RU2560698C1 - Topical agent for acne - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention represents a topical agent for acne containing azelaic acid, silicone glycerohydrogel, propylene glycol, Carbomer, triglycerides, phosphatidylcholine, benzoic acid, emulsion wax, glyceryl stearate, triethanolamine and purified water. The ingredients of the agent are taken in a certain ratio, wt %.

EFFECT: higher therapeutic efficacy, avoiding side effects and ensuring physiological properties of the skin.

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Description

The invention relates to medicine, namely to dermatology, and can be used to treat patients with acne (acne vulgaris).

Acne (juvenile acne) is an extremely common skin disease that occurs in 65.0-95.0% of adolescents and young adults, often causing a marked decrease in the quality of life of patients, the formation of depressive states and, even in severe cases, limit social adaptation and the life prospects of boys and girls [1, 2].

Acne therapy involves the use of a wide arsenal of external agents of various pharmacotherapeutic actions, among which preparations containing azelaic acid (creams and gels for topical use) occupy a significant place, as indicated in the clinical recommendations of the Russian Society of Dermatovenerologists [2, 3], in international clinical recommendations , including the European Union [3].

Studies in patients with acne showed that external use of a cream with 20% azelaic acid (AK) for 4–8 weeks resulted in a tenfold decrease in the content of Propionibacterium acnes in follicles [4].

In addition to antimicrobial effects, azelaic acid has a biological, tissue effect as a weak cytostatic, which normalizes the keratinization processes in the follicle, and also has an anti-inflammatory effect, including by suppressing the metabolism of neutrophils [5, 6]. The ability of azelaic acid to reduce skin pigmentation due to exposure to enzymatic systems of activated melanocytes has also been established [7].

Thus, azelaic acid blocks the main mechanisms of acne development: critically reduces the population of Propionibacterium acnes, inhibits hyperkeratinization, which provides an anti-comedogenic effect; allows you to reduce the symptoms of post-acne - hyperpigmentation that occurs during the healing of inflammatory acne elements.

The main drugs on the pharmacological market of the Russian Federation containing azelaic acid are: Skinoren cream (20%), Skinoren gel (15%), manufactured by INTENDIS MANUFACTURING, S.p.A; azix-derm 20% cream, manufactured by Ranbaxi (India); domestic preparation Azelik gel containing 15% azelaic acid, manufactured by Akrikhin company [8, 9, 10]. In other countries, similar drugs are marketed under the trade names Azelex, Finevin (20% creams), Finacea (15% gel) [11, 12, 13].

Preparations containing azelaic acid (cream of 20% azelaic acid and gel 15%), applied 2 times a day in patients with acne, have proven effectiveness in patients with mild to moderate severity, reduce the number of acne eruptions by more than 50% of the initial in 65-85% of patients [14, 15]. According to N.V. Kungurov et al. [16], when treating with a cream of 20% AK, regression of the general severity of acne (OTU) by 50-75% of the initial value was observed in 40.63% of acne patients. It was shown that a gel with azelaic acid reduces the total number of acne manifestations by 60.6% from the initial values and reduces the severity of acne by the ASI index by 65.2% [17].

Thus, it should be noted that the overall effectiveness of skinorene acne therapy is moderate, and more than a third of patients dynamically assessed using standardized acne severity indices do not achieve high degrees of regression of manifestations (less than 75% and 90% of the initial state).

A feature of acne therapy using 20% cream and 15% azelaic acid gel is its duration of at least 8-12 weeks (maximum period of use is 24 weeks), which determines the extremely high cost characteristics of the course of treatment (table 1) [18, 19, twenty].

