TR201910214A2 - INTELLIGENT HYDROGELS WITH ANTIFUNGAL FEATURES THAT DELIVER CONTROLLED DRUGS SENSITIVE TO TEMPERATURE - Google Patents

Abstract

Meet; It is about smart hydrogels with controlled drug release, temperature sensitive and antifungal properties. Smart hydrogels have been developed for use in the treatment of nail fungus disease. The hydrogel formulation subject to the invention; It contains at least one natural polymer (polysaccharide and / or protein) substance, at least one inorganic or organic additive and an antifungal drug active substance. Hydrogen. In the hand formulation, the antifungal drug is released in a controlled manner, thus eliminating the difficulty of regularly applying the drug to the fungal area, shortening the treatment time and reducing the amount of drug used.

Description

DESCRIPTION TEMPERATURE SENSITIVE ANTIFUNGAL WITH CONTROLLED DRUG RELEASE FEATURED SMART HYDROGELS Technical Field of the Invention Meet; controlled drug release, temperature sensitive and smart antifungal properties relates to hydrogels. Smart hydrogels to be used in the treatment of nail fungus disease has been developed for. The hydrogel formulation of the invention; at least one natural polymer (polysaccharide and/or protein) substance, at least one inorganic or organic additive and an antifungal drug active ingredient. hydrogel In its formulation, the antifungal drug is released in a controlled manner and thus Since the difficulty of applying medication regularly to the fungus area is eliminated, both treatment duration is shortened and the amount of drug used is reduced.

State of the Art of the Invention (Prior Art) Nail fungus disease, dermatophytes and nail caused by molds and yeasts are infections. Treatment of nail fungus disease; chemical or surgical intervention removal of the infected nail, use of systemic or topical medication or their It may contain a combination [1]. For the treatment of this disease, mostly oral and topical treatment methods are preferred. Current topical treatment methods; polish, spray and It covers cream applications, topical products on the market are mostly methyl vinyl ether, from chemicals such as maleic acid monobutyl ester copolymer, ethyl acetate and 2-propanol is formed.

One of the most frequently followed methods in the treatment of this disease is oral systemic medication. is a scholar. Relapse of the disease and complete cure in treatments provided by the oral method failure to provide are common conditions. Moreover; oral therapy, potential side effects therefore, it is not suitable for many patients [2].

In a study by Korting et al., griseofulvin fungicide was administered at a daily dose of 990 mg. It was administered to patients for 78 weeks. 6% of full recovery after treatment It is stated in the section that the nail fungus occurs due to the side effects of the drug. Some of the patients with the disease could not complete the treatment. Your patients are another It was noted that the disease recurred after the completion of the treatment period in the part of the patient. With the active ingredients of ciclopirox and amorolfine in the treatment of nail fungus in the current technique. It has been reported that the application was successful with the prepared nail polishes. this quote varnishes; 2-n-nonyl-1,3-dioxolane or similar water-insoluble film-forming ability The substance is prepared with a plasticizer and a volatile solvent. However; ciclopirox redness, rash, nail deformity in the nail folds of patients using polish, Side effects such as irritation, stinging toenails and discoloration have been observed [4, 5].

Nail fungus for fingernails in topical nail polish containing the active ingredient amorolfine While the duration of treatment for the disease is about 6 months, this period is about 6 months in the treatment of toenails. It takes 9-12 months. In the use of nail polish containing amorolfine, both the long-term treatment This is the persistence of complaints such as itching, pain and stinging around the nail bed. It is one of the disadvantages of the product [5]. In its application, chitosan, a chloride that provides the removal of mold from surfaces and The source is a solution consisting of a surfactant and water. Subject of this application It is stated that the invention prevents the development of Aspergillus niger species for up to 8 weeks.

