HUP0200101A2 - Dermatological compositions containing a liquid crystal vehicle and method of preparing same - Google Patents

Description

PUBLICATION COPY

Dermatological preparations containing a liquid crystal carrier and a process for preparing such preparations

The invention relates to the preparation of dermatological preparations using liquid crystals of the lyotropic phase.

The need to maintain the fluid form of the epidermal bilayers - to avoid crystallization due to drying - has increased interest in improving hydration and enhancing water retention in the skin.

As a result, the use of liquid crystals in topical preparations has become increasingly common in the last ten years, especially in preparations in which the release of active compounds and skin moisturizing is gradual and controlled.

In the stratum corneum, the surface layer of the skin, the intracellular material is arranged in a lamellar form, and this material is sometimes said to have a liquid crystal structure.

Previously, macrogol carriers (polyethylene glycols) were used mainly in patients who were allergic to other carriers. The hygroscopicity and osmotic activity of these carriers result in the extraction of water from the skin, which is undesirable since the controlled release of the active ingredients from the carrier and their delivery to the skin requires an equilibrium between the carrier and water, which is extracted from the epidermal cells under such conditions. A technical disadvantage is that the viscosity of these materials is highly dependent on temperature.

Carriers containing cetyl stearyl alcohol emulsifier, liquid paraffin and white petrolatum are widely used, but their major disadvantage is that anionic emulsifiers are not compatible with compounds of ionic nature. As a result of a chemical reaction, the active ingredient or its salts can be converted into insoluble compounds, which destroy the solvate shell, followed by the breakdown of the emulsion. Such carriers also include those containing nonionic emulsifiers (Milan Chalabada et al., Technologie léku. Gálén®, 1997). Certain manufacturers use this type of carrier for preparations containing urea.

Creams and milks are often complex systems containing several surfactants with higher HLB (hydrophilic-lipophilic balance) values and fatty amphiphilic compounds. Fatty amphiphilic substances, such as long-chain alcohols, acids, monoglycerides, some other fatty acid esters, and the like, are often the dominant emulsifiers, but are too lipophilic to stabilize oil-in-water emulsions.

Liquid crystals can serve to control the release of active ingredients by preventing the rapid release of the drug substance dissolved in the oil phase of the emulsion (Tyle P., Dissertation University Microfilms International, 1985). In a liquid crystal emulsion, the release was a thousand times slower than in other emulsions (Friberg S., J. Soc. Cosmet. Chem . , 197 9 ) .

Suzuki T., Takei H. and Yamazaki S. (J. Colloid Interface Sci., 1989) demonstrated in vivo that the application of liquid crystals increases the time the skin remains moist threefold compared to emulsions not containing liquid crystals.

A disadvantage of the prior art production of dermatological preparations based on liquid crystals is that the manufacturing process of the liquid crystal carrier and the lamellar phase itself is technically complex.

The invention provides dermatological preparations containing a liquid crystal carrier and a process for their preparation. By using the lamellar phase of liquid crystals as a carrier, the release of the active ingredient from the carrier is improved, and at the same time the wetting effect of the carrier itself is exploited, thereby improving not only the subjective skin feel, but also the objective softness and smoothness of the skin.

The lamellar phase of liquid crystals consists of a bilayer formed by a surfactant, in which the hydrocarbon chains are arranged in a disordered manner, just as in liquid paraffin. The bilayers are separated by aqueous layers. Such a phase is relatively fluid even at high concentrations of surfactant, so that the lamellae can easily slide past each other.

Creams and milks are often complex systems containing several surfactants with higher HLB (hydrophilic-lipophilic balance) values and fatty amphiphilic compounds. Fatty amphiphilic substances, such as long-chain alcohols, acids, monoglycerides, some other fatty acid esters, and the like, are often the dominant emulsifiers, but they are too lipophilic to stabilize oil ^{-in- water emulsions} . When fatty amphiphilic compounds are dispersed in water in the presence of a surfactant with a higher HLB value, a lamellar phase is obtained.

At temperatures around the melting point of the hydrocarbon chain, the surfactant penetrates the layers of the amphiphilic material and promotes swelling. In this way, swollen lamellar crystalline phases are obtained, and a significant amount of water is incorporated into the spaces between the lamellae. When the temperature is reduced, a gel reticular phase is formed. The ability to incorporate a significant amount of water into the interlamellar spaces distinguishes gel and liquid crystal phases from ordered lamellar phases (see Fig. i, where part a) shows the arrangement of molecules in a crystal, part b) shows the formation of a lamellar mesophase and part c) shows the formation of a gel phase).

