EA044884B1 - COMPOSITION FOR CARE OF THE ORAL CAVITY AND ITS APPLICATION FOR XEROSTOMIA OR MUCOSITIS OF THE ORAL CAVITY AND/OR PHARYNGE - Google Patents

Description

Throughout the invention, certain publications are indicated along the way. Full citations of such publications are provided immediately before the claims. The contents of these publications are therefore incorporated by reference into the present invention in their entirety.

Prior Art

Xerostomia is a subjective sensation of dry mouth and may be associated with decreased or deficient salivary secretion. Saliva and drooling help prevent the accumulation of microorganisms in the oral cavity (Nederfors et al. 1997). Saliva is also essential for effective dental remineralization (Narhi et al. 1999). Salivation initiates the digestion of food and helps dissolve and remove food particles from the mouth. Saliva also lubricates the oral mucosa, facilitating speech, eating, and swallowing, and preventing mechanical damage to oral surfaces. Xerostomia is a common disorder and leads to a higher risk of oral disease.

Various symptoms and consequences are associated with xerostomia. Symptoms include bad breath, soreness, burning sensation in the mouth, difficulty swallowing and changes in taste. Xerostomia also causes dental disorders, including oral ulcers, dental caries and periodontitis, oral infections, and respiratory tract infections.

Known causes of xerostomia include various diseases that cause organic changes in the salivary glands; pathological changes in the salivary glands caused by systemic diseases; damage to the salivary glands due to radiation therapy; HIV infection (AIDS); secretory hypofunction due to aging; and the effects of administering various drugs. Mental disorders or stress may also be factors.

Various medications also lead to xerostomia as a side effect. Examples of drugs that can cause xerostomia include: diuretics such as trichlormethiazide and furosemide, antihypertensives such as reserpine and clonidine hydrochloride, anticholinergics such as atropine sulfate, and antihistamines such as chlorphenylamine maleate. Other examples include various expectorants/cough suppressants, anti-Parkinsonian drugs, psychotropic drugs, antidepressants, tranquilizers, muscle relaxants, opiates and other drugs. Radiation therapy has become even more important for the treatment of malignancies in oral surgery and otolaryngology, and almost inevitably causes damage to the salivary glands from ionizing radiation. Such damage can lead to particularly severe xerostomia. Drugs are thought to be responsible for a significant proportion of xerostomia cases, especially in older age (Nedefors et al. 1997). The list of drugs that are likely to affect salivary levels includes more than 400 agents (Narhi et al. 1999).

Xerostomia is most common among older adults and women (Hochberg et al. 1998; Nederfors et al. 1997). One study reported that xerostomia occurred in 21.3% of men and 27.3% of women (Nederfors et al. 1996). In another study of elderly patients with type 2 diabetes, the incidence of dry mouth was up to 25% (Borges BC et al. 2010). The incidence of xerostomia in different populations varies from 0.9 to 46% (Orellana, M.F. et al. 2006).

There are various treatment options for xerostomia, although many result in unpleasant side effects and limited effectiveness (Cassolato, S.F. et al. 2003; Gupta, A. et al. 2006; Silvestre-Donat, F.J. et al. 2004). For example, malic and citric acid are used as salivation stimulants. However, they have a demineralizing effect on tooth enamel (Anneroth, G. et al. 1980; Davies, A.N. 2000).

Essence

The present invention describes an oral care composition containing:

a) 5-10 wt.% emu fat;

b) 1-5 wt.% emulsifying agent;

c) 0.1-40 wt.% protease enzyme;

d) 0.1-50% by weight of a remineralizing agent based on soluble calcium phosphate and

e) one or more whitening agents, where the emulsifying agent is soy lecithin; and wherein the composition is formulated as a tablet, gel or emulsion.

The present invention also describes the use of the said composition for the preparation of a medicament for the treatment of a patient suffering from xerostomia or mucositis of the oral cavity and/or pharynx.

Brief description of drawings

Fig. 1. Two-layer tablet, including a fast-disintegrating layer and a slowly decomposing layer.

Fig. 2. A two-layer tablet, including a fast-disintegrating core and a slowly decomposing outer layer.

- 1 044884

Detailed description

The present invention provides an oral care composition comprising:

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, the composition includes:

a) emu fat;

and two or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more calcium phosphate remineralizing agents;

e) one or more bleaching agents.

In one embodiment of the invention, the composition includes:

a) emu fat;

and three or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, the composition includes:

a) emu fat;

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, the oral care composition advantageously consists of:

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, the composition advantageously consists of:

a) emu fat;

and two or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, the composition consists essentially of:

a) emu fat;

and three or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, the composition consists essentially of:

a) emu fat;

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, a composition wherein one or more of the protease enzymes is selected from the group consisting of papain, trypsin, chymotrypsin, aminopeptidase, carboxypeptidase, pepsin and cathepsin.

In one embodiment of the invention, the protease enzyme is bromelain from the stems. Bromelain from the stems provides an anti-inflammatory effect.

- 2 044884

In one embodiment of the invention, 50 mg of bromelain from the stems is present in the composition.

In one embodiment of the invention, a composition wherein one or more bleaching agents is selected from the group consisting of carbamide peroxide and hydrogen peroxide.

In one embodiment of the invention, the composition wherein the one or more soluble calcium phosphate based remineralizing agents is selected from the group consisting of dibasic calcium phosphate, monocalcium phosphate, tricalcium phosphate and tetracalcium phosphate.

In one embodiment of the invention, the composition wherein the soluble calcium phosphate-based remineralizing agent is amorphous calcium phosphate.

In one embodiment of the invention, the composition wherein one or more emulsifying agents are phospholipids.

In one embodiment of the invention, the composition wherein the phospholipid is lecithin.

In one embodiment of the invention, the composition wherein the lecithin is dairy-free and/or egg-free. Non-milk and non-egg lecithin provides a composition with a longer half-life compared to lecithin derived from eggs or milk.

In one embodiment of the invention, the composition wherein the lecithin is soy lecithin. In one embodiment of the invention, the composition wherein lecithin is derived from soybeans.

In one embodiment of the invention, the composition, wherein the composition further comprises isomalt.

In one embodiment of the invention, the composition wherein the isomalt is selected from the group consisting of galenIQ™ 720 and galenIQ™ 721.

In one embodiment of the invention, the composition, wherein the composition further includes a disintegrant.

In one embodiment of the invention, the composition wherein the disintegrant is crospovidone.

In one embodiment of the invention, the composition, wherein the composition further comprises magnesium stearate.

In one embodiment of the invention, the composition, wherein the composition further includes glycerin.

In one embodiment of the invention, the composition, wherein the composition further includes fluoride.

In one embodiment of the invention, the composition wherein the remineralizing agent is white in color.

In one embodiment of the invention, the composition is formulated as a tablet, bilayer tablet, multilayer tablet, chewing gum, toothpaste, lozenge, powder, gel, viscous gel, ointment, cream, liquid, mouthwash, or candy.

In one embodiment of the invention, the composition is formulated as a round flat tablet or a round concave tablet.

In one embodiment of the invention, the composition is formulated as a bilayer tablet.

In one embodiment of the invention, the composition wherein the bilayer tablet includes a fast disintegrating layer and a slow disintegrating layer.

In one embodiment of the invention, a composition wherein one or more whitening agents are present only in the rapidly disintegrating layer.

In one embodiment of the invention, a composition wherein emu oil and one or more proteases are present only in the slowly decomposing layer.

In one embodiment of the invention, a composition wherein one or more whitening agents are present only in the rapidly disintegrating layer; and emu oil and one or more proteases are present only in the slowly decomposing layer.

In one embodiment of the invention, the composition wherein the rapidly degrading layer comprises carbamide peroxide in an amount of from 0.1 to 10.0 wt.%.

In one embodiment of the invention, the composition where the fast degrading layer includes carbamide peroxide in an amount of 1.0 wt.%.

In one embodiment of the invention, the composition wherein the slowly decomposing layer comprises emu oil in an amount of from 0.1 to 15% by weight.

In one embodiment of the invention, the composition wherein the slowly decomposing layer comprises emu oil in an amount of 10% by weight.

In one embodiment of the invention, the composition wherein the slowly decomposing layer comprises papain in an amount of from 0.1 to 20% by weight.

In one embodiment of the invention, the composition wherein the slowly decomposing layer comprises papain in an amount of 10% by weight.

The present invention provides a method of treating a patient suffering from xerostomia,

- 3 044884 which comprises administering to a patient an amount effective to treat xerostomia with a composition of the present invention.

In one embodiment of the invention, the method wherein the composition further whitens teeth in the patient's oral cavity.

In one embodiment of the invention, the method wherein the composition further remineralizes teeth in the patient's oral cavity.

In one embodiment of the invention, the method wherein the composition further whitens and remineralizes teeth in the patient's oral cavity.

In one embodiment of the invention, the method wherein the composition further reduces the sensitivity of the patient's teeth.

In one embodiment of the invention, the method wherein the composition further treats dental caries of the patient.

In one embodiment of the invention, the method wherein the patient is a human.

In one embodiment of the invention, the method wherein the patient is a non-human animal.

In one embodiment of the invention, the method where the patient has an autoimmune disease, diabetes, Sjögren's syndrome, or has recently undergone radiation therapy or chemotherapy.

In one embodiment of the invention, a method wherein the patient is currently receiving one or more medications that cause xerostomia.

