WO2015023226A1

WO2015023226A1 - Use of a composition comprising chitosan and a negatively charge polysaccharide for the treament of salivary dysfuntion

Info

Publication number: WO2015023226A1
Application number: PCT/SE2014/050938
Authority: WO
Inventors: Olle Larm; Lars Adolfsson
Original assignee: Exthera Ab
Priority date: 2013-08-16
Filing date: 2014-08-15
Publication date: 2015-02-19

Abstract

The present invention relates to a composition comprising an ionic complex of chitosan and a negatively charged polysaccharide, selected from the group consisting of heparin, chondroitin sulfate, dermatan sulfate and dextran sulfate, for use in the treatment of salivary dysfunction in a mammalian subject, to a method of preventing or treating salivary dysfunction in a mammalian subject, by applying topically a composition comprising an ionic complex of chitosan and a negatively charged polysaccharide, selected from the group consisting of heparin, chondroitin sulfate, dermatan sulfate and dextran sulfate.

Description

Use of a composition comprising chitosan and a negatively charge polysaccharideor the treament of salivary dysfuntion

Field of the invention

The present invention relates to compositions for treatment of salivary dysfunction and symptoms thereof.

Background

Chronically dry mouth, also known as xerostomia or hyposalivation, is one of the most common complaints in medicine. For some people, the inability to produce sufficient amounts of saliva is simply a discomfort,

whereas for others, it may result in painful mouth sores, yeast infections and tooth decay.

The problems of salivary dysfunction are increasing with the increased use of prescription medications and with an increasing number of people surviving radiation treatments for head and neck cancer. A disorder called Sjogren's syndrome, with symptoms including dry mouth, is also becoming more widely diagnosed.

Human saliva comprises about 99.5% water, while the other 0.5% consists of electrolytes, mucus, glycoproteins, enzymes, and antibacterial compounds such as secretory IgA and lysozyme. The enzymes found in saliva are essential in beginning the process of digestion of dietary starches and fats. These enzymes also play a role in breaking down food particles entrapped within dental crevices, protecting teeth from bacterial decay. Saliva is produced by the salivary glands and is important because it keeps the mouth moist, lubricated and comfortable and disposes of dead cells and micro-organisms from the oral cavity, it assists chewing, taste, and

swallowing, it contains proteins and minerals that protect tooth enamel and prevent tooth decay and gum disease, and it helps keep dentures securely in place. Normally, the body is always producing saliva, up to 2 to 4 pints per day.

Patients suffering from more severe forms of salivary dysfunction often include patients undergoing or recovering from treatment of cancer by radiotherapy, chemotherapy or stem cell therapy, patients under high dose or multiple medications, and patients in palliative care. These patients may often require assistance of dental hygienists to tend to their oral/dental care. Oral care may reduce not only the microbial load of the mouth but the risk for pain and oral infection as well.

Description of the invention It is an object of the present invention to provide a topical

pharmaceutical composition which, when administered to a patient suffering from salivary dysfunction relieves the symptoms caused by the salivary dysfunction.

Another object of the present invention is to provide a topical pharmaceutical composition which compensates for at least part of the reduction in salivary function in a patient suffering from salivary dysfunction.

Another object of the present invention is to facilitate cleaning of the oral cavity and teeth of a patient suffering from salivary dysfunction.

The above mentioned objects, as well as further objects which will become apparent to a person skilled in the art in view of the present disclosure, are achieved by the various aspects of the present invention.

In a first aspect thereof, the present invention provides a composition comprising an ionic complex of chitosan and a negatively charged

polysaccharide, selected from the group consisting of heparin, chondroitin sulfate, dermatan sulfate and dextran sulfate, for use in the treatment of salivary dysfunction in a mammalian subject.

Treatment of salivary dysfunction in accordance with the present disclosure is mainly symptomatic, i.e. the treatment mainly addresses the symptoms of the condition. However, as the symptoms of the salivary dysfunction could also exacerbate the salivary dysfunction itself, treatment of the symptoms may also contribute to reduce the salivary dysfunction causing the symptoms. By the term "treatment of salivary dysfunction" as used herein is thus meant the treatment of salivary dysfunction as such and/or the treatment of symptoms of salivary dysfunction. Symptoms of salivary dysfunction include oral candidiasis, ascending (suppurative) sialadenitis, dysgeusia and dysosmia, intraoral halitosis, oral dysesthesia, saliva that appears thick or ropey, mucosa that appears dry, dysphagia, the tongue may stick to the palate causing a clicking noise during speech or the lips may stick together, fissured tongue with atrophy of the filiform papillae and a lobulated, erythematous appearance of the tongue, difficulty wearing dentures, there may be generalized mucosal soreness and ulceration of the areas covered by the denture, dry, sore, and cracked lips and angles of mouth, and thirst.

