EP2544669A1

EP2544669A1 - Adhesive patch for therapeutic agent delivery

Info

Publication number: EP2544669A1
Application number: EP10707914A
Authority: EP
Inventors: Robin List
Original assignee: Sylphar
Current assignee: Sylphar
Priority date: 2010-03-11
Filing date: 2010-03-11
Publication date: 2013-01-16
Also published as: WO2011110225A1

Abstract

An adhesive patch for the delivery of at least one therapeutic agent, said patch comprising a soluble film incorporating said at least one therapeutic agent.

Description

"Adhesive patch for therapeutic agent delivery"

The present invention relates to an adhesive patch for the delivery of at least one therapeutic agent.

Such adhesive patches are already known, for instance, for the transdermal delivery of therapeutic agents. However, they are relatively uncomfortable, usually do not offer a significant physical barrier, and require to be removed after use, which, for instance, may easily lead to re-infection.

The present invention solves these problems in that it comprises a soluble film incorporating said at least one therapeutic agent. Such a soluble film provides a fast, accurate dosing that can be expected to increase compliance. There is no need for water or measuring, and upon dissolution of the film, an accurate dose of the at least one therapeutic agent is absorbed. Today's consumers cite better portability, ease and accuracy of dosing, and overall convenience as the product attributes they seek most in medicine.

In a preferred embodiment, said adhesive patch is an adhesive patch for buccal or sublingual application for the treatment of mouth ulcers. Aphthous stomatitis is an illness that causes small ulcers or "canker sores" to appear in the mouth, usually inside the lips, on the cheeks, or on the tongue.

According to research reported by the National Institute of Dental and Craniofacial Research, canker sores may be caused by a faulty immune system that uses the body's defence against disease to attack and destroy the normal cells of the mouth or tongue. According to 2001 WHO data, aphthous stomatitis is one of the two major oral health problems around the world

Recent epidemiological data, published by Kovac and Kavcic, in Journal of Oral Pathology and Medicine (2000), Vol 29, Page 331 , show that the incidence of aphthous stomatitis is around 60% in the adult population over the course of a year. According to Community Dent Oral Epidemiol. 1994 Aug;22(4):243-53, 37% of all schoolchildren in the US reported a history of recurrent aphthous ulcers.

All these epidemiological data show that mouth ulcers have a very high incidence with recurrent character.

The adhesive patch of the invention presents the following advantages for the treatment of mouth ulcers:

- The film creates a physical barrier over the ulcer;

- there is a lower risk on cross contamination of external triggers: e.g. contaminated fingers;

- the patch ensures a single use application;

- there is no dilution, or wash off effect; and

- there is a slow and sustained release of the at least one therapeutic agent.

Advantageously, said soluble film may comprise carbomer and/or polyethylene dioxide. These ensure a good adhesion of the film to the buccal mucosa, and a controlled dissolution of the film in the buccal environment.

Advantageously, said at least one therapeutic agent may comprise hyaluronic acid, red mangrove, and/or polyvinylpyrolidone.

Hyaluronic acid initiates the production of new cells and is responsible for initiating the healing process after trauma. Not only does it reduce the pain of canker sores but it also accelerates the healing of injured tissues in the mouth. Besides the inflammation, hyaluronic acid can reduce the healing time for the repair of damaged tissue by up to 50%. Red mangrove (Rhizophora mangle), and in particular its aqueous bark extract (RMABE), also reduces the time to repair mucosal tissue, erythema, ardour and pain persistence.

Polyvinylpyrolidone (PVP) has an ability to form complexes with a large number of substances, which can be used to reduce the toxicity of certain therapeutic agents. Moreover, it has a strong adhesive and binding power, which in this case ensures the adhesion of the patch to the buccal mucosa and forms a protective physical film covering the ulcerated area and isolating any infected tissue.

Advantageously, the adhesive patch may also further comprise an insoluble ingestible backing over said soluble film, the facilitate handling and placing the adhesive patch over the mouth sore. Since this backing is ingestible, it may be swallowed, even inadvertently, by the patient, after the soluble film dissolves entirely. Preferably, said insoluble ingestible layer may comprise ethylcellulose. Ethylcellulose is also a barrier forming agent: it forms a thin barrier over the exposed nerve endings on the mucosa, bringing pain relief.

