GB2462664A

GB2462664A - Wound-healing formulation comprising fast- and sustained-release components

Info

Publication number: GB2462664A
Application number: GB0817194A
Authority: GB
Inventors: James Joseph Brennan
Original assignee: BK PHARMA SYSTEMS Ltd
Current assignee: BK PHARMA SYSTEMS Ltd
Priority date: 2008-08-11
Filing date: 2008-09-19
Publication date: 2010-02-17
Also published as: GB0817194D0; WO2010018559A3; WO2010018559A2; IE20080661A1; EP2315606A2

Abstract

A formulation for a two-phase management of wound healing comprises:- a substrate containing a rapid release form of a first active agent in the form of an inclusion complex with a cyclic molecule, preferably a cyclodextrin, the active being accommodated in a cavity of the cyclic molecule, and- at least one sustained release form, preferably microcapsules, of a second active agent which is released to the wound in response to a trigger by a wound constituent. The formulation can be applied directly to a wound or formulated into a dressing for application to a wound.

Description

I

* Description

Formulations for a two-phase management of wound healing and dressings incorporating such formulations.

Field of the invention

This invention relates to formulations and dressings, in particular, to wound formulations and dressings which can be used to manage and promote the healing process. The formulations and dressings according to the invention have particular application in the alleviation of the pain associated with interventions by medical staff and the healing process, while promoting the healing process.

Background Art

The healing process of a wound is multi-factorial.

One of the common complications of wound healing is pain which remains an integral part of wound diagnosis as well as local wound management and, unfortunately, one area which is still neglected in conventional medicine is pain control.

The reasons for wound pain are numerous and include the following: -Vasculitis due to inflammation occurring in the capillaries with swelling within the lumen preventing blood from successfully reaching the tissues; * -Persistent inflammation; -Oedema resulting from fluid in the tissues reducing the supply of nutrients and blood to the wound, leading to pain; -Trauma on dressing removal due to adherence of dressings to the wound bed, either because they dry out and behave like adhesives or because granulation tissue has grown into the dressing; -Ischaemic disease due to poor peripheral blood supply; and -Contamination by pseudomonas and other pathogens which causes tissue destruction.

A recent survey of patients in the United Kingdom and Sweden revealed that 64% of patients with leg ulcers suffered from pain and, in addition, 32% of these patients were not provided with effective analgesia (Glynn, C. (2003) Proceedings from EWMA Conference, Pisa).

Another study of wounds identified that a quarter of patients reported pain associated with their wounds, but none received analgesia before dressing changes (Bux, M. and Maihi, J.S. (1996) Journal of Wound Care 5: 305-308). Chronic wound pain is distressing and influences the patient's ability to function. Incorrect diagnosis and inexperience may lead to selection of dressings with the potential to increase pain within the wound bed.

Modern wound dressings are designed to do one or more of the following: * -Protect; -Debride; and -Absorb excess exudates.

However, dressings should also be selected on the basis of and influenced by the symptoms associated with the wound, especially pain.

The materials of which wound dressings are made is important in this regard.

Wound dressings broadly fall into a number of classes, depending on the material of which they are made and, in selecting the appropriate dressing, the clinician should be aware of the particular characteristics of each class of wound dressing and the impact this can have on wound healing.

It is possible that many clinicians may not always be informed that: -Dry dressings may increase pain, due to the pulling' or osmotic effect of the dressing; -Intermittent pain is often related to dressing removal or recent applications of new dressings; -Wet' dressings (i.e. hydrocolloids, hydrogels or Tenderwet (Tenderwet is a trade mark dressing) may bathe the exposed nerve endings in a wound and sooth and relieve the pain; and -Any dressing that adheres to the wound when removed should not be used on the same wound again.

Local would management involves addressing at least four factors: -Critical clinical infection or colonisation; -Periwound skin; -Oedemalexudates; and -Persistent inflammation.

Preventing patient pain and tissue trauma to the wound and surrounding skin are key considerations at the time of dressing changes.

Pain has two components that need to be assessed in each patient: a physical component and an emotional component. These two components are always present in each patient, but whereas the physical component always needs treatment, the emotional component may not need treatment in every patient. However, this must be linked to quality of life and consistent pain will reduce the quality of life in most people.

The management of pain in wounds has two distinct phases: -Initial pain which is experienced on mechanical interventions such as dressing application or change; and -Chronic pain which may be experienced throughout the healing process associated with a number of factors as outlined above.

* Although moist wound healing has been proven to aid wound healing and relieve pain, a more direct means of treating wound pain is required.

It is known to incorporate pain relieving agents into dressings for the treatment of pain across the skin. The skin is an effective barrier and the active pain relieving agent needs to be formulated in such a way that it is capable of penetrating this barrier. Intact skin will require a higher concentration of the active agent in order to pass through the skin.

Current products may be in the form of transdermal patches, ointments or gels.

The inclusion of various other active agents in dressings is known.

WO 2007/024972 discloses a device for the treatment of wounds comprising an absorbent wound dressing material having incorporated therein inherent non-leachable antimicrobial activity and inherent non-leachable anti-protease activity and a releasable antimicrobial agent and a releasable anti-protease agent that are iomcally stabilised within the device so as to be released therefrom in a controlled manner. The inherent non-leachable antimicrobial and/or anti-protease activity is provided by polymeric quaternary ammonium molecules which are non-leachably bonded to the wound dressing via covalent chemicals bonds.

