DE202023100057U1 - System for the development of antimicrobial quercetin dihydrate nail polish for the treatment of paronychia - Google Patents

Abstract

A system for the development of antimicrobial quercetin dihydrate nail polish for the treatment of paronychia, the system comprising:
a solution preparation unit for preparing a solution of quercetin dihydrate by dissolving quercetin dihydrate in a required amount of ethanol, adding the dissolved quercetin dihydrate into a polymer solution prepared by dissolving polymer in ethanol;
an addition unit for adding plasticizer, permeation enhancer and keratolytic agent into the prepared solution of quercetin dihydrate, and after the addition, the mixer is properly mixed using a magnetic stirrer; and
a packaging unit for decanting the prepared antimicrobial quercetin dihydrate into a narrow-mouthed glass bottle with a plastic screw cap.

Description

FIELD OF THE INVENTION

The present disclosure relates to the field of antimicrobial nail polish development. In particular, the present disclosure relates to a system for developing an antimicrobial quercetin dihydrate nail polish for the treatment of paronychia.

BACKGROUND OF THE INVENTION

Nail infections are not necessarily life-threatening, but they can be excruciatingly painful, cause inconvenience in everyday activities, and have significant physical, psychological, and emotional consequences that affect people's quality of life. Human nails are used not only for protection and decoration, but also for the administration of medicines, especially for nail diseases such as onychomycosis, paronychia and psoriasis. Such nail diseases are usually treated with oral medications. When a drug is administered orally or systemically, its effectiveness at the site of action is reduced. To avoid this loss of effectiveness of the drug, the topical route is chosen.

Topical administration of drugs is preferable to oral administration because it has fewer systemic side effects, is non-invasive, has better patient compliance, acts locally (site-specific effect), and potentially reduces treatment costs. Dermatological ointments, creams, gels, lotions and powders are not suitable for transungual administration. Such formulations are easily removed by washing or rubbing after use, resulting in uneven drug release. New formulations are proposed in place of the traditional topical formulations. The best formulations are medicated nail polishes. Medical nail polishes are made by adding rate-controlling polymers to cosmetic nail polishes. This technique is considered an effective therapy for nail diseases, since a film forms a depot of the active substance in the affected nail plate.

Due to the high bioavailability of the active ingredient, fewer applications are required to achieve effective therapy. The active ingredients are stored in a film on the surface of the nail plate, which enables optimal and continuous active ingredient diffusion. The continuous diffusion of the active substance leads to therapeutic concentrations in the nail tissue, which are necessary for the effective treatment of nail diseases. Therefore, there is a need for an antimicrobial nail polish formulation for the treatment of paronychia.

Quercetin is a chemical that has antioxidant, anti-inflammatory, analgesic, antibacterial, antifungal and antiviral properties and hence can be used in formulation for treatment.

In view of the foregoing, it is clear that a system is needed to develop an antimicrobial quercetin dihydrate nail polish for the treatment of paronychia.

SUMMARY OF THE INVENTION

The present disclosure relates to a system for developing an antimicrobial quercetin dihydrate nail polish for the treatment of paronychia. The aim of the present disclosure is to alleviate paronychia through the development of an antimicrobial quercetin dihydrate nail polish, which nail polish contains different types of polymers, concentrations and plasticizers that can treat paronychia. Twelve different formulations of the developed nail polish are made to optimize which polymer and which concentration leads to a better release based on in vitro permeability studies and the effects of the plasticizers on the properties of the film such as flexibility, gloss and adhesive properties. Among all the formulations developed, a best formulation is selected that gives the best results in terms of factors such as drying time, non-volatile content, viscosity, water resistance, drug content, in vitro drug release study, antimicrobial test and other characteristics, examining all these factors, where as well other factors such as good flow and gloss, optimum drying time and viscosity, tack and permeation testing are examined. The results showed that the formulation F2 is the best formulation among all other formulations (F1-F12), the formulation F2 showed a penetration rate of 51.93% after 24 hours and good antimicrobial activity. Based on the results obtained, it can be concluded that the developed medical antimicrobial quercetin dihydrate nail polish represents a promising alternative to the currently available treatments of paronychia.

