A dermal filler formulation containing polymeric nanoparticles and a method for the production of this formulation

Abstract

The invention belongs to the technical field of dermatology and relates to a dermal filler formulation containing polymeric nanoparticles that creates volume in various parts of the skin for cosmetic or medical purposes, removing lines, wrinkles, irregularities caused by trauma and / or moisturizing, as well as removing or minimizing infections frequently encountered during dermal filler applications.

Description

[0001] A DERMAL FILLER FORMULATION CONTAINING POLYMERIC NANOPARTICLES AND A METHOD FOR THE PRODUCTION OF THIS FORMULATION

[0002] TECHNICAL FIELD

[0003] The invention belongs to the technical field of dermatology and relates to a dermal filler formulation containing polymeric nanoparticles that creates volume in various parts of the skin for cosmetic or medical purposes, removing lines, wrinkles, irregularities caused by trauma and / or moisturizing, as well as removing or minimizing infections frequently encountered during dermal filler applications.

[0004] The invention also relates to a method for the production of a characterized dermal filler formulation containing polymeric nanoparticles.

[0005] PRIOR ART

[0006] During the natural aging process of the skin, there is a decrease in subcutaneous adipose tissue and dermal support tissue, and the skin becomes thinner and loses its elasticity. In addition to superficial and deep wrinkles, the cheeks and lips begin to lose their fullness, and unwanted skin imperfections may appear. Today, many methods have been developed in facial aesthetics in order to look younger and flawless. Among these methods, dermal filler injections are a reliable alternative for those who do not prefer plastic surgery operations.

[0007] Filler injection is the process of placing various fillers into the dermis. The injected material creates volume in the dermis and provides removal of lines and wrinkles. It is an ideal treatment for static wrinkles on the skin. These substances can be used not only to remove wrinkles, but also to moisturize the skin and remove irregularities that occur as a result of trauma.

[0008] The components in dermal filler formulations should consist of components that can be applied to the skin, as well as have vascularization, thickness, tension, mechanical movements, tissue surface and line and wrinkle depth suitable for the skin. At the same time, it is expected that the permanence of the patients will be high and the side effects will be low.

[0009] For the relevant technical field, studies are continuing to obtain new dermal filler formulations that are suitable for the expectations of patients and provide additional technical solutions and advantages.

[0010] BRIEF DESCRIPTION OF THE INVENTION

[0011] The technical field to which the present invention relates is the technical field of dermatology.

[0012] The present invention relates to dermal filler formulations suitable for use in the skin for medical and / or cosmetic purposes to create volume by injecting it into the skin and thus to remove irregularities caused by trauma, especially scratches and / or wrinkles due to aging.

[0013] The dermal filler formulation of the present invention is injectable into the skin. It has suitable vascularization, thickness, tension, tissue surface, mechanical movements, line and / or wrinkle depth for the skin.

[0014] The dermal filler formulation, which has all of these properties, also has compatible components for the skin and does not cause late complications and side effects.

[0015] Together with the components therein, the dermal filler formulation helps to minimize the infections that occur after the injection.

[0016] DETAILED DESCRIPTION OF THE INVENTION

[0017] In this detailed description, the subject of the invention relates to a dermal filler formulation for the skin and is explained only with examples that will not create any limiting effect for a better understanding of the subject.

[0018] The dermal filler formulation of the present invention is injectable into the skin. With the tests performed in the skin area, it is possible to obtain a formulation with characterizing parameters suitable for the skin. The main feature of the dermal filler formulation is to add volume to the skin according to the scratches and / or wrinkles and / or irregularities on the skin.

[0019] Accordingly, the main component of the dermal filler formulation is hyaluronic acid (hereinafter abbreviated as HA). HA, as it is known in the art, is the main component in the polysaccharide structure naturally found in the dermis layer. Wrinkles, scratches and / or irregularities in the dermis layer of the skin also cause HA loss. As the main component, HA is a pioneer in regaining the targeted volume by adding it in predetermined amounts when it is lost in wrinkles, scratches and / or irregularities and therefore causes volume loss. In addition, due to its structure, HA allows elasticity to be gained instead of elasticity loss.

