FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
l.TITLE OF THE INVENTION:
"Pharmaceutical Oral Composition of H2 Receptor Antagonist and Lactulose and Method for Decreasing the Side Effect of H2 Receptor Antagonist in a Human"

2. APPLICANT:
(a) NAME: M/S. INDOCO REMEDIES LIMITED.
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956.
(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East),
Mumbai - 400 098. Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.


Field of the Invention
The present invention relates to novel combination pharmaceutical compositions comprising ranitidine, lactulose and other suitable pharmaceutical excipients in effective amounts for reducing the side effect associated with use of ranitidine. The novel pharmaceutical compositions prepared according to the present invention serves as a convenient dosage form mainly for the geriatrics who have the problem of acidity, habitual constipation, difficulty in swallowing and are on multiple medications. The present invention further relates to a method of reducing adverse side effect of constipation associated with the oral use of ranitidine during acid-related gastrointestinal conditions.
Background of the Invention
The H2-receptor antagonists belong to a class of drugs which are used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells.
The prototypical H2 antagonist first developed was cimetidine, by GlaxoSmithKline and was first marketed in 1976 under the trade name of Tagamet. The use of quantitative structure-activity relationships (QSAR) led to the development of other agents—starting with ranitidine, famotidine and nizatidine.
Ranitidine was introduced in 1981 and by 1988, it became the world's largest selling prescription drug. It is now available over the counter in USA, India and U.K market and is accessible in oral tablet, effervescent tablets and oral syrup dosage form.

Ranitidine
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Ranitidine is widely used in the treatment of duodenal ulcer, gastric ulcer, gastroesophageal reflux disease and erosive esophagitis. The clinical use of ranitidine stems from their capacity to inhibit gastric acid secretion, especially in patients with peptic ulceration. It also inhibits acid secretion elicited by gastrin and to a lesser extent by muscarinic agonists.
Although ranitidine is an excellent antacid drug used especially in duodenal ulcer and gastric ulcer; however, the common problem associated with the drug is its inherently bitter taste which constitutes a disadvantage with certain types of oral preparation. As a consequence of this limitation, numerous alternatives have been proposed by the innovators. For e.g. Corbo et al in both U.S Pat. No. 6,551,617 and U.S Pat. No. 6,663,893 and Hoy et al in U.S Pat. No. 5,489,436 discloses that the taste of the drug can be masked by the coating solution of polyvinyl acetate, and a dimethylaminoethyl methacrylate and neutral methacrylic acid a cellulose ester polymer, and an alkaline modifier. In U.S Pat. No 6,265,449, Caricofe claims that the bitter taste of ranitidine in an aqueous solution can be masked by low color, metal, turbidity (LCMT) sucrose. Bye et al in U.S Pat no. 5,593,685 claims that the suitable pharmaceutical chewable tablets of ranitidine can be made by using a chewable base selected from sucrose, glucose, lactose, maltose, or a mixture thereof, a flavouring agent and optionally, an intense sweetener.
All the foregoing disclosures overcome the problem of bitter taste of ranitidine, however, another problem associated with its use is the constipation which is caused by the decrease in the gastric motility. This problem is even more severe in the elderly patient which lays them feeling bloated, uncomfortable and sluggish. It also impairs the quality of life of the patients who are already on the multiple medications. For this reason, during administration of ranitidine, it is very important to control constipation.
Many studies and attempts have been made to address the issue of constipation induced by the intake of drugs, of which few noteworthy disclosures are: U.S Pat. No. 6,982,283, by Ueno discloses the use of a 15-keto-prostaglandin compound for treating drug-
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induced constipation. U.S Pat. No. 5,418,220 by Schmidt et al claim the use of dimethicone as an agent for treating constipation Further, many new molecules are being introduced by the innovators for the use in the treatment of constipation. For e.g. U.S Pat. No. 6,673,368 by Ukei et al discloses and claim aminothiazole derivative for the treatment of irritable bowel syndrome, constipation, intestinal atony or drug-induced colonic motor dysfunction and U.S Pat. No. 6,294,555 by Kato et al claim the piperidine derivatives which are useful as a gastrointestinal motility enhancer or a gastrointestinal prokinetic agent. Still further, again Ueno in both U.S Pat. No. 6,610,732 and U.S Pat. No. 6,414,016 claim halogenated-bi-cyclic compound which can be used to treat constipation without substantive side-effects, such as stomachache.