The most studied agent is skinoren gel for external use, containing 15% azelaic acid (ATX-D10AX03 azelaic acid; pharmacological group - acne treatment rash [Dermatotropic drugs]. Azelaic acid (micronized) is included in the skinore gel preparation as an active substance: 0 , 15 g (15 wt.%). As excipients it includes: propylene glycol - 0.12 g (12 wt.%); Polysorbate 80-0.015 g (1.5 wt.%); Lecithin - 0.01 g (1 wt.%); polyacrylic acid - 0.01 g (1 wt.%); triglycerides - 0.01 g (1 wt. %); sodium hydroxide - 0.002 g (0.2 wt.%); disodium edetate - 0.001 g (0.1 wt.%); benzoic acid - 0.001 g (0.1 wt.%); purified water - 0.681 g (68.1 wt.%) - prototype.

During clinical trials and the widespread use of skinoren in clinical practice, the facts of the occurrence of side effects during therapy with drugs containing AK were established: the appearance of additional areas of hyperemia, itching and tingling of the skin, peeling in 18.7% [21, 22]. The noted side effects are named in the Medical Instructions for Skinoren Cream (No. N014589 / 01, 2008-11-01 from Intendis Manufacturing SpA, Italy) and Skinoren Gel (P N014589 / 02, 2008-12-08 from Intendis Manufacturing SpA, Italy ): “At the beginning of treatment, a locally irritating effect, hyperemia and peeling of the skin, burning, erythema, and itching are rarely possible. In most cases, side effects are mild, stop during treatment and do not require discontinuation of the drug. In very rare cases, allergic skin reactions (such as a rash) can occur. ”

The creation of original domestic topical preparations containing azelaic acid, according to experts, should be accompanied by optimization of the composition of the main active ingredients and modernization of the base in order to:

- increasing the effectiveness of the treatment of acne patients;

- reducing the duration of the course of treatment until the time to achieve clinical remission of the disease;

- reducing the frequency and severity of side effects of therapy;

- increasing the compliance of treatment, including by preserving the physiological parameters of the skin during the course of therapy;

- improving pharmaco-economic indicators by reducing the cost of the course of treatment for acne patients;

- import substitution funds for external use in patients with acne.

Possible ways to achieve these goals is to change the content of the active substance, azelaic acid, in new preparations with an increase in its concentration directly in target cellular structures, including the sebaceous glands, where the microbial flora develops; the introduction of additional substances with an anti-inflammatory effect into the drug; enrichment of the basis of drugs with additional moisturizing non-comedogenic ingredients, etc.

The objective of the invention is to develop the component composition of the product for external use in patients with acne, providing regression of acne elements while moisturizing, softening and enhancing skin regeneration, which also has good tolerance while minimizing the side effects of therapy.

The technical result that will be achieved from the use of this invention is to increase the effectiveness of therapy, patient satisfaction after treatment, elimination of side effects and maintaining the physiological properties of the skin.

The technical result is achieved by the fact that in an external therapy for acne patients, including azelaic acid as an active substance, propidenglycol, a gelling agent as a humectant, triglycerides as one of the emollients, 0.1% wt. Benzoic acid as a preservative, and purified water, additionally contains another active substance - organosilicon glycerohydrogel, a carbomer is used as a gelling agent, phosphatidylcholine is used as a second emollient, and tionary - emulsifiers: emulsifying wax, glyceryl stearate and triethanolamine in the following ratio, wt.%:

Azelaic acid 10.0 Silicone Glycerohydrogel 20,0 Propylene glycol 10.0 Carbomer 0.2 Triglycerides 3.0 Phosphatidylcholine 1,5 Benzoic acid 0.1 Emulsion wax 4.0 Glyceryl stearate 3.0 Triethanolamine 0.2 Purified water Rest

The invention consists in a combination of these components.

The use of organosilicon glycerohydrogel as an active substance (along with azelaic acid) provides anti-inflammatory (decongestant), regenerating and penetrating effects, improves the penetration of azelaic acid into deeper layers of the skin, and also, since organosilicon glycerohydrogel contains silicon glycerates that are structurally compatible with the lipid component of cell membranes, softens the skin and contribute to the retention of its own moisture in the upper layers of the epidermis. Organosilicon glycerohydrogel is one of the most modern "conductors" - substances that enhance the penetration into the skin of active substances introduced into the composition.

