SK283697B6 - Dermatological compositions containing a liquid crystal vehicle and method of preparing same - Google Patents

Abstract

Dermatological topical compositions based on liquid crystals as vehicle, containing, as the active substance, urea, bifonazole, sodium lactate, organic and inorganic filters, sodium gluconate, a disinfectant and adjuvants and a method of preparation, comprising forming a system of liquid crystals in an oil-in-water emulsion with an anisotropic lamellar phase such that the layer of the water phase and oil is separated with another water layer, which is entrapped at the phase interface of the emulsifying system, thus forming a lamella. The originality consists in the method of preparing and use of the lamellar phase of liquid crystals as vehicle in dermatological compositions making use of their physical and chemical properties for improvement of performance of the active substances contained in the given vehicle.

Description

Technical field

The present invention is in the field of the manufacture of dermatological preparations based on the use of liquid crystals of the lyotropic phase.

BACKGROUND OF THE INVENTION

The need to maintain the liquid form of the epidermal bilayers in order to avoid crystallization due to drying has increased the interest in improving hydration and increasing water retention in the skin. Therefore, over the last decade, there has been an increasing interest in the use of liquid crystals in topical formulations, but especially in formulations where the release of the active ingredients and the moisturizing of the skin are controlled.

The intercellular substance in the stratum comeum of the skin surface layer is lamerically arranged and is also called the liquid crystal structure.

Previously used macrogol vehicles (polyethylene glycols) have been used mainly in cases where patients were allergic to other vehicles. In these vehicles, the hygroscopicity and osmotic activity cause water to be removed from the skin, which is disadvantageous because the controlled release of the active substances from the vehicles and their transfer to the skin requires a balance between the vehicle and the water taken from the epidermal cells. A technological disadvantage is the large dependence of their viscosity on temperature.

Vehicles comprised of emulsifying cetyl stearyl alcohol, liquid paraffin and white petrolatum are widespread, but a major disadvantage is that the anionic emulsifier is incompatible with ionic compounds. The chemical reaction can form insoluble active compound compounds or salts that disrupt the solvation shell followed by emulsion decomposition. Also included are vehicles containing non-ionic emulsifiers (Milan Chalabala et al .: Drug Technology, Galen®, 1997). Some manufacturers use this type of vehicle for urea-containing formulations.

Creams and lotions are often complex systems containing several different surfactants with higher hydrophilic-lipophilic balance (HLB) and fatty amphiphils. Fatty amphiphiles, e.g. long chain alcohols, acids, monoglycerides, some other fatty acid esters and the like. are often dominant emulsifiers, but are too lipophilic to stabilize an oil-in-water emulsion.

Liquid crystals can serve for the controlled release of the active ingredients by preventing the rapid release of the drug dissolved in the oil phase of the emulsion (Tyle P., Dissertation University Microfilms Intemational, 1985). In the liquid crystal emulsion, the release was 1000 times lower than in other emulsions (Friberg S., J. Soc. Cosmet. Chem., 1979).

Suzuki T., Takei H., and Yamazaki S., J. Colloid Interface Sci., 1989, demonstrated in vivo conditions that the use of liquid crystals increased the wetting time by a factor of three compared to emulsions without liquid crystals.

A disadvantage of the hitherto known processes for the production of liquid crystal dermatological preparations is the technological difficulty of preparing the liquid crystal vehicle itself and its lamellar phase.

SUMMARY OF THE INVENTION

The present invention provides a composition of dermatological liquid crystal formulations as vehicles and a process for their preparation. The use of the lamellar phase of the liquid crystal in the function of a vehicle improves the release of the active agent from the vehicle, utilizing the moisturizing effect of the vehicle itself, not only improving the subjective skin feel, but also objectively softening and smoothing the skin.

The lamellar liquid crystal phase consists of bilayers consisting of a surfactant in which the hydrocarbon chains are in a disordered state, similar to liquid paraffin. The bilayers are separated by aqueous layers. Such a phase is relatively fluid even at high surfactant concentrations so that the slats can easily slide one after the other.

Creams and lotions are often complex systems containing several different higher HLB surfactants and fatty amphiphils. Fatty amphiphiles, e.g. long chain alcohols, acids, monoglycerides, some other fatty acid esters, etc. are often dominant emulsifiers, but are too lipophilic to stabilize an oil-in-water emulsion. When the fatty amplifiers are dispersed in water in the presence of a higher HLB surfactant, a lamellar phase is obtained.

