WO2003037355A1

WO2003037355A1 - Polyacrylate compositions for use in protecting mucosa

Info

Publication number: WO2003037355A1
Application number: PCT/GB2002/004906
Authority: WO
Inventors: Peter Dettmar; Ian Ronald Flockhart
Original assignee: Reckitt Benckiser Healthcare (Uk) Limited
Priority date: 2001-10-30
Filing date: 2002-10-30
Publication date: 2003-05-08
Also published as: GB0126064D0; EP1441745A1

Abstract

The invention discloses use of a mucoadhesive agent which is a polyacrylate or a salt thereof and a biological response modifier for the preparation of pharmaceutical composition for simultaneous or sequential use in the prevention or treatment of radiation and/or chemotherapy induced damage to mucosal surfaces.

Description

POLYACRYLATE COMPOSITIONS FOR USE IN PROTECTING MUCOSA

The present invention relates to the use of mucoadhesive agents for the prevention and treatment of radiation and chemotherapy induced damage to mucosal surfaces and to compositions therefore.

In many countries radiation and/or chemotherapy are the methods of choice for treating human cancers. Unfortunately both methods of treatment can produce many unpleasant side effects. Various treatment regimes have been developed in an attempt to reduce these side effects. One potentially useful radio-therapy technique is "compressed fraction radio-therapy", wherein smaller doses of radiation are used but with a higher frequency of dosing. All of these regimes still have the drawbac that a proportion of normal cells are damaged as well as the cancerous cells. Particularly susceptible areas of the body to radiation damage are the mucosae. Damage to the mucosae will occur directly during treatment of gastrointestinal cancers. However, secondary damage may also occur during the treatment of cancer in other parts of the body, either due to the passage of radiation beams or the transit of chemotherapy agents .

Damage to mucosal surfaces may lead to immediate symptoms (early damage) but also to symptoms which only appear months or even years after treatment (late damage) .

In the gastrointestinal tract early damage includes disruption of the mucus layer and mucosal cell loss leading to changes in absorption capacity, increased susceptibility to caustic intraluminal contents, mucosal inflammation, diarrhoea, colitis and blood loss.

Such symptoms are very distressing to patients and may lead to poor compliance with treatment regimes.

Certain compositions for the treatment of oral mucositis have been proposed in the prior art. For example, Int. J. Radiation Oncology, 1998, 40(5), 1033-1037 (M. Oguchi et al.) describes a mucoadhesive water-soluble polymer film comprising hydroxypropyl cellulose dissolved in ethyl alcohol containing anaesthetic agents and antibiotics. This paper addresses the roles of pain and secondary infections produced by damage to the mucosae and concomitant invasion into the damaged areas of micro organisms. The paper does not disclose any treatment which is designed to accelerate the healing process (i.e. biological response modifiers) , although good protection of the mucosal surfaces will, in itself, allow the normal repair processes to occur. The treatment disclosed is designed as a palliative (pain relief) and prophylactic (antibiotic) .

Medline Abstract Accession No. 90375985 discloses the use of sodium alginate on the treatment of oral mucositis associated with radiotherapy. This paper discloses the use only of sodium alginate as a protective film forming agent. No biological response modification is disclosed. Strahlenther. Onkol . 173 (1997), 247-252 (C.

Belka et al.) discloses the use of polyaluminium- sucrose complex sucralfate compositions for the prevention and treatment of mucosal reactions. Sucralfate does have biological response modifying activity as well as mucous-adhesive properties, the problems associated with its use are two-fold. The first is the quantity of compound required, certainly for head and neck and other oropharyngeal treatments where a slurry of 1+ gm sucralfate is required several times/day (together with only very modest benefits to these treatment areas) . The second problem is associated with an aluminium- containing compound which may be considered to interact with continued radiation treatment, thereby ruling out this particular approach until after the cessation of radiotherapy.

WO 92/03124 discloses a polymeric complex composition formed by the interaction of a polycarbophil component with alginic acid or a salt thereof in the presence of a divalent cation and an active agent which is a medicinal or cosmetic agent. The composition provides a suitable delivery system for the delivery of active agents to the oral, buccal or gingival skin or mucosa over a period of time. There is no disclosure of the use of such compositions for the prevention, reduction or treatment of radiation damage.