The present invention provides an oral care composition for teeth whitening, comprising one or more whitening agents, wherein the composition is formulated as a two-layer tablet comprising:

(i) rapidly deteriorating layer; and (ii) a slow-degrading layer, wherein the one or more bleaching agents are each an oxidizing agent and each is present only in the fast-degrading layer.

In one embodiment of the invention, an oral care composition for teeth whitening consists primarily of one or more whitening agents, wherein the composition is formulated as a two-layer tablet comprising: (i) a fast-disintegrating layer; and (ii) a slow-degrading layer, wherein the one or more bleaching agents are each an oxidizing agent and each is present only in the fast-degrading layer. In one embodiment of the two-layer composition, the composition wherein one or more whitening agents is selected from the group consisting of carbamide peroxide and hydrogen peroxide.

In one embodiment of a two-layer composition, the composition wherein the bleaching agent is carbamide peroxide and is present in an amount between 0.1 and 10.0 wt.% of the disintegrating layer.

In one embodiment of a two-layer composition, the composition wherein the bleaching agent is carbamide peroxide and is present in an amount of 1.0 wt.% of the breaking layer.

In one embodiment of a two-layer composition, the composition further includes one or more of the following:

a) emu fat;

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate.

In one embodiment of a two-layer composition, the composition further includes two or more of the following:

a) emu fat;

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate.

In one embodiment of a two-layer composition, the composition further includes three or more of the following:

a) emu fat;

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate.

In one embodiment of a two-layer composition, the composition further includes each of the following:

a) emu fat;

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate.

- 4 044884

In one embodiment of a two-layer composition, the composition further includes each of the following:

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate.

In one embodiment of a two-layer composition, the composition wherein emu oil, one or more emulsifying agents, and one or more protease enzymes are present only in the slowly decomposing layer.

In one embodiment of the two-layer composition, the composition wherein one or more soluble calcium phosphate remineralizers are present only in the rapidly degrading layer.

The present invention provides a method of treating a patient suffering from xerostomia, which includes administering to the patient an amount effective to treat the xerostomia of a bilayer composition of the present invention.

In one embodiment of the invention, the method wherein the two-layer composition further whitens teeth in the patient's mouth.

In one embodiment of the invention, the oral care composition includes:

a) bleaching agent;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate.

In one embodiment of the invention, the oral care composition includes:

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate.

In one embodiment of the invention, the oral care composition consists primarily of:

a) bleaching agent;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate.

In one embodiment of the invention, the oral care composition consists primarily of:

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate.

The present invention provides packaging including:

i) a first oral care composition comprising:

a) bleaching agent;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate;

ii) a second oral care composition comprising

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate; and iii) instructions for use of the first oral care composition and the second oral care composition for treating a patient suffering from mucositis or xerostomia.

The present invention provides a package consisting primarily of:

i) a first oral care composition comprising:

a) bleaching agent;

- 5 044884 and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate;

ii) a second oral care composition comprising:

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate; and iii) instructions for use of the first oral care composition and the second oral care composition for treating a patient suffering from mucositis or xerostomia.

The present invention provides a therapeutic package for administration, or for use in administration to a patient suffering from mucositis or xerostomia, which includes:

i) a first oral care composition comprising:

a) bleaching agent;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate;

ii) a second oral care composition comprising:

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate; and iii) instructions describing the use of said package in the treatment of said patient.

The present invention provides a therapeutic package for administration or for use in administration to a patient suffering from mucositis or xerostomia, which consists primarily of:

i) a first oral care composition comprising;

a) bleaching agent;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate;

ii) a second oral care composition comprising:

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate; and iii) instructions describing the use of said package in the treatment of said patient.

The present invention provides a method of treating a patient suffering from mucositis or xerostomia, comprising administering a first oral care composition followed by one or more second oral care compositions.

The present invention provides a method of treating a patient suffering from mucositis or xerostomia, consisting advantageously of administering a first oral care composition followed by one or more second oral care compositions.

The present invention provides a method of treating a patient suffering from mucositis or xerostomia, comprising administering one first oral care composition followed by five second oral care compositions.

The present invention provides a method of treating a patient suffering from mucositis or xerostomia, consisting advantageously of administering one first oral care composition followed by five second oral care compositions.

In one embodiment of the invention, the first oral care composition includes:

a) bleaching agent;

and one or more of the following:

b) one or more emulsifying agents;

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c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate; and a second oral care composition comprising:

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate.

In one embodiment of the invention, the first oral care composition consists primarily of:

a) bleaching agent;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate; and the second oral care composition consists primarily of:

a) emu fat;

and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes; And

d) one or more remineralizing agents based on soluble calcium phosphate.

In one embodiment of the invention, the first oral care composition and one or more second oral care compositions are administered within 24 hours.

In one embodiment of the invention, the package is a sealed package.

In one embodiment of the invention, the sealed package is a blister pack.

In one embodiment of the invention, the blister pack contains one first oral care composition and five second oral care compositions.

In one embodiment of the invention, the first oral care composition further comprises isomalt.

In one embodiment of the invention, the first oral care composition further comprises sucralose.

In one embodiment of the invention, the second oral care composition further comprises potassium nitrate.

In one embodiment of the invention, the first oral care composition is a tablet. In one embodiment of the invention, the tablet is an 800 mg tablet. In one embodiment of the invention, the tablet is a 1000 mg tablet.

In one embodiment of the invention, the second oral care composition is a tablet. In one embodiment of the invention, the tablet is an 800 mg tablet. In one embodiment of the invention, the tablet is a 1000 mg tablet.

In one embodiment of the invention, the bleaching agent is carbamide peroxide. In one embodiment of the invention, the amount of carbamide peroxide in the tablet is 1-5 mg. In one embodiment of the invention, the amount of carbamide peroxide in the tablet is 1-4 mg. In one embodiment of the invention, the amount of carbamide peroxide in the tablet is 2-3 mg. In one embodiment of the invention, the amount of carbamide peroxide in the tablet is 1 mg. In one embodiment of the invention, the amount of carbamide peroxide in the tablet is 2 mg. In one embodiment of the invention, the amount of carbamide peroxide in the tablet is 2.5 mg.

In one embodiment of the invention, the emulsifying agent is soy lecithin. In one embodiment of the invention, the concentration of soy lecithin is from 1 to 5 wt.%. In one embodiment of the invention, the concentration of soy lecithin is from 2 to 5 wt.%.

In one embodiment of the invention, the soluble calcium phosphate remineralizing agent is tricalcium phosphate. In one embodiment of the invention, the concentration of tricalcium phosphate is from 1 to 10 wt.%. In one embodiment of the invention, the concentration of tricalcium phosphate is from 3 to 10 wt.%. In one embodiment of the invention, the tricalcium phosphate concentration is 10% by weight.

In one embodiment of the invention, the concentration of emu oil is from 5 to 10 wt.%. In one embodiment of the invention, the concentration of emu oil is from 5 to 7 wt.%. In one embodiment of the invention, the emu oil concentration is 6% by weight.

In one embodiment of the invention, the protease enzyme is bromelain from the stems. In one embodiment of the invention, the amount of bromelain from the stems in the tablet formulation is

- 7 044884 25-75 mg. In one embodiment of the invention, the amount of bromelain from the stems in the tablet is 40-60 mg. In one embodiment of the invention, the amount of bromelain from the stems in the tablet is 50 mg.

The present invention provides an oral care composition comprising:

a) one or more omega fatty acids; and one or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, the composition includes:

a) one or more omega fatty acids; and two or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, the composition includes:

a) one or more omega fatty acids; and three or more of the following:

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, the composition includes each of the following:

a) one or more omega fatty acids;

b) one or more emulsifying agents;

c) one or more protease enzymes;

d) one or more remineralizing agents based on soluble calcium phosphate;

e) one or more bleaching agents.

In one embodiment of the invention, the composition wherein it or more omega fatty acids include omega-3 fatty acids or omega-6 fatty acids.

In one embodiment of the invention, a composition wherein the omega-3 fatty acid is alpha-linoleic acid and the omega-6 fatty acid is gamma-linoleic acid.

In one embodiment of the invention, the composition is for the treatment of xerostomia. In one embodiment of the invention, a composition for treating dry mouth. In one embodiment of the invention, a composition for treating mucositis.

In some embodiments of the present methods, the mucositis is mucositis of the oral cavity and pharynx. In some embodiments of the present methods, the xerostomia is xerostomia of the oral cavity and pharynx.

In one embodiment of the invention, a teeth whitening composition.

In one embodiment of the invention, a composition for remineralizing teeth.

In one embodiment of the invention, a composition for whitening and remineralizing teeth.

In one embodiment of the invention, the composition has a caryostatic effect on the patient's teeth. In one embodiment of the invention, the composition has an anti-caries effect on the patient's teeth.

In one embodiment of the invention, the concentration of emu oil in the composition is from 0.1 to 60 wt.%.

In one embodiment of the invention, the concentration of peroxide in the composition is from 0.1 to 50 wt.%. The concentration of peroxide in excess of 40 wt.% is intended for professional use.

In one embodiment of the invention, the concentration of soluble calcium phosphate in the composition is from 0.1 to 50 wt.%.

In one embodiment of the invention, the concentration of protease enzyme in the composition is from 0.1 to 40 wt.%.

In one embodiment of the invention, the concentration of phospholipids in the composition is from 0.1 to 20 wt.%.

