WO2016084099A1

WO2016084099A1 - Soft gelatin capsule composition of anti-tussive agents

Info

Publication number: WO2016084099A1
Application number: PCT/IN2015/000434
Authority: WO
Inventors: Dattatray Deo Kishor; Hanjagimutt Umesh; Praveen Varghese Koshy; Prasad Gaddam Rajendra; Dev Mantena Narender
Original assignee: Biological E Limited
Priority date: 2014-11-25
Filing date: 2015-11-23
Publication date: 2016-06-02

Abstract

The present invention relates to a soft-gelatin capsule formulation of antitussive agents. More particularly, the present invention relates to soft-gelatin capsule formulation comprising Noscapine or its pharmaceutically acceptable salts alone or in combination with one or more therapeutically active agents.

Description

Soft Gelatin Capsule Composition of Anti-Tussive Agents

Field Of The Invention

Background Of The Invention

Noscapine (also known as Narcotine, Nectodon, Nospen), is a benzylisoquinoline alkaloid from plants of the Papaveraceae family. Noscapine is used in cough suppressants in Japan, throughout the Asian continent and certain European countries. Noscapine is a natural product found in opium that can cross the blood-brain barrier to exert its effect upon the central nervous system, resulting in cough suppression.

In addition, noscapine has been shown in animal studies to reduce tumor growth, and exploratory research into the use of noscapine as an anti-tumor agent is ongoing.

Noscapine in salt form is characterized by a bitter taste, rendering it unpalatable and for the most part used in liquid form for treating persons with severe coughing spells. In the past, the usual procedure for processing noscapine has been to either use the salt of noscapine, which is a soluble compound in aqueous solution or to acidify the noscapine alkaloid base in order to render it more soluble by conversion to the salt; however, in either event, the characteristic bad taste remains in the resulting mixture or solution. To solve this problem, Virgil et.al (US patent No. 4,029,797) developed a process for delivering noscapine in a palatable cough syrup which method comprises:

the step of adding the noscapine alkaloid base separately from the ingredients of the carrier vehicle until just prior to mixing it in the final resulting mixture; also strictly adhering to an alkaline pH, that is one over seven, to guard against an acidic condition, in which event a salt would form causing an undesirable taste characteristic of noscapine which would render the product of the process unpalatable.

US patent No. 8,394,814 disclosed a method for separating noscapine from an opium source without substantially changing the color of the noscapine.

Soft gelatin capsules (referred to as soft elastic gelatin capsules, liquid gels or softgels) are a unique drug delivery system that can provide distinct advantages over traditional dosage forms such as tablets, hard gelatin capsules and liquids. Softgel is a hermetically sealed, one-piece capsule with a liquid or semisolid fill. The softgel consists of two major components, the gelatin shell and the fill. In the finished product gelatin shell is primarily composed of gelatin, plasticizer and water. The fill material can include a wide variety of vehicles and can either be a solution or a suspension.

The gelatin used for gelatin capsules is traditionally produced by extraction from collagen containing mammalian tissues, particularly such as pig skin and bovine bone. Gelatin from pig and bovine origin are preferably used for their gelling, film forming and surface-active properties. Gelatin capsules from fish origin are known from WO 99/33924. To improve the workability, in particular the flowing properties, of the aforementioned "alternative" gelatins, to be employed in the pharmaceutical, veterinary, food or cosmetics field, the incorporation of a setting system comprising hydrocolloids and optionally cations and/or sequestering agents in amounts of less than 5%, preferably 0.01 to 3% is described.

Development of soft gelatin capsule (softgel) dosage form is of growing interest for the oral delivery of poorly water soluble compounds. After a method for the production of soft gelatin capsules had been found in the thirties by which a capsule can be produced and filled in a single operation, soft gelatin capsules, gained more and more importance as a form of medicine. The softgel dosage form offers several advantages over other oral dosage forms and one major advantage being the masking of unpleasant taste and odour of drug substances as well as its appearance. There are quite a number of active substances which because of their sensitivity to oxidation and light, their thermal instability, or their hygroscopicity cannot be processed into other forms of medicines, but which can be enclosed in softgel capsules without their efficiency being impaired.

Soft gelatin capsules are favored by many people for oral administration of medications, at least in part because of their ease of swallowing. The soft gelatin shell makes the capsule easier to swallow, especially for the elderly, than a tablet or a hard capsule. Furthermore, the contents of a soft gelatin capsule can be more bioavailable following ingestion due to rapid rupture of the capsule and release of the contents in the digestive tract.