WO 96/13973 discloses compositions having high bioadhesion, mucoadhesion and viscoelasiticity containing mixtures of synthetic polymers, such as polyvinyl alcohol and polycarbophil, and of biopolymers such as alginic acid, hyaluronic acid and dermatan sulphate. The compositions are stated to be useful in the treatment of skin and mucosal tissue dryness and dehydration. There is no disclosure of the use of such compositions for the prevention, reduction or treatment of radiation damage .

US-A-5750136 discloses a bioadhesive composition that adheres to a mucosal surface and which is capable of delivering drugs in a sustained fashion. The mucoadhesive composition is preferably provided as a patch for adhesion to mucosal surfaces, such as the oral mucose. There is no disclosure of the use of the compositions or patches for the prevention, reduction or treatment of radiation damage.

WO 97/47310 disclosed the use of glyceryl poly (meth) acrylate gel based pharmaceutical compositions locally applied for the treatment of various conditions, including the treatment of light burns and post-radiotherapy burns. There is no disclosure in this document of the incorporation of biological response modifiers into the compositions. JP-A-7316038 discloses a sustained release composition which is based upon an acrylic acid- alkyl (meth) acrylate copolymer and which incorporates a drug such as an angiotonic agent, antiallergenic agent, antibiotic, antibacterial agent or anti- inflammatory agent therein.

EP-A-0516141 discloses a sustained release pharmaceutical composition which comprises a bioadhesive polymer and at least one active ingredient. The bioadhesive polymer is preferably a mucoadhesive polymer.

Despite these proposals in the prior art, there is still a need for improved pharmaceutical compositions to prevent or reduce the occurrence of radiation and/or chemotherapy induced damage to mucosal surfaces. A further need exists for an improved pharmaceutical composition to repair radiation and/or chemotherapy induced damage of mucosa surfaces.

According to the invention, there is provided the use of a mucoadhesive agent which is a polyacrylate or a salt thereof and a biological response modifier for the preparation of a pharmaceutical composition for simultaneous or sequential use in the prevention or treatment of radiation and/or chemotherapy induced damage to mucosal surfaces.

The compositions of the present invention possess the advantages that a known film-forming agent can be used which can bind reversibly to mucous thus offering some mechanical protection to areas of underlying tissue where a depleted supply of mucous exists. Polyacrylate mucoadhesive agents are known to slow the rate of gastric transit, thereby maximising the efficiency of both the protective effect and the time required for delivery of repair agents into the underlying tissue.

The composition which is used in the present invention either comprises or is co-administered with a biological response modifier. The polyacrylate mucoadhesive agents used in the present invention are considered to be those agents capable of reversible adhesion to mucus or a mucosal surface. The polyacrylate compositions which are used in the present invention may contain low levels, e.g.. up to 10% by weight, preferably less that 1% by weight of a polyol, such as glycerol. Most preferably, however, the polyacrylate is used as the sole gelling agent in the composition of the present invention. Preferably the polyacrylate mucoadhesive agent is a carbomer e.g. Carbopol 910, Carbopol 934P, Carbopol 940,1 Carbopol 971P, Carbopol 974PNF, Carbopol 1342, Carbopol 5984, ETD 2001, ETD 2020 or ETD 2050 (all available from Noveon Pharma GmbH) or salt thereof. Most preferably the mucoadhesive agent is a pharmaceutically acceptable grade of carbomer (e.g. Carbopol 974PNF) or a salt thereof (e.g. sodium carbomer) . Mixtures of the above mucoadhesive agents may also be used. Thus in a preferred embodiment of this aspect to the present invention there is provided the use of carbomer for the preparation of a pharmaceutical composition for the prevention or treatment of radiation induced early damage to the mucosa surface of the gastro intestinal tract of a mammal. Preferably the mammal is a human.

The mucoadhesive agents may be applied to the mucosal surfaces in doses ranging from 10 mg to lOg, preferably 100 mg to 4g, more preferably 200 mg to 2g and most preferably 400 mg to lg.

