PROCESS FOR THE PREPARATION OF AN ANTIPSORIATIC PHARMACEUTICAL COMPOSITION

Abstract: The invention relates to a process for the preparation of an antipsoriatic pharmaceutical composition containing 17,18-dehydroapovincaminol 3',4',5'-trimethoxybenzoate or its pharmaceutically acceptable acid addition salts, which comprises dissolving one equivalent of 17,18-dehydroapovincaminol 3',4',5'-trimethoxybenzoate or its pharmaceutically acceptable acid addition salt in 1.1 to 50, preferably 5 to 20, equivalents of an organic acid containing no basic group and being soluble in water or in a water-miscible monovalent or polyvalent alcohol or in a mixture thereof, or in a solution prepared from the organic acid with water or with a water-miscible monovalent or polyvalent alcohol or with a mixture thereof, and a) formulating the solution to a pharmaceutical composition as such or, if desired, together with therapeutically active agents showing no synergism with the active ingredient and/or with pharmaceutical auxiliary materials (additives), or b) diluting the solution with 5 to 50 parts by weight of water and formulating the thus-obtained gel, containing the active ingredient in a homogenous molecular distribution, as such or together with therapeutically active agents showing no synergism with the active ingredient and/or with a pharmaceutically acceptable auxiliary materials to a pharmaceutical composition.

Description: PROCESS FOR THE PREPARATION OF AN ANTIPSORIATIC PHARMACEUTICAL COMPOSITION The invention relates to a process for preparing an antipsoriatic pharmaceutical composition containing 17,18- -dehydroapoviπcaminol 3' ,4' ,5'-trimethoxybeπzoate or pharmaceu ly acceptable acid addition salts thereof. It is known from the literature /Ann. Rev. Pharmacol. Toxicol. _17_, 441 (1977)/ that in the case of several diseases such as asthma, psoriasis, thrombosis and the like, a pathologically high level of the phosphodiesterase enzyme can be observed in the affected tissues. It has also been proved for the psoriasis /Arch. Dermatol. 104, 352 (1971)/ that substances inhibiting the action of phosphodiesterase are potentially useful for the treatment of this illness. Based on this novel approach differing from the traditional methods of the psoriasis therapy, the prepara¬ tion and successful use of the phosphodiesterase-inhibitiπg 17,18-dehydroapovincaminol ' , ' ,5' -trimethoxybeπzoate and its acid addition salts in the treatment of psoriasis were disclosed in the Hungarian patent specification No. 183,323 (equivalent to the Belgian patent specification No. 892,069), according to which the active ingredient was used .in a formula tion containing it partly in a heterogeneous phase, partly in a dissolved form. The various toxicological and precliπical investiga¬ tions carried out on this formulation in the meantime gave newer results. In addition to the therapeutical effect observed, a dose-depeπdance was searched for formulations containing the active ingredient in a heterogeneous phase. It has been proved in our experiments that, in the ab-ove formulations, a part " of the active ingredient only contributes to the action whereby a whole bioavailability cannot be achieved. Based on the description cited above, the dose- -depeπdance can be stated as a consequence of the limited solubility for formulations containing the active ingredient in a dissolved form; however, there is no possibility to develop sn optimum concentration of the formulation. Thus, the development and the therapeutical use of an optimal pharmaceutical formulation are made difficult by these problems arising from the physical properties of the active ingredien . Thus, the aim of the invention is to provide a process for incorporating the active ingredient into the pharmaceutica formulation in a dissolved form, with essentially higher concentration limits than earlier. It is known from the literature that, on using analogous compounds with an eburnane skeleton as medicaments, the active ingredient can be brought into solution, if desired, in various pharmaceutically acceptable organic solvents (alcohols, esters) in the presence of water and a solubiliziπg agent (polyviπylpyrrolidone, teπsides) or in a mixture thereof. However, it has been unsuccessful till now to adjust the desired concentration interval of 17,18-dehydroapovincaminol 3 ' ,4' ,5'-tri ethoxybenzoate or its acid addition salts by using these methods and simultaneou ly, in the course of the formulating, the active ingredient was precipitated from the solution by the eventually required dilution with water. It has been recognized in the course of our experiment that, on preparing formulations containing 17,18-dehydro- apoviπcamiπol 3 ', ',5'-trimethoxybenzoate or its acid addi¬ tion salts as active ingredient, the active ingredient could be dissolved in the presence of a higher than stoichiometric amount of pharmaceutically acceptable organic acids in water, alcohols or aqueous alcohols as pharmaceutically acceptable carriers within significantly wider concentration limits than by using the methods described earlier. Thus, the whole bioavilaoility of the active ingredient can be utilized, the optimal therapeutical dose can be established and simultaneously, an improved resorption of the active ingredient can be promoted by using a solubiliziπg acid. In the case of several formulations such as ointments, creams, gels, etc. a further advantage resides in the surprising recognition that a stable gel is formed without any additive by the solution prepared according to the invention in the course of its dilution with water within defined limits if a defined ratio of the active ingredient to the solubilizing acid is used. It can be stated that the active ingredient is present in a homogeneous, molecular distribution in this gel. Thus, the present invention relates to a process for preparing an antipsoriatic pharmaceutical formulation containing 17,18-dehydroapovincaminol 