At a temperature around the melting point of the hydrocarbon chain, the surfactant penetrates into the amphiphilic layers and allows swelling. In this way swollen lamellar crystalline phases are obtained and a significant amount of water is incorporated in the space between the lamellas. When the temperature is lowered, a gel-like phase is formed. The ability to incorporate a significant amount of water into the interlinear space distinguishes the gel and liquid crystal phases from the ordered lamellar phase (see Figure 1, where a) shows the orientation of the molecules in the crystal, b) forming lamellar mesophase and c) .

The lamellar liquid crystalline phase is obtained according to the process of the present invention by specifically mixing fatty amphiphiles and surfactants which form micellar solutions of very low concentration.

The advantage of using liquid crystals as a vehicle is an increased emulsion stability. Multiple layers around the oil droplets act as a rheological barrier to prevent coalescence. Also, Van der Waals' attractive forces between two oil drops become extremely low.

The lamellar liquid crystal phases comprise swollen aqueous layers. In these structures, 50% of the total water content of the oil-in-water emulsion may be bound. This water is then less rapidly exposed to evaporation, less rapidly subject to evaporation, and provides a long lasting effect.

The dermatological preparations according to the invention are composed of the active ingredient and organic and inorganic filters in an amount of 1 to 16% by weight, a disinfectant in an amount of 0.3% by weight. and excipients. By the specific process of the present invention, the processing of excipients creates a liquid-crystal system in an oil / water emulsion with an anisotropic lamellar phase such that the aqueous phase and oil layer is separated by another water layer which is trapped at the interfacial interface of the emulsifier system and thereby forms a lamella. Due to their structure, the liquid crystals formed can be observed, similar to the true crystals, by X-ray diffraction of a polarized light microscope (see Fig. 2).

The dermatological formulations of the present invention are significant in that the use of the raw materials and the preparation process of the present invention provides formulations in which the controlled delivery of moisture and active ingredients to the skin can be coordinated.

The present invention provides a process for the preparation of liquid crystal vehicles and a process for the preparation of dermatological preparations themselves.

SK 283697 Β6

Technological process of preparation for preparations containing active substances: urea, sodium lactate.

In this procedure, the auxiliary raw materials are metered into the sterilization boiler and the contents of the sterilization boiler are heated to 80 ± 5 ° C with continuous mixing. To the resulting emulsifying fluid is added prepared disinfectant. The prescribed amount of water is metered into the homogenizer. Under continuous stirring, propylene glycol is added and the H 2 content is heated to 70 ± 5 ° C. At this temperature, the aqueous phase with the active ingredient is emulsified with an emulsifying fluid heated to 80 ± 5 ° C very slowly over a period of 20 to 30 minutes. with stirring at a speed of 14.5 to 22 rpm. depending on the homogenizer used. After emulsification, the contents of the homogenizer are homogenized for exactly 1 minute.

Technological preparation procedure for preparations containing active substances: bifonazole, organic and inorganic filters.

In this procedure, the auxiliary raw materials are metered into the sterilization boiler and the contents of the sterilization boiler are heated to a temperature of 75 to 95 ° C with continuous stirring. Active substances and a disinfectant are added to the resulting emulsifying fluid. The prescribed amount of water is metered into the homogenizer. Propylene glycol and sodium gluconate are added under stirring. The HZ content is heated to 70 ± 5 ° C. At this temperature, the aqueous phase is emulsified with an emulsifying fluid heated to 80 ± 5 ° C very slowly over a period of 20 to 30 minutes. with stirring at a speed of 14.5 to 22 rpm. depending on the homogenizer used.

After emulsification, the contents of the homogenizer are homogenized for exactly 1 minute. Anchor and spiral stirrers, or anchor and disolver, homogenizer are started and the HZ heating is switched off at the same time. After homogenization, cooling is switched on while the stirrers are running and the mixture is cooled to 27-28 ° C. This procedure produces a dermatological liquid crystal formulation in an oil-in-water emulsion with an anisotropic lamellar phase, characterized by increased moisture delivery efficiency, progressive diffusion of active ingredients based on skin requirements, prolonged activity, and improved bioavailability.

Depending on the type of active substance, the use of the dermatological preparations according to the invention can be indicated as emulsions and protective agents, antifungals or protective cream with UV filters.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 in part a) shows the orientation of the molecules in the crystals, in part b) the formation of lamellar interphase and in part

c) forming a gel phase.

Fig. 2 is a X-ray diffraction pattern of a polarized light microscope.

The invention is further illustrated by the following examples without being limited thereto.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Active substance:

Urea (urea) 5 wt.

