An aloe vera GEL formulation containing solid lipid nanoparticles and production method

Abstract

The invention relates to an aloe vera gel formulation containing betamethasone valerate-loaded solid lipid nanoparticles developed for use in the health and pharmaceutical sectors, and in particular in eczema treatments, as well as to a production method of the same

Description

[0001] DESCRIPTION

[0002] AN ALOE VERA GEL FORMULATION CONTAINING SOLID LIPID NANOPARTICLES AND PRODUCTION METHOD

[0003] Technical Field

[0004] The invention relates to an aloe vera gel formulation containing betamethasone valerate-loaded solid lipid nanoparticles developed for use in the health and pharmaceutical sectors, and in particular in eczema treatments, as well as to a production method of the same.

[0005] State of the Art

[0006] Atopic dermatitis, commonly known as eczema, is an epidermal disease that occurs acutely or chronically due to genetic and environmental factors. Although eczema can occur in people of all ages, the symptoms and the areas affected by the disease can change with age. Eczema causes problems such as itching, burning, and redness that can limit the patient's daily life. Eczema is a disease seen in people with atopic tendencies, affecting 20-25% of children and 2-3% of adults. Eczema most commonly starts in infancy between 3-6 months. While most patients recover during adolescence, 10-30% of a patient group do not recover. Hand eczema, which is the most common type of eczema, according to the data obtained in the researches, it is seen that 5.5 out of every 1000 people have hand eczema annually. When classified according to gender, this rate was found to be 9.6 per 1000 in women and 4.0 per 1000 in men. According to a study conducted in Sweden, the incidence rate of hand eczema was highest in women aged 20-29 years (11.4 per 1000 people per year), compared to 6.3 and 4.8 per 1000 people per year in women aged 10-19 and 30-65 years, respectively. It has been found that the rate of incidence in men increases as they approach the age of 23 [1],

[0007] In the current state of the art, there are many types of eczema treatments. The most effective of these are topical corticosteroids and calcineurin inhibitors. Topical corticosteroids have antiinflammatory properties and calcineurin inhibitors have immunosuppressive properties. Commonly used high potency topical corticosteroids are clobetasol propionate, mometasone furoate. Other commonly used calcineurin inhibitors are pimecrolimus and tacrolimus. Topical calcineurin inhibitors, tacrolimus and pimecrolimus, which exert their effects by inhibiting calcineurin phosphatase, a cytoplasmic enzyme, suppress the synthesis of inflammatorycytokines in T cells, keratinocytes, and Langerhans cells. Both tacrolimus and pimecrolimus are not approved for use under 2 years of age. Whether long-term use predisposes to malignancy is one of the most controversial issues regarding the use of topical calcineurin inhibitors.

[0008] Calcineurin inhibitors have certain side effects depending on the dose used. These include nephrotoxicity, glucose intolerance, alopecia for tacrolimus and various side effects such as burning, stinging, itching, reactions at the site of application (erythema, skin discoloration), and fever for pimecrolimus. The effects of topical corticosteroids on eczema are due to their suppressive properties on inflammation. They bind to intracellular corticosteroid receptors and suppresses many genes, especially genes encoding proinflammatory cytokines.

[0009] The most important point to be considered in the use of corticosteroids in order to achieve an effective result and to protect the patient from side effects is the selection of the right strength and appropriate carrier. In this decision, factors such as the characteristic of the lesion, its location, and the patient’s age should be taken into account. Very strong topical corticosteroids should not be used on the face, eyelids, genital area, neck and intertriginous areas, which are more sensitive to local side effects. Since infants and children are more at risk for both local and systemic side effects than adults, very strong steroids should not be used in patients in this age group.

[0010] Side effects of topical corticosteroids include burning, stinging, redness, open wounds, itching, thinning of the skin barrier, changes in skin color, worsening and spreading of existing skin problems, atrophy, acneiform rashes, rosacea, perioral dermatitis, hypertrichosis, telangiectasia / purpura / stria formation, hypopigmentation, aggravation of skin infections, delayed wound healing. These side effects are more likely with prolonged and widespread use and with the use of highly potent corticosteroids. To minimize possible side effects, it is recommended to switch to another drug of lower strength.

