GB2035085A - Cycloheximide or an analogue thereof compositions - Google Patents

Abstract

Pharmaceutical compositions for the treatment of proliferative skin diseases comprise a non-steroidal anti-inflammatory agent such as flurbiprofen and the antibiotic cycloheximide or an analogue thereof in association with a pharmaceutically acceptable carrier. The compositions may be applied topically.

Description

SPECIFICATION Pharmaceutical compositions comprising cycloheximide or an analogue thereof Proliferative skin diseases are widespread.

Their nature, their symptoms and known methods for treating them are discussed in Patent Application No. 14241/77 (Serial No.1560227) which describes and claims compositions comprising an analogue of cycloheximide, either as the sole active ingredient or in combination with an anti-inflammatory glucocorticoid. These compositions can be used to alleviate proliferative skin diseases.

According to the present invention, a pharmaceutical composition comprises a non-steroidal anti-inflammatory agent and a compound of formula I or il

wherein R, is hydrogen or C12 alkyl; either R2 is hydrogen, halogen, hydroxy, C12 alkoxy, C24 alkanoyloxy, -CH2COCH3 -CH2COC6H5 -CH2COCH2COOCH3, -CH2CH2COOH or styryl and R3 is hydrogen or R2 and R3 together are oxo; R4 is hydrogen or methyl; R5 is hydrogen, hydroxy or acetoxy; R6 is hydrogen, hydroxy or acetoxy;R7 is hydrogen or methyl; either X1 and X2 are the same or different and are each hydrogen, hydroxy, acetoxy or piperidino or X, and X2 together are oxo, = NOH, = N-NH-CONH2 = N-NHCH,.

= N-N(CH3)2-, = N-NH-CSNH2, = N-NH-COC6H5, = N-NH2 or = N-NH-COCH2C6H5; P9 is hydrogen or hydroxy; and R,o is methyl or 2-hydroxyprop-2yl; in association with a pharmaceutically acceptable carrier.

The combination of a non-steroidal antiinflammatory agent with a compound of formula I or II can act synergically. Compared with known compositions, the compositions of this invention can allow increased inhibition of DNA synthesis or increased anti-mitotic effect, longer duration of activity and/or greater suppression of the rebound in DNA synthesis after the activity has disappeared, lesser amounts of active ingredients, lower frequency of administration, fewer side-effects and/or faster response to treatment.

Examples of compounds of formula I are cycloheximide and those compounds given as examples of formula I in Application No.

14241/77 (Serial No.1560227). The compounds of formula II are known analogues of cycloheximide and are the compounds, 5,7 dimethyl-2-hydroxy-4-oxonona-6, 8-dienylglu- tarimide and 2-hydroxy-5-(2-hydroxy-prop-2 yl)-7-methyl-4-oxonona-6, 8-dienylglutarimide.

The compositions of the invention may be administered topically or by injection, e.g.

intradermally (by positioning the composition in the high dermis by needle injection or by high pressure air injection), intra- or perilesionally (by positioning the composition into the lesion or into the tissue adjacent to the lesion) or subcutaneously.

The term "topical", as used in this specification, relates to the use of the active ingredients incorporated in a suitable pharmaceutical carrier and applied at the site of the disease for the exertion of local action. Accordingly, topical compositions of the invention include those pharmaceutical forms in which the compound is applied externally by direct contact with the skin surface to be treated. Conventional pharmaceutical forms for this purpose include solutions, suspensions, ointments, lotions, pastes, jellies, sprays, aerosols and bath oils. The term "ointment" embraces formulatins (including creams) having oleaginous, absorption, water-soluble and emulsion-type bases, e.g. petrolatum, lanolin and/or polyethylene glycols.

The carrier used in this invention may be, for example, a solid or a sterile liquid. In particular, it may be semi-solid so that the compositions have semi-solid characteristics, by which mean that they are not fluid, i.e.

they can take up a predetermined shape, but are deformable under shear and thus can be dispensed, e.g. through an orifice as from a deformable tube.

