GB2179552A - Medicaments containing mepyramine - Google Patents

Abstract

Topical, oral or parenteral medicaments for treatment of herpes simplex contain mepyramine (pyrilamine).

Description

SPECIFICATION Medicament The present invention relates to the treatment of herpes simplex and in particular to medicaments suitable for use in such treatments.

Herpes simplex is, in common with many other viruses, on the one hand particularly difficult to treat effectively and on the other hand an often recurring problem causing considerable suffering over very long periods of time. Whilst a number of attempts have been made to provide an effective treatment these are generally of limited effectiveness and/or involve undesirable side effects.

It is an object of the present invention to avoid or minimize one or more of the above disadvantages.

The present invention provides the use of mepyramine or a physiologically acceptable acid addition salt or bioprecursor thereof on the preparation of a medicament for use in the therapeutic and/or prophylactic treatment of herpes simplex.

Mepyramine, also known as pyrilamine, may be used in any suitable form such as a physiologically acceptable acid addition salt for example mepyramine maleate which is commercially available under the Trade Name "Anthisan".

While it is possible for the mepyramine or other form thereof (hereinafter referred to as the "active compounds") to be administered as the raw chemical it is preferred that the active compound is presented in the form of a pharmaceutical composition comprising the active compound together with a pharmaceutically acceptable carrier therefor. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Such carriers are solid, liquid or gaseous materials recommended for the purpose of administering the medicament.

These pharmaceutical compositions may be administered orally or parenterally (including subcutaneous, intramuscular and intravenous injection) or as a suppository or pessary or may be applied topically.

For topical administration the composition may be presented in ointments, creams, pastes, jellies, sprays, aerosols and bath oils. Ointments and creams may contain oleaginous absorption colloidal clays, thickening agents such as gum tragacanth or sodium alginate and other pharmaceutically acceptable accessory ingredients such as humectants, preservatives, buffers and antioxidants which are useful in such formulations. Particular accessory ingredients which may be mentioned are dimethylsulphoxide (DMSO) and polyethylene glycol (PEG).

For oral administration the pharmaceutical compositions may be prescribed as a draught in water or in a syrup, in capsules, cachets, boluses or tablets, as an aqueous or oleaginous solution or suspension or in suspension in a syrup, such suspensions optionally including suspending agents or as an oil-in-water or water-in-oil emulsion. Where desirable or necessary flavouring, sweetening, preserving, thickening or emulsifying agents may be included in the formulation.

Tablets may contain the active compound as a powder or granules optionally mixed with binders, lubricants, inert diluents or surface-active or dispersing agents and may be formed by compression or by moulding in inert liquid diluent. Such tablets may be optionally scored and/or coated.

Capsules and cachets may contain the active compound alone or in admixture with one or more accessory ingredients. Capsules may also contain the active compound in aqueous or oleaginous solution suspension or emulsion optionally in association with accessory ingredients.

For administration as a suppository or pessary the active compound may be presented in admixture with a suitable carrier such as cocoa butter and other material commonly used in the art, the formulation conveniently being shaped by moulding.

For administration in discrete dosage forms such as the tablets, capsules, suppositories and pessaries described above the active compound is preferably presented at 5 mg to 2.5 g, most preferably 50 mg to 1 g per tablet, capsule, suppository or pessary.

For parenteral administration the active compound may be presented in sterile solutions or suspensions in aqueous or oleaginous vehicles, which may also contain preservatives and material for rendering the solution or suspension isotonic with the blood of the intended recipient. Such formulations may conveniently be presented in unit-dose or multi-dose sealed containers.

The active compound may be administered once or several times daily.

In a further aspect of the present invention there is therefore provided a method for treating herpes simplex infections comprising the administration in an effective dose of an active compound of the invention or a pharmaceutical formulation to a human subject and method for preventing the development of herpes simplex infections comprising the administration in an effective dosage of an active compound of the invention or a pharmaceutical formulation thereof, to a human subject.

The active compounds of the invention may in general be administered orally at a daily dosage rate of from 0.1 to 50 mg per kg bodyweight, preferably from 1 to 20 mg/kg e.g. about 6 mg/kg. In the case of topical formulations the active compounds are generally used at a concentration of from 0.1 to 10% w/v, preferably from 1 to 5% w/v e.g. 2% w/v. The duration of treatment may vary from one individual to another but will generally be in the range from 3 to 7 days.

The effective dosage obviously depends on the activity of the compound and also on the speed with which it is absorbed into the body and on other well-known pharmaceutical considerations.

Further preferred features and advantages will appear from the following example given by way of illustration only.

EXAMPLE 1 Testing of 'In' Vitro 'Anti' Herpes Virus Activity Materials Mepyramine Maleate The sample used consisted of 1 gm obtained from May & Baker Ltd, Research Laboratories. This bore the reference number M1685.

Dilutions were made in tissue culture maintenance medium (Earle's salt base) containing 2% foetal bovine serum plus the following antibiotics-pencillin, streptomycin and mycostatin at 10 microgrammes and 50 units per ml. An initial dilution was made by weighing to 10 mgm/ml and from this, after complete solution, further dilutions were made to 1 mgm/ml and 100 microgrammes/ml.

For use in tissue culture experimental work each dilution of mepyramine was diluted a further 1:10 by adding 0.1 ml of each dilution to 0.9 ml maintenance medium in the tissue culture tube.

