KR101670249B1 - Drug Delivery Systems for Cancer Therapy and Preparation Method Thereof - Google Patents
Drug Delivery Systems for Cancer Therapy and Preparation Method Thereof Download PDFInfo
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- KR101670249B1 KR101670249B1 KR1020160017558A KR20160017558A KR101670249B1 KR 101670249 B1 KR101670249 B1 KR 101670249B1 KR 1020160017558 A KR1020160017558 A KR 1020160017558A KR 20160017558 A KR20160017558 A KR 20160017558A KR 101670249 B1 KR101670249 B1 KR 101670249B1
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- A61K9/00—Medicinal preparations characterised by special physical form
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
Abstract
The present invention relates to an anticancer drug delivery system and a method for preparing the same, and more particularly, to an anticancer drug delivery system applied to a tumor tissue site or a tumor removal site and converted into a gel and firmly attached to release an anticancer drug. will be.
Description
The present invention relates to an anticancer drug delivery system and a method for preparing the same, and more particularly, to an anticancer drug delivery system which is applied to a tumor tissue site or a tumor removal site and is converted into a gel, .
The chemotherapy regimen developed so far has been carried out in an extremely limited range, and the anticancer drug also acts on normal cells and has many side effects. Therefore, research is being conducted to develop an anticancer drug that selectively acts on cancer cells without affecting normal cells. The first research direction is to manufacture an anticancer drug-polymer complex that links an anticancer drug to a polymer, and the second is to use a transmucosal drug delivery system.
The anticancer drug-polymer complex can treat cancer cells using the pathophysiological characteristics of cancer tissues different from normal cells. Generally, cancer tissues generate more blood vessels than normal tissues in order to receive more nutrients than normal tissues, and they have a large and loose structure. Therefore, the polymer constituting the complex is more easily penetrated into cancer tissues than normal tissues or organs and is not easily released from cancer tissues. The characteristic phenomenon of such cancer tissues is called EPR (enhanced permeability and retention) effect. However, in the case of the anticancer drug-polymer complex, the range of the molecular weight of the applied polymer and the dosage regimen are limited. In most cases, the drug is required to react in the organic solvent, which may cause toxicity, biocompatibility, There is a drawback that it is not easy to remove from the body.
Since the transmucosal delivery system exhibits rapid drug clearance as well as rapid drug efficacy in the systemic or localized manner by administration of the drug, the bioavailability of the drug is lowered . Most anticancer drugs work by inhibiting the synthesis of hexane, the body of intracellular genes, or by directly binding to hexane and impairing its function. However, the current method of administration of anticancer drugs does not selectively act on cancer cells only in the process of injecting vasculogenic mucous membranes, but also damages normal cells, particularly, tissue cells that are active in cell division, resulting in various side effects such as bone marrow dysfunction, gastrointestinal mucosal injury, and hair loss . That is, the above-described problems arise because accurate injection and release are not achieved at the target site.
In addition, studies have been made to increase the solubility and water absorption of anticancer drugs and to develop micelles or emulsions using a surfactant such as
The present invention provides a new type of anticancer drug delivery system having a function of preventing cancer metastasis through microvascularization by acting as a chemotherapeutic agent and forming artificial barriers by being applied to a lesion such as a tumor tissue site or a tumor removal site .
It is another object of the present invention to provide a method for producing the above-mentioned anticancer drug delivery system.
In order to solve the above problems, the present invention provides a pharmaceutical composition comprising an anticancer drug; A hydrogel polymer containing the drug inside the core; And a temperature-sensitive polymer which is converted into a gel in the body; An anticancer drug delivery system.
According to a preferred embodiment of the present invention, the drug delivery vehicle comprises from 0.6 to 2.2% by weight of an anticancer drug; 6.2 to 21.7% by weight of a hydrogel polymer containing the drug in the core; And 76.1 to 93.2% by weight of a temperature-sensitive polymer which is converted into a gel in the body; May be included.
According to a preferred embodiment of the present invention, the anticancer drug is selected from the group consisting of cyclophosphamide, Ifosfamide, Procarbazine, Busulfan, Carmustine, Lomustine, Dacarbazine, Cisplatin, Methotrexate, 5-Fluorouracil, Capecitabine, Cytosine Arabinoside, Gemcitabine ), Vinblastine, vincristine, paclitaxel, docetaxel, etoposide, topotecan, irinotecan, mitomycin-C Doxorubicin, Bleomycin, L-asparaginase, Hydroxyurea, Rituximab, Trastuzumab, and the like, Imatinib, Pitti nip (Gefitinib), Ilo tinip (Erlotinib), may be at least one member selected from the group consisting of pharmaceutically acceptable salts and hydrates.
According to a preferred embodiment of the present invention, the hydrogel polymer may be prepared by hydrogeling a crosslinked polymer formed by crosslinking a hydrophilic polymer having a hydroxy functional group and a crosslinking agent having an epoxy functional group.
According to a preferred embodiment of the present invention, the hydrophilic polymer having a hydroxy functional group has a weight average molecular weight of 10,000 to 1,000,000 g / mol, and is selected from the group consisting of alginic acid, hyaluronic acid, dextran, hydroxypropyl methylcellulose, carboxymethylcellulose, A salt of an alkali metal or an alkaline earth metal.
According to a preferred embodiment of the present invention, the crosslinking agent having an epoxy functional group is selected from the group consisting of epichlorohydrin, epibromohydrin, butanediol diglycidyl ether, ethylene glycol diglycidyl ether, hexanediol diglycidyl ether, propylene Glycol diglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether , Diglycerol polyglycidyl ether, polyglycerol polyglycidyl ether, glycerol polyglycidyl ether, trimethylpropane polyglycidyl ether, bis (epoxypropoxy) ethylene, pentaerythritol polyglycidyl ether, and Sorbitol polyglycidyl ether, and sorbitol polyglycidyl ether.