The present invention also relates to a method of producing an adhesive patch comprising a soluble film incorporating said at least one therapeutic agent for buccal or sublingual application for the treatment of mouth ulcers, wherein said soluble film may contain carbomer and/or polyethylene dioxide, and said at least one therapeutic agent may comprise hyaluronic acid, red mangrove, polyvinylpyrolidone and/or cellulose.

In another preferred embodiment, said adhesive patch is an adhesive patch for labial application for the treatment of labial herpes. The herpes simplex virus (HSV) causing herpes labialis cold sores is highly prevalent, and those cold sores unpleasant and embarrassing to the patients. The use of this adhesive patch for the treatment of herpes labialis presents the advantages of ease of application, reducing the risk of cross-contamination when applying or removing the patch, since it can be simply washed away, and ensuring a long contact time of the at least one therapeutic agent. Moreover, the patch will create a protective barrier, thus ensuring pathogenic isolation of the cold sores caused by the viral infection.

Advantageously, said soluble film may comprise polyvinyl alcohol (PVA) and/or hydroxypropyl methyl cellulose (HPMC). Both kinds of soluble films present physical properties that facilitate their handling and their use in the present application.

Advantageously, said at least one therapeutic agent may comprise a zinc salt, preferably zinc sulphate; an immunomodulator, more preferably a glucan, in particular β-1 ,3-D-glucan; and/or at least one sulphated polysaccharide, preferably from an algal extract.

A topical zinc solution, such as that formed by dissolving a zinc salt like zinc sulphate, has been shown to reduce both the number of episodes and the time to recovery of herpes labialis, as well as irreversibly inhibit HSV replication in vitro. Moreover, it has a preventive effect, against relapse of both herpes labialis and post-herpetic erythema multiforme. It improves wound healing, and stops pain, tingling and burning.

An immunomodulator such as β-1 ,3-D-glucan modulates wound healing via an indirect mechanism in which macrophages are stimulated to release growth factors and cytokines, enhancing immune system function and preventing subsequent infection.

Sulphated polysaccharides, such as those from algal extracts, present anti-inflammatory, UV-protective and antiviral properties.

Advantageously, the adhesive patch may be pigmented, so as to help conceal unsightly cold sores.

The present invention also relates to a method of producing an adhesive patch comprising a soluble film incorporating said at least one therapeutic agent for labial application for the treatment of labial herpes, said at least one therapeutic agent may comprise a zinc salt, preferably zinc sulphate; an immunomodulator, preferably a glucan, in particular β-1 ,3-D-glucan; and at least one sulphated polysaccharide, preferably from an algal extract.

In yet another preferred embodiment, the adhesive patch is an adhesive patch for dermal application for the treatment of skin wounds and/or ulcers.

Particular embodiments of the invention will now be described in an illustrative, but not restrictive form.

In a first embodiment of the invention, the adhesive patch is a patch for buccal or sublingual application for the treatment of mouth ulcers. An aphthous ulcer is a clearly defined painful, round or ovoid, shallow ulcer inside the oral cavity mainly in the mouth or upper throat and caused by a break in the mucous membrane. The term aphthea means ulcers; it has been used for many years to describe areas of ulceration on mucous membranes. Aphthous ulceration is a condition which is characterized by recurrent discrete areas of ulceration with chronic inflammatory properties and therefore sometimes referred as recurrent aphthous ulceration (RAU).

Recurrent aphthous ulceration can be distinguished from other oral diseases with similar-appearing oral lesions by their tendency to recur and their multiplicity. Aphthous ulcers are classified according to the diameter of the lesion into minor, major and/or Herpetiform aphthea. Each of them associated with specific clinical features, (see table 1 ).

Minor aphthea Major aphthea Herpetiform

aphthea

Size <1 ,0 cm >1 ,0 cm <0,1 cm

Shape Round-oval Ragged, oval, Round-oval craterifrom (may

coalesce into plaques)

Number 1 -5 1 -10 10-100

Location Non keratinized Non keratinized Any intraoral site mucosa mucosa

Healing period heal take 10-30 days heal in 7-10 spontaneously or more to heal, days

in 7-10 days and may leave

scars

% of RAUs 80-85% 10-15% 5-10%

Table 1 : Clinical features of aphtheous ulceration

There is no single or specific cause of aphthous ulceration. The overall view of its pathogenesis is a pluralistic or multifactorial one, that includes inducing and/or precipitating factors and triggers. The primary disorder appears to be the result of activation of the cell- mediated immune system. Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of other immune systems like macrophages and cytotoxic T- lymphocytes.