Soft gelatin capsules are predominantly used to contain liquids wherein the active ingredients are present in the dissolved or suspended state. A particularly good bioavailability of the pharmacologically active substance is attained if the active substance is successfully dissolved in a suitable solvent and the encapsulated solution is administered to the patient. Solutions also provide the best liquid form to obtain optimal "content uniformity" in softgel fill. In addition, a solution provides a faster and more uniform absorption of a pharmaceutical agent than a suspension. Because of these distinct technical advantages, solutions are preferred over suspensions or other dispersions.

US patent No. 4,744,988 disclosed a soft gelatin capsule comprising a shell of gelatin and a softener, and a filling consisting of a polyethylene glycol and a low polyhydric alcohol and at least one active substance, characterized in that

a) the dried shell of the capsule contains 4 to 40% by weight of sorbitol or sorbitanes; b) at least 50% by weight of the polyethylene glycol used in the filling for dissolving or suspending the active substance is a polyethylene glycol having a mean molecular weight of 600; and

c) the capsule filling comprises up to 20% by weight of glycerol and/or 1,2-propylene glycol. US Patent No. 5,071,643 disclosed a soft gelatin capsules containing concentrated acetaminophen solution comprising 25-40% by weight acetaminophen, hydroxide ions (potassium hydroxide), water and polyethylene glycol.

US Patent No. 5,505,961 disclosed a method for increasing the solubility of acetaminophen alone or in combination with antihistamines, antitussives, decongestants and expectorants to form clear solutions for encapsulation in soft gelatin capsules. The compositions comprising acetaminophen, potassium or sodium acetate, polyethylene glycol and polyvinyl pyrrolidone permits 325 mg dose to be administered in the same size soft gel as a 250 mg dosage product.

US patent No. 6,251,426 disclosed a liquid softgel fill formulations containing ibuprofen in free acid form, and softgel capsules comprised of a gelatin sheath enclosing such fill formulations, prepared by dissolving more than 30% of ibuprofen in free acid form in polyethylene glycol and at least 10% by weight of a polyvinyl pyrrolidone having an average molecular weight of from about 2,000 to about 54,000. The formulations may also include a surfactant to increase the bioavailability of the ibuprofen.

WO 201 1/088553 disclosed pharmaceutical formulations of naproxen for soft gel encapsulation and combinations thereof.

WO 2009/066146 A2 disclosed a stable pharmaceutical composition comprising soft gelatin capsules containing at least one sparingly soluble active drug selected from antipyretic or an analgesic drug, preferably Paracetamol (Acetaminophen), Ibuprofen, Dexibuprofen alone or in combination with freely soluble active drug selected from antihistamines, antitussives and decongestants; preferably Chlorpheniramine maleate, Doxylamine succinate, Dextromethorphan HBr and Pseudoephedrine hydrochloride and a solvent system, wherein the solvent system comprises of solvent, co-solvent, solubilizer(s), surfactant, aqueous solution of alkali and crystal growth inhibitor. Soft gelatin capsules containing paracetamol alone or in combination with other soluble drug(s) such as antihistamines like chlorpheniramine maleate, doxylamine succinate; antitussive like dextromethorphan HBr; and decongestants like pseudoephedrine hydrochloride, phenylephrine hydrochloride are known in the literature. Various drugs which are available in the market in the form of soft gelatin capsules include Progesterone, Lubiprostone marketed under the trade name Amitiza® in the USA, Isotretinoin (Sotret®), Cyclosporine capsules (Sandimmune®), Paricalcitol (Zemplar®) and the like. Apart from this, many over-the-counter drugs available as soft gelatin capsules in the USA. Even though Noscapine is known since many years, soft gelatin capsules containing Noscapine is not known in the literature.

Noscapine being bitter taste drug, it is desirable to mask the taste. Noscapine and its combination with other therapeutically active substances are available in the market in the form of liquid oral dosage forms. However, liquid oral dosage forms have disadvantage of harder to measure accuracy, need special storage conditions, easily affected by microorganisms, bulky to carry around, requirement of measuring dose. Hence, there is a need to have patient compliant dosage form mainly for the conditions such as cough, cold etc. Hence, the inventors of the present invention developed soft gelatin capsules of Noscapine or its pharmaceutically acceptable salts like hydrochloride, which improved the patient acceptability as well as desirability of the dosage form.

Objective of the invention

The main objective of the present intention is to provide soft gelatin capsule formulations of Noscapine.

Yet another objective of the present invention is to provide soft gelatin capsule formulations comprising Noscapine in combination with one or more other therapeutically active substances. Yet another objective of the present invention is to provide stable soft gelatin capsule formulations comprising Noscapine which mask the bitter taste of Noscapine.

