WO2018224897A1

WO2018224897A1 - Treatment of oral candidiasis

Info

Publication number: WO2018224897A1
Application number: PCT/IB2018/052843
Authority: WO
Inventors: Patrick Hulisani DEMANA; Eugene Ivan OLIVIER; Gedeon MULAMBA
Original assignee: University Of Limpopo
Priority date: 2017-06-07
Filing date: 2018-04-24
Publication date: 2018-12-13
Also published as: EP3634457A1; ZA201908255B

Abstract

A composition that is useful for the treatment of oral candidiasis in a human or animal subject comprises a masticatory gum base that includes and/or carries at least one essential oil that is effective against Candida albicans.

Description

TREATMENT OF ORAL CANDIDIASIS

FIELD OF THE INVENTION

THIS INVENTION relates to treatment of oral candidiasis in a human or animal subject. The invention provides a composition that is useful for treatment of oral candidiasis in a human or animal subject. The invention also provides a composition for use in the treatment of oral candidiasis in a human or animal subject. The invention further provides for the use of one or more essential oils in the preparation of a composition for treating oral candidiasis in a human or animal subject. The invention still further provides for a method of treating oral candidiasis in a human or animal subject. The invention also provides for the use of a composition in the treatment of oral candidiasis in a human or animal subject. The invention further provides a method of preparing a composition that is useful for treatment of oral candidiasis in a human or animal subject.

BACKGROUND TO THE INVENTION

FUNGAL INFECTIONS have become a major cause of morbidity and mortality among immuno-compromised patients. About 50 fungal species, or 30% of known fungal species cause diseases in humans.

Oral candidiasis is a fungal infection of the mouth cavity mostly caused by Candida albicans. This disease occurs in babies, infants, adults, diabetic patients and may be fatal in people with a compromised immune system. Candida albicans is the most common cause of fungal infection and is responsible for candidiasis. In humans and animals, C. albicans resides in the gastrointestinal tract, respiratory tract, vaginal area, and mouth, as a part of the normal microflora. However, Candida species are opportunistic pathogens and under favourable conditions such as changes in the body environment, can proliferate, overgrow, and local or systemic candidiasis may occur.

The present invention seeks to provide for the treatment of oral candidiasis in human or animal subjects suffering therefrom. SUMMARY OF THE INVENTION

IN ACCORDANCE WITH A FIRST ASPECT OF THE INVENTION IS PROVIDED a composition that is useful for treatment of oral candidiasis in a human or animal subject, the composition comprising a masticatory gum base that includes and/or carries at least one essential oil that is effective against Candida albicans.

The composition is therefore, in one embodiment thereof, effectively a medicated chewing gum (MCG), comprising at least one essential oil as an active pharmaceutical agent (API). With respect to determining efficacy of the at least one essential oil against Candida albicans, the Minimum Inhibitory Concentration (MIC) test may be employed. As persons skilled in the art would know, MIC is the lowest concentration of a chemical (in this case an essential oil) that prevents visible growth of a bacterium (in this case Candida albicans). It will be appreciated that the composition may include more than one essential oil. A combination of two essential oils is preferred.

Typically, the essential oil may be selected from

lemongrass oil;

peppermint oil; and

a combination of peppermint oil and lemongrass oil.

The essential oil may be natural, or it may be synthetic. In the case of peppermint oil and lemongrass oil, when natural oils are used, the peppermint oil be that of Mentha piperita, and the lemongrass oil may be that of Cymbopogon citratus. Similarly, when synthetic oils are used, the synthetic oils may be based on that of Mentha piperita in the case of synthetic peppermint oil and on that of Cymbopogon citratus in the case of synthetic lemongrass oil.

Lemongrass oil is most preferred for the composition, and it is therefore preferred for the composition to comprise at least lemongrass oil.

In one embodiment, the composition of the invention comprises two essential oils. In such a case, the essential oils may be in a volumetric ratio, based on their combined volume, of 75%:25%, 50%:50%, or 25%:75%.