The present disclosure aims to provide a system for developing an antimicrobial quercetin dihydrate nail polish for treating paronychia. The system comprises: a solution preparation unit for preparing a solution of quercetin dihydrate, wherein quercetin dihydrate is dissolved in a required amount of ethanol, the dissolved quercetin dihydrate is added into a polymer solution prepared by dissolving polymer in ethanol; an addition unit for adding plasticizer, permeation enhancer and keratolytic agent into the prepared solution of quercetin dihydrate, and after the addition, the mixer is properly mixed using a magnetic stirrer; and a packaging unit for transferring the prepared quercetin dihydrate antimicrobial nail polish into a narrow mouth glass bottle with a plastic screw cap.

An aim of the present disclosure is to provide a system for the development of an antimicrobial quercetin dehydrate nail polish for the treatment of paronychia.

Another object of the present disclosure is to develop an antimicrobial dihydrate nail polish using a transungual delivery system.

Another aim of the present disclosure is to develop different formulations of the proposed nail polish, doing this in order to optimize which polymers and concentrations give better results in the treatment of paronychia.

Another subject of the present disclosure is to study various factors such as drying time, non-volatile content, viscosity, water resistance, drug content, in vitro drug release study, antimicrobial test, good flow and gloss, optimal drying time and viscosity, adhesiveness and permeation tests to select the best formulation for the treatment of paronychia.

Another aim of the present disclosure is to provide a promising alternative to the currently used treatments for paronychia treatment.

In order to further clarify the advantages and features of the present disclosure, a more detailed description of the invention is provided by reference to specific embodiments that are illustrated in the accompanying figures. It is understood that these figures represent only typical embodiments of the invention and therefore should not be considered as limiting the scope of the invention. The invention will be described and illustrated with additional specificity and detail with the accompanying figures.

character list

• 1 ein Blockdiagramm eines Systems zur Entwicklung eines antimikrobiellen Quercetindihydrat-Nagellacks für die Behandlung von Paronychie gemäß einer Ausführungsform der vorliegenden Offenbarung zeigt;
• 2 ein Flussdiagramm zur Entwicklung eines antimikrobiellen Quercetindihydrat-Nagellacks zur Behandlung von Paronychie gemäß einer Ausführungsform der vorliegenden Offenbarung zeigt; und
• 3 eine Tabelle zeigt, die die verschiedenen Formulierungen des entwickelten Nagellacks gemäß einer Ausführungsform der vorliegenden Offenbarung darstellt.

These and other features, aspects, and advantages of the present disclosure will be better understood when the following detailed description is read with reference to the accompanying figures, in which like characters represent like parts throughout the figures, wherein:

• 1 Figure 10 shows a block diagram of a system for developing an antimicrobial quercetin dihydrate nail polish for the treatment of paronychia according to an embodiment of the present disclosure;
• 2 Figure 10 shows a flow chart for the development of an antimicrobial quercetin dihydrate nail polish for the treatment of paronychia according to an embodiment of the present disclosure; and
• 3 Figure 12 shows a table presenting the different formulations of the developed nail polish according to an embodiment of the present disclosure.

Those skilled in the art will understand that the elements in the figures are presented for simplicity and are not necessarily drawn to scale. For example, the flow charts illustrate the method of key steps to enhance understanding of aspects of the present disclosure. In addition, one or more components of the device may be represented in the figures by conventional symbols, and the figures only show the spec fish show details that are relevant to understanding the embodiments of the present disclosure in order not to clutter the figures with details that are readily apparent to those skilled in the art familiar with the present description.

DETAILED DESCRIPTION

For the purposes of promoting an understanding of the invention, reference will now be made to the embodiment illustrated in the figures and specific language will be used to describe the same. It should be understood, however, that no limitation on the scope of the invention is intended, and such alterations and further modifications to the illustrated system and such further applications of the principles of the invention set forth therein are contemplated as would occur to those skilled in the art invention would normally come to mind.

Those skilled in the art will understand that the foregoing general description and the following detailed description are exemplary and explanatory of the invention and are not intended to be limiting.

When this specification refers to "an aspect," "another aspect," or the like, it means that a particular feature, structure, or characteristic described in connection with the embodiment is present in at least one embodiment included in the present disclosure. Therefore, the phrases "in one embodiment," "in another embodiment," and similar phrases throughout this specification may or may not all refer to the same embodiment.

