WO2024144676A1 - Hydrogel and organogel formulations containing propolis and dexpanthenol nanoemulsions - Google Patents

Abstract

The present invention relates to new generation dermal drug delivery formulations for external use that improve pain, aching and inflammation in a very short time by applying a thin film on the skin in wound or burn treatments; comprising dexpanthenol and propolis in the form of nanoemulsion nanodroplets to provide a synergistic effect; and provide extended release by trapping them in hydrogels/organogels, which are new generation gels.

Description

HYDROGEL AND ORGANOGEL FORMULATIONS CONTAINING PROPOLIS AND DEXPANTHENOL NANOEMULSIONS

Field of the Invention

The invention relates to the novel drug formulations in the form of hydrogel and organogel structure containing nanoemulsion of propolis, which has anticancer, anti-inflammatory, antioxidant and antimicrobial effects, and is effective on skin diseases (wounds, acne, warts, etc.), oral problems (gingivitis, prosthetic adhesive, fungal infections), cardiovascular system diseases (atherosclerosis, hypertension etc.), diabetes and reproductive health, and dexpanthenol, which is found in many semi-solid dosage forms in the world pharmaceutical sector, which has many properties such as stimulating epithelization, moisturizing the skin, preserving the elasticity of the skin, improving the irritated skin, preventing itching and being a scatrizant among its features, for external use in the field of medicine.

State of the Art

The skin is the largest organ in the human body and serves as the main target and main barrier for dermal drug delivery. Due to the readily available large surface area, it has gained a great deal of research interest as a non-invasive alternative route to conventional oral or injectable drug administration. Drug application to the skin offers different advantages such as increasing the bioavailability of drugs damaged by the gastrointestinal environment and/or hepatic first-pass effects, the potential to carry drugs at a constant rate for a long time, reducing side effects and improving patient compliance. Despite all this, drug transport through the skin is still both an attractive and a difficult issue. In particular, there is need to overcome individual variability between different places on the skin and to maintain the effective barrier that this organ creates between the organism and the environment. Conventional semi-solid dosage forms cannot overcome these problems. For this reason, a new generation of nanotechnology products is needed.

Advances in modern technologies enable the dermal delivery of many drugs, including traditional hydrophobic small-molecule drugs, hydrophilic drugs, and macromolecules. There has been an increasing interest in colloidal drug delivery systems for dermal applications in recent years. Especially nanocarriers in the size range of 500 nm exhibit positive properties. In previous years, the focus of application of nanocarriers has been primarily on parenteral and oral administration. However, nanocarriers applied to the skin offer many advantages. Nanocarriers can be used for both a local effect for the skin (dermal drug delivery) and a systemic effect accompanied by passage through the skin (transdermal drug delivery). Nanotechnology based delivery systems offer several advantages by reducing the size of topically applicable drugs to nanometers. It is known that there are differences in the physicochemical properties of nanoscale materials. Some nanoformulations contain surfactants that act as permeability enhancers, thereby providing the ability to alter the molecular structure of membranes from transient pore formation to relaxation of tight junctions between epithelial cells, thereby increasing penetration of drug molecules into deeper layers by reversing the barrier functions of the skin. Conventional formulations accumulate in the superficial layers of the skin due to the larger size of the particles, while nanoformulations can penetrate deep into the dermal layer. Nanocarriers not only provide direct contact of the therapeutic agent with the stratum corneum and other extensions of the skin, but also increase their physical and chemical stability by increasing their retention time on the skin surface.

Most conventional dermal treatments work by forming thin films on the skin surface, but the use of nanocarriers prevents the accumulation of free drugs in these film layers. These film layers form a concentration gradient that advances therapeutic agents through diffusion into the skin layers. In recent years, different nanocarriers such as nanoemulsions, nanostructured lipid transporters, solid lipid nanoparticles, polymeric nanoparticles, liposomes, ethosomes, transferosomes, niosomes, aquasomes and mentosomes have been extensively investigated to solve various skin problems. Nanoemulsions are heterogeneous isotropic systems in which a liquid is dispersed into nano-sized droplets in another liquid. The droplet sizes can range from 20 to 500 nm. They are thermodynamically unstable and kinetically stable systems. Therefore, they need surfactants and/or auxiliary surfactants to provide energy and colloidal stability for their formation. Nanoemulsions can be made in a variety of dosage forms, such as liquids, creams, sprays, gels, aerosols, and foams. There are oral, intravenous, intranasal, pulmonary, ocular and topical routes of administration.