[0020] The dermal filler formulation of the present invention comprises HA component with certain molecular weights. In preferred applications, the HA component is expected to have a molecular weight in the range of 500 kDa and 4000 kDA. The HA component, which has a molecular weight lower than the determined values, can cause inflammation.

[0021] The dermal filler formulation of the present invention comprises the HA component at a concentration of 10 mg / ml to 25 mg / ml.

[0022] The dermal filler formulation of the present invention comprises the HA component with determined weight amounts and molecular weights in hydrogel form with cross-linking processes. In this invention, at least one of the group of compounds polyethylene glycol) diglycidyl ether (abbreviated as PEGDE), divinyl sulfone (abbreviated as DVS), 1 -ethyl- 3-(3 dimethylaminopropyl) carbodiimide (abbreviated as EDC), 1 ,2,7,8-diepoxyoctane and glutaraldehyde (abbreviated as GA), 1 ,4-butanediol diglycidyl ether (abbreviated as BDDE) is used for the performance of cross-linking processes so that HA can be in hydrogel form. Here, the amount of the cross-linker is determined by the amount of HA that should be included in the dermal filler formulation. In a preferred application, the amount of the cross-linker is between 1% and 5% by weight of the HA contained in the dermal filler formulation. The hydrogel obtained after cross-linking is a longer-lasting material than it was before cross-linking. With this process, the duration of HA in the body increases even more. The more cross-linkers used, the harder and denser the gel is obtained. Another main component in the dermal filler formulation of the present invention is the L-Lysine component. As is known, L-Lysine is an amino acid that is one of the 20 essential amino acids. The expression L, as is known, indicates that it is left rotary (known as levorotatory in the technique). It is involved in gaining the elasticity and strength of the skin and repairing the tissues for the filling process to be performed on the skin. Today, the amino acid L-lysine is used in the treatment of HSV infections. It is offered to patients in tablet forms. With the research and development studies carried out by the present inventors, the amino acid L-lysine is available as the main component together with HA in dermal filler formulation. In addition to the functions of elasticity, strength and repair of tissues for the skin, it allows the infections such as HSV to be minimized at least after filler injections. The L-Lysine component is one of the key components that is also used by the body for the production of collagen. Collagen increases skin elasticity. Adequate intake of L-Lysine makes the skin healthier. In addition, L-Lysine can contribute to the wound healing process. Collagen supports tissue repair, which is necessary for the healing of wounds. Increasing the intake of L-Lysine can speed up this process.

[0023] L-lysine is a component that can be taken into the body in certain weight ratios as it is known in the art. One of the innovative aspects of the present invention is the determination of the quantities of L-Lysine component suitable for the injectable dermal filler formulation. In dermal filler formulation, the L-lysine component can be contained in a concentration value in the range of 1 mg / ml to 20 mg / ml.

[0024] The dermal filler formulation of the present invention contains polymeric nanoparticles obtained by electrostatic interactions of L-Lysine and HA components. This electrostatic interaction takes place between the positively charged amino groups in the L-Lysine component and the negative carboxylate groups in the HA component. Accordingly, in the most preferred embodiment of the present invention, L-Lysine and HA components are included as polymeric nanoparticle form in dermal filler formulation. Polymeric nanoparticles can be included in the present invention to provide injection, transfer and controlled release of components into the skin. Polymeric nanoparticles are used to optimize this process and deliver components to the body in a more effective and controlled manner. Accordingly, the dermal filler formulation of the present invention contains polymeric nanoparticles containing HA and L-Lysine-HA in the form of cross-linked hydrogels.

[0025] In this invention, the previously provided amounts of HA and L-Lysine were determined for the production of HA hydrogels and polymeric nanoparticles containing HA-L-Lysine. In addition, having parameter values to be injected compatible with the skin area can be achieved with determined amounts.

[0026] The dermal filler formulation of the present invention may contain additional side components if preferred. In particular, the dermal filler formulation may contain at least one of the anti-inflammatory and / or analgesic compounds.

[0027] If preferred, the dermal filler formulation of the present invention contains the lidocaine hydrochloride compound as a pain reliever.