[0011] Betamethasone valerate (Betamethasone 17-valerate) is a steroid ester, betamethasone, in which the hydroxy group at the 17 alpha position has been converted to the corresponding pentanoate ester and has the molecular formula C27H37FO6.

[0012] In general terms, drug delivery systems aim to minimize the problems that arise in drug use and to provide more effective delivery of the drug to the target tissue. Targeted drug deliverysystems enable drugs to be delivered to the target more efficiently and more practically than current drugs. Failure of drugs to show their effects in a certain period of time, the inability of the active substance to overcome the barrier in the body and act on the target area or the effect of the active substance on tissues outside the targeted area are undesirable events. Drug carriers are used to solve these phenomena. However, these drug carriers have some shortcomings in terms of ease of application for topical use. These drug carriers may resist drug passage due to the hydrophobic nature of the stratum corneum layer of the skin. This limits the efficacy of particularly hydrophilic or large molecule drugs. Furthermore, topical formulations often have a low capacity to reach deep tissues or systemic circulation, limiting treatment efficacy. Formulation stability is another factor affecting the efficacy of drug delivery systems, and problems such as viscosity change, crystallization or degradation can be seen over time. In terms of use, the difficulty in providing homogeneous dosage, the need for frequent administration due to the short duration of action and the low comfort of the user in administering the drug may pose problems.

[0013] In a study of the state of the art, the role of dermal administration of active compounds in [2], liposomes and niosomes was examined. It was found that liposomes and niosomes can serve as solubilization matrices, as a local depot for sustained release of dermally active compounds, as penetration enhancers or as rate-limiting membrane barriers for modulation of systemic absorption of drugs. However, in studies on liposomes in general, researchers have conducted research on the same doses of different drugs, but data on their performance in different dosages have not been fully obtained. The thermodynamic activity and solubility of drugs in various formulations are different, resulting in differences in drug transport.

[0014] In another study [3]in another state of the art, a corticosteroid-encapsulated liposome in the treatment of eczema was found to be more effective than other drugs, even at a smaller ratio. Topical glucocorticoids are a first-line pharmacologic treatment, although there is limited data from studies to confirm their efficacy in the treatment of eczema.

[0015] There is a need to provide developments in order to eliminate said disadvantages stated above and in the state of the art.Summary of the Invention

[0016] In order to eliminate the above-mentioned disadvantages and to provide new advantages to the relevant technical field, the present invention relates to an aloe vera gel formulation containing betamethasone valerate-loaded solid lipid nanoparticles developed for use in the health and pharmaceutical sectors, and in particular in eczema treatments, as well as to a production method of the same.

[0017] The invention minimizes the toxic effects and side effects associated with the drugs used in eczema treatments and enhances drug delivery to cellular levels. In addition, by providing effective and safe treatment at low doses, the desired level of pharmacological response is achieved in the target area without damaging healthy tissues.

[0018] With the betamethasone valerate-loaded solid lipid nanoparticles contained in the invention, the toxic effect is reduced and possible side effects that may occur are minimized and a faster and more effective safe delivery to the target area is provided. In addition, these solid lipid nanoparticles (SLN) enable the active substance to reach the target tissue without showing activity outside the targeted area. It is thus protected in locations outside the targeted area.

[0019] Thanks to the aloe vera gel contained in the invention, skin with impaired epidermal barrier function due to eczema is easily moisturized and soothed. Furthermore, this method eliminates the disadvantages associated with the ointments and creams currently used by patients to treat eczema, such as the greasy and sticky sensation they leave on the treated areas due to their high lipid content, the itching and sweating they cause, and the damage to the epidermis resulting from the need to apply them by rubbing.