The lamellar liquid crystal phase is obtained by the method of the present invention by specifically mixing fatty amphiphilic substances and surfactants, thus obtaining micellar solutions of very low concentration.

The advantage of using liquid crystals as a carrier is that the stability of the emulsion is increased. The multiple layers around the oil droplets act as a rheological barrier against coalescence. In addition, the Van der Waals forces between the two oil droplets become extremely small.

Lamellar liquid crystal phases contain swollen water layers. Up to 50% of the total water content of an oil-in-water emulsion can be bound in these structures. This water is then less susceptible to evaporation, evaporates less quickly and provides a long-lasting effect.

The dermatological preparations according to the present invention comprise an active ingredient, organic and inorganic filters in an amount of 0.5-25% by weight, a disinfectant in an amount of 0.3% by weight and adjuvants. According to the specific method according to the present invention, the adjuvants are incorporated into a liquid crystal system, an oil-in-water emulsion with an anisotropic lamellar phase, such that the aqueous phase and the oil layer are separated by another aqueous layer, which is trapped at the phase boundary of the emulsifying system, thus forming a lamellar layer. Due to their structure, the liquid crystals formed can be detected by X-ray diffraction, similar to real crystals, using a microscope using polarizing light (see Figure 2).

The importance of the dermatological compositions of the present invention lies in the fact that, with the help of the starting materials and the method of the invention, compositions are obtained in which moisture and controlled release of active ingredients into the skin can be coordinated.

The invention also solves the problem of producing the carrier liquid crystals and subsequently the dermatological preparations themselves.

Technological process for the production of preparations containing urea and sodium lactate as active ingredients

In this process, the adjuvants are placed in a sterilizing vessel and the contents of the sterilizing vessel are heated to 80+5 °C with continuous stirring. The prepared disinfectant is added to the emulsifying liquid formed. Then the prescribed amount of water is poured into the homogenizer. Propylene glycol is added to the mixture with continuous stirring and the contents of the homogenizer are heated to 70+5 °C, then the active ingredient is added. At this temperature, the aqueous phase is emulsified with the emulsifying liquid preheated to 80-15 °C very slowly, for 20-30 minutes, using a low-speed mixer selected depending on the homogenizer used.

Technological process for the production of preparations containing bifonazole as an active ingredient, organic and inorganic filters

In this process, the adjuvants are weighed into a sterilizing vessel and the contents of the sterilizing vessel are heated to 75-95 °C with continuous stirring. The active substances and the prepared disinfectant are added to the resulting emulsifying liquid. A predetermined amount of water is charged into a homogenizer and propylene glycol and sodium gluconate are added with continuous stirring. The contents of the homogenizer are heated to 70±5 °C. At this temperature, the aqueous phase is emulsified with the emulsifying liquid preheated to 80±5 °C very slowly for 20-30 minutes using a low-speed mixer selected depending on the homogenizer used.

After emulsification, the contents of the homogenizer are homogenized for exactly 1 minute.

The anchor and spiral type mixers or an anchor mixer and a dissolver, as well as the homogenizers are started and at the same time the heating of the homogenizer is stopped. After homogenization, while the mixers are operating, the cooling is started and the mixture is cooled to 27-28 °C. This process results in a dermatological preparation based on liquid crystals in an oil-in-water emulsion with an anisotropic lamellar phase, which is characterized by a higher activity in terms of moisture release, progressive diffusion of active ingredients according to the needs of the skin and a longer duration of activity, which improves the bioavailability.

Depending on the type of active ingredient, the dermatological preparations according to the invention may be indicated for use as emollient and protective, antifungal or UV-filtering protective creams.

The following examples are intended to illustrate the invention, but are not intended to limit the invention.

Example 1

Active ingredient:

Urea 5.00-10.0% by weight

Disinfectant:

Triclosan 0.3% by weight

Adjuvants:

Steareth-21 2.0 % by weight Steareth-2 3.0 % by weight PPG-15-stearyl ether 5, 0 crowd! Isohexadecane 4.0 % by weight Cetyl stearyl alcohol Page 1 crowd! Stearic acid _L / □ crowd! Dimethicone 1, p. crowd! Cera alba 0.5 crowd!

