GB2408937A - pH dependent medicinal compositions - Google Patents

Abstract

The present invention provides a medicinal composition comprising water and a pH-dependent gelling or thickening agent, whereby at 30{C and pH about 11 the composition is substantially liquid, and at 30{C and pH about 7 the composition is semi-solid. The invention further provides a thickening or gelling compound for use in a gelling composition as described herein. Alternatively, cationic quaternary nitrogen, phosphonium or sulfonium compounds for use as pH-dependent thickening or gelling agents. The preferred compound is OTs-(CH2)8-1,4-diazabicyclo[2.2.2]octane-(CH2)12.

Description

pH DEPENDENT MEDICINAL COMPOSITIONS

FIELD OF THE INVENTION

This invention relates to medicinal compositions having flow properties that are pH-dependent. The invention also relates to the use of such compositions, for example in wound dressings, and to compounds for preparing and using such compositions.

BACKGROUND OF THE INVENTION

It is desirable to control the condition of a wound to encourage the healing process by maintaining it sufficiently moist so as to absorb or to eliminate the formation of dry crusty tissue in the vicinity of the wound, while also absorbing materials exuded from the wound, including dead leucocytes, epidermal and dermal cells.

At the same time, it is desirable to prevent access to the wound of agents, whether bacterial or fungal, which can lead to infection. Secreting skin wounds, such as decubitus ulcers, venous stasis ulcers, infected traumatic wounds, open surgical wounds and burns have long been a medical problem to keep clean and dry. If blood, serum and purulent matter are allowed to accumulate in the craters and crevices of these wounds, bacterial growth and crusted organic matter will promote infection and delay healing. In addition, secreting skin wounds may lead to anemia, infections, shock and even death through the loss of body proteins, electrolytes, fluids and heat.

Methods used in the past to cover and protect secreting skin wounds have consisted of gauze dressings, nonwoven fabrics, and a variety of other cellulose and synthetic products. Enzyme preparations and other chemical agents have also been used to digest organic secretions from skin ulcers.

More recently, however, it has been proposed to apply a gel material over the wound. A suitable gel material is disclosed in U.S. Pat. No. 4,226, 232. It comprises a hydrolysed copolymer of starch and an acrylonitrile. The polymer is prepared in gel form by mixture with water, to an extent which gives the copolymer an appropriate viscosity which enables it to be manipulated as a gel, especially when applying it to a wound and while it is applied to the wound.

However, all of these approaches have shortcomings related to application, absorption capacities, wound cleaning, body movement, expense and effectiveness.

Therefore, a need has arisen for a wound dressing that can provide control over moisture levels at the wound surface, while also providing an elastic barrier between the body's internal environment and the external environment thereby allowing for body movement without breakage of the barrier between the wound and external environment.

Appropriate properties for a gel, for use as a wound dressing include a viscosity that makes the material capable of being manipulated before administration to a wound and then applied appropriately over the area of the wound, and suitably an ability to absorb exudate from the wound.

SUMMARY OF THE INVENTION

In accordance with a first aspect of the present invention, there is provided a medicinal composition comprising water and a pH-dependent gelling or thickening agent, whereby at 30 C and pH about 11 the composition is substantially liquid, and at 30 C and pH about 7 the composition is semi-solid.

In a further aspect of the present invention, there is provided a thickening or gelling compound for use in a gelling composition as described herein.

The present invention is concerned with pharmaceutically acceptable compositions that generally increase in viscosity and/or gelling as the pH of the composition decreases from alkaline pH to physiological pH. The composition may exhibit a linear or non-linear inversely proportional relationship with pH. The composition may exhibit a linear or non-linear inversely proportional relationship with pH across a portion or the entire range of pH. Suitably, the compositions of the present invention exhibit a viscosity that is linearly or non-linearly inversely related to pH over a pH range of about 3 to 10, suitably 4 to 9, suitably 5 to 8, more suitably in the range of 5.5 to 7.8, more suitably in the range of 6 to 7.5, more suitably in the range of 6.25 to 7.25.

Gelling may be initiated by a specific or in a narrow range of pH. The viscosity may increase sharply at a specific pH or over the narrow range of pH. Where this is the case, the initiation of gelling suitably occurs in the range of physiological pHs exhibited by a typical wound. At a pH outside this range, suitably above this range, suitably substantially no gelling occurs.

The term "semi-solid" encompasses viscous liquids and gels. The term "gel" is used in the usual sense of an aqueous composition that bounces rather than flows at low shear, and that exhibits a gel melting endotherm in DSC.

Suitably, the composition remains substantially ungelled, suitably a water-soluble liquid, at a pH greater than the physiological pH of a typical wound, suitably at a pH of about 8 or more. Suitably, the composition forms a gel at the physiological pH of a wound, typically about 6.5 to about 7.5.

Suitably, the gelling composition remains substantially ungelled, suitably a low viscosity liquid, at a pH of greater than about 8, suitably greater than about 8.2, suitably greater than about 8.5, suitably greater than about 9. On lowering the pH of the composition, the composition becomes relatively viscous or semi-solid compared to the composition when at a pH of greater than about 8.

Suitably, gelling is initiated at a pH of less than about 8, suitably in the range of 8 to 5.5, suitably in the range of 7.8 to 6, suitably in the range of 7.5 to 6.2, suitably in the range of 7.2 to 6.5, suitably less than 7. Suitably, the pH of the gel should lie in a therapeutically desirable range. Suitably the pH of the gel should not be lower than pH 5. 5. The pH may be adjusted, if necessary, in the customary manner, for example, by adding a measured amount of acid or alkali.

Suitably, at a pH of less than about 8, the composition becomes less water-soluble, suitably substantially water-insoluble. Suitably, as pH decreases, the composition becomes decreasingly water-soluble. Suitably, this decreasing solubility is observed in the pH range of 8 to 4 suitably 8 to 5, suitably 8 to 6, suitably 7.75 to 6.25, suitably 7.5to6.5.

Suitably, at a pH of greater than about 8, suitably greater than about 8. 2, suitably greater than about 8.5, suitably greater than about 9, the gelling composition remains fluid and pourable, suitably for more than 1 hour, suitably more than 1 day, suitably more than 1 week. The gelling composition typically has a viscosity of less than 6000 Pas (Pascal Seconds) at pH of 9 or greater, suitably less than 5000 Pas, suitably less than 4000 Pas, for example less than 3000 Pas.

The composition of the present invention suitably has a low viscosity at a pH greater than the physiological pH of a wound. Thus, the composition can be easily manipulated and applied to a number of wound morphologies as it has a viscosity that is relatively low compared to the gelled state. In the ungelled state, the gelling composition may be poured, wiped, spread, etc. such that it may be applied to a wound bed or the area adjacent a wound. The composition at above-physiological pH is suitably of such a viscosity that it can, to some extent, flow or be manipulated if necessary, into the desired position. This low viscosity state (ungelled) is suitably maintained for a period of 10 seconds to 20 minutes, suitably seconds to 10 minutes, suitably 30 seconds to 5 minutes after initial application to the wound. This allows the user to manipulate the composition for a short time after application, thereby allowing repositioning if necessary.

Once the composition is in the desired position, i.e. at or adjacent a wound bed, the physiological pH of the wound bed or adjacent area (including material exuded by the wound) decreases the pH of the composition, thereby effecting thickening or gelling of the composition. Substantially complete thickening or gelling may take place over a period in the order of seconds, minutes or hours, suitably in less than 1 hour, suitably in less than 20 minutes, suitably about 10 minutes.

Gelling or thickening may be effected by wound exudate, and/or by the addition of a pH modifying agent, to the composition prior, during or after application to the wound.

The pH modifying agent is suitably selected from medically acceptable acidic materials. Preferred acidic materials are selected from organic or inorganic protic acids. Preferred acidic materials are selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, for example, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, maleic acid, fumaric acid, pyruvic acid, phenylacetic acid, benzoic acid, 4- hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, ascorbic acid, and combinations or mixtures thereof.

Upon thickening or gelling of the composition, the viscosity suitably increases to greater than about 6000 Pas, suitably greater than about 10000 Pas.

In a preferred embodiment, at a substantially fixed pH, once gelling has been initiated, the addition of solvent, for example, water or an organic solvent such as DMSO, ethanol or ether, causes viscosity of the composition increases. This is particularly evident with water.

