Field of the Invention

This invention relates to compositions for alleviating pain associated with tooth eruption.

Background to the Invention

Teething is the process of primary teeth erupting through the gums and appearing in a baby's mouth. Although the average time for the appearance of the first teeth is between five and seven months of age, there is a wide normal variation of timing. Teething usually starts approximately two months before the first tooth erupts, and proceeds intermittently. All of the primary teeth are usually in place by the age of 20 to 30 months.

Most children have 20 primary teeth which are eventually replaced by 32 permanent teeth. Primary teeth enable children to chew food and pronounce words properly and hold a place in the jaw for the permanent teeth.

The first permanent molars usually appear between the ages of 6 and 7 years but the last of the permanent teeth (the third molars or wisdom teeth) do not begin to erupt until between the ages of 17 to 21 years.

The intrusion of a hard, sharp tooth through tender, swollen gums can be a source of significant pain, especially for very young children. Work by

Shapira, J. et al (Pediatr. Dent. (2003) pp. 441-8) revealed high levels of inflammatory cytokines during the primary teething period, evaluated in gingival crevicular fluid of erupting primary teeth. Data showed statistically significant differences in TNFα and IL-1 β levels between the teething period and the control period. Correlations were found between cytokine levels and some of the clinical symptoms of teething: IL-1β and TNFα were correlated with fever and sleep disturbances; IL-δ was correlated with gastrointestinal disturbances and

IL-1 β was correlated with appetite disturbances. These data indicate a rationale basis for baby systemic discomfort and suggest that there is a need to control both gum pain and gum inflammation.

Teething gel products that are currently available on the market can be separated into those containing local anaesthetic and those containing only natural ingredients. Products containing local anaesthetics dominate the Western market and major brand names include Bonjela ^® , Dentinex ^® and Anbesol ^® . They contain mainly lidocaine or benzocaine. Both are local anaesthetics that give immediate temporary pain relief. The average concentrations of benzocaine (between 7.5 to 10%) and lidocaine (between 0.33% to 1.0%) are low, although factors such as the young age of the subjects and the highly permeable and vascularised application area, should be taken into account when considering their safety.

Local anaesthetics act at the cell membrane to prevent the generation and conduction of nerve impulses in axons of the peripheral nervous system. In addition, however, local anaesthetics interfere with the function of all organs in which conduction or transmission of impulses occurs. Thus, they have important effects on the central nervous system (CNS), autonomic ganglia, and neuromuscular junctions. The risk of adverse reactions is proportional to the concentration of circulating local anaesthetic achieved. The side effects of lidocaine that are seen with increasing dose include drowsiness, tinnitus, dysgeusia (critical in the baby), dizziness and twitching. As the dose increases, seizures, coma, and respiratory depression and arrest may occur. Clinically significant cardiovascular depression usually occurs at serum lidocaine levels that produce marked CNS effects. Benzocaine can cause methemoglobinemia. Dosing recommendations must be followed carefully since methemoglobinemia is dependent on the total dose administered. Because benzocaine may be used in topical creams with a concentration as high as 20%, it is not difficult to administer a dose sufficient to cause this effect. This side effect is potentially life-threatening, as methemoglobinemia reduces the amount of haemoglobin that is available for oxygen transport. This is particularly significant in infants and neonates due to the decreased resistance of foetal haemoglobin to oxidant stresses and the immaturity of enzymes that convert methemoglobinemia back to the ferrous state. Methemoglobinemia is not usually a problem in healthy adults. Some individuals are hypersensitive to local anaesthetics, although this is uncommon. The reaction may manifest itself as an allergic dermatitis or a typical asthmatic attack. Hypersensitivity occurs more frequently with local anaesthetics of the ester type (e.g. benzocaine) and frequently extends to chemically related compounds.

The class of products containing only natural ingredients is generally recognised as safe, but not free of risks. This is particularly true for some "natural" ingredients, normally considered safe, but which have presented a number of important risks. For example, concerns about the possible toxicity of honey in infants under one year of age were first raised at the end of the 1970s when the appearance of infant botulism was thought to be related to the ingestion of honey. The analysis of honey in samples in the United States revealed the presence of spores and toxins of Clostridium botulinum.

