polymer-16 of Table 3 were blended at a ratio of 1:1, and mixed Polymer physiological saline solution mix-6 was prepared at a concentration of 25 wt% using physiological saline as a vehicle. The change of rheological properties such as storage modulus and loss modulus of the polymer aqueous system with temperature was measured by a rotational rheometer according to example 9. The results show that the intersection point of the storage modulus and the loss modulus of the 25 wt% Mixture-6 polymer solution at the test temperature shows that the polymer solution can generate sol-gel phase transition and has the property of thermal gelation, and the phase transition temperature is 35 ℃.
Example 16
Polymer-11 of Table 2 of example 5 and Polymer-15 of Table 3 were blended at a ratio of 1:1, and mixed Polymer physiological saline solution mix-7 was prepared at a concentration of 25 wt% using physiological saline as a vehicle. The change of rheological properties such as storage modulus and loss modulus of the polymer aqueous system with temperature was measured by a rotational rheometer according to example 9. The results show that the intersection point of the storage modulus and the loss modulus of the 25 wt% Mixture-7 polymer solution at the test temperature shows that the polymer solution can generate sol-gel phase transition and has the property of thermal gelation, and the phase transition temperature is 28 ℃.
Example 17
Polymer-2 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 1:2, and a 25 wt% aqueous solution of the Polymer Mixture-1 was prepared using physiological saline as a vehicle, and was sterilized by filtration through a 0.22 μm sterile filter head. About 0.2mL of the solution was taken, and the solution was injected subcutaneously into the back of a mouse under anesthesia using an ICR mouse as a model experimental animal. Mice were sacrificed at regular intervals and the degradation of the composition gel in the mice was followed. The results show that the injectable material can be degraded in vivo for seven weeks, after which no visible gel is visible. Meanwhile, the injection part does not have the phenomena of edema, tissue necrosis and the like in the experimental process.
Example 18
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 1:1, and a 25 wt% aqueous solution of the Polymer Mixture-2 was prepared using physiological saline as a vehicle, and was sterilized by filtration through a 0.22 μm sterile filter head. About 0.2mL of the solution was taken, and the solution was injected subcutaneously into the back of a mouse under anesthesia using an ICR mouse as a model experimental animal. Mice were sacrificed at regular intervals and the degradation of the composition gel in the mice was followed. The results show that the injectable material can be degraded in vivo for five weeks, after which no visible gel is present. Meanwhile, the injection part does not have the phenomena of edema, tissue necrosis and the like in the experimental process.
Example 19
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 2:1, and a 25 wt% aqueous solution of the Polymer Mixture-2 was prepared using physiological saline as a vehicle, and was sterilized by filtration through a 0.22 μm sterile filter head. About 0.2mL of the solution was taken, and the solution was injected subcutaneously into the back of a mouse under anesthesia using an ICR mouse as a model experimental animal. Mice were sacrificed at regular intervals and the degradation of the composition gel in the mice was followed. The results show that the injectable material can be degraded in vivo for three weeks, after which no visible gel is present. Meanwhile, the injection part does not have the phenomena of edema, tissue necrosis and the like in the experimental process.
Example 20
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 1:2, and a mixed Polymer physiological saline solution was prepared at a concentration of 25 wt% using physiological saline as a vehicle. Then adding Gem drug of 3 μmol/L, dissolving uniformly to obtain gel drug sustained release preparation, storing at-20 deg.C or below for use, and re-dissolving before use.
Example 21
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 1:2, and a mixed Polymer physiological saline solution was prepared at a concentration of 25 wt% using physiological saline as a vehicle. Then adding 3 mu mol/L GemC8 medicine, dissolving uniformly to obtain gel medicine sustained release preparation, storing at-20 deg.C or below for use, and re-dissolving before use.
Example 22
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 1:2, and a mixed Polymer physiological saline solution was prepared at a concentration of 25 wt% using physiological saline as a vehicle. Then adding 3 mu mol/L GemC16 medicine, dissolving uniformly to obtain gel medicine sustained release preparation, storing at-20 deg.C or below for use, and re-dissolving before use.