Propylene glycol

Purified water

Example 1

Production process

4.0% by weight

Up to 100.0% by weight

The adjuvants steareth-21, steareth-2, PPG-15-stearyl ether and isohexadecane are weighed into a sterilisation vessel, followed by the addition of cetyl stearyl alcohol, stearic acid and Cera alba. The contents of the sterilisation vessel are heated to 80±5°C with continuous stirring. In a container made of a material belonging to class 17, the disinfectant is dissolved in dimethicone and the mixture is added to the emulsifying liquid in the sterilisation vessel. A predetermined amount of purified water is then drawn into the jacketed homogeniser using vacuum. Propylene glycol is added to the mixture through the liquid inlet of the homogeniser with continuous stirring. The contents of the homogeniser are heated to 70±5°C. At this temperature, while continuously stirring, the active ingredient is also added through the opening for dosing powdered substances of the homogenizer. After that, the aqueous phase containing the active ingredient is emulsified at 70±5 °C with the emulsifying liquid preheated to 80±b °C very slowly for 20-30 minutes, for which a low-speed mixer selected depending on the homogenizer used is used. After emulsification, the contents of the homogenizer are homogenized for exactly 1 minute. An anchor and spiral type mixer (500 rpm homogenizer) or an anchor type mixer and a dissolver (Fryma) and a 2900-3000 rpm homogenizer are operated, while the heating of the homogenizer is stopped.

After homogenization, low-speed mixers appropriate for the type of homogenizer used are turned on and cooling is initiated, then continued until the temperature of the mixture reaches 27 °C.

Example 2

Active ingredient:

Bifonazole 0.5-10.0 wt.

Disinfectant:

Triclosan 0.3 tour% Give me a call: Steareth-21 2.0 % by weight Steareth-2 3.0 % by weight PPG-15-stearyl ether 5.0 crowd! Isohexadecane 4.0 % by weight Cetyl stearyl alcohol 1 to 5 crowd! Stearic acid 1.5 crowd! Dimethicone 1 ! 0 crowd! Cera alba 0.5 crowd! Propylene glycol 4.0 crowd! Purified water 100, 0 weight!-up

The preparation process is the same as that described in Example 1, with the difference that the active ingredient is part of the emulsifying liquid, which is heated to 75-85 °C. The temperature of the aqueous phase is /515

Example 3

Active ingredient:

Urea

Sodium lactate

Gamma-linolenic acid

To be a husband is to be a husband:

Triclosan

Adjuvants:

Steareth-21

Steareth-2

PPG-15-stearyl ether

Isohexadecane

Cetyl stearyl alcohol

Stearic acid™

Dimeticone

White wax

Propylene glycol

Purified water

The production process

Example 4

Active ingredient:

Titanium dioxide

Sodium gluconate

4-Methylbenzylidene camphor

Butyl methoxydibenzoylmethane

Disinfectant:

Triclosan

5.00-10.0% by weight

2.0-10.0% by weight

0.5-5.0% by weight

0.3% by weight

2.0% by weight

3.0% by weight

5.0% by weight

4.0% by weight

1.0% by weight

1.5% by weight

1.0% by weight

0.5 wt%

4.0% by weight

up to 100.0% by weight identical to that described in Example 1 wt% wt% wt% wt% wt%

0.3% of the total

1.0-5.0

-A r U ^— Ö _f U

1.0 — 4.0

1., 0-4.0

Give me the following:

Steareth-21 2, 0 tour% Steareth-2 o, u % by weight PPG-15-stearyl ether 5, 0 % by weight Isohexadecane 4.0 % by weight Cetyl stearyl alcohol 1, p. % by weight Stearic acid 1, 5 % by weight Dimethicone 1 0 % by weight Cetyl Dimethicone 0.5 % by weight Propylene glycol 4.0 % by weight Purified water 100, Up to 0% by weight

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

The invention can be used in the pharmaceutical industry for the production of dermatological and cosmetic preparations, as well as protective creams, in which it enables the coordination of moisture and controlled release of the active ingredient.