Treatment of salivary dysfunction in accordance with the present disclosure remedies or ameliorates many of the mentioned symptoms.

When solutions of negatively charged polysaccharide and the positively charged polysaccharide chitosan are mixed, an ionic complex is immediately formed and precipitates. Due to an excess of chitosan in the complex, the final formulation will end up with a slight positive charge, which makes it adhere to dead cells and microorganisms which have negatively charged surfaces. Furthermore, it has also been found that the complex acts to encapsulate and remove dead cells and microorganisms from surfaces of the oral cavity. Encapsulation and removal of dead cells and microorganisms is evidenced by the formation of white flakes comprising heparin chitosan complex as well as dead cells and microorganisms. As a result, cleaning of the oral cavity and teeth of patients suffering from salivary dysfunction, and build-up of dead cells and microorganisms as a result thereof, is significantly facilitated. In other words, the composition acts to effectively replace the native saliva in the important function removing dead cells and microorganisms from the oral cavity.

Treatment with the composition of the invention may further help reduce the microbial load in the oral cavity, thus preventing the introduction of bacteria into wounds, sores or ulcers on mucous membranes, thereby reducing the risk of infection.

The composition may thus be used in the treatment of patients suffering from salivary dysfunction and one or more symptoms thereof.

The composition may also advantageously be used for prophylactic treatment of a patient at risk of developing salivary dysfunction and one or more symptoms thereof.

The compositions, methods and uses for treatment of salivary dysfunction disclosed herein are applicable to mammalian subjects in general and to human subjects in particular.

The composition of the invention may preferably be applied topically to a site in need of treatment, such as for example as a mouthwash, gel, cream or toothpaste, with or without the assistance of mechanical rubbing or abrasion.

Chitosan is a positively charged linear 1 ,4-bound polysaccharide based on β-D-glucosamine residues. Chitosan is formed by partial N-deacetylation of chitin, a polymer comprised, e.g., in crab and shrimp shells. N- deacetylation may for example be performed by treatment of the chitin with a strong base or acid and results in the conversion of acetamido groups to amine groups. In vivo, chitosan is degraded by lysozyme and other

glycosaminodases to mono- and oligomers. Chitosan which is rich in N- acetyl-D-glucosamine is degraded faster in vitro, and probably also in vivo, than a chitosan with a high proportion of D-glucosamine residues. The chitosan used with the composition of the invention may generally have a degree of deacetylation in the range of 50 to 99 %. It has been found, however, that a chitosan having a degree of deacetylation in the range of about 80 to 95 % is especially useful in a composition for treatment of patients suffering from salivary dysfunction. Thus, in an embodiment, the chitosan used in the composition has a degree of deacetylation in the range of 50 to 99 %, preferably in the range of 80 to 95 %.

Chitosan degrades under physiological conditions in mammals to physiologically acceptable, non-harmful and readily metabolized subcomponents. The negatively charged polysaccharides also degrade under physiological conditions, such as the conditions that may be present in the oral cavity, to non-harmful and readily metabolized sub-components, such as carbohydrate mono- and oligomers. Examples of negatively charged polysaccharides that degrade in vivo to naturally occurring sub-components include heparin, chondroitin sulfate, dermatan sulfate and dextran sulfate. The composition may preferably comprise chitosan and a negatively charged polysaccharide selected from the group consisting of heparin, chondroitin sulfate, dermatan sulfate and dextran sulfate. Such a composition is advantageous in that it may be biologically degradable and form non-toxic, naturally occurring and/or readily metabolized residues upon degradation.

