MXPA00004908A - Composition with azelaic acid - Google Patents

Abstract

The invention relates to a pharmaceutical composition having the following constituents:azelaic acid, polyacrylic acid, triacylglyceride, propylene glycol, polysorbate, soya lecithin, water and salts. The composition is a hydrogel which is suited for the treatment of rosacea, presbyderma, melasma or skin irritations.

Description

A COMPOSITION WITH AZELAIC ACID WHICH IS USED IN QUALITY OF ACTIVE THERAPEUTIC SUBSTANCE OR OF MEDICINE FOR THE TREATMENT OF VARIOUS SKIN DISEASES The invention relates to a composition with azelaic acid in the form of a hydrogel. The invention also encompasses the use of the azelaic acid-based hydrogel as a medicament. The present application claims the priorities of German documents No. 19.753.044, filed on November 19, 1997, and No. 19.808.086, filed on February 20, 1998. State of the art In the European patent application no. 0 336 880 A2, filed on 29.3.1998, a pharmaceutical composition is described which is composed of (i) azelaic acid in a concentration of 20% by weight, (iii) triacylglycerides and diacylglycerides, (iv) propylene glycol, (v) polysorbate , for example, polyethylene (20) sorbitan monooleate, and (vii) water and salts. This composition is applied externally or topically and is used to treat various changes that the skin undergoes with age. The composition is presented as a cream. The use of azelaic acid is also known to combat inflammatory and infectious dermatoses such as, for example, acne and rosacea. In the red list of 1996 (ISBN 3-87193-167-5) a pharmaceutical composition with the name of "Skinoren" is described under the number 32 282 which is composed of (i) azelaic acid in a concentration of 20% by weight , (iii) triacylglycerides and diacylglycerides, (iv) propylene glycol, (v) polysorbate, for example, macroalleterate 1000, and (vii) water and salts. This composition is applied externally for the treatment of acne and comes in the form of cream. This document is considered within the state of the art as the closest to the present application. In the international patent application no. 96/11700, filed October 29, 1993, describes a pharmaceutical composition that is used as auxiliary material for a vaccine. This composition will replace the Freund additive. It is applied as an injection. As (i) pharmaceutical active substances are used, p. ex. , surface proteins of hepatitis B. They are also used (ii) polyacrylic acid, (iii) triacylglycerides and / or diacylglycerides such as IGLYOL, (iv) propylene glycol, and (v) polysorbates in the form of TWEEN, EMULROR and SIMULSOL M-53. It also adds (vi) soy lecithin. The composition consists of (vii) an aqueous phase with salts. The composition is not applied topically. The emulsion has particles of a size between 0.03 and 0.5 μm, preferably between 0.05 and 0.2 μm. In the international patent application No. 95/05163, filed on August 5, 1994, a pharmaceutical composition is described which is presented in the form of an emulsion and is used to administer biologically active substances on the surface of the skin. This composition contains particles of a size comprised between 30 and 500 nm, preferably between 70 and 200 nm. As (i) pharmaceutical active substances, for example, anti-inflammatory drugs are used. They are also used (ii) polyacrylic acid, (iii) triacylglycerides and / or diacylglycerides, (iv) propylene glycol, and (v) polysorbates in the form of TWEEN, EMULROR, TRITON X and SIMÜLSOL M-53.

