BACKGROUND OF THE INVENTION The following is a list of references that considered to be relevant as background to the invention. Appearance of a document in this list should not be construed as implying that the document is relevant to the patentability of the invention.

WO 00/30641, describes formulations of nicotine for use in nicotine replacement therapy. These formulations are intended for application in the oral cavity, whereupon the uptake of nicotine mainly takes place through the buccal mucosa. They essentially comprise of polar, apolar and surface active components.

WO 02/47607 describes a process for the preparation of fast dissolving dosage form, which disintegrates quickly in the mouth. The process includes blending a pharmaceutically active ingredient with a cementing agent, which preferably melts between 40 and 60°C.

US 4,786, 502 describes lipid-containing, molded pharmaceutical compositions, comprising: (a) from about 10% to about 50% of a lipid material having a melting point of from about 26°C. to about 37°C. ; (b) from about 10% to about 50% of a particulate dispersant material; (c) from about 0.1% to about 3% of an emulsifier; and (d) a safe and effective amount of a pharmaceutical active material; wherein the particulate materials in said composition have a

mean particle size of from about 4 microns to about 10 microns, with less than about 10% of the particulates greater than about 30 microns in size.

US 5,573, 255 describes a chewable medicinal tableting composition comprising as proportions of the total composition: capric triglyceride: about 30 to about 95% by weight, and a medicinally active ingredient: up to 60% by weight.

SUMMARY OF THE INVENTION According to one aspect of the present invention there is provided a mouth-melt pharmaceutical composition that includes water-sensitive ingredient embedded in a hydrophobic fatty matrix having a melting point of between 30 and 40°C.

According to one embodiment of the present invention the pharmaceutical composition comprises a water sensitive active ingredient embedded in said fatty hydrophobic matrix.

According to another embodiment of the present invention the pharmaceutical composition comprises an active ingredient, and a water sensitive excepient embedded in said fatty hydrophobic matrix.

According to a preferred embodiment of the present invention, the pharmaceutical composition is consisting of a fatty matrix embedding therein water sensitive ingredient, possibly together with water-insensitive ingredients, the water sensitive ingredient being an active ingredient or an excepient.

Preferably, a pharmaceutical composition according the present invention is in the form of a tablet, capsule, or a bar, when tablet is most preferable.

A pharmaceutical composition according to the present invention has the double benefit of having long shelf-life (despite of the water-sensitivity of one of its ingredients) and being easy to swallow. Thus, it may be used for administrating water-sensitive active ingredients to elderly subjects, or to any other population that has difficulty in swallowing hard tablets. On the other hand, it may be useful for administrating any kind of pharmaceutical composition with a water sensitive excepient. One example of such an excepient is popping, gas entrapped excepient, as described in copending US patent application no. 10/173, 814.

A pharmaceutical composition is considered to be mouth melt if it has a melting point at a temperature between 30 and 40°C, preferably between 34 and 38°C. Melting point of a pharmaceutical composition is a temperature wherein, under atmospheric pressure, said composition turns from solid to liquid (possibly with solids dispersed within said liquid). According to the invention the melting point of the pharmaceutical composition is within range as that of the fatty hydrophobic matrix.

Naturally, a mouth-melt pharmaceutical composition is intended for oral administration, and as such, it typically includes a flavoring agent.

It should be noted that the term pharnzaceutical composition"should be construed in a broad sense and includes any composition for the purpose of achieving a therapeutic effect in humans or animals. It may be sold as a pharmaceutical composition carrying a label as to the intended indication, whether as a prescription drug or over the counter, or it may be sold without any specific indication, for example as a neutraceutical (neutraceuticals are often referred to as 'fiood additives"or'>ood supplements").

The term"active if2gredient"should be construed in a broad sense as including any ingredient considered to have a therapeutic effect when delivered to a subject in need thereof. The active ingredient may be an analgesic, an antipyretic agent, an anti-inflammatory agent, an expectorant, an antibiotic, an anti-hypertensive, an anti-anginal, an antiepileptic, an anxiolytic, an antipsychotic, and anti-allergic, an antidepressant, a hormone, a steroid, an hypolipidaemic, a

diuretic, etc. Thus, it may be a drug such as isosorbide-mononitrate, enalapril maleate, sodium valporate, aspirin, alprazolam, amitriptyline, amoxicillin, benzocaine, celecoxib, dexamethazone, famotidine, lansoprazole, simvastatin, lorazepam, testosterone, verapamil, etc. It may also be a vitamin or mineral such as vitamin C, vitamin E, biotin, selenium, zinc, etc. It may further be a food additive such as echinacea, propolis, soy extract, etc. The active ingredient may be taste masked, for instance by coating or microencapsulation.

A hydrophobic matrix according to the invention is a substance or mixture of substances that is not water soluble in room temperature. Preferable hydrophobic matrices phase separate from water at any temperature up to 50°C, and most preferable are matrices that phase separate from water at any temperature up to 100°C.

A fatty matrix, is a matrix made substantially of fatty acids, fatty acid alcohols, hydrogenated vegetable oils, glyceric esters of fatty acids, cocoa butter, and the like. The fatty matrix according to the invention has a sharp melting point, between 30 and 40°C, preferably between 34 and 38°C. A sharp melting point is one that may be defined within a 4°C interval, preferably within a 2°C interval.

The term water sensitive should be construed within the context of the present description and claims as the feature of developing more than 0. 1% degradation products per year, preferably more than 0.2%, when packed in a conventional PVC blister and stored at 25°C and 60% relative humidity (hereinafter RH). Another way to express the idea of water sensitivity is that a water sensitive substance packed for more than one year in a conventional PVC blister at 25°C and 60% RH changes its characteristics in a manner that makes it non-effective for the purpose it should serve in the pharmaceutical composition.