Nanoemulsals are basically topical gel formulations containing emulsions. Since nanoemulsion gels contain both nanomulsions and gel bases, they exhibit a dual character. It is among the suitable options as drug delivery systems. While the nanoemulsion in the structure of the nanoemulsion ensures the preservation of the active substance, the gel provides thermodynamic stability to the nanoemulsion by increasing the viscosity of some aqueous phase. Hydrogels and organogels are among the different types of gels in the art. In general, hydrogels or organogels can be categorized according to the polarity of the external liquid component. While the hydrogels are prepared with water, the organogels are formulated using non-polar solvents such as hexane, isopropyl myristate, sunflower oil, corn oil or others as the external liquid component. Hydrogels and organogels are semi-solid systems prepared from a polymer/gelling agent that can self-assemble and form a three-dimensional network structure. The chemical or physical crosslinks that ensure the network structure and physical integrity of the hydrogels make the hydrogels insoluble. Research on these systems has gained momentum in recent years.

The most well-known bee product, propolis, is a mixture of resins collected from different plants by Apis mellifera (honey bee). There are more than 300 components in the content of propolis. In general, propolis consists of approximately 50% resin, 30% wax, 10% aromatic oils, 5% various organic compounds and 5% pollen. Propolis is the richest bee product in terms of polyphenol content. Although propolis is not considered a therapeutic agent in traditional medicine, it is one of the few natural products that has maintained its popularity for a long time. It is widely used as a component in cosmetic and pharmaceutical products such as anti-acne creams, face and body creams, ointments, lotions, and in various formulations for oral hygiene. Doctors have used propolis to treat wounds during the Second World War (1939-1945). Propolis has anticancer, immunomodulator, anti-inflammatory, antioxidant and antimicrobial effects. At present, it is used especially in skin diseases (wounds, acne, warts, etc.), oral problems (gingivitis, prosthetic adhesive, fungal infections), cardiovascular system diseases (atherosclerosis, hypertension), diabetes and reproductive health problems.

Dexpanthenol, a component of coenzyme A, is an alcohol containing analogue of pantothenic acid (Vitamin B₅). Inside the body, dexpanthenol is converted to pantothenic acid, the active form required for epithelial cells. Although its precise mechanism is unknown, topical dexpanthenol acts as a moisturizer that improves stratum corneum hydration, reduces transepidermal water loss, and maintains the softness and elasticity of the skin. Its moisturizing effect is related to its hygroscopic property. The most prominent effects of dexpanthenol are the stimulation of epithelialization and the prevention of itching. Nevertheless, positive results were observed in patients treated for skin transplantation, wounds, burns and different dermatoses.

At present, semi-solid preparations containing dexpanthenol are in cream, ointment and gel form. All three of these dosage forms are conventional dosage forms and do not contain new generation nanotechnology products in their structures. In general, creams are classic emulsion-type preparates containing excipients such as preservatives, propylene glycol, cetyl alcohol, stearyl alcohol, lanolin, white petrolatum, emulsifiers and distilled water. Ointments, on the other hand, are preparates consisting mostly of oilbased excipients with a higher viscosity than creams. Unlike the other two dosage forms, gels are dosage forms of polymeric substances with three-dimensional web formed with gel-forming agents.