According to a preferred embodiment of the present invention, the temperature-sensitive polymer has a weight average molecular weight of 500 to 500,000 g / mol and is a polymer containing an ether functional group, and may be a poly (ethylene oxide), a poly (ethylene oxide-propylene oxide) random copolymer , Poly (ethylene glycol) -poly (L-lactic acid) -poly (ethylene glycol), alkylated polyethylene oxide block copolymer and poly (vinyl methyl ether) May be at least one selected from the group consisting of
According to a preferred embodiment of the present invention, the drug delivery vehicle can be applied directly to the tumor tissue site or the tumor removal site.
According to a preferred embodiment of the present invention, the drug delivery vehicle may have a function of preventing the metastasis of cancer through microvessels by being applied to a tumor removal site to form a function of an anticancer drug and artificial barrier.
According to a preferred embodiment of the present invention, the drug delivery vehicle can be formulated as a liquid, powder or film.
Another aspect of the present invention relates to a method for preparing an anticancer drug delivery system,
(Step 1) A first step of preparing a crosslinked polymer having ether crosslinking by reacting a hydrophilic polymer having a hydroxy functional group with a crosslinking agent having an epoxy functional group;
(Step 2) A second step of mixing an anticancer drug and a temperature-sensitive polymer which is converted into a gel in the body, and stirring the mixture at a temperature of 40 to 60 ° C to pretreat the anticancer drug; And
(Step 3) A third step of preparing an anticancer drug delivery system by mixing the cross-linked polymer prepared in the first step and the anticancer drug pretreated in the second step and hydrogeling at 60 to 110 ° C .; The method comprising the steps of: preparing a drug delivery vehicle;
The drug delivery system of the present invention has an effect of reducing side effects of anticancer drug because it is applied to a site such as a tumor tissue site or a tumor removal site so that an anticancer drug contained in the hydrogel polymer is slowly released and has little effect on normal cells have.
The drug delivery system of the present invention has an effect of preventing cancer metastasis through microvessels by being applied to the affected part and then being converted into gel by body temperature to form artificial barrier.
1 is a cryo-TEM analysis of the anticancer drug delivery system of the present invention.
FIG. 2 is a graph showing a process in which the anticancer drug delivery system of the present invention is changed from a sol to a gel to release an anticancer drug.
3 is a graph showing the results of confirming the growth of a precipitate (crystal of an anticancer drug) while preserving the drug delivery vehicle of the present invention for 14 days under an aqueous solution condition.
4 is a photograph showing changes in the state of the reaction solution before and after the hydro-gelling reaction.
FIG. 5 is a graph comparing the plasma concentration of docetaxel with time in the method of directly administering the anticancer drug delivery vehicle of the present invention to the tumor removal site (5 mg / kg) and the method of administering the anticancer drug in an intravenous administration (5 mg / kg) It is a graph.
6 is a graph comparing MTT analysis results of a drug delivery vehicle, a positive control (Teflon) and a sodium carboxymethyl cellulose (SCMC) polymer eluent, from which an anticancer drug is removed.
The present invention relates to an anticancer drug delivery system and a method for producing the same.
The anticancer drug delivery vehicle according to the present invention may be an anticancer drug; A hydrogel polymer containing the drug inside the core; And a temperature-sensitive polymer which is converted into a gel in the body; .
In the case of the hydrogel polymer constituting the anticancer drug delivery vehicle according to the present invention, the anticancer drug is contained in the core of the hydrogel to transport the anticancer drug to the tumor site or the tumor site. In addition, the temperature-sensitive polymer is gelated by body temperature at the lesion and serves to intensively inject anticancer drugs into the target site.
That is, the anticancer drug delivery vehicle according to the present invention is a drug delivery vehicle for targeting an anticancer drug to the affected part, achieves 'passive targeting' by a hydrogel polymer having a core in which a drug can be contained, &Quot; Active targeting " can be achieved by the sensitive polymer.
The 'manual targeting' in the present invention can be achieved by the hydrogelation reaction of the crosslinked polymer. The crosslinked polymer in the present invention is prepared by cross-linking a hydrophilic polymer having a hydroxy functional group with a crosslinking agent having an epoxy functional group. The crosslinked polymer is composed of a hydrophobic part of the carbon chain constituting the main backbone and a hydrophilic part in which the hydroxy functional group is distributed. Accordingly, during the hydrogeling reaction of the crosslinked polymer, the anticancer drug having hydrophobicity is densely packed inside the hydrophobic part of the crosslinked polymer and the hydrophilic group is directed to the outside, so that the anticancer drug is wrapped in the crosslinked polymer by the hydrophobic-hydrophobic interaction between them, Core-shell " structure. That is, the anticancer drug constitutes a core by the hydrogelation reaction, and the core is surrounded by the crosslinking polymer to form a shell, thereby achieving manual targeting. In addition, the hydrogel polymer of the present invention is hydrophilic due to distribution of hydroxy functional groups on the surface of the shell, thereby protecting the anticancer drug from various immune mechanisms in the human body.
The 'active targeting' in the present invention can be achieved by a temperature-sensitive polymer having a property of being gelled and adhered by body temperature at the affected part.
In addition, the temperature-sensitive polymer acts as a passive targeting agent for releasing the anticancer drug by physical force in addition to the active targeting function of fixing the anticancer drug to the desired lesion, thereby intensively administering the drug to the affected part. When the temperature-sensitive polymer is gelled by body temperature, the overall volume of the drug delivery system is gradually reduced, and the anticancer drug contained in the core of the hydrogel polymer is slowly released through the gel wall due to the contracting pressure.
Thus, the anticancer drug delivery system according to the present invention releases the anticancer drug to the affected part by the physical and chemical double sustained release system. For example, when an anticancer drug delivery vehicle is applied to the affected part, the temperature sensitive polymer is first gelled by body temperature, and the anticancer drug contained in the hydrogel core is gradually released by physical force. When the temperature sensitive polymer is discharged to the outside of the body, the hydrogel polymer is hydrolyzed secondarily and the anticancer drug contained in the core is gradually released. Therefore, the anticancer drug delivery system according to the present invention has a double sustained release system.
