FIELD OF THE INVENTION

The invention relates to a dispersible tablet composition comprising a therapeutically effective amount of Ursodiol or its pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients, having disintegration time of less than 2 minutes in a dispersion medium.

The invention also relates to a process of preparing a dispersible tablet composition comprising a therapeutically effective amount of Ursodiol or its pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients, having disintegration time of less than 2 minutes in a dispersion medium.

The invention further, relates to provide a method of administering the medicament in a liquid administration form containing Ursodiol, for the treatment of Primary biliary cirrhosis in adults and geriatrics, and cholestatic hepatic diseases in infants and children.

BACKGROUND OF THE INVENTION

Primary biliary cirrhosis, often abbreviated PBC, is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts of the liver, with the intralobular ducts (Canals of Hering) affected early in the disease. When these ducts are damaged, bile builds up in the liver (cholestasis) and over time damages the tissue. This can lead to scarring, fibrosis and cirrhosis. It was previously thought to be a rare disease, but more recent studies have shown that it may affect up to 1 in 3,000 people; the sex ratio is at least 9: 1 (female to male).

The cause of the disease is unknown at this time, but research indicates that there is an immunological basis for the disease, making it an autoimmune disorder. Most of the patients (>90%) seem to have anti-mitochondrial antibodies against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria. PBC is a deadly disease. PBC is said to be "primary" because it is not induced by alcohol abuse or drugs or infectious hepatitis. The evolution of the disease varies, usually between 2 years and 10 years. The symptomatology starts with fatigue, itching followed by increased liver size and icterus. Hepatic transplantation is the only long term survival means for the disease.

Earlier it was thought that the disease was an autoimmune one because mitochondrial antibodies were observed in the patients. This is why all the treatments used so far have been immunosuppressive, such as high doses of corticoids and azathioprine. Raoul Poupon et al in US4859660 covers a method of treating primary biliary cirrhosis which comprises administering an effective amount of ursodeoxycholic acid (Ursodiol) to a patient suffering from primary biliary cirrhosis.

Earlier before 1980s Ursodeoxycholic acid (UDCA) is a known compound that has been used for the dissolving treatment of cholesterolic biliary lithiasis, and Raoul Poupon et al in US4859660 taught the use of Ursodiol for the treatment of primary biliary cirrhosis, and the treatment is based on the hypothesis that the symptomatology and the extent of the disease are not immunological, but are due to the toxicity of the biliary acids synthesized by the liver. These acids are involved in the lipids metabolism. The biliary acids are involved in a closed cycle of elimination by the bile and reabsorption by the intestine. When administered chronically, ursodeoxycholic acid, which is non-toxic, substitutes itself for these biliary acids which allows the elimination from the body.

Ursodeoxycholic acid is normally present as a minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of Ursodeoxycholic acid is absorbed by passive diffusion and its absorption is incomplete. Once absorbed, Ursodeoxycholic acid undergoes hepatic extraction to 5 the extent of about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. In the liver, Ursodeoxycholic acid is conjugated with glycine or taurine, then secreted into bile. These conjugates of Ursodeoxycholic acid are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. Non-absorbed ursodiol passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some Ursodeoxycholic acid is epimerized to chenodiol (CDCA) via a 7-oxo intermediate. Chenodiol also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine, or taurine and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces.

Ursodeoxycholic acid is marketed in France as DELURSAN ^® 250mg tablets or RUSOLVAN ^® 200mg capsules. After administration of 13 to 15 mg/kg/day of ursodeoxycholic acid to patients for 2 years, the total concentration of serum bile acids was unaltered; the percentage of patients having pruritus fell from 53 to 8%; the patients' blood bilirubin concentration became less than 34 μΜ; the serum alkaline phosphatase, transaminase and y-glutamyl transferase activities decreased in all the patients; and the levels of prothrombin, albumin, y-globulins and immunoglobulins M were unaltered. Results obtained during the last 5 years confirm previous results. With increased numbers of patients, it can be shown that the therapeutic effect increases with time and with no adverse effects.

In clinical practice today, UDCA possesses a defined role in treating patients with cholestatic liver diseases. UDCA has been used in clinical practice for more than 20 years and is marketed either as oral tablets or oral capsules with different strengths typically ranging from 50 mg, 150 mg and 300 mg tablets as well as 250 mg capsules.

JP 6209441 covers a long acting preparation of UDCA conciting of different kinds of granules, viz a rapid release granule agent and a slow release granule agent.