Summary Of The Invention

Accordingly, the invention provides soft-gelatin capsule dosage form comprising Noscapine alone or in combination with one or more therapeutically active substances. one or more therapeutically active substance is selected from chlorpheniramine, phenylephrine, guaiphenesin, acetaminophen, doxylamine, dextromethorphan, pseudoephedrine, cetirizine, diphenhydramine, loratadine and its pharmaceutically acceptable salts or solvates thereof.

Detailed Description Of The Invention

The present invention provides a composition comprising 0.1 to 20% by weight of Noscapine alone or in combination with one or more therapeutically active substances, 5 to 95 % by weight of solvent system and one or more pharmaceutically acceptable excipients filled in soft gelatin capsule.

The invention provides soft-gelatin capsule composition comprising Noscapine alone or in combination with one or more therapeutically active substances selected from chlorpheniramine, phenylephrine, guaiphenesin, acetaminophen, doxylamine, dextromethorphan, pseudoephedrine, cetirizine, diphenhydramine, loratadine and its pharmaceutically acceptable salts or solvates thereof.

One more of the therapeutically active substances of the present invention, including Noscapine may be used in the form of pharmaceutically acceptable salts selected from hydrochloride, hydrobromide, maleate, succinate, tartrate, oxalate, nitrate, sulfate, phosphate and the like. As used herein the terms dosage form, composition or formulation may be interchangeably used.

Preferable soft gelatin capsule dosage form of the present invention include one of the following combination of therapeutic agents:

a) Noscapine hydrochloride and Chlorpheniramine maleate;

b) Noscapine hydrochloride, Chlorpheniramine maleate and Phenylephrine hydrochloride,

c) Noscapine hydrochloride, Guaiphenesin and Phenylephrine hydrochloride;

d) Noscapine hydrochloride, Chlorpheniramine maleate and Acetaminophen e) Noscapine hydrochloride, Phenylephrine hydrochloride and Acetaminophen f) Noscapine hydrochloride, Doxylamine succinate and Acetaminophen.

In yet another embodiment, the solvent system composed of solvent, co-solvent and crystal growth inhibitor.

Suitable solvent(s) used according to the present invention is polyethylene glycol (PEG) having molecular weight from about 200 to about 6000 Daltons. The solvent may comprise combinations of PEGs, preferably 400 and 1000 Dalton, to enable the active medicament remain sustained in the solubilized form. The solvent may be used in the range of about 20% to 95% % by weight of the composition.

Suitable co-solvent used is selected from the group consisting of water, propylene glycol, glycerin, ethyl alcohol, glycerol and the like or mixtures thereof. Binary use of PEGs in the solvent system avoids the frequent, problem of leaking of the gelatin shell. The co-solvent is used in an amount ranging from 1 to 20 % by weight of composition.

Soft gelatin capsules are sensitive to pH, thus the capsules containing concentrated solution of weekly acidic drugs may hydrolyze the gelatin shell, which results into leaking of the capsule. Soft gelatin capsules containing concentrated solution of weekly acidic drug(s) may results into crystallization on long time storage of the dosage form. It may also cause migration of active substance from the soft gelatin shell.

Suitable crystal growth inhibitors used according to the present invention are selected from polyvinyl alcohol, sodium carboxymethyl cellulose (CMCNa) and polyvinyl pyrrolidone (povidone) and the like. The crystal growth inhibitor used may be in the range of about 0 to 25% by weight of the composition.

In yet another embodiment, the fill composition further comprises one or more excipients selected from antioxidants, solubilizer, surfactant, hydroxide ion source and the like or mixture thereof.

Suitable antioxidants used may be selected from butylated hydroxy toluene, propyl gallate, sodium bisulfite, sodium metabisulfite, ascorbic acid, tocopherols and butylated hydroxy anisole and is present in amount of 0.01 to 2% w/w.

Suitable solubilizers used for solubilization may be selected from polyvinyl pyrrolidone, macrogol 15 hydroxystearate, propylene glycol caprylate, polyoxyl 40 hydrogenated castor oil and the like.

Suitable surfactants used may be selected from sodium lauryl sulphate, propylene glycol caprylate, polysorbate 20, diethylene glycol mono ethyl ether, polysorbate 80, gelucire 44/14 and the like.

Suitable hydroxide ion source is selected from sodium hydroxide or potassium hydroxide.

In yet another embodiment, the capsule fill of the dried capsule may additionally contain about 4 and 20% by weight of water. Elastic shell of a soft gelatin capsule further comprises one or more softening agents, plasticizers, opacifiers, preservatives, flavouring agents and colouring agents. Suitable softening agent used is selected from the group consisting of lecithin, polysorbate and the like. Suitable plasticizer used is selected from glycerin, propylene glycol, sorbitol, sorbitan anhydrides maltitol, sugar alcohol, polyethylene glycol 200 (PEG 200) and the like and is present in the amount of about 5 to 30% by weight of the capsule shell composition.

