Injectable smart hydrogel sensitive to temperature and light and having enhanced mechanical strength and method of making same

Abstract

The present invention relates to injectable smart hydrogels that are sensitive to temperature and light and have enhanced mechanical properties, as well as to a process for the preparation of these hydrogels, which can be used in the technical field of biomaterials, in particular in controlled drug release and drug carrier system applications.

Description

Technical Field

[0001] The invention relates to an injectable smart hydrogel which is sensitive to temperature and light and has enhanced mechanical properties and a preparation method of the hydrogel. The hydrogel can be used in the field of biomaterial technology, in particular in the application of controlled drug release and drug carrier system. Background Art

[0002] Smart materials are a class of materials whose chemical composition and physical conditions change; they have one or more physical (optical, magnetic, electrical, mechanical) or physicochemical (rheological) properties that can be significantly changed by external factors (stimuli) such as pressure, temperature, humidity, pH, electric or magnetic fields. Injectable gel systems present within the scope of these smart materials self-assemble to form networks as a response to specific stimulants. Therefore, they are classified according to specific triggering factors such as pH, UV polymerization, charge interactions, ultrasound, electromagnetic radiation and temperature. These factors inevitably affect the physical, structural and mechanical behavior of the gel matrix during and after injection. The mechanical behavior reflects the structural characteristics of the hydrogel in relation to the transport through different media that may affect the structural transformations, stability, drug loading and release of the drug delivery system occurring during application.

[0003] Block copolymers are one of the important groups of polymers used to form these hydrogel systems. The two most important characteristics of these polymer solutions are the formation of micelles depending on temperature and the formation of gels. Poloxamers, in other words pluronics, are present in the class of block copolymers, they have gelling properties under specific conditions and they can show interactions between themselves and between molecules due to their hydrophilic and hydrophobic areas.

[0004] Pluronics or poloxamers are triblock copolymers of polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO). This synthetic polymer group is thermoreversible in aqueous solution. The sol-gel transition is controlled by the composition, molecular weight and concentration of the component block polymers. The hydrophilic ethylene oxide and the hydrophobic propylene oxide provide the amphiphilic structure for Pluronics. This description means that it has polar water-soluble groups bonded to hydrocarbon chains that are nonpolar and insoluble in water.

[0005] The amphiphilic block copolymer molecules self-assemble into micelles (packaged molecular chains) in aqueous solution. The formation of micelles depends on temperature and affects the degradation characteristics of the biomaterial. By a specific characteristic temperature called the critical micelle temperature, both the ethylene oxide and propylene oxide blocks are wetted and the PPO block becomes soluble.

[0006] Pluronic F127 (PF127 or F127), a member of the Pluronic class, has a wide range of uses due to its solubility and structure, hydrophobic interactions, and it can interact with different molecules.

[0007] Pluronic F127, also known as Poloxamer 407, is frequently used in tissue engineering due to the product's commercial properties of being consistent and undergoing a sol-gel transition at near physiological pH and temperature.

[0008] The disadvantage of Pluronic is that it degrades quickly in vivo. In order to overcome this technical problem, Pluronic is often cross-linked with another α-hydroxyl or amino acid in the art to change the chemical structure of the depsipeptide unit.

[0009] In a recent study, a special degradation ratio occurred that could be obtained by using UV irradiation without any harmful side effects on the critical micelle temperature or sol-gel transition of the field and cross-linking with amino acids.

[0010] In terms of applications, while Pluronics are known to prevent surface tissue adhesion of various cell types, they have been successfully used in framework applications including hematopoietic stem cells and lung tissue.

[0011] Therefore, the subject triblock copolymer can be used in various technical fields due to its various properties as a smart material.

[0012] The subject of the article entitled "Injectable hydrogels based on Pluronics" by S deals with the formation of gel systems based on F127. In this direction, hyaluronic acid, cyclodextrin and its derivatives, gelatin and polylactic-polyglycolic acid (which can be abbreviated as PLGA) / polyethylene glycol (which can be abbreviated as PEG) structures have been added to the solution including F127, and four different systems have been developed. For each formulation, the flow behavior and characteristics of the structure when the concentration is varied have been examined in detail. These findings have shown that the F127-HA-SD gel has the desired properties in the target direction, cell culture studies of this triple system have been realized, and it is considered that it can be used for a variety of different applications in the literature, and it is planned that the gels obtained in the target direction will be used in ear surgery in the following period.

[0013] Patent No. WO2017173453 A1 relates to the development of solid polymer nanoparticles (NPs) that are sensitive to stimulants and can be used to deliver therapeutic and diagnostic agents including nucleic acids, proteins, chemotherapeutic drugs or other small molecules. Synthesized polymer structure PEO-PPO-PEO The triblock amphiphilic copolymer comprises a method of adding auxiliary components to the Pluronic F127 structure, which more particularly transforms into a gel form at a concentration exceeding 15% (m / m).

