LT4910B - Dermatological compositions containing a liquid crystal vehicle and method of preparing same - Google Patents

Abstract

Dermatological topical formulations based on liquid crystalline solvent as active ingredients containing urea, bifonazole, sodium lactate, organic and inorganic filters, sodium gluconate, disinfectant and adjuvants, and a method for their preparation, comprising forming an liquid-crystalline oil-in-water emulsion with an anisotropic lamellar phase as follows: that the aqueous phase and the oil layer are separated by another aqueous layer which is embedded within the phases of the emulsified system, thereby forming a lamella. The originality of the liquid crystal lamellar phase as a solvent in dermatological compositions using their physical and chemical properties to improve the performance of the active substances present in this solvent.

Description

Technical area

The present invention relates to the field of making dermatological compositions using liquid crystals of the lyotropic phase.

Origin of the Invention

The need to maintain the liquid form of the epidermis bisocks to prevent crystallization during drying has increased interest in improving hydration and enhancing water retention in the skin.

As a result, interest in the use of liquid crystals in topical formulations has increased in the past decade, especially in those where the release of active ingredients and the moisturizing of the skin are gradual, controlled.

The intracellular material of the surface layer of the skin in the stratum corneum of the epidermis is lamellar and is also sometimes classified as a liquid crystalline structure.

In the past, macrogel solvents (polyethylene glycols) have been used, mainly when patients are allergic to other solvents. The hygroscopic and osmotic activity of these solvents results in an undesirable deprivation of water from the skin, since the controlled release of active substances from the solvents and their transfer to the skin requires an equilibrium between the solvent and the water deprived of the epidermal cells. The technological disadvantage is the high dependence of their viscosity on temperature.

Solvents consisting of emulsifying cetylstearyl alcohol, liquid paraffin and white petroleum jelly have been widely used, but have a major disadvantage due to the incompatibility of the anionic emulsifier with ionic compounds. The chemical reaction can produce insoluble active compound compounds or salts that would break the solvating shell and then break down the emulsion. Such solvents also include solvents containing non-ionic emulsifiers (Milan Chalabala et al., Technologie lite, Galen®, 1997). Some manufacturers use this type of solvent for urea-containing compositions.

Creams and lotions are often complex systems that include several different surfactants with higher hydrophilic-lipophilic balance (HLB) values and fatty amphibious compounds. Fatty amphiphiles, such as long chain alcohols, acids, monoglycerides, some other fatty acid esters, etc., are often predominant emulsifiers but are too lipophilic to stabilize oil-in-water emulsions.

Liquid crystals can serve to control the release of active ingredients by interfering with the rapid release of the drug dissolved in the oil phase of the emulsion (Tyle P., Dissertation University Microfilms International, 1985). The liquid crystalline emulsion had a 1000 fold lower release than other emulsions (Friberg, S., J. Soc. Cosmet. Chem., 1979).

Suzuki T., Takei H., and Yamazaki S., J. Colloid Interface Sci., 1989, have shown in vivo that the use of liquid crystals increases the duration of skin hydration three times as much as liquid crystal emulsions.

The disadvantage of previous liquid crystalline dermatological compositions is that it is technologically difficult to produce the liquid crystal solvent itself and its lamellar phase.

Description of the Invention

The present invention provides dermatological compositions comprising a liquid crystalline solvent and a process for their preparation. The use of a solvent-lamellar liquid crystal phase improves the release of the active ingredient from the solvent and at the same time utilizes the moisturizing effect of this solvent, thereby improving not only the subjective sensation of the skin but also the objective softening and smoothing of the skin.

The liquid crystalline lamellar phase consists of bis-layers consisting of a surfactant wherein the hydrocarbon chains are in a disordered state similar to a liquid paraffin. The bilayers are separated by aqueous layers. Such a phase is relatively liquid, even at high surfactant concentrations, so that the lamellae can easily glide on top of each other.

Creams and lotions are often complex systems containing several different HLB surfactants and fatty amphiphilic compounds. Fatty amphiphiles, such as long chain alcohols, acids, monoglycerides, some other fatty acid esters and the like, are often predominant emulsifiers but are too lipophilic to stabilize oil in water emulsions. When the fatty amphiphiles are dispersed in water in the presence of a higher HLB surfactant, a lamellar phase is obtained.

