GB2339533A

GB2339533A - Topical pharmaceutical preparations

Info

Publication number: GB2339533A
Application number: GB9815280A
Authority: GB
Inventors: James Martin Biggs
Original assignee: Individual
Current assignee: Individual
Priority date: 1998-07-14
Filing date: 1998-07-14
Publication date: 2000-02-02
Also published as: GB9815280D0

Description

2339533 TOPICAL PHARMACEUTICAL PREPARATIONS This invention relates to

topical pharmaceutical preparations for use in connection with male erectile dysfunction.

As explained by A. Gomaa et al. in the British Medical Journal, volume 312, pages 1512-1515 (15 June 1996), a common pharmacological treatment for most types of erectile dysfunction, which is a very distressing disease or psychological condition, is based on the intracorporeal injection of vasoactive agents which either induce erection or facilitate it. Such agents include papaverine, phenoxybenzamine, prostaglandin E, thymoxamine, phentolamine, nicergoline and dihydroergocryptine. However, these agents need to be injected intracavernously at each use. This is painful and stressful, becomes less effective in time and may give rise to infection and other undesirable side effects such as priapism. Compounds which induce penile erection after oral ingestion have recently been introduced, but their long-term safety has not yet been demonstrated.

In this paper, Gomaa et al. indicated that some vasodilators, particularly glyceryl trinitrate, have been applied topically to the penis for the management of erectile dysfunction but that, although some studies have indicated a satisfactory positive response after such application, later papers had concluded that glyceryl trinitrate is not useful clirkally and induced headaches at all concentrations used. Gomaa et al then tested the effect of various vasodilators, includina, isosorbide dinitrate, aminophylline and co-dergocrine mesylate in a cream formulation. Positive results were obtained but the authors could only conclude that more studies with creams containing a vasodilator are needed and that topical treatment with such creams may be considered for use before the intracavernous injection of vasoactive drugs.

The problem underlying the present invention can therefore be seen as a need to produce an improved, or at least an alternative, effective pharmaceutical preparation for topical use in cases of male erectile dysfiinction.

It is believed that this problem can be solved by the incorporation of a vasodilator, particularly glyceryl trinitrate, in a hydrogel preparation. It is believed that the hydrophilic nature and water content of the hydrogel preparation facilitates the transdermal transmission of the vasodilator into the blood stream within the penis and, surprisingly, glyceryl trinitrate i's sufficiently stable within the hydrogel environment for it to retain its potency to allow a satisfactory shelf life for pharmaceutical preparation of this type.

Accordingly, the present invention provides pharmaceutical preparations for use 0 in the treatment of male erectile dysfunction which are characterised by comprising a vasodilator incorporated into a hydrocrel formulation.

Hydrogels are preparations based on hydrophilic polymers in equilibrium with a high proportion of water, often of about 50 per cent. by weight of the polymer. This is 0 In p'ble because of the hydrogen bonding which occurs between the hydrophilic groups ossi 0 in the polymer structure and the water molecules. Such polymers may be cross-linked in order to produce solid products, and hydrogels of this type now form the basis of most forms of soft contact lenses.

Hydrogels with a lower degree of cross-linkincy have an amorphous gellike consistency and have found use as wound dressincrs. Cornmercial products of this type include those sold under the trade names of Intrasite and Aquaform, wEch are each believed to include a graft copolymer based on corn starch, together with a modified carboxymethylcellulose, propylene glycol as humectant, and preservative, all equilibrated with water and supplied in the form of sterilised sachets. For present purposes, this type of hydrogel formulation can be used but with the incorporation therein of a vasodilator, particularly glyceryl trinitrate, in an appropriate amount which is usually from I - 5 per cent. by weight of the total hydrogel formulation.

:1 - I ID However, for present purposes, hydrogels formed from wholly synthetic polymers are preferred. A particularly useful hydrogel for the purposes of the present invention is 0 one based on N-polyvinylpyrrolidone, but hydrogels based on polymers of hydroxyethyl methacrylate are also useful, as also are polyacrylan-de polymers.

These polymers may be prepared vAth a sufficiently high molecular weight so that, after equilibration with water and any humectant, they have a viscosity which makes the hydrocrel suitable for topical administration. This requires the hydrocrel to be in the form of a paste or thick syrup so that it can be conveniently applied to the penis without loss resulting ., from undue fluidity of the composition. For this, purpose, the preparations of the invention can include a thickening agent, such as carboxymethy1cellulose.