Chitosan exists in the form of chitosan salt in solution, and it is in the invention subject to application. Mostly chitosan glutamate or chitosan chloride salt is used. In formulation, It relates to a chitosan-based biopolymer that cures fungal skin infections. In the invention; chitosan, active pharmacological compound, emulsifying compounds, wax, acid, preservative agents, buffering agents, antioxidants, chelating agents and humectants A cream containing

Oral treatments in the current technique take a very long time and the patient suffers from headache, gastrointestinal distress (diarrhea and/or dyspepsia), rash, elevated liver enzymes It is exposed to severe side effects such as values and drug interactions. topical cream application, on the other hand, is not practical for patients. cream on nail surface If it is found, the patient should continue his routine life, wash his hands or Even basic movements such as wearing socks can be difficult. Providing effective treatment For this purpose, topical products need to be applied to the nail surface frequently, which negatively affects the daily life of the patient. Well; state of the art The success rate of treatment options is low, and the treatment periods are long and arduous.

Due to the inadequacy of the existing solutions on the subject, there is a problem in the relevant technical field. development is necessary. The invention in question; state of the art to be used in the treatment of nail fungus disease, where the disadvantages are eliminated It relates to the formulation of a smart hydrogel with antifungal properties and its preparation method.

Brief Description and Objectives of the Invention In the present invention, at least one natural polymer (polysaccharide and/or protein) substance, at least one inorganic or organic additive and antifungal Intelligent hydrogel with antifungal properties obtained from special drug active ingredient formulation is described.

An aim of the invention is; Biocompatible and biodegradable for the treatment of nail fungus is the development of a hydrogel formulation.

Another purpose of the invention; To provide a hydrogel with antifungal properties without toxic effects and thus the patient has no adverse effects during the treatment of nail fungus. to avoid seeing it.

Another purpose of the invention is; liquid at room conditions but on nail surface An antifungal that turns into a gel when the body reaches the outside temperature (32 °C) when applied. is the development of a special hydrogel formulation. The hydrogel formulation of the invention This feature provides ease of use to patients.

The hydrogel formulation, which is the subject of the invention, also provides controlled drug release on the applied surface. is performing. With this feature, the patient's nail fungus area on a regular basis. The obligation to administer drugs is eliminated and thus the duration of treatment is shortened. and the amount of drug used is reduced.

Description of Figures Explaining the Invention Figure 1: Heat elastic for hydrogel sample without additives modulus (G”) and viscous modulus (G”) graphs Figure 2: Resistant to temperature for hydrogel sample containing 5% additive elastic modulus (G”) and viscous modulus (G”) graphs Figure 3: SEM of hydrogel systems containing 0% and 5% additives images Figure 4: TGA of hydrogel systems containing 0% and 5% additives graphics Figure 5: DSC of hydrogel systems containing 0% and 5% additives graphics Figure 6: %transmittance of hydrogels containing 0% and 5% additives wavelength graphs against values Figure 7: Compression test of hydrogels containing 0% and 5% additives stress-strain graphs Figure 8: Antifungal drug from hydrogels containing 0% and 5% additives time-varying graphs of release quantities Figure 9: Stored at +4 °C for 3 months, loaded with drug active ingredient, 0% and 5% The amount of antifungal drug release from hydrogels containing additives graphs of change over time Figure 10: Stored at +4 °C for 6 months, loaded with drug active ingredient, 0% and 5% The amount of antifungal drug release from hydrogels containing additives graphs of change over time Detailed Description of the Invention The invention deals with intelligent hydrogels with controlled drug release, temperature sensitive, antifungal properties and It's about the method of their preparation. The subject of the invention is the intelligent hydrogel; chitosan and its at least one natural polymer, at least one inorganic or organic additive and at least one antifungal active drug active ingredient.

As a natural polymer in the invention; chitosan, collagen, starch, gelatin, dextran, actin, agar, alginate, chitin, keratin, cellulose, guar gum, carrageenan, gelan gum, scleroglucan, cyclodextrin, xanthan gum, pectin, inulin, hyaluronic acid, glucomannan and/or at least one or combination of hyaluronan and/or derivatives thereof can be used.