At temperatures close to the melting point of the hydrocarbon chain, the surfactant penetrates into the amphiphilic layers and causes swelling. In this way, swollen lamellar crystalline phases are obtained and large quantities of water intervene between the lamellas. Lowering of the temperature produces a gel reticular phase. The ability to insert large amounts of water between the lamellae separates the gel and liquid crystalline phases from the ordered, lamellar phase (see Figure 1, where (a) indicates the orientation of the molecules in the crystal, (b) indicates the formation of the lamellar mesophase;

The lamellar liquid crystalline phase is obtained by the specific process of mixing fatty amphiphilic substances and surfactants which form micellar solutions in very low concentrations.

The use of liquid crystals as a solvent has the advantage of increasing the stability of the emulsion. Many layers around oil droplets act as a rheological barrier against coalescence. In addition, Van der Walt's pulling forces between the two droplets of oil become extremely low.

Lamellar liquid crystalline phases contain increased aqueous layers. These structures can bind 50% of the total water content of the oil-in-water emulsion. This water is then less volatile, less volatile and has a lasting effect.

The dermatological compositions of the present invention are comprised of an active ingredient and an organic and inorganic filter in an amount of 0.5 to 25% by weight, a disinfectant in an amount of 0.3% by weight and an adjuvant. In a specific embodiment of the present invention, the adjuvants are introduced into the liquid crystalline system in 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 embedded within the phase of the emulsion system. Because of their structure, the resulting liquid crystals can be screened in a similar manner to true crystals using X-ray diffraction polarized light microscopy (see Figure 2).

The dermatological compositions of the present invention are important in that the starting materials and method of the invention provide compositions which can coordinate the controlled delivery of moisture and active ingredients to the skin.

The present invention solves the problem of making a solvent, a liquid crystal, followed by a method of making the same dermatological compositions.

Technological route of preparation for compositions containing urea and sodium lactate as active ingredients

In this method, the adjuvants are placed in a sterilization boiler and the contents of the sterilization boiler are heated to 80 ± 5 ° C with continuous mixing. A prepared disinfectant is added to the resulting emulsified liquid. Add the necessary amount of water to the homogenizer. Under continuous stirring, propylene glycol is added and the contents of the homogenizer is heated to 70 ± 5 ° C and the active substance is then added. At this temperature, the aqueous phase is emulsified with an emulsified liquid which has been very slowly heated to 80 ± 5 ° C for 20-30 minutes using a low speed mixer depending on the homogenizer used.

Technological Production Method for Compositions Containing Bifonazole, Organic and Inorganic Filters as Active Ingredients

In this method, the adjuvants are incorporated into a sterilization boiler and the contents of the sterilization boiler are heated to 75-95 ° C with continuous stirring. The resulting emulsified liquid comprises the active ingredients and a disinfectant prepared. Add the necessary amount of water to the homogenizer. Propylene glycol and sodium gluconate are added with continuous stirring. Heat the contents of the homogenizer at 70 ± 5 ° C. At this temperature, the aqueous phase is emulsified with an emulsified liquid which has been very slowly heated to 80 ± 5 ° C for 20-30 minutes using a low speed mixer depending on the homogenizer used.

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

The anchor and spiral mixer or anchor mixer and solvent are started to operate and the homogenizer is stopped heating at the same time. After homogenization, the agitators begin to cool and the mixture is cooled to 27-28 ° C. This method provides a dermatological composition in a liquid crystal based oil-in-water emulsion with an anisotropic lamellar phase characterized by higher moisture delivery activity, increased skin diffusion of active ingredients based on skin requirements, and prolonged activity, which increases bioavailability.

Depending on the type of active ingredient, the dermatological compositions of the present invention may be used as emollient and antifungal, antifungal compositions, or sunblock creams.