On the basis of this data, the Centre for Disease Control and Prevention has recommended that children aged less than 12 months should not be fed honey.

As reported in the 34th edition of Martindale (2005), it is important that clinicians are aware of the risk and refrain from recommending products or supplements which contain honey or the use of honey as flavouring in this age range.

There is a clear need for the development of new pharmaceutical compositions capable of relieving the pain and inflammation associated with teething without producing any of the potentially harmful side effects associated with the use of chemical compounds such as local anaesthetics and some natural compounds. Summary of the Invention

The present invention provides a topical composition for use during tooth eruption.

According to a first aspect of the invention, a composition comprises a glycosaminoglycan, or a pharmaceutically acceptable salt thereof, glycyrrhetinic acid and, together or separate, extract of Aloe vera and extract of saffron.

According to a second aspect of the invention, a composition according to the first aspect of the invention is used in the preparation of an oral medicament for reducing algesia and inflammation associated with tooth eruption. According to a third aspect, the present invention provides a method of reducing algesia and inflammation associated with tooth eruption, comprising the oral administration of the composition of the invention.

According to a fourth aspect, the present invention provides an applicator for topical oral administration of the composition of the invention, wherein the applicator comprises a flexible hollow cylindrical tube portion which is open at one end and attached at the other end to a slanted head portion, wherein the external slanted surface comprises flexible bristles, and wherein a hole in the centre of the head portion extends into the tube portion. Description of the Drawings

The present invention is described with reference to the accompanying figures, wherein:

Figures 1A and 1 B are graphs showing the pain experienced by test subjects, evaluated according to the visual analogue pain scale (100mm VAS). Figure 1A shows the 100mm VAS value for each subject on days 1 , 14 and 30 and Figure 1 B shows the median 100mm VAS values for the test group at days

1 , 14 and 30;

Figure 2 is a graph showing the median sleep values for the test group, measured using a 4-point ordinal scale at days 1 , 14 and 30; Figures 3A and 3B are graphs showing the appetite of test subjects, measured using a 4-point ordinal scale. Figure 3A shows the ordinal scale value for each subject on days 1 , 14 and 30 and Figure 3B shows the median improvement in appetite of the group from day 14 to day 30;

Figure 4 is a graph showing the median improvement in the frequency of test subjects crying, measured according to a 4-point ordinal scale; and

Figures 5A and 5B are graphs showing the improvement in salivation of test subjects over the course of the study. Figure 5A shows the median salivation value for the test group, measured according to a 4-point ordinal scale at days 1 , 14 and 30 and Figure 5B shows the median improvement in salivation of the group from day 14 to day 30. Detailed Description of the Invention

The present invention provides a composition, and means for applying said composition, that is useful in the topical treatment of algesia and inflammation associated with tooth eruption. As used herein, the term 'tooth eruption' refers to the process of teeth pushing through the gums and becoming visible in the mouth.

As used herein, the term 'primary teeth ¹ refers to the first set of teeth that erupt through the gums during the first 2 to 3 years of life. Primary teeth are also known as "deciduous teeth". As used herein, the term 'permanent teeth ¹ refers to the second set of teeth which erupt into the mouth following the shedding of primary teeth. An adult usually has 32 permanent teeth, 28 of which appear between the ages of 6 to 12 years.

As used herein, the term 'wisdom teeth ¹ refers to the four third molars (two upper and two lower) which are the final permanent teeth to erupt, usually between the ages of 17 to 21 years. Wisdom tooth eruption can cause significant pain and discomfort and wisdom tooth extraction, to correct an existing problem or prevent future problems, is a common procedure.

The composition of the present invention is suitable for therapeutic use to relieve algesia and inflammation associated with all forms of tooth eruption, and in particular, primary tooth eruption.

The term 'algesia' is defined herein as sensitivity to pain. The term 'inflammation' is defined as a localised protective response elicited by tissue irritation, injury or infection, characterised by pain, redness and swelling. As used herein, the term 'subject' refers to a mammal including a non- primate (e.g. a cow, pig, horse, dog, cat, rat and mouse) and a primate (e.g. a monkey and human), and more preferably a human.

