GB2375048A

GB2375048A - Formulation

Info

Publication number: GB2375048A
Application number: GB0107902A
Authority: GB
Inventors: Stuart Pearce
Original assignee: SOLPORT Ltd
Current assignee: SOLPORT Ltd
Priority date: 2001-03-29
Filing date: 2001-03-29
Publication date: 2002-11-06
Anticipated expiration: 2021-03-29
Also published as: GB0107902D0; GB2375048B

Abstract

A composition comprising silver nitrate and a pharmaceutically acceptable carrier/diluent in the form of a liquid and preferably being suitable for cauterising tissue and/or for the treatment of warts and/or verucas and/or non-malignant skin growths and/or granuloma and/or granulation tissue, wherein the liquid is preferably viscous or a gel. The composition may comprise a thickening agent, preferably about 4 wt% of colloidal silica. Further, the silver nitrate is preferably present in a concentration of from 8 wt% to 50 wt % or more.

Description

FORMULATION The present invention relates to formulations comprising silver nitrate. More specifically, the invention relates to formulations comprising silver nitrate which are in liquid or gel form.

As well as widespread use in the photographic industry, silver nitrate has also found numerous applications in medical and pharmaceutical fields. For example, silver nitrate pills have been used to treat dyspepsia, vomiting, gastric ulceration, diarrhoea, epilepsy, chorea and other nervous diseases, although there is some doubt as to the efficacy of silver nitrate on the central nervous system (British Pharmaceutical Codex, 1907, P124-125). More commonly, silver nitrate is known to be a topical anti-infective, astringent, and caustic agent (American Society of Health System Pharmacists, 1995 P1889).

A variety of different silver nitrate formulations are disclosed in the art. By way of example, it is known in the art that low concentrations of silver nitrate can be used in wound dressings. US 4,391, 799 (United States of America as represented by the Secretary of the Army) discloses a protective aqueous gel composition for treating white phosphorus bum wounds which comprises 0.01 to 1% by weight of a water soluble silver salt, such as silver nitrate, and a water-soluble hydrogel matrix consisting essentially of 0.5 to 3% by weight alkali metal alginate, about 8 to 12% by weight glycerin and about 82 to 90% by weight water.

Furthermore, US 4,376, 764 (BASF Wyandaotte Corporation) discloses gel compositions suitable for treating bum wounds and superficial ulcers which contain a polyoxybutlyene-polyoxyethylene block copolymer, water and an effective amount of a water-soluble or insoluble silver salt. Such compositions maintain their gel characteristics at temperatures below 20 C and typically contain silver salts (such as silver nitrate) in amounts of between about 0.1 to 5% by weight.

US 5,019, 096 (Trustees of Columbia University, New York) discloses a method for making an infection-resistant material by incorporating an effective amount of an antimicrobial agent into a matrix comprising a polymeric component, and wherein the antimicrobial agent includes a synergistically effective amount of a silver salt and a biguanide. On contact with fluids, the matrix allows controlled release of the antimicrobial agent at a level sufficient to suppress infection.

US 5,869073 (Biopolymerix, Inc. and Surfacine Development Company, Inc. ) discloses a liquid composition for applying a non-leachable antimicrobial coating. The liquid composition consists of a solution, dispersion or suspension of a biguanide polymer reacted with a cross-linking agent to form an adduct, and an antimicrobial metal material (such as silver nitrate). The resulting antimicrobial coating is advantageous as it does not release biocidal levels of leachables into the surrounding solution.

Finally, unexamined Chinese Patent Application CN 1137392 (Ma Guangyin) discloses a healthcare preparation for giving up smoking. The preparation is in the form of an oral liquor and comprises areca seed extract, puccoon extract, 95% alcohol, 10% silver nitrate solution, medical glycerin and distilled water.