In an embodiment, the negatively charged polysaccharide is heparin. Thus, in this embodiment, the inventive composition consists of a chitosan- heparin ionic complex. In such an ionic complex, the weight ratio of chitosan to heparin may be from about 1 : 1 to 10: 1 , such as from about 1 : 1 to about 5: 1 . Examples of more specific intervals are from about 2: 1 to about 4: 1 , and from about 2: 1 to about 3:1 . In an embodiment, the weight ratio of chitosan to heparin is about 2.5: 1 . The weight ratio of chitosan to heparin in the ionic complex affects the physical characteristics of the complex, in particular its rheological properties and adhesiveness. Furthermore, having an excess of heparin would entail a risk of unwanted blood-anticoagulation, due to the interaction between heparin and plasma proteins in blood. The ranges given above are to be seen as guidelines for the skilled person to find the optimal ratio based on the particular situation and administration form in which the composition is to be used.

In a preferred embodiment of the composition according to this aspect of the invention, the number of positive charges contributed by said chitosan are in excess over the number of negative charges contributed by said negatively charged polysaccharide in the ionic complex. Upon administration of this embodiment of the inventive composition, with an excess of chitosan in comparison to negatively charged polysaccharide on a charge basis, the composition adheres to dead cells and microorganisms which have negatively charged surfaces. In an embodiment of the composition, the charge ratio of positive charges in said chitosan to negative charges in said negatively charged polysaccharide is in the range of from 10: 1 to 10:8, preferably in the range of from 10:3 to 10:6, more preferably in the range of from 10:4 to 10:5. A charge ratio in the range of from 10:4 to 10:5 is especially advantageous, since it provides very good adhesion to the surface of dead cells and

microorganisms.

The composition may preferably be formulated for topical

administration. The composition may for example be formulated as a mouthwash, gel cream or paste. In an embodiment, the composition is applied in the form of a mouthwash.

The composition may be in the form of a suspension of particles of the complex of chitosan and heparin in a liquid medium. The liquid medium may preferably be water or water based. Depending on the concentration of the complex in the composition, the composition may be referred to as a suspension or a gel.

The total concentration of the complex of chitosan and said negatively charged polysaccharide in said composition may preferably be selected such that efficient encapsulation and removal of dead cells and microorganisms is achieved.

The viscosity of the composition generally increases with increasing concentration of the complex of chitosan and said negatively charged polysaccharide. The total concentration of the complex of chitosan and said negatively charged polysaccharide in said composition may preferably be selected such that a suitable viscosity for applying the composition to the oral cavity of the patient is achieved.

The total concentration of chitosan and negatively charged

polysaccharide in the composition may generally be in the range of from 0.1 to 5 %, preferably in the range of from 0.1 to 3 % by weight, based on the total weight of the composition.

A suitable viscosity may for example be obtained when the total concentration of said chitosan and said negatively charged polysaccharide in the composition is in the range of from 0.1 to 5 %, based on the total weight of the composition. A total concentration in the range of from 0.1 to 3 % by weight, based on the total weight of the composition, is preferred.

It has been found that when the composition is provided in the form of a mouthwash, a total concentration of said chitosan and said negatively charged polysaccharide in the composition in the range of from 0.1 to 0.5 % by weight, for example in the range of 0.2 to 0.4 % by weight, based on the total weight of the composition is useful. Thus, in an embodiment, the total concentration of said chitosan and said negatively charged polysaccharide in the composition is in the range of from 0.1 to 0.5 % by weight, based on the total weight of the composition, for example in the range of 0.2 to 0.4 % by weight, based on the total weight of the composition.

In a more specific embodiment thereof, the present invention provides a pharmaceutical composition suitable for topical administration comprising a suspension of chitosan and heparin, wherein said chitosan has a degree of deacetylation in the range of 80 to 95 %, the charge ratio of positive charges in said chitosan to negative charges in said negatively charged

polysaccharide is in the range of from 10:4 to 10:5, and the total

concentration of said chitosan and said negatively charged polysaccharide in said composition is in the range of from 0.1 to 5 %, preferably in the range of from 0.1 to 0.5 % by weight, based on the total weight of the composition. Such composition has been found by the inventors to provide a very beneficial combination of properties for treating salivary dysfunction. The beneficial combination of properties includes good encapsulation and removal properties as well as suitable viscosity for application to the oral cavity of the patient.

In an embodiment, the composition consists solely of a suspension of particles of the complex of chitosan and heparin in water or physiologically acceptable buffer, without further additives. This embodiment may be advantageous for patients having painful sores or ulcers in the oral cavity, which may be irritated by additional components in the composition. The complex of chitosan and heparin itself has been found not to cause pain or discomfort even in patients experiencing highly painful sores or ulcers in the oral cavity. In some embodiments, the composition may further comprise various pharmaceutically acceptable excipients and additives. Examples of such excipients and additives include, but are not limited to buffers, surfactants, viscosity adjusting agents, flavoring agents, and antimicrobial agents, such as anti-fungal agents and anti-bacterial agents. The composition may also comprise an antifoaming agent.