[0028] The dermal filler formulation of the present invention may contain pH-regulating compounds to optimize the pH value of the targeted final product.

[0029] The innovative aspect of the invention here is the formulation of components that have different uses with different functions in the art in the form of injectable hydrogel suitable for use in dermal filler injection processes. In order for this formulation to be in the mentioned configurations, it is essential that the components are within the value ranges determined within the formulation. In addition, there are some parameters that the formulation must have in order to be suitable for scratches, wrinkles or volumizing processes in some parts of the skin. Accordingly, the formulation may vary according to pH, osmolality, elastic modulus, tand, particle size, residual BDDE value, bacterial endotoxin, bioburden values, injection site and the problem.

[0030] The present invention also includes corresponding research and development studies. Accordingly, if the dermal filler formulation of the present invention has a configuration for the removal of fine wrinkles and the improvement of skin quality, it has the characterizing parameters provided in Table 1.

[0031] Table 1. Configuration of the dermal filler formulation of the present invention for the removal of fine wrinkles and the improvement of skin quality

[0032] Accordingly, if the dermal filler formulation of the present invention has a configuration for lip volumizing and removal of medium-depth wrinkles, it has the characterizing parameters provided in Table 2.

[0033] Table 2. Configuration of dermal filler formulation for lip volumizing and removal of medium-depth wrinkles Accordingly, if the dermal filler formulation of the present invention has a configuration for the removal of deep wrinkles and filling the areas of volume deficiency, it has the characterizing parameters provided in Table 3. Table 3. Configuration of dermal filler formulation for the removal of deep wrinkles and filling the areas of volume deficiency

[0034] The injectable dermal filler formulation obtained within the scope of the present invention is a viscoelastic gel to be used in the field of dermatology to maintain the natural balance of the dermis in the process of photoaging, to maintain natural remodeling by increasing collagen synthesis and reducing its destruction, to minimize oxidative stress due to photoaging and inflammation, and to correct cosmetic defects.

[0035] Cross-linked HA developed in the present invention can be used in dermatology and orthopedic applications as well as drug delivery systems. The polymeric nanoparticles in the formulation facilitate the controlled release of the drug active ingredient.

[0036] In a preferred application, formulations are filled into glass or plastic syringes with a filling volume of 1 to 5 ml and injected by the specialist into the related skin areas, as characterized by the invention.

[0037] The present invention also provides a method for the production of the characterized dermal filler formulation. The production method of the present invention comprises the following basic process steps.

[0038] Synthesis of polymeric nanoparticles The synthesis of the polymeric nanoparticles mentioned here can be achieved by electrostatic interactions between the positively charged amino group of L-lysine and the negatively charged carboxylate groups of HA.

[0039] As the first process step, 1 to 7.5 ml of L-Lysine aqueous solution between 0.1 and 0.75 mg / ml concentration values is prepared.

[0040] Separately, an aqueous solution of 1 to 7.5 ml of HA is prepared at a concentration value in the range of 0.5 to 5 mg / ml.

[0041] The resulting water-L-lysine solution is added to a mixer and while mixing at a constant value, water-HA solution is dropped at a rate of 1 to 3 ml / min and polymeric nanoparticles can be obtained. The obtained polymeric nanoparticles are centrifuged at a value between 500 and 5000 rpm for 5 to 20 minutes. The polymeric nanoparticles obtained as a result of these processes were dried at 30 to 50 °C for at least 24 hours.

[0042] Synthesis of cross-linked HA hydrogels

[0043] First, sodium hyaluronate and sodium hydroxide solution is prepared. Here, the concentration value of sodium hyaluronate is a value in the range of 0.1 to 0.5 M. Sodium hyaluronate is present in the sodium hydroxide solution-sodium hyaluronate solution in the range of 10% to 20% by weight.

[0044] At least one cross-linker is added to the resulting solution for the realization of crosslinking operations and mixing operations are carried out. The said cross-linking compound is adjusted to be 1% to 5% of HA by weight. This mixture is subjected to cross-linking processes for at least 180 minutes at a constant temperature between 30 and 50 °C. At the end of these periods, preferably 0.1 M hydrochloric acid is added to the mixture in gel form to adjust the pH value to 7.