As an inorganic or organic additive in the invention; kaolinite, halloysite, vermiculite, saponite, nantronite, disodium hydrogen phosphate (Na2HPO4), sodium bicarbonate (NaHCOs), sodium dihydrogen phosphate (NaH2PO4), illite, montmorillonite, chlorite, attapulgite, sepiolite, bentonite, zeolite, fumed silica, starch, modified starch and talc and/or carbonate, ß- glycerolphosphate, benzoate, acetate, phosphate, malate, lactate, succinate, acrylate and sulfatein sodium At least one of (Na) and/or potassium (K) and/or calcium (Ca) salts or their combination can be used.

As an antifungal active drug substance in the invention; fluconazole, itraconazole, griseofulvin, It has antifungal properties such as ketoconazole, clotrimazole, oxiconazole, miconazole and econazole. any of the active pharmaceutical ingredient(s) and/or salts thereof, or their combination can be used.

The method of preparation of hydrogels with antifungal properties, which is the subject of the invention; In the range of 0.02 M - 2.0 M hydrochloric acid, acetic acid, succinic acid, sulfuric acid, as weight/volume (w/v) in oxalic acid or phosphoric acid or distilled water preparation, In inorganic or organic salt solution(s) in the range of 0.2 M to 5.0 M preparation of the solution(s), In the process step (ii) with the solution prepared in the process step (i) The ratio of the prepared solution/solutions to each other is between 10% - 90% by weight. 5 - 9 by adding 0.01 M - 1.0 M acid, base or salt solution to the pH value of the mixture be set to be in the range, In inorganic or organic salt solution(s) in the range of 0.2 M - 5.0 M Total amount of additive(s) is in the range of 0.01% - 5.0% (w/v) containing at least one inorganic or organic additive preparation of the solution The ratio of the solutions prepared in the process steps (iii) and (v) to each other (solution(v) : solution (iii)) mixing at most 20% by weight, In water, acid, base or an organic solvent, an antifungal drug is active. It is antifungal, with the ratio of the substance being in the range of 0.01% - 5.0% (w/v). Preparation of drug active ingredient solution, In the process step (vi) with the prepared antifungal drug active ingredient solution mixing the resulting solution, In one embodiment of the invention, the preparation method of hydrogels with antifungal properties; In the range of 0.05 M - 1.0 M hydrochloric acid, acetic acid, succinic acid, sulfuric acid, as weight/volume (w/v) in oxalic acid or phosphoric acid or distilled water preparation, In inorganic or organic salt solution(s) in the range of 0.25 M - 2.0 M preparation of the solution(s), The solution in the process step (i) and the solution prepared in the process step (ii) the ratio of solution(s) to each other will be between 15% and 75% by weight mixing in a way, 5 - 9 by adding 0.01 M - 1.0 M acid, base or salt solution to the pH value of the mixture be set to be in the range, In inorganic or organic salt solution(s) in the range of 0.25 M - 2.0 M Total amount of additive or additives 001% - 5.0% (w/v) containing at least one inorganic or organic additive preparation of the solution The ratio of the solutions prepared in the process steps (iii) and (v) to each other (solution(v) : solution (iii)) at most 20% by weight mixing, An antifungal drug active in water, acid, base or an organic solvent. A drug with antifungal effect, with the ratio of the substance in the range of 0.1% to 2.5% (w/v). preparation of the active ingredient solution, In the process step (vi) with the prepared antifungal drug active ingredient solution mixing the resulting solution, The acid used in the invention; hydrochloric acid, acetic acid, succinic acid, sulfuric acid, oxalic acid or phosphoric acid. The base used in the invention; sodium hydroxide, ammonia or sodium carbonate. As an organic solvent in the invention; nail polish remover, acetonitrile, benzene, diethyl ether, dimethyl formamide, dimethyl sulfoxide, ethyl alcohol, ethyl acetate, heptane, hexane, chloroform, xylene, petroleum ether, methyl alcohol, carbon tetrachloride or toluene is used.