The device can also contain releasable bioactive agents which aid in wound healing, such as growth factors, vitamins and/or nutrients.

WO 2005/0350 12 discloses a wound dressing for targeted release of one or more therapeutic ingredients contained in liposomes. The dressing comprises exudates handling means, such as hydrocolloids, hydrogels, etc., and the liposomes include releasing means, which are triggered by a wound constituent resulting in release of the therapeutic ingredients from the liposomes.

When one or more active agent(s) is/are incorporated in a wound dressing, three main problems must be addressed: Reaction of the active agent with the dressing; Reaction of the different active agents with one another when there is more than one active agent, and; The active agent should be confined to the wound area and not enter the systemic circulation.

WO 2004/084961 describes a wound dressing comprising a web of gel-forming fibres, for example silver calcium alginate fibres or fibres soluble in wound exudates attached to a reinforcing layer. The dressing provides sustained or controlled release of active ingredient and is easy to remove from the wound area without trauma for the patient. The dressing is stated to provide a moist wound healing environment.

WO 2002/09782 describes non-adhering wound dressings containing cyclodextrms. The dressings incorporate cyclodexirins as odour absorbent material and WO 2002/09782 also describes the use of cyclodextnn-perfume complexes to combat wound associated odours.

WO 2004/030711 describes enzyme-sensitive therapeutic wound dressings. The wound dressings include a therapeutic agent and a matrix S comprising polymers joined by cross-linkages, cleavable by a protease associated with wound fluid. The dressing may comprise, or consist essentially of, particles such as microspheres of therapeutic agent (e.g. antimicrobial material) encapsulated in a layer comprising the cross-linked matrix material, from which the therapeutic agent is released through wound-associated protease.

It is an object of the present invention to provide a wound dressing which overcomes the disadvantages of known dressings which can be used, for example, to manage and minimise the pain associated with wound healing and, in particular, the two-phase nature of wound-associated pain.

Disclosure of the Invention

Accordingly, the invention provides a formulation for a two-phase management of wound healing, said formulation comprising a substrate containing a rapid release form of a first active agent in the form of an inclusion complex with a cyclic molecule, the first active agent being accommodated in a cavity of the cyclic molecule, for rapid release of the first active agent on application of the formulation to a wound and at least one sustained release form of a second active agent which is released to the wound in response to a trigger by a wound constituent.

By sustained release herein is also included controlled release or triggered release in response to a wound constituent.

* The formulation according to the invention can be used to treat pressure ulcers, bed sores, bums, MRSA Methicillin resistant Staphylococcus aureus) infection and other infections caused by resistant microorganisms by management of the wound healing process.

Thus, the formulation according to the invention can be used in the treatment of both acute and chronic wounds and can be applied to all areas of the body.

Preferably, the substrate is in the form of a foam, a gel, a hydrocolloid, a matrix or a paste.

A formulation according to the invention, wherein the substrate is in the form of a foam, a gel, a hydrocolloid, a matrix or a paste can be applied directly to a wound.

The nature of the substrate is such that it will typically form a three-dimensional structure on application to the wound so as to provide the requisite adherency and rigidity while in contact with the wound, but will be readily removable from the wound when required. Specifically, the formulation is a non-adhering wound formulation as known in the art, namely, that the wound contacting surface is not in the form of pressure sensitive adhesive.

Such substrates when topically applied offer the advantage of intimate contact with the often irregular surface of a wound, something that may be difficult to achieve with a rigid wound dressing.

Preferably, the cyclic molecule of the inclusion complex has a toroidal shape.

Further, preferably, the cyclic molecule is a cyclodextrin.

Cyclodextrins by virtue of their toroidal (a shape like an anchor-ring) shape are able to accommodate organic molecules within an internal cavity defined by the toroidal shape, giving rise to inclusion complexes.

It will be appreciated that other similar types of molecules capable of forming inclusion complexes or clathrate compounds can also be used in accordance with the invention, provided that they have the requisite properties for ensuring rapid release of the first active agent on application of the formulation to a wound. Other possible cyclic compounds include crown ethers.

When a cyclodextrin is used, it is preferably selected from a- cyclodextrins, modified or unmodified 3-cyclodextnns and y-cyclodextrms or a mixture thereof.

Further, preferably, the cyclodexlnn is J3-cyclodextrin, 2-hydroxypropyl- 3-cyclodextrin or dimethyl-J3-cyclodextrin or a mixture thereof.

According to one embodiment of the invention, the first and second active agents are the same.

According to a preferred embodiment of the invention, when the first active agent has been released from the cyclodextrin, the cyclodextrin serves as a means for trapping odiferous compounds, in particular malodorous molecules, associated with wound healing.

Thus, an advantage of using cyclodextrins for the delivery of active agents is that once the active agent has been released to the wound, it is then available to trap odiferous compounds associated with wound healing by complexing them within the cavity defmed by the toroidal shape.

Preferably, the sustained release form of the second active agent is microencapsulated.

The microcapsules preferably consist of a polymeric material.

By microcapsule herein is also meant microparticles, microbeads and like particles hereinafter referred to collectively as microcapsules, which serve to keep the encapsulated active ingredient in a discrete form.

The active agent can be encapsulated in a manner known per se such as by air suspension coating, coacervation, fluid-bed coating or spray drying.

Further, preferably, the polymeric material is a polysaccharide gel.

Still further, preferably, the polysaccbaride gel is an alginate.

Other suitable polymeric materials include starch and polyvinyl alcohol.