Suitable opacifier used is selected from titanium dioxide and/or iron oxides and is present in an amount of 0.2 to 1% by weight of the capsule shell composition.

The preservative is selected from methyl paraben or propyl paraben and is present in the amount of 0.01 to 2 % by weight of the capsule shell composition.

The colouring agent is iron oxide yellow and is present in the amount of 0.1 to 1 % by weight of the capsule shell composition.

In yet another embodiment, the thickness of the soft gelatin film may range from about 0.6 to 1.2 mm. The size of soft gelatin capsules may vary in accordance to the volume of the solution intended to be filled.

In a preferred embodiment, the present invention provides a soft-gelatin capsule dosage form comprising Noscapine and / or one or more other therapeutically active substances comprises:

a) a shell of gelatin and plasticizers, and

b) a fill composition comprising Noscapine HCl alone or in combination with one or more other therapeutically active substances, solvent system and one or more pharmaceutically acceptable excipients.

In yet another embodiment, the fill composition further comprises a low polyhydric alcohol such as propylene glycol, glycerol and the like or mixtures thereof. In a preferred embodiment, the present invention provides soft gelatin capsule dosage form comprising about 5 to 20mg of Noscapine or its pharmaceutically acceptable salts.

In yet another embodiment, one or more therapeutically active substance comprises:

2 to 5 mg of Chlorpheniramine maleate;

1 to 20mg of Phenylephrine HCl,

25 to lOOmg of Guaiphenesin

250 to 750mg of Acetaminophen

5 to 15 mg of Doxylamine succinate.

Preferred fill compositions of the present invention in soft gelatin capsule include:

5 to 20mg of Noscapine HCl, 250 to 500mg of Acetaminophen (Paracetamol); 5 to 20mg of Phenylephrine HCl, 2 to 20% w/w of water, 40 to 85% w/w polyethylene glycol; 0 to 10 % w/w of propylene glycol, 0.5 to 10% w/w of crystal growth inhibitor and 0.01 to 2 % w/w of antioxidants;

5 to 20mg of Noscapine HCl, 25 to lOOmg of Guaiphenesin, 5 to 20mg of Phenylephrine HCl, 2 to 10% w/w of water, 70 to 85 w/w polyethylene glycol; 0 to 5 % w/w of propylene glycol, 1 to 5 % w/w of crystal growth inhibitor and 0.01 to 2 % w/w of antioxidant;

5 to 20mg of Noscapine hydrochloride, 2 to 5 mg of Chlorpheniramine maleate, 2 to 10% w/w of water, 80 to 95 w/w polyethylene glycol; 0 to 5 % w/w of propylene glycol, 1 to 5 % w/w of crystal growth inhibitor and 0.01 to 2 % w/w of antioxidant; 5 to 20mg of Noscapine HCl, 2 to 5 mg of Chlorpheniramine maleate, 5 to 20mg of Phenylephrine HCl, 2 to 10% w/w of water, 80 to 95 w/w polyethylene glycol; 0 to 5 % w/w of propylene glycol, 1 to 5 % w/w of crystal growth inhibitor and 0.01 to 2 % w/w of antioxidant.

In another Preferred embodiment, the present invention provides a soft gelatin capsule composition which includes:

a) 5 to 20mg of Noscapine HCl, 250 to 500mg of Acetaminophen (Paracetamol); 5 to 20mg of Phenylephrine HCl, 2 to 20% w/w of water, 40 to 85% w/w polyethylene glycol; 0 to 10 % w/w of propylene glycol, 0.5 to 10% w/w of povidone and 0.01 to 2 % w/w of antioxidants;

b) 5 to 20mg of Noscapine HCl, 25 to lOOmg of Guaiphenesin, 5 to 20mg of Phenylephrine HCl, 2 to 10% w/w of water, 70 to 85 w/w polyethylene glycol; 0 to 5 % w/w of propylene glycol, 1 to 5 % w/w of povidone and 0.01 to 2 % w/w of antioxidant;

c) 5 to 20mg of Noscapine HCl, 2 to 5 mg of Chlorpheniramine maleate, 2 to 10% w/w of water, 80 to 95 w/w polyethylene glycol; 0 to 5 % w/w of propylene glycol, 1 to 5 % w/w of povidone and 0.01 to 2 % w/w of antioxidant;

d) 5 to 20mg of Noscapine HCl, 2 to 5 mg of Chlorpheniramine maleate, 5 to 20mg of Phenylephrine HCl, 2 to 10% w/w of water, 80 to 95 w/w polyethylene glycol; 0 to 5 % w/w of propylene glycol, 1 to 5 % w/w of povidone and 0.01 to 2 % w/w of antioxidant.