[0020] With the invention, the solid lipid nanoparticle (SLN) encapsulates the drug, increasing the delivery speed and efficiency of the drug and preventing the drug from acting in non-targeted areas.

[0021] The invention provides the development of a drug delivery system suitable for most age profiles and with fewer side effects by using betamethasone valerate with high / normal potency.

[0022] The invention offers a more effective and targeted treatment with fewer side effects than the highly potent corticosteroids used in the current art, and has a wider range of uses and a widerage range. In particular, thanks to the aloe vera gel contained in the product, it offers a more water-based, non-perspirative, and easily applied possibility / option, rather than the greasy texture of other creams and ointments used in current treatments for patients living in humid regions who sweat profusely.

[0023] The drug delivery system contained in the gel formulation subject to the invention is included in the aleo vera gel, and by loading and applying the drug on solid lipid nanoparticles, the rate of action, effectiveness and absorption of the drug from the skin are increased. Solid lipid nanoparticles reduce the dosage of the drug that should be used in treatment by affecting the area that the drug should affect at higher rates, thus protecting patients from possible side effects and providing a positive effect on their economic status by using the drug for a shorter period of time. At the same time, thanks to the antimicrobial, anti-inflammatory, wound healing, antioxidant and immune-boosting properties of aloe vera extract, the disease-causing factors are treated and the possibility of disease recurrence are reduced.

[0024] Description of the Drawings

[0025] The embodiments of the invention, briefly summarized above and discussed in more detail below, can be understood with reference to the example embodiments of the invention described in the accompanying drawings. It should be noted, however, that the accompanying drawings only illustrate typical embodiments of this invention and are not to be considered as limiting to its scope.

[0026] Fig. 1. A representative SEM image of a solid lipid nanoparticle (SLN) in the empty state. Fig. 2. A representative SEM image of a solid lipid nanoparticle (SLN) loaded with betamethasone valerate (BMV).

[0027] Fig. 3. A representative view of the FT-IR plot of a solid lipid nanoparticle.

[0028] Fig. 4. A representative view of the FT-IR plot of cetyl palmitate loaded with betamethasone valerate.

[0029] Fig. 5. A representative view of the in vitro drug release graph at pH 5.5, 37°C and 32°C. Fig.6. A representative view of the in vitro drug release graph at pH 7.4 and temperatures 37°C and 32°C.

[0030] Fig. 7. A representative view of the in vitro free drug release graph at pH 7.4 and 37°C.

[0031] Fig. 8. A representative view of the in vitro free drug release graph at pH 5.5 and 37°C.Detailed Description of the Invention

[0032] The example embodiments are described in more detail below with reference to the accompanying descriptions. Furthermore, the embodiments can be established in different forms and should not be interpreted as being limited to the embodiments specified herein. Rather, these example embodiments are provided so that this description will be thorough, and will fully convey the scope to those skilled in the art.

[0033] The invention relates to the synthesis of a solid lipid nanoparticle (SLN), the loading of betamethasone valerate into the synthesized solid lipid nanoparticle, the formulation of a gel with aloe vera and betamethasone valerate-loaded solid lipid nanoparticles, and the production method of said gel formulation by performing characterization analysis studies of the solid lipid nanoparticle and betamethasone valerate solid lipid nanoparticle and in vitro drug release tests. The gel formulation subject to the invention is used topically in the health and pharmaceutical sectors and especially in eczema treatments.

[0034] The invention relates to a gel formulation for use in eczema treatments particularly, and comprises:

[0035] aloe vera extract,

[0036] a cross-linked polyacrylic acid polymer gel, and

[0037] drug nanoparticle dispersion.

[0038] The cross-linked polyacrylic acid polymer gel mentioned in said formulation is Carbopol 940.

[0039] In an embodiment of the invention, the gel formulation subject to the invention for use in eczema treatments comprises:

[0040] aloe vera extract in the range of 20-21% by weight,

[0041] a cross-linked polyacrylic acid polymer gel in the range of 55-56% by weight, and drug nanoparticle dispersion in the range of 23–24% by weight.