In an embodiment, the composition further comprises an antimicrobial agent, such as an antifungal agent or an antibacterial agent. Examples of such agents include, but are not limited to, methyl paraben and propyl paraben.

In an embodiment, the composition further comprises an antifoaming agent, for example a silicone based antifoaming agent. An antifoaming agent is useful to prevent foaming of the composition when applied, for example, in the form of a mouthwash.

The composition may also comprise additional pharmaceutically active agents, that may further improve the healing or pain relieving effects of the composition. Examples of such additional pharmaceutically active agents include, but are not limited to, analgesic agents, anti-inflammatory agents and antibiotics.

The composition may be useful in the treatment of all types of salivary dysfunction. The ability of the complex to encapsulate and remove dead cells and microorganisms makes it well suited for treatment of patients

experiencing or at risk of being subject to symptoms and effects of salivary dysfunction.

Examples of conditions encompassed by the term "salivary

dysfunction" or "salivary gland dysfunction" or "xerostomia", as used herein include, but are not limited to hyposalivation which may be physiologically induced, disease induced, caused by medications or medical treatment such as radiation treatment or stem cell treatment, Sjogren's syndrome. Rarer causes include diabetes (dehydration), hyperparathyroidism, cholinergic dysfunction (either congential or autoimmune), salivary gland aplasia or atresia, sarcoidosis, human immunodeficiency virus infection (due to antiretroviral therapy, but also possibly diffuse infiltrative lymphocytosis syndrome), graft-versus-host disease, renal failure, hepatitis C virus infection, and Lambert-Eaton syndrome.

In an embodiment, the salivary dysfunction is xerostomia,

hyposalivation or Sjogren's syndrome.

In an embodiment, the salivary dysfunction is drug induced salivary dysfunction.

A common cause of salivary dysfunction is the treatment of cancer by radiotherapy, chemotherapy or stem cell therapy. The composition is especially useful for treatment of this group patients, since the onset of salivary dysfunction may be relatively accurately predicted in relation to the commencement of a radiotherapy, chemotherapy or stem cell therapy procedure. The possibility of predicting the onset of salivary dysfunction allows prophylactic treatment of patients at risk of developing salivary dysfunction, thereby allowing treatment of the patient even before any symptoms are experienced. Furthermore, treatment with the composition, and especially prophylactic treatment, may enable the use of higher dosages of chemotherapy, radiotherapy and/or stem cell therapy in the treatment of cancer in a patient, without causing more suffering for the patient.

Thus, in an embodiment, the composition is for use in the treatment of salivary dysfunction caused by treatment of cancer. The treatment of cancer may include one or more therapies selected from the group consisting of chemotherapy, radiotherapy or stem cell therapy.

In a second aspect thereof, the present invention provides a method of preventing or treating salivary dysfunction in a mammalian subject, by applying topically a composition comprising an ionic complex of chitosan and a negatively charged polysaccharide, selected from the group consisting of heparin, chondroitin sulfate, dermatan sulfate and dextran sulfate, to a site in need of treatment.

The term "mammalian", as used herein, includes humans unless otherwise specifically stated.

The term "topical", as used herein, generally means the application of a pharmaceutical composition to body surfaces such as the skin or mucous membranes, particularly the skin or mucous membranes of the oral cavity. The composition may preferably be applied in an amount sufficient to provide efficient removal of dead cells and microbes from the surface under treatment. The composition may be applied once or a suitable number of times during administration, in order to achieve the desired degree of removal of dead cells and microbes.

The composition may preferably be applied in the form of a gel or a suspension. In an embodiment, the composition is administered in the form of a mouthwash. In an embodiment, the composition is administered in the form of a gel. In an embodiment, the composition is administered in the form of a toothpaste. In an embodiment, the composition is administered in the form of a chewing gum.

The composition used in the method of the second aspect of the invention may be further defined as described above in respect of the first aspect of the invention.

In a third aspect thereof, the present invention further provides the use of a composition comprising an ionic complex of chitosan and a negatively charged polysaccharide, selected from the group consisting of heparin, chondroitin sulfate, dermatan sulfate and dextran sulfate, in the manufacture of a medicament for use in the treatment of salivary dysfunction in a mammalian subject. In other words, the present invention further provides a composition comprising an ionic complex of chitosan and a negatively charged polysaccharide for use in the treatment of salivary dysfunction in a mammalian subject.