In addition, the anticancer drug delivery system according to the present invention can be applied to lesions in which tumors have been removed, thereby increasing the probability of cure through continuous chemotherapy, and also forming artificial barriers to prevent cancer metastasis by microvessels .
If the tumor is incompletely resected through surgery, the cancer cells will penetrate into the new blood vessels and migrate to other organs or tissues. Then, the cancer cells begin to divide and multiply again, and after a certain period of time, do. Therefore, although chemotherapy is important for cancer, it is also very important to inhibit the transfer of cancer cells to other organs or tissues. From this point of view, the anticancer drug delivery system of the present invention is of great significance in that it has a function of inhibiting cancer metastasis in addition to the anticancer therapy function.
In addition, the anticancer drug delivery vehicle according to the present invention can be formulated into pharmaceutical preparations by a conventional formulation method. Specifically, the anticancer drug delivery vehicle according to the present invention can be formulated into a liquid, a powder or a film, and the formulation of the anticancer drug delivery vehicle according to the present invention is not limited thereto.
The composition of the anticancer drug delivery system according to the present invention will be described in more detail as follows.
(1) Anticancer drugs
In the present invention, no particular limitation is imposed on the selection of the anticancer drug. Any anticancer drug well known in the art can be used.
Examples of the anticancer agent include cyclophosphamide, ifosfamide, Procarbazine, Busulfan, Carmustine, Lomustine, and the like as the alkylating agents. , Dacarbazine, Cisplatin, and the like. Antimetabolites may include Methotrexate, 5-Fluorouracil, Capecitabine, Cytosine Arabinoside, Gemcitabine, and the like. Vinca alkaloid-based natural substances include Vinblastine, Vincristine and the like. Taxane drugs such as Paclitaxel, Docetaxel and the like may be included. Epipodophyllotoxin A drug such as etoposide may be included. As Camptothecin drugs, Topotecan, Irinotecan and the like may be included. Antitumor Antibiotics may include Miitomycin-C, Daunorubicin, Doxorubicin, Bleomycin, and the like. As an enzyme-based drug, asparaginase (L-asparaginase) and the like may be included. Urea-based drugs such as hydroxyurea may be included. Tyrosine kinase inhibitors may include Rituximab, Trastuzumab, Imatinib, Gefitinib, Erlotinib, and the like. The anticancer drug exemplified above can be used in the form of their pharmaceutically acceptable salts or hydrates. In addition, one or more of the above-mentioned anticancer drug may be used.
The anticancer drug may be contained in the drug carrier in an amount of 0.6 to 2.2% by weight. The content of the anticancer drug may differ depending on the drug effect of the drug. If the content is less than 0.6% by weight, the anticancer effect may not be exhibited properly. If the content exceeds 2.2% by weight, It is possible.
(2) Hydrogel polymers
In the present invention, the hydrogel polymer acts as a carrier containing an anticancer drug.
The hydrogel polymer is prepared by hydrogeling a crosslinked polymer having a hydrophilic polymer having a hydroxy functional group and a crosslinking agent having an epoxy functional group crosslinked through an ether (-O-) covalent bond, thereby forming a stabilized network structure.
In addition, the hydrogel polymer has a core-shell structure in which the core portion of the gel is hydrophobic and the surface of the gel is hydrophilic. Accordingly, when the crosslinked polymer is hydrogelized under the condition that the anticancer drug is present, the anticancer drug may be contained in the core of the microhepatic hydrogel due to interaction between the hydrophobic part of the crosslinked polymer and the hydrophobic anticancer drug. Thus, the anticancer drug contained in the core portion of the hydrogel polymer can be stably released to the lesion stably without being crystallized under the aqueous solution condition.
In addition, since the outer surface of the hydrogel polymer is hydrophilic, it is possible to safely protect the anticancer drug from various immune mechanisms in the body.
In addition, the hydrogel polymer can achieve the sustained release effect in which the ether cross-linking is hydrolyzed in an aqueous solution and the anticancer drug contained in the core is gradually released.
The hydrogel polymer may be contained in the drug carrier in the range of 6.2 to 21.7 wt%. If the content of the hydrogel polymer is less than 6.2 wt% or exceeds 21.7 wt%, it may be difficult to contain the anticancer drug in the core of the hydrogel polymer.
The hydrophilic polymer constituting the hydrogel polymer is a polymer having a hydroxy functional group and having a weight average molecular weight ranging from 10,000 to 1,000,000 g / mol. Specific examples thereof include alginic acid, hyaluronic acid, dextran, hydroxypropyl methylcellulose, carboxymethyl Cellulose, and salts of alkali metals or alkaline earth metals thereof.
The crosslinking agent constituting the hydrogel polymer is a compound having an epoxy functional group, and specifically includes epichlorohydrin, epibromohydrin, butanediol diglycidyl ether, ethylene glycol diglycidyl ether, hexanediol diglycidyl Diethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, polyglycerol polyglycidyl ether, Glycerol polyglycidyl ether, trimethylpropane polyglycidyl ether, bis (epoxypropoxy) ethylene, pentaerythritol polyglycidyl ether, glycerol polyglycidyl ether, glycerol polyglycidyl ether, polyglycerol polyglycidyl ether, glycerol polyglycidyl ether, And at least one member selected from the group consisting of epoxycyclohexyl glycidyl ether, There.
(3) Temperature-sensitive polymers
In the present invention, the temperature-sensitive polymer is phase-changed from a sol to a gel by body temperature.
When the drug delivery vehicle of the present invention is applied to the affected part, the temperature responsive polymer is gelated by body temperature, and the drug carrier is fixed to the affected part by adhesion. As the gelation of the temperature sensitive polymer proceeds, the volume of the drug delivery vehicle is gradually contracted, and the anticancer drug contained in the core of the hydrogel polymer is slowly released through the gel wall due to the contracting pressure. Thus, the temperature-sensitive polymer is gelled in the body to actively target the drug carrier to the target region, and to perform the manual targeting function to intensively release the anticancer drug contained in the hydrogel core at the target site of the lesion.