Silver nitrate occurs as colourless or white crystals which, upon exposure to light or in the presence of organic matter, turn grey or grey-black due to reduction to metallic silver. The antiseptic, germicidal, astringent and caustic or escharotic activity of silver nitrate is a result of silver ions readily combining with biologically important groups such as sulfhydryl, carboxyl, phosphate and amino moieties, which are attached to proteins and other biological molecules. On interaction with these groups, the silver ions usually alter the physical properties, resulting in denaturation and/or precipitation of the protein. In a similar manner, silver ions are able to react with the surface of bacteria to cause significant changes in the cell wall and membrane. Accordingly, the germicidal activity of silver nitrate may be attributed to the denaturation of bacterial proteins by liberated silver ions.

The diffusion of silver ions into tissue is prevented to any great extent by their propensity to combine with proteins. Moreover, silver ions are readily precipitated by biologically ubiquitous ions such as chloride, thus ionizable silver salts do not easily penetrate into tissue in solution.

The extent of antiseptic, germicidal, astringent and caustic activity of silver nitrate depends on a number of factors, importantly including concentration, together with the time period during which the substance is allowed to react. For example, if the silver nitrate concentration is low, precipitation prevents deep tissue penetration and only superficial activity will result.

Dilute aqueous solutions may be used externally as a collyrium (0.2 to 0. 6%), for application to the eyes (1-2%), injection into the urethra (0.025 to 0.2%) and application to various kinds of ulcer (2-6%), whereas a 5% solution in spirit of nitrous ether forms a good means of application to the skin (British Pharmaceutical Codex, 1907,124-125). In addition, compresses soaked in a 0.5% solution of silver nitrate have been applied to severe bums to reduce infection (Martindale: The Complete Drug Reference, 32nd Edition, 1999, pl629).

For cauterising purposes, silver nitrate is sometimes made in sticks, often in the form of toughened caustics, and is used to destroy warts and other small skin growths.

Verruca vulgaris or common warts are benign, spontaneously regressing epithelial tumours of the skin and mucosa caused by human papilloma viruses (HPVs). Although there are many successful treatment models disclosed, few have been adopted in routine practice due to various undesirable side effects and hazards. However, the clinical treatment of common warts with silver nitrate pencils (Yazar and Basaran, The Journal of Dermatology, Vol. 21: 329-333,1994) has been shown to be an effective, economic and easily applicable alternative. Moreover, the only side-effect observed is a discolouration of the wart following the silver nitrate application.

In addition to the above, silver nitrate applicators are also useful in the treatment of epistaxis or nasal haemorrhaging (Epistaxis: Postgraduate Medicine Vol. 70, No. 5, November 1981, p231-235), and in the treatment of vasomotor rhinitis (Al-Samarrae, The Journal of Laryngology and Otology, April 1991, Vol. 105, p285-287). In the latter case, 20% silver nitrate is applied by means of a swab stick after anaesthetising the affected area with 5% cocaine hydrochloride spray.

Silver nitrate caustic pencils and applicators typically have a small tip of solid silver nitrate caustic mixture mounted onto the end of a plastic holder. Immediately before use, the tip is dipped into clean water, and the moistened tip rubbed gently over the area to be treated. This operation is carried out at appropriate time intervals depending on the exact nature of the problem to be treated. Caustic pencils and applicators, supplied by the applicant, come in various strengths ranging from 40% to 95% silver nitrate, each diluted with the balance to 100% with potassium nitrate (for example, silver nitrate 95% and 5% potassium nitrate). In each case the silver nitrate is the active material, and the potassium nitrate is merely the diluent, which performs no pharmacological function apart from diluting and imparting mechanical strength to the solid active tip so that it is resistant to fracture. Indeed such silver nitrate/potassium nitrate mixtures are often referred to as'toughened silver nitrate'in some quarters (British Pharmacopoeia 1980, p402).