In one embodiment of the invention, the concentration of emu oil in the slowly decomposing layer is from 0.1 to 15 wt.%. In one embodiment of the invention, the concentration of emu oil in the slowly decomposing layer is from 1.0 to 10 wt.%. In one embodiment of the invention, the concentration of emu oil in the slowly decomposing layer is from 5 to 10 wt.%. In one embodiment of the invention, the concentration of emu oil in the slowly decomposing layer is 10 wt.%.

In some embodiments, the bleaching agent is an oxidizing agent.

- 8 044884 detergent.

Various oxidizing agents can be used in the composition. Examples of oxidizing agents include, but are not limited to, peroxides. In some embodiments, the bleaching agent is selected from the group consisting of one or more urea peroxides and hydrogen peroxide.

In one embodiment of the invention, the concentration of peroxide in the deteriorating layer is from 0.1 to 20 wt.%. In one embodiment of the invention, the concentration of peroxide in the deteriorating layer is from 1.0 to 20 wt.%. In one embodiment of the invention, the concentration of peroxide in the deteriorating layer is from 1.0 to 10 wt.%. In one embodiment of the invention, the concentration of peroxide in the deteriorating layer is from 1.0 to 5 wt.%. In one embodiment of the invention, the peroxide concentration in the deterioration layer is 1.0 wt.%.

Various protease enzymes can be used in the composition. Examples of proteases include, but are not limited to, the group consisting of one or more of papain, trypsin, chymotrypsin, aminopeptidase, carboxypeptidase, pepsin and cathepsin.

In one embodiment of the invention, papain is used. In one embodiment of the invention, the protease enzyme is obtained from papaya extract.

In one embodiment of the invention, the concentration of protease enzyme in the slowly decomposing layer is from 0.1 to 20 wt.%. In one embodiment of the invention, the concentration of protease enzyme in the slowly decomposing layer is from 1 to 20 wt.%. In one embodiment of the invention, the concentration of protease enzyme in the slowly decomposing layer is from 1 to 10 wt.%. In one embodiment of the invention, the concentration of protease enzyme in the slowly decomposing layer is from 5 to 15 wt.%. In one embodiment of the invention, the concentration of protease enzyme in the slowly decomposing layer is 5 wt.%. In one embodiment of the invention, the concentration of protease enzyme in the slowly decomposing layer is 10% by weight.

In one embodiment of the invention, the soluble calcium phosphate remineralizing agent is selected from the group consisting of one or more of dibasic calcium phosphate, monocalcium phosphate, anhydrous dicalcium phosphate, tricalcium phosphate and tetracalcium phosphate. In one embodiment of the invention, tricalcium phosphate, anhydrous dicalcium phosphate, tetracalcium phosphate or anhydrous dibasic calcium phosphate is used. In one embodiment of the invention, tricalcium phosphate is used.

In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the decomposition layer is from 0.1 to 50% by weight. In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the degrading layer is from 1 to 25% by weight. In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the degrading layer is from 5 to 25% by weight. In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the degrading layer is from 9.5 to 20% by weight. In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the degrading layer is 9.5% by weight. In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the degrading layer is 20% by weight.

In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the slowly decomposing layer is from 0.1 to 50% by weight. In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the slowly decomposing layer is from 1 to 35% by weight. In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the slowly decomposing layer is from 10 to 35 wt.%. In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the slowly decomposing layer is 10% by weight. In one embodiment of the invention, the concentration of the soluble calcium phosphate remineralizing agent in the slowly decomposing layer is 35% by weight.

In one embodiment of the invention, the concentration of phospholipids in the slowly decomposing layer is from 0.1 to 20 wt.%. In one embodiment of the invention, the concentration of phospholipids in the slowly decomposing layer is from 1 to 10 wt.%. In one embodiment of the invention, the concentration of phospholipids in the slowly decomposing layer is from 1% to 2 wt.%. In one embodiment of the invention, the concentration of phospholipids in the slowly decomposing layer is 2 wt.%. In one embodiment of the invention, the concentration of phospholipids in the slowly decomposing layer is 1 wt.%.

For the purpose of the remineralizing effect of calcium phosphate, it is preferable that the calcium phosphate is in soluble form. If a significant portion of calcium phosphate settles in solution, it

- 9 044884 acts as an abrasive agent that does not remineralize. The addition of glycerin to the composition helps prevent the formation of calcium phosphate precipitate.

In one embodiment of the invention, the composition further includes glycerin. In one embodiment of the invention, the glycerol concentration is from 10 to 60 wt.%.

In one embodiment of the invention, the composition further includes a fluoride, for example sodium fluoride. In one embodiment of the invention, the concentration of sodium fluoride is from 0.01 to 0.5 wt.%.

In one embodiment of the invention, the remineralizing agent is white in color. Therefore, consuming a remineralizing agent may contribute to the whitening effect.

In one embodiment of the invention, the composition contains potassium nitrate, which can act as a desensitizing agent.

The composition may be presented in a carrier. In various embodiments of the invention, the carrier is selected from the group consisting of tablet, bilayer tablet, multilayer tablet, chewing gum, candy, toothpaste, lozenge, powder, gel, viscous gel, ointment, cream, liquid, mouth rinse and candy.

In one embodiment of the invention, the liquid carrier or mouthwash carrier further comprises sodium bicarbonate.

In some embodiments, the bilayer tablet includes a disintegrating layer and a slow disintegrating layer. The different relative rates of release of the active ingredient content from the disintegrating layer and the slowly disintegrating tablet layer can be achieved in various ways.

Various release rates can be achieved by using the first layer, which is a rupture layer that releases a portion of the contents of the active material over a relatively short period of time, for example including, but not limited to, 1 minute, 10 minutes, 30 minutes, or 1 hour, and a second layer which is a slowly decomposing layer which releases a portion of the contents of the active material over a relatively long period of time after administration or after a delay period after administration.

The disintegrating layer may have a composition similar to that of known rapidly disintegrating tablets. Slow-disintegrating layers may have a composition similar to that of known slow-disintegrating tablets and may include some active material together with a slow-release material.

In some embodiments, the composition is a single-layer tablet including a disintegrating fraction and a slow disintegrating fraction. The degradable fraction may be mixed homogeneously or randomly with the slowly degrading fraction. In some embodiments of the invention, the bleaching agent is detected only in the degrading fraction.

In some embodiments, the composition is a bilayer tablet comprising a slowly disintegrating tablet core and a disintegrating outer layer. In some embodiments, the bleaching agent is present only in the degradable outer layer.

Advantages of the compositions described herein include possible synergistic effects between the actions of the protease and the whitening agent, and ease of use at home or in a veterinary setting. The compositions described herein are believed to provide improved effects on both external tooth coloration and previously unavailable internal tooth coloration. It is believed that the removal of chromogen from enamel is facilitated by the presence in the composition of a protease enzyme capable of reacting with chromogen proteins and the film layer, creating enhanced mechanisms for the penetration of the bleaching agent with oxygen free radicals (for example, hydrogen peroxide molecules from a solution of carbamide peroxide or a solution of hydrogen peroxide). It is believed that one of the effects of incorporating proteases with the bleaching agents according to the present patent is greater penetration of the bleaching agents into the enamel, in addition to the beneficial effect of the proteases reacting with protein chromogens.

The composition provides the advantageous ease of use in that it allows the treatment of xerostomia, and the whitening agent, protease enzyme and remineralizing agent can be applied to the teeth using only one composition, without the need to apply the different components in separate compositions. This is particularly advantageous for home and veterinary use and when the composition is supplied in certain carriers such as, for example, chewing gum, toothpaste, lozenges, mouthwash and candy.

The composition has the additional advantage that when the available application time is limited, the whitening agent, the protease enzyme and the remineralizing agent can be simultaneously applied to the teeth for the entire duration of the application time. Conversely, for the same treatment time available, if the whitening agent, protease enzyme and remineralizing agent

- 10 044884 are applied in separate compositions, the application time of each component will be reduced in order to keep the total treatment time constant.

In one embodiment of the composition, silica is added to the composition to increase the viscosity of the composition. In other embodiments, the composition contains methylcellulose (10-20% by weight) or xanthan gum (10-20% by weight).

In some embodiments, a sweetener or flavoring agent may be added to the composition. In one embodiment of the invention, the concentration is about 0.2-10 wt.%. In one embodiment of the invention, the sweetener is saccharin or aspartame. In one embodiment of the invention, the flavoring agent is peppermint or clove.

In some embodiments, the sweetener is maltitol, isomaltitol, mannitol, lactitol, acesulfame potassium, thaumatin, or other known sweeteners. The pH of the composition can be adjusted. In one embodiment of the invention, the pH is from about pH 6 to 7.5. In one embodiment of the invention, baking soda is used as a pH neutralizer.

Advantageous methods for teeth whitening and remineralization are also described. The methods include applying to teeth any of the compositions described herein to whiten and remineralize teeth.

In a further embodiment of any of the methods for whitening and remineralizing a patient's teeth described herein, a gel polymer is used at the base of the teeth to apply the whitening and remineralizing compositions to the teeth to prevent them from contacting the gums. In various embodiments of the invention, the gel includes polyethyl methacrylate or polymethyl methacrylate with plasticizers. An impression tray or spacer can also be used to isolate the dentin.