The use according to the third aspect of the invention may be further defined as described above in respect of the first aspect of the invention.

All features of all embodiments of all aspects of the invention can be used in any possible combination thereof, provided that such combination is not demonstrably unfeasible as determined without undue experimentation by a person having ordinary skill in the art. Brief description of the drawings

Figure 1 a is a photograph of the inside right cheek of the patient taken on 4 April 2012 before treatment with the composition.

Figure 1 b is a photograph of the inside right cheek of the patient taken on 8 May 2012 after treatment with the composition.

Examples

For the further understanding of the invention the following non-limiting examples are given:

Example 1 - Preparation of a topical composition for treatment of salivary dysfunction

Methyl paraben (2.0 g) and propylparaben (0.2 g) were dissolved in purified water (approx. 600 g) during stirring and heating. When the parabens had been completely dissolved, the solution was cooled to room temperature.

To the paraben solution sodiumacetate trihydrate (1 .6 g) was added and dissolved. By addition of acetic acid pH was adjusted to 4.6 ± 0.05.

To the paraben solution saccharin sodium (0.8 g) was added and dissolved under stirring. 2.5 g of chitosan (ChitoClear®, Primex ehf, Norway) with a degree of deacetylation of 90% was then added and the solution was stirred until all of the chitosan had been dissolved.

To purified water (approx. 50 g) heparin sodium (Scientific Protein Laboratories) (1 .0 g) was added and dissolved during stirring.

The heparin solution and the chitosan solution were combined and the suspension formed was stirred during 5 minutes. 200 g of a sorbitol solution (70% solution in water) was then added to the suspension and the stirring was continued for another 2 minutes. Peppermint oil (0.8 g) was dissolved in polyethylene glycol sorbitan monolaurate (tween 20, 4.0 g) under stirring, and the peppermint solution was added to the heparin/chitosan mixture and stirring was continued for another 5 minutes.

Purified water was added to a total weight of 1.00 kg and pH was controlled and adjusted if necessary to 5.0 ± 0.1 .

Example 2 - Preparation of a topical composition for treatment of salivary dysfunction without additives

To purified water (approx. 800 g) chitosan (ChitoClear®, Primex ehf, Norway) (2.5 g) with a degree of deacetylation of 90% was added. Diluted hydrochloric acid was adding during stirring and control of pH. When all chitosan was dissolved and pH was 5.0 ± 0.2, the addition of acid was stopped.

To purified water (approx. 50 g) was heparin sodium (Scientific Protein Laboratories) (1 .0 g) added and dissolved during stirring.

The heparin and chitosan solutions were then combined and the suspension formed was stirred during 5 minutes. Purified water was added to a total weight of 1 .00 kg and pH was controlled and adjusted if necessary to 5.0 ± 0.1 .

Example 3 - Treatment of a human cGVHD patient with salivary dysfunction

Background

Graft-versus-host disease (cGVHD) is a frequent complication of allogeneic Bone Marrow Transplantations (BMT:s). In cGVHD, the donor's bone marrow attacks the patient's organs and tissues, impairing their ability to function, and increasing the patient's susceptibility to infection due to open sores in the oral cavity. Treatment

The patient, male 71 years old, had a highly viscous saliva and had to tend to his dental care at least six times a day, but still got intensive plaque formation (dead bacteria) on the teeth.

Rinsing with 20 mL of a heparin-chitosan suspension prepared in accordance with Example 1 , twice a day in connection with tooth brushing caused the dental plaque to disappear within only a few days and the surface of the turned from rough to glossy. This improvement is also illustrated in Figures 1 a and 1 b representing photographs of the oral cavity of the patient before and after treatment with the heparin-chitosan suspension.

Sampling of the saliva from the cGVHD patient.

After thorough rinsing of the oral cavity of the patient with approximately 15 mL of heparin-chitosan suspension, white flakes in the sample were observed in the expelled suspension. The flakes were analyzed in respect of heparin (ExThera) and cellular material (Oral Pathology, Malmo University).