The terms "comprises," "including," or other variations thereof are intended to cover non-exclusive inclusion, such that a method or method that includes a list of steps includes not only those steps, but may also include other steps that are not expressly stated or pertaining to any such process or method. Likewise, any device or subsystem or element or structure or component preceded by "comprises...a" does not, without further limitation, exclude the existence of other devices or other subsystem or other element or other structure or other component or additional device or additional subsystems or additional elements or additional structures or additional components.

When this specification refers to "an aspect," "another aspect," or the like, it means that a particular feature, structure, or characteristic described in connection with the embodiment is present in at least one embodiment included in the present disclosure. Therefore, the phrases "in one embodiment," "in another embodiment," and similar phrases throughout this specification may or may not all refer to the same embodiment.

Embodiments of the present disclosure are described in detail below with reference to the attached figures.

1 12 shows a block diagram of a system for developing an antimicrobial quercetin dihydrate nail polish for the treatment of paronychia according to an embodiment of the present disclosure. The system 100 includes a solution preparation unit 102 for preparing a solution of quercetin dihydrate by dissolving quercetin dihydrate in a required amount of ethanol, adding the dissolved quercetin dihydrate into a polymeric solution prepared by dissolving polymer in ethanol.

In one embodiment, an addition unit 104 is used for the addition of emollient, permeation enhancer, and keratolytic agent into the prepared solution of quercetin dihydrate, and after the addition, the mixer is properly mixed with a magnetic stirrer.

In one embodiment, a packaging unit 106 is used to transfer the prepared quercetin dihydrate antimicrobial nail polish into a narrow neck glass bottle with a plastic screw cap.

In one embodiment, the quercetin dihydrate nail polish is made by a simple mixing process.

In one embodiment, the quercetin is a bioflavonoid rich in polyphenols and has properties such as antioxidant, anti-inflammatory, analgesic, antibacterial, antifungal and antiviral activities, such that quercetin dihydrate is considered in the treatment of paronychia.

In one embodiment, N-acetylcysteine is used as a penetration enhancer, which primarily helps to improve the penetration of drugs from the nail plate to the nail bed, the inclusion of N-acetylcysteine and quercetin in the formulation of the nail polish creates a synergistic effect and a more effective therapeutic effect.

In one embodiment, different formulations of antimicrobial nail polish are developed considering different polymers and different concentrations with different plasticizers, producing twelve different formulations. The different formulations are developed with the aim of optimizing the appropriate polymer and its concentration for the quercetin dihydrate nail polish based on the drug permeability studies and also to optimize the effect of the plasticizer on the film properties such as gloss and adhesive properties.

2 Figure 12 shows a flow chart for the development of an antimicrobial quercetin dihydrate nail polish for the treatment of paronychia according to an embodiment of the present disclosure. The Quercetin Dihydrate Nail Polish was made using a simple mixing method and a magnetic stirrer. Using a magnetic stirrer at constant speed, quercetin dihydrate was dissolved in the required amount of ethanol. Ethanol was used to dissolve the polymer. The polymeric solution was infused with the dissolved drug. Finally, the desired amounts of emollient, permeation enhancer, and keratolytic were added and mixed thoroughly with a magnetic stirrer. The prepared nail polish was transferred to a narrow mouth glass bottle with a plastic screw cap.

3 Figure 12 shows a table presenting the different formulations of the developed nail polish according to an embodiment of the present disclosure. The nail polish formulation was made by combining different polymers [Eudragit RL100 & ethyl cellulose] in different concentrations [5-15%] with different plasticizers [castor oil & PEG 400]. The formulation has been optimized by creating twelve different formulations.

The polymer Eudragit RL 100 was used for the first tests. As in the table in 2 shown, the formulations F1-F3 were produced with 5-15% Eudragit RL 100 and castor oil as plasticizer. Formulations F4-F6 were made with 5-15% Eudragit RL 100 and PEG 400 as plasticizers.