The composition will suitably be applied to a wound in a layer of thickness at least about 1mm, suitably at least about 2 mm, suitably at least about 4 mm, for example at least about 5 mm. A dressing applied to certain wounds with this thickness can be left in situ for as much as seven days or more.

The composition of the invention can be administered to a wound in a sachet from which it can be extruded through an opening, formed for example by means of a knife, by the application of pressure to the sachet.

The composition can conveniently be administered to a wound in a syringe, from which it can be extruded in a controlled manner directly onto a wound so that it is appropriately located to ensure that the wetness of the wound is controlled.

The composition can be administered in a porous container such as a pouch or sachet made of a material that is suitably porous to the fluids to be absorbed by the dressing when in place on the wound. Examples of materials that might be suitable for the sachet or pouch include paper based materials and organic materials such as polyamides and polyesters, especially in the form of a non- The composition of the invention can conveniently be applied directly to a wound.

It is envisaged that, in most circumstances, the dressing will be changed after a period of, perhaps, hours or days, according to the condition of the wound, for example about 2 to 3 days (although shorter periods can be appropriate under certain conditions, for example when the amount of material exuding from the wound is high). When the dressing is to be changed, the gel-like characteristics of the composition facilitate its removal from the wound, and which may be assisted by irrigation. In particular, the pH dependent characteristics of the gel composition of the present invention may e used to great advantage ion this regard. By increasing the pH of the gel, for example, by irrigating with an alkali solution, the gel may be rendered soluble, therefore more easily removable.

When gelling takes place, the gel at pH7 and 30 C suitably has an elasticity greater than 300 Newtons/m2 Suitably the elasticity of the gel is less than 3500 Newtons/m2. The elasticity of the gel is suitably in the range of from 500 to 3000 Newtons/m2, suitably the elasticity is in the range of from 1000 to 2500 Newtons/m2, suitably the elasticity of the gel is in the range of from 1500 to 2500 Newtons/m2.

In a further aspect, the present invention provides a compound for use as the thickening or gelling agent in a composition according to the present invention, said compound having the formula (1): A-X (1) wherein: X comprises a group -(R-Vm±R4-R2) q(YP); R is selected from divalent hydrocarbon radicals; V represents a positively charged moiety; m represents an integer; R' is selected from divalent hydrocarbon radicals; R2 is selected from the group consisting of -H. -SH, -F. -Cl, -Br, -I, oR3, HN(o)CR4, or-O(O)CR5, wherein R3, R4 and R5 are independently selected from the group consisting of -H and monovalent hydrocarbon radicals; Y represents an anion; q represents m/pi and, p represents an integer; lS A is selected from the group consisting of -OC(0)-Ra, -C(0)-ORb, -C(0)- NRCRd, - C(S)-NHRC, and-OSO2-Re; Ra is selected from -H and monovalent hydrocarbon radicals; Rb is selected from -H and monovalent hydrocarbon radicals; Rc is selected from -H and monovalent hydrocarbon radicals; Rd is selected from -H and monovalent hydrocarbon radicals; Re is selected from -H and monovalent hydrocarbon radicals; or a pharmaceutically acceptable derivative of a compound of formula (1).

Suitably, A is selected from the group consisting of of-OC(O)-Ra, -C(0)ORb and OSO2-Re.

Suitably, A comprises -OSO2-Re.

Ra, Rb, RC, Rd. Re are suitably independently selected from the group consisting of -H. C' 20 alkyl, C2 20 alkenyl, C2 20 alkynyl, C3 30 cycloalkyl, C3 30 cycloalkenyl, C4 30 cycloalkynyl, C7 30 aralkyl, C7 30 alkaryl and C5 30 aryl.

Ra, Rb, RC, Rd. Re are more suitably independently selected from the group consisting of -H. C,,5 alkyl, C25 alkenyl, C25 alkynyl, C320 cycloalkyl, C320 cycloalkenyl, C4 20 cycloalkynyl, C7 20 araikyl, C7 20 alkaryl and C6 20 aryl.

Ra, Rb, RC, Rd. Re are more suitably independently selected from the group consisting of -H. straight chain C, '0 alkyl, C2 '0 alkenyl, C6 '2 alkaryl and C6 '2 aryl.

Most suitably, Ra, Rb, RC, Rd. Re are independently selected from the group consisting of -H. methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, octyl, nonyl, dodecyl, eicosyl, norbornyl and adamantyl, vinyl, propenyl, cyclohexenyl, benzyl, phenylethyl, phenylpropyl, phenyl, nitrophenyl, tolyl, dimethylphenyl, trimethylphenyl, ethylphenyl, propylphenyl, biphenyl, naphthyl, methyinaphthyl, anthryl, phenanthryl, benzylphenyl, pyrenyl, acenaphthyl, phenalenyl, aceanthrylenyl, tetrahydronaphthyl, indanyl, biphenyl, particularly methyl, ethyl, propyl and isopropyl.

Suitably, when A comprises -OC(0)-Ra, Ra is selected from the group consisting of -H. methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, octyl, nonyl, dodecyl, eicosyl, norbornyl and adamantyl, benzyl, phenylethyl, phenylpropyl, phenyl, nitrophenyl, and tolyl.

Suitably, when A comprises -C(0)-ORb, Rb is selected from the group consisting of -H. methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, octyl, nonyl, dodecyl, eicosyl, norbornyl and adamantyl, benzyl, phenylethyl, phenylpropyl, phenyl, nitrophenyl, and tolyl.

Suitably, -OSO2-Re is selected from alkyl- and arylsulfonates such as mesylate (- OSO2CH3), tosylate (-OSO2-p-C6H4-CH3), triflate (-OSO2CF3), nosylate (- OSO2-p- C6H4-NO2), brosylate (-OSO2-p-C6H4-Br).

R is suitably selected from the group consisting of C' 20 alkanediyl, C2 20 alkenediyl, C2 20 alkynedlyl, C3 30 cycloalkanedlyl, C3 30 cycloalkenediyl, C5 30 cycloalkynedlyl,, C7 30 aralkylenediyl, C7 30 alkarylenediyl and C5 30 arylenedlyl.

R is more suitably selected from the group consisting of C'-6 alkanedlyl, C2,6 alkenediyl, C2,6 alkynediyl, C4 20 cycloalkanediyl, C4 20 cycloalkenedlyl, C5 20 cycloalkynedlyl, C7 20 aralkylenedlyl, C7 20 alkarylenedlyl and C6 20 arylenedlyl.

R is more suitably selected from the group consisting of straight chain C'-6 alkanedlyl, C2 '6 alkenediyl, C6,6 aralkylenedlyl and C6 6 alkarylenedlyl.

Most suitably, R is selected from methylene, 1,2-ethylene, 1,2-propylene, 1,3 propylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 1,5-pentylene, 1, 6-hexylene, 1,8-octylene, 1,10-decylene and 1,12-dodecylene.

Suitably, R has greater than 2 carbon atoms in the chain, suitably 3 to 10, and more suitably 3, 6, 8 or 10.

Suitably, R contains no heteroatoms. Suitably, R contains only saturated carbon atoms.

R' is suitably selected from the group consisting of C' 30 alkanedlyl, C2 30 alkenedlyl, C2 30 alkynediyl, C3 35 cycloalkanediyl, C3 35 cycloalkenediyl, C5 35 cycloalkynediyl, C7 35 aralkylenediyl, C7 35 alkarylenedlyl and C5 35 arylenedlyl.

R' is more suitably selected from the group consisting of C-8 alkanediyl, C2'8 alkenediyl, C2 '8 alkynediyl, C4 20 cycloalkanediyl, C4 20 cycloalkenediyl, C5 20 cycloalkynedlyl, C7 20 aralkylenediyl, C7 20 alkarylenediyl and C6 20 arylenediyl.

R' is more suitably selected from the group consisting of straight chain C'-8 alkanediyl, C2,8 alkenedlyl, C6,8 aralkylenediyl and C6 '8 alkarylenedlyl.

R2 is suitably -H.