In the beginning of an aphthous ulceration, a cluster of macrophages and white blood cells (predominantly cytotoxic and natural- killer T cells) are noticed at the preulcerative base, followed by formation of a real ulcer. It has also been noticed that patients with RAUs have a different proportion of cell types in the their blood: they have an increased numbers of cytotoxic CD8+ cells and decreased numbers of helper CD4+ cells.2

Some precipitating factors of RAU include:

- Trauma: Local injury, such as that caused by an accidental bite, toothbrush bristle, ...may precipitate aphthous ulcers in individuals who are susceptible.

- Stress: The role of psychological and physiologic stress as risk factors for aphthous ulcers is controversial. Individuals with aphthous ulcers have had higher-than-average anxiety scores and Cortisol levels. Antidepressant therapy may be effective in some patients.

- Genetic predisposition: A family history of RAU is common, though familial penetrance has not been identified as a specific category.

- Local infection: Several infectious agents have been identified in association with aphthous ulcer lesions, including human herpes virus and cytomegalovirus.

- Nutritional deficiencies: Deficiencies of iron; folic acid; zinc; and vitamins B-1 , B-2, B-6, B-12, and C have all been implicated in RAU.

- Gastro-lntestinal disorders, such as ulcerative colitis, may result in aphthous ulcers. The ulcers may be the only presenting symptom or the only symptom that is evident for a number of years in patients with Gl disorders.

- Systemic disorders: Disorders such as Behget disease, or HIV infection may result in aphthous ulcers.

- Food allergy and hypersensitivity: Flavoring agents, essential oils, benzoic acid, cinnamon, gluten, cow's milk, coffee, chocolate, potatoes, cheese, figs, nuts, citrus fruits, and certain spices have been implicated in some individuals with RAUs.

- Hormonal fluctuations: In some women, RAUs are associated with the menstrual cycle, with outbreaks most commonly occurring during ovulation or before menstruation. - Chemical exposures: High levels of nitrates in drinking water have been associated withaphthous ulcers. Sodium lauryl sulfate (SLS), a detergent commonly used in toothpaste, may be a trigger of aphthous ulceration in some individuals.

- Significant correlations have been shown between the severity of aphthous stomatitis and hygiene of the oral cavity. Good hygiene reduces not only the number of outbreaks but also the severity.

The goal of RAU treatment is to provide the patient with control over this condition by increasing comfort, decreasing the frequency of future ulceration, and promoting healing of existing ulcers. The main over-the-counter preparations consist of topical gels, creams, pastes and/or liquids containing topical anesthetics.

The downside of those products is the short and limited therapeutic action, this is the result of two factors:

- The minimal contact time of the therapeutic device with the ulcerated tissue due to the wash away effect of the saliva; and

- the galenic matrix (gel, creams, pastes, liquids) in which the active ingredient are embedded. Those classic delivery devices do not stick long enough to the infected area due the intrinsic properties of the oral tissues.

Beside the limited therapeutic action, those devices are focused on pain treatment and not on promoting healing of existing ulcerated areas.

If the RAU persist, prescription medication is additionally advised by the clinician such as tetracycline, acyclovir, colchicine and prednisone suspensions. Sometimes anxiolytic agents or antidepressants are prescribed because they may be helpful for some patients if RAU are precipitated by stress.

The delivery device that the adhesive patch of this first embodiment uses is a thin, soluble, mucoadhesive film. Such a film provides fast, accurate dosing and increased patient compliance. This thin, soluble, mucoadhesive film is loaded with active ingredients. Those therapeutic agents will be released slowly and in a sustained manner onto the infected area. This will heal and decrease pain instantly but also in time.