3', ' ,5 '-trimethoxy¬ benzoate or its pharmaceutically acceptable acid addition salts, which comprises dissolving one equivalent of 17,18- -dehydroapovincamiπol 3 ' , ' ,5'-trimethoxybenzoate or its pharmaceutically acceptable acid addition salt in 1.1 to 50, preferably 5 to 2G, equivalents of an organic acid containing no basic group and being soluble in water or in a water-miscible monovalent or polyvalent alcohol or in a mixture thereof, or in a solution prepared from the organic acid with water or with a water-miscible monovalent or polyvalent alcohol or with a mixture thereof, and a) formulating the solution to a pharmaceutical composition as such or, if desired, together with therapeutical¬ ly active agents showing no synergism with the active ingredient and/or with pharmaceutical auxiliary materials (additives), or b) diluting the solution with 5 to 50 parts by weight ' of water and formulating the thus-obtained gel, contai ing the active ingredient in a homogeneous molecular distribution, as such or together with therapeutically active ingredients showing no synergism with the active ingredient and/or with pharmaceutically acceptable auxiliary materials to a pharmaceutical composition. In the process of the invention, the solvent is the solubiliziπg acid or optionally a solution thereof in water or in water-miscible monovalent or polyvalent alcohols or in their mixtures. If the acids are liquid (such as lactic or acetic acic), the active ingredient may be dissolved in the acid itself. If the acid is solid (such as tartaric or ascorbic acid), the active ingredient is dissolved in an ethanolic or aqueous ethanolic solution of the acid. Ethanol, propylene glycol or glycerol may preferab¬ ly be used as monovalent or polyvalent alcohols. As solubilizing agents organic acids may be used which do not contain any basic group and are soluble in water or in water-miscible monovalent or polyvalent alcohols or in their mixtures. In the case of acids containing a basic group, the active ingredient cannot be dissolved in the above system or the solution or gel, respectively, obtain¬ ed is unstable whereby the active ingredient precipitates from the solution. The solubilizing acid is used in an amount of 1.1 to 50, preferably 5 to 20, equivalents as calculated for the active ingredient. If the molar excess is low (e.g. 1.1 to 5 equivalents), a lower concentration maximum will be achieved on dissolution, or the gel prepared will not be hard enough from the viewpoint of formulating. On increasing the molar excess (up to 5 to 20 equivalents) both the obtainable concentration maximum and the hardness of the gel prepared become higher. If the amount of the solubilizing acid is between 20 and 50 equivalents, the irritating effect of the composi¬ tion also increases with the increasing concentration and gel hardness; over 50 equivalents, the composition cannot be used therapeutically because of the irritating effect. The rasorption-iπcreasing action of the solubilizing acid was verified by a study carried out with the tritiated active ingredient. In the course of the resorption study made with the tritiated active ingredient, a suspension, an acid-free solution and an acid-solubilized solution of the same concentration (2 %) were compared on rats with an external application. Based on these experiments, the resorption showed the following order: Acid-solubilized solution > solubilized solutioπ> > suspension. The higher therapeutical bioavailability of the active_ingredient was verified in clinical trials carried out on patients suffering from psoriasis. In this study, a suspension ointment containing 2 % of active ingredient was compared to an acid-solubilized ointment containing 0.2 % of active ingredient. On using the acid-solubilized ointment containing 0.2 % of active ingredient, the same recovery ratio was observed as compared to the suspension composition contain¬ ing 2 % of the active ingredient. Within this comparison study, 50 % of the patients gave an advantageous response to the treatment; 25 % showed a good reaction; and 25 % did not give any response. It seems unambiguously from these data that one tenth of the active ingredient (0.2 % of acid- -solubilized active ingredient) resulted in the same preferable clinical experiences as observed on the treatment with the suspension ointment containing 2 % of active ingredient. The process of the invention is illustrated in detail by the following non-limiting Examples. Example 1 17,18-Dehydroapovincaminol 3' ,4 r , '-trimethoxybeπzoate in a water-iπ-oil type ointment Composition: 17,18-Dehydroapoviπcamiπol 3' ,4' ,5'-tri- ethoxybenzoate 2.0 Lactic acid 3.0 5-Chloro-2-(2,4-dichloropheπoxy)pheπol (triclαsaπe) 0.1 Magnesium sulfate 0.5 Aerosil R-972 1.0 White wax (cera alba) 1.5 Elfacos ST 37 (emulsifier; manufacturer: AKZ0, The Netherlands) 1.5 Composition: Propylene glycol 3.0 Cetiol V (emulsifier; manufacturer: Henkel, FRG) 5.0 Nεo PCL Selbstemulgierend (emulsifier; Dragoco, Austria) 23.0 Distilled water 59.4 The active Ingredient is dissolved in lactic acid, propylene glycol is added to the solution and after adding an aqueous solution of triclosaπe and magnesium sulfate, a gel is prepared. A melt of the remaining components kept at 50 °C is added to the gel heated to 50 °C and the thus- -obtained cream is stirred until it cools down. Example 2 17,18-Dehydroapovincaminol 3' ,4' ,5 '-trimethoxy¬ benzoate in a tincture Composition: %. 17,18-Dehydroapoviπcamiπol 3' ,4' ,5' -tri¬ methoxybenzoate 2.0 Triamcinolone acetonide 0.1 Tartaric acid 3.0 Propylene glycol 30.0 Ethaπol 96 % up to 100.0 A tincture is prepared by using the above components (ingredients) . Example 3 The process of Example 1 is followed, except that 2.0 g of 17,18-dehydrαapovincaminol 3 ' ,4 ' , ' -tri ethoxy- benzoate hydrochloride are used as active ingredient. Example 4 The process of Example 2 is followed, except that 15.0 % of glycerol are used instead of propylene glycol.

