FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
LITTLE OF THE INVENTION:
"COMPOSITION OF MORPHINE AND ITS ANALOGS AND LACTULOSE
AND METHOD FOR DECREASING THE SIDE EFFECTS OF MORPHINE
AND ITS ANALOGS 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 pharmaceutical compositions comprising morphine or its analogs, lactulose and other suitable pharmaceutical excipients in effective amounts for reducing the side effect associated with use of morphine and its analogs during cough. The present invention further relates to a method of reducing adverse side effect of constipation associated with the oral use of morphine and its analogs during cough.
BACKGROUND OF THE INVENTION
Cough is a suddenly and often repetitively occurring defense reflex which helps to clear large breathing passages from excess secretions, irritants, foreign particles and microbes. Cough can occur both voluntarily as well as involuntary. However, in many instances, frequent or severe coughing usually indicates the presence of a disease which may warrant treatment. Various medicines have been used since ages for the treatment of cough and related conditions, yet morphine and its analogs are the strongest cough suppressants known and a number of its derivative has been employed. Morphine and codeine are obtained from the unripe seed capsules of the poppy plant, papaver somniferum; however, many other semisynthetic derivatives are made by relatively simple modifications of morphine. To name a few are, ethylmorphine, dihydrocodeine, benzylmorphine, nicocodeine, nicodicodeine, hydrocodone, pholcodeine, noscapine, cetylmorphone. Few of the other synthetic morphine analogs that are commonly used as antitussives are dimemorfan and dextromethorphan.

Morphine Codiene Dihydromorphine
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Ethyl morphine