Topical ointments can be prepared by dispersing the active compound in a suitable ointment base such as petrolatum, lanolin and/or polyethylene glycols. Advantageously, the compound is finely divided by means of a colloid mill utilizing light liquid petrolatum as a levigating agent prior to dispersing in the ointment base. Topical creams and lotions are prepared by dispersing the compound in the oil phase prior to the emulsification of the oil phase in water.

For injection, fluid dosage forms are prepared utilizing the active compound and a sterile vehicle, water being preferred. The compound, depending on the form and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, a water-soluble form of the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use.Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before it is suspended in the sterile vehicle.

Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution.

The term "unit dosage" as used herein refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of active material calculated to provide the desired therapeutic effect. Each dosage of a composition of this invention may comprise 0.1, 0.5, 1 or 5% w/w of a compound of formula I or II for topical or localised treatment, or 0.1 to 15 % w/v for parenteral treatment. The concentration of the non-steriodal anti-inflammatory agent is determined with reference to the usual topical concentrations of such compounds.

Many non-steroidal anti-inflammatory agents are known. Examples are flurbiprofen, aspirin, acetominophen, phenacetin, phenylbutazone, oxyphenbutazone, tolmetin, fenoprofen, indoxol, -indomethacin, naproxen, ibuprofen, alclofenac, amfenac, azapropazone, bendazac, benorylate, benoxaprofen, benzoaxepine, carprofen, cintazone, clonixin, clopirac, diclofenac, diflumidone, diflunisal, diftalone, fenbufen, fenclofenac, fendosal, fenoprofen and feprazone. Flurbiprofen is the preferred anti-inflammatory agent for use in this invention. The preferred compound of formula I or II is cycloheximide.

When the compositions of this invention are administered, it is preferred to use ultra-violet radiation and/or an occlusive bandage as concurrent treatment. For example, in addition to applying the novel compositions, a patient with psoriasis may have localised or general body area lesions treated by exposure to one or more minimal erythema doses (MED) or ultra-violet radiation using multiple weekly exposures and decreasing weekly exposure frequences until the lesions improve or clear.

The duration of the timed exposures intensity of the exposures (the number of MED) may be increased during the treatment, depending on the tolerance of the patient. A suitable ultraviolet exposure spectrum is from 295 to 400 nm, preferably from 320 to 40D nm.

The following Examples illustrate the invention. Compound A is 3-t2-hydroxy-2-(5-hy- droxy-3-5-dimethyl-2-oxocyclohexyl)ethylJglu- tarimide and Compound B is the acetate thereof.

Example 1 Parenteral solution A sterile aqueous solution for intra-lesional use, containing 75 mg of Compound A and 50 mg of flurbiprofen per cc, is prepared from the following types and amounts of materials: Compound A 75 gm Flurbiprofen 50 gm.

Methylparaben 2.5 gm.

Propylparaben 0.17 gm.

Water for injection q.s. 1 000 cc.

The ingredients are dissolved in the water and the solution sterilized by filtration. The sterile solution is filled into vials and the vials sealed.

The composition is useful in the intralesional treatment of psoriasis at a dose of 0.1 cc. four times a day.

Example 2 Parenteral Solution A sterile aqueous solution for intradermal use, containing in 1 cc. 5 mg. of Compound A and 5 mg of flurbiprofen, is prepared from the following types and amounts of ingredients: Compound A 5 gm.

Flurbiprofen 5 gm.

Sodium chloride 10% Solution q.s.

Water for injection q.s. 1000 cc.

The Compound A and flurbiprofen are added to the water and sufficient sodium chloride added to form an isotonic solution and the solution sterilized by filtration.

The sterile solution can be administered intradermally by high pressure injection for treatment of psoriasis.

Example 3Topical Ointment One thousand gm. of 0.25% ointment is prepared from the following types and amounts of ingredients: Compound B 2.5 gm.

Flurbiprofen 2.5 gm.

Liquid petrolatum (heavy) 250 gm.

Wool fat 200 gm.

White petrolatum q.s. 1000 gm.