The smart hydrogel exists in a liquid state at room conditions and has a body temperature of 32 When heated to °C, it takes the form of gel. Liquid intelligent hydrogel with the method of the invention When this hydrogel is applied to the skin surface, it is heated by body heat. it gels.

The subject of the invention is the hydrogel; at least 15% chitosan and at least one natural polymer, at least 3% at least one inorganic or organic additive and at least 0.1% Contains antifungal drug active ingredient.

Elastic modulus (G) and viscous modulus (G") of the hydrogel samples that are the subject of the invention values were obtained by rheological analysis. Measurements are made gradually It is made by increasing from ,0 °C to 60.0 “C. As a result of rheological analysis, hydrogel The graphs in which the gelling temperatures of the systems are determined, additive rates of 0% and 5% are presented in Figure 1 and Figure 2, respectively, for smart hydrogels containing This gelling temperature values obtained from the graphics with and without additives It was found in the range of 32.0 °C - 25.3 °C for systems.

Hydrogel for performing scanning electron microscopy (SEM) analysis of hydrogels. samples were coated with a thin layer of gold/palladium and then SEM images are obtained. Smart hydrogels containing 0% and 5% additives SEM images are presented in Figure 3. When SEM images are examined, the subject of the invention It is seen that smart hydrogels have a porous structure. Also, hydrogel The addition of additive to the matrix has a significant effect on the pore size in the structure. leads to a decrease.

Thermal gravimetric analysis (TGA), 30 - veteran carried out in the atmosphere. 0% and 5% additives presented in Figure 4 According to the TGA results of hydrogel systems containing and it was found to be 175 °C. The obtained TGA results; additive in the matrix As the amount of substance increases, the amount of percent mass loss in the material decreases. shows.

Additive-free by differential scanning calorimetry (DSC) analysis of hydrogels Glass transition temperature (Tg) of hydrogels containing (°/o 0) and 5% additive values have been determined. Containing 0% and 5% additives in Figure 5 The endothermic peak in the DSC graphs of the hydrogels indicates the Tg values of the hydrogels. shows. The Tg values of the hydrogels containing 0% and 5% additives are 63.7, respectively. °C and 76.8 °C. Additive in hydrogel matrix With an increase in the amount of Tg, an increase occurs.

The contact angle measurements of the hydrogels were carried out and all the prepared smart hydrogels were measured. contact angle values were found to be less than 90°. This situation is the subject of the invention This shows that smart hydrogels are hydrophilic in nature.

To calculate the opacity (O) values of the hydrogels, the % transmittance values are 300-800 It was measured with a UV-Vis spectrophotometer device in the nm wavelength range (Figure 6) and The opacity values of the hydrogels were calculated using the following equation.

O = Absiaooi/x Here, AbS(600) is the absorbance value of the sample at 600 nm* and x is the mm of the sample. denotes the thickness in terms of thickness. Containing 0% and 5% additives calculated. These obtained values are the additive in the hydrogel matrix. It shows that the opacity of the hydrogel increases and becomes slightly dull with the presence of

Mechanical durability tests of additive and non-additive hydrogels Cylindrical hydrogel samples of the same dimensions to perform has been prepared. Then, with a speed of 'I mm/min' using a 500 N load cell. Compression tests were applied to the samples. As a result of the applied compression test, the hydrogel any physical deformation or breakage on the samples (fragmentation) was not observed. When the physical force is removed; 5% contribution hydrogel sample containing 615% hydrogel without additives sample returned to its former form at a rate of 462%. This result contains additive The hydrogel sample retains its elasticity more against the applied force. shows. Applied to hydrogels containing 0% and 5% additives. Compression stress and compression strain values obtained as a result of compression tests. The graph shown in Figure 7 was obtained. Compressive stress value of hydrogels matrix It increases with the increase in the amount of additive added into it.