Dimemorphan

Hydromorphene

Nicocodiene

Dextromethorphan

Commonly used Antitussive Drugs
Most of these drugs produce their major effects by acting on the μ receptor or depressing the cough reflex by a direct effect on a cough centre in the medulla. Although most of these drug are very effective and are widely used in suppressing cough; however, the frequent side effect observed with its use is the constipation which is mediated by n and 5 opiod receptors in the bowel.
Constipation is caused by administering the dose of morphine or its analogs necessary for effecting antitussive action and it is hard to become tolerant, thus constipation continues as long as the administration of morphine or its analog is continued. This problem is even more severe in the elderly patients which lays them feeling bloated, uncomfortable and sluggish. It also impairs the quality of life of the patients who are already on the multiple
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medications. For this reason, during administration of morphine, it is very important to control constipation.
As a consequence of the above mentioned side effect of morphine and its analogs, numerous proposals have been made by the innovators For e.g. In U.S. Pat. No. 6,982,283, by Ueno discloses the use of a 15-keto-prostaglandin compound for treating drug-induced constipation. US 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. 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. 5,418,220 by Schmidt et al claim the use of dimethicone as an agent for treating constipation and U.S. Pat. No. 6,294,555 claim the piperidine derivatives which are useful as a gastrointestinal motility enhancer or a gastrointestinal prokinetic agent. Still further, 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 above mentioned 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 the problem of constipation which is associated with the intake of morphine or its analogs for the treatment of cough without placing the extra burden of an additional drug on the patient.
SUMMARY OF THE INVENTION
The main objective of our invention is to provide a combination composition for reducing adverse side effect of constipation associated with the oral use of morphine and its analogs during cough.
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As a result of diligent research, the present inventors have found that the problem of constipation associated with morphine or its analogs could be resolved by the use of lactulose.
A single combination formulation of morphine or its analogs and lactulose would not only evict the problem of constipation but would also have several other advantages in older patients. For e.g., combining the separate drugs like morphine or its analogs 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 involves a novel combination therapy comprising the administration of a single composition of the therapeutically effective amount of morphine and its analogs with a therapeutically effective amount of a lactulose to a mammal, and more particularly, to a human. The combination therapy is used to inhibit the side effect of constipation which is associated when morphine or any of its analog is administered in mammals for the treatment of cough; without substantially losing the main effect of the drug.
Lactulose employed in the formulation is a synthetic sugar, being widely used for the treatment of both constipation and hepatic encephalopathy. It is a disaccharide formed from simple sugars like fructose and galactose.
In the treatment of constipation, when lactulose is combined with the morphine or its analogs; it draws water into the bowel and causing a cathartic effect through osmotic action. Thus, lactulose acts as a mild laxative without causing diarrhea. According to one aspect of the invention, the pharmaceutical compositions of morphine or its analog in combination with lactulose are preferably given orally in the form of liquid or tablet.
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Advantageously, the liquid formulation of morphine or its analogs with lactulose produced according to the present invention exhibit excellent stability and hence are more preferred.
As used herein, the term "morphine or its analog" can be understood to include synthetic or semisynthetic derivatives of morphine like codeine, ethylmorphine, dihydrocodeine, benzylmorphine, nicocodeine, nicodicodeine, hydrocodone, pholcodeine, noscapine, cetylmorphone, dimemorfan dextromethorphan and thebaine.
As used herein, the term "excipient" can be understood to include any inert substance combined with an active agent such as morphine or any of its analog 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 ortherapeutic agents for administration.
As used herein, the term "therapeutically effective amount" can be understood to include an amount of morphine or its analog in combination with lactulose that is effective for the treatment of cough without causing the side effect of constipation.
According to the present invention, a stable composition of morphine or its analog can be prepared by mixing lactulose with other suitable excipients in any oral dosage form.
In addition to morphine or any of its analog and lactulose other suitable additives can be included in the present liquid formulation like buffering agents, flavoring agents and colors.
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
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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.
Optionally, the composition further comprises a coloring agent.
However, since lactulose is very sweet in taste; the need for an additional sweetener in the formulation is evaded.
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.
A composition of the present invention can be used in treatment of cough, by orally administering to a subject in need thereof, a therapeutically effective amount of the composition. It is contemplated that the composition removes the side effect of constipation which is associated with morphine or its analog, patient discomfort and also increases the convenience and cost-effectiveness of the treatment.
Some typical examples illustrating the embodiments of the present invention are provided; however, these are exemplary only and should not be regarded as limitations of the present invention.
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Example 1:
Codeine Phosphate 2 mg/ml
Chlorpheniramine Maleate 0.8 mg/ml
Pseudoephedrine Hydrochloride 6 mg/ml
Lactulose 750 mg/ml
Menthol 2 mg/ml
Methyl Hydroxybenzoate 1 mg/ml
Propyl Hydroxybenzoate 0.2 mg/ml
Sodium Saccharin 2.5 mg/ml
Flavour Peppermint 1 mg/ml
Colour Carmoisine 0.1 mg/ml
Water q.s to 1 ml
Procedure:
i) taking 10 % of water into a vessel to dissolve specified quantity of Codeine
Phosphate and Chlorpheniramine Maleate;
ii) mixing the solution till the Codeine Phosphate and Chlorpheniramine Maleate is
completely solubilized; iii) adding lactulose to the solution of step (ii) with continuous stirring; iv) adding and dissolving Methyl Hydroxybenzoate, Propyl Hydroxybenzoate and
menthol to the solution of step (iii); v) adding and dissolving Sodium Saccharin to step (iv) with continuous stirring; vi) adding colour and flavour and mixing; vii) adding water to make quantity sufficient to 100 ml; viii) filtering the solution through filter press; and ix) filling the solution into the suitable containers.
Example 2:
Dextromethorphan 2 mg/ml
Pseudoephedrine Hydrochloride 6 mg/ml
Lactulose 750 mg/ml
Sodium Saccharin 2.5 mg/ml
Flavour Pineapple 1 mg/ml
Colour Carmoisine 0.1 mg/ml
Menthol 2 mg/ml
Methyl Hydroxybenzoate 1 mg/ml
Propyl Hydroxybenzoate 0.2 mg/ml
Water q.s to 1 ml


Procedure:
i) taking 10 % of water into a vessel to dissolve specified quantity of
Dextromethorphan and Pseudoephedrine Hydrochloride; ii) mixing the solution till the Dextromethorphan and Pseudoephedrine
Hydrochloride is completely solubilized; iii) adding lactulose to the solution of step (ii) with continuous stirring; iv) adding and dissolving Methyl Hydroxybenzoate, Propyl Hydroxybenzoate and
menthol to the solution of step (iii); v) adding Sodium Saccharin to step (iv) with continuous stirring; vi) adding colour and flavour and mixing thoroughly; vii) adding the water to make quantity sufficient to 100 ml; viii) filtering the solution through filter press; and ix) filling the solution into the suitable containers.
Example 3:
Pholcodine 0.03 mg/ml
Diphenhydramine Hydrochloride 0.25 gm/ml
Lactulose 750 mg/ml
Sorbic acid 2 mg/ml
Sodium Saccharin 2.5 mg/ml
Flavour Mixed fruit 1 mg/ml
Colour Carmoisine 0.1 mg/ml
Purified water q.s to 1 ml
Procedure:
i) taking 10 % of water into a vessel to dissolve specified quantity of Phalcodine and
Diphenhydramine Hydrochloride; ii) mixing the solution till the Phalcodine and Diphenhydramine Hydrochloride is
completely solubilized; iii) adding lactulose to the solution of step (ii) with continuous stirring; iv) adding and dissolving sorbic acid to the solution of step (iii); v) adding and dissolving Sodium Saccharin; vi) adding colour and flavour and mixing thoroughly; vii) add the water to make quantity sufficient to 100 ml;
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viii) filtering the solution through filter press; and ix) filling the solution into the suitable containers