The composition may include one or more additives, such as excipients, colourants, flavourants, sweeteners, and compression adjuvants such as glidants, anti-adherants and lubricants. Suitable gum bases may include Health in Gum ® by CAFOSA (Barcelona, Spain), and Pharmagum ®. Health in Gum ® is preferred. Pharmagum ® is a commonly used direct compression excipient. It is a mixture of polyols or sugars with a gum base. It can be compacted into a gum with a conventional tablet press offering rapid and cost effective development of a gum delivery system. It is typically available in three forms namely Pharmagum S, M and C. Pharmagum M has a 50% greater gum base content compared to Pharmagum ® S. Pharmagum ® S consists primarily of gum base and sorbitol. Pharmagum ® M contains gum base, mannitol and isomalt. Formulations made with Pharmagum ® M & S are similar in appearance to a tablet.

The composition may have a coating applied to it. The coating may be a film coating, involving deposition of the coating by spraying a thin film of a polymer formulation onto the composition. Another possibility is sugar coating. Either way, the coating may be an edible coating, i.e. suitable for human or animal consumption.

Film coating may increase the total weight of the coated composition by 2 to 7%, and sugar coating may increase the total weight of the composition by 30 to 50%. Such coating may assist in improving stability of the composition, due to the volatile nature of some essential oils.

At least some of the essential oil may be included in the coating. It will be appreciated that in such a case the gum base would be regarded as carrying the essential oil as opposed to including it when the essential oil is included within the gum base. In accordance with the invention the gum base may, of course, include the essential oil, or carry the essential oil, or include and carry the essential oil. In other words, the composition may therefore have the essential oil included in the gum base, may have the essential oil included in the coating (in which case the gum base carries the essential oil), or may have the essential oil included both the gum base and in the coating.

Coating is preferred due to the volatile nature of the essential oils. Thus, a coating is expected to afford the composition with stability insofar the essential oil is concerned.

The composition, coated or uncoated, may comprise the essential oil or combination of essential oils in a concentration of from about 0.5 to about 30% by weight, based on the weight of the composition. More generally, effective concentrations may be determinable by means of the MIC test, whether with reference to lemongrass oil, peppermint oil, or any other effective essential oils or combinations thereof.

The composition is preferably formed into a predetermined shape, e.g. through use of a tablet press or similar shaping equipment. Such forming would typically occur / have occurred prior to coating, with coating thus succeeding forming.

IN ACCORDANCE WITH A SECOND ASPECT OF THE INVENTION IS PROVIDED

a composition according to the first aspect of the invention for use in a method of treating oral candidiasis in a human or animal subject. IN ACCORDANCE WITH A THIRD ASPECT OF THE INVENTION IS PROVIDED use of at least one essential oil that is effective against Candida albicans in the manufacture of a composition for treating oral candidiasis in a human or animal subject.

The composition may be a composition according to the first aspect of the invention.

IN ACCORDANCE WITH A FOURTH ASPECT OF THE INVENTION IS PROVIDED

a method of treating oral candidiasis in a human or animal subject, the method including masticating or having a in a human or animal subject masticate a composition comprising a masticatory gum base which contains at least one essential oil which is effective against Candida albicans.

IN ACCORDANCE WITH A FIFTH ASPECT OF THE INVENTION IS PROVIDED use of a composition of the first aspect of the invention in treating oral candidiasis in a human or animal subject. IN ACCORDANCE WITH A SIXTH ASPECT OF THE INVENTION IS PROVIDED a method of preparing a composition for treating oral candidiasis in a human or animal subject, the method including

producing a masticatory gum base that includes at least one essential oil that is effective against Candida albicans; and/or coating a / the masticatory gum base with a coating that includes at least one essential oil that is effective against Candida albicans.

IN ACCORDANCE WITH A SEVENTH ASPECT OF THE INVENTION IS PROVIDED

an essential oil that is effective against Candida albicans for use in treating oral candidiasis in a human or animal subject. The essential oil may be as hereinbefore described in accordance with the first aspect of the invention.

IN ACCORDANCE WITH AN EIGTH ASPECT OF THE INVENTION IS PROVIDED

use of an essential oil that is effective against Candida albicans in the manufacture of a composition for treating oral candidiasis in a human or animal subject.

The essential oil may be as hereinbefore described in accordance with the first aspect of the invention. The composition may be a composition according to the first aspect of the invention.

IN ACCORDANCE WITH A NINTH ASPECT OF THE INVENTION IS PROVIDED use of an essential oil that is effective against Candida albicans in treating oral candidiasis in a human or animal subject. EXAMPLES

Gum base

GUM BASES DETERMINE the release profile of active ingredients and flavours, and define the characteristics of chewing gums, such as texture, softness, hardness, elasticity, crumbliness, stickiness and mouth feel.