In the old technique/method: i. Traditional topical formulations (applied on the skin) accumulate in the superficial layers of the skin due to the larger size of the particles, but the possibility of nanoformulations and the nanoemulsion gels (hydrogel or organogel) containing them to penetrate deep into the dermal layer, ii. Most of the traditional treatments used in topical treatments act by forming a thin film on the skin surface, but the use of nanoformulations preventing the accumulation of free drugs in this film, iii. The failure to achieve an extended release with conventional topical formulations (such as gel, cream, ointment), iv. Since traditional topical formulations cause poor absorption of active substances from the skin, them being insufficient in the treatment of diseases such as acne, alopecia and psoriasis on the skin, v. The fact that the penetration of large active substances with high molecular weight through the skin is little or none with traditional topical formulations, but with the new generation drug delivery systems, penetration through the skin can be achieved by bringing the size to the nanoscale, vi. Limited passage of drugs to the lower layers of the skin in treatments with traditional topical formulations, vii. Conventional topical formulations being unsuitable systems for target-specific or cellspecific drug delivery, but it being possible to perform receptor-mediated drug release at the site of action of nanosized drug molecules through organogels or hydrogels, viii. Patient compliance being low and recovery being time-consuming with traditional topical formulations, patient compliance is low, recovery is time-consuming, or such disadvantages are present. When the studies in the current art are examined, it is seen that some commercially available topical dosage forms have a low diffusion coefficient on the skin compared to hydrogel and/or organogels, and therefore, there is a focus on the application of nanoemulsioncontaining gels (such as hydrogel, organogel) in the field of dermatology and that this is a need.

Detailed Description of the Invention

In this detailed description, the invention is described only for a better understanding of the subject matter and without the creation of any limiting effect.

The structural and characteristic features and all the advantages of the invention will be understood more clearly thanks to the detailed description given below, and therefore the evaluation should be made by taking this detailed description into consideration.

The present invention relates to formulations in the form of hydrogel and organogel containing nanoemulsion that meet the above-mentioned requirements, eliminate all disadvantages and bring some additional advantages.

There is a wide variety of bacteria on the skin surface, including staphylococci, streptococci, candidiasis, and non-pathogenic mycobacteria. When the skin is damaged, it becomes vulnerable to infections from the outside environment and microorganisms can accumulate around the wound and cause infection. The skin, which prevents direct contact with the internal and external environment, is constantly exposed to many factors that can cause damage to the skin. Apart from these, the skin is the primary target and main obstacle for dermal/transdermal drug delivery. Due to its large, easily accessible surface area, it has gained great research interest as a non-invasive alternative route to conventional oral or injectable drug administration.

Dermal/transdermal drug administration offers obvious advantages such as increasing the bioavailability of drugs damaged by the gastrointestinal environment and/or hepatic first-pass effects, transporting drugs at a constant rate for a long time, reducing side effects and increasing patient compliance. Despite all this, dermal/transdermal drug delivery is still an attractive and challenging issue. Advances in modern technologies allow the dermal/transdermal delivery of a large number of drugs, including traditional hydrophobic small-molecule drugs, hydrophilic drugs, and macromolecules. Recently, nanoemulsion based gels have become very popular for dermal drug delivery, overcoming the disadvantages of traditional semi-solid drug forms. The aim of this invention is to prepare and characterize nanoemulsion-based hydrogel and organogels containing propolis and dexpanthenol active substances in combination, to examine their stability, and to compare their antimicrobial and cytotoxicity properties. Within the scope of characterization studies, organoleptic properties, drug content, morphology, pH, gel-sol transition temperature, spreadability, viscosity, FT-IR and release properties were evaluated in hydrogel and organogels. Characterization studies were subjected to a 3 month short-term stability evaluation at room temperature and in the refrigerator. No phase separation was observed in any of the formulations stored in the refrigerator. When the results of the release study were examined, an extended release was obtained for propolis and dexpanthenol. In the antimicrobial susceptibility study, hydrogels from our formulations were found to be active against S. aureus, while organogels were found to be active against both S. aureus and S. epidermidis. In the cytotoxicity study against HDFa cells, it was found that both hydrogels and organogels were non-toxic at low doses and even showed a proliferative effect. These hydrogels and organogels, which contain propolis and dexpanthenol together for the first time, are promising systems that can be used in wound and burn models in the future.

With the invention, hydrogel and organogel-based nanoemulsion formulations containing dexpanthenol and oil-based propolis in the inner phase were developed to be used in future wound/burn skin epithelial regeneration model studies and in vitro characterization tests were performed. In addition, these formulations were evaluated for stability, antimicrobial activity and cytotoxicity.