Example 4:
Codeine Phosphate 2mg/ml
Paracetamol 25 mg/ml
Lactulose 750 mg/ml
Propylene glycol 150 mg/ml
Methyl Hydroxybenzoate 1 mg/ml
Propyl Hydroxybenzoate 0.2 mg/ml
Sodium Saccharin 2.5 mg/ml
Flavour Banana 1 mg/ml
Colour Carmoisine 0.1 mg/ml
Purified water q.s to 1 ml
i) taking 10 % of water into a vessel to dissolve specified quantity of Codeine
Phosphate; ii) taking Propylene glycol into a separate vessel to dissolve specified quantity of
Paracetamol; iii) adding Methyl Hydroxybenzoate and Propyl Hydroxybenzoate to the solution of
step (ii) with continuous stirring; iv) mixing the solutions of step (ii) and (iii); v) Add and dissolve Sodium Saccharin, vi) adding colour and flavour and mixing thoroughly; vii) adding the water to make quantity sufficient to 100 ml; viii) filtering the solution through filter press; and ix) filling the solution into the suitable containers.

Example 5:
Codeine Phosphate 2 mg/ml
Lactulose 750 mg/ml
Propylene glycol 200 mg/ml
Methyl Hydroxybenzoate 1 mg/ml
Propyl Hydroxybenzoate 0.2 mg/ml
Sodium Saccharin 2.5 mg/ml
Flavour orange 1 mg/ml
Colour Carmoisine 0.1 mg/ml
Purified water q.s to 1 ml
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i) taking 10 % of water into a vessel to dissolve specified quantity of Codeine Phosphate;
ii) adding Methyl Hydroxybenzoate and Propyl Hydroxybenzoate to the solution of step (i) with continuous stirring;
iii) adding and dissolving Sodium Saccharin;
iv) adding colour and flavour and mixing thoroughly;
v) adding the water to make quantity sufficient to 100 ml;
vi) filtering the solution through filter press; and
vii) filling the solution into the 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 composition comprising lactulose and morphine or any of its analog useful for the treatment of constipation associated with use of morphine and its analogs during cough.
2. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises morphine or any of its analog, lactulose and other pharmaceutical excipients in a single dosage form.
3. The pharmaceutical composition as claimed in claim 1, wherein the morphine analog are synthetic or semisynthetic derivatives of morphine.
4. The pharmaceutical composition as claimed in claims 1 and 3, wherein morphine analog is selected from codeine, ethylmorphine, dihydrocodeine, benzylmorphine, nicocodeine, nicodicodeine, hydrocodone, pholcodeine, noscapine, cetylmorphone, dimemorfan and dextromethorphan.
5. The pharmaceutical composition as claimed in claim 2, wherein suitable pharmaceutical excipients is selected from buffering agents, flavoring agents and coloring agents.
6. A method of treating adverse side effects associated with the oral use of morphine and its analogs during cough in patients, wherein said method comprises administering to said patient an effective amount of pharmaceutical composition according to any one of preceding claims.
7. A method of treating adverse side effects as claimed in claim 6, wherein the side effect is constipation.
8. A method of treating adverse side effects as claimed in claims 6 and 7, wherein the method comprises of administering patients a novel pharmaceutical composition of morphine or its analog, lactulose and other pharmaceutical excipients.
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9. A method of treating adverse side effects as claimed in claims 6, 7 and 8, wherein
the novel pharmaceutical composition is in oral dosage form.
10. A method of treating adverse side effects as claimed in claims 6 to 9, wherein the
oral dosage form is oral liquid or tablet.
Dated this 19tb day of August, 2008
i
Dr. Gopakumar G. Nair Agent for the applicant
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