The total application time of the whitening and remineralizing compositions can usually vary from 20-30 minutes to 2-3 hours. For home use, the compositions can be applied to the teeth at night. For home use kits, treatment time can vary from 1-2 weeks to several weeks depending on the color. In one embodiment of the invention, the whitening and remineralizing composition includes a light-activated photostimulant as an indicator of exposure time.

The compositions, kits and methods described herein can be used on both natural teeth and certain types of artificial teeth.

Using the compositions, kits and methods described herein, calcium loss that may develop during teeth whitening can be restored through remineralization so that a more effective whitening composition can be used safely with greater effect.

Advantageous methods for treating dental sensitivity are also described herein and include applying any of the compositions described herein to the patient's teeth. Whitening may cause tooth sensitivity. Such sensitivity can be treated using the described compositions, kits and methods for whitening and remineralizing teeth. In addition, the compositions, kits and methods described can be used to treat tooth sensitivity that develops in the absence of whitening. Remineralization may reduce sensitivity by reducing dentin permeability. In addition, the described compositions, kits and methods for teeth whitening and remineralization may be used in other applications where remineralization would be beneficial, such as in the treatment of dental caries.

Following the whitening and remineralization procedures described herein, additional compositions for restorative or cosmetic purposes may be applied to the teeth.

As used herein, treatment means preventing, slowing, stopping or reversing the progression of a condition, disease or infection. Treatment can also mean improving one or more symptoms of a condition, disease, or infection.

The compositions used in the method described in this patent specification can be administered in various forms, including those described in the present description. Treatment with the compositions may be a component of combination therapy or adjunctive therapy, i.e. the subject or patient in need of receiving the composition is being treated or receiving another drug or composition for a condition, disease or infection in combination with one or more of the present compositions. Such combination therapy may be sequential therapy, where the patient first receives one composition or drug and then another, or the two are given simultaneously. They can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms used.

As used herein, a pharmaceutically acceptable carrier is a pharmaceutically acceptable solvent, suspending agent, or vehicle for delivering the present composition to an animal or human. The carrier may be liquid or solid and

- 11 044884 is selected according to the planned route of administration. Liposomes are also a pharmaceutically acceptable carrier.

The dosage of the compositions administered in treatment varies depending on factors such as the pharmacodynamic characteristics of the compositions and their variant and route of administration; age, gender, metabolic rate, absorption efficiency, health status and body weight of the recipient; the nature and severity of symptoms; type of concomitant treatment administered; frequency of treatment; and the desired therapeutic effect.

The unit dosage form of the composition used in the method of the present invention may include one composition or mixtures thereof with additional agents. The compounds can be administered in oral dosage forms such as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.

The compositions used in the method of the present invention may be administered in mixtures with suitable pharmaceutical diluents, excipients, excipients or carriers (collectively referred to herein as a pharmaceutically acceptable carrier), suitably selected with respect to the intended form of administration and in accordance with normal pharmaceutical practice .

The compositions can be administered alone or mixed with a pharmaceutically acceptable carrier. Such a carrier may be solid or liquid, and the type of carrier is usually selected based on the type of administration used.

Methods and compositions for preparing dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Holland, Ed., 1993) ; Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.) All of the above publications are incorporated by reference herein.

Tablets may contain suitable binders, lubricants, disintegrants, coloring agents, flavoring agents, flow inducing agents and melting agents. For example, for oral administration in unit dosage form of a tablet or capsule, the active drug component may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, phosphate dicalcium, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants useful in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

In the present invention, all numbers and percentages described are approximate values, regardless of the word about or approximately used in conjunction with them. They can vary by 1 percent, 2 percent, 5 percent or up to 20 percent. If a numerical range with a lower limit or an upper limit is described, any number falling within the specified range is specifically described.

Each embodiment described herein is intended to be applicable to each of the other embodiments described.

Therefore, all combinations of the various elements described herein are within the scope of the invention.

The present patent specification will be better understood by reference to experimental details below, but one skilled in the art will readily understand that the specific experiments described are only illustrative of the invention, as described more fully in the claims that follow thereafter.

Details of experiments.

Materials and methods.

Where possible, pharmacopoeial (eg OSP) or pharmaceutical grade chemicals were obtained.

- 12 044884

Carbamide peroxide is an oxidizing agent commonly used for its oxygen-releasing effect in the topical treatment and hygienic prevention of minor infections and inflammation or irritation of the gums and mouth, including ulcerative stomatitis (canker sores), gingivitis, periodontitis, stomatitis, and Vincent's infection. The drug is also used in the treatment of minor inflammation caused by false teeth, oral appliances (orthodontic), or dental procedures. The resulting material is a white crystalline powder with a relatively large particle size.

Omega fatty acids include omega-3 fatty acids, omega-6 fatty acids and omega-9 fatty acids. Omega-3 fatty acids are a family of unsaturated fatty acids that generally have a terminal carbon-carbon double bond at the n-3 position, the third bond from the methyl end. Omega-6 fatty acids are a family of unsaturated fatty acids that generally have a terminal carbon-carbon double bond at position n-6, that is, the sixth bond counted from the methyl end. Omega-9 fatty acids are a family of unsaturated fatty acids that generally have a terminal carbon-carbon double bond at the n-9 position, that is, the ninth bond counted from the methyl end.

Omega-3 fatty acids include, but are not limited to, hexadecatrienoic acid (HTA), alphalinolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), geneticosapentaenoic acid (HPA), docosapentaenoic acid (DPA), clupadonic acid, docosahexaenoic acid (DHA), tetracosapentaenoic acid or tetracosahexaenoic acid.

Omega-6 fatty acids include, but are not limited to, gamma-linolenic acid (GLA), calendic acid, eicosadienoic acid, dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenic acid, docosapentaenoic acid, tetracosatetroenoic acid or tetracosapentaenoic acid.

Omega-9 fatty acids include, but are not limited to, oleic acid, elaidic acid, gondoic acid, midic acid, erucic acid, nervonic acid.

Essential fatty acids cannot be synthesized by the human body and must be obtained from dietary sources. Because humans do not have the necessary enzyme to make carbon-carbon double bonds on carbon atoms after the ninth carbon in unsaturated fatty acids (the ninth carbon from the omega end of the chain). Gamma-linolenic acid (ω-6 fatty acid) and alpha-linolenic acid (ω-3 fatty acid) are essential fatty acids that must be obtained from a dietary source for good health.

Non-limiting examples of suitable fatty materials include oleic canola oil (Brassica campestris, B, napus, B. rapa; characterized by an olein content of greater than 70%, e.g. high oleic canola oil, very high oleic canola oil or partially hydrogenated canola oil), marula kernel oil (Sclerocarya birrea), palm oil (Elaeis Guineensis Oil), palm olein, palm stearin, palm superolein, pecan oil, pumpkin seed oil, oleic safflower oil (Carthamus Tinctorius; characterized by an olein content of greater than about 30% and omega-6 fatty acid content acids less than about 50%, e.g. high oleic safflower oil), sesame oil (Sesamum indicum, S. oreintale), soybean oil (Glycine max, e.g. high oleic soybean, low linoleic soybean oil, partially hydrogenated), oleic sunflower oil (Helianthus annus ; characterized by an oil content of more than about 40%, for example, medium oleic or high oleic sunflower oil), and mixtures thereof. Oleic canola oil, palm oil, sesame oil, high oleic safflower oil, high oleic soybean oil, medium oleic sunflower oil and high oleic sunflower oil are common vegetable oils and can also be derived from non-genetically modified organisms (non-GMO).

The above oils are commercially available from a number of suppliers.

Emu oil is an oil obtained from the fat of the emu, a bird native to Australia. Undiluted emu oil can vary widely in color and viscosity, but is typically a yellow liquid consisting of approximately 70% unsaturated fatty acids. The largest component is oleic acid, a monounsaturated omega-9 fatty acid. Emu oil also contains approximately 20% linolenic acid (an omega-6 fatty acid) and 1-2% linolenic acid (an omega-3 fatty acid). Emu oil is marketed and promoted as a dietary supplement with a wide variety of claimed health benefits. Commercial emu oil supplements are not standardized and vary widely in effectiveness. The emu oil used herein is sold as Pro-Emu Oil from Progressive Emu Inc., PO Box 590088, Birmingham, AL 35259 and is a formulated product that includes some vitamin E.

Emu oil is an oil obtained from the fat of the emu, a bird native to Australia. Undiluted emu oil can vary widely in color and viscosity, but is typically a yellow liquid consisting of approximately 70% unsaturated fatty acids. The largest components

- 13 044884 volume is oleic acid, a monounsaturated omega-9 fatty acid. Emu oil also contains approximately 20% linoleic acid (an omega-6 fatty acid) and 1-2% linolenic acid (an omega-3 fatty acid). Emu oil is marketed and promoted as a dietary supplement with a wide variety of claimed health benefits. Commercial emu oil supplements are not standardized and vary widely in their effectiveness. The emu oil used herein is sold as Pro-Emu Oil from Progressive Emu Inc., PO Box 590088, Birmingham, AL 35259 and is a formulated product that includes some vitamin E.

Lecithins vary widely in physical form, from viscous semi-liquids to powders, depending on their free fatty acid content. They can also vary in color from brown to light brown, depending on whether they are bleached or unbleached, or the degree of purity. When they are exposed to air, rapid oxidation develops, also resulting in a dark yellow or brown color. The lecithin used in the present invention is a brown to light yellow waxy material that may be difficult to distribute into a solid powder by conventional mixing. It should be noted that lecithin is incompatible with esterases due to hydrolysis and is also incompatible with oxidizing agents. Therefore, lecithin must be separated from carbamide peroxide.