The following examples are offered by way of illustration, but not of the invention

for definition limitation. 1 oavvzdvs Active ingredient: Urea 5.00-10.0% by weight When disinfecting material: Triclosan 0.3% by weight Adjuvants: Stearet-21 2.0% by weight Stearet-2 3.0% by weight PPG-15 stearyl ether 5.0% by weight Isohexadecane 4.0% by weight Cetylstearyl alcohol 1.0% by weight Stearic acid 1.5% by weight Dimethicone 1.0% by weight White wax 0.5% by weight Propylene glycol 4.0% by weight distilled water up to 100.0% by weight

example - Method of production

The adjuvants steareth-21, steareth-2, stearyl ether PPG-15 and isohexadecane are added to a sterilization boiler, followed by the addition of cetyl stearyl alcohol, stearic acid and white wax. The contents of the sterilization boiler are brought to 80 ± 5 ° C with continuous mixing. In a Class 17 container, the disinfectant is removed in dimethicone and added to the emulsified liquid in a sterilization boiler. aspirate a predetermined amount of water into the envelope homogenizer. Under continuous stirring, propylene glycol is added through the opening of the homogenizer to absorb liquid materials. Heat the contents of the homogenizer at 70 ± 5 ° C. At this temperature, the active ingredient is added, with continuous stirring, through the opening of the homogenizer to suck in powder form. At 70 ± 5 ° C, the aqueous phase with the active ingredient is emulsified with an emulsified liquid which has been very slowly heated to 80 ± 5 ° C for 20-30 minutes using a low speed mixer dependent on the homogenizer used. After emulsification, the contents of the homogenizer are homogenized for exactly 1 minute. Anchor and spiral mixers (500 rpm homogenizer) or anchor mixer and solvent (Fryma) and 29003000 rpm homogenizer are started and the homogenizer is stopped heating at the same time.

After homogenization, low speed stirrers corresponding to the type of homogenizer used are started to cool and the mixture is cooled to 27 ° C.

example

Active ingredient:

Bifonazole

When disinfecting material:

Triclosan Adjuvants:

Steareth-21 Steareth-2 PPG-15 Stearyl Ether Isohexadecane Cetyl Stearyl Alcohol Stearic Acid

0.5-10.0% by weight

0.3% by weight

2.0% by weight

3.0% by weight

5.0% by weight

4.0% by weight

1.5% by weight

1.5% by weight

Ί

Dimethicone White wax Propylene glycol Distilled water

1.0 wt% 0.5 wt% 4.0 wt% to 100.0 wt%

The method of preparation is the same as that of Example 1 except that the active ingredient is part of an emulsified liquid which is heated to 75-85 ° C. The temperature of the aqueous phase is 75 ± 5 ° C.

Example 3 Active ingredient: Urea 5.00-10.0% by weight Sodium lactate 2.0-10.0% by weight Gamma-linolenic acid 0.5-5.0% by weight When disinfecting material: Triclosan 0.3% by weight Adjuvants: Stearet-21 2.0% by weight Stearet-2 3.0% by weight PPG-15 stearyl ether 5.0% by weight Isohexadecane 4.0% by weight Cetylstearyl alcohol 1.0% by weight Stearic acid 1.5% by weight Dimethicone 1.0% by weight White wax 0.5% by weight Propylene glycol 4.0% by weight distilled water up to 100.0% by weight

The method of preparation is the same as in Example 1.

example

Active ingredient:

Titanium dioxide

Sodium gluconate

4-Methylbenzylidene camphor

Butylmethoxydibenzoylmethane

When disinfecting material:

Triclosan

Adjuvants:

Steareth-21 Steareth-2 PPG-15 Stearyl Ether Isohexadecane Cetyl Stearyl Alcohol Stearic Acid

1.0-5.0% by weight 1.0-5.0% by weight 1.0-4.0% by weight 1.0-4.0% 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

Dimethicone Cetyldimethicone Propylene glycol Distilled water

1.0 wt% 0.5 wt% 4.0 wt% to 100.0 wt%

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

Opportunities for industrial application

The present invention is suitable for use in the pharmaceutical industry in the production of dermatological and cosmetic compositions and protective working creams, in which it enables the coordinated delivery of moisture and active ingredients.