* By the correct choice of materials from which to construct the microcapsules, it is possible to determine a mechanism which will trigger the collapse of the capsule and therefore the release of the active agent.

One such triggering mechanism is the increase in moisture content in the substrate or formulation matrix which results from the absorption of wound exudates. As indicated herein, the absorption of exudate is one of the major advantages which has taken place in the area of wound care in the recent past. The present invention utilises this technology as a triggering mechanism for a strategy which addresses the need for effective wound management.

Many wound care products are based on aqueous formulations in order to generate a moist environment for the wound to heal. In such formulations, the triggering mechanism for the release of pain-relieving agent can not be based on the absorption of water, as the substrate or formulation is already effectively saturated in water. In accordance with the invention, the triggering mechanism can be driven by the process of evaporation/absorption of water from the substrate as a function of time during use. This causes a concentrating effect in the substrate for electrolytes, for example calcium ions, and the elevated concentration of these ions can cause an increase in cross-linking of the polymeric material comprising the microcapsule, where the polymeric material is for example alginate. The increase in the cross-linking leads to extreme brittleness and the capsule ruptures, releasing the entrapped active agent(s). In this way, a sustained release mechanism for an active agent in wound care products is achieved.

S The simple inclusion of an active agent into a wound dressing leads to a situation where the delivery of active principle is not maintained at a constant level, but drops off over the period of application. This situation leads to an excessive level of pain-relieving agent at the time of application and a deficiency at a later stage during the application.

However, the use of a microencapsulated form of the active agent in accordance with the invention, has been shown to control the rate of release of active principle and thus provides a sustained delivery of active principle over the period of application.

According to a preferred embodiment of the invention, the first and second active agents are each a pam relieving agent.

Preferably, the first and second active agents are selected from analgesics and anti-inflammatory agents.

Further, preferably, the first and second active agents are non-steroidal anti-inflammatory agents (NSAIDs) selected from salicylates, arylalkanoic acids, 2-aryipropionic acids, N-arylanthranilic acids, pyrazolidine derivatives, oxicams and COX-2 inhibitors.

A common feature of many NSAff)s is that they have limited aqueous solubility and therefore restricted bioavailability. This limited aqueous solubility results from the general lipophilic nature of many of these molecules. However, this limitation can be addressed by the formation of an inclusion complex between the NSAID and cyclodextrin molecule.

* The structure of the cyclodextrin molecule which is toroidal or more generally annular in shape, has the majority of its hydroxyl groups pointing outwards and providing a relatively lipophilie interior. This ensures that relatively stable inclusion complexes are formed with molecules such as typical analgesic or anti-inflammatory agents. The hydroxyl groups which are oriented towards the exterior of the complex ensure that the complexes are quite hydrophilic. This feature greatly increases the bioavailability of the pain relieving agent which is then transported rapidly to where it is required. This enhanced delivery mechanism ensures that the need for rapid pain relief is achieved.

Without the use of complexation by cyclodextrins or other clathrate compounds, there is a much slower delivery of active agent to the sites required and therefore a much longer onset period before the analgesic effect is experienced.

Preferably, the or each N SAID is: A salicylate selected from acetylsalicylic acid, amoxiprin, benorylate, choline magnesium salicylate, diflunisal, ethenzamide, faislamine, methyl salicylate, magnesium salicylate, salicyl salicylate and salicylamide; An arylalkanoic acid selected from diclofenac, aceclofenac, acemetacin, alciofenac, bromfenac, etodolac, indometacm,, nabumetone, oxametacin, proglumetacin, sulindac and tolmetin; * A 2-Aryipropionic acid selected from ibuprofen, alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen and tiaprofenic acid; A N-Arylanthranilic acid selected from mefenamic acid, flufenamic acid, meclofenamic acid and tolfenamic acid; A pyrazolidine derivative selected from phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, phenylbutazone and sulfinpyrazone; An oxicam selected from piroxicam, droxicam, lornoxicam, meloxicam and tenoxicam; and; A COX -2 inhibitor selected from celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib and valdecoxib.

According to one embodiment of the invention, the or each NSAID is an arylalkanoic acid.

Preferably, the arylalkanoic acid is diclofenac.

According to an alternative embodiment of the invention, the or each NSAID is a 2-arylpropiomc acid.

S Preferably, the 2-arylpropiomc acid is ibuprofen, ketoprofen or a mixture thereof.

Many NSAIDs such as ketoprofen, although highly effective anti-inflammatory agents and effective in the reduction of pain, are, however, relatively poorly soluble in water and therefore have high bioavailability characteristics which are not compatible with the rapid delivery of active principle to the necessary receptors.

It has now been demonstrated that complexes of ketoprofen and other NSAIDs with cyclodextrin derivatives such as a-cyclodexlrin, lE- cyclodextrin, 2-hydroxypropyl--cyclodextrin and dimethyl-f3-cyclodextrm exhibit greatly enhanced solubility and bioavailability properties.

Preferably, the formulation will not contain more than 10% by weight of the pain-relieving agent, more especially less than 5% by weight.

Typically, the formulation will contain between I and 4 % by weight of the pain-relieving agent, more especially 2% by weight. In that event, 0.5% by weight of the pain-relieving agent will be in the rapid release form and the remainder will be in the form of the sustained release encapsulated form.