Further testing focused on a different polymer [ethyl cellulose: 5-15%] and two different plasticizers [castor oil in F7-F9 and PEG 400 in F10-F12]. The aim was to optimize which polymer and which concentration are suitable for the quercetin dihydrate nail polish based on drug permeability studies and to investigate the effect of the plasticizer on the film properties such as gloss and adhesive properties.

In one embodiment, the developed nail polish is evaluated by determining various factors and parameters, with the detailed evaluation process described below.

Drying time: The prepared nail polish was evenly applied to a Petri dish with a brush. A stopwatch was used to measure the time it took for a dry, touchable film to form. If, after touching the film, no sample remained on the finger, it was considered sufficiently dry (no tack).

Smoothness of Flow: The sample was poured into a glass plate from a height of 1.5 inches and spread on a glass plate. It was allowed to rise vertically and checked visually for flowability.

Gloss: This is determined by visual inspection.

Nonvolatile Content: First, the initial weight of the Petri dish (M1) was determined, then 1 g (M) of each sample was placed in the Petri dishes and distributed evenly. The weight of each petri dish containing the sample was then recorded. The Petri dish was placed in a forced air oven at 105±2°C for 1 hour. After 1 hour the petri dish was cooled and weighed again (M2). The weight difference was used to calculate the percent non-volatile content. $$\%\mathbf{Not}fl\ddot{\mathrm{and}}cHtiGe\mathrm{right}InHalt=\frac{\mathbf{M}2-\mathbf{M}1}{\mathbf{M}}\times 100$$

Water Resistance Test: The water resistance test is used to determine the water resistance of the formulation. In this test, the required amount of nail polish was applied to an even area of a glass plate and allowed to dry. The glass sample was weighed and then placed in a beaker filled with distilled water. After 24 hours the plate was dried with filter paper and weighed again. Water resistance was calculated from the initial and final weight difference and the results were expressed as a percentage of the weight loss.

Viscosity: The viscosity of the formulated nail polish was calculated at room temperature using spindle #63 at 20 rpm on a Brookfield viscometer (model LVF).

In vitro film adhesion test: A uniform film was formed on a glass plate with a paint brush and dried at room temperature for 24 hours. Equal areas of 1 mm were created by cutting into the film in parallel and perpendicular directions with a scalpel (0.37 mm blade thickness). Next, a free piece of pressure-sensitive cellophane tape was placed on top of the foil and smoothed (not glued) with your finger. After a few minutes, the NL film was peeled off manually at an angle of 60° by grasping the free end of the unbonded tape. The total number of squares of film adhered to the tape was determined and the percent peel calculated using the following formula. $$\%\mathbf{flake\; off}=\frac{\mathbf{initial\; squares}\mathrm{i.e}esfilms-\mathbf{end\; squares}\mathrm{i.e}esfilms}{\mathbf{initial}Q\mathrm{and}a\mathrm{i.e}\mathrm{right}ate\mathrm{i.e}esfilms}\times 100$$

Percent active ingredient content: 1 mg of nail polish was dissolved in 50 ml of a phosphate buffer solution of pH 7.4. The solution was then sonicated for 15 minutes. The resulting solution was filtered and diluted to 100 ml with a phosphate buffer solution of pH 7.4. The diluted solution was then determined spectrophotometrically at a wavelength of 367 nm to determine the percentage of active ingredient.

The procedure of the in vitro transungual permeation study is detailed below.

Hoof preparation: Because human nails are difficult to obtain in large quantities, pig hooves were used as a membrane for in vitro transungual permeation studies. Pig hooves have been used for in vitro studies because of their thickness and their resemblance to human nail structure. The hooves were washed, cleaned and hydrated for 24 hours in a phosphate buffer solution (PBS) at pH 7.4. The soft tissue of the hooves was removed with a blade. They were then sliced thinly and stored for later use. The thickness and diameter of the pig claws were 0.8 mm ± 0.5 and 25 mm ± 0.8, respectively, as measured with a micrometer.