The temperature-sensitive polymer is a polymer having an ether functional group and a weight average molecular weight ranging from 500 to 500,000 g / mol. Specific examples of the polymer include poly (ethylene oxide), poly (ethylene oxide-propylene oxide) random copolymer, polyethylene oxide- - one selected from the group consisting of polyethylene oxide triblock copolymer, poly (ethylene glycol) -poly (L-lactic acid) -poly (ethylene glycol), alkylated polyethylene oxide block copolymer and poly (vinyl methyl ether) Or more.
The temperature-sensitive polymer may be contained in the drug carrier in an amount ranging from 76.1 to 93.2% by weight. If the content of the temperature responsive polymer is less than 76.1% by weight, it may fail to actively target the drug carrier to immobilize the drug carrier on the lesion, and it may not be able to help the physical release of the anticancer drug contained in the core of the hydrogel. On the other hand, if the content of the temperature sensitive polymer exceeds 93.2% by weight and is contained in an excessive amount, the initial release amount of the anticancer drug may be excessive.
The present invention also features a method for producing an anticancer drug delivery system. The method for preparing an anticancer drug delivery system according to the present invention comprises:
(Step 1) A first step of preparing a crosslinked polymer having ether crosslinking by reacting a hydrophilic polymer having a hydroxy functional group with a crosslinking agent having an epoxy functional group;
(Step 2) A second step of mixing an anticancer drug and a temperature-sensitive polymer which is converted into a gel in the body, and stirring the mixture at a temperature of 40 to 60 ° C to pretreat the anticancer drug; And
(Step 3) A third step of preparing an anticancer drug delivery system by mixing the cross-linked polymer prepared in the first step and the anticancer drug pretreated in the second step and hydrogeling at 60 to 110 ° C .; .
The method for preparing the drug delivery vehicle according to the present invention will be described below in detail.
The first step is a process for producing a crosslinked polymer by reacting a hydrophilic polymer having a hydroxy functional group with a crosslinking agent having an epoxy functional group.
The hydrophilic polymer having a hydroxy functional group has a weight average molecular weight of 10,000 to 1,000,000 g / mol and is composed of alginic acid, hyaluronic acid, dextran, hydroxypropylmethylcellulose, carboxymethylcellulose and salts of alkali metals or alkaline earth metals thereof And the like.
The crosslinking agent having an epoxy functional group may be selected from the group consisting of epichlorohydrin, epibromohydrin, butanediol diglycidyl ether, ethylene glycol diglycidyl ether, hexanediol diglycidyl ether, propylene glycol diglycidyl ether, polyethylene glycol Diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, Polyglycerol polyglycidyl ether, glycerol polyglycidyl ether, trimethylpropane polyglycidyl ether, bis (epoxypropoxy) ethylene, pentaerythritol polyglycidyl ether and sorbitol polyglycidyl ether May be included.
When the cross-linking reaction proceeds, the content ratio of the hydrophilic polymer and the cross-linking agent ranges from 1/1 to 1/20, preferably from 1/8 to 1/20, of the functional group molar ratio of [OH] / [epoxy] And the like. If the molar ratio of the functional group of [OH] / [epoxy] is less than 1/1, the yield of the crosslinked polymer may be lowered. If the molar ratio of the functional group of [OH] / [epoxy] exceeds 1/20, A large amount of unreacted hydroxy functional groups may remain in the crosslinked polymer, resulting in undesired side reactions, resulting in partial gelation and lowering the yield of the hydrogel.
The crosslinking reaction may be carried out in a mixed solution of water and at least one dispersing aid selected from the group consisting of acetone and alcohols having 1 to 6 carbon atoms. It is preferable to use an organic solvent which is excellent in compatibility with water and has a lower boiling point than water and does not dissolve the hydrophilic polymer having a hydroxy functional group. The dispersion aid is preferably at least one selected from the group consisting of acetone and an alcohol having 1 to 6 carbon atoms. The alcohol may include one or more selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, pentanol, and hexanol.
In preparing the mixed solution, it is preferable to mix the dispersing aid in an amount of 1 to 20 parts by weight based on 1 part by weight of water. When the content of the dispersing aid is less than 1 part by weight based on 1 part by weight of water, the hydrophilic polymer having a hydroxy functional group may partially aggregate in the solution to cause the crosslinking reaction not to occur uniformly in the whole solution . On the other hand, if the content of the dispersing aid exceeds 20 parts by weight based on 1 part by weight of water, the solubility of the hydrophilic polymer having a hydroxy functional group is low and the crosslinking reaction can not proceed smoothly, so that the yield of the crosslinked polymer may be lowered.
In the crosslinking reaction, a hydrophilic polymer having a hydroxy functional group and a crosslinking agent having an epoxy functional group react with each other to produce an ether crosslinked polymer. Thus, it may be important to adjust the pH and reaction temperature to form an ether bridge. The pH suitable for the ether cross-linking according to the present invention is in the range of 9-13 and the reaction temperature is in the range of 25-60 < 0 > C.
In order to adjust the pH of the crosslinking reaction solution, an acid or base strength can be adjusted by mixing with water, and a conventional pH adjusting agent used for preparing a buffer solution can be used. In the present invention, there is no particular limitation on the selection of the pH adjusting agent, specifically, an acid such as hydrochloric acid, nitric acid, or a base such as sodium hydroxide may be used. However, if the pH of the crosslinking reaction solution is less than 9, the ester bond and the ether bond can be formed at the same time by the carboxyl groups in the molecular structure. If the pH is more than 13, the etherification may be partially caused, and it may be difficult to obtain a homogeneous polymer. Therefore, it is preferable to adjust the pH of the crosslinking reaction solution in the range of 9-13.