This substance has low toxicity and can be classified as hazard class IV; high transcutaneous activity, as well as anti-inflammatory (decongestion) and regenerative effects with improved morphological and structural parameters of the skin. Thus, organosilicon hydrogels with transcutaneous (percutaneous) activity have a set of positive properties for use in creating new topical preparations for the treatment of acne: non-toxicity, structural compatibility with the lipid component of cell membranes, the ability to protect tissues from drying out and edema, and increase their oxygenation. At the same time, the presence of an essential silicon microelement has an active stimulating effect on all types of tissues: skin, epithelial, bone, connective, contributing primarily to proliferative and reparative processes that occur in them. The high transcutaneous activity of silicon glycerates and glycerohydrogels based on them in relation to various medicinal and biologically active additives increases the effectiveness of the pharmaceutical compositions and reduces the dose of active additives in them. Organosilicon glycerohydrogel is economical and easy to obtain, corresponding to its presentation, storage stability [23, 24, 25].

The use as emulsifiers of a combination of emulsion wax, glyceryl stearate and triethanolamine promotes the activation of the active components of the composition; Moreover, this emulsifying system is universal for any type of skin.

The use of triglycerides and phosphatidylcholine as emollients helps to reduce transepidermal moisture loss; regulates the amount of secreted sebum, gives the skin a feeling of softness and silkiness.

The use of propylene glycol as a moisturizer does not cause complications from the liver and kidneys, and also does not cause allergies. Introduction to the composition of the claimed means of carbomer, which is a gelling agent, is necessary for the formation of the optimal consistency and structural stability of the agent in the form of an emulsifier.

The qualitative and quantitative composition of the components of the product are selected experimentally and are necessary and sufficient to provide antimicrobial, anti-comedonal, anti-inflammatory, moisturizing, softening and regenerating effects on the skin of acne patients.

From the analysis of scientific, technical and patent literature, the claimed combination of components that provide antimicrobial, anti-comedonal, anti-inflammatory, moisturizing, softening and regenerating effects on the skin of patients with acne without side effects, we have not identified, which allows us to draw conclusions about the compliance of the proposed solutions with the criteria of "novelty" and "inventive step".

The invention is as follows. A method of obtaining the claimed composition of external therapy includes the preliminary preparation of the hydrophobic phase, hydrophilic phase, azelaic acid solution and their subsequent mixing.

To prepare the hydrophobic phase take: emulsion wax 4.0 g (4.0 wt.%); glyceryl stearate 3.0 g (3.0 wt.%); phosphatidylcholine 1.5 g (1.5 wt.%); triglycerides of caprylic and capric acids 3.0 g (3.0 wt.%) and heated to 80 ° C until a homogeneous transparent mass is obtained.

To prepare the hydrophilic phase take: carbomer 0.2 g (0.2 wt.%), Benzoic acid 0.1 g (0.1 wt.%), Organosilicon glycerohydrogel 20.0 g (20 wt.%), Purified water 48.0 g (48.0 wt.%) And heated to 80 ° C until a homogeneous transparent mass.

To prepare a solution of azelaic acid, 10.0 g (10.0 wt.%) Of propylene glycol was taken, heated to 80 ° C, and 10.0 g (10.0 wt.%) Of azelaic acid was gradually added with constant stirring to obtain a clear solution.

Then, at a temperature of 80 ° C, a solution of azelaic acid, a hydrophobic phase are added to the hydrophilic phase, thoroughly homogenized. During cooling, add triethanolamine 0.2 g (0.2 wt.%) And constantly stir until thickened. Get 100 g (100 wt.%) Soft homogeneous mass of white.

The proposed composition is a physically / chemically complex multicomponent disperse system in which the spatial network of the dispersed phase is formed by a carbomer with a gellant in combination with an organosilicon glycerohydrogel, and a hydrophobic phase is dispersed and stabilized by an emulsifier in the conjugated hydrophilic phase. Such a composition can be attributed to a gel with cream elements essentially being an emulsifier.