Claims (7)

Patent claims: 1. Dermatological topical preparations containing an active ingredient selected from urea, bifonazole, sodium lactate and/or organic and inorganic filters in an amount of 0.5-25% by weight, - disinfectant in an amount of about 0.3% by weight, and a mixture of surfactants with higher HLts values and fatty amphiphilic compounds, as well as purified water, in an amount corresponding to the remaining 100% by weight. 2. The composition according to claim 1, which contains as active ingredients urea, bifonazole, sodium lactate and/or organic and inorganic filters in an amount of 0.5-25% by weight, a disinfectant in an amount of about 0.3% by weight, steareth-21 as an adjuvant 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, isohexadecane in an amount of about 4% by weight, cetyl-1-stearic alcohol in an amount of about 1-1.5% by weight, stearic acid in an amount of about 1.5% by weight, dimethicone in an amount of about 1% by weight, cera alban or cetyl dimethicone in an amount of about 0.5% by weight, propylene glycol in an amount of about It contains 4% by weight and purified water in an amount corresponding to the remaining 100% by weight. 3. The composition according to claim 1 or 2, characterized in that the carrier portion of the vehicle consists of oily type liquid crystals. 4. A method for preparing dermatological topical preparations according to claim 1, 2 or 3, characterized in that at least one surfactant with a higher HLB value is sterilized, then at least one fatty amphiphilic compound is added, the mixture thus obtained is heated to a temperature of 80±5 °C with continuous stirring, a disinfectant is added to the formed emulsifying liquid with continuous stirring, then purified water and then propylene glycol, the aqueous phase with the active ingredient is emulsified at 70±5 °C with the emulsifying liquid heated to 80-90 °C very slowly for 20-30 minutes, then the mixture is homogenized with continuous stirring, after which the heating is stopped and the homogenization is completed, then the mixture is stirred for about It is cooled to 27°C, where the active ingredient is added together with an antiseptic or propylene glycol. 5. The method according to claim 4 for the preparation of topical dermatological preparations containing urea and/or sodium lactate, characterized in that the carrier part of the carrier material is formed by oily liquid crystals, which are formed by measuring the adjuvants steareth-21, steareth-2, PPG-15-stearyl ether and isohexadecane into a sterilizing vessel, then cetyl stearyl alcohol, stearic acid and cera alba are added to the above-L materials, and the resulting mixture is heated to 80±5 °C with continuous stirring, the disinfectant mixed with drmethicone is added to the emulsifying liquid thus prepared, purified water is sucked into the jacketed homogenizer using a vacuum, propylene glycol and the active ingredient are also added while continuously stirring, the aqueous phase with the active ingredient is heated to 70±5 It is emulsified very slowly for 20-30 minutes with an emulsifying liquid heated to 80-90°C, then the contents of the homogenizer are homogenized with continuous stirring, the heating is stopped and the homogenization is completed, finally the mixture is cooled to approx. 27°C while stirring. 6. The method according to claim 4 for the preparation of topical dermatological preparations containing bifonazole and/or organic and/or inorganic filters as active ingredients, characterized in that the carrier part of the carrier material consists of oily liquid crystals, which are formed by measuring the adjuvants steareth-21, steareth-2, PPG-15-stearyl ether and isohexadecene into a sterilizing vessel, then adding cetyl stearyl alcohol, stearic acid and cera alba to the above materials, the 80 °C mixture thus obtained is heated to a temperature of 90-15 °C with continuous stirring, the active ingredient and the disinfectant are added to the formed emulsifying liquid in a form mixed with dimethicone, purified water is sucked into the jacketed homogenizer, then propylene glycol is added with continuous stirring, the 70-15 °C aqueous solution containing the active ingredient is The phase is emulsified very slowly for 20-30 minutes with the emulsifying liquid heated to 80-90 °C, then the contents of the homogenizer are homogenized with continuous stirring, then the heating is stopped and the homogenization is completed, finally the mixture is cooled to approx. 27 °C while stirring. 7. The method according to claim 4, 5 or 6, characterized in that the aqueous phase containing the active ingredient is emulsified with low-speed mixers selected depending on the homogenizer, and after emulsification, the contents of the homogenizer are homogenized exactly 1 time, an anchor and spiral type mixer is operated in the case of a 500 rpm homogenizer, or an anchor mixer and a drssolver are operated in the case of a Fryma device, the homogenizer is set to 2900-3000 rpm, at the same time the heating is stopped, and after homogenization, the low-speed mixers selected depending on the type of homogenizer used are turned on and cooling is started. advopatent PATENT AND TRADEMARK OFFICE BÉLA KARÁCSONYI patent attorney