The use of inclusion complexes and microcapsules in the formulation according to the invention provides for a physical separation of the pain-relieving agent from the substrate during storage. This separation allows for the inclusion of other agents in the dressing such as antibacterial agents, for example, ionic or metallic silver, essential oils, humectants, * pigments, surfactants, and other bioactive molecules, such as chrondroitin sulphate and hyaluronic acid, which might be chemically incompatible with the first and second active agent(s).

The formulation according to the invention can also include additional active agents in an encapsulated form.

According to a further embodiment of the invention, the first active agent is selected from analgesics and anti-inflammatory agents and the second active agent is selected from antibiotics, anti-microbial agents, antiseptics, chondroitin sulphate, collagen, cooling agents, enzymes such as proteases, growth factors such as vascular endothelial growth factor (VEGF), haemostatic agents, hyaluronic acid, local anaesthetics, matrix metalloproteases, nutrients, odour reducing agents, peptides, protease inhibitors of inflammatory enzymes, for example secretory leukocyte protease inhibitor (SLPI), proteins, retinoids, tissue healing agents such as RGD tripeptides, steroids and vitamins.

As indicated above, the formulation according to the invention can be applied directly to a wound.

The invention provides a dressing which has a formulation as hereinbefore defined disposed on a wound-contacting surface thereof.

The dressing according to the invention can be of a size and thickness as required by the circumstances.

A typical thickness ranges from 0.1-10 mm, more especially 0.5-2 mm.

S

The tensile strength of the dressing is typically less than 400g/cm with an adhesive specification greater than 400g/cm2, and a cold flow

specification less than 3%.

In one embodiment, the dressing is a wet dressing.

Preferably, the substrate comprises an absorbent material.

The absorbent material is preferably selected from a foam, a hydrocolloid, an aqueous or bydrogel, a matrix or a paste supported on a backing layer, as required. However, it will be appreciated that the substrate can also be a film, a non-woven or a woven material as known inthe art.

Many such absorbent materials are known and are commercially available, such as those sold under the trade marks AQUACEL �, marketed by ConvaTec, Ltd., which is composed of fibres of sodium hydroxymethylcellulose and which absorbs exudates to form a soft coherent gel.

Suitable foams for use in the formulation and the dressing according to the invention are polyurethane foams and silicone foams.

Suitable hydrocolloids for use in the formulation and the dressing according to the invention include sodium carboxymethylcellulose, polyvinyl alcohol and polyvinyl pyrrolidone (PVP) or cross-linked PVP.

The hydrocolloids as used herein may be water absorbable or water swellable.

* Suitable hydrogels for use in the formulation and the dressing according to the invention include the products sold under the Trade Mark AQUACEL� above, as well as acrylic polymers, such as methacrylates, chitosan salts, ethylene oxide polymers and polyurethaiies.

A matrix for use in the formulation and the dressing according to the invention can comprise gel-forming fibres or fibres soluble in wound exudates. Alternatively, the matrix can comprise cross-linked polymers, wherein the polymers are natural or synthetic polymers, especially synthetic polymers, such as poiyvinyi alcohol or polyolefins suitable for topical use.

The substrate in whatever form will be manufactured in a manner known per se so as to produce a homogenous end product.

The above materials allow for the effective management of wound exudates in a manner which allows exudates to be absorbed by materials which have a high absorptive capacity and also which do not adhere excessively to the wound on dressing change, causing mechanical damage to the newly emerging tissue, as a wound heals.

The dressing according to the invention is flexible and also facilitates non-traumatic removal of the dressing from the wound bed.

Preferably, the dressing is provided with a release liner for easy application to a wound.

Preferably, the release liner is provided with a silicone adhesive.

* The release liner will typically have a thickness of 100-5O0im or less.

Modes for Carrying out the Invention The invention will be further illustrated by the following Examples:

Example 1

A hydrocolloid formulation according to the invention containing ketoprofen was manufactured using the ingredients set forth in Table I as follows.

Table 1

Ingredient % w/w Oppanol B50 26.0 OppanolBlS 37.0 Cekol 10.0 Ethyl Parabens 1.5 Ketoprofen 1.5 (complexed) ____________________ Ketoprofen 5.0 (encapsulated) _____________________ Wingtack 9.5 Enerpar 9.5 A blend of Oppanol B50 and Oppanol B15, which are polyisobutylene polymers with differing chain lengths and consequent physiochemical characteristics were obtained from BASF. These were added to a Baker Perkins mixer, with ventilation. The mixer was driven in the forward position at 5 rpm. for 3 mm., and subsequently driven in the reverse * position for 7 miii. at 5 rpm. The mixer and the ventilation were then turned off.

To this blend, 50% of the Cekol (Noviant) which is a carboxymethyl cellulose, was added. The mixer was driven in the forward position at 5 rpm. for 2 mm., without ventilation.

Wingtack (Goodyear Chemical Company), an adhesive, and Enerpar (BP), a lubricant were added over a 5 mm. period, with mixing and without ventilation. The mixer was driven in the forward position at 5 rpm. for 2 mm., with the ventilation turned off. The ventilation was turned on and the mixer speed was maintained for a further 3 mm. The mixer and ventilation were then turned off.

Ketoprofen (1.5% w/w) obtained from Teva Pharmaceuticals was complexed with hydroxypropyl --cyclodextrin on a 1:1.5 molar basis to form the complexed ketoprofen. Ketoprofen (5.0% w/w) (Teva Pharmaceuticals) was microencapsulated using a Glatt batch fluidised bed system described below, and polyvmyi alcohol as the encapsulation material.