Biological response modifiers (BRM's) are those agents known to be active in the repair or regeneration of damage caused to normal tissue. In particular, BRM's include any agent capable of inducing a modification of the biological response of normal mucosae to radiation and/or chemotherapy. Suitable BRM's include vitamins (e.g. A, E,,B5 or C) and their esters and precursors; prostaglandins (e.g. PG_X) and their fatty acid precursors and esters/salts thereof; sulphur containing amino acids; dimethyl sulphoxide; methyl sulphonylmethane and alkyl sulphoxides and sulphonyl compounds of the form R₁R₂SO or R₁R₂S0₂ (wherein R_λ and R₂ are independently selected from alkyl CI to C12, preferably CI, C8 or CIO) ; non steroidal anti flammatory agents (e.g. benzydamine) ; acetyl salicylic acid; growth factors (e.g. epidermal growth factor) ; tumour necrosing factors, and evening primrose oil, borage oil, sea-buckthorn oil or extracts thereof, lanolin or derivatives thereof and other oils of vegetable, animal or marine origin either wholly natural or semi-synthetic in origin and containing single or multiple unsaturated carbon-carbon bonds. Preferably the BRM is benzydamine. BRM's may also be adduced from a miscellaneous group of natural compounds known to have wound healing or skin regenerating activities e.g. allantoin, bisabolol and oils or essences or active fractions prepared from plant tissue e.g. Aloa Vera, or andrographis; provided that they are acceptable for the specific purpose intended. The biological response modifiers may preferably be selected for their ability to stimulate surviving clonogenic stem regrowth in the treated tissue. Mixtures of one or more BRM's may be used in the invention.

The preferred concentrations of the BRM's in the pharmaceutical compositions used in the present invention are between 0.001 and 20% by weight of the pharmaceutical composition, the actual concentration depending upon the intrinsic activity of the BRM and the tissue being treated. Thus growth factors and prostaglandins find their concentration in the range 0.001 to 2.0% of the pharmaceutical composition, whereas vegetable or marine oils are preferably in the range 5 - 20%. Most other agents described herein as BRM's will find their concentration intermediate between these ranges.

It will be understood that a combination of BRM's and mucoadhesive agents of the invention may be particularly efficacious for the treatment of damage at mucosal surfaces, as the mucoadhesive agent will act to hold the BRM's at the surface (i.e. targeted delivery). According to a second aspect of the present invention, there is provided a method of preventing or treating radiation and/or chemotherapy induced damage to a mucosal surface which comprises administering a pharmaceutically effective amount of a mucoadhesive agent, which is a polyacrylate or a salt thereof, in combination with or sequentially with a biological response modifier, to the mucosal surface.

In a preferred embodiment of this aspect of the present invention, there is provided a method for the prevention or treatment of radiation induced early damage to a mucosal surface of the gastro intestinal tract comprising administering a pharmaceutically effective amount of carbomer, in combination with or sequentially with a biological response modifier, to the mucosal surface.

The pharmaceutical compositions used in the present invention may be in any conventional pharmaceutical form, depending upon the size of the dose required and the site to which it is to be administered. The compositions may therefore include conventional formulation excipients according to the form of the composition.

Forms in which the compositions can be presented for use in the invention include tablets

(comprising from 20 to 800 mg mucoadhesive) , hard or soft capsules (comprising 10 to 400mg mucoadhesive) , sachets of granules or powders to be taken in a drink (comprising 20 to 800 mg mucoadhesive) , liquid compositions (comprising up to 20% w/v mucoadhesive) , gel compositions (comprising up to 20% w/v mucoadhesive) , buccal compositions (comprising 10 to 500 mg mucoadhesive) , enemas (comprising 10 mg to 2 g per 100ml mucoadhesive) , pessaries (comprising 10 mg to 1 g mucoadhesive) , suppositories (comprising 20 mg to 2 g mucoadhesive) or mousse compositions (comprising up to 20% mucoadhesive) . These compositions may be produced using conventional techniques well known in the art. it will be understood that multiple units of a particular composition may need to be administered (or mixtures of two or more compositions types may be used) to achieve very high mucoadhesive doses. Where the mucoadhesive agent and the BRM are intended to be administered to a particular mucosal surface within the gastrointestinal tract, the composition containing the mucoadhesive agent and optionally the BRM may need to be modified to allow the mucoadhesive agent and BRM to reach that area. For example oral tablets or capsules may be enterically coated so that the mucoadhesive and BRM are not released until the composition reaches the small intestine. Alternatively compositions may be designed to stay in the stomach and not to progress further along the gastrointestinal tract if protection or treatment is only needed in the stomach. If the whole gastrointestinal tract is to be protected or treated simple oral administration may suffice, as the mucoadhesive will adhere all along the tract. Furthermore mucoadhesive agents which bind to upper regions of the mucosal tract may be rebound at lower regions following the sloughing off from the mucosal surface of the upper regions. Dosing frequency of the pharmaceutical compositions may be up to 8 times daily during the first 48 hours following radiation therapy, or up to 4 times daily at other times.