Suitably, R4-R2, in combination, form a monovalent hydrocarbon radical selected from the group consisting of straight chain C 20 alkyl, C2 20 alkenyl, C2 20 alkynyl, C3 30 cycloalkyl, C3 30 cycloalkenyl, C4 30 cycloalkynyl, C7 30 aralkyl, C7 30 alkaryl and C5 30 aryl.

Suitably, R'-R2, in combination, form a monovalent hydrocarbon radical selected from the group consisting of straight chain C4-8 alkyl, C41B alkenyl, C4-,8 alkynyl, C6 20 cycloalkyl, C6 20 cycloalkenyl, C6 20 cycloalkynyl, Coo 20 aralkyl, C,0 20 alkaryl and C6 20 aryl.

Suitably, R'-R2, in combination, form a monovalent hydrocarbon radical selected lO from the group consisting of straight chain C,0,8 alkyl, C1O 1B alkenyl, C,0,8 alkaryl and C,0,8 aralkyl.

Suitably, R4-R2, in combination, have greater than 10 carbon atoms in the chain, suitably 10 to 18, and more suitably 10, 12, 14 or 16.

Y suitably represents an anion, or plurality of anions, which may be the same or different, that balance the charge of positively charged moiety V. The anion may be singly charged, in which case p in formula (1) is 1, doubly charged, in which case p in formula (1) is 2, and so on.

Examples of suitable anions, Y. include, N-hydroxysuccinimidyl, Nhydroxybenzotriazolyl, nitrate, sulfate, bisulfate, phosphate (mono-, bi-, or triphosphate), carbonate, bicarbonate, acetate, tosylates, mesylates, brosylates, and halides including chloride, bromide, and iodide, and mixtures thereof.

Suitably, m is an integer of 1, 2, 3, 4, 5 or 6. Suitably, p is an integer of 1, 2, 3, 4, 5 or 6. Suitably, m is 1, 2 or 3, suitably 1 or 2. Suitably p is 1, 2 or 3, suitably 1 or 2.

Suitably, the overall charge of the compound of formula (1) is neutral, therefore, for example, when m = 2 and p = 1, q = 2. Alternatively, for example, when m = 2 and p = 2, q = 1. Alternatively, for example, when m = 1 and p = 1, q = 1. Alternatively for example, when m = 1 and p = 2, q = 1/. Alternatively for example, when m = 3 and p = 2, q = 3/2. Alternatively for example, when m = 2 and p = 3, q = 2/3.

A mixture of anions may be employed, having a mixture of charges. Thus, for any particular tri-cationic moiety V (m = 3), Y may be, for example, Cl- and CO32-. Thus, the overall negative charge contributed by the anions, Y. for that V moiety is -3. In this case, q is 2, and p is 1 and 2 for Cl- and CO32- respectively.

Where there is more than one anion, Y. in a compound of formula (1) and/or where q = 2 or more, Y may be the same or different, suitably the same.

R3, R4 and R5 are suitably independently selected from the group consisting of -H.

Cat 20 alkyl, C220 alkenyl, C220 alkynyl, C330 cycloalkyl, C330 cycloalkenyl, C430 cycloalkynyl, C7 30 aralkyl, C7 30 alkaryl and C5 30 aryl.

R3, R4 and R5 are more suitably independently selected from the group consisting of -H. C, ,5 alkyl, C2,5 alkenyl, C2 '5 alkynyl, C3 20 cycloalkyl, C3 20 cycloalkenyl, C4 20 cycloalkynyl, C7 20 aralkyl, C7 20 alkaryl and C6 20 aryl.

R3, R4 and R5 are more suitably independently selected from the group consisting of -H. straight chain C, O alkyl, C2,0 alkenyl and C6 '2 aryl.

Most suitably, R3, R4 and R5 are independently selected from the group consisting of-H, methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, octyl, nonyl, dodecyl, eicosyl, norbornyl and adamantyl, vinyl, propenyl, cyciohexenyl, benzyl, phenylethyl, phenylpropyl, phenyl, tolyl, dimethylphenyl, trimethylphenyl, ethylphenyl, propylphenyl, biphenyl, naphthyl, methyinaphthyl, anthryl, phenanthryl, benzylphenyl, pyrenyl, acenaphthyl, phenalenyl, aceanthrylenyl, tetrahydronaphthyl, indanyl, biphenyl, particularly methyl, ethyl, propyl and isopropyl.

V in formula (1) represents a positively charged moiety. The positively charged moiety may, for example, be a singly or a doubly charged moiety. In some compounds, V may comprise 3, 4, 5 or 6 positive charges. In a singly charged moiety, m in formula (1) represents 1. In a doubly charged moiety, m represents 2.

The singly or doubly charged moiety may, for example, comprise one or two positively charged nitrogen atoms, one or two positively charged phosphorous atoms, one or two positively charged sulfur atoms, or mixtures thereof, suitably nitrogen atoms.

In one embodiment, the positively charged moiety comprises a singly charged quaternary ammonium, quaternary phosphonium or sulfonium group, having the formula ±NR62-, ±PR72-, or ±SR8-, respectively, wherein R6, R7 and R8 are independently selected from the group consisting of -H and monovalent hydrocarbon radicals.

R6, R7 and R8 are suitably independently selected from the group consisting of -H.

C'20 alkyl, C220 alkenyl, C220 alkynyl, C330 cycloalkyl, C330 cycloalkenyl, C430 cycloalkynyl, C7 30 aralkyl, C7 30 alkaryl and C5 30 aryl.

R6, R7 and R8 are more suitably independently selected from the group consisting of -H. C, 45 alkyl, C2,5 alkenyl, C2,5 alkynyl, C3 20 cycloalkyl, C3 20 cycloalkenyl, C4 cycloalkynyl, C7 20 aralkyl, C7 20 alkaryl and C6 20 aryl.

R6, R7 and R8 are more suitably independently selected from the group consisting of -H. straight chain C, ,O alkyl, C2 '0 alkenyl and C6,2 aryl.

Most suitably, R6, R7 and R8 are independently selected from the group consisting of methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, octyl, nonyl, dodecyl, eicosyl, norbornyl and adamantyl, vinyl, propenyl, cyclohexenyl, benzyl, phenylethyl, phenylpropyl, phenyl, tolyl, dimethylphenyl, trimethylphenyl, ethylphenyl, propylphenyl, biphenyl, naphthyl, methyinaphthyl, anthryl, phenanthryl, benzylphenyl, pyrenyl, acenaphthyl, phenalenyl, aceanthrylenyl, tetrahydronaphthyl, indanyl, biphenyl, particularly methyl, ethyl, propyl and isopropyl.

In the quaternary ammonium ions, the two R6 groups on the N atom may be the same, or different. Suitably, both R6 groups represent methyl or ethyl.

In the quaternary phosphonium ions, the two R7 groups on the P atom may be the same, or different. Suitably, both R7 groups represent methyl or ethyl.

In a preferred embodiment, positively charged moiety V comprises two positively charged nitrogen atoms, such as, for example, -+NR62-R9-NR62+or a group (B): fCH2)a -N\CH2N (B) (CH2)b wherein a, b and c independently represent 1-10, suitably, 1-5, more suitably 1-3, most suitably 2. Suitably, a = b = c. In a particularly preferred embodiment, (B) is the dication of 1,4- diazoniabicyclo[2.2.2]octane.

In another embodiment, V comprises two positively charged sulfur atoms, such as, for example, -+SR8-R40-SR8+ or a group (C) (CH2)d -S\ /S- (C) (CH2)e wherein d and e independently represent 1-10, suitably, 1-5, more suitably 1-3, most suitably 2. Suitably, a = b = c. In a particularly preferred embodiment, (C) is the dication of 1,4- dithioniumcyclohexane.

In another embodiment, V comprises two positively charged phosphorus atoms, such as, for example, -+PR72-R9-PR72±, or a group (D).

(cH2)a _ p(CH2 p_. (D) (CH2)b wherein a, b and c independently represent 1-10, suitably, 1-5, more suitably 1-3, most suitably 2. Suitably, a = b = c. In a particularly preferred embodiment, (D) is the dication of 1,4diphosphoniabicyclo[2.2.2]octane.

