TECHNICAL FIELD

The present invention relates to injectable smart hydrogels that are sensitive to temperature and light and with increased mechanical properties and which can be used in biomaterial technical field, particularly in controlled drug release and in drug carrier system applications, and the production method of these hydrogels.

PRIOR ART

Smart materials are the class of materials whose chemical composition and physical conditions are changing; they have one or more than one physical (optical, magnetic, electrical, mechanical) or physicochemical (rheological) characteristic that can substantially change by means of external factors (stimulant) like pressure, temperature, humidity, pH, electrical or magnetic field. Injectable gel systems that exist within the scope of these smart materials self-assemble form a network as a response to specific stimulants. Accordingly, they are classified in accordance with specific triggers like pH, UV photo-polymerization, charge interaction, ultrasound, electromagnetic radiation and temperature. These factors affect physical, structural and mechanical behaviors of the gel matrix in an unavoidable manner during and after injection. Mechanical behavior reflects the structure-characteristic relation of hydrogel, and transfers by passing through different mediums which may affect structural transitions, stability, drug loading and release of the drug distribution systems that occur during application.

Block copolymers are among important polymer groups used in the formation of these hydrogel systems. The two most important characteristics of these polymer solutions are the becoming of micelle depending on temperature and gel formation. Poloxamers, in other words pluronics, exist in said block copolymer class, and they have gelling characteristics at specific conditions, and they can show interactions in themselves and between molecules thanks to their hydrophilic and hydrophobic regions. Pluronics or poloxamers are the triple block copolymers of polyethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) (PEO-PPO-PEO). This synthetic polymer group is thermally reversible in aqueous solutions. Sol-gel transition is managed by the composition, molecular weight and concentration of each component block polymer. Hydrophilic ethylene oxide and hydrophobic propylene oxide provide amphiphilic structure to pluronics. This description means that it has a polar, water soluble group bonded to a hydrocarbon chain that is not polar and which does not dissolve in water.

Amphiphilic block copolymer molecules are self-assembled in micelles (a packaged molecule chain) in the aqueous solution. Micelle formation depends on temperature and affects degradation characteristics of the biomaterial. By means of specific characteristic temperature known as critical micelle temperature, both ethylene and propylene oxide blocks are humidified and PPO block becomes soluble.

The member that exists in pluronic class and which has hydrophobic interactions because of both solubility and the structure thereof and which has wide usage area since it can interact with different molecules is pluronic F127 (PF127 or F127).

Pluronic F127 also known as poloxamer 407 is frequently used in tissue engineering since it has the commercial characteristics of a product that is consistent and that shall be subjected to sol-gel transition that is close to pH and physiological temperature.

A disadvantage of pluronics is the rapid degradation rate in vivo. In order to overcome this technical problem, in the art, pluronic is frequently crosslinked with another a-hydroxy or amino acid in order to change the chemical structure of depsipeptide unit.

In a recent study, a special degradation proportion has occurred which can be obtained by using UV irradiation without any harmful side effect on the critical micelle temperature or solgel transition and cross-linking with the amino acid of the field.

In terms of applications, while it is known that pluronics prevent surface tissue adhesion for various cell types, they are successfully used for framework applications comprising hematopoietic root cells and lung tissue.

As a result, the triple block copolymers, which are the subject matter, can be used in various technical fields thanks to various characteristics as a smart material. The subject of the article titled “Injectable hydrogels based on pluronic” that belong to Seger S, relates to the formation of gel systems based on F127. In this direction, hyaluronic acid, cyclo-dextrins and derivatives, gelatin and poly(lactic-co-glycolic acid) (it can be abbreviated as PLGA)/polyethylene glycol (it can be abbreviated as PEG) structures have been added to the solutions including F127, and four different systems have been worked on. For each formulation, the flow behaviors and characteristics of structures with changing concentrations have been examined in a detailed manner. As a result of these studies, it has been seen that F127-HA-SD gels have the desired characteristics in the aimed direction, cell culture studies of this triple system have been realized, and it is considered that it can be used in various different applications in the literature, and the gels which shall be obtained in the direction of the targeted aim are planned to be used in ear surgical operations in the following periods.

The patent no WO2017173453 A1 relates to the development of solid polymeric nanoparticles (NPs) which are sensitive to the stimulant and can be used for providing therapeutic and diagnostic agents including nucleic acids, proteins, chemotherapeutic drugs or other small molecules. The synthesized polymer structure, PEO-PPO-PEO (PLURONICS® or POLOXAMERS®) triple block of amphiphile copolymer comprises the method of adding auxiliary components to Pluronic F127 structure which turns into gel form more particularly in concentrations over 15% (m/m).

