LV 12781
DERMATOLOGICAL COMPOSITIONS CONTAINING A LIQUID CRYSTAL VEHICLE AND METHOD OF PREPARING SAME
Technical Field 5
The invention relates to the field of production of dermatologicai compositions using liquid crystals of the lyotropic phase.
Background Art 10
The need for maintaining the liquid form of the epidermal bilayers in order to avoid crystallization due to drying, has increased the interest in improving hydration and enhancing retention of vvater in the skin. 15 During the iast decade, an interest in use of liquid crystals in topical compositions has therefore increased, especially for those compositions in vvhich release of the active compounds and moisturizing of the skin are gradual, controlled. 20 The intracelluiar substance in the stratum corneum of the superficial layer of the skin is arranged in a lamellar manner and is also sometimes designated as a liquid crystal structure.
Prior macrogol vehicles (poiyethyleneglycols) have been used mainly in 25 cases of patients allergic to other vehicles. Hygroscopicity and osmotic activity of these vehicles results in withdrawal of vvater from the skin, vvhich is undesirable, as controlled release of the active substances from vehicles and their transport into the skin require formation of an equilibrium betvveen the vehicle and vvater vvhich is vvithdravvn from epidermal celis. A technological dravvback is great dependence of 30 their viscosity on temperature. 2
Vehicles consisting of emuisifying cetyl stearyl alcohol, liquid paraffin and vvhite vaseline have been broadly used, but have a great drawback in incompatibility of the anionic emulsifier with compounds of ionic nature. A Chemical reaction may create insoluble compounds of the active substance or salts, vvhich 5 damage the solvating envelope, follovved by decomposition of the emulsion. Such vehicles include also those containing non-ionic emulsifiers (Milan Chalabala et al.: Technologie ļeku, Galen®, 1997). Some producers use this type of vehicles for compositions containing urea. 10 Creams and lotions are often complex systems which comprise several different surface active substances having higher values of hydrophilic-lipophilic balance (HLB) and fatty amphiphilic compounds. Fatty amphiphilics, such as long chain alcohols, acids, monoglycerides, some other fatty acid esters and the like, are often dominant emulsifiers, but they are too lipophilic to stabilizē oil-in-water 15 emulsions.
Liquid crystals can serve for controlled release of active substances by preventing rapid release of the pharmaceutical dissolved in the oil phase of the emulsion (Tyle P., Dissertation University Microfilms International, 1985). In a 20 liquid crystal emulsion, 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, have demonstrated in vivo that use of liquid crystals will increase the duration of skin 25 moistening three times in comparison with emulsions vvithout liquid crystals. A drawback of prior art methods of production of dermatological compositions based on liquid crystals is technological difficulty of the manufacturing process of the liquid crystal vehicle itself and of the lamellar phase 30 thereof. 3 LV 12781
Disclosure of the Invention
The invention provides dermatological compositions containing a liquid crystal vehicle and a method for the preparation thereof. Use of the lamellar phase 5 of liquid crystals as vehicle improves release of the active substance from the vehicle and at the same time the moisturizing effect of the vehicle itself is utilized, thus improving not only subjective skin feel, but also objective softening and smoothing of the skin. 10 The lamellar phase of the liquid crystals consists of bilayers formed by a surface active substance in which the hydrocarbon chains occur in an unordered State, similarly to parafTin in the liquid State. The bilayers are separated by aqueous layers. Such phase is relatively liquid even in high concentrations of the surfactant such that the lamellas can easily slide one on another. 15
Creams and lotions are often complex systems which comprise several different higher HLB surfactants and fatty amphiphilic compounds. Fatty amphiphilics, such as long chain alcohols, acids, monoglycerides, some other fa#y acid esters and the like, are often dominant emulsifiers, but they are too lipophilic 20 to stabilizē oil-in-water emulsions.
When fatty amphiphilics are dispersed in water in the presence of a surfactant having higher HLB, a lamellar phase is obtained.