The external preparation thus prepared was used for the external treatment of acne patients.

Example: Patient Α., 22 years old with a diagnosis of acne, is under the supervision of a dermatovenerologist at the Federal State Budgetary Institution UrNIIDViI. Sick from the age of 14, the process is constantly localized on the skin of the face, in adolescence she used cosmetics for problem skin, with a moderate and unstable effect. In recent years, she used external drugs with antibiotics (lincomycin ointment, fucidin cream) without a significant effect. When prescribing benzoyl peroxide (gel Baziron AS) and topical retinoids (Differin cream), it noted burning, hyperemia, severe dry skin, as a result of which the therapy was stopped. When using cream and gel, Skinoren noted the appearance of hyperemia of the face, itching in the first week of use, at the insistence of the attending physician she continued treatment, however, after a 6-week course of therapy with the drug skin gel gel, the patient and her attending physician did not notice pronounced positive dynamics (general acne severity index - OTU ) decreased by only 47.5% of the original, based on these data, therapy with the specified drug was canceled. The patient was prescribed a new external agent 2 times a day on the skin in the face. The use of a new external agent was carried out for 22 days, which contributed to the regression of pustular and papular elements of acne, fresh rashes were not observed during the course of applications, the state of clinical remission of the disease was achieved. Complaints about side effects (hyperemia, itching, burning and dry skin) were absent, the patient noted excellent tolerance to the drug, was satisfied with the properties of the skin after treatment.

This external agent was used to treat mild acne patients (n = 13), while the standardized acne severity index (total acne severity - OTU) before treatment was 21.7 ± 2.5 points. The comparison group (according to the prototype) was composed of mild acne patients (n = 16), before the start of therapy, the average group OTU index was 19.6 ± 2.9 points, that is, it did not statistically differ from the index of the main group (p> 0.05). Patients in the comparison group used skinoren gel as an external agent. After the completion of the 6-week course of treatment in both groups, the OTU was assessed by the attending physician and the subjective attitude of the patients to the external treatment (therapy compliance factors) was studied.

A comparative assessment of the characteristics of the skin, side effects and tolerance when using the inventive external funds and skinore gel (prototype) are shown in table 2.

Comparative studies showed that the standardized OTU index in acne patients who used the inventive remedy regressed by 69.3% from the initial one after treatment, which revealed a tendency to increase the efficiency of using the inventive remedy compared to the prototype. Subjective sensations (itching and burning of the skin) when using the claimed funds were noted 2.4 and 1.6 times, respectively, less often than when using gel skinoren; peeling of the skin - 2.4 times less often; there were practically no such undesirable effects as redness of the skin and skin tightening. In the opinion of all acne patients, when using the claimed external remedy, there was no general discomfort from treatment; 93.3% showed overall patient satisfaction with the properties of the skin after treatment, all 100% of patients showed excellent and good tolerance to the drug and satisfaction with the use of the claimed external agent, whereas the same indicators in patients receiving skinoren gel (prototype), respectively, 1 , 5 and 1.8 times lower.

Literature

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Claims (1)

An external therapy for acne patients, including azelaic acid as an active substance, propidenglycol, a gelling agent as a humectant, triglycerides as one of the emollients, and 0.1 mass% benzoic acid as a preservative. %, and purified water, characterized in that it additionally contains a second active substance - organosilicon glycerohydrogel, a carbomer is used as a gelling agent, phosphatidylcholine is used as a second emollient, and additionally contains emulsifiers: emulsion wax, glyceryl stearate and triethanolamine in the following ratio of components, mass %:
Azelaic acid 10.0 Silicone Glycerohydrogel 20,0 Propylene glycol 10.0 Carbomer 0.2 Triglycerides 3.0 Phosphatidylcholine 1,5 Benzoic acid 0.1 Emulsion wax 4.0 Glyceryl stearate 3.0 Triethanolamine 0.2 Purified water Rest