As mentioned above, the active, silver nitrate, owes its astringent and caustic activity to the fact that the silver ion can bind readily to certain parts of proteins and other biological molecules, and is a moderately powerful oxidising agent. In order to function as such, the silver nitrate is preferably present in at least moderately strong (concentrated) solution in water. With solid-tipped caustic pencils and applicators, a strong solution is provided in actual use by the film of water into which the tip is dipped immediately prior to application, which rapidly dissolves the silver nitrate of the tip to high concentration, or near or complete saturation. As the moistened tip is applied to the treatment area, the strong or saturated solution of silver nitrate is spread over the appropriate surface area where it is partially absorbed. The silver nitrate then acts as a caustic to the treated tissue as described. Obviously some of the potassium

nitrate is dissolved in the same solution, but this component is largely inactive and has no substantial caustic effect.

In most cases, the film of water present on the wetted tip, which is applied to the skin, is known to form a strong or saturated solution of silver nitrate. However, it is never possible to predict or prescribe exactly what the percentage composition of silver nitrate is likely to be. This is because the micro-environment of each individual moistening and application is unpredictable and variable. For example, if the film of moisture is thinner, or is left on the tip for longer before application, or the environment is warmer, and/or there is some agitation, the solution present is likely to be closer to saturation. In contrast, if the circumstances are less favourable to rapid dissolution of the solid, then a weaker (but nonetheless still quite strong) solution may be obtained.

However, the precise composition of the solution upon application is not usually crucial. A long history of the use of these devices has demonstrated that the product is efficacious in spite of these variations in concentration. Indeed, under the right circumstances the silver nitrate will actually take up moisture when present on the skin as the dry solid, with the aid of such vehicles as perspiration, whereupon it will be at least partially absorbed by the tissue from the solution produced.

A series of simple chemical trials were carried out by the applicant on a number of caustic pencils and applicators to ascertain the actual silver nitrate concentrations obtained from the film of water at the caustic tips, under a range of typical operating situations. The results revealed an average concentration of about 50% silver nitrate, although the actual value varied from between about 20 and 70%.

The present invention seeks to provide an alternative pharmaceutical formulation comprising silver nitrate that is suitable for a wide range of different applications.

More particularly, the invention seeks to alleviate the problems associated with prior art silver nitrate caustic pencils and applicators, and provide a pharmaceutical composition in which a standardised concentration of silver nitrate can be administered, but which has a stable shelf life.

In a broad aspect, the present invention relates to formulations comprising silver nitrate which are in liquid form.

More specifically, a first aspect of the invention relates to a pharmaceutical composition for cauterising tissue and/or for the treatment of warts and/or verrucae and/or non-maligant skin growths and/or granuloma and/or granulation tissue, said composition comprising silver nitrate and a pharmaceutically acceptable diluent, excipient or carrier, and wherein the composition is in the form of a liquid.

By way of definition, the term"liquid"refers to any liquid, and encompasses very low viscosity liquids (for example, water or alcohol), through to moderately viscous liquids ("treacle-like"liquids) through to high viscosity liquids (for example, gels).

In a preferred embodiment, the liquid is a viscous or gelatinous liquid.

In an even more preferred embodiment, the composition of the invention is in the form of a gel.

More specifically, the term"gel"may encompass lyophilic colloids that have coagulated to a rigid or jelly-like solid. In a gel, the dispersed and continuous phases form a loosely-held three-dimensional network of linked molecules throughout the material.

By way of definition, the term"cauterising"refers to any operation involving the chemical searing of tissue, for example, the small scale sealing of skin/tissue to stop nose bleeds or seal post-bioptic cervical nicks.

In a preferred embodiment, the pharmaceutical composition of the invention is a caustic agent.

In another preferred embodiment, the composition of the invention further comprises a thickening agent.

In a particularly preferred embodiment, the thickening agent is colloidal silica. By way of definition, the term"colloidal silica"refers to silica that is capable of forming a colloid on mixing with a liquid (continuous) phase. The term"colloid"refers to a system in which there are two or more phases, with one (the dispersed phase), in very finely divided form, distributed throughout the other (the continuous phase).