At temperatures around melting point of the hydrocarbon chain the 25 surfactant penetrates into the layers of the amphiphilic material and enables svvelling. In this manner, svvollen lamellar crystalline phases are obtained and significant amounts of vvater become incorporated in spaces betvveen the lamellas. When the temperature is lovvered, a gel reticular phase forms. The ability to incorporate significant amounts of vvater in interlamellar spaces distinguishes the 30 gel and liquid crystal phases from the ordered, lamellar phase (see Fig. 1 vvherein part a) shovvs orientation of the molecules in a crystal, part b) shovving formation of a lamellar mesophase and part c) shovving formation of a gel phase). 4
The lamellar liquid crystal phase is obtained by the method of this invention by specific mixing of fatty amphiphilic materiāls and surfactants which form micellar Solutions of very low concentrations. 5 Use of liquid crystals as the vehicle has an advantage of increased stability of the emulsion. Multiple layers around oil droplets act as a rheological barrier against coalescence. In addition, Van der VVaals attractive forces betvveen two oil droplets become extremely low. 10 Lamellar liquid crystal phases comprise svvollen aqueous layers. Fifty per cent of the total vvater content of an oil-in-water emulsion may be bound in these structures. Said water is then less rapidly exposed to evaporation, undergoes evaporation less rapidly and provides a long-term effect. 15 The dermatological compositions of this invention are composed of an active substance and organic and inorganic filters in an amount of 0.5 to 25 % by vveight, a disinfectant in the amount of 0.3 % by weight and adjuvants. The specific method of this invention works the adjuvants up into a liquid crystal system in an oil-in-water emulsion with an anisotropic lamellar phase such that the aqueous 20 phase and oil layer is separated with another water layer, vvhich is entrapped at the phase interface of the emulsifying system and thus a lamella is formed. Due to their structure, the formed liquid crystals can be monitored similarly as true crystals by means of X-ray diffraction polarized light microscopy (see Fig. 2). 25 The dermatological compositions of this invention are important in that by means of the starting materiāls and the method of the invention compositions are obtained in vvhich it is possible to coordinate controlled delivery of moisture and of active substances into the skin. 30 The invention solves a method of preparing the vehicle-liquid crystals-and, subsequently, a method of preparing the dermatological compositions themselves. 5 LV 12781
Technological process of preparing in case of compositions containing the active substances urea and sodium lactate:
In this process, adjuvants are charged into a sterilizing kettle and under 5 continuous stirring the contents of the sterilizing kettle is heated to a temperature of 80±5 °C. The prepared disinfectant is added to the resulting emulsifying liquid. The prescribed amount of water is charged into a homogenizer. Propyleneglycol is added under continuous stirring and the contents of the homogenizer is heated at 70±5 °C, follovved by addition of the active substance. At this temperature the 10 aqueous phase is emulsified with the emulsifiying liquid preheated to 80±5 °C very slowly for 20 to 30 minūtes using a low-speed aģitator dependent of the homogenizer used.
Technological process of preparing in case of compositions containing the 15 active substances bifonazole, organic and inorganic filters:
In this process, adjuvants are charged into a sterilizing kettle and under continuous stirring the contents of the sterilizing kettle is heated to a temperature '·«** -4*1··.·:« - of 75 to 95 °C. The active substances and prepared disinfectant are added to the 20 resulting emulsifying liquid. The prescribed amount of water is charged into a ’lļSŅ homogenizer. Propyleneglycol and sodium gluconate are added under continubus stirring. The contents of the homogenizer is heated at 70±5 °C. At this temperature the aqueous phase is emulsified with the emulsifiying liquid preheated to 80±5 °C very slowly for 20 to 30 minūtes using a low-speed aģitator dependent of the 25 homogenizer used.
After emulsifying, the contents of the homogenizer are homogenized for exactly 1 minūte. 30 Aģitators of anchor and spiral type, or an anchor aģitator and dissolver, and homogenizers are set to operation and at the same time, heating of the homogenizer is stopped. After homogenizing, under aģitators running, cooling is started and the mixture is cooled down to a temperature of 27 to 28 °C. This process provides a dermatological composition based on liquid crystals in an oil-in- 6 water emulsion with an anisotropic lamellar phase, characterized by higher activity in delivery of moisture, Progressive diffusion of active substances based on the requirements of the skin, prolonge activity and vvhich improves bioavailability. 5 According to the type of the active substance, dermatological compositions of the invention may be indicated for use as emollients and protectives, antimycotics or protective creams with UV filter.
The follovving examples are offered to illustrate, but not to limit the claimed 10 invention.