In these embodiments, R6, R7 and R8 are as defined above, and R9, R9 and R' are suitably independently selected from the group consisting of C, 20 alkanedlyl, C2 20 alkenedlyl, C2 20 alkynediyl, C3 30 cycloalkanedlyl, C3 30 cycloalkenediyl, C5 30 cycloalkynedlyl, C7 30 aralkylenedlyl, C7 30 alkarylenediyl and C5 30 arylenediyl.

JO R9, R9 and R' are more suitably independently selected from the group consisting of C-6 alkanedlyl, C2,6 alkenedlyl, C2,6 alkynediyl, C420 cycloalkanedlyl, C420 cycloalkenediyl, C520cycloalkynediyl, C720aralkylenediyl, C720alkarylenediyl and C6 20 arylenedlyl.

R9, R9 and R' are more suitably independently selected from the group consisting of straight chain C,-,6 alkanedlyl, C2,6 alkenedlyl, C6,6 aralkylenedlyl and C6,6 alkarylenedlyl.

Most suitably, R9, R9 and R' are independently selected from methylene, 1,2 ethylene, 1,2-propylene, 1,3-propylene, 1,2-butylene, 1,3-butylene, 1, 4-butylene, 1,5-pentylene, 1,6-hexylene, 1,8-octylene, 1,10-decylene and 1,12- dodecylene.

When V comprises -+PR72-R9-PR72±, each R7 is suitably phenyl and R9 is suitably ethyl, propyl or butyl.

In a particularly preferred embodiment, the compound of formula (1) comprises A (R-Vm±R4-R2) wherein A, R. V, m, R' and R2 are as defined above. Suitably, A-(R-Vm±R'-R2) comprises the structure: (CH2)a A-(CH2)h -- N(CH2 N-(CH2)CH3 (CH2)b wherein A is selected from the group consisting of -OC(0)-Ra, -C(0)-ORb and OSO2-Re; wherein Ra, Rb and Re are as defined above; h represents 1-10; a, b, and c are as defined above; and, i represents 7-17.

More suitably, A-(R-Vm±R'-R2) has the structure: +/ \+ A-(CH2)h N: IN (CH2)iCH3 wherein A is selected from the group consisting of -OC(0)-Ra, C(0)-ORb and OSO2-Re; wherein Ra, Rb and Re are as defined above; h represents 3-10; and, i represents 1 1, 15 or 17.

The compound having formula (1) may be used in a gelling composition as described herein. Suitably, the compounds having the formula (1) exhibit some or all of the pH dependent properties described for the gelling composition of the invention.

The composition according to the present invention may comprise one or a plurality of compounds having the formula (1). In such a composition, each compound having the formula (1) may be the same or different. In particular, for each compounds having the formula (1) in a gelling composition, the definitions of A, R. V, m, R4, R2, Y. q, and p are independently selected and may be the same or different.

In a further aspect of the present invention there is provided a process for the preparation of a compound having formula (2): (R2-R'-Vm+) q(YP) (2) wherein: V, R', R2, m, p, q and Y are as defined above; comprising reacting a compound having the formula V', wherein V' is a precursor to a positively charged moiety V, as defined above; with a compound having the formula (3) R4-R2-L (3) wherein; L is a leaving group.

V' is suitably a group that may be oxidised to form a mono- or polycationic moiety V. Suitably, V' is 1,4-diazoniabicyclo[2.2.2]octane or a derivative thereof.

The term "leaving group" generally refers to groups readily displaceable by a nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N- hydroxybenzotriazole, nitrate, sulfate, bisulfate, phosphate (mono-, hi-, or triphosphate), carbonate, bicarbonate, acetate, tosylates, mesylates, brosylates, and halides including chloride, bromide, and iodide. Suitably, L is a halide, suitably chloride.

The process to produce (2) is suitably carried out in a suitable solvent. The solvent may comprise one or more organic solvents. Suitable organic solvents include aliphatic, alicyclic and aromatic hydrocarbon solvents such as hexane, pentane, cyclohexane, xylene, benzene and toluene; ether type solvents such as diethyl ether, tetrahydrofuran, diphenyl ether, anisole and dimethoxybenzene; halogenated hydrocarbon solvents such as methylene chloride, chloroform and chlorobenzene; ketone type solventssuch as acetone, methyl ethyl ketone and methyl isobutyl ketone; alcohol type solvents such as methanol, ethanol, propanol, isopropanol, n-butyl alcohol and tert-butyl alcohol; nitrile type solvents such as acetonitrile, propionitrile and benzonitrlie; ester type solvents such as ethyl acetate and butyl acetate; carbonate type solvents such as ethylene carbonate and propylene carbonate; and mixtures thereof. Preferred solvents are selected from the group consisting of ester type solvents. Suitably the solvent comprises ethyl acetate. Suitably the solvent is substantially anhydrous.

The process to produce (2) is suitably carried out at a temperature of 50 C to 250 C, suitably greater than 0 C, suitably greater than 1 0 C, suitably about 25 C.

The process to produce (2) is suitably carried out for a period of between 10 minutes and 10 days, suitably greater than 1 hour, suitably between 2 hours and 5 days, l O suitably between 2 and 3 days.

In a further aspect of the present invention there is provided a process for the preparation of a compound having formula (4): (R2-R'-Vm±RZ) q(YP) (4) wherein: R', R2, V, R. m, p, q and Y are as defined above; and Z is selected from the group consisting of -C(0)0H or- OH; comprising reacting a compound having the formula (2) with a compound having the formula (5) Z-R-L1 (5) wherein; Z is as defined above; R is as defined above; and, L' is a leaving group.

L' is suitably selected from the same group as defined for L above.

The process to produce (4) is suitably carried out in a suitable solvent. The solvent may comprise one or more organic solvents. Suitable organic solvents include aliphatic, alicyclic and aromatic hydrocarbon solvents such as hexane, pentane, cyclohexane, xylene, benzene and toluene; ether type solvents such as diethyl ether, tetrahydrofuran, diphenyl ether, anisole and dimethoxybenzene; halogenated hydrocarbon solvents such as methylene chloride, chloroform and chlorobenzene; ketone type solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; alcohol type solvents such as methanol, ethanol, propanol, isopropanol, n-butyl alcohol and tert-butyl alcohol; nitrile type solvents such as acetonitrile, propionitrile and benzonitrile; ester type solvents such as ethyl acetate and butyl acetate; carbonate type solvents such as ethylene carbonate and propylene carbonate; and mixtures thereof. Preferred solvents are selected from the group consisting of nitrile type solvents such as acetonitrile, propionitrile and benzonitrile. Suitably the solvent comprises acetonitrile. Suitably the solvent is substantially anhydrous.

The process to produce (4) is suitably carried out at a temperature of 10 C to 250 C, suitably greater than 20 C, suitably greater than 30 C, suitably greater than 40 C.

The process to produce (4) is suitably carried out for between 10 minutes and 10 days, suitably greater than 1 hour, suitably between 2 hours and 5 days, suitably between 1 and 2 days.

In a further aspect of the present invention there is provided a process for the preparation of a compound having formula (1) as defined above; comprising reacting a compound having the formula (4), with a compound having the formula (6) RX L2 (6) wherein; Rx is selected from the group consisting of -ORa, -ORb, -OC(0)Ra, -OC(0)Rb and SO2-Re; Wherein Ra, Rb and Re are as defined above; and, L2 is a leaving group or H. L2 is suitably selected from the same group as defined for L above.

The process to produce (1) is suitably carried out in the presence of a basic compound. Organic or inorganic basic compounds may be used. For example, the Group I and Group II metal hydroxides, carbonates and bicarbonates are preferred, in particular CaCO3, NaCO3, NaHCO3, NaOH and KOH. Bicarbonates are particularly preferred. NaHCO3 is most preferred.

The process to produce (1) is suitably carried out in a suitable solvent. The solvent may comprise water and/or one or more organic solvents. Suitable organic solvents include aliphatic, alicyclic and aromatic hydrocarbon solvents such as hexane, pentane, cyclohexane, xylene, benzene and toluene; ether type solvents such as diethyl ether, tetrahydrofuran, diphenyl ether, anisole and dimethoxybenzene; halogenated hydrocarbon solvents such as methylene chloride, chloroform and chlorobenzene; ketone type solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; alcohol type solvents such as methanol, ethanol, propanol, isopropanol, n-butyl alcohol and tert-butyl alcohol; nitrile type solvents such as acetonitrile, propionitrile and benzonitrile; ester type solvents such as ethyl acetate and butyl acetate; carbonate type solvents such as ethylene carbonate and propylene carbonate; and mixtures thereof. Particularly preferred solvents include water and/or alcohol(s).