Suitable mucosal surfaces include the gastro intestinal tract, oral, nasal, vaginal, rectal and oesophageal surfaces, plus the bladder and anus. Most particularly the mucoadhesive agents may be used for the treatment or prevention of radiation or chemotherapy induced damage to the mucosal surfaces of the gastro intestinal tract. All forms of radiation or chemotherapy induced damage to mucosal surfaces may be prevented or treated by the methods and/or compositions of the invention, most particularly early damage.

According to a further aspect to the present invention there is provided a system comprising:

i) a mucoadhesive agent which is a. polyacrylate or a salt thereof; ii) a biological response modifier; and iϋ) instructions for the use thereof in the prevention or treatment of radiation and/or chemotherapy induced damage to mucosal surfaces.

The invention will now be illustrated by reference to the following Examples.

EXAMPLE 1

Liquid Formulation mg per 10ml

Carbopol 974PNF 100 Sodium bicarbonate 100 Calcium carbonate 100 Methyl paraben 30 Propyl paraben 4 . 5 Sodium Saccharin 5 Natural source Vitamin E 1 . 0 Dexpanthenol (85% w/v) 12 . 5 Flavour 5 μl Sodium hydroxide solution (20%) qs

Deionised water to 10 ml

1. The carbomer is dispersed in 2/3 of the deionised water in a first vessel and neutralised with the sodium hydroxide solution.

2. The sodium bicarbonate is dispersed in a small amount of deionised water in a separate vessel and then added to the neutralised carbomer and mixed (carbomer phase) .

3. The calcium carbonate, sodium saccharin, methyl paraben, propyl paraben, Vitamin E and dexpanthenol are dispersed in deionised water in a second vessel (dispersion phase) .

4. A small amount of the carbomer phase is added to the dispersion phase, mixed and then added back into the carbomer phase with further mixing.

5. The flavour is added and the volume adjusted with deionised water, and the final pH of the gel formulation adjusted to pH 8.2 with sodium hydroxide solution.

An animal study was conducted as follows:

Groups of 40 female Sprague-Dawley rats were divided into five treatment groups. Each subgroup received a standardised dose of β-radiation from a ⁹o_Sr/^9θγ pi_ague to the tip of the tongue. The time of application was varied to give a dose escalation of radiation and mucositis incidence as follows: Group No. Radiation Dose Incidence of

Mucositis in Untreated Animals

1 12 . 0 Gy 0% (0/8)

2 13 . 5 Gy 31.25% (2.5/8)

3 15 . 0 Gy 50.0% (4/8)

4 16 . 5 Gy 68.8%

( 5 . 5 / 8 )

55 1188..00 GGyy 100% (8/8)

Three formulations were tested for their potential activity in ameliorating the incidence or severity of mucositis . Formulation :

1) Saline (control treatment)

2) Gel formulation detailed above (lOOμl applied topically)

3) Aerosol delivery system, 0.5mg Vitamin E in ethanol/diethylene glycol monoethyl ether solution, 50 l/delivery. The application of each formulation commenced 24 hours after the irradiation and continued daily for two weeks. Scoring of the tissue response was carried out independently by two trained observers.

Results :

The saline controls exhibited a nil response to the treatment, each of the irradiation groups exhibiting a response in line with historic controls (ED50 14.8 Gy, historic control 14.9 ± 0.6 Gy) . The Vitamin E spray exhibited only a small and nonsignificant modification to the ED50 value (15.4 ± 0.8 Gy) , whereas the gel-based formulation of the invention gave a highly significant alteration to the ED50 of 17.7 ± 0.9 Gy - a dose modification factor of 1.25 ± 0.08 (Observer 1) or 1.17 ± 0.06 (Observer 2) .

From these data, it can be inferred that the mucin-binding carbomer formulation of the invention containing Vitamin E and dexpanthenol exhibits a significant effect on the course of radiation- induced damage to mucous membranes/tissue.

EXAMPLE 2

Chewable Tablet Formulation mg per tablet Carbopol 974PNF 100 Calcium carbonate 100

Sodium bicarbonate 100

Microcrystalline cellulose 100

Mannitol 360

Xylitol 200 Benzydamine hydrochloride 30

Flavour 15

Citric acid 10

Aspartame 5

Magnesium stearate 10 Granulation Fluid - Deionised water qs

1. The calcium carbonate, sodium bicarbonate, microcrystalline cellulose and mannitol are sieved through a 500 μτa (30#) sieve, added to the carbomer and blended in a high speed food processor.