GB 2036558 covers a UDCA formulation that releases the active principle over a prolonged period of time that is buildup of UDCA that releases immediately and UDCA with a delayed or retarded release.

WO2008/1130234 covers an immediate release oral pharmaceutical formulation in the form of a multiparticulate comprising between 400 to 3000 mg ursodeoxycholic acid or its pharmaceutically acceptable salt, in a monodose container and comprising a single type of particles that contain a core with said ursodeoxycholic acid, and a coating. EP0599282 covers a controlled release pharmaceutical compositions for Ursodeoxycholic acid containing microgranules, wherein microgranules are prepared by extrusion-spheronization technique. EP1317925 covers a taste masked microgranules for the oral administration of

Ursodeoxycholic acid, which consists of plasticiser and copolymer of (meth) acrylic acid having a molecular weight ranging between 100,000 and 850,000.

EP0524395 covers a sustained release pharmaceutical compositions of Ursodeoxycholic acid containing agar, one or more substances suitable for gel formation and a basic buffer.

EP0625353 covers a slow-release pharmaceutical composition containing a bile acid as active ingredient and comprising at least one bioadhesive substance and at least one high specific gravity substance, and provided in the form of 0.5-2 mrn diameter coated particles or of tablets, characterized by having an aliquot enteric coated with gastro-resistant substances and the remainder non-enteric coated.

EP0508312 covers a controlled release pharmaceutical formulations for oral use coated by an entero-soluble gastro-resistant film containing therapeutically effective amounts of a mixture of bile acids and their salts with alkali metals or organic bases.

US5262172 covers a granular, microencapsulated bile acid composition for the treatment of bile acid deficiency of a mammal comprising, by weight per weight percentages based on the total weight of the composition:

a) from about 60 to about 89% of a buffered-bile acid mixture in a 1 to 1 neutralization equivalent ratio in a micropulverized powder form, wherein the buffering agent is selected from the group consisting of sodium carbonate (anhydrous), sodium bicarbonate, potassium carbonate, potassium bicarbonate, tromethamine, diethanolamine and triethanolamine;

b) up to about 5% of an additional buffering agent selected from the group consisting of sodium carbonate (anhydrous), sodium bicarbonate, potassium carbonate, potassium bicarbonate, tromethamine, diethanolamine and triethanolamine;

c) from about 1.0 to about 16% of a disintegrant selected from the group consisting of starch and modified starches, microcrystalline cellulose and propylene glycol alginate; d) from about 2 to about 19% of an adhesive polymer selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, cellulose acetate phthalate, methyl cellulose and propylene glycol alginate; and

e) from about 8% to about 16% of an non-porous, gastric acid-resistant and pharmaceutically acceptable polymer-coating which contains less than 2% talc and which is insoluble in the pH range of from about 1.5 to about 5 but is soluble in the pH range of from about 5.5 to about 9.

WO2013/057741 covers a pharmaceutical composition of Ursodeoxycholic acid, wherein the composition comprises micronized Ursodeoxycholic acid having a particle size of dgo less than 25 microns and one or more pharmaceutically acceptable excipients.

EP0640344 covers a medicament in a liquid administration form containing ursodeoxycholic acid as the active agent, particularly for the treatment of cholestatic hepatic diseases in infants, characterized in that the liquid to be taken is a suspension prepared accompanied by the addition of a swelling and/or thickening agent, which contains the active agent mainly in a finely crystalline form as the disperse phase and only in a much smaller proportion dissolved in the aqueous dispersant.

Because of the high dose of UDCA, treatment options has been found to be more cumbersome and also highly unsafe, due to irregular dose treatment in a number of cholestatic hepatic diseases.

The dose requirement in patients is up to 1-2 grams daily, the currently available treatments imply that the patients will need to swallow 4-8 tablets or alternatively 4 to 8 capsules daily and hence presently available dosage strengths are not optimal for this high dose treatment. Moreover, the currently available tablet and capsule formulations are already bulky and higher dose formulations are becoming very difficult to swallow, especially for Bed ridden patients and geriatrics, children and infants. Since, UDCA is extremely bitter-tasting and causes in most patients esophageal reflux, nausea and/or vomiting, the currently available Immediate Release tablets and capsules. Hence, substantial taste masking of the bitter taste of the drug formulation is a prerequisite. Furthermore, there were attempts made to prepare Oral liquid dosage forms for Ursodiol, however, these attempts were failed due to liquid stability issues in product shelf-life and/or during transportation. Therefore, there has been a long felt need for an improved dosage form of Ursodiol, which provides an easy mode of administration, suitable for all age groups, ensuring patient compliance with palatable taste and odor of the medicament to be administered.