The advantages and innovations of this invention are given below. i. In wounds and burns, especially in cases of bacterial contamination, the introduction of both substances to the patient through new generation gels (hydrogel and organogel) is extremely advantageous for the patient compliance. ii. With these formulations, there is also a prolonged effect and a rapid effect due to a rapid penetration. This is not possible with traditional topical treatments (such as creams, ointments and gels). iii. Both dexpanthenol and propolis have been reduced to nano-size and it is possible to take effect for a longer time with less dose. iv. Due to the lower dose of dexpanthenol and propolis content, the possibility of side effects will also be reduced or eliminated. v. Although they are washable water-based, organogels do not leave a greasy feeling. Therefore, they are less irritating to the skin and more effective than traditional semisolid dosage forms. They can be used safely without the possibility of causing any allergic reaction in pediatrics, geriatrics and pregnant women. vi. Applying drugs to the skin with new drug delivery systems increases the bioavailability of drugs that are damaged by the gastrointestinal environment and/or hepatic first-pass effects. vii. It creates the potential to carry drugs at a constant rate for a long time. viii. Nanoformulations can be used in the skin for both a local effect for the skin (dermal drug delivery) and a systemic effect accompanied by passage through the skin (transdermal drug delivery). ix. Nanoformulations not only provide direct contact of the therapeutic agent with the stratum corneum and other extensions of the skin, but also increase their physical and chemical stability by increasing their retention time on the skin surface. x. The administration of therapeutic agents via nanoformulations also causes it to have a longer half-life in the skin, and the resulting films form a concentration gradient that attracts therapeutic agents to the skin layers through diffusion. xi. Nanoemulsions have the potential to overcome many disadvantages of conventional drug formulations. Depending on the higher surface area-volume ratio of the nanoemulsions, they ensure that their bioavailability is higher than that of conventional emulsions. xii. The loading of poorly water-soluble drugs into suitable nanoemulsions increases their wettability and/or solubility. As a result, they improve their pharmacokinetics and pharmacodynamics through different routes of administration of these substances. xiii. The droplets in the nanoemulsions act as a drug reservoir, ensuring that the nanoemulsion is a multifunctional platform for treating various diseases. Nanoemulsions show significant advantages, such as protecting the drug from enzymatic or oxidative reactions. xiv. Nanoemulsion have the advantage that they can be converted into various dosage forms such as liquids, creams, sprays, gels, aerosols and foams. xv. There are oral, intravenous, intranasal, pulmonary, ocular and topical routes of administration. xvi. Hydrogel and organogels are important as drug delivery systems because they contain both nanoemulsion and gel base, which means, they exhibit dual characters. The nanoemulsion protects the active ingredients from enzymatic degradation and reactions such as hydrolysis, while the gel base provides thermodynamic stability to the emulsion by increasing the viscosity of the aqueous phase by reducing the interface and surface tension. This is extremely beneficial for therapeutic efficacy. xvii. Nanodroplet size can improve the efficacy of the formulation by improving the permeability and spreadability of the drug in the presence of appropriate penetration enhancers. xviii. Hydrogels are increasingly used today as new generation drug delivery systems with their mucoadhesive and bioadhesive properties used to increase drug resistance time and complete tissue permeability. xix. Hydrogels have the ability to self-heal even if their structure is damaged. xx. Hydrogels become insoluble due to the presence of chemical or physical crosslinks. Which increases their stability as well as obtaining long release times. xxi. Hydrogels are used in a wide range of biomedical and pharmaceutical applications due to their high-water content and consequently excellent biocompatibility. xxii. Organogels are considered liquid-filled structures and solid fiber-based gels, depending on the mechanism of formation of the three-dimensional gel skeleton. xxiii. Organogels can provide long-term stability by forming a three-dimensional network of either cross-linked or entangled chains. xxiv. Organogels are thermo-reversible and have the ability to contain both hydrophilic and hydrophobic compounds within the gel structure. This feature expands the areas of use as controlled drug delivery systems that can be taken by different routes of administration. In its most basic form, a formulation in the form of an organogel or hydrogel-based nanoemulsion dosage contains the combination of dexanthenol and propolis. In the invention, the preferred ratio of dexanthenol to propolis is 10:1. It contains the same amount of dexanthenol and propolis in all formulations developed.