[0042] Said drug nanoparticle dispersion comprises:

[0043] cetyl palmitate,

[0044] surfactant,

[0045] - betamethasone valerate, anddistilled water.

[0046] In one embodiment of the invention, the drug nanoparticle dispersion comprises:

[0047] cetyl palmitate in the range of 4-5% by weight.

[0048] surfactant in the range of 1-2% by weight,

[0049] - betamethasone valerate at 0.01% by weight, and

[0050] distilled water in the range of 88-89% by weight.

[0051] In the invention, 23-24% by weight of the drug nanoparticle dispersion mixture, whose weight percentages are given in the invention, is used in the gel formulation subject to the invention. Thus, the gel formulation subject to the invention comprises aloe vera extract, a cross-linked polyacrylic acid polymer gel, cetyl palmitate, surfactant, and betamethasone valerate.

[0052] The surfactant mentioned in said drug nanoparticle dispersion is polysorbate 80.

[0053] The invention relates to the production method of a gel formulation for use in eczema treatments and comprises the following process steps:

[0054] i. melting cetyl palmitate in a water bath and dissolving betamethasone valerate in acetonitrile-distilled water mixture and adding it to the melted cetyl palmitate, ii. preparing and heating the surfactant in aqueous phase,

[0055] iii. to cetyl palmitate to which betamethasone valerate solution was added, adding the heated aqueous phase and mixing in a homogenizer,

[0056] iv. homogenizing the mixture in a sonic bath and gradually cooling its temperature and raising its temperature to room temperature after cooling,

[0057] v. obtaining drug-bound nanoparticles by placing the mixture in dialysis bags and dialyzing it against distilled water at room temperature,

[0058] vi. adding a cross-linked polyacrylic acid polymer gel to distilled water in a separate container and mixing, then adding triethanolamine in a mixer to obtain a gel mixture, vii. adding aloe vera extract to said gel mixture,

[0059] viii. adding the drug-bound nanoparticles mentioned in step (v.) to the mixture.In a preferred embodiment of the invention, a production method of a gel formulation for use in eczema treatments comprises the process steps of:

[0060] i. melting cetyl palmitate in a water bath at a temperature of 65°C and dissolving betamethasone valerate in a 1:1 mixture of acetonitrile-distilled water to achieve a concentration of 1 mg / ml and adding it to the melted cetyl palmitate,

[0061] ii. preparing the surfactant in aqueous phase to a final concentration of 2% by weight (g / g) and heating to 65°C,

[0062] iii. to cetyl palmitate to which betamethasone valerate solution was added, adding the heated aqueous phase and mixing in a homogenizer at 22,000 rpm for 2 minutes, iv. homogenizing the mixture in a sonic bath for 1 minute and gradually cooling the temperature, first at 4°C and then increasing it at room temperature to 25°C, v. obtaining drug-bound nanoparticles by placing the mixture in pre-soaked dialysis bags for 4 hours, and dialyzing it against distilled water at room temperature,

[0063] vi. adding a cross-linked polyacrylic acid polymer gel to distilled water in a separate container and stirring continuously for 16-18 hours at 1200 rpm in a magnetic stirrer until swelling and adding 1% by weight triethanolamine at 3000 rpm in a mechanical stirrer at the end of stirring to obtain the gel mixture,

[0064] vii. adding aloe vera extract at 20-21% by weight to said gel mixture,

[0065] viii. adding 23-24% by weight of the drug-bound nanoparticles mentioned in step (v.) to the mixture.

[0066] In the process step (i.) of the method steps subject to the invention, a temperature of 65°C, which is above the melting temperature of lipid, is preferred. In this way, the lipids remain in a melted state without being returned to their frozen state, allowing the formation of nanoparticles.