Thus the inventors of the said application have surprisingly found a suitably taste-masked dispersible tablet comprising Ursodiol or its salts thereof, with one or more pharmaceutically acceptable excipients, having fast disintegration time in a dispersion medium, rapid onset of action and comparable bioavailability to that of commercially available Ursodiol tablets and capsules.

SUMMARY OF INVENTION

Accordingly, it is an object of the present invention to provide a dispersible tablet composition comprising a therapeutically effective amount of Ursodiol or its pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients, having disintegration time of less than 2 minutes in a dispersion medium.

It is yet an object of the present invention to provide a wet granulation process of preparing dispersible tablet composition comprising a therapeutically effective amount of Ursodiol or its pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients, having disintegration time of less than 2 minutes in a dispersion medium.

It is a further object of the present invention is to provide a formulation which is taste masked dispersible tablet composition comprising a therapeutically effective amount of Ursodiol or its pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients, having disintegration time of less than 2 minutes in a dispersion medium selected from water, orange juice, carbonated water and breast milk. It is a further object of the present invention is to provide a method of administering the medicament in a liquid administration form containing Ursodiol for the treatment of Primary biliary cirrhosis in adults and geriatrics, and cholestatic hepatic diseases in infants and children. ABBREVIATIONS

DETAILED DESCRIPTION

As set forth herein, aspects of the present invention describes a dispersible tablet composition comprising Ursodiol or its pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients, having ideal disintegration time and also palatable taste for masking bitter taste of Ursodiol.

The term "The pharmaceutically acceptable excipients" are selected from the group consisting of diluents, binders, disintegrants, wetting agents, Lubricants, glidants, sweeteners, flavouring agents and combinations thereof. The term "therapeutically effective amount" as used herein means the amount of drug that when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.

As used herein, the term "diluents" is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, Lactose monohydrate, Lactose anhydrous and combinations thereof and other such diluents known to those of ordinary skill in the art.

As used herein, the term "binders" means excipients which are used to bring adhesion of powder particles in tablet granulations, and binders include without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g. NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, Povidone and Pregelatinized starch, combinations thereof and other binder excipients known to those of ordinary skill in the art.

As used herein, the term "disintegrants" is intended to mean excipients used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, Crospovidone, Sodium starch glycolate, Crosscarmellose sodium, starches such as com starch, potato starch, pregelatinized and modified starched thereof and other disintegrants known to those of ordinary skill in the art.

As used herein, the term "glidants" is intended to mean excipients used in tablet formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, include colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such glidants known to those of ordinary skill in the art.

As used herein, the term "lubricants" is intended to mean excipients used in tablet formulations to reduce friction during tablet compression. Such excipients include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other lubricants known to those of ordinary skill in the art. As used herein, the term "sweetening agent" is intended to mean excipients used to impart sweetness to a tablet containing bitter drugs. Such excipients include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

As used herein, the term "wetting agents" are intended to mean excipients used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, Sodium lauryl sulfate, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, etostearyl alcohol, cetomacrogol, emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene, sorbitan fatty acid esters, (e.g., TWEEN.TM.s), and other wetting agents known to those of ordinary skill in the art.

As used herein, the term "Flavoring agents" are intended to mean excipients used in the formulation to improve the flavor or give a pleasant taste to the formulation. Flavoring agents are mostly restricted to the formulations in which are intended to be released in the mouth or for Dispersible tablets or chewable tablets. Exemplary Flavoring agents include, by way of example and without limitation, Mint flavour and Banana flavour, and other flavoring agents known to those of ordinary skill in the art.

As used herein, the term "Ursodiol" or "Ursodeoxycholic acid" are intended to mean Ursodiol or its pharmaceutically acceptable salts thereof.

In one of the embodiments of the present invention, describes a taste masked dispersible tablet composition comprising a therapeutically effective amount of Ursodiol or its pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients, having disintegration time of less than 2 minutes in a dispersion medium selected from water, orange juice, carbonated water and breast milk. The taste masking of the bitter taste of the drug is partly and/or substantially masked by the incorporation of conventional sweetening agents and flavoring agents in the dispersible tablets.