Equipment: GLATT GPCG-1.1 (lab scale) Configuration: Top spray coating mode Nozzle position: Head Nozzle diameter: 1.2 mm Filter: PES (Polyethersulfone) Air flow rate: 50 m3/h hilet Temp.: 60°C Outlet Temp.: 30°C Spray rate: 0.6 kg/h

S

The typical resulting particle size range was of the order of 200-300 micron.

The complexed ketoprofen and the encapsulated ketoprofen were then added to the mixer. The mixer was driven in the forward position at 5 rpm. for 3 mm., with the ventilation turned off. The ventilation was turned on and the mixer speed was maintained for a further 6 mm. The mixer and ventilation were then turned off. I0

A mixture of ethylparabens, a preservative, was added to the mixture.

The mixer was driven in the forward position at 5 rpm. for 2 mm., with the ventilation turned off. The ventilation was turned on and the mixer speed was maintained for a further 4 miii. The mixer and ventilation were then turned off.

The remaining 50% of the Cekol was added. The mixer was driven in the forward position at 5 rpm. for 2 mill., with the ventilation turned off. The ventilation was turned on and the mixer speed was maintained for a further 7 mm. at 5 rpm. The mixer and ventilation were then turned off.

The temperature of the mixture was monitored throughout manufacture using a temperature probe. Temperatures were normally in the range of 80-95 °C.

The coherent mass thereby formed was cut into wound dressings, pouched, sterilised and stored.

S

The thickness of the dressing was 1.25 mm and was supported by a backing layer of polyurethane 50 jtm in thickness. The tensile strength was less than 400 g/cm2. The adhesive specification was greater than 400 g/cm and the cold flow specification was less than 3%.

Example 2

A hydrocolloid formulation according to the invention containing ketoprofen and diclofenac was manufactured using the ingredients set forth in Table 2 as follows.

Table 2

ingredient % w/w OppanolB5O 26.0 OppanolBlS 37.0 Cekol 10.0 Ethyl Parabens 1.5 Diclofenac 1.5 (complexed) ____________________ Ketoprofen 5.0 (encapsulated) ______________________ Wingtack 9.5 Enerpar 9.5 Diclofenac (1.5% w/w) obtained from Teva Pharmaceuticals was complexed with hydroxypropyl -13 -cyclodextrin on a 1:1.5 molar basis to form the complexed diclofenac. The complexed diclofenac was * incorporated into the hydrocolloid by inclusion during the manufacture thereof as hereinafter described. Ketoprofen (5.0% w/w) which was microencapsulated using the Glatt batch fluidised bed system as described in Example 1 and poiyvinyi alcohol as the encapsulation material was also included in the hydrocolloid.

The mixing conditions of the hydrocolloid components were as described in Example 1.

Example 3

A hydrocolloid formulation according to the invention containing diclofenac and hyaluronic acid was manufactured using the ingredients set forth in Table 3 as follows.

Table 3

________________________ ________________________

Ingredient % wiw OppanolBSO 26.0 OppanolBl5 37.0 Cekol 10.0 Ethyl Parabens 1.5 Diclofenac 1.5 (complexed) ___________________ Hyaluronic acid 5.0 (encapsulated) ______________________ Wingtack 9.5 Enerpar 9.5 Diclofenac (1.5% w/w) obtained from Teva Pharmaceuticals was complexed with hydroxypropyl --cyclodextrin on a 1:1.5 molar basis to form the complexed diclofenac. The complexed diclofenac was incorporated into the hydrocolloid by inclusion during the manufacture thereof as hereinafter described. Hyaluronic acid (5.0% w/w) obtained from Federal Laboratories Corporation, New York, USA was microencapsulated using the Glatt batch fluidised bed system as described in Example 1 and polyvinyl alcohol as the encapsulation material, and was also included in the hydrocolloid.

Example 4

A hydrocolloid formulation according to the invention containing diclofenac and platelet-derived growth factor (PDGF) was manufactured using the ingredients set forth in Table 4 as follows.

Table 4

Ingredient % wiw QppanolBSO 26.0 OppanolBlS 37.0 Cekol 10.0 Ethyl Parabens 1.5 Diclofenac 1.5 (complexed) ____________________ PDGF 5.0 (encapsulated) _______________________ Wingtack 9.5 Enerpar 9.5 * Diclofenac (1.5% w/w) obtained from Teva Pharmaceuticals was complexed with hydroxypropyl --cyclodextrin on a 1:1.5 molar basis to form the complexed diclofenac. The complexed diclofenac was incorporated into the hydrocolloid by inclusion during the manufacture thereof as hereinafter described. PDGF (5.0% w/w) which was microencapsulated using the Glatt batch fluidised bed system as described in Example I and polyvinyl alcohol as the encapsulation material was also included in the hydrocolloid.

The mixing conditions of the hydrocolloid components were as described m Example 1.

Example 5

A hydrocolloid formulation according to the invention containing ibuprofen and ketoprofen was manufactured using the ingredients set forth in Table 5 as follows.

* Table 5

Ingredient % w/w Oppanol B50 26.0 OppanolBlS 36.5 Cekol 10.0 Ethyl Parabens 1.5 Ibuprofen 2.0 (complexed) ____________________ Ketoprofen 5.0 (encapsulated) _______________________ Wingtack 9.5 Enerpar 9.5 Ibuprofen (2% w/w) obtained from Teva Pharmaceuticals was complexed with hydroxypropyl --cyclodextrin on a 1:1.5 molar basis to form the coinpiexed ibuprofen. The complexed ibuprofen was incorporated into the hydrocolloid by inclusion during the manufacture thereof as hereinafter described. Ketoprofen (5.0% w/w) which was microencapsulated using the Glatt batch fluidised bed system as described in Example 1 and polyvinyl alcohol as the encapsulation material was also included in the hydrocolloid.