[0067] In process step (ii.) of the method steps subject to the invention, the preparation of the surfactant in the aqueous phase at a final concentration of 2% (g / g) by weight is carried out with distilled water. In a preferred embodiment of the invention, said surfactant is polysorbate 80.

[0068] In a preferred exemplary embodiment in process step (iii.) of the method steps subject to the invention, the total mixture volume is completed to 2 ml.In the process step (iv.) of the method steps subject to the invention, the temperature of the homogenized mixture in the sonic bath is gradually increased. First, it is cooled at 4°C, preferably in the refrigerator, and then it is brought to room temperature and its temperature is raised to room temperature, which is 25°C. With this step, nanoparticles are obtained.

[0069] Purified drug-bound nanoparticles are obtained with the process step (v.) of the method steps subject to the invention. The molecular weight cut-off (MWCO) of the dialysis bags mentioned in this process step is in the range of 12,000-14,000 Da. Furthermore, the room temperature specified in the same process step is 25°C in an exemplary embodiment of the invention.

[0070] The gel structure of carbopol, which is a cross-linked polyacrylic acid polymer gel in process step (vi.) of the method steps subject to the invention, is formed by using triethanolamine and pH adjustment is provided. In a preferred embodiment of the invention, said cross-linked polyacrylic acid polymer gel is Carbopol 940.

[0071] The aloe vera extracts mentioned in the process step (vii.) of the method steps subject to the invention are realized with the following process steps:

[0072] cutting the aloe vera leaves at the edges and removing the gel inside, homogenizing the gel with a blender and then filtering with cotton and funnel.

[0073] With the method steps subject to the invention, cream in gel form is obtained for use in eczema treatments.

[0074] The pH of the final gel obtained by the steps of the method subject to the invention was measured as 5.5-6 and it is at applicable values for the skin. The characterization of the solid lipid nanoparticles obtained from the process steps i-iv. of the production method of the gel formulation subject to the invention developed for use in eczema treatments has been carried out, and the chemical bonds of the obtained nanoparticles were determined by FTIR analysis and the size and morphology of the synthesized nanoparticles were determined by SEM analysis. According to the SEM analysis results, the size of the empty nanoparticles was found to be approximately 200 nm (Fig. 1) and the size of the drug-loaded nanoparticles was found to be approximately 495 nm (Fig. 2). According to the FTIR analysis results of the solid lipid nanoparticle, the following were observed: 2916 and 2847 cm-1 (C-H stretching band), 1732 cm-1 (C=O stretching band), 1462 cm-1 (C-H bond bending band), between 1090 and 1300cm-1 (C-0 bond stretching band), and 720 cm-1 (C-H bond bending band), as shown in Fig. 3. According to the literature, the characteristic peaks in the FTIR analysis of betamethasone valerate include the -OH stretching band at 3422 cm-1, the -CH stretching bands at 2955 and 2872 cm-1, the C=O stretching band at 1731 cm-1, the C=C stretching band at 1616 cm-1, and the -CF stretching bands at 1298 and 1264 cm-1[4]. According to the FRIR spectrum analysis of the betamethasone valerate-loaded cetyl palmitate mentioned in process steps v-vii. of the production method steps of the gel formulation subject to the invention developed for use in eczema treatment, the following were observed: 2916 and 2847 cm-1(C-H stretching band), 1732 cm-1(C=O stretching band), 1464 cm-1(C-H bending band), 1099 and 1182 cm-1(C-O stretching band), and 730 cm-1(C-H bending vibration), as shown in Fig. 4. These FTIR spectra analyses showed that the betamethasone valerate-solid lipid nanoparticle (BMV-SLN)-specific functional groups on the surface of the nanoparticles exhibited almost identical chemical properties to cetyl palmitate and displayed the main characteristic peaks of the entrapped drug.