In one of the embodiments of the present invention, describes a dispersible tablet composition comprising a therapeutically effective amount of Ursodiol or its pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients, having disintegration time of less than 2 minutes in a dispersion medium.

In one of the embodiments of the present invention, describes a process of preparing dispersible tablet composition comprising a therapeutically effective amount of Ursodiol or its pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients, having disintegration time of less than 2 minutes in a dispersion medium, wherein the composition is prepared by wet granulation, direct compression and dry granulation. In one of the particular embodiments of the present invention, describes a process of preparing a dispersible tablet composition comprising a therapeutically effective amount of Ursodiol, wherein the process comprising:

(a) Drymix the sifted material of Urslodiol or its pharmaceutically acceptable salts, diluent and disintegrant in RMG. The drymix step can be carried for appropriate time till the homogeneous powder mixture is obtained. (b) Prepare the binder solution by dissolving binder in purified water.

(c) Granulate step (a) material with the binder solution of step (b).

(d) Dry the wet granules of step (c) to achieve LOD in the range of 0.5-1.5%w/w;

(e) Sifting the dried granules of step (d) through an appropriate sieve;

(f) Optionally, milling the dried granules which are sieve retentions of step (e);

(g) Sift the extra granular excipients comprising Diluent, Disintegrant, Glidant and Sweetening agent through an appropriate sieve.

(h) Separately sift the Extra granular flavouring agents through an appropriate sieve.

(i) Separately sift the Lubricant through an appropriate sieve.

(j) Blend the material of step (e) and (f) with sifted materials of steps (g) and (h) in a blender.

(k) Blend the material of step (i) with sifted Lubricant of step (j) in a blender.

(1) The final Lubricated blend of step (k) is compressed into tablets with appropriate tablet tooling.

According to the present invention the sweetening agents and flavoring agents can be incorporated in many ways as known to those of ordinary skill in the art. The incorporation of these excipients may be Intragranular and/or Extragranular portions of the invention compositions.

In one of the embodiments of the present invention, describes a dispersible tablet composition comprising a therapeutically effective amount of Ursodiol or its pharmaceutically acceptable salts thereof, wherein the Ursodeoxycholic acid is between 50 to 500 mg.

In a particular embodiments of the present invention describes API particle size for the invention compositions of Ursodiol dispersible tablets, wherein the Ursodiol or its pharmaceutically acceptable salts thereof, in the form of micronized particles having a particle size of d ₉ o less than 90 microns.

In a particular embodiments of the present invention describes API particle size for the invention compositions of Ursodiol dispersible tablets, wherein the Ursodiol or its pharmaceutically acceptable salts thereof, in the form of micronized particles having a particle size of dgo less than 25 microns. In one of the preferred embodiments of the present invention, describes a dispersible tablet composition comprising a therapeutically effective amount of Ursodiol, Microcrystalline cellulose, Lactose monohydrate, Povidone, Crospovidone, Colloidal silicon dioxide, Magnesium stearate, Aspartame, Mint flavor and Banana flavor, having disintegration time of less than 2 minutes in a dispersion medium.

Usually a dispersible tablet must be protected from the ambient humidity. The dispersible tablets should not be divided or chewed. The quality of the packaging is critical to guarantee the conservation of the product.

According to present invention Dispersible tablets are usually packed in blisters (Aluminium/PVC) or strips (aluminium). Dispersible tablets must be used immediately after removal from the blister packaging. According to present invention dissolution profiling of dispersible tablets to be followed according to the Dissolution Method for Ursodiol tablets USP.

Ursodiol tablets USP Method: Medium: Simulated intestinal fluid without pancreatin and adjusted with O. IN Sodium hydroxide or O. IN Hydrochloric acid to a pH of 8.0, Volume: 900 ml, Apparatus: Paddle, RPM: 75, Time intervals: 5, 10, 15, 30, 45 and 60 minutes & Q Point - NLT 80% in 45 min.

Usually, patients suffering from Primary biliary cirrhosis, an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts of the liver, and in few instances it could be difficult for the patients to swallow conventional IR tablets of Ursodiol, especially, the elderly persons with swallowing difficulties (Dysphagia), and also for children and infants.