The process to produce (1) is suitably carried out at a temperature of 0 C to 100 C, suitably greater than 1 0 C, suitably greater than 20 C, suitably about 25 C.

The process to produce (1) is suitably carried out for between 10 minutes and 48 hours, suitably greater than 30 minutes, suitably between 2 and 8 hours, suitably between 3 and 6 hours.

The above processes may be carried out separately or in combination, to provide an intermediate (2) or (4), or to provide a compound (1).

For the specific purposes of this invention, the components suitably, collectively, retain the following characteristics: hydrophylia, nontoxicity, sterilizability and inertia at normal body temperatures to skin.

The present invention is concerned with providing anti-microbial compositions, compounds and processes for the production thereof. More particularly, the present invention suitably provides anti-microbial wound dressing materials.

The bacteria include both gram positive and gram negative bacteria. Some examples of Gram positive bacteria include, for example. Bacillus cereus. Micrococcus luteus, and Staphylococus aureus. Some examples of Gram negative bacteria include, for example, Eschenchia colt, Enterobacter aerogenes, Enterobacter cloacae, Proteus vulgaris and Pseudomonas aeringosa. Strains of yeast include, for example, Saccharomyces cerevisiae, Candida and Aspergillus.

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a composition or compound of the present invention in combination with a pharmaceutically acceptable excipient.

According to a further aspect of the present invention there is provided a method of preparing a pharmaceutical composition comprising the step of combining a compound of the present invention with a pharmaceutically acceptable excipient.

The compositions and compounds of the present invention may be used in a method of medical treatment, of the human or animal body, by way of therapy.

The compositions and compounds of the present invention may be used in a method of preparing a medicament, used in the treatment of bacterial infection.

The present invention further provides a method of treating a patient for bacterial infection, comprising administering a therapeutically effective amount of a composition or compound according to the present invention.

The compositions and compounds of the present invention are suitably used in the manufacture of anti-microbial materials. The compounds of formula (1) are suitable for manufacturing objects, such as clothing, bandages, sutures, protective gear, containers, and the like. s

The present invention provides improved wound dressing materials for mammalian wounds, and especially for human, chronic wounds, such as venous ulcers, decubitis ulcers and diabetic ulcers. Such chronic wounds generally exhibit little or no bleeding or adhesion to other body tissues.

Compositions, compounds and materials according to the present invention may also comprise one or more structural proteins selected from the group consisting of fibronectin, fibrin, laminin, elastin, collagen and mixtures thereof. Suitably the protein comprises collagen, and more suitably it consists essentially of collagen.

Compositions and materials manufactured from a compound according to the present invention may also comprise 0-10% by weight, suitably 0-5% by weight of one or more therapeutic agent. Any of the following kinds of biologically active substances can be included in the gel composition: medications and disinfectants as well as wound healing enhancers, e.g., a vitamin preparation, blood coagulants for battlefield applications, antiinflammatory drugs, angiogenesis promoters, antiseptic compounds, antibiotic compounds, or a source of oxygen. Among other biologically active substances are astringents, oxidants, proteolytic enzymes, collagen cross-link inhibitors such as natural or synthetic diamines, e.g. , cystamine or histadine, putrescine, spermidine, cadaverine, alpha, omega diamino polyethylene or polypropylene oxide and the like, various growth factors, amino acids, macrophage stimulating factors, narcotic analgesics, anesthetics, and the like. All of the above percentages are on a dry weight basis.

Preferred biologically active substances which can be included in the gel composition includes anti-inflammatory drugs, in particular NSAIDs, steroids and antibodies.

Examples of NSAIDs include sulindac, sulindac sulfide, sulindac sulfone, aspirin, indomethacin, ibuprofen, meclofenamic acid, flurbiprofen, naproxen, ketrolac tromethamine, diclofenac sodium, suprofen and piroxicam.

Examples of steroid drugs include dexamethasone, budesonide, beclomethasone, flucticasone, tioxocortol, cortisone, prednisolone, prednisone, and hydrocortisone In addition to the aforementioned components, the present invention can also include additives which further enhance its utility. Examples of such additional components include, but are not limited to: crevice fillers, and medicaments which specifically fortify the protective gel as a barrier against infectious carriers (e.g., anti-bacterial and anti-viral agents). The concentrations of such fillers and medicaments in the present composition will vary depending upon the particular additive employed, but in all instances will be an amount effective for the intended 1 5 purpose.

It is also possible to modify the compositions of the present invention to influence the release profiles of the therapeutic agents discussed above. For example it is possible to co-deliver the compositions of the present invention with a low pH buffer (for example, a pH of 5 or 6) which causes a fast onset of gelling and have a slower release rate of the therapeutic agent.

It may be appropriate for a secondary dressing to be applied over the gel composition wound dressing, to retain it in place on a wound and to provide a degree of physical protection for the gel dressing. The nature of the secondary dressing will depend on the characteristics of the wound. For example, if the wound has eschar (dry crusty tissue) associated with it, a moisture vapour permeable dressing may be appropriate. If the wound is malodorous, an activated carbon dressing may be appropriate.

An appropriate secondary dressing can suitably exclude bacteria from the wound, retain the dressing material in place on the wound, and permit exchange of moisture with the atmosphere. Suitably, the dressing is transparent so that the The gel composition of the present invention is easy to ship and mix. It may also be easy to apply and use. It is suitably supple, elastic, relatively transparent pliable, soft, semi- solid and conforms naturally to the contours of the wound. The dressing is suitably non-irritating, suitably has no odor and suitably promotes healing. The dressing will remain in place after application but can be easily removed when required.

Where the wound dressing of the present invention contains a gel, the elasticity of the gel is such that the gel may be readily applied to the wound and yet not flow out. Thus the physical properties of the gel are such that it easily reaches into wound cavities and crevices and thus comes into intimate contact with the area to be treated. This feature not only ensures that all areas to be treated come into contact with the gel but it also reduces or in some cases eliminates the pain experienced by the patient during application and removal of the gel from the

wound as compared to prior art gel dressings.

In those embodiments of the invention where the gel is the sole component of the dressing, the gel should suitably have an elasticity greater than 300 Newtons/m2 Suitably the elasticity of the gel is less than 3500 Newtons/m2. The elasticity of the gel is suitably in the range of from 500 to 3000 Newtons/m2, suitably the elasticity is in the range of from 1000 to 2500 Newtons/m2, suitably the elasticity of the gel is in the range of from 1500 to 2500 Newtons/m2.

In those embodiments of the invention where the dressing comprises additional components to the gel, eg. a backing material as hereinafter described, the gel may have an elasticity greater than 300 Newtons/m2. Suitably the elasticity of the gel may be less than 13,000 Newtons/m2.

Suitably, the wound dressing further comprises a backing sheet extending over the active layer opposite to the wound facing side of the active layer. Suitably, the backing sheet is larger than the active layer such that a marginal region of width 1mm to 50 mm, suitably 5mm to 20mm extends around the active layer to form a so-called island dressing. In such cases, the backing sheet is suitably coated with a pressure sensitive medical grade adhesive in at least its marginal region. s

Suitably, the backing sheet is substantially liquid-impermeable. The backing sheet is suitably semipermeable. That is to say, the backing sheet is suitably permeable to water vapour, but not permeable to liquid water or wound exudate. Suitably, the backing sheet is also microorganismimpermeable. Suitable continuous conformable backing sheets will suitably have a moisture vapor transmission rate (MVTR) of the backing sheet alone of 300 to 5000 gim2124hrs, suitably 500 to 2000 gim2124hrs at 37.5 C at 100% to 10% relative humidity difference. The backing sheet thickness is suitably in the range of 10 to 1000 micrometers, more suitably 100 to 500 micrometers.