The invention is intended for external use and is drug formulations that have a wide use in skin disorders as a new generation dermal drug delivery systems that shows improvement in pain, aching and inflammation in a very short time by applying a thin film on the skin in wound or burn treatments, contains dexpanthenol and propolis in a way to provide a synergistic effect together, contains these active substances in the form of nanodroplets in nanoemulsion form and provides extended release by trapping in hydrogels/organogels, which are new generation gels.

The invention its preferred state is novel drug formulations in hydrogel and organogel structure comprising nanoemulsion of propolis and dexpanthenol suitable for external use in the field of health, propolis has anticancer, anti-inflammatory, antioxidant and antimicrobial effects, effective on skin diseases, oral problems, cardiovascular system diseases, diabetes and reproductive health, and dexpanthenol is included in many semi-solid dosage forms in the world pharmaceutical sector, especially with many features such as stimulating epithelialization, moisturizing the skin, protecting the elasticity of the skin, improving the irritated skin, preventing itching and being a scatrizant.

In its more preferable state, the invention is hydrogel and organogel formulations comprising nanoemulsions of propolis and dexpanthenol.

The primary aim of the invention is to increase the quality of life of patients with hydrogel and organogel dosage forms containing dexanthenol and propolis nanoemulsions together.

Another object of the invention is to accelerate the onset of wound healing, scatrizant effect.

Another object of the invention is that the effect can penetrate deep into the skin.

Another object of the invention is to extend the duration of action and to obtain a pharmacological effect with a lower dose of drug use compared to conventional semi-solid preparations. Another object of the invention is to observe fewer side and toxic effects compared to conventional semi-solid preparations and to reduce the expenditure paid for two separate drugs economically.

The formulation developed in a preferred embodiment of the invention preferably comprises at least one of the following excipients in accordance with the amounts given in Table 1 for tablets prepared with "hydrogel": i. No other chemicals can be used instead of dexpanthenol and propolis extract. ii. At least one surfactant (preferably tween 60) selected from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, caprylol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, iii. At least one surfactant selected (preferably tween 20) from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, capyrlol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, iv. At least one gel forming agent (preferably sodium carboxymethyl cellulose) selected from the group comprising carbopol 980, carrageenan, carbopol 934, carbopol 974, carbopol 971 , carbopol 981 , gelatin, glyceryl palmitostearate, polycarbophil, pectin, polyoxyethylene alkyl ethers, propylene carbonate, propylene glycol alginate, xanthan gum, calcium alginate, sodium alginate, ethyl cellulose, hydroxy methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose or a combination thereof, v. At least one solvent (preferably sodium distilled water) selected from the group comprising distilled water, aromatic waters or a combination thereof may be used. Table 1.

The formulation developed in a preferred embodiment of the invention preferably comprises at least one of the following excipients in accordance with the amounts given in Table 2 for tablets prepared with "organogel": i. No other chemicals can be used instead of dexpanthenol and propolis extract. ii. At least one surfactant (preferably tween 60) selected from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, caprylol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, iii. At least one surfactant selected (preferably tween 20) from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, capyrlol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, iv. At least one surfactant selected (preferably span 80) from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 80, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, caprylol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, v. At least one surfactant (preferably tween 20) selected from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 20, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, caprylol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, vi. At least one gel forming agent (preferably carbopol 980) selected from the group comprising carrageenan, carbopol 934, carbopol 974, carbopol 971 , carbopol 980, carbopol 981 , gelatin, glyceryl palmitostearate, polycarbophil, pectin, polyoxyethylene alkyl ethers, propylene carbonate, propylene glycol alginate, xanthan gum, calcium alginate, sodium alginate, ethyl cellulose, hydroxy methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose or a combination thereof, vii. At least one oil phase (preferably sunflower oil) selected from the group comprising sesame oil, sunflower oil, cotton oil, flax seed oil, olive oil or a combination thereof, viii. At least neutralizing agent (preferably sodium hydroxide) selected from the group comprising sodium hydroxide (NaOH), potassium hydroxide (KOH), Calcium hydroxide (CaOH) or a combination thereof, ix. At least one solvent (preferably distilled water) selected from the group comprising distilled water, aromatic waters or a combination thereof may be used.