Example 6

A hydrocolloid formulation according to the invention containing ibuprofen and diclofenac was manufactured using the ingredients set forth in Table 6 as follows.

* Table 6

Ingredient % wiw Oppanol B50 26.0 OppanolBl5 36.5 Cekol 10.0 Ethyl Parabens 1.5 Ibuprofen 2.0 (complexed) ____________________ Diclofenac 5.0 (encapsulated) ______________________ Wingtack 9.5 Enerpar 9.5 Diclofenac (2% w/w) obtained from Teva Pharmaceuticals was complexed with hydroxypropyl --cyclodextrin on a 1:1.5 molar basis to form the complexed diclofenac. The complexed diclofenac was incorporated into the hydrocolloid by inclusion during the manufacture thereof as hereinafter described. Ketoprofen (5.0% w/w) which was microencapsulated using the Glatt batch fluidised bed system as described in Example I and polyvinyl alcohol as the encapsulation material was also included in the hydrocolloid.

Example 7

A gel formulation according to the invention containing ketoprofen and diclofenac is manufactured using the ingredients set forth in Table 7 as follows.

Table 7

Ingredient % w/w Purified Water 84.5 Glycerol 1.0 Disodium EDTA I 5 Carbopol 940 1.5 Sorbital 5.0 Ketoprofen 1.5 (complexed) ____________________ Diclofenac 5.0 (encapsulated) _______________________ Ketoprofen (1.5% w/w) obtained from Teva Pharmaceuticals is complexed with hydroxypropyl -13 -cyclodextrin on a 1:1.5 molar basis to form the complexed ketoprofen The complexed ketoprofen is incorporated into the gel by use of a gelling agent Carbopol 940 (1.5% w/w).

A chelating agent, ethylenediaminetetraacetic acid (EDTA), is used to stabilise the gel and to allow subsequent sustained release of the encapsulated diclofenac. An Omni mixer and homogemser are used with a Z arm mixing blade to mix the EDTA, water and glycerol. Mixing speeds are kept below 40 rpm to prevent any shear thinning of the formulation.

S Purified water is placed in the mixing vessel and the mixer is turned on.

The EDTA is added slowly over a 15 mm. period. Glycerol and the complexed ketoprofen are added over a period of 10 mm. The formulation is mixed at 25-40 rpm for a further 15 mm.

Carbopol, a gelling agent, is added to the formulation over a period of 20 mm. This is followed by the addition of sorbitol, a modified starch polymer, added to the mixture over a 10 mm. period.

Diclofenac (5.0% w/w) which is microencapsulated using the Glatt batch fluidised bed system as described in Example 1 and alginate as the encapsulation material is also included in the gel by mixing over a 15 mm. period.

The formulation is mixed for a further 15 mm. to ensure a homogeneous consistency. The formulation is then allowed stand for 20 mm, in the mixer after which it is extruded into a tube for application.

Example 8

A gel formulation according to the invention containing ketoprofen, diclofenac and hyaluromc acid is manufactured using the ingredients set forth in Table 8 as follows.

* Table 8

Ingredient % w/w Purified Water 84.5 Glycerol 1.0 Disodium EDTA 1.5 Carbopol 940 1.5 Sorbital 5.0 Ketoprofen 1.5 (complexed) ___________________ Diclofenac 2.0 (encapsulated) ______________________ Hyaluronic acid 3.0 (encapsulated) _____________________ Ketoprofen (1.5% w/w) obtained from Teva Pharmaceuticals is complexed with hydroxypropyl --cyclodextrin on a 1:1.5 molar basis to form the complexed ketoprofen. The complexed ketoprofen is incorporated into the gel by use of a gelling agent Carbopol 940 (1.5% w/w). Hyaluromc acid (3.0% w/w) obtained from Federal Laboratories Corporation, New York, USA and diclofenac (2.0% w/w) are microencapsulated using the Glatt batch fluidised bed system as described in Example 1 and alginate as the encapsulation material are also included in the gel by mixing over a 15 mm. period.

The mixing conditions of the gel components are as described in

Example7.

* Example 9

A gel formulation according to the invention containing ketoprofen, diclofenac and PDGF is manufactured using the ingredients set forth in

Table 9 as follows.

Table 9

Ingredient % w/w Purified Water 84.5 Glycerol 1.0 Disodium EDTA 1.5 Carbopol 940 1.5 Sorbital 5.0 Ketoprofen 1.5 (complexed) ____________________ Diclofenac 2.0 (encapsulated) _______________________ PDGF 3.0 (encapsulated) ______________________ Ketoprofen (1.5% wlw) obtained from Teva Pharmaceuticals is complexed with hydroxypropyl --cyclodextrin on a 1:1.5 molar basis to form the complexed ketoprofen The complexed ketoprofen is incorporated into the gel by use of a gelling agent Carbopol 940 (1.5% w/w). PDGF (3.0% w/w) and diclofenac (2.0% w/w) which are microencapsulated using the Glatt batch fluidised bed system as described in Example I and alginate as the encapsulation material are also included in the gel by mixing over a 15 mm. period.