In addition to other pharmaceutical excipients, agglomerated isomalt was chosen as an excipient for the tablet formulation. Specifically, galenIQ™ 720 (low solubility) and galenIQ™ 721 (high solubility) are agglomerated spherical isomalts for use in direct compression. In general, such excipients are of non-animal origin, they have very little hygroscopicity, are available in varying solubilities, they have excellent chemical stability, and are highly resistant to degradation by enzymes and acids, they are generally regarded as non-toxic, non-allergic and non-irritating materials and they have pleasant sugar-like natural sweet flavor profile. The highest degree of solubility is suitable for a quickly degrading layer, while a low degree of solubility will be suitable for a slowly degrading layer.

Papain is a white or grayish white, slightly hygroscopic powder. Its potency varies depending on how it is obtained, but in normal purity, it digests 35 times its lean meat weight. Papain is incompatible with strong oxidizing agents and is inactivated by oxidation. Papain as used herein is referred to as USP.

Example 1.

The original study (Table 1) focused on the inclusion of emu oil and lecithin in a solid dosage form (slowly disintegrating tablet). Emu oil has a very high melting point and the material used here exists as a free-flowing semi-solid at room temperature.

- 14 044884

Table 1

Initial composition for a slowly disintegrating tablet layer containing an oil, a surfactant and a remineralizing agent

Paragraph Component Macc% in mixture Weight per tablet (mg) Exact weight per batch (g) 1 Isomalt (galenIQ 720) 80, 9 202.4 7.1994 2 Anhydrous Dibasic Calcium Phosphate (Anhydrous Emcompress, J.R.S. Pharma) 11.5 28, 68 1.0202 3 Emu fat (Pro-Emu Oil, Progressive Emu) 5, 68 14.21 0.5054 4 Lecithin NF (Spectrum) 1.91 4,764 0.1695 TOTAL 100.0 (approx.) 250.0 8,895

The following results were obtained from the original study conducted.

The powder mass accumulated oil well; a very clean and dust-free mixture was obtained.

The lecithin distribution was patchy, and subsequent processing attempts involved melting the lecithin and/or mixing it with emu oil to form a liquid form before mixing it with the powder.

The mixture was easily compressed on a Carver Press to form hard tablets. The oil probably reduced friction against the mold wall enough to eliminate the need to add a lubricant.

When placed in water, the tablet degraded slowly and complete destruction was observed after approximately 5 minutes. During this time, the liquid became cloudy, mainly due to emulsification of the oil. Dicalcium phosphate appeared as insoluble particles.

The tablet had a neutral taste; Isomalt did not provide noticeable sweetness, nor did it provide the endothermal cooling associated with the filler like sorbitol.

The procedure for obtaining the composition described in table. 1.

1) Accurately weigh the emu fat (step 3) in a disposable plastic weighing cup;

2) accurately weigh the isomalt (step 1) in a disposable polyethylene weighing cup;

3) Take some of the isomalt weighed in step 2 and transfer it to a cup containing emu oil. Use a spatula to mix the powder with the oil. After mixing, transfer the resulting mass into a glass mortar. Repeat this procedure using additional parts of isomalt until the emu fat is completely absorbed on the powder. Transfer all remaining isomalt to a glass mortar;

4) accurately weigh anhydrous dibasic calcium phosphate (item 2) in a disposable polyethylene weighing cup and transfer to a glass mortar containing a mixture of isomalt and emu oil;

5) grind the mixture in a mortar and pestle to obtain a homogeneous mixture;

6) accurately weigh the lecithin (step 4) and transfer it to the mixture in a mortar;

7) grind the mixture in a mortar and pestle to obtain a homogeneous mixture;

8) press powder samples into tablets using a Carver press.

Example 2.

A second similar composition was obtained. With the taste evaluation condition described above, aspartame was included as a sweetener (Table 2). In terms of processing, in this case, lecithin was added to emu oil and the mixture was heated in a microwave oven to obtain a liquid mixture. The resulting mixture was then added to a mixture of isomalt and anhydrous dicalcium phosphate.

- 15 044884

table 2

Modified composition of a slowly decomposing tablet layer containing

mung bean Iо, surface Paragraph core active substance Component stvo and repair Mass% in mixture Mirror mass on tablet (mg) real thing Exact weight per batch (g) quality 1 Isomalt (galenIQ 720) Anhydrous dibasic phosphate 82.0 207.5 8.3000 2 calcium (Anhydrous 100 25.00 1.0000 Emcompress, J.R.S. Pharma) Emu fat (Pro-Emu 3 Oil, Progressive 6.00 15.00 0.6000 Emu) 4 Lecithin NF (Spectrum) 100 2.50 0.1000 5 Aspartame (Equal, Merisant Co.) 1.00 2.50 0.1000 TOTAL 100, 0 252.5 10,144

Heating of the lecithin/emu oil mixture was accomplished by placing the beaker in the microwave and heating for 30 second intervals. After each interval the mixture was stirred. Lecithin fragments continued to be present and a total of approximately 5 intervals were required; it is likely that the lecithin eventually melted and/or dissolved into the oil. It should be noted that in subsequent treatments, heating for longer time intervals resulted in clear decomposition of lecithin.

Tablets were prepared from this mixture, and they had similar physical characteristics to those obtained previously. Adding aspartame provided a slight improvement in flavor, but additional sweetener may have been required.

Method for obtaining the composition described in table. 2.

1) Accurately weigh the lecithin (step 4) into a 50 ml glass beaker;

2) determine the mass of the glass containing lecithin and accurately weigh emu fat (step 3) into the glass containing lecithin;

3) accurately weigh the anhydrous dibasic calcium phosphate (step 2) into a disposable polyethylene weighing cup;

4) transfer anhydrous dibasic calcium phosphate (step 2) into a glass mortar. Grind until fine powder is obtained;

5) accurately weigh the isomalt (step 1) into a disposable polyethylene weighing cup. Transfer the isomalt to a mortar containing anhydrous dibasic calcium phosphate. Grind to obtain a homogeneous mixture and then transfer the mixture to a weighing cup;

6) place the glass containing lecithin and emu oil in the microwave and heat until the lecithin melts. Use a spatula to mix the lecithin into the oil;

7) Take part of the powdered mixture obtained in 5 and transfer it to a glass containing a mixture of lecithin and emu oil. Use a spatula to mix the powder with the oil. After mixing, transfer the mixture to a glass mortar. Repeat this procedure using additional portions of the powder mixture until all the lecithin and emu oil have been absorbed into the powder. Transfer any remaining powder to a glass mortar;

8) grind the mixture in a mortar with a spatula to obtain a homogeneous mixture;

9) accurately weigh the aspartame (step 5) and transfer it to the mixture in a mortar. Grind to obtain a homogeneous mixture;

10) press powder samples into tablets using a Carver press.

Example 3.

Presented in table. 3 is a two-layer tablet composition. The initial composition was developed for a rapidly disintegrating layer, built around a model using a directly compressed dicalcium phosphate carrier and also including crospovidone, a so-called super disintegrant. Dicalcium phosphate is probably a good choice since it is inorganic and therefore incompatible with the strong oxidizing agent carbamide peroxide. Also

- 16 044884 rapid destruction releases a significant amount of remineralizing substance. Due to its incompatibility with strong oxidizing agents, papain was included in the slowly degradable layer and isomalt was replaced with sorbitol.

Table 3

Initial composition of a two-layer tablet

Collapse layer Paragraph Component Mass/in mixture Weight per tablet (mg) Exact weight per batch (g) 1 Urea peroxide (Spectrum) 1.0 2.5 0.1018 2 Anhydrous Dibasic Calcium Phosphate (Anhydrous Encompress, J.R.S. Pharma) 94.5 236, 3 9, 508 3 Crospovidone 3.50 8.75 0.3528 4 Magnesium stearate 1.00 2.5 0.1040 TOTAL 100, 0 250 10.0666 Slowly decomposing layer Paragraph Component Mass/in mixture Weight per tablet (mg) Exact weight per batch (g) 5 Sorbitol 78.0 390.0 7.7701 6 Anhydrous Dibasic Calcium Phosphate (Anhydrous Encompress, J.R.S. Pharma) 100 50.00 1.0565 7 Papain USP30 (Anhui) 50 25.00 0.5664 8 Emu fat (Pro-Emu Oil, Progressive Emu) 6.00 30.00 0.6488 9 Lecithin NF (Spectrum) 100 5.00 0.1399 TOTAL 100 500.00 10.1817

The following results were obtained from this study.

Sorbitol, which has a larger particle size than isomalt, did not accumulate oil well. The overall nature of the mixture for the slow decomposition layer was more oily.

Each individual mixture was compressed more easily to form strong tablets, like a combination of materials for a two-layer tablet.

When placed in water, the degrading layer actually decomposed faster, releasing insoluble dicalcium phosphate particles.

The second layer decomposed slowly.

Sorbitol did not improve taste.

The procedure for obtaining the composition described in table. 3.

Collapsed layer.