Example 1 Active ingredient:
Urea 15 Disinfectant: Triclosanum Adjuvants:
Steareth-21
Steareth-2 20 PPG-15 Stearyl Ether isohexadecane Alcohol cetylstearylicus Acidum stearicum Dimeticonum 25 Cera alba
Propylenglykolum Aqua purificata 5.00-10.0 % by weight 0.3 % by weight 2.0 % by weight 3.0 % by weight 5.0 % by weight 4.0 % by weight 1.0 % by weight 1.5 % by weight 1.0 % by weight 0,5 % by weight 4.0 % by weight ad 100.0 % byweight
Example 1- Process of the preparation
Adjuvants steareth-21, steareth-2, PPG-15 stearyl ether and isohexadecane are charged into a sterilizing kettle, follovved by cetyl stearyl alcohol, stearic acid 7 LV 12781 and Cera alba. Under continuous stirring the contents of the sterilizing kettle is heated to a temperature of 80±5 °C. In a Container of a class 17 material the disinfectant is triturated in dimethicone and added to the emulsifying liquid in the sterilizing kettle. The prescribed amount of purifīed vvater is vacuum sucked into a 5 jacketed homogenizer. Propyleneglycol is added under continuous mixing by means of an opening in the homogenizer, destined for sucking of liquid materiāls. The contents of the homogenizer is heated at 70±5 °C. At this temperature, the active substance is added under continuous mixing by means of an opening in the homogenizer, destined for sucking of powdery materiāls. At 70±5 °C the aqueous 10 phase with the active substance is emulsified with an emulsifiying liquid preheated to 80±5 °C very slowly for 20 to 30 minūtes using a low-speed aģitator depending of the homogenizer used. After emulsifying, the contents of the homogenizer are homogenized for exactly 1 minūte. Aģitators of anchor and spiral type (500 rpm homogenizer), or an anchor aģitator and a dissolver (Fryma) and a 2900 to 3000 15 rpm homogenizer are set to operation and at the same time, heating of the homogenizer is stopped.
After homogenizing, low-speed aģitators corresponding to the homogenizer type used are actuated and cooling is started and continued until the mixture is 20 cooled down to 27 °C.
Example 2
Activeingredient: 0.5-10.0 % by vveight 0.3 % by vveight 2.0 % by vveight 3.0 % by vveight 5.0 % by vveight 4.0 % by vveight 25 Bifonazole Disinfectant: Triclosanum Adjuvants:
Steareth-21 30 Steareth-2 PPG-15 Stearyl Ether lsohexadecane δ
Alcohol cetylstearylicus Acidum stearicum Dimeticonum Cera alba 5 Propylenglykolum Aqua purificata 1.5 % by weight 1.5 % by weight 1.0 % by weight 0,5 % by vveight 4.0 % by weight ad 100.0 % by vveight
The process of the preparation is the same as in Example 1 except the fact that the active substance is a part of the emulsifying liquid, vvhich is heated to 75 to 10 85 °C. The temperature of the aqueous phase is 75±5 °C.
Example 3
Activeingredient: 15 Urea
Sodium lactate Gamma-linolenic acid Disinfectant: Triclosanum 20 Adjuvants:
Steareth-21
Steareth-2 PPG-15 Stearyl Ether lsohexadecane 25 Alcohol cetylstearylicus Acidum stearicum Dimeticonum Cera alba Propylenglykolum 30 Aqua purificata 5.00- 10.0 % by vveight 2.0- 10.0 % by vveight 0.5-5.0 % by vveight 0.3 % by vveight 2.0 % by vveight 3.0 % by vveight 5.0 % by vveight 4.0 % by vveight 1.0 % by vveight 1.5 % by vveight 1.0 % by vveight 0,5 % by vveight 4.0 % by vveight ad 100.0 % by vveight
The process of the preparation is the same as in Example 1. 9 LV 12781
Example 4 Active ingredient: Titanium dioxide 1.0-5.0 % by weight Sodium gluconate 1.0-5.0 % by weight 4-methylbenzylidene camphor 1.0-4.0 % by weight Butyl methoxydibenzoylmethane 1.0-4.0 % by weight Disinfectant: Triclosanum Adjuvants: 0.3 % by weight Steareth-21 2.0 % by vveight Steareth-2 3.0 % by weight PPG-15 Stearyl Ether 5.0 % by weight lsohexadecane 4.0 % by weight Alcohol cetylstearylicus 1.0% by vveight Acidum stearicum 1.5% by vveight Dimeticonum 1.0 % by vveight Cetyl Dimethicone 0,5 % by vveight Propylengiykolum 4.0 % by vveight Aqua purificata ad 100.0 % by vveight 20
The process of the preparation is the same as in Example 2. Sodium gluconate is a part of the aqueous phase.