If the crosslinking reaction temperature is lower than 25 ° C, the crosslinking reaction rate is slow and the reaction time is long, which may cause side reactions. If the crosslinking reaction temperature is higher than 60 ° C, the solvent may be evaporated rapidly and it may be difficult to induce uniform crosslinking. Therefore, the temperature of the crosslinking reaction is preferably kept in the range of 25 to 60 ° C.
In addition, in carrying out the crosslinking reaction, the present invention does not particularly limit the order of introduction of water, a dispersion aid, a hydrophilic polymer having a hydroxy functional group, and a crosslinking agent. For example, a cross-linking reaction can be performed by simultaneously introducing a hydrophilic polymer having a hydroxy functional group and a cross-linking agent into a mixed solution obtained by mixing a dispersion auxiliary agent and water. In addition, the hydrophilic polymer having a hydroxy functional group may be first added to the dispersion aid, and then water and a crosslinking agent may be added thereto. However, when the dispersing aid and the hydrophilic polymer having a hydroxy functional group are first introduced, it is necessary to vigorously stir the composition supplied with the dispersion aid while slowly adding water. Otherwise, the hydrophilic polymer having a hydroxy functional group may exist locally in a solution state.
The crosslinked polymer thus prepared is a water-insoluble gel, which has high solubility in water and low solubility in water. Therefore, if a dispersion aid having a lower boiling point than water is selectively removed by a conventional solvent removal method, a crosslinked polymer in a water-insoluble gel state can be easily obtained.
The solvent removal method that can be applied to remove the dispersion auxiliary agent may include a pressure method, a depressurization method, a heating method, a cooling method, a freeze drying method, a membrane permeation method, and the like. A rotary distillation apparatus or the like may also be used. The solvent removal method or the removal device can be appropriately selected in consideration of the characteristics of the dispersion aid used. Further, it is preferable to continuously stir to maintain the concentration of the reaction solution evenly while removing the dispersion auxiliary agent. Rotary distillation or similar equipment may be useful to remove the dispersion aid while maintaining constant agitation. The removal of the dispersion aid is carried out until the reaction solution is converted into a clear solution state.
In addition, the reaction solution from which the dispersion auxiliary agent has been removed is allowed to stand at room temperature for about 1 to 72 hours, and then the crosslinked polymer in a water-insoluble gel state is separated. Separately obtained crosslinked polymer is appropriately dried. The drying may be performed under reduced pressure. Further, the dried crosslinked polymer may be further washed with distilled water or phosphate buffered saline (PBS), and the pH may be adjusted to neutral before drying.
The second step is a step of pretreating the anticancer drug with a temperature sensitive polymer.
In order to prevent crystallization of the anticancer drug easily in an aqueous solution to precipitate or phase separation, it is preferable to mix the anticancer drug with the temperature responsive polymer in advance. Anticancer drugs are hydrophobic drugs and can easily be crystallized or phase separated in aqueous solution because they are not well soluble in water. Therefore, the anticancer drug may partially crystallize during the hydrogelation reaction of the crosslinked polymer, and may be difficult to be encapsulated in the core of the hydrogel polymer. In order to solve this problem, in the present invention, the anticancer drug is pre-mixed with the temperature-sensitive polymer in advance and stirred to achieve stabilization of the anticancer drug.
Examples of the anticancer agent include cyclophosphamide, ifosfamide, Procarbazine, Busulfan, Carmustine, Lomustine, and the like as the alkylating agents. , Dacarbazine, Cisplatin, and the like. Antimetabolites may include Methotrexate, 5-Fluorouracil, Capecitabine, Cytosine Arabinoside, Gemcitabine, and the like. Vinca alkaloid-based natural substances include Vinblastine, Vincristine and the like. Taxane drugs such as Paclitaxel, Docetaxel and the like may be included. Epipodophyllotoxin A drug such as etoposide may be included. As Camptothecin drugs, Topotecan, Irinotecan and the like may be included. Antitumor Antibiotics may include Miitomycin-C, Daunorubicin, Doxorubicin, Bleomycin, and the like. As an enzyme-based drug, asparaginase (L-asparaginase) and the like may be included. Urea-based drugs such as hydroxyurea may be included. Tyrosine kinase inhibitors may include Rituximab, Trastuzumab, Imatinib, Gefitinib, Erlotinib, and the like. The anticancer drug exemplified above can be used in the form of their pharmaceutically acceptable salts or hydrates. In addition, one or more of the above-mentioned anticancer drug may be used.
The temperature-sensitive polymer is a polymer having an ether functional group and a weight average molecular weight ranging from 500 to 500,000 g / mol. Specific examples of the polymer include a poly (ethylene oxide), a poly (ethylene oxide-propylene oxide) random copolymer, a polyethylene oxide- (Ethylene glycol) -poly (ethylene glycol), alkylated polyethylene oxide block copolymers, and poly (vinyl methyl ether), wherein the poly (ethylene glycol) is selected from the group consisting of propylene oxide-polyethylene oxide triblock copolymers, It may be more than one kind.
The third step is a process for preparing an anticancer drug delivery vehicle by hydrogeling a crosslinked polymer.
Specifically, the crosslinking polymer prepared in the first step and the anticancer drug pretreated in the second step are mixed and subjected to a hydrogel reaction. As a result, the anticancer drug delivery system can be manufactured in such a state that the hydrogel polymer and the temperature sensitive polymer contained in the core of the anticancer drug are evenly dispersed.
The hydrogelisation reaction is preferably carried out at a reaction temperature of 60 to 110 DEG C such that the hydrophobic part of the anticancer drug and the hydrophobic part of the crosslinking polymer can effectively interact with each other. If the hydrogelisation temperature is lower than 60 deg. C, the partial gelation and the anticancer drug may not be completely melted and the core of the hydrogel may not be formed. If the temperature is maintained at a temperature higher than 110 deg. C, The anticancer drug is not contained in the core and is released to the outside of the hydrogel, so that the efficacy of the sustained release can not be achieved.
FIG. 1 is a photograph showing a cryo-TEM analysis of an anticancer drug delivery system according to the present invention. 1, it can be seen that the drug delivery vehicle of the anticancer drug is uniformly dispersed in the hydrogel polymer and the temperature sensitive polymer, and that the core of the hydrogel polymer stably contains an anticancer drug.