Compressive stress values of hydrogels containing 0% and 5% additives The compressive stress value of hydrogels is the amount of additive added into the matrix. increases with the increase. This is due to the fact that the addition of the additive makes the hydrogels It shows an increase in mechanical strength.

In order to examine drug releases from smart hydrogels; drug-containing hydrogel samples dried in a vacuum oven. Dry hydrogel samples were taken with a body temperature of 32 It should be placed in a buffer solution at physiological pH at °C and shaken and the temperature Release studies by shaking at 32 °C and 60 rpm with a controlled water bath has been made. As seen in Figure 8, the additive in the hydrogel matrix A significant decrease was observed in the release of antifungal drug with the increase in the amount of the drug. Experiment The % drug release amounts calculated at the end of the period of time are for the system without additives. has been found. With the addition of additive into the hydrogel matrix, the amount of release was determined. was found to be controllable.

In the course of time, hydrogels loaded with antifungal drug active ingredient A drug with antifungal properties in order to monitor whether it can protect the drug in it. Hydrogel samples loaded with active ingredient 3 and 6 months in a light and moisture proof environment It was stored at 4 °C for a period of time. UV-Vis spectrophotometer after storage times The drug release measurements from the hydrogels were performed with (Figure 9 and Figure 10). 3 month period for systems containing additives at the rate of 0% and 5% at the end of the drug release It was observed that the % release amount of hydrogels stored for months did not change much.

To test the antifungal properties of hydrogels; Trichophyton in lyophilized form It was activated by opening the mentagrafites strain. %transmittance value of the inoculum solution It was adjusted to 70% at 520 nm with a UV-Vis spectrophotometer device. The spore number of the solution was measured with a hemocytometer and determined as 5.0x106 spores/mL. has been found. Effect of hydrogels against fungi that will grow in the medium. Disc diffusion method was used to see Trichophyton mentagrafites The inoculum solution of the fungus was inoculated into Saboroud medium. at 0% hydrogel containing additive, 0% additive and antifungal drug hydrogel containing active ingredient, hydrogel containing 5% additive, 5% Examples of additives and antifungal active ingredients and control groups prepared and placed in the media and at the end of the incubation period, the gels were surrounded by The resulting inhibition diameters were measured. In hydrogels that do not contain active pharmaceutical ingredients Inhibition area is not formed. 0% and 5% additives and antifungals Inhibition areas formed by hydrogels containing specific drug active ingredient, respectively loaded with antifungal drug active ingredient It was determined that hydrogels were highly effective against Trichophyton mentagrafites fungus. has been made.

Claims (3)