[0014] In the relevant technical field, in the field of biomaterials, especially for controlled drug release and drug carrier system applications, the hydrogels in the prior art do not have the necessary properties of increased mechanical strength and increased light and heat sensitivity. It is known that Pluronic solutions have disadvantages due to their insufficient mechanical strength, which become gel-like when exceeding the temperature and become liquid when cooled.

[0015] Therefore, due to the above problems, improvements are needed in the related art. Summary of the invention

[0016] The present invention relates to injectable smart hydrogels that are sensitive to heat and light and have increased mechanical strength and methods for preparing these hydrogels, which can be used in the field of biomaterial technology, especially in controlled drug release and drug carrier system applications, in order to eliminate the above-mentioned disadvantages and bring new advantages to the relevant technical field.

[0017] One of the objects of the present invention is to provide a hydrogel that changes into a gel form at body temperature.

[0018] One of the objects of the present invention is to provide a hydrogel with improved mechanical strength.

[0019] One of the objects of the present invention is to provide a hydrogel with improved mechanical strength.

[0020] One of the objects of the present invention is to provide a hydrogel with high light intensity and thermal intensity.

[0021] One of the objects of the present invention is to provide an injectable hydrogel.

[0022] In order to achieve the above objects and the objects derived from the detailed description below, the present invention relates to a hydrogel comprising a pluronic copolymer as an essential component, the pluronic copolymer being a biocompatible material. Therefore, the present invention is characterized in that it comprises an amphiphilic copolymer-pluronic copolymer component comprising a chromophore functional group for increasing the mechanical strength value.

[0023] In one possible embodiment of the present invention, the chromophore functional group is one of azobenzene and / or coumarin compounds or a mixture thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] exist Figure 1In the figure, the temperature profile view of PF127 and PRF127-Mx micelle systems is shared. A) PF127-M1 (·) and PF127-M2 (▲), B) PF127-M3 (▼) and PF127-M4 (■).

[0025] exist Figure 2 In Figure 2, the values ​​of loss modulus (G”, open symbols), storage modulus (G’, full symbols) and loss factor (tan δ) are given, which are the ratio of the two parts of the viscoelastic behavior of the amphiphilic diblock terpolymers.

[0026] exist Figure 3 In FIG. 5 , graphs of the G′ values ​​before and after the UV irradiation process are shared in a time-dependent manner. DETAILED DESCRIPTION

[0027] In this detailed description, the subject matter relates to injectable smart hydrogels that are sensitive to heat and light and have increased mechanical strength (which can be used in the field of biomaterial technology, particularly in controlled drug release and drug carrier system applications), as well as methods for producing these hydrogels, and is explained with reference to examples without forming any limiting effect, only to make the subject matter easier to understand.

[0028] In the present invention, "smart material" refers to a class of materials whose chemical composition and physical state change; it has one or more physicochemical properties that can be significantly changed by external factors (stimuli) such as pressure, temperature, humidity, pH, electric field or magnetic field.

[0029] The subject matter of the present invention "hydrogel" describes a three-dimensional polymer network structure that does not dissolve when interacting with water, but can swell by incorporating large amounts of water into its structure.

[0030] In the present invention, "amphiphilic block copolymer" describes polymeric micelles, building blocks of macromolecules having different hydrophobic and hydrophilic blocks.

[0031] In the present invention, "polymer micelles" refer to spherical colloidal particles with nanometer size, hydrophilic periphery and hydrophobic core, which are formed by amphiphilic block copolymers and exist in liquid.

[0032] In the present invention, "Pluronic" or "Poloxamer" describes a structure in which hydrophilic polyethylene oxide (PEO) and hydrophobic polypropylene oxide (PPO) chains are combined in the form of PEO-PPO-PEO triblocks.

[0033] In the present invention, "PF127" or "Pluronic F127" describes a member present in the Pluronic class and having hydrophobic interactions in both solubility and structure, and has a wide range of applications because it can interact with different molecules. In the detailed description of the present invention, the term "PF127" will be used to describe it.

[0034] The subject hydrogel comprises a pluronic block copolymer as an essential component. As known in the art, the pluronic block copolymer comprises hydrophilic PEO and hydrophobic PPO monomers. The pluronic copolymer having the above structure has the characteristics of an amphiphilic block copolymer.

[0035] Therefore, in the present invention, the hydrogel comprises a Pluronic block copolymer obtained by polymerization synthesis known in the art as an essential component, and the essential component acts as a framework in determining the mechanical, chemical and physical properties of the hydrogel. The synthesis of the essential components present in the present invention does not belong to the protection scope of the present invention and can be obtained by any synthesis method.

[0036] As known in the art, Pluronic copolymers are suitable for use as carrier agents in drug delivery systems because they have been approved by the FDA and have biocompatibility characteristics for use in humans. However, the mechanical strength of Pluronic copolymers and hydrogels and similar smart materials obtained from them is quite weak. Pluronic copolymers are expected to have high mechanical strength in order to be able to be used in media such as the human body, where there are various quite complex mechanical factors.