The liquid/gel product should preferably possess at least a moderate viscosity in order to adhere to the surface to be treated, although even a mobile (low viscosity) liquid will so adhere to some extent. In view of the fact that silver nitrate reacts with and is thus chemically incompatible with most substances commonly used for thickening liquid products, silicon dioxide is used as it does not so react. The colloidal silicon dioxide ('fumed silica') is present in order to impart viscosity to the mixture. Indeed silica and silver nitrate are mutually compatible in aqueous solution for extended periods of time.

Typically, a content of around 4% silica is found to impart the optimum degree of viscosity to the product with regard to manufacture, application in use, and adherence to the skin. Since silica is chemically highly inert (unreactive), it is safe to leave on the skin after treatment. Indeed silica is used in many household, cosmetic and medical products. Fumed silica, which is very finely-divided and has a very small particle size, imparts viscosity to aqueous solutions due to a physico-chemical gelling effect which will be familiar to those skilled in the relevant art.

In a particularly preferred embodiment of the invention, the pharmaceutical composition is thixotropic.

By way of definition, the term"thixotropic"refers to a liquid which acts as a viscous liquid or gel when left undisturbed, but becomes more mobile (less viscous) when subjected to sudden stress (for example, pressure or rapid movement).

In a preferred embodiment, the diluent of the composition of the invention comprises a solvent.

In a particularly preferred embodiment, said solvent is an aqueous solvent, even more preferably water.

In contrast to the silver nitrate applicators disclosed in the prior art, one of the advantages of the present invention is that it enables the actual operation concentration of the silver nitrate solution to be standardised. Such standardisation of formulations is welcomed by the pharmaceutical industry and, in particular, regulatory bodies. In addition, the pre-made liquid preparations of the invention do not require moistening before use and are thus safer and more convenient. Moreover, more viscous liquid and gel preparations have the additional advantage over more mobile liquid preparations in that the former usually exhibit more favourable adhesive properties to the skin or treatment area.

The compositions of the present invention also exhibit improved stability and userconvenience over the silver nitrate applicators of the prior art in that they are easier to administer, do not require formulation immediately prior to use, and allow the application of a reliable, standardised concentration of silver nitrate to the desired area.

The compositions of the present invention can be stored and preferably have a shelf life of at least one hour, more preferably at least six hours, and even more preferably one day, one week, one month, six months, twelve months, or five years.

In one preferred embodiment, the invention relates to a composition as described above which comprises greater than 8% by weight of silver nitrate.

In a more preferred embodiment, the invention relates to a composition as described above which comprises greater than 10% by weight of silver nitrate.

In an even more preferred embodiment, the composition of the invention comprises greater than 25% by weight of silver nitrate, and even more preferably equal to or greater than 50% by weight of silver nitrate.

To date the prior art has neither taught nor suggested such highly concentrated silver nitrate liquid or gel formulations.

Several different factors must be taken into consideration when determining the concentration of silver nitrate suitable for the compositions of the present invention.

During experimentation, manufacturing and patient trials, a concentration of 50% silver nitrate was found to be a good compromise between two opposing factors. The first of these factors is clinical efficacy, which favours a stronger solution but for which 50% silver nitrate was found to be entirely adequate. The second factor is the ease of manufacture, storage and use; a solution that is too concentrated throws up more difficulties during manufacture, and is more likely to solidify out of solution, or become encrusted around the container tip after it has been stored and/or dispensed.

This would be undesirable in view of the caustic and staining nature of the material, which ideally should not be allowed to disperse, 'wander'around the treatment area (skin or mucous membrane) or contaminate the local environment during or after use.

By comparison with the silver nitrate caustic pencils and applicators and of the prior art, the pharmaceutical composition of the present invention adheres more easily to the surface to be treated as a film of suitable thickness, and is less liable to disperse.

Moreover, the composition of the invention, upon application, adheres and then dries to form a very thin crust. Absorption of any remaining silver nitrate may then take place within a short time via moisture derived from perspiration, which can then help carry the silver nitrate partially into the tissue. Ideally, the treated area should be covered by an adhesive plaster for further safety and protection.