It has been mentioned that Health in gum ® is the preferred gum base for the composition according to the invention. This is so since it is a free flowing directly compressible co-processed gum material, which lends itself to simple processing in producing medicated chewing gums, such as that provided by the composition according to the invention. It is manufactured under cGMP conditions and complies with food chemical specifications and is 'generally regarded as safe' (GRAS) product regulated by FDA title 21 C.F.R Section 172.615.

Without binding itself to theory, the applicant understands that, chemically, Heath in gum ® and analogues thereof are mixtures of polyols (sorbitol/xylitol/mannitol) and of sugar with gum, plasticizers and anticaking agents. In producing medicated chewing gums, such gum materials can be directly compressed on a pharmaceutical in-house tablet compression machine, which enables rapid and low cost production.

Generic formulas proposed for medicated chewing gums using Health in gum ® as the gum base include: Excipient Formulation A Formulation B Formulation C

Health in gum^® 92.75% 91 .45% 91 .70%

Powder flavour 2.00% 3.00% 3.00%

Encapsulated flavour 2.00% 2.00% 2.00%

Lubricant 1 .50% 1 .50% 1 .50%

Silicon dioxide 1 .00% 1 .00% 1 .00%

Liquid flavour 0.55% 0.85% 0.60%

Intensive sweeteners 0.20% 0.20% 0.20%

The active pharmaceutical ingredient in a medicated chewing gum can be included in the gum core or coat or in both.

Typically, the API varies from 0.5-30% of the final gum weight.

A small, unionized, lipophilic and enzymatically stable API would generally speaking be absorbed more readily.

A saliva soluble drug will be completely released from the MCG within 10-15 minutes of chewing whereas a lipophilic drug will first dissolve in the gum base and then be slowly and completely absorbed. Composition according to the invention

FORMULAS OF EXEMPLARY COMPOSITIONS in accordance with the invention, in the form of antifungal masticatory gums, preferably using Health in Gum ® by CAFOSA as the gum base, include:

MCG formula 1

Ingredient Function Percentage (w/w)

Health in Gum® Gum base 91 .7%

Lemongrass oil/Peppermint oil API 2.00%

Stevia Sweetener 0.50%

Magnesium stearate Lubricant 1 .50%

Silicon dioxide Glidant 1 .00%

Talc Anti-adherent 3.3%

MCG formula 2

Ingredient Function Percentage (w/w)

Health in Gum® Gum base 91 .7%

Lemongrass oil API 2.00%

Peppermint oil API 2.00%

Stevia Sweetener 0.50%

Magnesium stearate Lubricant 1 .50%

Silicon dioxide Glidant 1 .00%

Talc Anti-adherent 1 .3% Discussion

THE USE OF CHEWING GUM for active pharmaceutical agent delivery offers advantages including fast onset of action due to the rapid release of the active pharmaceutical agent from the dosage form in the buccal cavity; good bioavailability because the active pharmaceutical agent avoids the first pass metabolism; ease of administration, patient acceptability especially for children; and aesthetic and attractive appeal.

Disadvantages of medicated chewing gums include pain in the facial muscles; earache in children; ulcers in the oral cavity due to some flavouring agents and adherence of chewing gum to enamel dentures and fillers.

Considering the advantages offered by a medicated chewing gum such as rapid drug release, fast onset, good bioavailability, it is regarded as advantageous to formulate an antifungal chewing gum containing an essential oil for the treatment of oral candidiasis, such as that which is provided by the composition of the present invention.

According to the European Pharmacopoeia (EP) and the guidelines for pharmaceutical dosage forms issued in 1991 by the Committee for Medicinal Products for Human Use (CPMP), medicated chewing gums are defined as solid single dose preparations with a base consisting mainly of gum that are intended to be chewed but not to be swallowed, providing a slow steady release of the medicine contained. It is a drug delivery system containing a gum base and one or more active pharmaceutical ingredients released by the action of chewing and intended to be used for the treatment of local diseases or systemic delivery after absorption through the buccal mucosa.

Chewing gums have been used worldwide since ancient times after man experienced the pleasure of chewing a variety of substances. The first commercial chewing gum named 'state of Maine pure spruce gum' was marketed in the United States in 1848 and the first patent was filed as a dentifrice in 1869.