Example 23
The drug-loaded polymer solutions of example 20, example 21 and example 22 were taken to be about 1mL, and the changes of rheological properties such as storage modulus, loss modulus and the like of the polymer water system after drug loading were measured with a rotational rheometer according to example 9. As shown in FIG. 5, the addition of the drug did not change the thermal gelation temperature and gel strength of the polymer aqueous system.
Example 24
0.5g of the Gem drug-loaded polymer solution of example 20 was added to a glass release tube, placed in a 37 ℃ water bath shaker for 15min to gel, then 5mL of a phosphate buffer (containing 1.0 wt% of Tween 80, 1.0 wt% of sodium dodecylsulfate and 0.025 wt% of sodium azide, pH7.4) was slowly added, sampling was performed periodically, the concentration of the drug in the release sample was measured by high performance liquid chromatography, and the cumulative release profile of the drug was calculated as shown in FIG. 6, with Gem being substantially completely released in three days.
Example 25
0.5g of the polymer solution loaded with GemC8 drug of example 21 was added to a glass release tube, placed in a 37 ℃ water bath shaker for 15min to gel, then 5mL of phosphate buffer (containing 1.0 wt% Tween 80, 1.0 wt% sodium dodecylsulfate and 0.025 wt% sodium azide, pH7.4) was slowly added, sampling was performed periodically, the concentration of the drug in the release sample was detected by high performance liquid chromatography, and the cumulative release profile of the drug was calculated to be as shown in FIG. 7, with the GemC8 release period extending to about three weeks.
Example 26
0.5g of the polymer solution loaded with GemC16 drug of example 22 was added to a glass release tube, placed in a 37 ℃ water bath shaker for 15min to gel, then 5mL of phosphate buffer (containing 1.0 wt% Tween 80, 1.0 wt% sodium dodecylsulfate and 0.025 wt% sodium azide, pH7.4) was slowly added, sampling was performed periodically, the concentration of the drug in the release sample was detected by high performance liquid chromatography, and the cumulative release profile of the drug was calculated to be as shown in FIG. 8, with a GemC16 release period of more than one month.
Example 27
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 1:2, and a mixed Polymer physiological saline solution was prepared at a concentration of 25 wt% using physiological saline as a vehicle. Then adding 3 mu mol/L GemC20 medicine, dissolving uniformly to obtain gel medicine sustained release preparation, adding 0.5g medicine-carrying polymer solution into a glass release tube, placing in a water bath shaker at 37 ℃ for 15min to gelatinize, slowly adding 5mL phosphate buffer (containing 1.0 wt% of Tween 80, 1.0 wt% of sodium dodecyl sulfate and 0.025 wt% of sodium azide, pH7.4), sampling periodically, detecting the concentration of the medicine in the release sample by high performance liquid chromatography, and the result shows that the release period of GemC20 reaches more than 6 weeks.
Example 28
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 1:2, and a mixed Polymer physiological saline solution was prepared at a concentration of 25 wt% using physiological saline as a vehicle. Then 0.3 mu mol/L GemC16 drug is added to be dissolved evenly to form a gel drug sustained release preparation, 0.5g drug-loaded polymer solution is added into a glass release tube, the glass release tube is placed in a water bath shaker at 37 ℃ for 15min to be gelatinized, 5mL phosphate buffer solution (containing 1.0 wt% of Tween 80, 1.0 wt% of sodium dodecyl sulfate and 0.025 wt% of sodium azide, pH7.4) is slowly added, sampling is carried out periodically, the concentration of the drug in the release sample is detected by high performance liquid chromatography, and the result shows that the GemC16 release period is more than 4 weeks.
Example 29
Polymer-1 obtained in example 1 and Polymer-9 obtained in example 2 were blended at a ratio of 1:2, and a mixed Polymer physiological saline solution was prepared at a concentration of 25 wt% using physiological saline as a vehicle. Then adding 30 mu mol/L GemC16 drug, dissolving uniformly to obtain gel drug sustained release preparation, adding 0.5g drug-loaded polymer solution into a glass release tube, placing in a water bath shaker at 37 ℃ for 15min to gelatinize, slowly adding 5mL phosphate buffer (containing 1.0 wt% of Tween 80, 1.0 wt% of sodium dodecyl sulfate and 0.025 wt% of sodium azide, pH7.4), sampling periodically, detecting the concentration of the drug in the release sample by high performance liquid chromatography, and the result shows that the release period of GemC16 reaches more than 6 weeks.