[0037] In order to eliminate the technical disadvantages, the inventors have endeavored to obtain an improved pluronic hydrogel, the mechanical strength characteristics of which have been improved with respect to the relevant technical field. The inventors have found that the modification must be provided by using chromophore functional groups. Therefore, in the present invention, while aiming to improve the mechanical properties of pluronic hydrogels, the construction is achieved by mixing with an amphiphilic copolymer, wherein at least one type of chromophore functional group is added to the repeating unit of the pluronic hydrogel.

[0038] In the present invention, "chromophore" is described as the part of the molecule that absorbs and, after a stimulation process, undergoes a major change in geometry or electron density etc. In a preferred application of the present invention, one or both of azobenzene and / or coumarin compounds are used as chromophores.

[0039] In the present invention, by adding an amphiphilic copolymer containing a chromophore in the repeating unit to the Pluronic solution, the structure, which is already temperature sensitive, also becomes light sensitive due to the chromophore.

[0040] Therefore, the basic goal is that the subject hydrogel has an amphiphilic structure. To this end, in order to provide the polymer to form micelles in water by forming an amphiphilic structure, the chromophores are expected to form hydrophobic blocks since they are hydrophobic.

[0041] Due to all the mentioned chromophore-Pluronic copolymer interactions, the hydrogels comprising the basic components can have improved mechanical, physical and chemical properties. Moreover, while providing all of these, the obtained hydrogels still have high biocompatibility and can be used as agents in drug delivery systems.

[0042] The subject hydrogel has high mechanical strength and is sensitive to heat and light. It changes from a solution form to a gel form at a specific temperature. Therefore, the hydrogel has a form that can be injected into the body.

[0043] In the present invention, PF127 reference samples and various PF127-Mx micellar solutions are used in the test. The Mx value of the part encoded as PF127-Mx is an indicator of the micellar solution. The micellar solutions corresponding to M1, M2, M3 and M4 codes are obtained from PEG-bP (tBMA-r-CEMA) -1, PEG-bP (tBMA-r-CMA) -1, PEG-bP (tBMA-r-CEMA) -2 and PEG-bP (tBMA-r-CMA) polymers, respectively. Here, the CEMA and CMA structures are coumarin structures known in the art.

[0044] exist Figure 1 The temperature profiles of the PF127 and PF127-Mx systems are shared in FIG. 1. In the present invention, a rapid increase in G' value is observed through the sol-gel transition of the PF127 system, and the temperature increases, as expected based on the demonstration described.

[0045] When considering the relationship between gel strength and frequency, it can be expressed as Figure 2 Characterization studies are shown to determine the increase in gel strength by UV irradiation.

[0046] Figure 3 In Figure 1, the change in the elastic modulus (G') value before and after UV irradiation is given as a function of time. The samples were tested with the UV device turned off and on for 10 minutes. At a fixed cutting speed and frequency, the elastic modulus (G') of the tested gel was monitored as a function of time. The formulation placed between the rheometer plates was first measured without UV irradiation. It has been detected that the G modulus values ​​of the structure containing CEMA before UV irradiation are higher than the G modulus values ​​of the structure containing CMA.

[0047] After 10 min of UV irradiation, a rapid increase in G' values ​​was observed in all systems with UV effect at 24 °C.

[0048] The disadvantages of the hydrogel component are known in the art, but it has FDA-approved biocompatibility and, due to this property, can be used in various applications, such as biocompatible smart materials or drug delivery systems, can be added to the pluronic copolymer, in particular, chromophore functional groups can be added to increase the mechanical strength values. The mechanical strength values ​​of the hydrogels containing the modified pluronic copolymer as a component have been increased, and their physical and chemical properties have been stabilized. From this point of view, the use of the obtained hydrogels as biomaterials will be further increased.

[0049] The scope of the invention is set forth in the appended claims and is not limited to the illustrative disclosure given above in the detailed description. Because, those skilled in the relevant art can obviously conceive similar embodiments based on the above disclosure without departing from the main principles of the invention.

Claims

1. A hydrogel comprising a Pluronic copolymer as a basic component, wherein the Pluronic copolymer is a biocompatible material, characterized in that: The hydrogel includes an amphiphilic copolymer-Pluronic copolymer component that contains chromophore functional groups for increasing mechanical strength values.

2. The hydrogel according to claim 1, wherein The chromophore functional group is one of azobenzene and / or coumarin compounds or a mixture thereof.

3. Use of a hydrogel according to any one of the preceding claims in a controlled drug release system, the hydrogel comprising an amphiphilic copolymer-Pluronic copolymer component, the amphiphilic copolymer-Pluronic copolymer component comprising a chromophore functional group.

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