In one particularly preferred embodiment, the composition of the invention comprises 50% by weight of silver nitrate, 4% by weight of colloidal silica, and 46% by weight of water.

The compositions of the invention comprise one or more of the following: a pharmaceutically acceptable diluent, carrier, or excipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described,

for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R.

Gennaro edit. 1985).

Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water.

The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder (s), lubricant (s), suspending agent (s), or solubilising agent (s).

Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.

Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

Preservatives, stabilizers and dyes may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

The pharmaceutical composition of the invention is intended for topical application to the skin, mucous membranes and related surfaces in the form of a lotion, solution, cream, gel, hydrogel, ointment or by use of a skin patch. In particular, the composition is suitable for the treatment of common warts (including plantar verrucae) and other small non-malignant skin growths, for granuloma and granulation tissue, for cautery and as a caustic. The composition is typically applied as a thin film, which adheres and then dries to form a very thin crust over the treatment area.

For topical application, the agent of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

In a particularly preferred aspect of the invention, the composition is provided in the form of an applicator which is suitable for the topical administration of the product to the skin or tissue to be treated.

A second aspect of the invention relates to the use of silver nitrate in the preparation of a medicament for cauterising tissue and/or for the treatment of warts and/or verrucae and/or non-maligant skin growths and/or granuloma and/or granulation tissue, wherein said medicament comprises silver nitrate and a pharmaceutically acceptable diluent, excipient or carrier, and wherein the medicament is in the form of a liquid.

In a preferred embodiment, the liquid is a viscous or gelatinous liquid.

In another preferred embodiment, the medicament is in the form of a gel.

In one preferred aspect, the medicament further comprises a thickening agent, even more preferably colloidal silica.

A third aspect of the invention relates to a process for preparing a pharmaceutical composition according to the invention, said process comprising admixing silver nitrate with a pharmaceutically acceptable diluent, excipient or carrier, and optionally adding a thickening agent.

A further aspect of the invention provides a pharmaceutical composition comprising silver nitrate in an amount greater than 30% by weight, and a pharmaceutically acceptable diluent, excipient or carrier, wherein said composition is in the form of a liquid.

In a particularly preferred embodiment, the liquid is a viscous or gelatinous liquid, and is even more preferably a gel.

In a particularly preferred embodiment, said liquid or gel composition comprises silver nitrate in an amount equal to or greater than 50% by weight.

The invention will now be described further by way of example.

Examples Method of Manufacture 5.00 kg of silver nitrate is transferred to a suitable mixing vessel, of about 15 litres total internal volume, equipped with a well-fitting lid and stirrer, all constructed of a silvernitrate-resistant material. 1.80 kg of deionised water is added and the mixture stirred for 15 minutes to dissolve as much as possible of the solid. The mixture is allowed to reach room temperature (it will have cooled and possibly'iced'). 3.20 kg of a 12% aqueous suspension of colloidal silica is then added to this carefully and gradually to the mixture in the vessel with continuous, thorough stirring. After the addition is complete, the mixture is stirred for at least 15 minutes more until a uniform product is obtained (as described below). The product should be well sealed and stored away from light until required.

Chemical and Physical Testing of Product

A Appearance and Description The product is a gelatinous, moderately viscous, colourless or grey, clear or slightly cloudy liquid. This liquid is thixotropic, i. e. it flows easily under high stress (pressure or rapid movement), but is thicker and tends to stick when subjected to lower physical stress.

, Assay to determine the Concentration of Silver Nitrate as % AgNOs w/w in Liquid Product The following method is described in the British Pharmacopoeia monograph for silver nitrate pure material (BP 2000, pl371-1372).