In addition, FIG. 2 shows a process in which the anticancer drug delivery system according to the present invention is applied to the body to change from a sol to a gel, thereby releasing the anticancer drug. As shown in FIG. 2, in the sol state, the anticancer drug is contained inside the hydrogel polymer, but when the body is coated, the hydrogel polymer shrinks and releases the encapsulated anticancer drug.
The present invention as described above will be described in more detail based on the following examples.
However, these examples are provided for illustrative purposes only in order to facilitate understanding of the present invention, and the scope and scope of the present invention are not limited by the following examples.
[Example]
Example 1. Evaluation of the state of a hydrophilic polymer solution according to a mixing ratio of water and a dispersion aid
In this Example 1, a mixing ratio of water and a dispersion auxiliary agent used for crosslinking a hydrophilic polymer having a hydroxy functional group is determined.
As the hydrophilic polymer having a hydroxy functional group, sodium carboxymethyl cellulose (hereinafter, abbreviated as 'SCMC') was typically used. As the dispersing aid, acetone, ethanol or a mixed solution thereof was used.
Specifically, distilled water and a dispersing aid were added to a 500 mL reaction vessel equipped with a stirrer at a composition ratio of the following Tables 1, 2 or 3, and sodium carboxymethyl cellulose (SCMC) was added thereto while stirring the mixed solution at room temperature and 80 rpm. After stirring for 10 minutes, the mixture was allowed to stand for 1 hour. The viscosity of the stagnant solution and the state of the SCMC particles were visually confirmed and evaluated according to the following criteria. The evaluation results are shown in Tables 1, 2 or 3 below.
[Criteria for determination of SCMC solution]
●: No significant change in viscosity after SCMC injection, and the particle state of SCMC is maintained
▲: There is no significant change in viscosity after SCMC injection, and SCMC shows aggregation phenomenon
×: Viscosity increases after SCMC injection, and SCMC is converted into solution
(Weight ratio, g)
(Weight ratio, g)
(Weight ratio, g)
As can be seen in Tables 1, 2 and 3, when the weight ratio of water: dispersion aid is less than 1: 1, the viscosity of the composition increases after the SCMC injection, and the SCMC partially agglomerates, . If the viscosity of the dispersion aid solution is increased, the mixing uniformity of the composition is lowered. Therefore, in order to obtain a homogeneous gel composition, the weight ratio of the water: dispersion aid is preferably 1: 1 or more, more preferably 1: 1 to 20.
Example 2 Evaluation of gel yield of crosslinked polymer according to mixing ratio of water and dispersion aid
In this Example 2, a mixing ratio of water and a dispersion auxiliary agent used for cross-linking a hydrophilic polymer having a hydroxy functional group with a crosslinking agent is determined.
Concretely, a mixed solution was prepared by adding distilled water and acetone as a dispersing aid to the 500 mL reaction vessel equipped with the stirrer at the composition ratio shown in Table 4 below. The mixed solution was added with sodium carboxymethyl cellulose (SCMC) while stirring at room temperature with stirring at 80 rpm, and then butanediol diglycidyl ether (BDDE) was added as a crosslinking agent and stirred at room temperature for 24 hours. At this time, the mixing ratio of sodium carboxymethyl cellulose (SCMC) and butanediol diglycidyl ether (BDDE) was adjusted so that the molar ratio of [OH] / [epoxy] functional group was 1/8. The whitened reaction solution was distilled in a vacuum distillation apparatus maintained at 25 ° C and -0.5 MPa to remove acetone, and the distillation was carried out until the reaction solution became completely transparent. When the reaction solution became transparent, the decompression was terminated. The crosslinked polymer thus prepared was lyophilized to obtain a powdery form. The crosslinked polymer powder was washed three times with distilled water for 24 hours. Every time the one-time washing process was finished, the gel was obtained using the filter paper, and the gel obtained after the completion of three times of washing was dried in a vacuum oven. The gel yield was calculated by measuring the weight of the dried gel.
[Equation 1]
As can be seen in Table 4 above, crosslinked gels could be formed when the weight ratio of distilled water: acetone was 1: 1 to 20 (crosslinked samples 2-2 to 2-7), and in the range of 1: 1 to 9 (Crosslinked samples 2-4 to 2-7) confirmed that the yield of the crosslinked gel was further improved. On the other hand, when the weight ratio of distilled water: acetone was less than 1: 1 or exceeded 1: 20 (crosslinked samples 2-1 and 2-8), a crosslinked gel could not be obtained.
Example 3 Evaluation of gel yield of crosslinked polymer according to molar ratio of [OH] / [epoxy] functional group
In Example 3, it is intended to determine the [OH] / [epoxy] functional group capable of maximizing gel yield when cross-linking a hydrophilic polymer having a hydroxy functional group with a crosslinking agent.
The mixing ratio of sodium carboxymethyl cellulose (SCMC) and butanediol diglycidyl ether (BDDE) was [OH] / [OH] / [ Epoxy] functional group molar ratio.
As shown in Table 5, crosslinking gel could be formed when the molar ratio of [OH] / [epoxy] functional group was 1/1 to 1/20, and the molar ratio of [OH] / [epoxy] 1/20, it was confirmed that the yield of crosslinked gel was further improved. On the other hand, when the molar ratio of [OH] / [epoxy] functional groups exceeded 1/20 (crosslinked sample 3-7), the yield of crosslinked gel was so low that measurement was impossible.
Example 4 Evaluation of Drug Delivery System of Anticancer Drugs According to Composition Ratio
In this Example 4, the state of the drug delivery vehicle prepared according to the composition ratio of the anticancer drug, the hydrogel polymer, and the temperature sensitive polymer constituting the drug delivery vehicle is compared and evaluated. Polyethylene oxide-polypropylene oxide-polyethylene oxide (PEP-PPO-2) was used as the temperature sensitive polymer. Cross-linked sample 3-5 of Example 3 was used as the crosslinked polymer forming the hydrogel, PEO) triblock copolymer was used.