The advantages provided by the invention is a dispersible tablet composition dispersible tablets composition comprising a therapeutically effective amount of Ursodiol or its pharmaceutically acceptable salts thereof, has the following advantages over conventional dosage forms:

a) Quicker onset action compared with conventional tablets because of improved disintegration/Rapid onset of action.

b) Suitable for children and elderly persons with swallowing difficulties (Dysphagia). c) More easy for transportation (less volume, less weight).

d) Dispersble tablets remain solid until administration. This aids the stability of pharmaceutically active agent, the dose accuracy, and storage of the tablets.

e) Dispersble tablets are easy to dispense and they require minimal manipulation by health professionals and parents prior to use which minimises the risk of errors.

f) Dispersble tablets require a small amount of water for administration.

In one of the embodiments of the present invention, describes a dispersible medium for preparing the liquid medicament for the Ursodiol dispersible tablet composition, wherein the dispersible medium selected from water, orange juice, carbonated water and breast milk.

The volume of dispersion medium for preparing liquid medicament is about 50 ml to 100 ml of water, 250 ml of orange Juice and may also be administered using carbonated water (SODA).

In one of the preferred embodiments of the present invention, describes a preparation of the liquid medicament for the Ursodiol dispersible tablet composition, wherein the dispersible medium is 50ml of water. In one of the embodiments of the present invention, describes a preparation of the liquid medicament for the Ursodiol dispersible tablet composition, wherein the dispersible medium is breast milk for administering to infants.

In one of the embodiments of the present invention, describes a method of administering the medicament in a liquid administration form containing Ursodiol, for the treatment of Primary biliary cirrhosis in adults and geriatrics, and cholestatic hepatic diseases in infants and children.

EXAMPLES

Comparative Example: - Ursodiol Immediate Release tablet composition and manufacturing process.

Manufacturing process:

1. Sift Ursodiol through mesh # 20.

2. Sift microcrystalline cellulose, Lactose monohydrate and Sodium starch together through mesh #40.

3. Prepare binder solution by dissolving Povidone in purified water.

4. Drymix the material of step 1&2 in rapid mixer granulator and granulated with binder solution of step 3.

5. Dry the wet granules in fluid bed drier till LOD attained between 0.5 - 1.5%

6. Sift the dried granules through mesh #24 and mill the retentions with co-mill using 1.5 mm screen at slow speed.

7. Sift microcrystalline cellulose, colloidal silicon dioxide, and Sodium starch glycolate through mesh # 40. 8. Sift Magnesium stearate through mesh #60.

9. Blend the material of step 7 and step 6 for 10 minutes in double cone blender.

10. Blend the sifted magnesium stearate to the material of step 9 and for 5 minutes.

11. Compress the lubricated final blend of step 11 using appropriate tablet tooling. The Tablet tooling and In-process tablet characteristics are tabulated below.

Dissolution profile of Ursodiol Immediate Release tablets 250mg & 500 mg according to

Dissolution method of Ursodiol Tablets USP -

Medium: Simulated intestinal fluid without pancreatin and adjusted with 0.1N Sodium hydroxide or 0.1N Hydrochloric acid to a pH of 8.0.

Volume: 900 ml.

Apparatus: Paddle.

RPM: 75.

Time intervals: 5, 10, 15, 30, 45 and 60 minutes.

Q Point - NLT 80% in 45 min.

Example 1:- Ursodiol dispersible tablet composition and manufacturing process.

Manufacturing process:

1. Sift Ursodiol through mesh # 20.

2. Sift microcrystalline cellulose, Lactose monohydrate and Crospovidone together through mesh #40.

3. Prepare binder solution by dissolving Povidone in purified water.

4. Drymix the material of step no.l & 2 in rapid mixer granulator, and granulated with binder solution of step 3.

5. Dry the wet granules in fluid bed drier till LOD attains to 0.5 - 1.5%.

6. Sift the dried granules through mesh #24 and mill the retentions in co-mill using 1.5 mm screen at slow speed.

7. Sift microcrystalline cellulose, colloidal silicon dioxide, Crospovidone and Aspartame together through mesh # 40.

8. Sift Mint flavour & Banana flavour through mesh # 40.

9. Sift Magnesium stearate through mesh #60. 10. Blend the material of step no. 7 & 8 to the material of step no. 6 for 10 minutes in double cone blender.

11. Blend the sifted magnesium stearate to the material of step no 10 for 5 minutes.

12. Compress the lubricated final blend of step 11 using appropriate tablet tooling. The Tablet tooling and In-process tablet characteristics are tabulated below.

Dissolution profile of Ursodiol dispersible tablets 250mg & 500 mg according to the Dissolution method specified for Ursodiol Tablets USP -

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.