Claims: CLAIMS 1. A process for the preparation of an aπtipsoriatic pharmaceutical composition containing 17, 18-dehydro- apoviπcaminol 3 ', ',5 ' -trimethoxybenzoate or its pharmaceutical¬ ly acceptable acid addition salts, which comprises dissolv¬ ing one eαμivaleπt of 17,13-dehydrαapbvincamIπαl 3',4',5 I - -trimethoxybenzαate or its pharmaceutically acceptable acid addition salt in 1.1 to 50, preferably 5 to 2C , equivalents of an organic acid containing no basic group and being soluble in water or in a water-miscible monovalent or polyvalent alcohol or in a mixture thereof, or in a solution prepared from the organic acid with water or with a water-miscible monovalent or polyvalent- alcohol or with a mixture thereof, and a) formulating the solution to a pharmaceutical composition as such or, if desired, together with therapeutically active agents showing no synergism with the active ingredient and/or with pharmaceutical auxiliary materials (additives), or b) diluting the solution with 5 to 50 parts by weight of water and formulating the thus-obtained gel, containing the active ingredient in a homogeneous molecular distribution, as such or together with therapeutically active agents showing no synergism with the active ingredient and/or with a pharmaceutically acceptable auxiliary materials to a pharmaceutical composition. 2. A process as claimed in Claim 1, which comprises using ethaπol, 1 ,2-propaπediol or glycerol as a monovalent or polyvalent alcohol, respectively. 3. Aπtipsoriatic pharmaceutical composition comprising 17,10-dehydroapovincaminol 3' , ',5 '-trimethoxybenzoate or its pharmaceutically acceptable acid addition salt together with an organic acid containing no basic group and being soluble in water or a water-miscible monovalent or polyva¬ lent alcohol or a mixture thereof, or in a solution prepared from the organic acid with water or with a water-miscible monovalent o polyvalent alcohol or with a mixture thereof, if desired, together with therapeutically active agents showing no synergism with the active ingredient and/or with pharmaceutical auxiliary materials. 4. A composition as claimed in claim 3, comprising 1 to 5 % of 17,18-dehydroapovincaminol 3 ' , ' ,5 ' -trimethoxybeπzo¬ ate or its hydrochloride, together with 2 to 40 % of propy¬ lene glycol or glycerol as a monovalent or polyvalent alco¬ hol, 2 to 40 % of lactic acid or tartaric acid as an organic acid and 15 to 95 % of emulsifiers, white wax, magnesium sulfate and ethanol as auxiliary materials.

Inventors: BALAZSNE ZAYER MARIA, BUKOVECZNE BARTA MARGIT, FEKETE GYOERGY, FORGACS LILLA, GALAMBOS JANOS, HANGAY GYOERGY, KARPATI EGON, KELEN ANDRAS, KEVE TIBOR, KIRALY ARPAD, KISS BELA, SOS GYOENGYVER, STEFKO BELA, SZPORNY LASZLO, ZSADON BELA, BALAZSNE ZAYER, MARIA, BUKOVECZNE BARTA, MARGIT, FEKETE, GYOERGY, FORGACS, LILLA, GALAMBOS, JANOS, HANGAY, GYOERGY, KARPATI, EGON, KELEN, ANDRAS, KEVE, TIBOR, KIRALY, ARPAD, KISS, BELA, SOS, GYOENGYVER, STEFKO, BELA, SZPORNY, LASZLO, ZSADON, BELA
Applicants: RICHTER GEDEON VEGYESZET, RICHTER GEDEON VEGYESZETI GYAR RT.
Application year: 1988
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K47, A61P17