An accurately-weighed quantity of product, expected to contain approximately 300 mg (0.3 g) of silver nitrate, is transferred to a suitable laboratory titration flask and dissolved in 50 ml of deionised water. 2 ml of dilute nitric acid is added, together with 2ml of ferric ammonium sulphate solution as indicator. The mixture is then titrated with 0.1 M aqueous ammonium thiocyanate solution to a reddish yellow end point. The content of the silver nitrate in the product is calculated from the following formula: 1 ml of 0.1 M ammonium thiocyanate is equivalent to 16.99 mg of silver nitrate.

Clinical efficacy Studies undertaken by the applicant have demonstrated that the product of the invention is equal to or better than the traditional solid products in delivering silver nitrate to the desired site. The results so far available, from approximately 30 subjects on whom testing has been completed, have shown that the new form of the product is easier to use and apply than the traditional products. Satisfaction has been voiced by all subjects in this regard. Furthermore, the new product is at least equally effective at removing warts as the prior art solid products: all of the total of 25 warts on the fingers and hands

have been removed after 3 applications; the 9 verrucae on the base of the foot so far tested have been removed after 6 or fewer applications.

Various modifications and variations of the described methods and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant art, or related fields, are thus intended to fall within the scope of the following claims.

Claims

CLAIMS 1. A pharmaceutical composition for cauterising tissue and/or for the treatment of warts and/or verrucae and/or non-maligant skin growths and/or granuloma and/or granulation tissue, said composition comprising silver nitrate and a pharmaceutically acceptable diluent, excipient or carrier, and wherein the composition is in the form of a liquid.

,
2. A pharmaceutical composition according to claim 1 wherein the liquid is a viscous or gelatinous liquid.
3. A pharmaceutical composition according to claim 1 or claim 2 wherein the composition is in the form of a gel.
4. A pharmaceutical composition according to any preceding claim wherein said composition is a caustic agent.
5. A composition according to any preceding claim further comprising a thickening agent.

6. A composition according to claim 5 wherein said thickening agent is colloidal silica.
6. A composition according to any preceding claim wherein said composition is thixotropic.
7. A composition according to any preceding claim wherein the diluent is a solvent.
8. A composition according to claim 7 wherein said solvent is an aqueous solvent.
9. A composition according to claim 8 wherein said aqueous solvent is water.

<Desc/Clms Page number 16>
10. A composition according to any preceding claim which comprises 8% or more by weight of silver nitrate.
11. A composition according to any preceding claim which comprises 10% or more by weight of silver nitrate.
12. A composition according to any preceding claim which comprises 25% or more by weight of silver nitrate.
13. A composition according to any preceding claim which comprises 50% or more by weight of silver nitrate.
14. A composition according to any preceding claim which comprises 50% by weight of silver nitrate, 4% by weight of colloidal silica, and 46% by weight of water.
15. Use of silver nitrate in the preparation of a medicament for cauterising tissue and/or for the treatment of warts and/or verrucae and/or non-maligant skin growths and/or granuloma and/or granulation tissue, wherein said medicament comprises silver nitrate and a pharmaceutically acceptable diluent, excipient or carrier, and wherein the medicament is in the form of a liquid.
16. Use according to claim 15 wherein the liquid is a viscous or gelatinous liquid.
17. Use according to claim 15 or 16 wherein the medicament is in the form of a gel.
18. Use according to any one of claims 15 to 17 wherein said medicament further comprises a thickening agent.
19. Use according to claim 18 wherein said thickening agent is colloidal silica

<Desc/Clms Page number 17>
20. A process for preparing a pharmaceutical composition according to claim 1, said process comprising admixing silver nitrate with a pharmaceutically acceptable diluent, excipient or carrier, and optionally adding a thickening agent.
21. A composition comprising silver nitrate in an amount greater than 30% by weight, and a pharmaceutically acceptable diluent, excipient or carrier, wherein said composition is in the form of a liquid.
22. A composition according to claim 21 wherein the liquid is a viscous or gelatinous liquid.
23. A composition according to claim 21 or claim 22 wherein said composition is in the form of a gel.
24. A composition according to any one of claims 21 to 23 comprising silver nitrate in an amount equal to greater than 50% by weight.