[0045] Swelling processes are carried out to bring the sodium hyaluronate obtained as a result of all these processes to the targeted weight amounts in the dermal filler formulation. For this purpose, it is necessary to carry out dialysis in a buffer solution. Preferably, phosphate-based buffer solution can be used for these processes. Preparation of injectable dermal filler formulation

[0046] Polymeric nanoparticles containing L-lysine and HA obtained in the previous process steps and hydrogels containing HA are mixed with a mixer for at least 20 minutes. The said mixing process is preferably carried out at a value between 100 and 500 rpm.

[0047] After mixing for the specified time, lidocaine hydrochloride component is added to the mixture to reduce injection pain for the skin, and sodium hydroxide solution is added to increase the pH value resulting from the addition of this compound, respectively.

[0048] The amount of said lidocaine hydrochloride is in the range of 1 to 5 mg / ml for the mixture.

[0049] The amount of sodium hydroxide solution referred to here is in the range of 0.5% to 1 .5% by weight for the mixture.

[0050] The mixture obtained by adding the mentioned chemicals is subjected to the mixing process again. The mixing process is carried out for at least 20 minutes. The mixing process is preferably carried out at a value between 100 and 500 rpm.

[0051] The resulting precursor dermal filler formulation in gel form is subjected to gel vacuuming.

[0052] As a result of all these processes, the dermal filler formulation of the present invention can be added to the injection devices for the procedures.

[0053] The protection scope of the invention is specified in the appended claims and cannot be limited to what is described in this detailed description for illustrative purposes. It is clear that a person skilled in the art can present similar structures in the light of the above, without leaving the main theme of the invention.

Claims

CLAIMS1. A dermal filler formulation that can be injected into the skin for cosmetic or medical purposes, characterized by comprising the following components:- cross-linked hyaluronic acid hydrogel obtained by the interaction of at least one cross-linker, and- polymeric nanoparticles obtained from the electrostatic interactions between hyaluronic acid and L-Lysine components.

2. A dermal filler formulation according to Claim 1 , characterized in that HA has a molecular weight in the range of 500 to 4000 kDa.

3. A dermal filler formulation according to one of the preceding claims, characterized in that HA component has a concentration value between 10 mg / ml and 25 mg / ml.

4. A dermal filler formulation according to one of the preceding claims, characterized in that said crosslinker is at least one of the group of polyethylene glycol) diglycidyl ether, divinyl sulfone, 1 -ethyl-3-(3 dimethylaminopropyl) carbodiimide, 1 ,2,7,8-diepoxyoctane and glutaraldehyde, 1 ,4-butanediol diglycidyl ether compounds.

5. A dermal filler formulation according to Claim 4, characterized in that the amount of the cross-linker is between 1% and 5% by weight of the total amount of HA in the formulation.

6. A dermal filler formulation according to one of the preceding claims, characterized in that the amount of said L-Lysine has a concentration in the range of 1 mg / ml to 20 mg / ml.

7. A dermal filler formulation according to one of the preceding claims, characterized in that the elastic modulus value is in the range of 50 to 250 Pa when it is used to remove fine wrinkles and improve skin quality.

8. A dermal filler formulation according to one of the preceding claims, characterized in that the complex viscosity value is in the range of 10 to 40 Pa.s when it is used to remove fine wrinkles and improve skin quality.

9. A dermal filler formulation according to one of the preceding claims, characterized in that the particle size is in the range of 50 to 350 pm when it is used to remove fine wrinkles and improve skin quality.

10. A dermal filler formulation according to one of the preceding claims, characterized in that the tand value is in the range of 0.1 to 0.4 when it is used to remove fine wrinkles and improve skin quality.

11. A dermal filler formulation according to one of Claims 1 -6, characterized in that the elastic modulus value is in the range of 100 to 400 Pa when it is used for lip volumizing and removal of medium-depth wrinkles.

12. A dermal filler formulation according to one of Claims 1 -6, characterized in that the complex viscosity value is in the range of 15 to 75 Pa.s when it is used for lip volumizing and removal of medium-depth wrinkles.