Disinfectant: Triclosanum 0.3 wt. Auxiliary raw materials: Steareth-21 2.0 wt. Steareth-2 3.0 wt. PPG-15 Stearyl Ether 5.0 wt. ISOHEXADECANE 4.0 wt. Alcohol cetystearylicus 1.0 wt. Acidum stearicum 1.5 wt. Dimeticonum 1.0 wt. Cera alba 0.5 wt. Propylenglykolum 4.0 wt. Aqua purificata ad 100.0 wt. Example 1 - Preparation Method

Steareth-21, Steareth-2, PPG-15, Stearyl Ether and Isohexadecane feedstocks are metered into the sterilization boiler. Alcohol cetylstearylicus, Acidum stearicum and Cera alba are then added. The contents of the sterilization boiler are heated to 80 ± 5 ° C with continuous stirring. In a container of material tr. 17, a trituration of the disinfectant in Dimeticone is prepared and added to the emulsifying fluid in a sterilization boiler. The prescribed quantity of purified water is sucked into a duplicator homogenizer (hereinafter HZ). Propylene glycol is added under continuous stirring through an HZ opening for sucking in liquid raw materials. The H 2 content is heated to 70 ± 5 ° C. At this temperature, the active ingredient is added continuously with stirring through an opening in the HZ, which is designed to suck up the raw materials. At 70 ± 5 ° C, the aqueous phase with the active ingredient is emulsified with an emulsifying fluid heated to 80 ± 5 ° C very slowly for about 20 to 30 minutes, with the anchor microswitch 14.5 rpm on, clockwise and a spiral stirrer 29 rpm / min., anti-clockwise direction (HZ 500), or 22 rpm. (Fryma) in clockwise direction. After emulsification, the H 2 content is homogenized for exactly 1 minute. Stirrers - anchor 29 rev / min, clockwise and spiral 58 rev / min, left-handed (HZ 500) or anchor 22 rev / min, right-handed and 2940 revolutions / min, left-handed ( At the same time, the homogenizer 2900 to 3000 revolutions per minute turns the clockwise direction and at the same time the HZ heating is switched off.

After homogenization, the stirrers are anchored 14.5 rpm, clockwise and spiral 29 rpm, left-handed (HZ 500) or anchor 22 rpm (Fryma) in clockwise direction, while cooling is switched on until the mixture cooled to 27 ° C.

Example 2

Active ingredient: bifonazole wt.

Disinfectant: Triclosanum

0.3 wt.

Auxiliary raw materials: Steareth-21 2.0 wt. Steareth-2 3.0 wt. PPG-15 Stearyl Ether 5.0 wt. ISOHEXADECANE 4.0 wt. Alcohol cetystearylicus 1.5 wt. Acidum stearicum 1.5 wt. Dimeticonum 1.0 wt. Cera alba 0.5 wt. Propylenglykolum 4.0 wt.

% Aqua purificata ad 100.0 wt.

The preparation method is the same as in Example 1 except that the active ingredient is part of an emulsifying fluid which is heated to 75-95 ° C. The temperature of the aqueous phase is 75 ± 5 ° C.

Example 3

Active substances:

Urea (urea)

Sodium lactate

Gamma linolenic acid

Disinfectant:

Triclosanum

Auxiliary raw materials:

Steareth-21

Steareth-2

PPG-15 Stearyl Ether isohexadecane

Alcohol cetystearylicus. Acidum stearicum Dimeticonum

Cera alba Propylene glycol Aqua purificata ad

The method of preparation is i

5.0 to 10.0 wt.

2.0 to 10.0 wt.

0.5 to 5.0 wt.

0.3 wt.

2.0 wt.

3.0 wt.

5.0 wt.

4.0 wt.

1.0 wt.

1.5 wt.

1.0 wt.

0.5 wt.

4.0 wt. 100.0 wt. as in Example 1.

Example 4

Active substances:

Titanium dioxide

Sodium gluconan

4-methylbenzylidene camphor

Butyl methoxydibenzoylmethane

Disinfectant: Triclosanum

Auxiliary raw materials:

Steareth-21

Steareth-2

PPG-15 Stearyl Ether Isohexadecane Alcohol cetystearylicus Acidum stearicum Dimeticonum

1.0 to 5.0 wt.

1.0 to 5.0 wt.

1.0 to 4.0 wt.

1.0 to 4.0 wt.

0.3 wt.

2.0 wt.

3.0 wt.

5.0 wt.

4.0 wt.

1.0 wt.

1.5 wt.

1.0 wt.

0.5 wt.

4.0 wt. 100.0 wt.

Cetyl Dimeticonum

Propylenglykolum

Aqua purificata ad

The preparation process is the same as in Example 2. Sodium gluconate is part of the aqueous phase.

Industrial usability

The invention is useful in the pharmaceutical industry in the manufacture of dermatological and cosmetic preparations and protective working creams in which the controlled delivery of moisture and active ingredients can be coordinated.