In the relevant technical field, in the field of biomaterials, especially for controlled drug release and drug carrier system applications, hydrogels in the current technique do not have the necessary properties to increase mechanical strength as well as increase light and heat sensitivity. It is known that the pluronic solution, which turns into a gel form when the temperature is exceeded and turns into a liquid state when cooled, has disadvantages due to its insufficient mechanical strength.

As a result, because of the abovementioned problems, an improvement is required in the related technical field.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to injectable smart hydrogels that are sensitive to heat and light and with increased mechanical strength and which can be used in biomaterial technical field, particularly in controlled drug release and in drug carrier system applications, and the production method of these hydrogels, for eliminating the abovementioned disadvantages and for bringing new advantages to the related technical field. An object of the present invention is to provide a hydrogel that shall turn into gel form at body temperature.

An object of the present invention is to provide a hydrogel whose mechanical strength is improved.

An object of the present invention is to provide a hydrogel whose mechanical strength is improved.

An object of the present invention is to provide a hydrogel whose light and heat strength is high.

An object of the present invention is to provide a hydrogel which is injectable.

In order to realize the abovementioned objects and the objects that are to be deducted from the detailed description below, the present invention relates to a hydrogel comprising pluronic copolymers, which are biocompatible materials, as basic components. Accordingly, the invention is characterized by comprising amphiphilic copolymer-pluronic copolymer component comprising chromophore functional group for increasing mechanical strength.

In a possible embodiment of the present invention, the chromophore functional group is one or mixtures of azobenzene and/or coumarin compounds.

BRIEF DESCRIPTION OF THE FIGURES

In Figure 1 , the views of temperature profiles of PF127 and PRF127-Mx micelle systems have been shared. A) PF127-M1 (•) and PF127-M2 (A), B) PF127-M3 (▼) and PF127-M4 (■)■

In Figure 2, the values of loss module (G”, open symbols), storage module (G’, full symbols) and loss factor (tand) which are the proportions of two parts of viscoelastic behavior of amphiphilic diblock terpolymers are given.

In Figure 3, the graphics of G’ values before and after UV irradiation process in a timedependent manner have been shared. DETAILED DESCRIPTION OF THE INVENTION

In this detailed description, the subject matter relates to injectable smart hydrogels that are sensitive to heat and light and with increased mechanical strength and which can be used in biomaterial technical field, particularly in controlled drug release and in drug carrier system applications, and the production method of these hydrogels, and is explained with references to examples without forming any restrictive effect only to make the subject more understandable.

In the invention, “smart material” is the class of materials whose chemical composition and physical condition are changing; it has one or more than one physicochemical characteristic that can substantially change by means of external factors (stimulant) like pressure, temperature, humidity, pH, electrical or magnetic field.

The subject of the invention, “hydrogel” describes three-dimensional polymer network structure do not dissolve when interacted with water but can inflate by taking big amount of water into its structure.

In the invention, “amphiphilic block copolymer” describes the structural units of polymeric micelles, macromolecules that have different hydrophobic and hydrophilic blocks.

In the invention, “polymeric micelle” describes spherical colloidal particles with nano-size and with hydrophilic periphery and hydrophobic core which exists in a liquid and which is formed by amphiphilic block copolymers.

In the invention, “pluronic” or “poloxamer” describes the structures where hydrophilic polyethylene oxide (PEO) and hydrophobic polypropylene oxide (PPO) chains are combined in the form of PEO-PPO-PEO triple block.

In the invention, “PF127” or “Pluronic F127” describes a member which exists in pluronic class and which has hydrophobic interactions both in terms of solubility and structure and which has wide application area since it can interact with different molecules. In the detailed description of the invention, it will be described with the term “PF127”.

The subject matter hydrogel comprises pluronic block copolymers as the basic component. As known in the art, pluronic block copolymers comprise hydrophilic PEO and hydrophobic PPO monomers. Pluronic copolymer which has said structure has amphiphilic block copolymer characteristics.

Accordingly, in the present invention, the hydrogel comprises pluronic block copolymers, obtained by means of polymerization synthesis known in the art, as the basic component, and said basic component functions as a frame in the determination of mechanical, chemical and physical characteristics of the hydrogel. The synthesis of the basic component which exists in the invention does not exist in the protection scope of the invention, and can be obtained by means of any kind of synthesis method.