Although the aforementioned drugs might be effective in providing relief, however, from the foregoing it would also be apparent that to get the relief from constipation, patients would be required to take an additional medicine/drug. However, in the older patients (where the age related diseases like diabetes, depression, heart diseases, joint problems and sleep disorders are very common), who are already on the multiple medications; prescribing an additional drug would definitely increase their complexity further.
Thus, the present invention is a step forward in this direction and overcomes both the problem of constipation as well as bitter taste which is associated with the intake of ranitidine without placing the extra burden of an additional drug on the patient.
SUMMARY OF THE INVENTION
The present invention arose from observations by the inventors that the treatment of patients with ranitidine for acid-related gastrointestinal conditions, although very effective, causes an unwanted side effect of constipation. Also, the bitter taste of the drug necessitated the step of either the coating of the drug with some polymer or addition of excipients like hydrolyzed gelatin, sucrose, lactose etc or the use of some agent that could
form a complex with drug and hide its bitter taste.
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However, none of the methods disclosed in the prior art unravels both the problems of bitter taste and constipation simultaneously.
As a result of diligent research, the present inventors have found that both the problem of constipation (without placing the burden of an additional drug on the patients) and the bitter taste associated with oral use of ranitidine could be resolved by the use of lactulose.
A single combination formulation of ranitidine and lactulose would not only evict the problem of constipation but would also mask the bitter taste associated with ranitidine. Further, combining the two easily available separate OTC drugs (over the counter drugs) like ranitidine and lactulose would reduce the complexity of prescribed regimens; patient discomfort like discomfort of swallowing multiple tablets and discomfort associated with opening large amounts of packaging and organizing each day's pill combinations and would also increase the convenience and cost-effectiveness of the treatment.
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes a novel pharmaceutical combination comprising ranitidine in association with lactulose along with one or more pharmaceutical excipients. The pharmaceutical combination of the present invention masks the bitter taste of the drug and also inhibits the side effect of constipation which is associated when ranitidine is administered to a mammal for the treatment of acid-related gastrointestinal conditions; without substantially losing the main effect of the drug.
The present invention further provides a novel combination therapy comprising the administration of a single composition of the therapeutically effective amount of ranitidine with a therapeutically effective amount of lactulose to a mammal, and more particularly, to a human. The combination therapy masks the bitter taste of the drug and also inhibits the side effect of constipation which is associated when ranitidine is administered in mammals for the treatment of acid-related gastrointestinal conditions; without substantially losing the main effect of the drug.
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Lactulose employed in the formulation is 4-0-(beta)-D-Galactopyranosyl-D-fructofuranose and is represented by the formula L It is a synthetic sugar (disaccharide formed from simple sugars like fructose and galactose), being widely used for the treatment of both constipation and hepatic encephalopathy.
The preparation of large separate doses of both the ranitidine (for the treatment of acid-related gastrointestinal disorder) and lactulose (for the treatment of constipation) in the oral dosage form has been always a constraint due to the bitter taste of ranitidine and very sweet taste of lactulose. However, it has been found that the combination of both ranitidine and lactulose overcomes this limitation and leads to the preparation of very successful dosage form as lactulose effectively masks the bitter taste of ranitidine.
In the treatment of constipation, when lactulose is combined with the ranitidine; it draws water into the bowel and causing a cathartic effect through osmotic action. Therefore, lactulose acts as a mild laxative without causing diarrhea.

Formula I
Thus, in a first embodiment, the invention provides a novel pharmaceutical composition comprising ranitidine and lactulose in effective amounts; wherein lactulose reduces the
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side effect of constipation when ranitidine is used for the treatment of acid-related gastrointestinal disorder.
In a second embodiment, the invention provides a pharmaceutical composition comprising ranitidine and lactulose; wherein lactulose effectively masks the bitter-taste of ranitidine.
In a third embodiment, the invention provides a method for the treatment of constipation when ranitidine is used for the treatment of acid-related gastrointestinal disorder, including administering to said mammal an effective amount of ranitidine and an effective amount of lactulose
The invention further provides a process of manufacturing a medicament for the treatment of constipation, when ranitidine is used for the treatment of acid-related gastrointestinal disorder, the composition including or consisting of ranitidine and lactulose.
According to one aspect of the invention, the pharmaceutical compositions of ranitidine In combination with lactulose and other pharmaceutical excipients are preferably given orally in the form of liquid or tablet.
Advantageously, both the oral formulations of ranitidine with lactulose produced according to the present invention exhibit excellent stability and hence are preferred.
As used herein, the term "acid-related gastrointestinal disorder" can be understood to include duodenal ulcer, gastric ulcer, gastroesophageal reflux disease and erosive esophagitis.