In addition to the intrinsic advantage offered by the mucoadhesive film, being an ideal vehicle for reversibly immobilizing and encapsulating active ingredients, there are a number of other properties of this technology that optimize the healing promotion and pain treatment:

Due to the unique physical properties of the delivery device, being a film that sticks to the infected area, a treatment therapy is possible, since the wash away and dilution effect of the saliva is avoided. The therapeutic agents are targeted onto the infected area by the mucoadhesive film and are not diluted. This lies in strong contrast with the classic delivery devices (creams, gels, pastes and liquids) that are currently used. By using this soluble film the contact time between the ulcerated surface and the active ingredients is maximized. This leads to a single-application treatment and therefore contributes to the therapy compliance. Also the physical properties of the film will create a strong barrier between the ulcerated area and the oral cavity. This will isolate the aphthous ulceration and will prevent painful stimuli (e.g. cold drinks, tongue, food,...) to reach the infected tissues.

Due to the single application of a mucoadhesive film there is a significant lower risk of cross contamination compared to the classic OTC drugs which are mainly applied physically ( e.g. multiple applications with contaminated fingers).

In a particular example of this first embodiment of the invention, the adhesive patch is a disc with 12 mm of diameter that can adhere to the mucosal lining of the cheek for up to 40 minutes. An ethylcellulose ingestible substrate, colored pink for identification, was employed as insoluble backing layer over a thin, soluble, mucoadhesive film containing carbomer, polyethylene oxide and active therapeutic agents, and having a red-brown color. In this specific example, the active therapeutic agents in the thin, soluble, mucoadhesive film are hyaluronic acid, in a concentration of 4.2 % wt. of the film, and red mangrove aqueous bark extract, in a concentration of 33.5 % wt. of the film.

Hyaluronic acid (HA) is a naturally occurring polysaccharide, a glycosaminoglycan, that consists of N-acetyl-diglucosamine and beta- glucoronic acid. HA is a vital substance produced by the body which initiates the production of new cells as part of the wear and tear process and is responsible for initiating the healing process after trauma. Therefore HA is present in the intercellular matrix of most connective tissues, especially skin where it has a protective, structure stabilizing and shock-absorbing role. Many of the biological processes mediated by HA are central to the wound healing process. Following injury, wound healing relies on a series of tightly regulated sequential events, e.g. inflammation, formation of granulation tissue, reepithelization, and remodeling.

In the domain of oral care, HA has been found to be particularly suited to reform gingival tissues and to regulate the healing of the gums to a normal physiological state.

Hyaluronic acid is also an indispensable component of intact, healthy gums and oral mucosal tissue. It is distributed in a selective, specific manner and it tends to concentrate particularly in those layers of the gingival epithelium closest to the surface where it acts as a barrier imparting stability and elasticity to the tissue.

One of the main actions of HA is that of normalizing the natural structure of the connective tissue, accelerating the rate of tissue reconstruction. HA regulates also the cell permeability and reduces the abnormally high capillary permeability. This helps to prevent infestation by nfectious micro-organisms, thus inhibiting the destruction of tissue.

A further biological function of Hyaluronic acid in tissue regeneration is its ability to influence the migration of fibroblasts (a cell that synthesizes and maintains the tissue matrix) with the result that scar tissue formation and wound healing are promoted. It has been shown by A. Nolan et al. in "The efficiency of topical hyaluronic acid in the management of RAU", JOPM (2006) 35: 461 -5, that HA not only reduces the pain of aphthous ulcerations but also accelerates the healing of injured tissues in the mouth.

Furthermore HA possesses an extremely high capacity to bind water (up to 50 times its own volume). Thanks to this property, HA possesses an anti-oedematous effect. According to Marco Averbeck et al., "Differential Regulation of Hyaluronan Metabolism in the Epidermal and Dermal Compartments of Human Skin by UVB Irradiation", Journal of Investigative Dermatology (2007) 127, 687-697, HA is also able to bind specific proteins and tissue polysaccharides and thus form a viscous macro-aggregate which will protect the injured area .

Another action of HA is the inactivation of the hyaluronidase enzyme of certain malign bacteria, which results in an anti-inflammatory effect. It has been confirmed by Innocenti et al., in "Efficacy of topical hyaluronic acid in reducing pain in palliative care patients with oral lesions: preliminary findings from an open pilot study, J Pain Symptom Manage, 24(5): 546-7, 2002, that HA has the ability to reduce inflammation and the healing time for the repair of damaged tissue by up to 50%. HA has also been found by Voinchet et al., in "Efficacy and safety of hyaluronic acid in the management of acute wounds", Am J Clin Dermatol. 2006;7(6):353-7, to be well tolerated and show no adverse events.