1) Accurately weigh the anhydrous dibasic calcium phosphate (item 2) into a disposable polyethylene weighing cup;

2) accurately weigh the urea peroxide (step 1) and transfer the powder into a glass mortar;

- 17 044884

3) geometrically add anhydrous dibasic calcium phosphate into a glass mortar, grinding after each addition to obtain a homogeneous mixture;

4) accurately weigh crospovidone (step 3) and add it to the powder mixture in a glass mortar. Grind to obtain a homogeneous mixture;

5) accurately weigh magnesium stearate (step 4) and add it to the powder mixture in a glass mortar. Grind lightly to obtain a homogeneous mixture;

6) transfer the mixture to a container and leave until tabletting.

Slowly decomposing layer.

7) Accurately weigh the lecithin (step 9) into a 50 ml glass beaker;

8) determine the weight of the glass containing lecithin and accurately weigh emu oil (step 8) into the glass containing lecithin;

9) accurately weigh anhydrous dibasic calcium phosphate (step 6) into a disposable polyethylene weighing bowl;

10) transfer anhydrous dibasic calcium phosphate (step 6) into a glass mortar. Grind until fine powder is obtained;

11) accurately weigh the sorbitol (step 5) into a disposable polyethylene weighing bowl, transfer the sorbitol to a mortar containing anhydrous dibasic calcium phosphate. Grind to obtain a homogeneous mixture and then transfer the mixture to a weighing cup;

12) place the glass containing lecithin and emu oil in the microwave and heat until the lecithin melts, use a spatula to mix the lecithin with the oil;

13) Take a portion of the powder mixture obtained in step 1 and transfer it to a glass containing a mixture of lecithin and emu oil. Use a spatula to mix the powder with the oil. After mixing, transfer the resulting mass into a glass mortar. Repeat this procedure using additional portions of the powder mixture until all the lecithin and emu oil on the powder is absorbed. Transfer the remaining powder to a glass mortar;

14) grind the mixture in a mortar and pestle to obtain a homogeneous mixture;

15) accurately weigh the papain (step 7) and add it to a glass mortar. Grind until a homogeneous mixture is obtained;

16) transfer the mixture to a container and keep until tableting.

Preparation of a two-layer tablet.

17) Weigh approximately 500 mg of powder for the slow decomposing layer and transfer it to the mold, press the powder into the first layer using a Carver press;

18) Weigh approximately 250 mg of collapsing layer powder and transfer it to the mold containing the first layer. Press the powder onto the first layer using a Carver press.

19) remove the tablet from the mold.

Example 4.

Modifications obtained in the following embodiment (Table 4) include the replacement of sorbitol with isomalt and the use of relatively large, capsule-like equipment to obtain tablets. A tablet size of 1.2 g was prepared with 400 and 800 mg for the collapsible and degradable layers, respectively.

Table 4

Compositions of bilayer tablets of carbamide peroxide (4 mg) and papain (40 mg)

Collapse layer Paragraph Component Mass% in mixture Weight per tablet (mg) Exact weight per batch (g)

- 18 044884

1 Urea peroxide (Spectrum) 1.0 4.00 0.1107 2 Anhydrous Dibasic Calcium Phosphate (Anhydrous Encompress, J.R.S. Pharma) 94.5 378.00 9, 479 3 Crospovidone 3.50 14.00 0.3601 4 Magnesium stearate 100 4.00 0.1053 TOTAL 100, 0 400, 0 10.0551 Slowly decomposing layer Paragraph Component Macc% in mixture Weight per tablet (mg) Exact weight per batch (g) 5 Isomalt 78.0 624.0 7.7967 6 Anhydrous Dibasic Calcium Phosphate (Anhydrous Encompress, J.R.S. Pharma) 100 80.00 1.0722 7 Papain USP30 (Anhui) 50 40.00 0.5243 8 Emu fat (Pro-Emu Oil, Progressive Emu) 6.00 48.00 0.6330 9 Lecithin NF (Spectrum) 1.00 8.00 0.1008 TOTAL 100 800.00 10.127

After the production of these two-layer tablets, two things became obvious. When processing the resulting tablet, it became obvious that the edges of the resulting layer were easily erased. Secondly, when placed in stimulated intestinal juice, a large amount of insoluble dicalcium phosphate was released, which can be granular and undesirable.

The procedure for obtaining the composition described in table. 4.

Collapsed layer.

1) Accurately weigh anhydrous dibasic calcium phosphate (item 2) into a disposable polyethylene weighing bowl;

2) accurately weigh the urea peroxide (step 1) and transfer the powder into a glass mortar;

3) geometrically add anhydrous dibasic calcium phosphate into a glass mortar, grinding after each addition to obtain a homogeneous mixture;

4) accurately weigh crospovidone (step 3) and add it to the powder mixture in a glass mortar. Grind to obtain a homogeneous mixture;

5) accurately weigh magnesium stearate (step 4) and add it to the powder mixture in a glass mortar. Grind lightly to obtain a homogeneous mixture;

6) transfer the mixture to a container and keep until tabletting. Slowly decomposing layer

7) accurately weigh the lecithin (step 9) in a 50 ml glass beaker.

8) determine the weight of the glass containing lecithin and accurately weigh emu oil (step 8) into the glass containing lecithin;

9) accurately weigh anhydrous dibasic calcium phosphate (step 6) into a disposable polyethylene weighing bowl;

10) transfer anhydrous dibasic calcium phosphate (step 6) into a glass mortar. Grind until fine powder is obtained;

- 19 044884

11) accurately weigh the isomalt (step 5) into a disposable polyethylene weighing bowl. Transfer the isomalt to a mortar containing anhydrous dibasic calcium phosphate. Grind to obtain a homogeneous mixture and then transfer the mixture to a weighing bowl;

12) place the glass containing lecithin and emu oil in the microwave and heat until the lecithin melts. Use a spatula to mix the lecithin into the oil;

13) Take part of the powder mixture obtained in step 11 and transfer it to a glass containing a mixture of lecithin and emu oil. Use a spatula to mix the powder with the oil. After mixing, transfer the resulting mass into a glass mortar. Repeat this procedure using additional portions of the powder mixture until all the lecithin and emu oil are absorbed into the powder. Transfer any remaining powder to a glass mortar;

14) grind the mixture in a mortar and pestle to obtain a homogeneous mixture;

15) accurately weigh the papain (step 7) and add it to a glass mortar. Grind until a homogeneous mixture is obtained;

16) transfer the mixture to a container and store until tabletting.

Preparation of a two-layer tablet.

17) Weigh approximately 650 mg of powder for the slow decomposing layer and transfer it to the mold, press the powder into the first layer using a Carver press;

18) Weigh approximately 350 mg of collapsing layer powder and transfer it to the mold containing the first layer. Press the powder onto the first layer using a Carver press.

19) remove the tablet from the mold.

Example 5.

The amount of phosphate salt was reduced and a soluble filler was added. Consequently, in the next option (Table 5), the concentration of dicalcium phosphate was reduced and isomalt was included as a soluble filler in the deteriorating layer. A two-layer tablet obtained from the composition in table. 5 showed no evidence of incompatibility in the dosage form. There was significant flexibility of the tablet with respect to both composition and weight and the weight of the respective layers.

Table 5

Modified composition of a two-layer tablet of carbamide peroxide (4 mg) and papain (40 mg)

Collapse layer Paragraph Component Mass% in mixture Weight per tablet (mg) Accurate mass per batch (g) 1 Urea peroxide (Spectrum) 1.0 4.00 0.1042 2 Anhydrous Dibasic Calcium Phosphate (Anhydrous Encompress, J.R.S. Pharma) 9, 5 38.00 0.969 3 Isomalt (galenIQ 720) 85, 0 340.0 8,519 4 Crospovidone 3.5 14.00 0.3488 5 Magnesium stearate 1.00 4.00 0.1087 TOTAL 100, 0 400, 0 10.0497 Slowly decomposing layer Paragraph Component Mass% in mixture Weight per tablet (mg) Exact weight per batch (g) 6 Isomalt (galenIQ 720) 78.0 624.0 7.8036

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7 Anhydrous Dibasic Calcium Phosphate (Anhydrous Encompress, J.R.S. Pharma) 100 80.00 1.406 8 Papain (Anhui) USP30 50 40.00 0.5454 9 Emu fat (Pro-Emu Oil, Progressive Emu) 6.00 48.00 0.6929 10 Lecithin (Spectrum) NF 1.00 8.00 0.1100 TOTAL 100 800.00 10.1925

The procedure for obtaining the composition described in table. 5.

Collapsed layer.

1) Accurately weigh anhydrous dibasic calcium phosphate (item 2) into a disposable polyethylene weighing bowl;

2) accurately weigh the urea peroxide (step 1) and transfer the powder into a glass mortar;

3) add anhydrous dibasic calcium phosphate into a glass mortar and grind to obtain a homogeneous mixture;

4) accurately weigh the isomalt (step 3) and add it to the powder mixture in a glass mortar. Grind to obtain a homogeneous mixture;

5) accurately weigh crospovidone (step 4) and magnesium stearate (step 5) and add them to the powder mixture in a glass mortar. Grind to obtain a homogeneous mixture;

6) transfer the mixture to a container and keep it for tableting.

Slowly decomposing layer.