The white petrolatum and wool fat are melted and 100 gm. of liquid petrolatum added thereto. The Compound B and flurbiprofen are added to the remaining liquid petrolatum and the mixture milled until the powder is finely divided and uniformly dispersed. The powder mixture is stirred into the white petrolatum mixture and stirring continued until the ointment congeals.

The foregoing ointment is usefully applied topically to the skin of animals for the treatment of mange.

Example 4 Cream One thousand gm. of a topical cream are prepared from the following types and amounts of ingredients: Compound B 50 gm.

Flurbiprofen 50 gm.

Tegacid Regular* 1 50 gm.

Spermaceti 100 gm.

Propylene glycol 50 gm.

Polysorbate 80 5 gm.

Methylparaben 1 gm.

Deionized water q.s. 1000 gm.

*Self-emulsifying glyceryl monostearate from Goldschmidt Chemical Corporation, New York, N.Y.

The Tegacid and spermaceti are melted together at a temperature of 70-80"C. The methylparaben is dissolved in about 500 gm.

of water and the propylene glycol, polysorbate 80, Compound B and flurbiprofen are added in turn, maintaining a temperature of 75-80" C. The methylparaben mixture is added slowly to the Tegacid and spermaceti melt, with constant stirring. The addition is continued for at least 30 minutes with continued stirring until the temperature has dopped to 40-45" C. The pH of the final cream is adjusted to 3.5 by incorporating 2.5 gm. of citric acid and 0.2 gm. of dibasic sodium phosphate dissolved in about 50 gm. of water. Finally, sufficient water is added to bring the final weight to 1000 gm. and the preparation stirred to maintain homogeneity until cooled and congealed.

The foregoing composition is useful for the treatment of psoriasis by applying to the lesions with occlusive bandage.

Cycloheximide or any of the compounds illustrating the scope of formulae I and 11 in Application No. 14241/77 (Serial No.1560227) can be used in the compositions of the preceding examples instead of Compound A or Compound B. Similarly, any of the anti-inflammatory agents listed above can be used instead of flurbiprofen.

The compositions of the Examples can be applied to psoriatic lesions 3 times daily, without an occlusive bandage. The lesions are exposed to a hot quartz lamp (high pressure mercury arc), beginning with a 30 second exposure each day and gradually increasing the daily exposure time to 1 5 minutes. Alternatively, a sun lamp made up of fluorescent tube (low pressure mercury arc) can be used with similar exposure times.

The compositions described above can be used for the treatment of atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, warts, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun-induced keratosis, non-malignant keratosis, acne and seborrhoeic dermatitis in humans and atopic dermatitis, warts and mange in domesticated animals.

Claims (5)

1. A pharmaceutical composition comprising a non-steriodal anti-inflammatory agent and a compound of formula I or II

wherein R, is hydrogen or C13 alkyl; either R2 is hydrogen, halogen, hydroxy, C13 alkoxy, C24 alkanoyloxy, -CH2COCH3, -CH2COC6H5, -CH2COCH2COOCH3, -CH2CH2COOH or styryl and R3 is hydrogen or R2 and R3 together are oxo; R4 is hydrogen or methyl; R5 is hydrogen, hydroxy or acetoxy; R6 is hydrogen, hydroxy or acetoxy;R7 is hydrogen or methyl; either X, and X2 are the same or different and are each hydrogen, hydroxy, acetoxy or piperidino or X, and X2 together are oxo, = NOH, = N-NH-CONH2, = N-NHCH3, = N-N(CH3)2-, = N-NH-CSNH2, = N-NH COC6H5, = N-N H2 or = N-NH-COCH2C6H5; P9 is hydrogen or hydroxy; and R,o is methyl or 2-hydroxyprop-2-yl; in association with a pharmaceutically acceptable carrier.

2. A pharmaceutical composition comprising a non-steroidal anti-inflammatory agent and cycloheximide is association with a pharmaceutically acceptable carrier.

3. A composition according to claim 1 or claim 2 in which the anti-inflammatory agent is flurbiprofen.

4. A composition according to any preceding vlaim in a form suitable for topical administration.

5. A composition according to claim 1 substantially as described in any of the Examples.