Rhizophora mangle (Rhizophoraceae), the red mangrove, is a subtropical/tropical tree which colonizes coastlines and brackish water habitats below the 20 °C isotherm in both the northern and southern hemispheres. It is widely distributed along the tropical and subtropical coasts of America from Bermuda to Florida, Occidental Africa and the islands of Fiji, Tonga and New Caledonia and is a characteristic tree of the lower and swampy zones of the Cuban archipelago. According to Roig et al., "Plantas medicinales, aromaticas y venenosas de Cuba", 1974 Editorial Revolucion y progreso, La Habana, p. 745, Rhizophora mangle has been used in traditional medicine as astringent, antiseptic and haemostatic with antifungic and antiulcerogenic properties.

Furthermore, according to Morton et al., "Atlas of medicinal plants of Middle America", 1981 Bahamas to Yucatan, the red mangrove has been widely used in folk medicine for the treatment of diarrhea, dyspepsia, epistaxis, eye ailments, inflammations, sore throat and wounds. The aqueous extract has shown, according to Melchor et al., "Antibacterial activity of Rhizophora mangle bark" , 2001 , Fitoterapia 72, 689-691 , antibacterial activity along with efficacy in the healing of open surgical wounds.

In the matter of toxicological safety of Rhizophora mangle , the US Environmental Protection Agency concluded in its study "Plant Extract Derived From Opuntia lindheimeri (Prickly Pear Cactus), Quercus falcata (Red Oak), Rhus Aromatica (Sumac), and Rhizophoria mangle (Mangrove): Exemption From the Requirement of a Tolerance" , Federal Register: May 7, 1997 (Volume 62, Number 88), that the results of the submitted acute toxicology and mutagenicity data of Rhizophoria mangle are of a low acute toxicity such that test requirements for subchronic, chronic, immune, endocrine, dietary and non-dietary studies were not triggered. The Agency has determined that all toxicology data requirements have been satisfied and that no harm will result from aggregate exposure, including infants and children, to residues of plant extract from Rhizophoria mangle (mangrove).

The ethylcellulose of the backing layer also has a therapeutic activity, as it is also a barrier forming agent: it forms a thin barrier over the exposed nerve endings on the mucosa, bringing pain relief. All these three kinds of therapeutic agents have been found to be particularly adapted for their delivery through a soluble film. In combination, they have turned out to be particularly effective.

In combination, or alternatively to each of these therapeutic agents, other therapeutic agents, such as polyvinylpyrolidone (PVP), could also be considered by the skilled person, preferably in the soluble film, but also in the backing layer.

PVP, for instance, is a very well known ingredient in the pharmaceutical industry and it has several applications in pharmaceuticals (see table 2).

PVP Properties

Solubility in all conventional solvents

Adhesive and binding power

Film formation

Affinity to hydrophilic and hydrophobic surfaces

Ability to form complexes

Availability in different average molecular weights Thickening properties

Table 2. General properties of PVP in pharmaceuticals

One of the functions of PVP is that of chemically stabilizing certain active ingredients. Because of its ability to form complexes with a large number of substances, PVP can be used to reduce the toxicity of certain active ingredients. In that matter PVP is also being used as a reducer of irritant or toxic effects of other substances, as shown in Wilkinson et al., CSMA Proceedings, 40th Midyear Meeting of the Chem. Spec. Manufacturers Ass. Inc. (1953).

Because of its excellent adhesion and physiological safety, PVP is also used as adhesives on the skin or mucous membranes. In transmucosal systems, PVP has been used, according to Vyas et al., Uppadbayay, Drug Dev. Ind. Pharm. 20 No. 1 , 101-1 10 (1994), as an adhesive, to improve or control transdermal absorption, or to stabilize active substances. In the specific field of mucoadhesive film applications PVP has been cited by Perioli et al., in "Development of mucoadhesive patches for buccal administration of ibuprofen", Journal of Controlled Release Volume 99, Issue 1 , 14 September 2004, Pages 73-8, as one of the best film forming agents 20.

Based on those properties, PVP may be used in the adhesive patch of the present invention mainly for its film forming action. Upon application, the abovementioned mucoadhesive film of forms a physical film barrier that covers the ulcerated area and therefore substantially isolates the infected tissues.