Specifically, docetaxel and PEP-PPO-PEO copolymer were added to 70 mL of water at a ratio shown in Table 6 below, and the mixture was stirred at 60 rpm at 100 rpm to pretreat the anticancer drug. The pre-treated docetaxel was mixed with SCMC-BDDE crosslinked polymer in the content ratio shown in Table 6 below under a nitrogen stream, and the mixture was stirred at 60 ° C for 24 hours. The reaction solution was allowed to stand at 25 ° C and 2 ° C for 24 hours to remove bubbles. After standing for 24 hours, the formation of the sediment was visually confirmed and is shown in Table 6 below.
drug
●: The drug carrier is completely soluble in water and is produced in a clear solution.
▲: The drug delivery system remains partly as particles
X: The drug carrier was prepared as a milky white dispersion without dissolution.
According to Table 6, the
Therefore, in constructing the anticancer drug delivery system of the present invention, the optimal content of the anticancer drug is 0.6 to 2.2 wt%, the optimal content of the hydrogel polymer is 6.2 to 21.7 wt%, and the optimal content of the temperature sensitive polymer is 76.1 to 93.2 wt% %. In the above composition ratio range, the anticancer drug is stably embedded in the core of the hydrogel polymer and is nano-sized and exists in the aqueous solution condition, so that there is no possibility that the anticancer drug is precipitated in water.
FIG. 3 is a graph showing the results of observing the growth of precipitates (crystals of docetaxel) while preserving the drug carrier 9 prepared in Example 4 in an aqueous solution for 14 days. According to FIG. 3, even when the drug delivery system of the present invention was stored for 14 days in an aqueous solution state, there was almost no crystal growth, and the drug carrier could safely be present in the core of the gel without releasing the anticancer drug out of the hydrogel.
4 shows a photograph of a sample of the drug carrier 9 prepared in Example 4 dissolved in water. 4 (a) shows the state of the reaction solution before the heat treatment, and (b) shows the state of the reaction solution after the heat treatment. The state of the pre-reaction solution in which the anticancer drug, the crosslinking polymer and the temperature-sensitive polymer are mixed is a whitish dispersion, but after the cross-linking polymer is hydrogelized by heating, the reaction solution changes transparently after the anticancer drug is contained in the core. Therefore, by confirming the change in the state of the reaction solution, it can be seen that the anticancer drug delivery system of the present invention stably encapsulates the anticancer drug in the hydrogel core.
Example 5: Evaluation of in vivo pharmacokinetics of anticancer drug delivery vehicle
In Example 5, the in vivo pharmacokinetics of the drug delivery system of the present invention using an injecting system that is directly injected through a blood vessel and a DDST (Drug Delivery System Therapy) system that is directly injected into a tumor incision site are compared .
The drug delivery vehicle 9 (containing 2.2% by weight of docetaxel) prepared in Example 4 was used as a drug delivery vehicle for DDST administration representative of the present invention, and Taxotere (TM) product commercially available as a docetaxel injection product was used as a control group Respectively. Male Sprague Dawley rats were used as experimental animals.
The anticancer drug delivery system of the present invention was directly administered (5 mg / kg) to the tumor removal site and the existing Taxotere (TM) injection was intravenously administered (5 mg / kg).
FIG. 5 shows the result of measuring the blood concentration (ng / mL) for 24 hours with respect to the method of directly administering the anticancer drug delivery vehicle of the present invention to the site of tumor removal and the conventional method of intravenously administering the anticancer drug injection. The measured blood concentration and time data for 24 hours are shown in Table 7 below by calculating the average of the pharmacokinetic parameters through non-compartmental analysis.
According to Table 7, the half-life of the drug delivery vehicle was 6 hours and the half-life of the injection was 4 hours. For the mean area under the curve (AUC) up to 24 hours, the drug delivery was 387 ng.hr/mL and the injection was 281 ng.hr/mL. For the average Cmax, the drug delivery was 1850 ng / mL, and the injected drug was 901 ng / mL.
The results showed that AUC24h and Cmax were significantly increased by 35% and 105%, respectively, when administered directly to the site of tumor removal by the drug delivery system rather than injecting agent. Thus, systemic clearance (CL) , Respectively.
As a result, compared with the intravenous injection of docetaxel anticancer drugs, the residence time in the body when administered directly to the anticancer site by the drug delivery vehicle is long, and when the same dose is administered, the AUC and the Cmax are markedly higher, Is improved.
Example 6: Evaluation of cytotoxicity of drug delivery vehicle
In Example 6, the cytotoxicity of a drug carrier comprising a hydrogel polymer and a temperature sensitive polymer except for an anticancer drug was confirmed in order to confirm the cytotoxicity of the drug carrier of the present invention.
Specifically, a drug delivery vehicle in which an anticancer drug was removed and a positive control teflon (1 cm × 1 cm) were eluted from the cell culture medium for 3 days at 37 ° C. to obtain an eluate. Fibroblasts were plated at a density of 1 x 10 < 4 > cells in a 96-well plate and cultured in vitro at 5% CO 2 and 37 ° C for one day. The drug delivery vehicle, the positive control (Teflon) and the hydrogel polymer eluate were dispensed into the fibroblast culture solution. The next day, 20 MTT Solution (2 mg / mL in PBS) was added and incubated for additional 4 hours. Then, the culture medium was removed, 100 μL of dimethylsulfoxide (DMSO) was added, and the absorbance at 570 nm was measured using a microplate reader.
FIG. 6 is a graph showing the results of MTT analysis of the drug delivery vehicle, the positive control (Teflon) and the sodium carboxymethylcellulose (SCMC) polymer eluate from which the anticancer drug was removed. According to FIG. 6, the drug delivery vehicle, the positive control (Teflon) and the hydrogel polymer eluate from which the anticancer drug was removed all had a high cell viability. In particular, the anticancer drug delivery vehicle of the present invention had a better cell survival rate than the positive control (Teflon) . Thus, it can be confirmed that the anticancer drug delivery system of the present invention and the polymer used for the preparation thereof are safe without cytotoxicity.