2. Approximately 40 ml of water is added to the powder whilst mixing to form granules.

3. The granules are dried at 60°C in a fluid bed drier for 25 minutes before screening through an 850 μτ (18#) sieve. 4. The xylitol, benzydamine hydrochloride citric acid and aspartame are screened through a 500 μm (30#) sieve, added to the dried granules and mixed in a high speed food processor.

5. Approximately 60 ml of deionised water is added to the powders, whilst mixing, to form granules.

6. The granules are dried at 600°C in a fluid bed drier for 25 minutes before screening through an 850 μm (18#) sieve.

7. The flavour and magnesium stearate are added to the dried granules and blended for 3 minutes. 8. The granules are formed into tablets by pressing on a tablet press to give tablets with a weight of Ig.

EXAMPLE 3 Enema Formulation mg per 100 ml Carbopol 974PNF 1000

Sodium chloride 800

Benzydamine hydrochloride 500 Sodium hydroxide solution (20%) qs

Deionised water to 100 ml

1. The carbomer is dispersed in 1/3 of the deionised water in a suitable mixing vessel . 2. A further 1/3 of the deionised water is added and the solution neutralised with the sodium hydroxide solution. 3. The sodium chloride and benzydamine hydrochloride, are dissolved in deionised water, added to the neutralised carbomer and the final volume adjusted with deionised water. 4. The final pH is adjusted using sodium hydroxide solution to within the range 7.45 - 7.55.

EXAMPLE 4

Liquid Formulation mg per 10ml Carbopol 974PNF 100

Sodium bicarbonate 100

Calcium carbonate 100

Methyl paraben 30

Propyl paraben 4.5 Sodium Saccharin 5

Flavour 5 PI

Methyl sulphonylmethane 100

Sodium hydroxide solution (20%) qs Deionised water to 10 ml 1. The carbomer is dispersed in 2/3 of the deionised water in a first vessel and neutralised with the sodium hydroxide solution.

3. The calcium carbonate, sodium saccharin, methyl paraben, propyl paraben and methyl sulphonylmethane are dispersed in deionised water in a second vessel (dispersion phase) .

4. A small amount of the carbomer phase is added to the dispersion phase, mixed and then added back into the carbomer phase with further mixing. 5. The flavour is added and the volume adjusted with deionised water.

EXAMPLE 5

Sachet Formulation mg per dose Carbopol 971P 400

Mannitol 2500

Sodium bicarbonate 400

Citric acid 700

Methyl Sulphonylmethane 50 Flavour 200

Aspartame 10

Acesulfame K 10

Colloidal silica 25

Vitamin E adsorbate 250 1U The process of Example 3 is used except that the Vitamin E adsorbate is added at the same time as the sodium bicarbonate, citric acid, flavour, aspartame and acesulfame K.

EXAMPLE 6

Gel Formulation mα/α Evening Primrose Oil (containing 10% GLA plus Antioxidant) 100 Pemulen TR 2 3

Phenonip 2.5

Carbopol 974 PNF 40

Deionised water 854

Sodium hydroxide 20% solution to neutralise qs 1. The Pemulen TR2 (B.F. Goodrich, Cleveland, Ohio) is slurried with the evening primrose oil using a blade mixer and the phenonip added to it (oil phase) . 2. The Carbopol 974 PNF (Noveon Pharma GmbH) is dispersed in deionised water until completely hydrated (aqueous phase) .

3. The aqueous phase is slowly added to the oil phase, increasing the mixing speed until uniformity is achieved.

4. The final pH of the product is adjusted using sodium hydroxide solution to within the range 7.4 - 8.0.

EXAMPLE 7

Gel Formulation mg/q

Evening Primrose Oil (containing

10% GLA plus Antioxidant) 100 Pemulen TR 2 3

Phenonip 2 . 5

Carbopol ETD 2020 40

Deionised water 854

Triethanolamide to neutralise 9 . 5 Vitamin E acetate ester 10

Vitamin A palmitate ester 1

Panthenol 12 . 5 The process of Example 6 is used adding Vitamin A and Vitamin E esters to the oil phase and adding panthenol to the aqueous phase. EXAMPLE 8

Liquid Formulation mg per 10ml

Carbopol 974PNF 100

Sodium bicarbonate 100

Calcium carbonate 100

Methyl paraben 30

Propyl paraben 4.5 Glycerol 10

Deqlycerrhicised liquorice extract 5

Flavour 5 μl

Sodium hydroxide solution (20%) qs

Deionised water to 10ml 1. The carbomer is dispersed in 2/3 of the deionised water in a first vessel and neutralised with the sodium hydroxide solution.