It also adds (vi) soy lecithin. The composition consists of (vii) an aqueous phase with salts. The composition is applied topically. In the European patent application No. 0 696 452, filed on July 26, 1995, a nanoemulsion is described which is used in a medicament for the treatment of the eyes and is applied in the form of eye drops for external use. This composition contains particles with an average size of 520 nm. As (i) pharmaceutical active substances are used, p. ex. , anti-inflammatory drugs. Also used are (ii) polyacrylic acid, (iii) triacylglycerides and / or diacylglycerides, (iv) propylene glycol, and (v) polysorbates in the form of polyoxyethylene-polyoxypropanylene colopiimers. The composition consists of (vii) an aqueous phase with salts and is applied topically. Problem to solve and its solution The objective is to provide a pharmaceutical composition containing azelaic acid as therapeutic active substance and in which the bioavailability of azelaic acid is increased. The objective is achieved by a composition according to the state of the art containing (i) azelaic acid as therapeutic active substance (iii) triacylglycerides, (iv) propylene glycol, and (v) polysorbates (vii) in an aqueous phase which includes water and salts, and which is characterized in that as other additives it contains (ii) polyacrylic acid and (vi) soy lecithin, and because it also presents in the form of hydrogel. Advantages: The composition of the invention has the advantage of allowing a greater amount of the pharmaceutical active substance to penetrate the dermis. In this way, the availability of azelaic acid in the composition of the invention is three to five times higher than in the azelaic acid-based cream of the state of the art. This availability was checked by the FRANZ cell circulation-diffusion test, which is described in detail in the examples. The dermis is precisely the desired destination of azelaic acid. The composition is particularly effective for incorporating high concentrations of azelaic acid. A more detailed formulation of the composition The most convenient composition is that which can be administered externally or topically. A composition according to the invention is preferred whose concentration of azelaic acid is between 5 and 20% by weight, preferably between 10 and 18% by weight, and more preferably between 14 and 16% by weight. The presence of polyacrylic acid is essential. It is decisive for the formation of the hydrogel. For the gel it is preferred to use soy lecithin as lecithin. It is advisable to use lecithin or soy lecithin in a concentration of at least 3% by weight, preferably at least 1.5% by weight, and more preferably at least 1% by weight. With this last concentration a hydrogel is obtained that is no longer a nanoemulsion. Advantage Surprisingly it was found that the composition of the invention does not form a classical nanoemulsification according to the state of the art when concentrations of lecithin less than or equal to a certain weight% are used. Rather, a gel is formed that is composed of a homogeneous mass that practically does not present vesicles, but that includes fragments of membrane. It could not be foreseen that the azelaic acid and the rest of the composition do not form a nanoemulsion. The situation could be understood only after using the images of the electron microscope of lattices. By observing through the electron microscope, the absence of a nanoemulsions could be verified. The composition of the invention has the advantage of allowing a great penetration in the dermis, which is not observed with creams. PREFERRED EMBODIMENTS OF THE INVENTION A composition is preferred in which the individual parameters can independently present the following concentrations: (ii) polyacrylic acid in a concentration comprised between 0.5 and 2% by weight, (iii) triacylglycerides in a concentration comprised between 0.5 and 5% by weight, (iv) propylene glycol in a concentration comprised between 5 and 15% by weight and (v) polysorbates in a concentration comprised between 0.5 and 3% by weight. It is understood that the components must be adjusted in such a way that the sum always reaches 100%. In particular, a composition in which the individual parameters can independently present the following concentrations is preferred: (ii) polyacrylic acid in a concentration of 1 ± 0.25% by weight, (iii) triacylglycerides in a concentration of 2 ± 1% by weight, (iv) propylene glycol in a concentration of 10 ± 2% by weight and (v) polysorbates in a concentration of 2 ± 0.5. % in weigh. It is understood that the components must be adjusted in such a way that the sum always reaches 100%. Definitions: Azelaic acid and its preparation are described in German Patent No. 28 17 133.7. It can also be compared with the text by Rompp, Chemie Lexikon, by Jurgen FALBE and Manfred REGNITZ, 1989, 9th edition, p. 323, Thieme Verlag Stuttgart, ISBN 3-13-734609-6. Polyacrylic acid is an active anionic polymer formed from acrylic acid and is only partially soluble in water. The 1% aqueous suspension has a pH of 3 and its viscosity resembles that of water. The formation of the gel and highly viscous products is produced once it is neutralized with inorganic or organic bases. See the text by Rudolf VOIGT and Manfred BORNSCHEIN, 1979, Lehrbuch der pharmazeutischen Technologie, p. 314, VEB Verlag Volk und Gesundheit Berlin. Compare also the text by Rompp, Chemie Lexikon, by Jürgen FALBE and Manfred REGNITZ, 1992, 9th edition, p. 3508, Thieme Verlag Stuttgart, ISBN 3-13-735009-3. The term "tri-glyceride" refers to the esters of glycerin, whose three hydroxyl groups are esterified with carboxylic acids. Fats and natural oils are triglycerides (neutral fats) that in the same glycerin molecule usually have different fatty acids. See J. Am. Oil Chem. Soc. Vol. 62, p. 730 (1985); and Parfüm. Kosmet. Vol. 58, p. 353, (1977) and Ropp, Chemie Lexikon, by Jürgen FALBE and Manfred REGNITZ, 1990, 9th edition, p. 1339 to 1342, Thieme Verlag Stuttgart, ISBN 3-13-734709-2. The propylene licol is described in H.P.FIEDLER: Lexikon der Hilfsstoffe, 4th edition, 1996, ISBN 3-87193-173, p. 1278 to 1282. Polysorbates are described in H.P.FIEDLER: Lexikon der Hilfsstoffe, 4th edition, 1996, ISBN 3-87193-173, pgs. 1251 to 1252. Lecithins are obtained by extraction of a biological material. Thus, a fraction of lecithin obtained from a soy bean (the most usual raw material) contains, for example, palmitic acid, stearic acid, palmitoleic acid, oleic acid, linoleic acid and linolenic acid. In general, the saturated fatty acid is esterified with the primary hydroxyl group of the glycerin, while the unsaturated fatty acid is esterified with the secondary hydroxyl group. Lecithins are components of the cell membranes of all living beings. In water, lecithins swell, in principle, similar to that of lipophilic colloids. Then they form transparent colloidal solutions. They can adopt different textures depending on the water content, forming layers composed of double layers of lipids. With a higher water content the liposomes are formed. Lit .: Pardun, Die Pflanzenlecithine, Augsburg: Veri. für Chem. Ind.