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As used herein, the term "excipients" can be understood to include any inert substance
combined with an active agent such as ranitidine to prepare a convenient dosage form
and vehicle for delivering the active agent.
As used herein, the term "dose" and "dosage" can be understood to mean a specific
amount of active or therapeutic agents for administration.
As used herein, the term "therapeutically effective amount" can be understood to include
an amount of ranitidine in combination with lactulose that is effective for the treatment of
acid-related gastrointestinal disorder without causing the side effect of constipation.
According to the present invention, a stable liquid combination composition of ranitidine and lactulose can be prepared by a simple step of addition of lactulose with the available marketed liquid composition of ranitidine. Conversely, the combination tablet dosage form may be prepared by mixing the ranitidine, lactulose Nvith other suitable excipients and granulating, blending and finally compressing the mixture by the methods known in the art.
In addition to ranitidine and lactulose other suitable additives can be included in the present oral formulation depending on the final dosage form viz. oral tablet or liquid.
For the tablet dosage form, the excipients that could be employed are disintegrants, fillers, binders, surfactants and lubricants.
The disintegrant is selected from alginic acid, carboxymethyl cellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, macrocrystalline cellulose, polyacrilin potassium, powdered cellulose, pregelatinized starch, sodium or calcium alginate and starch.
The filler is selected from calcium carbonate, calcium sulfate, compressible sugars, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil (type I), kaolin, lactose, magnesium
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carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tribasic calcium phosphate.
The binder is selected from acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil (type I), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminaum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, corn starch, and zein.
The surfactant is selected from anionic and cationic surfactants, such as sodium lauryl sulfate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride, benzethonium chloride, and cetrimide (alkyltrimethylammonium bromide).
The lubricant is selected from stearate acid metal salt (magnesium stearate or calcium stearate), stearic acid, sodium lauryl sulfate, sodium lauryl magnesium, powdered gum arabic, carnauba wax, anhydrous silicic acid, magnesium oxide, silic acid hydrate, boric acid, fatty acid sodium salt and leucine.
For the preparation of liquid formulation, the pharmaceutical excipients that can be included are buffering agents, flavoring agents and coloring agents.
Any suitable buffer system which will act as buffer, that is, permit only small variations of pH can be employed. These include potassium metaphosphate, potassium phosphate, sodium acetate, sodium citrate and the like, and mixtures thereof. Mixtures of buffering agents can also be used. However, when water is present, use of a buffer is optional and is generally needed only when higher pH values are desired.
The composition can comprise flavoring agent (flavorant). A "flavoring agent" herein is a substance capable of enhancing taste or aroma of a composition.
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Optionally, the composition further comprises a coloring agent.
Oral formulations produced according to the present invention will normally be in the form of a solution. When a thicker or thinner product is desired, however, an additive can be added accordingly. For instance, an edible thickener that is compatible with the present product can be included to produce a syrup-like product. Additives such as HPMC, PVP and Xanthan gum also increase the viscosity of the solution and therefore can be used to produce a thicker product. Suitable Alcohol like ethyl alcohol may or may not be added in the final dosage form.
A composition of the present invention can be used in treatment of acid-related gastrointestinal disorders, by orally administering to a subject in need thereof, a therapeutically effective amount of the composition. It is contemplated that the combination composition does not have any bitter taste, can be used for the acid-related gastrointestinal disorder and also removes the side effect of constipation which is associated with the use of ranitidine.
Some typical examples illustrating the embodiments of the present invention are provided herein below; however, these are exemplary only and should not be regarded as limitations of the present invention.
Example 1:
Ranitidine Hydrochloride 16.8 mg/ml
Flavour Pineapple 1 mg/ml
Colour Carmoisine 0.1 mg/ml
Lactulose q.s to 1 ml
Procedure:
i) taking specified quantity of Ranitidine Hydrochloride and dissolving in Lactulose solution in a vessel;
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ii) stirring the mixture and adding coloring agent and flavouring agent followed by
mixing; and iii) filling the solution into suitable containers.
Example 2:
Ranitidine Hydrochloride equiv to Ranitidine 16.8 mg/ml
Ethanol , 0.06 ml
Flavour Strawberry 1 mg/ml
Colour Carmoisine 0.1 mg/ml
Lactulose 983.14 mg/ml
Procedure:
i) taking specified quantity of Ranitidine Hydrochloride and dissolving in Lactulose
solution in a vessel, ii) adding Ethanol to the mixture of step (i) with continuous stirring; iii) adding coloring agent and flavouring agent followed by mixing; and iv) filling the solution into suitable containers.