7) Accurately weigh the lecithin (item 10) in a 50 ml glass beaker;

8) determine the mass of the glass containing lecithin and accurately weigh emu fat (step 9) into the glass containing lecithin;

9) accurately weigh anhydrous dibasic calcium phosphate (step 6) into a disposable polyethylene weighing bowl;

10) transfer anhydrous dibasic calcium phosphate (step 7) into a glass mortar. Grind until fine powder is obtained;

11) accurately weigh the isomalt (step 6) into a disposable polyethylene weighing bowl. Transfer the isomalt to a mortar containing anhydrous dibasic calcium phosphate. Grind to obtain a homogeneous mixture and then transfer the mixture to a weighing bowl;

12) place the glass containing lecithin and emu oil in the microwave and heat until the lecithin melts, use a spatula to mix the lecithin with the oil;

13) Take part of the powder mixture obtained in step 11 and transfer it to a glass containing a mixture of lecithin and emu oil. Use a spatula to mix the powder with the oil. After mixing, transfer the resulting mass into a glass mortar. Repeat this procedure using additional portions of the powder mixture until all the lecithin and emu oil are absorbed into the powder. Transfer any remaining powder to a glass mortar;

14) grind the mixture in a mortar and pestle to obtain a homogeneous mixture;

15) accurately weigh the papain (step 8) and add it to a glass mortar. Grind until a homogeneous mixture is obtained;

16) transfer the mixture to a container and store until tabletting;

Preparation of a two-layer tablet.

17) Weigh approximately 800 mg of powder for the slow decomposing layer and transfer it to the mold, press the powder into the first layer using a Carver press;

18) Weigh approximately 400 mg of collapsing layer powder and transfer it to the mold containing the first layer. Press the powder onto the first layer using a Carver press;

19) remove the tablet from the mold.

Example 6.

In fig. 7 shows another composition. Several changes have been made including: 1) the mass of the fast decomposition layer has been reduced and that of the slow decomposition layer has been increased - there is no need for more urea peroxide content, and the greater the mass of the slow decomposition layer, the more oil can be included; 2) the amount of emu fat was increased

- 21 044884 chili to 10% and the amount of lecithin was increased from 1 to 2%. Emu oil and lecithin were mixed in a glass and heated on a hotplate while stirring. The temperature required to melt the lecithin and incorporate it into the oil was quite high. While it is possible to obtain a single-phase solution of the two components, excessive heat may change the character of the oil and/or destroy the lecithin.

Table 6 Modified composition of a two-layer tablet of carbamide peroxide (2 mg) and papain (100 mg), including tricalcium phosphate

Collapse layer Paragraph Component Macc% in mixture Weight per tablet (mg) Exact weight per batch (g) 1 Urea peroxide (Spectrum) 10 2.00 0.2185 2 Tricalcium phosphate, Powder NF 20, 0 40.00 3,995 3 Isomalt (galenIQ 720) 73, 0 146, 0 14,605 4 Crospovidone 4.00 8.00 0.8164 5 Magnesium stearate 2.00 4.00 0.3880 TOTAL 100, 0 200, 0 20.0229 Slowly decomposing layer Paragraph Component Mass% in mixture Weight per tablet (mg) Accurate mass per batch (g) 6 Isomalt (galenIQ 720) 43, 0 430, 0 8.5481 7 Tricalcium phosphate, Powder NF 35, 0 350.00 7.0121 8 Papain USP30 (Anhui) 100 100.00 2.0847 9 Emu fat (Pro- Emu Oil, Progressive Emu) 10.00 100.00 2.0679 10 Lecithin NF (Spectrum) 2.00 20.00 0.4002 TOTAL 100 1000.00 20, ISO

The warm oil solution was added to the tricalcium phosphate with the expectation that it could be evenly distributed throughout the powder. The combination of fine powder and reduced temperature resulted in the formation of waxy aggregates that were very difficult to completely dissolve. After pressing, yellow spots remained on the surface of the tablet, indicating uneven distribution of lecithin. The oil, lecithin and powder mixture may need to be heated to obtain the desired uniformity. For larger production volumes, this can be accomplished in a high shear shell mixer. Perhaps including more oil and the consistency of a slow-decomposing layer might be good.

The procedure for obtaining the composition described in table. 6.

Collapsed layer.

1) Accurately weigh tricalcium phosphate (step 2) into a disposable polyethylene weighing bowl;

2) accurately weigh the urea peroxide (step 1) and transfer the powder into a glass mortar;

3) add tricalcium phosphate to a glass mortar and grind to obtain a homogeneous mixture;

4) accurately weigh the isomalt (step 3) and add it to the powder mixture in a glass mortar.

- 22 044884

Grind to obtain a homogeneous mixture;

5) accurately weigh crospovidone (step 4) and magnesium stearate (step 5) and add them to the powder mixture in a glass mortar. Grind lightly to obtain a homogeneous mixture;

6) transfer the mixture to a container and keep until tabletting.

Slowly decomposing layer.

7) Accurately weigh the lecithin (item 10) in a 50 ml glass beaker;

8) determine the mass of the glass containing lecithin and accurately weigh emu fat (step 9) into the glass containing lecithin;

9) accurately weigh tricalcium phosphate (step 7) into a disposable polyethylene weighing bowl;

10) accurately weigh the isomalt (item 6) into a disposable polyethylene weighing bowl;

11) place a glass containing lecithin and emu oil on the stove and heat until the lecithin and oil are mixed;

12) add tricalcium phosphate from step 9 to a glass containing a mixture of emu oil and lecithin. Use a spatula to mix the powder with the oil. After mixing, transfer the resulting mass into a glass mortar. Repeat this procedure using additional portions of the isomalt powder mixture from step 10 and continue until all the lecithin and emu oil have been absorbed into the powder. Transfer any remaining isomalt powder to a glass mortar;

13) grind the mixture in a mortar and pestle to obtain a homogeneous mixture;

14) accurately weigh the papain (step 8) and add it to a glass mortar. Grind until a homogeneous mixture is obtained;

15) transfer the mixture to a container and store until tabletting;

Preparation of a two-layer tablet.

16) Weigh approximately 1000 mg of powder for the slow decomposing layer and transfer it to the mold, press the powder into the first layer using a Carver press;

17) Weigh approximately 200 mg of collapsing layer powder and transfer it to the mold containing the first layer. Press the powder onto the first layer using a Carver press.

18) remove the tablet from the mold.

Example 7.

An attempt to increase the oil level to 15 wt.% is represented by a tablet described in table. 7. The said batch was produced in 100g size with the expectation that it could be pressed on a single-station tool press to evaluate the current. However, when a screening test was performed on the Carver press, the fast degrading layer did not adhere to the slow degrading layer. The pressure applied essentially squeezed the oil out of the carrier, giving a highly lubricated surface between the layers.

Table 7 Modified composition of a two-layer tablet of carbamide peroxide (2 mg) and papain (100 mg), including 15% emu oil

Collapse layer Paragraph Component Mass% in mixture Weight per tablet (mg) Exact weight per batch (g) 1 Urea peroxide (Spectrum) 1.0 2.00 1.0385

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2 Tricalcium phosphate, Powder NF 20, 0 40.00 20,090 3 Isomalt (galenIQ 720) 73, 0 146, 0 73,068 4 Crospovidone 4.00 8.00 3.9924 5 Magnesium stearate 2.00 4.00 2.0100 TOTAL 100, 0 200, 0 100.1989 Slowly decomposing layer Paragraph Component Mass/in mixture Weight per tablet (mg) Exact weight on batch (g 6 Isomalt (galenIQ 720) 38.0 380.0 37.9956 7 Tricalcium phosphate, Powder NF 35, 0 350.00 35.0067 8 Papain USP30 (Anhui) 100 100.00 10.0530 9 Emu oil (Pro-Emu Oil, Progressive Emu) 15.00 150.00 15.1024 10 Lecithin NF (Spectrum) 2.00 20.00 2.0863 TOTAL 100 1000.00 100.244

The procedure for obtaining the composition described in table. 7.

Collapsed layer.

1) Accurately weigh tricalcium phosphate (step 2) into a disposable polyethylene weighing bowl;

2) accurately weigh the urea peroxide (step 1) and transfer the powder into a glass mortar;

3) add tricalcium phosphate to a glass mortar and grind to obtain a homogeneous mixture;

4) accurately weigh the isomalt (step 3) and add it to the powder mixture in a glass mortar. Grind to obtain a homogeneous mixture;

5) accurately weigh crospovidone (step 4) and magnesium stearate (step 5) and add them to the powder mixture in a glass mortar. Grind lightly to obtain a homogeneous mixture;

6) transfer the mixture to a container and keep until tabletting.

Slowly decomposing layer.

7) Accurately weigh the lecithin (item 10) in a 50 ml glass beaker;

8) determine the mass of the glass containing lecithin and accurately weigh emu fat (step 9) into the glass containing lecithin;

9) accurately weigh tricalcium phosphate (step 7) into a disposable polyethylene weighing bowl;

10) accurately weigh the isomalt (item 6) into a disposable polyethylene weighing bowl;

11) place a glass containing lecithin and emu oil on the stove and heat until the lecithin and oil are mixed;

12) add tricalcium phosphate from step 9 to a glass containing a mixture of emu oil and lecithin. Use a spatula to mix the powder with the oil. After mixing, transfer the resulting mass into a glass mortar. Repeat this procedure using additional portions of the isomalt powder mixture from step 10 and continue until all the lecithin and emu oil are absorbed into the powder. Transfer any remaining isomalt powder to a glass mortar;

13) grind the mixture in a mortar and pestle to obtain a homogeneous mixture;

14) accurately weigh the papain (step 8) and add it to a glass mortar. Grind until a homogeneous mixture is obtained;

16) transfer the mixture to a container and store until tabletting.