(Ziolkowsky KG) 1988. J. GAREISS et al. Describe other leci-tines and their effects in Parfümerie und Kosmetik, 1994, Vol. /94, p. 652 to 659, Huthing GmbH, Heidelberg. A gel is characterized by the following properties: it is a dispersed system, stable, easily deformable, rich in liquid and eventually in gases, containing at least two components. Rompp, Chemie Lexikon, by Jurgen FALBE and Manfred REGNITZ, 1990, 9th edition, p511, Thieme Verlag Stuttgart, ISBN 3-13-734709-2; and Pharm. Userer Zeit Vol. 8, pgs. 179 to 188, (1979); and Parfúm. Kosmet. , Vol. 58. pp. 251 to 253 (1977). The aqueous phase may include preservatives. They include, for example, benzoic acid. This acid is particularly suitable as a preservative due to its antimicrobial nature. Characteristics for use as a medicament The composition of the invention has a pharmacological activity and can be used as a therapeutic active substance or as a medicament. It is preferred to employ the composition of the invention together with at least one pharmacologically acceptable additive or excipient from a physiological point of view. Pharmacological additives and excipients are described in Remington's Pharmaceutical Science15th ed. Mack Publishing Company, Easton Pennsylvania (1980). The composition of the invention is suitable for the treatment of different indications. The composition of the invention is preferably used as the active substance for the treatment of rosacea, aged skin, melasma, acne and / or skin irritations. The composition of the invention which is particularly preferred is that used as a therapeutic active substance for the treatment of rosacea, aged skin, melasma, acne and / or skin irritations, together with at least one additive or excipient pharmacological and acceptable from the physiological point of view. The treatment includes prophylactic and therapeutic measures, (i) The invention also provides () the use of the pharmaceutical composition of the invention to prepare a medicament for the treatment of rosacea, aged skin, melasma, acne and / or skin irritations; (ß) a method for the treatment of rosacea, aged skin, melasma, acne and / or skin irritations, which method includes administering a pharmaceutical composition according to the invention in an amount that suppresses the disease, and by means of which said pharmaceutical composition is administered to a patient in need of such medication; (and) a pharmaceutical composition for the treatment of rosacea, aged skin, melasma, acne and / or skin irritations, treatment including a pharmaceutical composition of the invention and at least one acceptable excipient and additive from the pharmaceutical point of view. The appropriate dose for these therapeutic effects is variable and depends, for example, on the concentration of the individual elements present in the pharmaceutical composition, the host, the type of administration and the type and the severity of the conditions. Be treated. The pharmaceutical composition of the invention can be administered externally in any usual manner. The gel is preferred. Using known methods it is possible to work and formulate the pharmaceutical composition of the invention together with the usual additives and / or excipients of galenic to obtain the usual forms that are intended for topical application. Examples: 1. Preparation of the pharmaceutical composition A pharmaceutical composition containing azelaic acid has the following formulation and requires for its preparation the following steps: usual concentrations of benzoic acid and EDTA are dissolved in 60 to 70 parts of water. With stirring a mixture of 1 part of triglycerides with intermediate chain lengths and 1.5 parts of polysorbate 80 is then added and homogenized (pre-emulsion). 1 part of lecithin is added to 12 parts of propylene glycol. The obtained solution is introduced with stirring into the pre-emulsion and then homogenized. After adding 1 part of polyacrylic acid, 15 parts of azelaic acid are added to the obtained pharmaceutical composition. The gel-forming agent is then adjusted with the necessary amount of sodium hydroxide solution. The availability of azelaic acid in the derm that has the resulting gel is approximately 4 times higher. 2. Evaluation of bioavailability in the skin The percutaneous absorption of azelaic acid was tested by comparing the formulations of the hydrogel of the invention with the Skinoren® cream. The objective of the trial was to describe the bioavailability of azelaic acid in the skin, the penetration of azelaic acid through the skin and the dermal metabolism of azelaic acid. To this end, erent preparations containing amazonic acid with C14 were applied on the intact skin of hairless mice (Mfl hr / hr Ola / Hsd, breeders: Winkelmann, Germany), following the in vitro model of the usion chamber of FRANZ. On a skin area of 2 cm2, 10 to 15 mg of the following compositions were applied: A) 20% azelaic acid in a cream whose formulation composition - additive corresponds to that of Skinoren® B cream) 15% azelaic acid in a composition according to the invention. The passage of the C14 azelaic acid with time was measured in the acceptor medium (Hepes Hanks Balanced Salt Solution: HHBSS) that circulates under the skin, at two-hour intervals and for a period of 24 hours. In addition, at the end of each experiment, radioactivity was determined on the surface of the skin, in the epidermal stratum corneum and in the rest of the skin. To determine the metabolism of azelaic acid in the skin, skin strains and fractions chosen from the acceptor medium were evaluated by ra-diochromatography (HPLC and radiometric detection). The C14 azelaic acid found in the skin at the end of the experiment was metabolized only in a fraction of 3 to 11%. For this reason the values of radioactivity in the skin can be equated in practice with the concentration of unmoed azelaic acid. The table below contains a summary of the results: Cream according to the composition according to the state of the invention the technique Average DS Average DS Azeilaic acid 79, 9? 14, 3? 63, 6, 20.6% that did not penetrate Azelaic acid in 0.9% 0.7 ^ 4.0 1.9% stratum corneum Acelaic acid in 3.7 2, I heard 27.3 17.1% the rest of the skin Azelaic acid in 16.3% 6.3 5,8 3,3 the acceptor medium DS = standard deviation When comparing with the standard cream it is observed that with the agent of the invention a considerably higher concentration of azelaic acid is reached in the skin.