3. The calcium carbonate, glycerol, methyl paraben, propyl paraben and deqlycerrhised liquorice extract are dispersed in deionised water in a second vessel (dispersion phase) .

5. The flavour is added and the volume adjusted with deionised water.

Claims

CLAIMS :

1. Use of a mucoadhesive agent which is a polyacrylate or a salt thereof and a biological response modifier for the preparation of a pharmaceutical composition for simultaneous or sequential use in the prevention or treatment of radiation and/or chemotherapy induced damage to mucosal surfaces.

2. Use as claimed in claim 1 wherein the composition contains a biological response modifier therein or is co-administered with a biological response modifier.

3. Use as claimed in claim 1 wherein the mucoadhesive agent is carbomer and the radiation induced damage to the mucosal surface is early damage .

4. Use as claimed in any one of the preceding claim wherein the mucoadhesive agents are be applied to the mucosal surfaces in doses ranging from 10 mg to lOg, preferably 100 mg to 4g, more preferably 200 mg to 2g and most preferably 400 mg to lg.

5. Use as claimed in any one of the preceding claims wherein the biological response modifier is selection from vitamins including A, E, B5 and C and their esters and precursors; prostaglandins including PG1 and their fatty acid precursors and esters/salts thereof; sulphur containing amino acids; dimethyl sulphoxide; methyl sulphonylmethane and alkyl sulphoxides and sulphonyl compounds of the form R₁R₂SO or R₁R₂S0₂ (wherein R and R₂ are independently selected from alkyl CI to C12, preferably CI, C8 or CIO) ; non steroidal anti inflammatory agents including benzydamine; acetyl salicylic acid; growth factors including epidermal growth factor; tumour necrosing factors, evening primrose oil, borage oil, seabuckthorn oil or extracts thereof, lanolin or derivatives thereof; other oils of vegetable, animal or marine origin either wholly natural or semi-synthetic in origin and containing single or multiple unsaturated carbon-carbon bonds and mixtures of the above.

6. Use as claimed in any one of the preceding claims wherein the concentration of the biological response modifier is between 0.001 and 20% by weight of the pharmaceutical composition.

7. A method of preventing or treating radiation and/or chemotherapy induced damage to a mucosal surface which comprises administering a pharmaceutically effective amount of mucoadhesive agent, which is a polyacrylate or a salt thereof, in combination with or sequentially with a biological response modifier, to the mucosal surface.

8. A method as claimed in claim 7 wherein the mucoadhesive agent is carbomer.

9. A method as claimed in claim 7 or claim 8 wherein the biological response modifier is selected from vitamins including A, E, B5 and C and their esters and precursors; prostaglandins including PG1 and their fatty acid precursors and esters/salts thereof; sulphur containing amino acids; dimethyl sulphoxide; methyl sulphonylmethane and alkyl sulphoxides and sulphonyl compounds of the form R₁R₂S0 or R₁R₂S0₂ (wherein R and R₂ are independently selected from alkyl CI to C12, preferably CI, C8 or CIO); non steroidal anti inflammatory agents including benzydamine; acetyl salicylic acid; growth factors including epidermal growth factor; tumour necrosing factors, evening primrose oil, borage oil, seabuckthorn oil or extracts thereof, lanolin or derivatives thereof; other oils of vegetable, animal or marine origin either wholly natural or semi-synthetic in origin and containing single or multiple unsaturated carbon-carbon bonds and mixtures of the above.

10. A method as claimed in any one of claims 7 to 9 wherein the concentration of the biological response modifier is between 0.001 and 20% by weight of the pharmaceutical composition.

11. A use or method according to any preceding claim wherein the mucosal surface includes the gastro intestinal tract, oral, nasal, vaginal, rectal and oesophageal surfaces, including the bladder and anus .

12. A system which comprises: i) a mucoadhesive agent which is a polyacrylate or a salt thereof ii) a biological response modifier; and iii) instructions for the use thereof in the prevention or treatment of radiation and/or chemotherapy induced damage to mucosal surfaces .