The composition of the invention is a gel formulation comprising a glycosaminoglycan, or a pharmaceutically acceptable salt thereof, glycyrrhetinic acid, and, together or separate, extract of Aloe vera and extract of saffron.

Glycosaminoglycans (GAGs) are long unbranched polysaccharides, which may be covalently linked to proteins to form proteoglycans that function as lubricants and structural components in connective tissue and mediate adhesion of cells to the extracellular matrix. GAGs consist of repeating disaccharide units of an N-acetyl-hexosamine and a hexone or hexuronic acid, either or both of which may be sulphated. Members of the GAG family include chondroitin sulphate, dermatan sulphate, keratan sulphate, heparin, heparin sulphate and hyaluronic acid. Pharmaceutically acceptable salts of GAGs, such as sodium hyaluronate, are also suitable for inclusion in the composition of the invention.

In a preferred embodiment of the invention, the glycosaminoglycan is hyaluronic acid (HA) or its salt hyaluronan. HA is a non-sulfated GAG comprising repeating disaccharide units composed of D-glucuronic acid and D- N-acetylglucosamine, linked together via alternating β-1 ,4 and β-1 ,3 glycosidic bonds.

In a further preferred embodiment, the hyaluronic acid is high molecular weight hyluronic acid, preferably with a molecular weight of between 500-1000 kDa. As used herein, the term "glycyrrhetinic acid" refers to the pentacyclic triterpenoid derived from the hydrolysis of glycyrrehizic acid obtained from herb liquorice. Glycyrrhetinic acid has the molecular formula C ₃₀ H ₄₆ O ₄ and is also known as enoxolone, glycyrrhetin, uralenic acid and glycyrrhetinate.

Aloe vera is a species of Aloe, also known as Aloe barbadensis and Aloe vulgaris. It is a stemless succulent plant with thick, fleshy lanceolate leaves with a serrated margin. As used herein, the term "Aloe vera extract" refers to the gel and latex products obtained by pulverising the leaves. Aloe vera gel is the leaf pulp or mucilage, a thin clear jelly-like substance obtained from the parenchymal tissue that makes up the inner portion of the leaves. The gel contains carbohydrate polymers such as glucomannans, and a variety of organic and inorganic compounds. Aloe latex is a bitter yellow exudate from the pericyclic tubules beneath the outer skin of the leaves.

In a preferred embodiment of the invention, the extract of Aloe vera is Aloe vera gel. As used herein 'extract of saffron ¹ refers to the golden-yellow coloured spice extract derived from the dried stigma of Crocus sativus. Extract of Aloe vera and extract of saffron may be present in the composition of the invention together or separately. In a preferred embodiment, both extracts are present in the composition.

Typically the composition comprises 0.05-2% w/w glycosaminoglycan, 0.005-0.2% w/w glycyrrhetinic acid, 0.1-5% w/w extract of Aloe vera and 0.005- 0.2% w/w extract of saffron.

The composition of the invention is preferably a gel formulation. Additional ingredients of the composition include, but are not limited to, water, viscosity increasing agents such as polyvinylpyrrolidene (PVP), xanthan gum and maltodextrin, humectants such as propylene glycol, chelating agents such as EDTA, sweeteners such as xylitol, flavourings, preservatives such as sodium benzoate and potassium sorbate, antibacterial agents such as cetylpyridinium and dispersants such as polyethylene glycol (PEG). Table 1 provides a non- limiting example of the composition according to the invention.

Table 1

The composition of the invention is suitable for therapeutic use to relieve oral algesia and inflammation caused by tooth eruption through the gums. An effective quantity of the composition (for example 1ml) is applied topically to the affected are of the subject. The composition is re-applied as required. According to an embodiment of the invention, optimal application of the composition may be achieved using the applicator of the invention. The applicator comprises a flexible hollow cylindrical tube portion which is open at one end and into which the composition of the invention is inserted. The other end of the tube portion is attached to a slanted head portion which comprises flexible bristles on the external slanted surface. A small hole (approximately 1mm in diameter, one tenth of the length of the slanted surface) extends from the centre of the head portion into the hollow tube portion. When pressure is applied to the sides of the tube portion, the composition is forced through the hole onto the bristles of the slanted surface of the head portion. The applicator is held at the base of the tube portion and the bristles are placed in contact with the affected area. The composition is massaged into the affected area of the subject (e.g. the gums) using a gentle combing action.