The mixing conditions of the gel components are as described in

Example 7.

* Example 10

A gel fonnulation according to the invention containing ketoprofen and diclofenac is manufactured using the ingredients set forth in Table 10 as follows.

Table 10

Ingredient % w/w Water 67.6 Glycerol 1.0 Propylene glycol 23.5 Triethanolamine 0.9 Carbopol98ONF 0.5 Ketoprofen 1.5 (complexed) ____________________ Diclofenac 5.0 (encapsulated) _______________________ Ketoprofen (1.5% w/w) is complexed with hydroxypropyl --cyclodextrin on a 1:1.5 molar basis. to form the complexed ketoprofen.

Diclofenac (5.0% wlw) is microencapsulated using the Glatt batch fluidised bed system as described in Example 1 and polyvinyl alcohol as the encapsulation material is also included in the gel. The complexed and encapsulated NSAID are added to an Omni mixer and homogemser with water.

To this mixture, Carbopol 980 NF, a gellmg agent is added and mixed for 30 mm. The propylene glycol and glycerol are added to the mixture and mixed for an additional 20 mm.

* The formulation is allowed to hydrate and swell for 60 mm.

The formulation is pH adjusted by the addition of triethanolamine with gentle mixing until a homogeneous gel is formed.

The formulation may then be stored in a tube and is suitable for topical application to a wound locus or the gel may be incorporated into a dressing as hereinabove described which can be applied to a wound.

Example 11

A gel formulation according to the invention containing ketoprofen and diclofenac is manufactured using the ingredients set forth in Table 11 as follows.

Table 11

Ingredient % w/w Water 27.5 Ethanol 63.5 Propylene glycol 1.0 Triethanolamine 0.5 Carbqpol98ONF 1.0 Ketoprofen 1.5 (complexed) ____________________ Diclofenac 5.0 (encapsulated) _______________________ Ketoprofen (1.5% w/w) is complexed with hydroxypropyl --cyclodextrin on a 1:1.5 molar basis to form the complexed ketoprofen.

Diclofenac (5.0% w/w) is microencapsulated using the Glatt batch * fluidised bed system as described in Example 1 and alginate as the encapsulation material is also included in the gel.

The ethanol, water and propylene glycol are mixed in an Omni mixer and homogeniser using the Z-ann blade at 55 rpm for 10 mm.

The complexed and encapsulated NSAID are dispersed in the ethanoll water! propylene glycol mixture prior to the addition of the gelling agent, carbopol 980 NF.

To this mixture, Carbopol 980 NF, a gelling agent is added and mixed for 30 mill, at room temperature.

The formulation is allowed to hydrate and swell for a further 60 mm.

The formulation is the pH adjusted by the addition of triethanolamine with gentle mixing until a homogeneous gel is formed.

The formulation may then be stored in a tube and is suitable for topical application to a wound locus or the gel may be incorporated into a dressing which can be applied to a wound.

S Example 12

A foam formulation according to the invention containing ketoprofen and ibuprofen is manufactured using the ingredients set forth in Table 12 as follows.

Table 12

Ingredient % w/w Prepolymer 51.4 Propylene glycol 14.0 Methylene Chloride 20.6 P-105 2.5 L-5305 1.0 Xanthan gum 1.0 Carboxymethyl 0.5 cellulose _______________________ Gelatin 1.0 Ketoprofen 1.0 (complexed) _____________________ Ibuprofen 7.0 (encapsulated) ______________________ Ketoprofen (1.0% w/w) is complexed with hydroxypropyl -cyclodextrin on a 1:1.5 molar basis to form the complexed ketoprofen.

Ibuprofen (7.0% wlw) is microencapsulated using the Glatt batch fluidised bed system as described in Example 1 and polyvinyi alcohol as the encapsulation material is also included in the foam.

The manufacture of the polyurethane foam involves the reaction of isocyanate-capped prepolymers with a polymerising compound.

S A pre-polymer obtained from Korea Polyol Co. Ltd., is manufactured by the gradual addition of 1257.5g of TR-705, an ethylene oxide/propylene oxide random copolymer having three hydroxyl groups and an ethylene oxide to 242.8 g of toluene diisocyanate at 60°C.

To the pre-polymer, methylene chloride and propylene glycol are added and the mixure is mixed at 45rpm for 20-24 mm.

To this mixture the remaining ingredients are added sequentially with constant mixing at 45rpm over a 35 mm period. First the surfactant P-manufactured by BASF Germany is added, followed by the silicone based surfactant L-5305 manufactured by Osi Co. Then the xanthan gum, carboxymethylcellulose, gelatine are added. Finally the complexed ketoprofen and encapsulated ibuprofen are added to the formulation.

The formulation is mixed for a further 15 mm. to ensure a homogeneous consistency. The formulation is then allowed stand for 10 mm, prior to pouring the formulation into a mould which provides for the characteristic final shape.

Example 13

A paste formulation according to the invention containing ketoprofen is manufactured using the ingredients set forth in Table 13 as follows.

* Table 13

Ingredient % w/w Carboxymethyl cellulose 8.0 Polyethylene glycol 400 20.0 Sucrose 30.0 Glucose 10.0 White petrolatum 25.0 Ketoprofen 1.0 (complexed) ____________________ Ketoprofen 6.0 (encapsulated) ______________________ The carboxymethyl cellulose, sucrose, glucose, ketoprofen (complexed) and ketoprofen (microencapsulated) are placed in a powder mixer and mixed for two hours at room temperature. The complexed ketoprofen and the encapsulated ketoprofen are prepared as described in Example 1.