The MVTR of the dressing according to the present invention as a whole is lower than that of the backing sheet alone, because the apertured sheet partially obstructs moisture transfer through the dressing. Suitably, the MVTR of the dressing (measured across the island portion of the dressing) is from 20% to 80% of the MVTR of the backing sheet alone, more suitably from 20% to 60% thereof, and most suitably about 40% thereof. It has been found that such moisture vapor transmission rates allow the wound under the dressing to heal under moist conditions without causing the skin surrounding the wound to macerate.

Suitable polymers for forming the backing sheet include polyurethanes and poly alkoxyalkyl acrylates and methacrylates such as those disclosed in GB-A- 1280631. Suitably, the backing sheet comprises a continuous layer of a high density blocked polyurethane foam that is predominantly closed-cell. A suitable backing sheet material is the polyurethane film available under the Registered Trade Mark ESTANE 5714F.

The adhesive (where present) layer should be moisture vapor transmitting and/or patterned to allow passage of water vapor therethrough. The adhesive layer is suitably a continuous moisture vapor transmitting, pressure-sensitive adhesive layer of the type conventionally used for island-type wound dressings, for example, a pressure sensitive adhesive based on acrylate ester copolymers, polyvinyl ethyl ether and polyurethane as described for example in GB-A-1280631. The basis weight of the adhesive layer is suitably 20 to 250 g/m2, and more suitably 50 to g/m2. Polyurethane-based pressure sensitive adhesives are preferred.

Further layers of a multilayer absorbent article may be built up between the active layer and the protective sheet.

The dressing may further comprise an absorbent layer between the active layer and the protective sheet, especially if the dressing is for use on exuding wounds.

The optional absorbent layer may be any of the layers conventionally used for absorbing wound fluids, serum or blood in the wound healing art, including gauzes, nonwoven fabrics, superabsorbents, hydrogels and mixtures thereof.

Suitably, the absorbent layer comprises a layer of absorbent foam, such as an open celled hydrophilic polyurethane foam prepared in accordance with EP-A 0541 391, the entire content of which is expressly incorporated herein by reference. In other embodiments, the absorbent layer may be a nonwoven fibrous web, for example a carded web of viscose staple fibers. The basis weight of the absorbent layer may be in the range of 50-500g/m2, such as 100-40Og/m2. The uncompressed thickness of the absorbent layer may be in the range of from 0.5mm to 10mm, such as 1mm to 4mm. The free (uncompressed) liquid absorbency measured for physiological saline may be in the range of 5 to 30 g/9 at 25 C. In another aspect, the present invention provides a method of treatment of a chronic wound in a mammal, such as a decubitis ulcer, a venous ulcer or a diabetic ulcer. The method comprises applying a dressing as defined above to the wound.

Suitably, the dressing is applied to the chronic wound for a period of at least 1 hour, more suitably at least 6 hours, and most suitably at least 12 hours. The treatment may be extended for several days or weeks, with dressing changes as appropriate, if necessary for chronic wounds.

As used herein, the term "divalent hydrocarbon radicals" refers to any straight chain, branched, cyclic, acyclic, heterocylic, saturated or unsaturated diradical, which contains a carbon backbone comprising one or more hydrogen atoms, optionally substituted with one or more heteroatoms in or on the carbon backbone.

The term "divalent hydrocarbon radical" is intended to encompass the terms "alkanedlyl", "alkenediyl", "alkynediyl", "cycloalkanedlyl", "cycloalkenediyl", "cycloalkynediyl", "arylenedlyl", "araikylenediyl" and "alkarylenediyl" as defined below.

The term "alkanedlyl" refers to a straight or branched saturated divalent hydrocarbon radical having the number of carbon atoms indicated, optionally substituted with one or more heteroatoms in or on the carbon backbone.

The terms "alkenedlyl" and "alkynedlyl" refer to straight or branched, unsaturated divalent hydrocarbon radicals, optionally substituted with one or more heteroatoms in or on the carbon backbone. An "alkenedlyl" is characterized by a carbon carbon double bond and an "alkynediyl" is characterized by a carbon-carbon triple bond.

The term "cycloalkanediyl" refers to a cyclic saturated divalent hydrocarbon radical having the number of carbon atoms indicated, optionally substituted with one or more heteroatoms in or on the carbon backbone.

The terms "cycloalkenedlyl" and "cycloalkynediyl" refer to cyclic unsaturated divalent hydrocarbon radicals, optionally substituted with one or more heteroatoms in or on the carbon backbone. A "cycloalkenediyl" is characterized by a carbon carbon double bond and a "cycloalkynediyl" is characterized by a carbon-carbon triple bond.

The term "arylenedlyl" refers to a divalent unsaturated aromatic carbocyclic radical having one or two rings, optionally substituted with one or more heteroatoms in or on the carbon backbone.

The term "alkarylenedlyl" refers to a divalent unsaturated mono- or dialkyl- substituted aromatic carbocyclic radical having one or two rings, optionally substituted with one or more heteroatoms in or on the carbon backbone. Binding is through the arylene group.

The term "aralkylenediyl" refers to a divalent unsaturated mono- or dialkyl- substituted aromatic carbocyclic radical having one or two rings, optionally substituted with one or more heteroatoms in or on the carbon backbone. Binding is through the alkylene group.

As used herein, the term "monovalent hydrocarbon radicals" refers to any straight chain, branched, cyclic, acyclic, heterocylic, saturated or unsaturated radical, which contains a carbon backbone comprising one or more hydrogen atoms, optionally substituted with one or more heteroatoms in or on the carbon backbone.

The term "monovalent hydrocarbon radical" is intended to encompass the terms "alkyl", "alkenyl", "alkynyl", "cycloalkyl", "cycloalkenyl", "cycloalkynyl", "alkaryl", "aralkyl" and "aryl" as defined below.

As used herein, the term "alkyl" refers to a straight or branched saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, optionally substituted with one or more heteroatoms in or on the carbon backbone.

As used herein, the term "alkenyl" refers to a straight or branched unsaturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, optionally substituted with one or more heteroatoms in or on the carbon backbone, and the distinguishing feature of a carboncarbon double bond.

As used herein, the term "alkynyl" refers to a straight or branched unsaturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, optionally substituted with one or more heteroatoms in or on the carbon backbone, and the distinguishing feature of a carboncarbon triple bond.

As used herein, the term "cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, optionally substituted with one or more heteroatoms in or on the carbon backbone.

As used herein, the terms "cycloalkenyl" and "cycloalkynyl" refer to cyclic unsaturated monovalent hydrocarbon radicals, optionally substituted with one or more heteroatoms in or on the carbon backbone. A "cycloalkenyl" is characterized by a carbon-carbon double bond and a "cycloalkynyl" is characterized by a carbon- carbon triple bond.

As used herein, the term "aryl" refers to a monovalent unsaturated aromatic carbocyclic radical having one or two rings, optionally substituted with one or more heteroatoms in or on the carbon backbone, such as phenyl, naphthyl, indanyl or biphenyl, or to a monovalent unsaturated aromatic heterocyclic radical, optionally substituted with one or more heteroatoms in or on the carbon backbone, such as quinolyl, dihydroisoxazolyl, furanyl, imidazolyl, pyridyl, phthalimido, thienyl, thiophenyl, pyrrolyl and the like. Exemplary heterocyclic radicals include pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7 azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, napthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyi, isochromanyl and carbolinyl.

As used herein, the term "alkaryl" refers to an aryl group with an alkyl substituent.

Binding is through the aryl group. Such groups have the number of carbon atoms as indicated, and may be substituted with one or more heteroatoms in or on the carbon backbone.

As used herein, the term "aralkyl" refers to an alkyl group with an aryl substituent, where binding is through the alkyl group. Such groups have the number of carbon atoms as indicated, and may be substituted with one or more heteroatoms in or on the carbon backbone.

As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

As used herein, the term "heteroatom" includes N. O. S. P. Si and halogen (including F. Cl, Br and 1).

By "a pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, ester or salt of such ester or any other compound which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound (1).

Pharmaceutically acceptable salts are generally acid addition salts, which are suitably such of therapeutically acceptable inorganic or organic acids, such as strong mineral acids, for example hydrohalic. Preferred salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic or aromatic carboxylic or sulfonic acids, for example, formic acid, acetic acid, propionic acid, succinic acid, glycollic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, maleic acid, fumaric acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid and ascorbic acid. For compounds having a free carboxy group, pharmaceutically acceptable salts are also derived from bases, for example, alkali metal salts, such as the sodium salt, or salts derived from pharmaceutically

acceptable amines.