Carrying out the transungual permeation study: The in vitro tests were carried out with a Franz diffusion cell. The hoof was placed in the receptor and donor chambers of the Franz diffusion cell (16 mL volume of receptor). The test vehicle (nail polish) in the amount of 1 mg was then evenly applied to the surface of the cuticle. To simulate nail plate conditions, a pH 7.4 phosphate buffer mixture was placed in the receptor compartment. The Franz diffusion assembly was placed on top of the Franz diffusion cell. At 37°C, the assembly was continuously stirred for 24 hours. After 30 minutes, 1, 3, 5, 7, 10, 13, 16, 20 and 24 hours, 10 mL of the sample was removed and replaced with fresh medium. A UV spectrophotometer set at 367 nm was used to analyze the samples.

In one embodiment, the selection of the best formulation among twelve prepared nail polish formulations (F1-F12) is performed based on a comparison of their physical properties and an in vitro drug permeation study. Drying time, flowability, gloss, non-volatile content, water resistance test, blush test and viscosity were used to compare the best formulation with the formulation on the market.

Various microbiological studies are carried out to select the best formulation and are detailed below.

Antibacterial in vitro study: The antibacterial activity of the prepared nail polish was determined using an agar well diffusion method. PBS pH 7.4 was used to dissolve the samples. The bacteria (Staphylococcus aureus) were cultured and diluted to 10 colonies per unit (CFU)/ml in sterile water. The suspension (100 L) was applied to the surface of the nutrient agar medium. Wells (4.6 mm diameter) were cut with a sterile drill and the formulations added. A PBS solution was used as a negative control. Gentamicin was dissolved in PBS buffer pH 7.4 and serially diluted to reach a concentration of 2-100 µg/ml. The inoculated plates were incubated at 37°C for 24 hours. The diameter of the zone of inhibition (DIZ) is measured and with it the antibacterial activity.

In vitro antifungal study: The antifungal activity of the prepared nail polish was tested using the agar-well diffusion method, in which Candida albicans was inoculated with melted potato dextrose agar at 45°C and allowed to set in a petri dish. The wells (4.6 mm in diameter) were cut in the same manner as the wells for antibacterial activity, and the formulations were placed in them. The negative control was carried out with PBS. Fluconazole antifungal control) were dissolved in PBS buffer pH 7.4 and serially diluted to reach concentrations of 2-100 µg/ml. The plates were incubated at 28°C for three days. The diameter of the zone of inhibition was measured.

Various other studies conducted to select the best formulation are listed below.

Ex vivo release kinetics: To determine the release pattern of the prepared nail polish formulation, the ex vivo release data was considered and treated with several mathematical models including zero-order, first-order, Higuchi and Korsmeyer-Peppas models. Using the R (correlation coefficient), n (diffusion exponent) and K (release constant) values obtained from curve fitting the release data, a model suitable for the nail polish formulation was determined.

Zero Order Release Kinetics: The release data were fitted into the following equation to study zero order release kinetics; $$\mathbf{dQ}/\mathbf{German}=\mathbf{knockout}$$

Where “Q” represents the amount of drug released, “Ko” the zero-order release rate constant, and “t” the release time. The graph shows percent cumulative drug release (%CDR) versus time.

First Order Release Kinetics: The release rate data is fitted into the following equation to study first order release kinetics; $${\mathbf{K}}_1\mathbf{Q}=\mathrm{i.e}Q/\mathrm{i.e}t$$

Where “Q” stands for the fraction of drug released, “K1” for the first-order release rate constant, and “t” for the release time. The graph shows the logarithmic proportion of remaining CDR versus time.

Higuchi Release Model: The release rate data is substituted into the following equation to study the Higuchi release model. $$\mathbf{Q}={\mathbf{<figure-callout\; id="1"\; label="K\; H\; t"\; filenames="DE202023100057U1\_0009.png"\; state="\{\{state\}\}">K</figure-callout>}}_H{\mathbf{t}}^{}{\mathbf{}}^{\raisebox{1ex}{$1$}\!\left/ \!\raisebox{-1ex}{$2$}\right.}$$

Where “Q” is the fraction of drug release, “KH” is the release rate constant, and “t” is the release time. The graph shows percent CDR versus square root of time.

Kosmeyers and Peppas Kinetics: To study the Kosmeyers and Peppas release kinetics, the release rate data is substituted into the following equation: $$\mathbf{Mt}/\mathbf{M}\infty ={\mathbf{K}}_{KP}{\mathbf{t}}^n$$

Where Mt/M∞ is the “fraction of drug release”, “PPP” is the release rate constant, “t” is the release time and “n” is the diffusion exponent associated with the mechanism of drug release. The graph is plotted as log % CDR versus time.