Example 3:
Lactulose 750 mg/ml
Ranitidine Hydrochloride 16.8 mg/ml
Sodium Methyl paraben 1 mg/ml
Sodium Propyl Paraben 0.25 mg/ml
EDTA Sodium 1 mg/ml
Flavour Orange 1 mg/ml
Colour Carmoisine 0.1 mg/ml
Water q.s to 1 ml
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Procedure:
i) taking specified quantity of Ranitidine Hydrochloride and dissolving in water in a
vessel; ii) dissolving Sodium methyl paraben, Sodium Propyl Paraben and EDTA Sodium in
part quantity of water in a separate vessel; iii) adding coloring agent and flavouring agent followed by mixing; iv) adding water to make up the required volume; v) filtering the solution and vi) filling the solution into suitable containers
Example 4:
Lactulose 666.6 mg/ml
Ranitidine Hydrochloride 16.8 mg/ml
Ethanol 75 mg/ml
Potassium dihydrogen Orthophosphate 0.95 mg/ml
Disodium Hydrogen Orthophosphate anhydrous 3.5 mg/ml
Methyl paraben 1 mg/ml
Propyl Paraben 0.1 mg/ml
Saccharin Sodium 2.5 mg/ml
Sorbitol 50 mg/ml
Sodium Chloride 10 mg/ml
Peppermint Flavor 3.5 mg/ml
Purified Water q.s to 1 ml
Procedure: i) taking specified quantity of water in a vessel and adding Ranitidine hydrochloride
followed by stirring the solution until it dissolves completely; ii) dissolving Potassium dihydrogen Orthophosphate, Disodium Hydrogen
Orthophosphate anhydrous, Sodium Propyl Paraben, sodium chloride, saccharin
sodium, Peppermint Flavor, Saccharin Sodium and EDTA Sodium in water in a
separate vessel and added sorbitol solution;


iii) mixing the two solutions obtained from step (i) and step (ii);
iv) adding lactulose to the solution of step (iii);
v) filtering the solution; and
vi) filling the solution into suitable containers.
Example 5:
Lactulose 750 mg/ml
Ranitidine Hydrochloride 16.8 mg/ml
Sodium Metabisulphite 2 mg/ml
Sodium Methyl paraben 1 mg/ml
Sodium Propyl Paraben 0.25 mg/ml
EDTA Sodium 1 mg/ml
Water q.s to 1 ml
Procedure:
i)taking specified quantity of water to dissolve Ranitidine Hydrochloride; undissolving Sodium Metabisulphite, Sodium methyl paraben, Sodium Propyl Paraben and EDTA Sodium in a separate vessel in part quantity of water followed by stirring until the contents dissolved completely; iii)mixing the solutions of step (ii) and (iii); iv)adding lactulose to the solution of step (iv); v)filtering the solution; and vi)filling the solution into suitable containers.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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We claim,
1. A novel oral pharmaceutical combination composition comprising: lactulose and ranitidine along with other pharmaceutical excipients useful for the treatment of constipation as well as acid-related gastrointestinal disorders.
2. The pharmaceutical combination composition of lactulose and ranitidine which can be used for the treatment of constipation as well as acid-related gastrointestinal disorders as claimed in claim 1, wherein said lactulose masks the bitter taste of ranitidine.
3. The pharmaceutical combination composition as claimed in claim 1, wherein the composition comprises ranitidine, lactulose and other pharmaceutical excipients in a suitable single oral dosage form.
4. The pharmaceutical combination composition as claimed in claim 1, wherein the acid-related gastrointestinal disorders are duodenal ulcer, gastric ulcer, gastroesophageal reflux disease and erosive esophagitis.
5. The pharmaceutical combination composition as claimed in claim 1, wherein the suitable oral dosage form is oral tablet or liquid.
6. The pharmaceutical combination composition as claimed claims 1 and 5, wherein the suitable excipients used in oral tablets are selected from disintegrants, fillers, binders, surfactants and lubricants.
7. The pharmaceutical combination composition of claim 1 and 5, wherein the suitable excipients used in liquid dosage form are selected from buffering agents, flavoring agents and colors.
8. A method of treating acid-related gastrointestinal disorders and constipation in humans wherein the method comprises administering to a human a novel oral pharmaceutical combination composition comprising lactulose and ranitidine along with other pharmaceutical excipients.
9. A method of treating acid-related gastrointestinal disorders and constipation in humans as claimed in claim 8, wherein the novel pharmaceutical composition is in oral dosage form.
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10. A method of treating acid-related gastrointestinal disorders and constipation in humans as claimed in claim 8, wherein the oral dosage form is oral liquid or tablet.