The invention will now be described with reference to the following Examples. It will be appreciated that what follows is by way of example only and that to modifications to detail may be made whilst still falling within the scope of the invention.

EXAMPLES

1. Preparation of OTs-(CH2)8-1,4-diazabicyclo[2.2.2]0ctane-(CH2)12 (3): i. 1-bromododecane (200 g) is added to a solution of 1,4 Diazabicyclo[2.2.2] octane (dabco, 1 equivalent) in 800 mL ethyl acetate. The concentration is 0.25 M. The reaction mixture is left to stir at room temp for 2-3 days. The resultant white precipitate is collected by suction filtration, washed with ethyl acetate (3x50 mL) and dried to produce compound (1), 1, 4 diazabicyclo[2.2.2]0ctane-(CH2), 2 ii. Alkylation of (1): Compound (1) is heated and dissolved in acetonitrile (800 mL). 8-chloro-1-octanol (1 equivalent) is added with stirring and the reaction mixture is left to stir at low heat for 1-2 days. The concentration is 0.75 M. The resultant precipitate is collected by suction filtration, washed with acetonitrile (3x50 mL) and dried to produce compound (2), HO-(CH2)8-1,4-d iazabicyclo[2.2.2]octane-(CH2)'2.

iii. Tosylation of (2): (2) is added with stirring to a solution of p-toluenesulfonyl chloride in saturated sodium bicarbonate. The mixture is allowed to stir for 3-6 hours at room temp.

The resultant material is a viscous gel and volatiles are evaporated under reduced pressure, then dried under high vacuum. The final gelled material collected is (3).

Claims (55)

1. A medicinal composition comprising water and a pH-dependent gelling or thickening agent, whereby at 30 C and pH about 11 the composition is substantially liquid, and at 30 C and pH about 7 the composition is semisolid.

2. A composition according to claim 1, wherein the composition is semisolid in the pH range of from about 6 to about 8.

3. A composition according to claim 1 or claim 2, wherein the semi-solid composition is a gel.

4. A composition according to claim 1 or claim 2, wherein the semi-solid composition is a viscous liquid.

5. A composition according to claim 4, wherein the viscous liquid has a viscosity of at least about 1 OOOOPas at 30 C and pH 7.

6. A composition according any preceding claim, wherein the composition is substantially liquid at a pH of about 10.

7. A composition according to any preceding claim, wherein the composition is a liquid having a viscosity of less than about 6000Pas at 30 C at a pH of 11.

8. A composition according to any preceding claim, wherein the composition is anti-microbial.

9. A composition according to any preceding claim, further comprising a therapeutic agent.

10. A composition according to claim 9, wherein the therapeutic agent is selected from the group consisting of antiseptics such as colloidal silver, silver sulfadiazine, povidone iodine and chlorhexidine, antibiotics, analgesics, steroids, growth factors, anti-inflammatory drugs, angiogenesis promoters and mixtures thereof.

11. A composition according to any preceding claim, further comprising a pH buffer.

12. A composition according to any preceding claim, wherein the buffer is selected to buffer the composition to a pH of from about 9 to about 12.

to

13. A composition according to any preceding claim, wherein the composition comprises by weight from about 49% to about 99% of water, from about 1% to about 25% of the gelling or thickening agent, from 0% to about 5% of said therapeutic agents, and from 0% to about 50% of humectants

14. A composition according to any preceding claim, wherein the composition is sterile and packaged in a microorganism-impermeable container.

15. A wound dressing consisting essentially of a composition according to any preceding claim.

16. Use of a composition according to any one of claims 1 to 14 for the preparation of a dressing for the treatment of wounds.

17. A compound for use as a pH-dependent thickening or gelling agent in a composition according to any of claims 1 to 13, said compound having formula (1): A-X (1) wherein: X comprises a group -(R-Vm±R4-R2) q(YP-); R is selected from divalent hydrocarbon radicals; V represents a positively charged moiety; m represents an integer; R' is selected from divalent hydrocarbon radicals; R2 is selected from the group consisting of -H. -SH, -F. -Cl, -Br, -I, - oR3, - HN(o)CR4, or-O(O)CR5, wherein R3, R4 and R5 are independently selected from the group consisting of -H and monovalent hydrocarbon radicals; Y represents an anion; q represents m/pi and, p represents an integer; A is selected from the group consisting of -OC(0)-Ra, -C(0)-ORb, -C(0)-NRCRd, C(S)-NHRC, and-OSO2-Re; Ra is selected from -H and monovalent hydrocarbon radicals; Rb is selected from -H and monovalent hydrocarbon radicals; Rc is selected from -H and monovalent hydrocarbon radicals; Rd is selected from -H and monovalent hydrocarbon radicals; Re is selected from -H and monovalent hydrocarbon radicals; or a pharmaceutically acceptable derivative of a compound of formula (1).

18. A compound according to claim 17, wherein A is selected from the group consisting of of-OC(O)-Ra, -C(0)-ORb and -OSO2-Re, suitably, A comprises OSO2-Re.

19. A compound according to claim 17 or claim 18, wherein Ra, Rb, RC, Rd. Re are independently selected from the group consisting of -H. C, 20 alkyl, C2 20 alkenyl, C2 20 alkynyl, C3 30 cycloalkyl, C3 30 cycloalkenyl, C4 30 cycloalkynyl, C7 30 aralkyl, C7 alkaryl and C5 30 aryl.

20. A compound according to any of claims 17 to 19, wherein Ra, Rb, RC, Rd. Re are independently selected from the group consisting of -H. C,5 alkyl, C25 alkenyl, C2,5 alkynyl, C3 20 cycloalkyl, C3 20 cycloalkenyl, C4 20 cycloalkynyl, C7 20 aralkyl, C7 20 alkaryl and C6 20 aryl.

21. A compound according to any of claims 17 to 20, wherein Ra, Rb, RC, Rd. Re are independently selected from the group consisting of -H. straight chain C' O alkyl, C2 '0 alkenyl, C6,2 alkaryl and C6,2 aryl.

22. A compound according to any of claims 17 to 21, wherein Ra, Rb, RC, Rd. Re are independently selected from the group consisting of -H. methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, octyl, nonyl, dodecyl, eicosyl, norbornyl and adamantyl, vinyl, propenyl, cyclohexenyl, benzyl, phenylethyl, phenylpropyl, phenyl, nitrophenyl, tolyl, dimethylphenyl, trimethylphenyl, ethylphenyl, propylphenyl, biphenyl, naphthyl, methyinaphthyl, anthryl, phenanthryl, benzylphenyl, pyrenyl, acenaphthyl, phenalenyl, aceanthrylenyl, tetrahydronaphthyl, indanyl, biphenyl, particularly methyl, ethyl, propyl and isopropyl.

23. A compound according to any of claims 17 to 22, wherein the group OSO2- Re is selected from alkyl- and arylsulfonates such as mesylate (-OSO2CH3), tosylate (-OSO2-p-C6H4-CH3), triflate (-OSO2CF3), nosylate (-OSO2-p-C6H4- NO2) and brosylate (-OSO2-p-C6H4-Br).

24. A compound according to any of claims 17 to 23, wherein R is selected from the group consisting of C' 20 alkanedlyl, C220 alkenediyl, C220 alkynedlyl, C330 cycloalkanediyl, C330 cycloalkenediyl, C530 cycloalkynedlyl, , C730 aralkylenediyl, C730 alkarylenedlyl and C530 arylenedlyl.

25. A compound according to any of claims 17 to 24, wherein R is selected from the group consisting of C,-6 alkanedlyl, C2 '6 alkenedlyl, C2 '6 alkynedlyl, C420 cycloalkanediyl, C420 cycloalkenediyl, C520 cycloalkynediyl, C720 aralkylenediyl, C7 alkarylenedlyl and C620 arylenedlyl.

26. A compound according to any of claims 17 to 25, wherein R is selected from the group consisting of straight chain C,-6 alkanedlyl, C2,6 alkenediyl, C6'6 aralkylenedlyl and C6 '6 alkarylenedlyl.