Claims (7)

Definition of the Invention 1. Liquid crystalline dermatological topical compositions, comprising: - an active substance selected from urea, bifonazole, sodium lactate and / or organic and inorganic filters in an amount of 0.5 to 25% by weight, - disinfectants in an amount of 0,3% by weight, - a balance up to 100% by weight of adjuvants which are a mixture of HLB-containing surfactants and fatty amphiphilic compounds and purified water. 2. The composition of claim 1, further comprising: - an active substance selected from urea, bifonazole, sodium lactate and / or organic and inorganic filters in an amount of 0.5 to 25% by weight, - disinfectants in an amount of 0,3% by weight, adjuvants include steareth-21 in an amount of about 2% by weight, steareth-2 in an amount of about 3% by weight, PPG-15 in stearyl ether in an amount of about 5% by weight, isohexadecane in an amount of about 4% by weight , cetyl stearyl alcohol containing from about 1% to about 1.5% by weight, stearic acid from about 1.5% by weight, dimethicone from about 1% by weight, white wax or cetyldimethicone at about 0%, 5% by weight of propylene glycol in an amount of about 4% by weight, and - a balance of up to 100% by weight of purified water. 3. The composition of claim 1 or 2, wherein the carrier portion of this solvent is an oleosome liquid crystal. 4. A process for the preparation of topical dermatological compositions according to claim 1, 2 or 3, comprising the step of sterilizing at least one HLB-containing surfactant followed by addition of at least one fatty amphiphilic compound, thereby heating the resulting mixture to 80 ± 5 ° C. adding, under continuous stirring, disinfectant to the resulting emulsified liquid, addition of purified water followed by continuous addition of propylene glycol, emulsification of the aqueous phase with the active ingredient at 70 ± 5 ° C with emulsified liquid heated very slowly to 80-90 ° C, -30 minutes, followed by homogenization of the mixture with continuous stirring, whereupon the mixture is cooled to approximately 27 ° C, with stirring being stopped and the homogenization is completed, to which the active ingredient is added with disinfectant or propylene glycol. 5. A process for the preparation of topical dermatological compositions containing urea and / or sodium lactate according to claim 4, wherein the solvent carrier is an oleosome liquid crystal obtainable by a process comprising steareth-21, steareth-2, PPG-15 stearyl. addition of ether and isohexadecane as adjuvants to the sterilization boiler, followed by addition of cetylstearyl alcohol, stearic acid and white wax, heating the resulting mixture to 80 ± 5 ° C with continuous stirring, adding the triturated dimethicone disinfectant to the resulting emulsified liquid, vacuum emptying of the aqueous phase with the active ingredient at 70 ± 5 ° C with emulsified liquid, very slowly heated to 80-90 ° C, for 20-30 minutes, followed by homogenization of the contents of the homogenizer, in a vacuum homogenizer, propylene glycol and the active ingredient with continuous stirring, whereupon the mixture is cooled to about 27 ° C while stirring to stop heating and complete homogenization. 6. A process for the preparation of topical dermatological compositions containing bifonazole and / or organic and / or inorganic filters according to claim 4, wherein the solvent carrier is an oleosome-type liquid crystal obtainable by a process comprising steareth-21, steareth-2, Addition of PPG-15 stearyl ether and isohexadecane as adjuvants to the sterilization boiler followed by addition of cetyl stearyl alcohol, stearic acid and white wax to heat the resulting mixture at 80 to 90 ± 5 ° C with continuous mixing of the triturated dimethicone active agents and disinfectant. adding to the resulting emulsified liquid, suctioning the purified water in a vacuum homogenizer, adding propylene glycol under continuous stirring, emulsifying the aqueous phase with the active ingredient at 70 ± 5 ° C with an emulsified liquid heated very slowly to 80-90 ° C for 20-30 minutes, to homogeneous homogenizing the contents of the emitter with continuous stirring, whereupon the mixture is cooled to about 27 ° C with stirring, when heating is stopped and homogenization is completed. 7. The method of claim 4, 5 or 6, wherein the aqueous phase with the active ingredient is emulsified with an emulsified liquid using low-speed mixers depending on the homogenizer used, and after emulsification, the contents of the homogenizer are homogenized for exactly 1 minute, triggered by anchor and helix. type mixers 500 rpm in the case of a homogenizer or an anchor-type mixer and a solvent for a Fryma device, while the homogenizer operates at 2900-3000 rpm, heating of the homogenizer is stopped at the same time and after homogenization the mixers of the homogenizer type are started and refrigerated.