Tissue Culture Cells The cells used were VERO and HEp2. Both are continuous cell lines and had been stored in liquid N2 prior to this experimental work. Both lines were checked for absence of possible mycoplasmal contamination. (VERO cells were derived from an African Green monkey while HEp2 cells were derived from a human nasopharyngeal carcinoma.) Viruses Herpes simplex types 1 and 2 were well-characterized standard strains which were obtained several years ago from the Central Virus Reference Laboratory, Colindale. These have been used, since, as reference strains and have been subjected to stringent identity checks for purity and homogeneity.

A locally isolated 'wild' strain of herpes simplex 2 was also used for some experiments, where indicated below. This strain was derived from a case of herpes genitalis during May, 1983. Its identity was proved by endonuclease restriction and by ELISA.

Each virus was used in the experiments at a concentration sufficient to cause infection in approximately 50 per cent of the tissue culture cells in the experiment. The extent of virus infection was assayed by immunofluorescence after the end of the experiment. Positive, negative and toxicity controls were included for every mepyramine maleate dilution.

Method A single experimental design was used throughout. This may be summarised as follows: 1. Normal tissue culture cells in monolayer pretreated for one hour with mepyramine maleate dilution in maintenance medium.

2. Medium removed.

3. Each tube inoculated at 4"C with enough herpes simplex virus (type 1 or type 2) to infect approximately 50% of the cells after standard incubation.

4. After one hour at 4"C each tube inoculated with 0.9 ml maintenance medium plus 0.1 ml mepyramine maleate dilution, each solution prewarmed to 37"C. This step initiates synchronous infection.

5. After 6 hours the medium plus drug was removed. The cells were stripped with trypsin :versene, resuspended in 0.1 ml phosphate buffer and placed in wells on PTFE coated microscope slides.

6. Each slide was allowed to dry in air and was then 'fixed' by immersion in acetone at ambient temperature for 5 minutes.

7. The slides were then stained by immunofluorescence in the normal way and examined in a Leitz ortholux microscope fitted with a Ploem epi-illuminator. A x25 water-immersion objective was used to count the proportion of herpes virus infected cells.

Results These are expressed as percentage virus growth compared with the virus control.

The figures are given in the accompanying table.

No difference was observed between cultures of VERO (monkey) and HEp2 (human) cells.

EXAMPLE 2 Preparation of Topical Formulation Mepyramine maleate (2 g) was triturated in a small aliquot of an aqueous cream base (British Pharmacopea (1973) page 184), comprising essentially hydrous emulsifying ointment (30% w/v, chiorocresol preservative (1% w/v, the balance being water) and the mixture then blended with the remainder of the aqueous cream base (total 100 g).

The resulting cream was then placed into a dark coloured jar which was sealed with a screwtop or into a tube and a label with the following instructions attached: "Apply to affected areas of lips or genitalia 3 to 5 times daily".

EXAMPLE 3 Preparation of Oral Formulation Mepyramine maleate was wet granulated with maize starch and lactose and the granules dried in a fluid bed oven. The dry granules were then passed through a 16 mesh screen and a magnesium stearate lubricant then blended in. The resulting mixture was then compressed into tablets in a tablet press to produce 200 mg tablets each having the following composition.

mepyramine maleate 50 mg maize starch 50 mg lactose 98 mg magnesium stearate 2 mg The tablets were then film-coated by spraying with hydroxypropylmethylcellulose with polyethylene glycol 400 plasticizer, in a side vented drum and dried.

The coated tablets were then placed in a screw-top bottle and a label with the following instructions attached: "Take 1 to 2 tablets three times daily".

TABLE Percentage Virus Growth in VERO and HEp2 Cells in the Presence of Different Concentrations of Mepyramine Maleate

llg/ml 1000 100 10 5 1 Virus Controi Herpes simplex I 0 0 0 40 80 100 Herpes simplex Il 0 0 0 35 80 j 100 Herpes simplex ll 0 0 0 40 75 100 (wild strain) Toxicity Control % 25 0 0 0 0

Claims (10)

1. The use of mepyramine or a physiologically acceptable acid addition salt or bioprecursor thereof in the preparation of a medicament for use in the therapeutic and/or prophylactic treatment of herpes simplex.

2. The use of mepyramine maleate according to claim 1.

3. The use according to claim 1 or claim 2 wherein the medicament comprises a topical formulation.

4. The use according to claim 3 wherein the topical formulation comprises an ointment or cream.

5. The use according to claim 3 or claim 4 wherein said formulation contains from 0.1 to 10% w/v of mepyramine or a physiologically acceptable acid addition salt or bioprecursorthereof.

6. The use according to claim 1 or claim 2 wherein the medicament comprises an oral formulation.

7. The use according to claim 5 wherein the oral formulation comprises is in unit dosage form.

8. The use according to claim 7 wherein said formulation is in the form of tablets or capsules.

9. The use according to claim 7 or claim 8 wherein each unit dose contains from 5 mg to 2.5 g.

10. The use of mepyramine or a physiologically acceptable acid addition salt or bio-precursorthereof in the preparation of a medicament for use in the treatment of herpes simplex substantially as described hereinbefore with particular reference to Example 2 or Example 3.