27. A compound according to any of claims 17 to 26, wherein R is selected from methylene, 1,2-ethylene, 1,2-propylene, 1,3-propylene, 1,2-butylene, 1,3 butylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,8-octylene, 1, 10-decylene and 1,12-dodecylene.

28. A compound according to any of claims 17 to 27, wherein R has greater than 2 carbon atoms in the chain, suitably 3 to 10, and more suitably 3, 6, 8 or 10.

29. A compound according to any of claims 17 to 28, wherein R. is selected from the group consisting of C' 30 alkanedlyl, C2 30 alkenedlyl, C2 30 alkynedlyl, C3 35 cycloalkanedlyl, C3 35 cycloalkenediyl, C5 35 cycloalkynedlyl, C7 35 aralkylenediyl, C7 alkarylenedlyl and C5 35 arylenedlyl.

30. A compound according to any of claims 17 to 29, wherein R' is selected from the group consisting of Co-ed alkanedlyl, C2,8 alkenedlyl, C2,8 alkynedlyl, C4 20 cycloalkanedlyl, C4 20 cycloalkenediyl, C5 20 cycloaikynediyl, C7 20 aralkylenedlyl, C7 alkarylenedlyl and C6 20 arylenedlyl.

31. A compound according to any of claims 17 to 30, wherein R. is selected from the group consisting of straight chain C'-8 alkanedlyl, C2'8 alkenediyl, C6'8 aralkylenedlyl and C6,8 alkarylenediyl.

32. A compound according to any of claims 17 to 31, wherein R2 is -H.

33. A compound according to any of claims 17 to 32, wherein Ri-R2, in combination, form a monovalent hydrocarbon radical selected from the group consisting of straight chain C' 20 alkyl, C2 20 alkenyl, C2 20 alkynyl, C3 30 cycloalkyl, C3 30 cycloalkenyl, C4 30 cycloalkynyl, C7 30 aralkyl, C7 30 alkaryl and C5 30 aryl.

34. A compound according to any of claims 17 to 33, wherein R'-R2, in combination, form a monovalent hydrocarbon radical selected from the group consisting of straight chain C4-8 alkyl, C4-8 alkenyl, C4-8 alkynyl, C6 20 cycloalkyl, C6 20 cycloalkenyl, C6 20 cycloalkynyl, C,0 20 aralkyl, C'0 20 aikaryl and C6 20 aryl.

35. A compound according to any of claims 17 to 34, wherein R'-R2, in combination, form a monovalent hydrocarbon radical selected from the group consisting of straight chain C,08 alkyl, C0-8 alkenyl, Cow alkaryl and C,0-8 aralkyl.

36. A compound according to any of claims 17 to 35, wherein R'-R2, in combination, have greater than 10 carbon atoms in the chain, suitably 10 to 18, and more suitably 10,12,14 or 16.

37. A compound according to any of claims 17 to 36, wherein Y represents an anion, or plurality of anions, which may be the same or different.

38. A compound according to claim 37, wherein Y is selected from the group consisting of N-hydroxysuccinimidyl, N-hydroxybenzotriazolyl, nitrate, sulfate, bisulfate, phosphate (mono-, hi-, or triphosphate), carbonate, bicarbonate, acetate, tosylates, mesylates, brosylates, and halides including chloride, bromide, and iodide, and mixtures thereof.

39. A compound according to any of claims 17 to 38, wherein m is an integer of 1, 2, 3,4, 5 or 6.

40. A compound according to any of claims 17 to 39, wherein p is an integer of 1, 2, 3, 4, 5 or 6.

41. A compound according to any of claims 17 to 40, wherein R3, R4 and R5 are independently selected from the group consisting of -H. C' 20 alkyl, C220 alkenyl, C2 20 alkynyl, C330 cycloalkyl, C330 cycloalkenyl, C430 cycloalkynyl, C730 aralkyl, C7 alkaryl and C530 aryl.

42. A compound according to any of claims 17 to 41, wherein R3, R4 and R5 are independently selected from the group consisting of -H. C' '5 alkyl, C2,5 alkenyl, C245alkyllyl, C320Cycloalkyl' C320Cycloalkenyl' C420Cycloalkynyl, C7-20aralkY', C7 alkaryl and C620 aryl.

43. A compound according to any of claims 17 to 42, wherein R3, R4 and R5 are independently selected from the group consisting of -H. straight chain C' JO alkyl, C2,0 alkenyl and C6 '2 aryl.

44. A compound according to any of claims 17 to 43, wherein R3, R4 and R5 are independently selected from the group consisting of -H. methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, octyl, nonyl, dodecyl, eicosyl, norbornyl and adamantyl, vinyl, propenyl, cyclohexenyl, benzyl, phenylethyl, phenylpropyl, phenyl, tolyl, dimethylphenyl, trimethylphenyl, ethylphenyl, propylphenyl, biphenyl, naphthyl, methyinaphthyl, anthryl, phenanthryl, benzylphenyl, pyrenyl, acenaphthyl, phenalenyl, aceanthrylenyl, tetrahydronaphthyl, indanyl, biphenyl, particularly methyl, ethyl, propyl and isopropyl.

45. A compound according to any of claims 17 to 44, wherein V comprises 1, 2, 3, 4, 5 or 6 positive charges.

46. A compound according to any of claims 17 to 45, wherein V comprises a singly charged quaternary ammonium, quaternary phosphonium or sulfonium group, having the formula ±NR62-, ±PR72-, or ±SR8-, respectively, wherein R6, R7 and R8 are independently selected from the group consisting of -H and monovalent hydrocarbon radicals.

47. A compound according to claim 46, wherein R6, R7 and R8 are independently selected from the group consisting of -H. C 20 alkyl, C2 20 alkenyl, C2 20 alkynyl, C3 30 cycloalkyl, C3 30 cycloalkenyl, C4 30 cycloalkynyl, C7 30 aralkyl, C7 30 alkaryl and C5 aryl.

48. A compound according to claim 47, wherein R6, R7 and R3 are independently selected from the group consisting of -H. C, ,5 alkyl, C2,5 alkenyl, C2 5 alkynyl, C3 20 cycloalkyl, C3 20 cycloalkenyl, C4 20 cycloalkynyl, C7 20 aralkyl, C7 20 alkaryl and C6 aryl.

49. A compound according to claim 48, wherein R6, R7 and R8 are independently selected from the group consisting of -H. straight chain C' JO alkyl, C2,0 alkenyl and C6,2 aryl.

50. A compound according to claim 46, wherein R6, R7 and R8 are independently selected from the group consisting of methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, octyl, nonyl, dodecyl, eicosyl, norbornyl and adamantyl, vinyl, propenyl, cyclohexenyl, benzyl, phenylethyl, phenylpropyl, phenyl, tolyl, dimethylphenyl, trimethylphenyl, ethylphenyl, propylphenyl, biphenyl, naphthyl, methyinaphthyl, anthryl, phenanthryl, benzylphenyl, pyrenyl, acenaphthyl, phenalenyl, aceanthrylenyl, tetrahydronaphthyl, indanyl, biphenyl, particularly methyl, ethyl, propyl and isopropyl.

51. A compound according to any of claims 17 to 44, wherein V comprises +NR62-R9-NR62± or a group (B): fCH2)a -N (CH2 N (B) (CH2)b wherein a, b and c independently represent 1-10, suitably, 1-5, more suitably 1-3, most suitably 2.

52. A compound according to claim 51, wherein a = b = c.

53. A compound according claim 51, wherein (B) is the dication of 1,4diazoniabicyclo[2.2.2]octane.

54. A compound according to any of claims 17 to 44, wherein the compound of formula (1)comprisesA-(R-Vm±R4-R2) having the structure: (cH2)a A(CH2)h N\CH2N--(CH2)CH3 (CH2)b wherein A is selected from the group consisting of -OC(0)-Ra, -C(0)-ORb and - OSO2-Re; h represents 1-10; a, b and c independently represent 1-5; and, i represents 7-17.

55. A compound according to any of claims 16 to 43, wherein A-(R-Vm±R'R2) has the structure: A-(CH2)h NAN (CH2)'CH3 wherein A is selected from the group consisting of -OC(0)-Ra, -C(0)-ORb and OSO2-Re; h represents 310; and, i represents 1 1, 15 or 17.