Claims (7)

PATENT CLAIMS Dermatological topical liquid crystal formulations as a vehicle, characterized in that they contain an active ingredient selected from urea, bifonazole, sodium lactate and / or organic and inorganic filters in an amount of 0.5 to 25% by weight, a disinfectant in an amount of 0 %, With the remainder up to 100 wt. they form excipients comprising a mixture of higher HLB surfactants and fatty amphiphilic compounds and purified water. Composition according to claim 1, characterized in that it contains an active ingredient selected from urea, bifonazole, sodium lactate and / or organic and inorganic filters in an amount of 0.5 to 25% by weight, a disinfectant in an amount of 0.3% by weight. as adjuvants steareth-21 in an amount of about 2% by weight, steareth-2 in an amount of about 3% by weight, PPG-15 Stearyl Ether in an amount of about 5% by weight, isohexadecan in an amount of about 4% by weight, cetylstearyl alcohol in an amount of about 1 to 1.5 wt%, stearic acid in an amount of about 1.5 wt%, dimeticone in an amount of about 1 wt%, cera alba or cetyldimeticone in an amount of about 0.5 wt%, propylene glycol in an amount about 4 wt. and the remainder to 100 wt. formed by purified water. Composition according to claims 1 and 2, characterized in that the carrier part of the vehicle consists of oleosome-type liquid crystals. Process for the preparation of dermatological topical preparations according to claim 1, 2 or 3, characterized in that at least one higher HLB surfactant is sterilized, at least one fatty amphiphilic compound is subsequently added, the mixture thus obtained is heated to a constant temperature with stirring. 80 ± 5 ° C, if a disinfectant is added to the resulting emulsifying fluid, then purified water is added, followed by continuous stirring with propylene glycol, the aqueous phase with the active substance is emulsified at 70 ± 5 ° C with an emulsifying fluid heated to 80 to 90 ° C slowly over a period of 20 to 30 minutes, then the mixture is homogenized with constant stirring and then the heating of the homogenizer is switched off and after homogenization the mixture is cooled to about 27 ° C with stirring, the active ingredient being added with disinfectant or propylene glycol. Process for the preparation of dermatological topical preparations containing urea and / or sodium lactate according to claim 4, characterized in that the carrier part of the vehicle consists of oleosome-type liquid crystals formed by the addition of the excipients Steareth-21, Steareth-2, PPG -15 Stearyl Ether and Isohexadecan are added to the sterilization cauldron, followed by the addition of cetyl stearyl alcohol, stearic acid and cera alba, the mixture is heated to 80-90 ± 5 ° C with continuous stirring and the resulting emulsifying fluid is added with trituration The ingredients in dimethicone are subsequently sucked into the duplicator homogenizer by vacuum cleaning the water, propylene glycol is added under continuous stirring, and at 70 ± 5 ° C the aqueous phase with the active substance is emulsified with an emulsifying liquid heated to 80 to 90 ° C very slowly over 20 to 30 minutes, followed by the contents of the homogenizer and homogenize with constant stirring and then turn off the heating of the homogenizer and complete the homogenization to cool to about 27 ° C with stirring. Method for the production of dermatological topical preparations comprising bifonazole and / or organic and / or inorganic filters according to claim 4, characterized in that the carrier part of the vehicle is liquid oleosome-type liquid crystals formed by the addition of Steareth-21 excipients, Steareth -2, PPG-15 Stearyl Ether and Isohexadecan are added to the sterilization cauldron, followed by the addition of cetyl 4 stearyl alcohol, stearic acid and cera alba, the mixture is heated to 80-90 ± 5 ° C with stirring and the resulting emulsifying liquid is added. trituration of the active ingredients and disinfectant in dimethicone, then purified water is sucked into a duplicator homogenizer, vacuum is added under continuous stirring, and at 70 ± 5 ° C, the aqueous phase with the active substance is emulsified with an emulsifying liquid heated to 80-90 ° C very slowly over 20 to 30 minutes, then the contents are homogeneous The homogenizer is homogenized with constant stirring and then the heating of the homogenizer is turned off and the homogenization is cooled to about 27 ° C with stirring. Method according to claims 4,5 or 6, characterized in that the aqueous phase with the active substance is emulsified with an emulsifying fluid while the low-speed stirrers are running, depending on the homogenizer used, and after emulsification, the contents of the homogenizer are emulsified for exactly 1 minute. anchor stirrers and spiral stirrers when using a 500 rpm homogenizer. or an anchor stirrer and a dissolver when using a Fryma and at the same time the homogenizer is started at 2900 to 3000 rpm, at the same time the heating of the homogenizer is switched off, after homogenization the low-speed stirrers are started depending on the homogenizer used and cooling started.