Example 30
The mixed polymer physiological saline solution mix-4 obtained in the example 13 is added with 3 mu mol/L GemC16 drug, the gel drug sustained release preparation is formed after even dissolution, 0.5g drug-loaded polymer solution is added into a glass release tube, the glass release tube is placed in a water bath shaker for 15min at 37 ℃ to be gelatinized, 5mL phosphate buffer solution (containing 1.0 wt% of Tween 80, 1.0 wt% of sodium dodecyl sulfate and 0.025 wt% of sodium azide and pH7.4) is slowly added, sampling is carried out periodically, the concentration of the drug in the release sample is detected by high performance liquid chromatography, and the result shows that the release period of GemC16 is more than 6 weeks.
Example 31
The mixed polymer physiological saline solution mix-5 obtained in the example 14 is added with 3 mu mol/L GemC16 drug, the gel drug sustained release preparation is formed after even dissolution, 0.5g drug-loaded polymer solution is added into a glass release tube, the glass release tube is placed in a water bath shaker for 15min at 37 ℃ to be gelated, 5mL phosphate buffer solution (containing 1.0 wt% of Tween 80, 1.0 wt% of sodium dodecyl sulfate and 0.025 wt% of sodium azide, pH7.4) is slowly added, sampling is carried out periodically, the concentration of the drug in the release sample is detected by high performance liquid chromatography, and the result shows that the release period of GemC16 is more than 4 weeks.
Example 32
The mixed polymer physiological saline solution mix-6 obtained in the example 15 is added with 3 mu mol/L GemC16 drug, the gel drug sustained release preparation is formed after even dissolution, 0.5g drug-loaded polymer solution is added into a glass release tube, the glass release tube is placed in a water bath shaker for 15min at 37 ℃ to be gelated, 5mL phosphate buffer solution (containing 1.0 wt% of Tween 80, 1.0 wt% of sodium dodecyl sulfate and 0.025 wt% of sodium azide, pH7.4) is slowly added, sampling is carried out periodically, the concentration of the drug in the release sample is detected by high performance liquid chromatography, and the result shows that the release period of GemC16 is more than 5 weeks.
Example 33
The drug-loaded gel drug sustained release preparation in example 26 is added with 1% of sucrose regulator to regulate the drug release rate, and the in vitro release of the drug can be realized for more than 4 weeks.
Example 34
The drug-loaded gel drug sustained release preparation in example 26 is added with 5% of polyethylene glycol 400 regulator to regulate the drug release rate, and the in vitro release of the drug for more than 3 weeks can be realized.
Example 35
The drug-loaded gel drug sustained release preparation in example 26 is added with 2% sorbitol regulator to regulate the drug release rate, and the in vitro release of the drug can be realized for more than 30 days.
Example 36
The drug-loaded gel drug sustained release preparation in example 26 was added with 5% mannitol regulator to regulate the drug release rate, and the drug release in vitro for more than 3 weeks could be achieved.
Example 37
The drug-loaded gel drug sustained-release preparation in example 26 is added with 8% xylitol regulator to regulate the drug release rate, and the in-vitro release of the drug can be realized for more than 3 weeks.
Example 38
Injecting 4T1 mouse-derived breast cancer cells into a mouse breast pad by taking Balb/c nude mice as model animals to form a tumor-bearing mouse until the tumor grows to about 80mm3Thereafter, 0.2mL of the gel preparation loaded with Gem in example 24 or with GemC16 in example 26 was injected peritumorally, while the blank gel not loaded with drug was used as a control, and 24 hours later, tumor sites of mice to which the gel drug sustained-release preparation containing Gem and GemC16 drugs was injected were locally irradiated with X-rays at a dose of 5 Gy/mouse once a week for three weeks. The results of this example show that the gemcitabine fatty acid derivative loaded gel drug sustained release preparation can effectively inhibit the growth of 4T1 tumor when used alone, and when used in combination with radiotherapy, has an obvious chemoradiotherapy synergistic effect, indicating that it has a long-acting radiotherapy sensitization effect, and the results are recorded in fig. 9; immunohistochemical staining analysis shows that the compound gel preparation has no obvious toxic side effect. Two groups of data are significantly different, and p<0.05, represents a significant difference between the two data sets, and p<0.01; represents that two groups of data have significant difference, and p<0.001; represents that two groups of data have significant difference, and p<0.0001。
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other. The method disclosed by the embodiment corresponds to the method disclosed by the embodiment, so that the description is simple, and the relevant points can be referred to the description of the method part.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (10)

1. A gel drug sustained release preparation based on a hydrophobically modified gemcitabine derivative, comprising: 10-40 wt% of gel carrier material, 0.3-30 mu mol/L of hydrophobic modified gemcitabine derivative and the balance of solvent; the gel carrier material is an amphiphilic block copolymer which is composed of polyethylene glycol as a hydrophilic block and polyester as a hydrophobic block; the hydrophobic modified gemcitabine derivative is a gemcitabine fatty acid derivative, the fatty acid chain modification site is located at the amino position of the gemcitabine molecule, and the fatty acid chain length is 8 to 20 carbons.