REQUESTS 1. It is a temperature sensitive and antifungal hydrogel preparation method that releases controlled drugs. 0.02 M - 2.0 M in hydrochloric acid, acetic acid, succinic acid, sulfuric acid, oxalic acid or phosphoric acid or 0.1% - 8.0% by weight/volume (w/v) in pure water Preparation of chitosan or chitosan salt solution to be in the range of 0,1 - 10.0% (w/v) in inorganic or organic salt solution/solutions in the range of 0.2 M - 5,0 M, Mixing the solution prepared in the process step (i) and the solution/solutions prepared in the process step (ii) in a way that the ratio of 10% to 90% of each other, pH value of the mixture is 0.01 M - 1.0 M acid, base or salt solution It should be adjusted to be between 5 and 9 by adding the minimum amount of additive(s) to be between 0.01% and 5.0% (w/v) in the inorganic or organic salt solution between 0.2 M and 5.0 M. the preparation of a solution containing one inorganic or organic additive. Mixing the solutions prepared in the process steps (iii) and (v) with each other in such a way that the ratio (solution (v) : solution (iii)) is maximum 20% by weight, Antifungal active drug substance in water, acid, base or an organic solution Preparation of the antifungal active drug active ingredient solution with a rate of 0.01% - 5.0% (w/v), mixing the prepared antifungal drug active ingredient solution with the solution obtained in the process step (vi), and includes the processing steps. 2. It is a method according to claim 1 and its feature is; In the range of 0.05 M - 1.0 M in hydrochloric acid, acetic acid, succinic acid, sulfuric acid, oxalic acid or phosphoric acid or in the range of 05 - 4.0% by weight/volume (w/v) in pure water Preparation of chitosan or chitosan salt solution, preparation of natural polymer solution(s) in the range of 0.25 M - 2.0 M in inorganic or organic salt solution/solutions, in the range of 025 - 5.0% (w/v), number (i) Mixing the solution in the process step with the solution/solutions prepared in the process step (ii) in a way that the ratio of the solution/solutions to each other will be between 15% and 75% by weight, at least one, with the total amount of additive or additives in the range of 0.01% - 5.0% (w/v) in inorganic or organic salt solution/solutions in the range of 0.25 M - 2.0 M. solution containing inorganic or organic additives Mixing the solutions prepared in the process steps (iii) and (v) with each other (solution(v) : solution (iii)) in such a way as to be a maximum of 20% by weight, Antifungal effective drug active drug in water, acid, base or an organic solvent Preparation of the antifungal active drug active ingredient solution with the ratio of the substance in the range of 0.1% - 2.5% (w/v), mixing the prepared antifungal drug active ingredient solution with the solution obtained in the process step (vi), and includes the processing steps. 3. A method according to claim 1 or 2 and its feature is; chitosan, collagen, starch, gelatin, dextran, actin, agar, alginate, chitin, keratin, cellulose, guar gum, carrageenan, gelan gum, scleroglucan, cyclodextrin, xanthan gum, pectin, inulin, hyaluronic acid, glucomannan and/or as natural polymers. or the use of hyaluronan and/or at least one of its derivatives or a combination thereof. . It is a method according to claim 1 or 2 and its feature is; as inorganic or organic additives kaolinite, halloysite, vermiculite, saponite, nantronite, disodium hydrogen phosphate (Na2HPO4), sodium bicarbonate (NaHCOg), sodium dihydrogen phosphate (NaH2PO4), illite, montmorillonite, chlorite, attapulgite, sepiolite, bentonite, zeolite fumed silica, starch, modified starch, talc with carbonate, ß-glycerolphosphate, benzoate, acetate, phosphate, malate, lactate, succinate, acrylate and/or sulphate sodium (Na) and/or potassium (K) and/or calcium (Ca) ) salts or a combination thereof. . It is a method according to claim 1 or 2 and its feature is; It is the use of at least one of fluconazole, itraconazole, griseofulvin, ketoconazole, clotrimazole, oxiconazole, miconazole and/or econazole or a combination of them as an antifungal active drug active ingredient. . It is a method according to claim 1 or 2 and its feature is; the acid is selected from hydrochloric acid, acetic acid, succinic acid, sulfuric acid, oxalic acid or phosphoric acid. . It is a method according to claim 1 or 2 and its feature is; the base is selected from sodium hydroxide, ammonia or sodium carbonate. . It is a method according to claim 1 or 2 and its feature is; using acetone, acetonitrile, benzene, diethyl ether, dimethyl formamide, dimethyl sulfoxide, ethyl alcohol, ethyl acetate, heptane, hexane, chloroform, xylene, petroleum ether, methyl alcohol, carbon tetrachloride or toluene as organic solvent. . Hydrogel with controlled drug release, temperature sensitive antifungal properties prepared by a method according to one of the preceding claims. 10. It is a hydrogel according to claim 9 and its feature is; It contains at least 15% chitosan and at least one natural polymer, at least 3% at least one inorganic or organic additive and at least 0.1% antifungal active drug substance. 11. It is a hydrogel according to claim 9 and its feature is; It is in liquid form at room conditions and in gel form at outside body temperature. 12. It is a hydrogel according to claim 11 and its feature is; body temperature is 32 °C. 13. Use of a hydrogel according to any one of claims 9-12 in the treatment of nail fungus.