GB2156676A - Pharmaceutical preparations containing vitamin A derivatives - Google Patents

Abstract

Pharmaceutical preparations containing 4-oxo- or 4-hydroxy-1 3-cis-vitamin A acid as the active substance can be used for the treatment of acne or seborrhoea.

Description

SPECIFICATION Pharmaceutical preparations The invention is concerned with pharmaceutical or cosmetic preparations which contain 4-oxo-or 4-hyd roxy- 1 3-cis-vitamin A acid.

4-Oxo- and 4-hydroxy-1 3-cis-vitamin A acid [in systematic nomenclature: (Z,E,E,E)-3,7- dimethyl-9-(2, 6, 6,trimethyl-3-oxo-1 -cyclohexen-1 -yl)-2,4,6,8-nonatetraenoic acid and (Z, E, E, E) 3,7-dimethyl-9-(2,6,6-trimethyl-3-hydroxy-1 -cyclohexen-1 -yl)-2,4,6,8-nonatetraenoic acid, respectively] are metabolites of 1 3-cis-vitamin A acid [J. Biol. Chem. 255, 8057 (1 980)].

It has now been found that 4-oxo- and 4-hydroxy-1 3-cis-vitamin A acid have a therapeutic activity. In particular, these compounds can be used in the treatment of acne and seborrhoea.

The preparations in accordance with the invention can be preparations for systemic or topical use. Preparations for oral administration, e.g. capsules, are preferred. In addition to the active substances the preparations can contain usual pharmaceutical adjuvants such as binding agents, filling materials or antioxidants. A dosage unit, e.g. a capsule, can contain about 10-100 mg of active substance.

For the treatment of acne and seborrhoea the active substances can be administered orally to human beings in dosages of 0.5-5 mg/kg daily, preferably 1-2 mg/kg daily.

For topical application the compounds can be present as a solution or lotion or can be incorporated in hair washes (shampoos). Solutions, lotions and shampoos can contain about 0.01-2%, preferably 0.1-0.5%, of active substance and can be applied to the skin once or several times daily or (shampoos) can be used for washing the hair once daily or once or twice a week.

The following Examples illustrate the invention further: Example 1 Manufacture of the active substances 56.2 g of [5-(3-oXo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2,4-pentadienyl]triphenylphos- phonium bromide and 11.4 g of 4-hydroxy-3-methyl-2-butenolide in 250 ml of isopropanol are treated at 0-5"C with 94.3 ml of 2.1 2 N KOH in isopropanol (0.2 mol). The reaction mixture is left at 5-10"C for 1 hour and then warmed to room temperature. After 30 minutes the reaction mixture is poured into 5% sodium chloride solution, acidified with sulphuric acid and extracted with ethyl acetate.The organic extract is washed with sodium chloride solution, dried and evaporated and yields a crude product from which pure (E,E,Z,Z)-3,7-dimethyl-9-(2,6,6-trime- thyl-3-oxo-1-cyclohexen-1-yl)-2,4,6,8,-nonatetraenoic acid of melting point 159-160 C is obtained by crystallization from hexane/ethyl acetate.

1 3.4 g of this acid in 600 ml of methanol are treated at 0 C with excess diazomethane. The reaction mixture is left to warm to room temperature and is evaporated after 30 minutes, whereby methyl (E,E.Z,Z)-3, 7,-dimethyl-9-(2,6, 6-trimethyl-3-oxo-l -cyclohexen-l -yl)-2,4,6,8-no- natetraenoate is obtained as the crude product, 14.2 g of crude product are isomerized in acetonitrile with 1.48 g of dichloro-bis-benzonitrile-Pd (II) and 2.5 ml of triethylamine.

Chromatographic purification yields methyl (Z, E, E, E)-3, 7-dimethyl-9-(2, 6, 6-trimethyl-3-oxo- 1 -cy- clohexen-1-yl)-2,4,6,8-nonatetraenoate. 13.3 9 of this ester are hydrolyzed by heating for 30 minutes with aqueous-ethanolic potassium hydroxide (13.8 g of KOH, 300 ml of ethanol). The reaction mixture is cooled, poured into ice-water, acidified with acetic acid and extracted with ethyl acetate. The extract is washed with sodium chloride solution, dried and evaporated and the crude product is crystallized from hexane/ethyl acetate. Recrystallization from ethyl acetate/hexane yields pure (Z, E, E, E)-3,7-dimethyl-9-(2,6,6-trimethyl-3-oxo-1 -cyclohexen- 1 -yl)-2,4, 6, 8-nona- tetraenoic acid of melting point 164-166"C.

0.314 g of (Z, E, E, E)-3, 7-dimethyl-9-(2, 6, 6-trimethyl-3-oxo- 1 -cyclohexen- 1 -yl)-2,4,6,8-nonatetraenoic acid in methanol/water is treated with sodium borohydride for 5 minutes. The reaction mixture is acidified with acetic acid and extracted with methylene chloride. The extract is washed with sodium chloride solution, dried and evaporated and the residue is crystallized from ethyl acetate/hexane. Pure (Z, E, E, E)-3, 7-dimethyl-9-(2, 6, 6-trimethyl-3-hydroxy- 1 -cyclohexen- 1 - yl)-2,4, 6,8-nonatetraenoic acid is obtained.

Example 2 Manufacture of a capsule for oral administration: An aqueous suspension of 27 wt.% of gelatine (Bloom 30), 41 wt.% of maltodextrin MD 05, 7 wt.% of sodium ascorbate and 25 wt.% of (Z,E,E,E)-3,7-dimethyl-9-(2,6,6-trimethyl-3-oXo-1- cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid are milled to an average particle size of 0.5 ym and spray-dried. In each case 25 mg of the thus-obtained powder, 20 mg of AVICEL PH 102, (microcrystalline cellulose), 34 mg of lactose and 6 mg of POLYPLASDONE (cross-linked polyvinylpyrrolidone; cross povidone) are mixed and filled into gelatine capsules.

Example 3 Manufacture of a lotion: (Z, E, E, E)-3, 7-Dimethyl-9-(2,6, 6-trimethyl- -3-oxo-1 -cyclohexene-1 -yl)-2,4,6,8-nonatetraenoic acid 0.01 -2.0 g Rectified alcohol 10.0-52.0 g Propylene glycol 0-50.0 9 Polyethylene glycol 0-50.0 g Dimethyl sulphoxide 0-50.0 9 The active substance is dissolved in the mixture of the solvents.

Claims (4)

1. A pharmaceutical or cosmetic preparation which contains 4-oxo- or 4-hydroxy-1 3-cis- vitamin A acid.

2. A preparation according to claim 1 in the form of capsules containing 10-100 mg of active substance.

3. 4-Oxo- and 4-hydroxy-1 3-cis-vitamin A acid for use as therapeutic or cosmetic active substances.

4. 4-Oxo- and 4-hydroxy-13-cis-vitamin A acid for use as active substances against acne and seborrhoea.