Example 7 Evaluation of Artificial Barrier Effect of Drug Delivery System
In Example 7, the effect of the artificial barrier against the drug delivery system of the present invention was confirmed, and the artificial barrier efficacy was confirmed through visual observation at the time of animal autopsy.
Specifically,
The drug carrier of the present invention in which the anticancer drug was removed was uniformly applied in 0.5 mL of the abdominal cavity. After the operation, the animals were given enough water and food. After 10 days, new incisions were made in the left lower abdomen, and pathological examinations were performed with gross findings.
Average degree of adhesion = Σ (number of individuals by grade × grade) / total number of individuals
The evaluation was classified according to the method of Knightly et al., From 0 to 4, and from 0 to 3 according to the method of Hooker et al. The results are shown in Table 8 below.
drug
2) Adhesion grading scale (Hooker score)
As shown in Table 8, it can be confirmed that the drug delivery system of the present invention has excellent adhesion and adhesion.
Example 8: Evaluation of anti-cancer effect of drug delivery system of anticancer drug
In Example 8, in order to confirm anticancer efficacy against the anticancer drug delivery vehicle according to the present invention, the survival rate of cancer cells was measured using MTT assay.
When a cancer cell line shown in Table 9 below was inoculated to a 24-well plate at 2 x 10 < 4 > cells / plate and 70% cancer cells were filled in the plate, the drug carrier 9 (containing 2.2% by weight docetaxel) And 150 μL of the solution was added to the solution. 12, 24, 48, 72 hours, MTT solution (50 ug / mL, Sigma) was added to each well and incubated for 4 hours in a 37 ° C incubator. When purple crystals were formed, 500 μL of DMSO solution was added and dissolved by stirring for 30 minutes. Absorbance was measured at 520 nm using an ELISA reader to confirm cell viability. The results are shown in Table 9 below.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (18)
At least one hydrophilic polymer selected from the group consisting of hydroxypropylmethylcellulose, carboxymethylcellulose and salts of alkali metals or alkaline earth metals thereof, and at least one hydrophilic polymer selected from the group consisting of butanediol diglycidyl ether, hexanediol diglycidyl ether, ethylene glycol di Glycidyl ether, propylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, and neopentyl glycol diglycidyl ether. A cross-linking agent formed by cross-linking at least one cross-linking agent selected from the group consisting of a hydrogel polymer containing the drug in the core; And
A temperature sensitive polymer which is converted into a gel in the body by at least one member selected from the group consisting of poly (ethylene oxide), poly (ethylene oxide-propylene oxide) random copolymer, polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer;
≪ / RTI >
0.6 to 2.2% by weight of an anticancer drug;
6.2 to 21.7% by weight of a hydrogel polymer containing the drug in the core; And
76.1 to 93.2% by weight of a temperature-sensitive polymer which is converted into a gel in the body;
≪ / RTI >
Wherein the anticancer drug is at least one selected from the group consisting of Paclitaxel, Docetaxel, a pharmaceutically acceptable salt thereof, and a hydrate thereof.
Wherein the hydrogel polymer has a molar ratio ([OH] / [epoxy]) of the hydroxy functional group of the hydrophilic polymer to the epoxy functional group of the crosslinking agent in the range of 1/1 to 1/20.
Wherein the hydrophilic polymer has a weight average molecular weight of 10,000 to 1,000,000 g / mol.
Wherein the temperature-sensitive polymer has a weight average molecular weight of 500 to 500,000 g / mol.
Wherein the drug delivery system is applied to a tumor removal site.
Wherein the drug delivery system has a function of preventing the metastasis of cancer through microvascular formation by forming a functional and artificial barrier as an anti-cancer therapeutic agent.
Characterized in that it is formulated as a liquid, powder or film.
A pharmaceutical composition comprising a Taxane anticancer drug and at least one temperature response selected from the group consisting of poly (ethylene oxide), poly (ethylene oxide-propylene oxide) random copolymer, polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer Mixing the polymer and stirring at a temperature of 40 to 60 DEG C to pretreat the anticancer drug; And
A third step of mixing the crosslinked polymer prepared in the first step with the anticancer drug pretreated in the second step and hydrogeling the mixture at a temperature of 60 to 110 ° C to prepare the drug delivery system of claim 1;
≪ / RTI >
Wherein the molar ratio ([OH] / [epoxy]) of the hydroxy functional group of the hydrophilic polymer to the epoxy functional group of the crosslinking agent is in the range of 1/1 to 1/20 in the crosslinking reaction of the first step Gt;
Wherein the hydrophilic polymer in the first step has a weight average molecular weight of 10,000 to 1,000,000 g / mol.
Wherein the crosslinking reaction in the first step is carried out in a mixed solution of water, acetone and at least one dispersing aid selected from the group consisting of alcohols having 1 to 6 carbon atoms.
Wherein the crosslinking reaction in the first step is carried out in a mixed solution of 1 part by weight of water and 10 to 20 parts by weight of a dispersing aid.
Wherein the crosslinking reaction of the first step proceeds at a pH of 9 to 13 and a temperature of 25 to 60 ° C.
Wherein the temperature-sensitive polymer in the second step has a weight average molecular weight of 500 to 500,000 g / mol.
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| KR20240003032A (en) | 2022-06-29 | 2024-01-08 | 주식회사 나노메디팜 | Ultra-small anticancer agent-loaded Nano-drug delivery platform with multiple mechanisms of action, a pharmaceutical composition including the same, and method for manufacturing the same |
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| KR20240003032A (en) | 2022-06-29 | 2024-01-08 | 주식회사 나노메디팜 | Ultra-small anticancer agent-loaded Nano-drug delivery platform with multiple mechanisms of action, a pharmaceutical composition including the same, and method for manufacturing the same |
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