According to Robinson et al., in "PVP - A Critical Review of the Kinetics and Toxicology of Polyvinylpyrrolidone (Povidone)", Lewis Publishers (1990), PVP is very well tolerated and possesses a good toxicological profile. Because of the good tolerance of PVP, its Accepted Daily Intake (ADI) was adjusted to 0 - 50 mg/kg body weight by the FAO/WHO Joint Expert Committee for Food Additives (JECFA) in 1987.

The adhesive patch may also comprise additional ingredients, such as colorants (for instance Allura Red [E129] and Titanium dioxide [E171 ] for the pink and red-brown colors), flavors (for instance mint flavor), sweeteners (for instance Acesulfame K [E950] and Sucralose [E955]), and lubricants/plasticizers such as dibutylsebicate.

In use, the patient can himself hold the adhesive patch by the pink-colored backing layer, moisten the red-brown-colored adhesive film, and stick the patch onto the mouth ulcer, where it will cover the ulcer and gradually release its at least one therapeutic agent. Once the soluble film dissolves substantially entirely, the backing layer will be ingested by the patient, usually inadvertently.

The present invention is alternatively embodied in an adhesive patch for labial application for the treatment of labial herpes. Previous OTC systems for the delivery of therapeutic agents for the treatment of labial "cold sores" caused by HSV infection are limited to gels and tablets. These delivery systems present side effects and lack effectiveness. Being usually based on acyclovir/penciclovir, they present a narrow treatment spectrum. Moreover, in the labial environment, these previous delivery systems only offer a short contact time for the effective delivery of the therapeutic agent, a particularly critical drawback considering that the timing of the treatment is crucial for its effectiveness. Frequent readministration using these previous OTC delivery systems only increases the risk of cross-contamination. While patches for concealing cold sores have been proposed under the "Compeed®" trademark, these do not comprise any therapeutic agent. Moreover, they require to be frequently removed and replaced by hand, greatly increasing the risk of cross-contamination.

For this embodiment of the adhesive patch of the invention, the soluble film may be chosen, for instance, from among those currently sold by Watson, Inc. under the designations QSA 2000 (a fast dissolving hot and cold water soluble film based on polyvinyl alcohol) or EM 1 100 (a food grade, edible, heat sealable, cold water soluble film based on hydroxypropyl methyl cellulose). Such soluble films offer the advantages of being breathable, yet forming a physical protective barrier over the cold sore, and gradually delivering the therapeutic agent or agents directly onto the infected area. Moreover, they can be directly washed off after use, thus very substantially reducing the risk of cross-contamination.

In a particular example of this embodiment of the invention the agents incorporated into the soluble film comprise zinc sulphate, β- 1 ,3-D-glucan as an immunomodulator, and an algal extract and comprising a sulphated polysaccharide. However, alternative combinations of these and related therapeutic agents could also be considered by the skilled person.

The gradual dissolution of such a soluble film containing a zinc salt such as zinc sulphate releases a topical zinc solution onto the cold sore. Topical zinc solutions have been shown, for instance by Park et al, "Topical Zinc Sulphate Therapy in Herpex Simplex", Korean J Dermatol 26(4): 529-535, to be an effective agent for the treatment and prevention of recurrence of HSV infection. Moreover, in Famiano et al, "Recurrent herpes labial is: a pilot study of the efficacy of zinc therapy", Oral Pathol Med (2005) 34: 423-5, systemic zinc sulphate appeared to reduce both the number of episodes and the time to recovery of herpes labialis. The preventive effect of low concentrations of zinc sulphate solution in recurrent herpes simplex of the skin and oral mucous membrane has been reported by Brody et al in "Topical treatment of recurrent herpes simplex and post-herpetic erythema multiforme with low concentrations of zinc sulphate solution", British Journal of Dermatology Vol 104, 2, pp. 191 -194. Topical zinc has been shown to improve wound healing by Agren MS in "Studies on zinc in wound healing", Acta Derm Venereol (Suppl), 1990; 154:1 -36, and topical zinc has also been shown to have an acute therapeutic effect on HSV infections by Eby GA and Halcomb WW in "Use of topical zinc to prevent recurrent herpes simplex infection: Review of literature and suggested protocols", Med Hypotheses, 1985; 17:157, by Wahba A et al in "Topical application of zinc solutions: a new treatment for herpes simplex infections of the skin", Acta Derm Venereol. 1980; 60(2): 175-77, by Godfrey et al in "A randomized clinical trial on the treatment of oral herpes with topical ZnO/glycine", Alternative therapies, May/June 2001 , vol. 7, no. 3, and by Finnerty EF in "Topical zinc in the treatment of herpex simplex", Cutis, 1986; 37:130-131 .