[0075] Furthermore, in vitro drug release tests are practiced in the invention. In the aforementioned in vitro release studies, free betamethasone valerate and the obtained nanoparticles were placed in pre-soaked dialysis bags (12,000-14,000 MWCO) and performed at temperatures of 37°C ± 0.5°C and 32°C ± 0.5°C in pH 5.5 ± 0.05 and pH 7.4 ± 0.05 at a speed of 300 rpm. In in vitro release tests of the free drug, BMV is dissolved in acetonitrile water 1: 1 (v / v) and placed in presoaked dialysis bags and performed at 37°C ± 0.5°C 300 rpm at pH 5.5 ± 0.05 and pH 7.4 ± 0.05. As a result of in vitro drug release experiments, at pH 7.4, 18.27% BMV was released at 37°C and 11.44% at 32°C at the end of 48 hours as shown in Fig. 6. Whereas at pH 5.5, 24.66% BMV was released at 37°C and 15.89% at 32°C from the nanoparticle at the end of 48 hours, as shown in Fig. 5. In the in vitro release trials of the free drug; as shown in Fig. 7, at pH 7.4, more than 50% of the free BMV was released in the first 2.5 hours and 84% of the free BMV was released at the end of 24 hours. At pH 5.5, more than 50% of the free BMV was released in the first 2 hours and 99% of the free BMV was released at the end of 24 hours, and the relevant result graph is shown in Fig. 8.

[0076] The betamethasone valerate contained in the invention enables the drug to be delivered to the target tissue more effectively and quickly with less risk. Furthermore, the aleo vera plant contained in the invention provides anti-microbial, anti-inflammatory, wound-healing, antioxidant, immune-boosting properties, and it can be easily applied and spread on the skin due toits lower lipid and higher water content. In this way, patients can access a more effective, faster and more comfortable treatment method for eczema.

[0077] The above embodiments are intended only to describe the technical concept and features of the present invention, and the purpose of the present invention is to ensure that those skilled in the art understand the content of the present invention and practice the present invention, and the scope of the present invention is not limited thereto. Equivalent changes or modifications made in accordance with the spirit of the invention are intended to be included in the scope of the invention.

[0078] Industrial Applicability of the Invention

[0079] The invention relates to an aloe vera gel formulation containing betamethasone valerate-loaded solid lipid nanoparticles developed for use in the health and pharmaceutical sectors, and in particular in eczema treatments, as well as to a production method of the same, and is industrially applicable.

[0080] The invention is not limited to the example embodiments above, and the person skilled in the art can readily present other different embodiments of the invention. These should be considered within the protection scope of the invention claimed by the claims.References

[0081] [1] Thyssen JP, Johansen JD, Linneberg A, Menné T. The epidemiology of hand eczema in the general population— prevalence and main findings. Contact Dermatitis. 2010 Feb;62(2):75-87, doi: 10.1111 / j.1600-0536.2009.01669.x.

[0082] [2] Schreier, H., & Bouwstra, J. (1994). Liposomes and niosomes as topical drug carriers: dermal and transdermal drug delivery. Journal of controlled release. 50(1), 1-15, ISSN 0168- 3659, https: / / doi.org / 10.1016 / 0168-3659(94)90039-6.

[0083] [3] Maia, C. S., Mehnert, W., & Schäfer-Korting, M. (2000). Solid lipid nanoparticles as drug carriers for topical glucocorticoids. International journal of pharmaceutics, 196(2), 165-167, doi 10.1016 / s0378-5173 (99)00413-5.

[0084] [4] Pandey, M., Choudhury, H., Gunasegaran, T. A., Nathan, S. S., Md, S., Gorain, B.,... & Hussain, Z. (2019). Hyaluronic acid-modified betamethasone encapsulated polymeric nanoparticles: fabrication, characterisation, in vitro release kinetics, and dermal targeting. Drug delivery and translational research, 9, 520-533, doi: 10.1007 / s13346-018-0480-1.

Claims

CLAIMS1. A gel formulation, characterized in that it comprises:aloe vera extract,a cross-linked polyacrylic acid polymer gel, anddrug nanoparticle dispersion.