The results of the various studies are listed below.

With the addition of rate-modifying polymers such as Eudragit RL100 and ethyl cellulose, sustained and full drug release of up to 48 hours can be achieved, making the formulation suitable for three-week use. With a drying time of 63 seconds and good gloss, flow and stickiness, F2 is the best of the twelve formulations (F1-F12). The best formulation, F2, achieved 51.93% drug permeation at 24 hours. The best formulation, F2, underwent in vitro antimicrobial testing. The results of a microbial study showed that the formulations are sensitive to the microorganisms Staphylococcus aureus and Candida albicans. The results of the previous studies allow the conclusion that the developed medicinal nail polish formulation can be a promising alternative to the currently available formulations for the treatment of paronychia. Besides treating nail infections, medicated nail polishes can also be used to beautify nails and are easy to apply. This increases patient acceptance and compliance.

The figures and the preceding description give examples of embodiments. Those skilled in the art will understand that one or more of the elements described may well be combined into a single functional element. Alternatively, certain elements can be broken down into multiple functional elements. Elements from one embodiment may be added to another embodiment. For example, the order of the processes described herein may be changed and is not limited to the manner described herein. Additionally, the actions of a flowchart need not be performed in the order shown; Also, not all actions have to be carried out. Also, the actions that are not dependent on other actions can be performed in parallel with the other actions. The scope of the embodiments is in no way limited by these specific examples. Numerous variations are possible, regardless of whether they are explicitly mentioned in the description or not, e.g. B. Differences in structure, dimensions and use of materials. The scope of the embodiments is at least as broad as indicated in the following claims.

Advantages, other benefits, and solutions to problems have been described above with respect to particular embodiments. However, the benefits, advantages, problem solutions, and components that can cause an advantage, benefit, or solution to occur or become more pronounced are not to be construed as a critical, required, or essential feature or component of any or all claims.

reference list

100

System for the development of antimicrobial quercetin dihydrate nail polish for the treatment of paronychia.

102

A unit for preparing a solution

104

An encore unit

106

A packaging unit

202

Obtaining Quercetin Dihydrate

204

Dissolving quercetin dihydrate in ethanol

206

Dissolve the polymer in ethanol

208

Dissolving the drug solution of quercetin in the polymer solution

210

Addition of emollient, permeation enhancer, keratolytic agent

212

The nail polish obtained is filled into a glass bottle with a narrow cap

Claims (6)

A system for the development of antimicrobial quercetin dihydrate nail polish for the treatment of paronychia, the system comprising: a solution preparation unit for preparing a solution of quercetin dihydrate by dissolving quercetin dihydrate in a required amount of ethanol, adding the dissolved quercetin dihydrate into a polymer solution prepared by dissolving polymer in ethanol; an addition unit for adding plasticizer, permeation enhancer and keratolytic agent into the prepared solution of quercetin dihydrate, and after the addition, the mixer is properly mixed using a magnetic stirrer; and a packaging unit for decanting the prepared antimicrobial quercetin dihydrate into a narrow-mouthed glass bottle with a plastic screw cap. system after claim 1 , where the quercetin dihydrate nail polish is made by a simple mixing process. The system after claim 1 , where the quercetin is a bioflavonoid rich in polyphenols and has properties such as antioxidant, anti-inflammatory, analgesic, antibacterial, antifungal and antiviral activities, so quercetin dihydrate is considered in the treatment of paronychia. system after claim 1 , using N-acetylcysteine as a penetration enhancer, which primarily helps to improve drug penetration from the nail plate to the nail bed, the incorporation of N-acetylcysteine and quercetin into the formulation of the nail polish creates a synergistic effect and a more effective therapeutic effect offers. system after claim 1 , developing several different formulations of antimicrobial nail polish considering different polymers and different concentrations with different plasticizers, producing twelve different formulations. system after claim 5 , in which different formulations are developed to optimize the appropriate polymer and its concentration for the quercetin dihydrate nail polish based on the drug permeability studies and also to optimize the effect of the plasticizer on the film properties such as gloss and adhesive properties.

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