β-1 ,3-D-glucan is an immunomodulator which has been shown to modulate wound healing, for instance by Duo Wei et al in "Glucan stimulates human dermal fibroblast collagen biosynthesis through a nuclear factor-1 dependent mechanism", Wound Repair and Regeneration, vol. 10, 3, pp 161 -168. It has been shown to enhance immune system reaction, see for instance Keller et al, "Compounding with -1 ,3-D-glucan", International Journal of Pharmaceutical Compounding, vol. 4, No. 5, September/October 2000, and Williams JD, Czop JK, Austen KF, "Release of leukotrienes by human monocytes on stimulation of their phagocytic receptor for particulate activators", J Immunol, 1984; 132:3034-3040.

Sulphated polysaccharides obtained from red algae were proposed as an effective anti-inflammatory for topical use by Matsui et al in "Sulfated Polysaccharides from Red Microalgae Have Antiinflammatory Properties In Vitro and In Vivo", Applied Biochemistry and Biotechnology, Vol. 104, 2003. They also have a positive effect as UV-protectors, according to Wu H-K et al, "Aging and wrinkle formation of skin caused by UV exposure are prevented and cured by the treatment of alga- extractive product", Fragr J, vol. 29, no. 3, pp. 56-61 (2001 ).

All these three kinds of therapeutic agents have been found to be particularly adapted for their delivery through a soluble film. In combination, they have turned out to be particularly effective.

In yet another embodiment of the invention, the adhesive patch may be an adhesive patch for dermal application for the treatment of skin wounds and/or ulcers. The soluble films and/or therapeutic agents in this embodiment may for example be chosen from among any of the soluble films and therapeutic agents of the previous embodiments.

Although the present invention has been described with reference to specific exemplary embodiments, it will be evident that various modifications and changes may be made to these embodiments without departing from the broader scope of the invention as set forth in the claims. Accordingly, the description and drawings are to be regarded in an illustrative sense rather than a restrictive sense.

Claims

I . An adhesive patch for the delivery of at least one therapeutic agent, said patch comprising a soluble film incorporating said at least one therapeutic agent.

2. An adhesive patch according to claim 1 for buccal or sublingual application for the treatment of mouth ulcers.

3. An adhesive patch according to claim 2, wherein said soluble film comprises carbomer and/or polyethylene dioxide.

4. An adhesive patch according to any one of claims 2 or 3, wherein said at least one therapeutic agent comprises hyaluronic acid.

5. An adhesive patch according to any one of claims 2 to 4, wherein said at least one therapeutic agent comprises red mangrove.

6. An adhesive patch according to any one of claims 2 to 5, wherein said at least one therapeutic agent comprises polyvinylpyrolidone.

7. An adhesive patch according to any one of claims 2 to 6, wherein said patch further comprises an insoluble ingestible backing over said soluble film.

8. An adhesive patch according to claim 7, wherein said insoluble ingestible layer comprises ethylcellulose.

9. An adhesive patch according to claim 1 for labial application for the treatment of labial herpes.

10. An adhesive patch according to claim 9, wherein said soluble film comprises polyvinyl alcohol and/or hydroxypropyl methyl cellulose.

I I . An adhesive patch according to any one of claims 9 or 10, wherein said at least one therapeutic agent comprises a zinc salt, preferably zinc sulphate.

12. An adhesive patch according to any one of claims 9 to 1 1 , wherein said at least one therapeutic agent comprises an immunomodulator, preferably a glucan, in particular -1 ,3-D-glucan.

13. An adhesive patch according to any one of claims 9 to 12, wherein said at least one therapeutic agent comprises at least one sulphated polysaccharide, preferably from an algal extract.

14. An adhesive patch according to any one of claims 9-13, wherein said patch is pigmented.

15. An adhesive patch according to claim 1 for dermal application for the treatment of skin wounds and/or ulcers.