The pre-mixed powders are then added slowly, with mixing to the polyethylene glycol 400 in a mixer equipped with contra-rotating blades for approximately 30 mm. until a homogeneous mixture is obtained.

The white petrolatum is placed in a tank which can be heated to 50°C to allow the material to liquefy. No mixing is required at this stage.

When the petrolatum has been completely melted, it is then added to the mixture of the powders and the polyethylene glycol until such time as a homogeneous product is achieved.

* Mixing is continued as the product is allowed to cool and is then ready for filling into appropriate containers, as required.

Example 14

A paste formulation according to the invention containing ketoprofen and hyaluronic acid is manufactured using the ingredients set forth in

Table 14 as follows.

Table 14

Ingredient % wiw Carboxymethyl cellulose 8.0 Polyethylene glycol 400 20.0 Sucrose 30.0 Glucose 10.0 White petrolatum 25.0 Ketoprofen 1.0 (complexed) ____________________ Hyaluronic acid 6.0 (encapsulated) _______________________ The complexed ketoprofen and the encapsulated hyaluronic acid are prepared as described in Example 1.

The manufacturing process is identical to that described in Example 13.

Claims

* Claims: - 1. A formulation for a two-phase management of wound healing, said formulation comprising a substrate containing a rapid release form of a first active agent in the form of an inclusion complex with a cyclic molecule, the first active agent being accommodated in a cavity of the cyclic molecule, for rapid release of the first active agent on application of the formulation to a wound and at least one sustained release form of a second active agent which is released to the wound in response to a trigger by a wound constituent.
2. A formulation according to Claim 1 or 2, wherein the substrate is in the form of a foam, a gel, a hydrocolloid, a matrix or a paste.
3. A formulation according to any one of Claims 1-3, wherein the cyclic molecule of the inclusion complex has a toroidal shape.
4. A formulation according to any one of Claims 1-4, wherein the cyclic molecule is a cyclodextrin.
5. A formulation according to Claim 5, wherein the cyclodextrm is selected from a-cyclodextrins, modified or unmodified 13-cyclodextrins and 7-cyclodextrins or a mixture thereof.
6. A formulation according to Claim 6, wherein the cyclodextrin is 3-cyc1odextrin, 2-hydroxypropyl-13-cyclodextrin or dimethyl-13-cyclodextrin or a mixture thereof.

*
7. A formulation according to any preceding claim, wherein the first and second active agents are the same.
8. A formulation according to any one of Claims 4-7, wherein when the first active agent has been released from the cyclodextrin, the cyclodextrin serves as a means for trapping odiferous compounds associated with wound healing.
9. A formulation according to any preceding claim, wherein second active agent is microencapsulated.
10. A formulation according to Claim 9, wherein the micro-capsules consist of a polymeric material.
11. A formulation according to Claim 10, wherein the polymeric material is a polysaccharide gel.
12. A formulation according to Claim 11, wherein the polysaccharide gel is an alginate.
13. A formulation according to Claim 10, wherein the polymeric material is poiyvinyl alcohol or a starch.
14. A formulation according to any preceding claim for a two-phase management of wound healing, wherein the first and second active agents are each a pain relieving agent.

S
15. A formulation according to Claim 14, wherein the first and second active agents are selected from analgesics and anti-inflammatory agents.
16. A formulation according to Claim 15, wherein the first and second active agents are non-steroidal anti-inflammatory agents (NSAIDs) selected from salicylates, arylalkanoic acids, 2-arylpropiomc acids, N-arylanthranilic acids, pyrazolidine derivatives, oxicams and COX-2 inhibitors.
17. A formulation according to Claim 16, wherein the or each NSAID is an arylalkanoic acid.
18. A formulation according to Claim 17, wherein the arylalkanoic acid is diclofenac.
19. A formulation according to Claim 16, wherein the or each NSAIID is a 2-aiylpropionic acid.
20. A formulation according to Claim 19, wherein the 2-aryipropionic acid is ibuprofen, ketoprofen or a mixture thereof.
21. A formulation according to Claim 14, wherein the first active agent is selected from analgesics and anti-inflammatory agents and the second active agent is selected from antibiotics, anti-microbial agents, antiseptics, chondroitin sulphate, collagen, cooling agents, growth factors, haemostatic agents, hyaluronic acid, local anaesthetics, matrix metalloproteases, nutrients, odour reducing agents, peptides, protease * inhibitors of inflammatory enzymes, proteins, retmoids, tissue healing agents, steroids and vitamins.
22. A formulation according to any preceding claim, which includes additional active agents in an encapsulated form.
23. A formulation according to any preceding claim, which can be applied directly to a wound.
24. A dressing which has a formulation according to any preceding claim disposed on a wound-contacting surface thereof
25. A dressing according to Claim 24, which is a wet dressing.
26. A dressing according to Claim 25, wherein the substrate comprises an absorbent material.
27. A dressing according to Claim 26, wherein the absorbent material is selected from a foam, a hydrocolloid or a hydrogel.
28. A formulation according to any one of Claims 1-23 or a dressing according to any one of Claims 24-27, which is provided with a release liner for easy application to a wound.
29. A formulation according to Claim 1 for a two-phase management of wound healing, substantially as bereinbefore described and exemplified.*
30. A dressing according to Claim 24, substantially as hereinbefore described and exemplified.