Preparation of a two-layer tablet.

17) Weigh approximately 1000 mg of powder for the slow decomposing layer and transfer it to the mold, press the powder into the first layer using a Carver press;

- 24 044884

18) Weigh approximately 200 mg of collapsing layer powder and transfer it to the mold containing the first layer. Press the powder onto the first layer using a Carver press;

19) remove the tablet from the mold.

Example 8.

The following compositions were prepared using the methods described above:

A composition comprising emu oil and one or more emulsifying agents. A composition comprising omega fatty acids and one or more emulsifying agents. A composition comprising omega fatty acids and one or more protease enzymes. A composition comprising omega fatty acids and one or more remineralizing agents based on soluble calcium phosphate. A composition comprising omega fatty acids and one or more whitening agents. A composition comprising omega fatty acids and two or more of the following: one or more emulsifying agents, one or more protease enzymes, one or more soluble calcium phosphate remineralizing agents, and one or more whitening agents. A composition comprising omega fatty acids and three of the following: one or more emulsifying agents, one or more protease enzymes, one or more soluble calcium phosphate remineralizing agents, and one or more whitening agents. A composition comprising omega fatty acids, one or more emulsifying agents, one or more protease enzymes, one or more soluble calcium phosphate remineralizing agents and one or more whitening agents.

A composition comprising emu oil and one or more emulsifying agents. A composition comprising emu oil and one or more protease enzymes. A composition comprising emu oil and one or more remineralizing agents based on soluble calcium phosphate. A composition comprising emu oil and one or more bleaching agents. A composition comprising emu oil and two of the following: one or more emulsifying agents, one or more protease enzymes, one or more soluble calcium phosphate remineralizing agents, and one or more whitening agents. A composition comprising emu oil and three of the following: one or more emulsifying agents, one or more protease enzymes, one or more soluble calcium phosphate remineralizing agents, and one or more whitening agents. A composition comprising emu oil, one or more emulsifying agents, one or more protease enzymes, one or more soluble calcium phosphate remineralizing agents and one or more whitening agents.

The above compositions are formulated as single-layer tablets, double-layer tablets or any of the compositions described above.

Example 9.

The composition of the present invention is administered to a patient or patients suffering from xerostomia and/or hyposalivation. The composition increases salivation in the patient(s). The composition also reduces the subjective sensation of dry mouth in the patient(s). The composition of the present invention is applied to the patient's teeth. The composition whitens the patient's teeth.

The bilayer tablet composition of the present invention, comprising one or more bleaching agents in a rapidly disintegrating layer and emu oil, is administered to a patient or patients suffering from xerostomia and/or hyposalivation. The composition of the two-layer tablet increases the patient's salivation. The composition also reduces the subjective sensation of dry mouth in the patient(s). The bilayer tablet composition of the present invention comprising one or more whitening agents in a rapidly disintegrating layer and emu oil is applied to the patient's teeth. A two-layer tablet whitens the patient's teeth.

The two-layer tablet composition of the present invention, comprising one or more whitening agents in a rapidly disintegrating layer, is applied to the patient's teeth. A two-layer tablet whitens the patient's teeth.

Example 10.

One oral care composition of the present invention followed by five second oral care compositions of the present invention is applied within 24 hours to a patient suffering from xerostomia of the oral cavity and pharynx. The composition increases salivation in the patient(s). The composition also reduces the patient's subjective feeling of dry mouth.

One oral care composition of the present invention followed by five second oral care compositions of the present invention is applied within 24 hours to a patient suffering from oral and pharyngeal mucositis. The compositions treat a patient suffering from oral and pharyngeal mucositis.

Discussion.

The composition described herein relates to a stable, multi-component solid dosage form for use in dental therapy that delivers an effective combination of emu oil, whitening/cleansing agent, protease enzyme, remineralizing agent and emulsifying agent to the oral cavity. The combination of ingredients was formulated and formulated into a bilayer tablet. There were no immediate signs of incompatibility in

- 25 044884 dosage form as such. The tablet has sufficient flexibility in terms of composition and weight and weight of layers, i.e. a slowly decomposing layer and a collapsing layer. However, the concentration of emu oil that may be contained in said dosage form is 15% or less (based on the slowly decomposing layer). Incorporation of lecithin is accomplished by dissolving the surfactant in emu oil. This approach requires high temperature. However, alternative processing approaches are available.

The bilayer tablet is described in FIG. 1 and 2. The tablet consists primarily of a rapidly disintegrating layer containing the bleach/cleanser (ie, carbamide peroxide) and a non-disintegrating, slowly disintegrating lozenge-like layer that contains other components. The bilayer tablet creates physical separation of the oxidizing agent from the other components of the product in the dosage form. This characteristic is especially desirable given that the peroxide may be incompatible with other agents (ie, papain).

When placed in the oral cavity, saliva causes rapid breakdown of the disintegrating layer, creating a liquid environment with an effective level of free hydrogen peroxide. At the same time, the second layer, which contains other components including emu oil and papain, begins to slowly decompose. The duration of the peroxide's whitening/cleansing action is relatively short, so that exposure to other components of oxidative destruction is limited and the release of such ingredients is maintained.

Links.

Anneroth G, Nordenram G, Bengtsson S. (1980) Effect of saliva stimulants (Hybrin and malic acid) on cervical root surfaces in vitro. Scand J Dent Res. 88, 214-8.

Borges B.C. et al. (2010) Xerostomia and hyposalivation: a preliminary report of their prevalence and associated factors in Brazilian elderly diabetic patients. Oral Health Prev. Dent. 8, 2, 153-158.

Cassolato SF, Turnbull RS. (2003) Xerostomia: clinical aspects and treatment. Gerodontology. 20, 64-77.

Davies AN. (2000) A comparison of artificial saliva and chewing gum in the management of xerostomia in patients with advanced cancer. Palliar. Med. 14, 197-203.

Hochberg MG, Tielsch J, Munoz B, et al. (1998) Prevalence of symptoms of dry mouth and their relationship to saliva production in community housing elderly: the SEE project. J

Rheumatol 25, 486-4891.

Nederfors, T. (1996) Xerostomia: prevalence and

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Claims (14)

pharmacotherapy. With special reference to beta-adrenoceptor antagonists, awed Dent J Suppl. 116, 1-70. Nederfors T, Isaksson R, Mornstad H, Dahlof C. (1997) Prevalence of perceived symptoms of dry mouth in an adult Swedish population-relation to age, sex and pharmacotherapy. Community Dent Oral Epidemiol, 25, 211-216. Narhi TO, Meurman JH, Ainamo A. (1999) Xerostomia and hyposalivation: causes, consequences and treatment in the elderly. Drugs & Aging 15, 103-116. Orellana MF, Lagravere MO, Boychuk DGJ, Major PW, FloresMir C. (2006) Prevalence of xerostomia in population-based samples: a systematic review. Journal of public health dentistry 66, 2, 152-158. Scully C, Bagan JV. (2004) Adverse drug reactions in the orofacial region. Crit Rev Oral Biol Med. 15, 221-39. Silvestre-Donat PJ, Miralles-Jorda L, Martinez-Mihi V. (2004) Protocol for the clinical management of dry mouth. Med Oral. 9, 273-9. CLAIM 1. Composition for oral care, containing: a) 5-10 wt.% emu fat; b) 1-5 wt.% emulsifying agent; c) 0.1-40 wt.% protease enzyme; d) 0.1-50% by weight of a remineralizing agent based on soluble calcium phosphate and e) one or more whitening agents, where the emulsifying agent is soy lecithin; and wherein the composition is formulated as a tablet, gel or emulsion. 2. The composition according to claim 1, where the composition is a tablet containing 40-60 mg of bromelain from the stems. 3. The composition according to claim 1, where the composition is a tablet containing a slowly degradable layer, and the slowly degradable layer contains 1-10 wt.% protease enzyme. 4. The composition according to any one of claims 1 to 3, wherein one or more bleaching agents are selected from the group consisting of carbamide peroxide and hydrogen peroxide. 5. The composition according to any one of claims 1 to 4, wherein one or more soluble calcium phosphate remineralizing agents are selected from the group consisting of dibasic calcium phosphate, monocalcium phosphate, tricalcium phosphate and tetracalcium phosphate. 6. Composition according to any one of claims 1 to 4, wherein the remineralizing agent based on soluble calcium phosphate is amorphous calcium phosphate. 7. The composition according to any one of claims 1 to 6, wherein the composition is a tablet containing a slowly decomposing layer, and the slowly decomposing layer contains 5-25 wt.% of a remineralizing agent based on soluble calcium phosphate. 8. The composition according to any one of claims 1 to 7, where the composition further includes isomalt. 9. The composition according to claim 1, additionally containing 0.1-10.0 wt.% urea peroxide. 10. The composition of claim 1, further comprising oleic canola oil, palm oil, sesame oil, oleic safflower oil, soybean oil or oleic sunflower oil. 11. The composition according to any one of claims 1 to 10, where the composition is a two-layer tablet or a viscous gel. 12. Use of a composition according to any one of claims 1 to 11 for the preparation of a medicinal product for the treatment of a patient suffering from xerostomia or mucositis of the oral cavity and/or pharynx. 13. Use according to claim 12, where the composition additionally whitens teeth in the patient's oral cavity. 14. Use according to claim 13, wherein the composition further remineralizes the teeth in the patient's oral cavity. -