Heparin analysis concluded that the white complex in the saliva sample consisted mainly, to between 60 and 70 % by weight, of heparin-chitosan complex. This conclusion is based on results from previous analyses in which heparin was extracted from samples containing known amounts of heparin- chitosan complex. Excerpts of the report from the pathologist:

"The flake is a few mm fragment of strong eosinophil and fibrous materials. You see some embedded desquamated epithelial cells, but the majority seems to be composed of non-human material. The material is partly strong PAS positive with PAS colors for carbohydrates. Parts of the material is PAS negative. It may therefore very well consist of heparin." Conclusion

The white streaks in Fig 1 a represent dead cells. Fig 1 b shows a significant wound healing and almost no dead cells. Consequently the complex encapsulates and removes dead cells.

Claims

1 . A composition comprising an ionic complex of chitosan and a negatively charged polysaccharide, selected from the group consisting of heparin, chondroitin sulfate, dermatan sulfate and dextran sulfate, for use in the treatment of salivary dysfunction in a mammalian subject.

2. A composition according to claim 1 , wherein said chitosan has a degree of deacetylation in the range of 50 to 99 %, preferably in the range of 80 to 95 %.

3. A composition according to any one of the preceding claims, wherein said negatively charged polysaccharide is heparin.

4. A composition according to any one of the preceding claims, wherein in said composition the charge ratio of positive charges in said chitosan to negative charges in said negatively charged polysaccharide is in the range of from 10: 1 to 10:8, preferably in the range of from 10:3 to 10:6, more preferably in the range of from 10:4 to 10:5.

5. A composition according to any one of the preceding claims, wherein the total concentration of said chitosan and said negatively charged polysaccharide in said composition is in the range of from 0.1 to 5 %, preferably in the range of from 0.1 to 3 % by weight, based on the total weight of the composition.

6. A composition according to claim 5, wherein the total concentration of said chitosan and said negatively charged polysaccharide in said

composition is in the range of from 0.1 to 0.5 % by weight, based on the total weight of the composition.

7. A composition according to any one of the preceding claims, wherein said composition consists solely of a suspension of particles of the complex of chitosan and heparin in water or physiologically acceptable buffer, without further additives.

8. A composition according to any one of the preceding claims, wherein the composition further comprises an antimicrobial agent.

9. A composition according to any one of the preceding claims, wherein the composition further comprises an antifoaming agent.

10. A composition according to any one of the preceding claims, wherein said salivary dysfunction is xerostomia, hyposalivation or Sjogren's syndrome.

1 1 . A composition according to any one of the preceding claims, wherein said salivary dysfunction is drug induced salivary dysfunction.

12. A composition according to any one of the preceding claims, wherein said salivary dysfunction is caused by treatment of cancer.

13. A composition according to any one of the preceding claims, wherein said salivary dysfunction is chemotherapy, radiotherapy or stem cell therapy induced salivary dysfunction.

14. A method of preventing or treating salivary dysfunction in a mammalian subject, by applying topically a composition comprising an ionic complex of chitosan and a negatively charged polysaccharide, selected from the group consisting of heparin, chondroitin sulfate, dermatan sulfate and dextran sulfate, to the oral cavity of the subject.

15. Method according to claim 14, wherein said composition is further defined in accordance with any one of claims 2-9.

16. Method according to any one of claims 14-15, wherein said salivary dysfunction is further defined in accordance with any one of claims 10-13.

17. Method according to any one of claims 14-16, wherein said patient has not yet developed salivary dysfunction or symptoms thereof, but is at risk of developing salivary dysfunction.

18. Method according to any one of claims 14-17, wherein said patient is to be subjected to chemotherapy, radiotherapy or stem cell therapy.

19. Method according to any one of claims 14-18, wherein said composition is administered in the form of a mouthwash.

20. Method according to any one of claims 14-18, wherein said composition is administered in the form of a gel.

21 . Method according to any one of claims 14-18, wherein said composition is administered in the form of a toothpaste.

22. Method according to any one of claims 14-18, wherein said composition is administered in the form of a chewing gum.

23. Use of a composition comprising an ionic complex of chitosan and a negatively charged polysaccharide, selected from the group consisting of heparin, chondroitin sulfate, dermatan sulfate and dextran sulfate, in the manufacture of a medicament for use in the treatment of salivary dysfunction in a mammalian subject.

24. Use according to claim 23, wherein said composition is further defined in accordance with any one of claims 2-9.

25. Use according to any one of claims 23-24, wherein said salivary dysfunction is further defined in accordance with any one of claims 10-13.