Industrial Applicability
The invention is useful in the pharmaceutical industry in the manufacture of dermatological and cosmetic compositions and protective vvorking creams, in vvhich it enables coordination of controlled delivery of moisture and active substances. 30 10 LV 12781
Claims 1. Dermatological topical compositions containing a liquid crystal vehicle, comprising 5 -an active substance selected from urea, bifonazole, sodium lactate and/or organic and inorganic filters in an amount of 0.5 to 25 % by vveight, -a disinfectant in an amount of about 0.3 % by vveight, -the balance up to 100 % by vveight being adjuvants comprising a mixture of surfactants having higher HLB and fatty amphiphilic compounds and purified 10 vvater. 2. A composition of claim 1, 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 vveight, 15 -a disinfectant in an amount of about 0.3 % by vveight, -as adjuvants, steareth-21 in an amount of about 2 % by vveight, steareth-2 in an amount of about 3 % by vveight, PPG-15 stearyl ether in an amount of about 5 % by vveight, isohexadecane in an amount of about 4 % by vveight, cetyl stearyl alcohol in an amount of about 1 to 1.5 % by vveight, stearic acid in an amount of 20 about 1.5 % by vveight, dimethicone in an amount of about 1 % by vveight, cera alba or cetyl dimethicone in an amount of about 0.5 % by vveight, propylene glycol in an amount of about 4 % by vveight, and -the balance up to 100 % by vveight being purified vvater. 25 3. A composition according to claim 1 or 2, characterised in that the carrier part of the vehicle are liquid crystals of an oleosome type. 4. A method for preparing dermatological topical compositions according to claim 1,2 or 3, comprising sterilizing at least one surfactant having higher HLB 30 follovved by addition of at least one fatty amphiphilic compound, heating thus obtained mixture at 80±5 °C under continuous stirring, adding a disinfectant to the resulting emulsifying liquid, adding purified vvater and then propylene glycol under 11 continuous stirring, emulsifying the water phase with the active substance at 70±5 °C with the emulsifying liquid heated to 80 to 90 °C very slowly for 20 to 30 minūtes, follovved by homogenizing the mixture under continuous stirring, whereafter the mixture is, after subsequent stopping of the heating and completing 5 homogenization, cooled down to about 27 °C under stirring, vvherein the active substance is added with disinfectant or with propylene glycol. 5. A method for preparing dermatological topical compositions containing urea and/or sodium lactate according to claim 4, characterized in that the carrier 10 part of the vehicle are liquid crystals of an oleosome type vvhich are formed in a process comprising charging steareth-21, steareth-2, PPG-15 stearyl ether and isohexadecane as adjuvants into a sterilizing kettle followed by addition of cetyl stearyl alcohoi, stearic acid and cera alba, heating thus obtained mixture at 80±5 °C under continuous stirring, adding prepared trituration of the disinfectant in 15 dimethicone to the resulting emulsifying liquid, vacuum sucking of purified water into a jacketed homogenizer, adding propylene glycol and the active substance under continuous stirring, emulsifying the vvater phase with the active substance at 70±5 °C with the emulsifying liquid heated to 80 to 90 °C very slowly for 20 to 30 minūtes, follovved by homogenizing the contents of the homogenizer under 20 continuous stirring, vvhereafter the mixture is, after subsequent stopping of the heating and completing homogenization, cooled down to about 27 °C under stirring. 6. A method for preparing dermatological topical compositions containing 25 bifonazole and/or organic and/or anorganic filters according to claim 4, characterized in that the carrier part of the vehicle are liquid crystals of an oleosome type vvhich are formed in a process comprising charging steareth-21, steareth-2, PPG-15 stearyl ether and isohexadecane as adjuvants into a sterilizing kettle follovved by addition of cetyl stearyl alcohoi, stearic acid and cera alba, 30 heating thus obtained mixture at 80 to 90±5 °C under continuous stirring, adding prepared trituration of the active substances and disinfectant in dimethicone to the resulting emulsifying liquid, vacuum sucking of purified vvater into a jacketed 12 LV 12781 homogenizer, adding propylene glycol under continuous stirring, emulsifying the water phase with the active substance at 70±5 °C with the emulsifying liquid heated to 80 to 90 °C very slowly for 20 to 30 minūtes, follovved by homogenizing the contents of the homogenizer under continuous stirring, vvhereafter the mixture 5 is, after subsequent stopping of the heating and completing homogenization, cooled down to about 27 °C under stirring. 7. A method according to claim 4,5 or 6, characterized in that the aqueous phase with the active substance is emulsified with the emulsifiying liquid using low-10 speed aģitators depending of the homogenizer used and after emulsifying, the contents of the homogenizer are homogenized for exactly 1 minūte, aģitators of anchor and spiral type in case of a 500 rpm homogenizer, or an anchor aģitator and a dissolver in case of a Fryma device are set to operation and the homogenizer is operated at 2900 to 3000 rpm and at the same time, heating of the 15 homogenizer is stopped, and, after homogenizing, low-speed aģitators corresponding to the homogenizer type used are actuated and cooling is started. 13 LV 12781
Abstract
Dermatological topical compositions based on liquid crystals as vehicle, containing, as the active substance, urea, bifonazole, sodium lactate, organic and 5 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 vvater 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 10 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. 1/2 LV 12781
Crystal lamellar masoņhass gel phasa Ί>\ +water T <Tt -* 2/2 LV 12781
Fig. 2