According to another aspect of the present invention there is provided a method for stabilizing a water sensitive ingredient in a pharmaceutical composition, comprising embedding said water-sensitive ingredient in a fatty hydrophobic matrix with a melting point of between 30 and 40°C.

Preferably, the method of the invention comprises: (a) melting the fatty hydrophobic matrix ; and (b) mixing into the melt matrix the other ingredients of the composition.

Preferably, the pharmaceutical composition according to the invention is formed into an oral administration dosage form, such as a tablet, capsule, bar, and the like. Thus, the present invention also provides a method for producing a dosage form of a pharmaceutical composition including a water sensitive ingredient comprising : (a) melting a fatty hydrophobic matrix; (b) mixing into the melt matrix the other ingredients of the composition; (c) molding the obtained mixture into a mold; and (d) cooling the molded mixture as to solidify it.

The mold according to the invention may be a blister, a hard capsule, a bar-mold, a tablet-mold, or any other kind of mold known in the art.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS In order to understand the invention and to see how it may be carried out in practice, several embodiments will now be described, by way of non-limiting example only.

Example 1: Enalapril Maleate 20mg tablet Ingredient mg/Tab Enalapril Maleate 20mg Aspartame 10mg Cherry Flavor 5 mg Cocoa Butter 200mg Preparation process: Enalapril Maleate, Aspartame, and flavor are mixed in Cocoa Butter heated to

40°C. The mixture is molded in tablet blisters and cooled to room temperature.

Blisters are sealed.

This example demonstrates the use of a composition according to the invention with a water sensitive active ingredient.

Stability of the above mentioned formulation was tested under accelerated conditions in parallel to conventional marketed tablets (hydrophilic formulation).

Results: Total Impurities and degradation products (%) 6 months at 6 months at 30°C/60% RH. 40°C/75% RH. Market Product 2. 7% 5. 1% Novel hydrophobic 0.2% 0.4% tablet Example 2: Propolis Bar Ingredient mg/Bar Propolis Extract 200.0 mg Popping Candy 1000. Omg Cocoa Butter 800.0 mg Chocolate Flavor 20.0 mg Preparation process: Cocoa butter was melt and while cooling propolis extract, chocolate flavor and the popping powder were added. The semi-solid mass was cast inside chocolate bar molds to yield the desired bars.

Popping candy is very sensitive to humidity. Immediately when exposed to moisture it elevates Carbon Dioxide. The above mentioned formulation protects this excipient form humidity penetration during storage. When bar is chewed or swallowed popping candy act in the mouth and gives a"jumping"sensation. This phenomenon is popular among children and improves better compliance to take the drug.

This example demonstrates a composition according to the present

invention, where the water-sensitive ingredient is and excepient.

Example 3: Sodium Valproate 200mg Capsule Ingredient mg/caps Sodium Valproate 200mg Hard Fat 300mg Mint Flavor lmg Saccharin Sodium 2mg Silicone Dioxide 2mg Preparation process Sodium Valproate, Mint flavor, Silicone Dioxide and Saccharin Sodium are mixed in Hard Fat heated to 45°C. The mixture is cooled to 40°C and filled inside hard gelatin capsules.

Example 4: Aspirin 100mg Tablet Ingredient mg/tab Aspirin 100mg Hydrogenated Palm Oil 500mg Strawberry Flavor 3mg Aspartame 5mg Starch 4mg Process for the preparation: Aspirin, Strawberry flavor, Starch and Aspartame are mixed in Hydrogenated Palm Oil heated to 45°C. The mixture is cooled to 40°C and filled inside blisters.

Example 5: Vitamin C effervescent melt lozenges

In the following Example both an active and a non-active ingredient (=excepient) are stabilized by the hydrophobic fatty matrix.

Ingredient mg/loz Ascorbic Acid 500mg Hydrogenated Vegetable Oil-Type II 700mg Orange Flavor 4mg Saccharin Sodium 4mg Sodium Bicarbonate 100mg Butylated Hydroxyanisole 0. 5mg Preparation process: Ascorbic Acid, Orange flavor, Butylated Hydroxyanisole and Saccharin Sodium are mixed in Hard Fat heated to 45°C. The mixture is cooled to 40°C and Sodium Bicarbonate is added. Mixture is cooled to 38°C and molded inside blisters.

Combination of edible acid and Sodium Bicarbonate is usually used to form effervescence effect in pharmaceutical dosage forms. When exposed to saliva a chemical reaction occurs and Carbon Dioxide is elevated. The above mentioned example is a way to protect acid/base reaction during storage. Ascorbic acid serves as active ingredient and as water sensitive excipient together with Sodium Bicarbonate.

Example 6: Ibuprofen 250mg Popping Tablet In the following example, water sensitive excepient is stabilized.

Ingredient mg/tab Coated Ibuprofen 270mg Hard Fat 500mg Strawberry Flavor 3mg

Aspartame 5mg Popping Candy 200mg Preparation process: Ibuprofen, Strawberry flavor and Aspartame are mixed in Hard Fat heated to 45°C.

The mixture is cooled to 38°C and Popping Candy is added. Mixture is filled inside pre-cooled blisters.

Example 7: Amoxycillin 250mg Popping Tablet Ingredient mg/tab Amoxycillin 250mg Hard Fat 600mg Vanilla Flavor 3mg Aspartame 5mg Popping Candy 250mg Preparation process Amoxycillin, Vanilla flavor and Aspartame are mixed in Hard Fat heated to 45°C.

The mixture is cooled to 38°C and Popping Candy is added. Mixture is filled inside pre-cooled blisters.

This example demonstrates a pharmaceutical composition according to the present invention, wherein both an active ingredient and an excepient are water sensitive.