However, the desired viscosity of the final formulation can better be achieved by the use of mildly cross-linked hydrogel-forming polymers. For example, hydroxyethyl methacrylate polymers can be cross-linked by copolymerisation with a small amount of ethylene dimethacrylate, diethylene glycol dimethacrylate or _3), 6- dioxaheptyl methacrylate; and poly-N-vinyl pyrroli done can be cross-linked by copolymerisation of N-vinyl pyrrolidone with a small amount of ethylene dimethacrylate or divinylbenzene.

Copolymers of n-vinylpyrrolidone and hydroxyethyl methacrylate can also be formulated as hydrogels useful for forming the pharmaceutical preparations of the present invention.

0 0 Although the preferred formulations of the present invention are in the form of thick pastes or syrups which can be readily dispensed from a tube or sealed sachet, an alternative formulation is to link the hydrogel to a solid substrate such as a porous fabric material, for example by linking the hydrogel polymer covalently with a polymeric substrate such as one based on polyvinyl chloride or polymethylmethacrylate or by the use of a silane linker to bind the hydrogel polymer to the substrate. With a substrate formulation, the hydrogel can more easily be applied to a tumescent penis.

A further embodiment of the present Invention is to provide a condom which ha been coated on its inner surface with a hydrogel formulation containing a vasodilator. For example, the hydrogel formulation may be used to coat the inner surface of a condom with 0 this formulation then bein bonded to that surface during a sterilsation of the condom by 9 C) irradiation thereof prior to its packaging.

0 As already stated, the preferred vasodilator for use in the present invention is glyceryl trinitrate. This compound is believed to induce penile erection by the formation of nitric oxide in the penile blood stream. Vasodilators which operate in a similar way may therefore also be used, particularly isosorbide dinitrate.

The amount of vasodilator incorporated into the formulations of the invention will usually be in the range of I to 5 percent. by weight of the total hydrogel formulation.

1 0 ?- The pharmaceutical preparations of the present invention will be formulated by rnixing the hydrogel polymer with water and with the vasodilator and any humectant and preservative which may be desired also to be incorporated in the final formulation. These inaredients are then blended together and excess water is extracted from the formulation by centrifugation or pressing the preparation against a sen-&permeable membrane which results in removal of excess water by osmosis. This concentrated hydrogel preparation may then, if desired, be attached to a solid substrate through a linking process such as one induced by radiation or by the use of a silane linking agent. However, more usually, the hydrogel preparation containing the vasodilator will be packaged into a collapsible tube or into sealed sachets.

If desired, the preparation can be formulated to contain a recognised 0 pharmacological humectant, such as propylene glycol or isopropyl myristate. It can also 0 contain an antiseptic and/or a spermicidal agent such as hexyl resorcinol.

0 In use, the preparations of the present invention will be applied topically to the penis, and preferably to its exposed glans, as late as possible prior to anticipated intercourse. Erection can then be expected to occur in a matter of a few minutes.

Claims

I A pharmaceutical preparation for use in the treatment of male erectile dysfunction which is characterised by comprising a vasodilator incorporated into a hydrogel formulation.
2. A pharmaceutical preparation according to claim 1, wherein the vasodilator is glyceryl trinitrate.
3. A pharmaceutical preparation according to claim 1, wherein the vasodilator is isosorbide dirftrate.
4. A pharmaceutical preparation according to either of claims I or 2, wherein the vasodilator is present in an amount of from 1 to
5 per cent. by weight of the total of hydrogel polymer, water and any humectant also present.

0 5. A pharmaceutical preparation according to any of the preceding claims, wherein the hydrogel is a polymer or copolymer of N-vinylpyrro li done.

0
6. A pharmaceutical preparation according to any of the preceding claims, wherein the hydrogel is a polymer or copolymer of hydroxyethylmethacryl ate.
7. A pharmaceutical preparation according to any of the preceding claims, wherein the hydrogel contains a copolymer derived from com starch.

0
8. A pharmaceutical preparation according to any of the preceding claims, which also 0 0 comprises carboxymethylcellulose as thickening agent.

1
9. A pharmaceutical preparation according to any of the preceding claims, wherein the hydrogel formulation has been linked to a solid substrate.

0 -(0-
10. A condom to which a pharmaceutical preparation according to any of the preceding claims has been applied to its inner surface prior to it being packaged I for sale.