2. The gel formulation according to claim 1, characterized in that it comprises:aloe vera extract in the range of 20-21% by weight,a cross-linked polyacrylic acid polymer gel in the range of 55-56% by weight, and drug nanoparticle dispersion in the range of 23–24% by weight.

3. The gel formulation according to any one of claims 1-2, characterized in that said drug nanoparticle dispersion comprises:cetyl palmitate,surfactant,- betamethasone valerate, anddistilled water.

4. The gel formulation according to claim 3, characterized in that said drug nanoparticle dispersion comprises:cetyl palmitate in the range of 4-5% by weight,surfactant in the range of 1-2% by weight,- betamethasone valerate at 0.01% by weight, anddistilled water in the range of 88-89% by weight.

5. The gel formulation according to any one of the claims 1-4, characterized in that the cross-linked polyacrylic acid polymer gel mentioned is carbopol 940.

6. The gel formulation according to any one of Claims 1–4, characterized in that said surfactant is polysorbate 80.

7. A production method of the gel formulation, characterized in that it comprises the process steps of:i. melting cetyl palmitate in a water bath and dissolving betamethasone valerate in acetonitrile-distilled water mixture and adding it to the melted cetyl palmitate, ii. preparing and heating the surfactant in aqueous phase,iii. to cetyl palmitate to which betamethasone valerate solution was added, adding the heated aqueous phase and mixing in a homogenizer,iv. homogenizing the mixture in a sonic bath and gradually cooling its temperature and raising its temperature to room temperature after cooling,v. obtaining drug-bound nanoparticles by placing the mixture in dialysis bags and dialyzing it against distilled water at room temperature,vi. adding a cross-linked polyacrylic acid polymer gel to distilled water in a separate container and mixing, then adding triethanolamine in a mixer to obtain a gel mixture,vii. adding aloe vera extract to said gel mixture,viii. adding the drug-bound nanoparticles mentioned in step (v.) to the mixture.

8. The production method of the gel formulation according to claim 7, characterized in that it comprises the process steps of:i. melting cetyl palmitate in a water bath at a temperature of 65°C and dissolving betamethasone valerate in a 1: 1 mixture of acetonitrile-distilled water to achieve a concentration of 1 mg / ml and adding it to the melted cetyl palmitate,ii. preparing the surfactant in aqueous phase to a final concentration of 2% by weight (g / g) and heating to 65°C,iii. to cetyl palmitate to which betamethasone valerate solution was added, adding the heated aqueous phase and mixing in a homogenizer at 22,000 rpm for 2 minutes, iv. homogenizing the mixture in a sonic bath for 1 minute and gradually cooling the temperature, first at 4°C and then increasing it at room temperature to 25°C, v. obtaining drug-bound nanoparticles by placing the mixture in pre-soaked dialysis bags for 4 hours, and dialyzing it against distilled water at room temperature, vi. adding a cross-linked polyacrylic acid polymer gel to distilled water in a separate container and stirring continuously for 16-18 hours at 1200 rpm in a magnetic stirrer until swelling and adding 1% by weight triethanolamine at 3000 rpm in a mechanical stirrer at the end of stirring to obtain the gel mixture,vii. adding aloe vera extract at 20-21% by weight to said gel mixture, viii. adding 23-24% by weight of the drug-bound nanoparticles mentioned in step (v.) to the mixture.

9. The production method for a gel formulation according to any one of claims 7-8, characterized in that the surfactant mentioned in step (ii) is polysorbate 80.

10. The production method of the gel formulation according to any one of claims 7-8, characterized in that the molecular weight cut-off value of the dialysis bags mentioned in process step (v.) is in the range of 12,000-14,000 Da.

11. The production method of the gel formulation according to any one of claims 7-8, characterized in that the cross-linked polyacrylic acid polymer gel mentioned in process step (vi) is carbopol 940.

12. A gel obtained by a method according to any one of claims 7-11.

13. A gel for use in eczema treatment obtained by the method according to any one of claims 7-11.

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