The first medicated chewing gum, Aspergum^® containing acetylsalicylic acid, as active for headaches, was launched in 1928. The success story of nicotine chewing gum for smoking cessation in the 1980s has led to more general acceptance of chewing gum as a drug delivery system. In 1991 , "Chewing Gum" was approved as a term for a pharmaceutical dosage form by the commission of European Council. Drugs are formulated into various solid dosage forms including tablets, capsules etc. and semi-solid dosage forms such as creams, ointments and gels. Chewing gum is being used worldwide as a convenient modified release drug delivery system.

An essential oil is a concentrated hydrophobic liquid containing volatile compounds. The liquid is generally obtained by steam or hydro distillation from leaves, stems, flowers, bark or roots of a plant. Essential oils are also defined as volatile substances containing a complex mixture of chemical compounds (terpenes, monoterpenes, terpenoids, alcohols, aldehydes, and ketones) synthesised from plants which in contact with air can evaporate. Essential oils from plants are generally recognized as safe (GRAS).

No flavour is required in the case of the composition of the invention as exemplified above because of the excellent palatability of the essential oils used. Talc is added in the formulation to overcome the sticking effect which can lead to the damage of tablet presses during manufacture, knowing that sticking is a frequent problem during compression due to the adhesive nature of the gum base. High intensity artificial sweeteners can also be used for longer lasting sweetness and flavour perception. Examples include sucralose, aspartame, saccharin, alitame and acesulfame. However, in the present invention, stevioside also known as stevia powder was used as a natural alternative sweetener. Stevioside is safe, stable, and non-caloric and its use as a dietary supplement has been associated with various health benefits. Stevioside tastes approximately 300 times sweeter than sucrose. Stevioside has been reported to enhance glucose tolerance making it a suitable alternative sweetener for diabetics and individuals on carbohydrate-controlled diets.

The present invention has been described with a limited number of suggestions, however it will be acceptable that amendments or modifications may be made to it. The applicant expects that other essential oils would also exhibit antimicrobial activity against Candida albicans and could therefore similarly be possible drug candidates for inclusion in the composition of the invention, as determinable by an MIC test. However, in considering other essential oils it should be borne in mind that there may be some that are toxic at specific levels. Consideration should also be given to palatability as chewing gums are expected to be pleasant medication for patient compliance. A particular advantage of the invention as described was unexpectedly found to arise from the inclusion of both lemongrass and peppermint oils, which was enhanced efficacy in comparison to the sum of their respective efficacies against Candida albicans.

Claims

1 . A composition that is useful for the treatment of oral candidiasis in a human or animal subject, the composition comprising a masticatory gum base that includes and/or carries at least one essential oil that is effective against Candida albicans.

2. The composition according to claim 1 , wherein the essential oil is selected from

lemongrass oil;

peppermint oil; and

a combination of lemongrass oil and peppermint oil.

3. The composition according to claim 2, wherein the lemongrass oil is that of or is based on that of Cymbopogon citratus.

4. The composition according to claim 2, wherein the peppermint oil is that of or is based on that of Mentha piperita. 3. The composition according to any claims 1 to 4, which comprises two essential oils in a volumetric ratio, based on their combined volume, of 75%:25%, 50%:50%, or 25%:75%.

8. The composition according to any of claims 1 to 7, which is has a coating applied to it, and at least some of the essential oil is included in the coating.

9. The composition according to any of claims 1 to 7, comprising from about 0.5% to about 30% by weight of the essential oil, based on the weight of the composition.

10. A composition according to any of claims 1 to 9, for use in a method of treating oral candidiasis in a human or animal subject.

1 1 . Use of at least one essential oil that is effective against Candida albicans in the manufacture of a composition according to any of claims 1 to 10 for treating oral candidiasis in a human or animal subject.

12. A method of treating oral candidiasis in a human or animal subject, the method including having the human or animal subject masticate a composition according to any of claims 1 to 9.

13. Use of a composition according to any of claims 1 to 9 in treating oral candidiasis in a human or animal subject. 14. A method of preparing a composition for treating oral candidiasis in a human or animal subject, the method including producing a masticatory gum base that includes at least one essential oil that is effective against Candida albicans.

15. A method of preparing a composition for treating oral candidiasis in a human or animal subject, the method including coating a masticatory gum base with a coating that includes at least one essential oil that is effective against Candida albicans.