Table 2.

The formulation developed in a preferred embodiment of the invention comprises dexpanthenol, Propolis extract (oil-based), tween 60, span 20, Sodium carboxymethyl cellulose (NaCMC) and distilled water.

The formulation developed in a preferred embodiment of the invention comprises dexpanthenol, propolis extract (oil-based), tween 60, span 20, sunflower oil, span 80, tween 20, carbopol 980, 0.2 M 1-2 drops of NaOH solution and distilled water.

The formulation developed in the "hydrogel" application of the invention is prepared by following the following process steps: Weighing all components of the formulation on a precision scale with a sensitivity of at least 1 mg; the weighed chemicals of propolis and span 20 are mixing constituting the oil phase in a beaker, dexpanthenol, tween 20 and distilled water which form the water phase homogeneous by mixing separately in a significant order in another beaker; pouring the water phase on the oil phase (while the sonicator probe is activated in the oil phase) and sonicating at 100% power and in the 3rd cycle for 5 minutes; mixing the distilled water (2g) with NaCMC (80 mg) until it is completely dissolved/swollen on the magnetic stirrer in a beaker at room temperature; adding the previously prepared nanoemulsion containing 250 mg dexpanthenol and 25 mg propolis on it (2g); mixing it at 750 rpm on the magnetic stirrer until it becomes homogeneous; finally preparing the hydrogel at a rate of 5 g by adding approximately 1 g of distilled water; and storing it away from moisture and light at room temperature until it is used. The formulation developed in the "organogel" application of the invention is prepared by following the following process steps: Weighing all components of the formulation on a precision scale with a sensitivity of at least 1 mg; mixing the propolis and span 20 constituting the oil phase in a beaker, making dexpanthenol, tween 20 and distilled water which form the water phase homogeneous by mixing separately in a significant order in another beaker; pouring the water phase on the oil phase (while the sonicator probe is activated in the oil phase) and sonicating at 100% power and in the 3rd cycle for 5 minutes; stirring sunflower oil, carbopol 980, span 80 and tween 20 in a beaker at room temperature on the magnetic stirrer at 750 rpm until a completely clear solution is obtained; adding the previously prepared nanoemulsion containing 250 mg dexpanthenol and 25 mg propolis (2 g); stirring at 750 rpm on the magnetic stirrer until homogeneous; finally preparing the organogels so that the final formulation is 5 g by adding about 1 g of distilled water; adding 0.2 M 1 -2 drops of NaOH to neutralize the medium if necessary; storing it away from moisture and light at room temperature until it is used.

Claims

1. A formulation in the form of hydrogel or organogel-based nanoemulsion, characterized by comprising; combination of dexanthenol and propolis.

2. Formulation according to claim 1 , characterized by that; the ratio of dexpanthenol to propolis at 10:1

3. Hydrogel according to claim 1 characterized by comprising; i. At least one surfactant selected from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, capyrlol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, ii. At least one surfactant selected from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, capyrlol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, iii. At least one gel forming agent selected from the group comprising carbopol 980, carrageenan, carbopol 934, carbopol 974, carbopol 971 , carbopol 981 , gelatin, glyceryl palmitostearate, polycarbophil, pectin, polyoxyethylene alkyl ethers, propylene carbonate, propylene glycol alginate, xanthan gum, calcium alginate, sodium alginate, ethyl cellulose, hydroxy methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose or a combination thereof, iv. At least one solvent selected from the group comprising distilled water, aromatic waters or a combination thereof may be used.