The applicator further comprises a removable cap which covers and protects the slanted head portion when the applicator is not in use. The tube portion can be made of flexible plastic materials. The head portion is preferably made of silicon or other suitable elastomeric material.

The present invention will now be exemplified by the following non- limiting example: Example 15 male and 15 female infants aged between 3 and 11 months (median age of 6 months) were recruited to a study to evaluate the safety and efficacy of the composition of the invention in soothing the discomfort associated with teething. The study duration was 30 days, with visits to the test centre at day 1 , day 14 and day 30. Parents/caregivers were instructed to apply the composition once or twice daily for the duration of the study using the applicator of the invention.

The study aimed to evaluate the efficacy of the composition with respect to a number of symptoms associated with teething. Pain was evaluated subjectivity by parents using the 100mm VAS (visual analogue scale).

Sleep patterns were evaluated according to the following ordinal scale: 0 Excellent, teething does not impact on sleeping at all

1 Good, teething disturbs sleep occasionally and for brief intervals

2 Scarce, teething impacts negatively on the child's sleep, the child experiences difficulty in falling asleep and wakes up several times during the night 3 Bad, it takes more than 1 hour for the child to fall asleep and wakes up frequently during the night

Frequency of crying was evaluated according to the following ordinal scale:

0 Hardly ever

1 No less and no more than usual

2 More than usual

3 Always

Appetite was evaluated according to the following ordinal scale:

0 Excellent, teething does not impact on the child's appetite at all

1 Good, the child eats at regular intervals even if in lesser quantity

2 Scarce, teething has a negative impact on the child's appetite, the child eats less and skips one or two meals 3 Bad, the child cannot eat

Salivation was evaluated according to the following ordinal scale:

0 Normal

1 Diminished 2 Increased a little

3 Increased a lot Results

As shown in Figure 1A, in each subject there was a significant decrease in pain suffered, as measured according to 100mm VAS, between visits 1 and 2, and between visits 2 and 3. As shown in Figure 1 B, the median values for pain across the entire test group were 40.93 at day 1 , 17.57 by day 14 and 2.40 by day 30. There was a median improvement in pain of 95% by day 30. These results indicate that the composition of the invention was effective in reducing the pain associated with teething.

As shown in Figure 2, sleep disturbances, measured according to the 4-point ordinal scale, were improved in all test subjects during the course of the trial. The median values for sleep loss due to discomfort were 1.8 at day 1 , 0.97 at day 14 and 0.1 by day 30. The median improvement in the quality of sleep was 96% at day 30.

As shown in Figure 3A, there was an improvement in the appetite of each test subject over the course of the study, as measured according to the 4-point ordinal scale. The median values for loss of appetite due to discomfort were 1.9 at day 1 , 0.93 at day 14 and 0.03 at day 30. As shown in Figure 3B, the median improvement in appetite was 98% by day 30.

As shown in Figure 4, there was a decrease in the frequency of crying over the course of the study. The median values for crying, measured according to the 4-point ordinal scale, were 1.8 at day 1 , 0.97 at day 14 and 0.47 at day 30. Overall, there was an improvement of approximately 72% by day 30.

As shown in Figure 5A, there was a significant decrease in the median vaues for salivation over the course of the study. The median values, measured according to the 4-point ordinal scale, were 2.3 at day 1 , 0.9 at day 14 and 0.07 at day 30. As shown in Figure 5B, the median improvement in salivation was

94% by day 30.

Overall, 24 parents considered the composition of the invention more effective than other products available on the market, in terms of children's reaction when the product was applied. 19 parents found the flavour to be "very good", and either "very easy" or "easy" to apply. All subjects completed the study, with no reported or observed adverse events.