2. The gel drug sustained-release preparation based on the hydrophobically modified gemcitabine derivative as claimed in claim 1, wherein the content of the hydrophobically modified gemcitabine derivative in the gel drug sustained-release preparation is 1-10 μmol/L.
3. The gel drug delivery formulation of claim 1, wherein the gel carrier material is present in an amount of 15-30 wt% of the gel drug delivery formulation; in the gel carrier material, the average molecular weight of the polyethylene glycol is 600-20000, and the content is 10-90 wt%; the content of the polyester is 10-90 wt%, and the polyester is selected from one of poly DL-lactide, poly L-lactide, polyglycolide, polyorthoester, poly epsilon-caprolactone, poly epsilon-alkyl substituted caprolactone, poly delta-valerolactone, polyesteramide, polyacrylate, polycarbonate and polyetherester; and the gel carrier material is formed by mixing at least two block copolymers.
4. The gel drug sustained-release preparation based on the hydrophobically modified gemcitabine derivative as claimed in claim 1, wherein the solvent is pure water, physiological saline, buffer solution, tissue culture fluid, cell culture fluid, animal or plant body fluid or other solvent medium without organic solvent as main component.
5. The gel drug sustained-release preparation based on the hydrophobically modified gemcitabine derivative as claimed in claim 1, further comprising a modifier; the content of the regulator in the gel drug sustained-release preparation is 0.01-15 wt%, and the regulator is selected from one or more of sugar, salt, sodium carboxymethylcellulose, iodoglycerol, dimeticone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, tween 20, tween 40, tween 80, xylitol, oligosaccharide, chondroitin, chitin, chitosan, collagen, gelatin, protein glue, hyaluronic acid and polyethylene glycol.
6. A method for preparing the hydrophobic modified gemcitabine derivative based gel drug sustained release formulation of claim 1, comprising the steps of:
dissolving the gel carrier material in the solvent at low temperature, storing at the temperature below-20 ℃ for later use, re-dissolving the gel carrier material dissolved in the solvent in a refrigerator at the temperature of 4 ℃ before use, adding the hydrophobic modified gemcitabine derivative, and uniformly mixing to obtain the gel drug sustained release preparation of the gemcitabine derivative.
7. The method for preparing a hydrophobic modified gemcitabine derivative based gel drug sustained release formulation as claimed in claim 6, wherein the low temperature is a temperature not higher than the sol-gel transition temperature of the amphiphilic block copolymer mixture.
8. Use of the hydrophobically modified gemcitabine derivative-based gel-drug delivery formulation of claim 1 or the gel-drug delivery formulation prepared by the method of claim 6 for the preparation of a tumor drug.
9. The use of the hydrophobic modified gemcitabine derivative based gel sustained release formulation of claim 8, wherein the tumor drug comprises two application forms of the drug used as chemotherapy drug alone or as a combined drug of radiotherapy and chemotherapy.
10. The use of a hydrophobically modified gemcitabine derivative based gel drug delivery formulation as claimed in claim 8, wherein the gel drug delivery formulation is in solution at low temperature and changes to gel at 4-37 ℃.
CN201911228075.4A 2019-12-04 2019-12-04 Gel drug sustained-release preparation based on hydrophobic modified gemcitabine derivative and preparation method and application thereof Pending CN111110626A (en)

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