4. Formulation according to claim 3, characterized by comprising; tween 60 as surfactant.

5. Formulation according to claim 3, characterized by comprising; span 20 as surfactant.

6. Formulation according to claim 3, characterized by comprising; sodium carboxymethyl cellulose as gel forming agent.

7. Formulation according to claim 3, characterized by comprising; distilled water as solvent.

8. “Organogel” according to claim 1 characterized by comprising; i. At least one surfactant selected from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, capyrlol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, ii. At least one surfactant selected from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, capyrlol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, iii. At least one surfactant selected from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, capyrlol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, iv. At least one surfactant selected from the group comprising poloxamer 407, sodium lauryl sulfate, poloxamer 188, span 20, span 40, span 60, span 65, span 80, span 85, tween 20, tween 21 , tween 40, tween 60, tween 61 , tween 65, tween 80, tween 81 , tween 85, glyceryl monostearate, isopropyl myristate, lecithin, PEG 40 castor oil, gelucire 48/16, capyrlol 90, lauroglycol 90, labrafil M, labrasol ALF, capmul PG 12, brij 72, captex 355, sterotex NF, acconon C-44, capmul MCM C-8, cetiol SB 45, geloil SC, polyvinyl alcohol (low molecular weight) or polyvinyl alcohol (high molecular weight) or a combination thereof, v. At least one gel forming agent selected from the group comprising carrageenan, carbopol 934, carbopol 971 , carbopol 974, carbopol 980, carbopol 981 , gelatin, glyceryl palmitostearate, polycarbophil, pectin, polyoxyethylene alkyl ethers, propylene carbonate, propylene glycol, propylene glycol alginate, xanthan gum, calcium alginate, sodium alginate, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose or a combination thereof, vi. At least one oil phase selected from the group comprising sesame oil, sunflower oil, cotton oil, flax seed oil, olive oil or a combination thereof, vii. At least neutralizing agent Selected from the group comprising sodium hydroxide (NaOH), potassium hydroxide (KOH), Calcium hydroxide (CaOH) or a combination thereof, viii. At least one solvent selected from the group comprising distilled water, aromatic waters or a combination thereof may be used.

9. Formulation according to claim 8, characterized by comprising; tween 60 as surfactant.

10. Formulation according to claim 8, characterized by comprising; span 20 as surfactant.

11. Formulation according to claim 8, characterized by comprising; span 80 as surfactant.

12. Formulation according to claim 8, characterized by comprising; tween 20 as surfactant.

13. Formulation according to claim 8, characterized by comprising; Carbopol 980 as gel forming agent.

14. Formulation according to claim 8, characterized by comprising; sunflower oil as oil phase.

15. Formulation according to claim 8, characterized by comprising; sodium hydroxide as gel neutralizing agent.

16. Formulation according to claim 8, characterized by comprising; distilled water as solvent.

17. Formulation according to claim 3, characterized by comprising; dexpanthenol, propolis, tween 60, span 20, sodium carboxymethyl cellulose (NaCMC) and distilled water.

18. Formulation according to claim 17, characterized by comprising; an amount of dexpanthenol between 2.5-15%, an amount of propolis extract between 10-30%, an amount of tween 60 between 0.5-5%, an amount of span 20 between 0.5-5%, an amount of sodium carboxymethyl cellulose between 0.4-6% and an amount of distilled water between 50-80% by total weight.

19. Formulation according to claim 17, characterized by comprising; 5% dexpanthenol, 15.17% propolis extract, 2% tween 60, 2% span 20, 1.6% sodium carboxymethyl cellulose and 74.23% distilled water by total weight.

20. Formulation according to claim 8, characterized by comprising; dexpanthenol, propolis, tween 60, span 20, sunflower oil, span 80, tween 20, carbopol 980, NaOH solution and distilled water.

21. Formulation according to claim 20, characterized by comprising; an amount of dexpanthenol between 2.5-15%, an amount of propolis extract between 10-30%, an amount of tween 60 between 0.5-5%, an amount of span 20 between 0.5-5%, an amount of sunflower oil between 0.5-5%, an amount of tween 20 between 0.5-5%, an amount of span 80 between 0.5-5%, an amount of carbopol 980 between 0.1-2%, 1-2 drops (if necessary) of NaOH solution and an amount of distilled water between 50-80% by total weight.

22. Formulation according to claim 21 , characterized by comprising; 5% dexpanthenol, 15.17% propolis extract, 2% tween 60, 2% span 20, 2% sunflower oil, 2% tween 20, 2% span 80, 0.4% carbopol 980 and 69.43% distilled water by total weight.