Pharmaceutical formulation

Details Pharmaceutical formulation Pharmaceutical formulation

1995-06-05

2002-10-22

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S264110

Reexamination Certificate

active

06469015

ABSTRACT:

This invention relates to a topical pharmaceutical formulation suitable for use in the treatment of virus infections of the skin and mucosa.
EP-A-141927 (Beecham Group p.l.c.) discloses the compound 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine, known as BRL 39123 or penciclovir, its salts and esters thereof and its use in the treatment of herpesvirus infections. Topical administration is disclosed as a suitable route. Hereinafter, references to penciclovir include salts and esters thereof.
It is important with a topical formulation of an antiherpesvirus drug that the quantity of drug released from the formulation is sufficient to exert a significant antiviral effect and that the drug rapidly reaches its site of action within the skin.
Rapid penetration is important, since in most cases, major virus induced epidermal pathology occurs within the first 24 hours post infection. Once the infection is established and the stratum corneum has been eroded, the rapid ingress of host resistant factors could make chemotherapy of questionable value.
A new antiviral topical formulation has now been discovered, having improved properties as compared with conventional formulations.
Accordingly, the present invention provides an oil-in-water topical pharmaceutical formulation or an aqueous formulation for the treatment of virus infections of the skin or mucosa, comprising at least 30% of propylene glycol and solubilised penciclovir.
Such a topical formulation may contain 0.075% to 10% w/w penciclovir and from 30% to 60% w/w of propylene glycol and from 15% w/w water (up to 50% when there is an oil phase).
In a preferred aspect the formulation comprises from 0.75 or 1% to 10% w/w penciclovir, from 30% to 50% w/w of propylene glycol, from 20% w/w water (up to 40%, when there is an oil phase). Examples of suitable formulations comprise from 2% to 5% w/w penciclovir, from 35% to 45% w/w of propylene glycol, from 25% to 40% w/w water together with an oil phase. A preferred formulation comprises 0.75% or 1% to 5% penciclovir. The formulation should preferably contain about 40% w/w of propylene glycol.
The amount of penciclovir present in the formulation should be at least sufficient to maintain an antivirally effective concentration at the site of infection between applications without showing signs of toxicity. The optimum concentration of penciclovir will depend on its solubility in the vehicle. Penciclovir may be included in the formulation at a level exceeding its solubility in order to provide a reservoir and to maintain the antiviral agent at a saturated concentration within the vehicle. One suitable amount in the above preferred formulation is 0.5-10% w/w, such as 2-8%, for example 5%. A preferred amount is less than 5%, such as 0.5 to 2%, for example 1%.
EP-A-416739 (Beecham Group p.l.c.) discloses a topical formulation comprising at least 30% propylene glycol, 0.1 to 10.0% decylmethylsulphoxide and solubilised penciclovir. It will be appreciated that the present formulation comprises less than 0.1% decylmethylsulphoxide.
The water used in the formulation is preferably purified water, purified that is by distillation by means of ion exchange or other appropriate method.
The oil phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it is desirably comprised of a mixture of at least one emulsifier with one or more excipients including oils, fats and/or waxes, together with optional film formers and stabilisers as well as thickening and bodying agents. Preferably, as explained in more detail below, an additional hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so called emulsifying ointment base which forms the oil dispersed phase of the emulsions.
Oil-in-water topical formulations may be formulated in a number of ways, all of which depend primarily on the alignment of the emulgent or emulsifying agent and emulsion stabiliser at the oil/water interface, with the non-polar or lipophilic groups soluble in the oil phase and the polar or hydrophilic groups in the aqueous or continuous phase. Thus the more polar hydrophilic emulgents result in oil-in-water emulsions. This principle has been systemised in the idea of a ‘hydrophilic-lipophilic balance’ (H.L.B.) Griffen, W. C.
J. Soc. Cosmet. Chem.,
1954, 5, 249 and the various emulgents have been allocated H.L.B. numbers from which their behaviour with constituents of the aqueous and oil phases (to which are applied theoretical required H.L.B. figures) may be predicted.
Emulgents and emulsion stabilisers suitable for use in the formulation of the present invention include polyoxyethylene sorbitan monostearate (polysorbate 60), sorbitan monostearate, sorbitan monooleate, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulphate, Cetomacrogol 1000 and Carbomer 940.
A preferred stabiliser is Cetomacrogol 1000 (Polyethylene Glycol 1000 Monocetyl Ether) and is preferably present in a percentage of 0.5 to 2% of the composition, such as 0.5 to 1%, for example 0.7 to 1.0%, preferably 0.9% to 1.0%, the optimum concentrations being 0.94%.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus the cream should preferably be non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Lipophilic substances with relatively high melting points, such as beeswax, partial glycerides of capric and caprylic acids, or silicone oil, white soft paraffin and/or liquid paraffin or other mineral or vegetable oils are suitable. Straight or branched chain, mono- or dibasic alkyl esters such as di-isopropyladipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixed ester of 2-ethyl hexanoic acid with a blend of cetyl or stearyl alcohols known as Crodamol CAP may also be used.
As well as creams, the aqueous/oil-in-water formulation may be a lotion, skin paint, gel, spray, aerosol, liniment or gel stick, which are formulated as known in the art, for example as described in standard text books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books, the British Pharmacopoeia, USP twenty-first revision (USP XXI) (1984), distributed by Mack Publishing Company.
The product may or may not be sterile, with adequate preservative capacity for single or multi-dose purposes.
In this description, the following terms are employed:
Aerosol-Pharmaceutical aerosols are products that are packaged under pressure and contain therapeutically active ingredients that are released upon activation of an appropriate valve system The term ‘aerosol’ has been used to refer to the fine mist of spray that is emitted from a pressurized container containing an active ingredient and a propellant. However, the term has been broadly applied to include all self-contained pressurized products, some of which deliver foams or semisolid fluids. Accordingly, unless indicated otherwise, a reference herein to an aerosol formulation of the present invention should be understood to include pharmaceutical compositions for topical use comprising a pharmaceutically acceptable carrier which includes a propellant, said compositions being adapted for use in a pressurized container that dispenses the composition as a spray, foam or semisolid liquid.
An aerosol generally comprises a container, a propellant, a concentrate containing the active ingredient, a valve (which may be a metered valve), and an actuator. The nature of these components determines characteristics such as delivery rate, foam density, and fluid viscosity Aerosols may be two-phase (gas and liquid)

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