Claims (10)

1. - A composition with azelaic acid comprising the following elements: (i) azelaic acid as therapeutic active substance, (iii) triacylglycerides, (iv) propylene glycol, and (v) polysorbates (vii) in an aqueous phase including water and salts, and which is characterized in that, as other additives, it contains (ii) polyacrylic acid and (vi) soy lecithin, and because it is in the form of a hydrogel.

2. A composition according to claim 1, characterized in that it is applied externally or topically.

3. Composition according to one of the preceding claims, characterized in that it contains azelaic acid in a concentration of 5 to 20% by weight.

4. Composition according to one of the preceding claims, characterized in that the lecithin used is soya lecithin.

5. Composition according to one of the preceding claims, characterized in that the lecithin is in a concentration of at least 1% by weight.

6. Composition according to one of the preceding claims, characterized in that the individual parameters independently present the following concentrations: (ii) polyacrylic acid in a concentration comprised between 0.5 and 2% by weight, (iii) triacylglycerides in a concentration comprised between 0.5 and 5% by weight, (iv) propylene glycol in a concentration comprised between 5 and 15% by weight and (v) polysorbates in a concentration comprised between 0.5 and 3% by weight.

7. Composition according to one of the preceding claims, characterized in that the individual parameters independently present the following concentrations: (ü) polyacrylic acid in a concentration of 1"0.25% by weight, (iii) triacylglycerides in a concentration of 2" 1% by weight, (iv) propylene glycol in a concentration of 10"2% by weight and (v) polysorbates in a concentration of 2" 0.5% by weight.

8. - Composition according to one of the preceding claims, characterized in that it is a therapeutic active substance.

9. Composition according to one of the preceding claims, characterized in that, as therapeutic active substance, it includes at least one additive or pharmacological excipient that is acceptable from a physiological point of view.

10. Composition according to claim 8 or 9, characterized in that it can be used as a therapeutic active substance for the treatment of rosacea, aged skin, melasma, acne and / or skin irritations.