As known in the art, pluronic copolymers are suitable for use as carrier agents in drug carrying systems since pluronic copolymers have been approved by FDA and have biocompatible characteristics for use on humans. However, the mechanical strength of pluronic copolymers and the hydrogel and similar smart material obtained from these are substantially weak. Pluronic copolymers are expected to have a high mechanical strength in order to be able to be used in mediums like the human body where there are various mechanical factors that are substantially complex.

In order to eliminate said technical disadvantage, the present invention holders have worked to obtain modified pluronic hydrogels whose mechanical strength characteristics have been improved for the related technical field. It has been detected by the present invention holders that said modification must be provided by using chromophore functional groups. Accordingly, in the present invention, while it is aimed to increase the mechanical properties of pluronic hydrogels, said configuration is realized by mixing with amphiphilic copolymers where at least one type of chromophore functional group is added to the repeated units of pluronic hydrogels.

In the invention, “chromophore” is described as the part where absorption of the molecule continues and where the main change in the geometry or electron density, etc. occurs after the stimulation process. In a preferred application in the invention, one or both azobenzene and/or coumarin compounds are used as the chromophore.

In the present invention, by adding amphiphilic copolymers, comprising chromophore groups in repeated units, to pluronic solutions, the structures that are already sensitive to temperature also become sensitive to light thanks to chromophore groups. Accordingly, the basic aim is that the subject matter hydrogel has amphiphilic structure. For this purpose, in order to provide becoming micelle of this polymer in water by forming an amphiphilic structure, chromophore groups are expected to form hydrophobic blocks because they are hydrophobic.

Thanks to all of the mentioned chromophore-pluronic copolymer interactions, hydrogels comprising said basic component may have improved mechanical, physical and chemical properties. Moreover, while all of these are provided, the obtained hydrogel still has high biocompatible, and can be used as an agent in drug carrying systems.

The subject matter hydrogel has high mechanical strength and is sensitive to heat and light. It passes from solution form into gel form over a specific temperature. Accordingly, hydrogel has a form that can be injected into the body.

In the invention, in the tests, PF127 reference samples and various PF127-Mx micelle solutions are used. Mx values that exist at the parts coded as PF127-Mx are the indicator of micelle solutions. Micelle solutions which correspond to M1 , M2, M3 and M4 codes are respectively obtained from PEG-b-P(tBMA-r-CEMA)-1 , PEG-b-P(tBMA-r-CMA)-1 , PEG-b- P(tBMA-r-CEMA)-2 and PEG-b-P(tBMA-r-CMA) polymers. Here, said CEMA and CMA structures are coumarin structures known in the art.

In Figure 1 , the temperature profile graphics of PF127 and PF127-Mx systems are shared. In the invention, a rapid increase is observed in G’ value by means of sol-gel transition for PF127 system together with the temperature increasing as expected in accordance with said arguments.

When the relation between gel strength and frequency is taken into account, the increase of the strength of gels by means of UV irradiation can be determined by means of characterization studies as shown in Figure 2.

In Figure 3, the change graphics of elastic module (G’) values as a function of time before and after UV radiation are given. The samples have been subjected to test by applying such that the UV device is in turned off and in turned on state for 10 minutes. The elastic modules (G’) of gels subjected to test have been monitored as a function of time at a fixed cutting speed and frequency. The formulations placed between plates of the rheometer have been first measured without UV light radiation. It has been detected that the G modulus values of the structures comprising CEMA before UV are higher than the structures comprising CMA. After UV radiation for 10 minutes, a rapid increase in G’ value has been observed in all systems that have UV effect at 24°C.

The hydrogel component, whose disadvantages are known in the art but which has biocompatible approved by FDA and which can be used in various applications like biocompatible smart materials or drug carrying systems thanks to this characteristic, can be added to pluronic copolymers and particularly chromophore functional groups for improving mechanical strength values can be added. The mechanical strength values of hydrogels, comprising the modified pluronic copolymers as a component, have been increased, and the physical, chemical characteristics thereof have been stabilized. In this perspective, the usage of the obtained hydrogels as biomaterial shall further increase.

The protection scope of the present invention is set forth in the annexed claims and cannot be restricted to the illustrative disclosures given above, under the detailed description. It is because a person skilled in the relevant art can obviously produce similar embodiments under the light of the foregoing disclosures, without departing from the main principles of the present invention.