13. A dermal filler formulation according to one of Claims 1 -6, characterized in that the particle size is in the range of 100 to 500 pm when it is used for lip volumizing and removal of medium-depth wrinkles.

14. A dermal filler formulation according to one of Claims 1 -6, characterized in that tand value is in the range of 0.1 to 0.3 when it is used for lip volumizing and removal of medium-depth wrinkles.

15. A dermal filler formulation according to one of Claims 1 -6, characterized in that the elastic modulus value is in the range of 150 to 800 Pa when it is used for the removal of deep wrinkles and filling the areas of volume deficiency.

16. A dermal filler formulation according to one of Claims 1 -6, characterized in that the complex viscosity value is in the range of 50 to 250 Pa.s when it is used for the removal of deep wrinkles and filling the areas of volume deficiency.

17. A dermal filler formulation according to one of Claims 1 -6, characterized in that the particle size is in the range of 150 to 1000 pm when it is used for the removal of deep wrinkles and filling the areas of volume deficiency.

18. A dermal filler formulation according to one of Claims 1 -6, characterized in that the tand value is in the range of 0.075 to 0.25 when it is used for the removal of deep wrinkles and filling the areas of volume deficiency.

19. A method for the production of a dermal filler formulation according to one of the preceding claims, characterized by comprising the following process steps: obtaining polymeric nanoparticles o preparing 1 to 7.5 ml of L-Lysine aqueous solution between 0.1 and 0.75 mg / ml concentration values, o preparing an aqueous solution of 1 to 7.5 ml of HA at a concentration value in the range of 0.5 to 5 mg / ml, o obtaining polymeric nanoparticles by adding water-L-lysine solution into a mixer and dropping water-HA solution at a rate of 1 to 3 ml / min while mixing at a constant value, obtaining cross-linked HA hydrogels o preparing sodium hyaluronate and sodium hydroxide solution, o adding at least one cross-linker to the resulting solution and the carrying out of mixing operations,- preparing the injectable dermal filler formulation o mixing cross-linked HA hydrogels with polymeric nanoparticles, o gel vacuuming.

20. A method according to Claim 19, characterized in that the resulting polymeric nanoparticles are centrifuged at a value between 500 and 5000 rpm.

21. A method according to Claim 20, characterized in that the polymeric nanoparticles are centrifuged for a period of 5 to 20 minutes.

22. A method according to one of the Claims 19-21 , characterized in that the polymeric nanoparticles are subjected to drying for at least 24 hours at a constant temperature between 30 and 50 °C.

23. A method according to one of the Claims 19-22, characterized in that the sodium hyaluronate compound is present in the sodium hydroxide solution-sodium hyaluronate solution in the range of 10% to 20% by weight.

24. A method according to one of the Claims 19-23, characterized in that said crosslinker is at least one of the group of polyethylene glycol) diglycidyl ether, divinyl sulfone, 1 -ethyl-3-(3 dimethylaminopropyl) carbodiimide, 1 ,2,7,8-diepoxyoctane and glutaraldehyde, 1 ,4-butanediol diglycidyl ether compounds.

25. A method according to Claim 24, characterized in that the amount of the crosslinker is between 1 % and 5% by weight of the total amount of HA in the formulation.

26. A method according to one of the preceding claims, characterized in that the crosslinker-HA solution is subjected to stirring for at least 180 min at a constant temperature between 30 and 50 °C.

27. A method according to one of the preceding claims, characterized in that the process of mixing polymeric nanoparticles with cross-linked HA hydrogels is carried out at a value between 100 and 500 rpm.

28. A method according to one of the preceding claims, characterized in that the process of mixing polymeric nanoparticles with cross-linked HA hydrogels is carried out for at least 20 min.

29. A method according to one of the preceding claims, characterized in that lidocaine hydrochloride is added into polymeric nanoparticles and cross-linked HA hydrogels.

30. A method according to Claim 29, characterized in that the amount of lidocaine hydrochloride added is between 0.5% and 1 .5% by weight in the formulation.

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