In yet another embodiment, the present invention provides a process for the preparation of soft gelatin capsules comprising Noscapine alone or in combination with one or more therapeutically active substances which comprises the steps of:

a) solubilization or suspension of Noscapine alone or in combination with one or more therapeutically active substances in a solvent system comprising one or more of solvent, solubilizer, co-solvent, surfactant, crystal growth inhibitor, viscosity modifiers, antioxidants and aqueous alkali or acid solution and

b) encapsulation of pharmaceutical active fill in soft gelatin shell.

In another embodiment, there is provided a method of treating a human suffering from cough by administering soft gelatin capsule dosage form of the present invention. The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any way.

Example 1

Soft Gel capsules containing Paracetamol, Noscapine HCl and Phenylephrine HCl mg/unit

Formulation

A B c D

Fill Ingredients

Paracetamol 325.00 325.00 325.00 325.00

Noscapine HCl 7.618 7.618 7.618 7.618

Phenylephrine HCl 5.00 5.00 5.00 5.00

Polyethylene Glycol 620.582 720.582 644.582 670.582

Propylene Glycol 60.00 60.00 - 60.00

Butylated hydroxyl toluene 0.60 0.60 0.60 0.60

Butylated hydroxyl anisole 1.20 1.20 1.20 1.20

Povidone 72.00 72.00 96.00 72.00

Water 108.00 108.00 120.00 108.00

Total 1200.00 1300.00 1200.00 1250.00

A mixture of polyethylene glycol, propylene glycol, and water was prepared and mixed until homogenous. Povidone was added to the above mixture slowly while stirring and under heating to a temperature of about 40 °C. This mixture was stirred until dissolved. Paracetamol was added slowly, along with other ingredients, while stirring and under heating to a temperature of about 70 °C. This mixture was stirred until homogenous. While mixing, the mixture was heated and a temperature of about 70 °C was maintained. The mixture was stirred until dissolved and a clear solution formed. The mixture was cooled. To this mixture, noscapine HCl solution in water, phenylephrine HCl solution in water were added under stirring and a clear solution is formed which was deaerated. The mixture was then encapsulated in conventional soft gelatin capsules using a conventional rotary die process. The dry finished soft gels are dried to an appropriate hardness and fill moisture.

Example 2

Soft Gel capsules containing Noscapine HCl, Guaiphenesin and Phenylephrine HCl

Polyethylene Glycol 363.907

Propylene glycol 4.50

Povidone 7.00

Butylated hydroxyl anisole 0.225

Butylated hydroxyl toluene 0.45

Sodium hydroxide 0.05

Water 11.25

Total 450.00

A mixture of polyethylene glycol, propylene glycol, and water was prepared and mixed until homogenous. Povidone was added to the above mixture slowly while stirring and under heating to a temperature of about 40 °C. This mixture was stirred until dissolved. Guaiphenesin was added slowly, followed by noscapine HCl along with other ingredients, while stirring. This mixture was stirred until homogenous. While mixing, the mixture was heated and a temperature of about 50 °C was maintained. The mixture was stirred until dissolved and a clear solution formed. The mixture was cooled. To this mixture, phenylephrine HCl solution in water was added under stirring and a clear solution was formed which was deaerated. The mixture was then encapsulated in conventional soft gelatin capsules using a conventional rotary die process. The dry finished soft gels are dried to an appropriate hardness and fill moisture.

Example 3

Soft Gel capsules containing Noscapine HCl and Chlorpheniramine maleate

A mixture of polyethylene glycol, propylene glycol, and water was prepared and mixed until homogenous. Povidone was added to the above mixture slowly while stirring and under heating to a temperature of about 40 °C. This mixture was stirred until dissolved. Noscapine HC1 was added slowly, along with other ingredients, while stirring. This mixture was stirred until homogenous. While mixing, the mixture was heated and a temperature about 50 °C was maintained. The mixture was stirred until dissolved and a clear solution formed. The mixture was cooled. To this mixture, Chlorpheniramine maleate solution in water and or phenylephrine HC1 were added under stirring and a clear solution is formed which was deaerated. The mixture was then encapsulated in conventional soft gelatin capsules using a conventional rotary die process. The dry finished soft gels are dried to an appropriate hardness and fill moisture.

Example 4

Soft Gel capsules containing Noscapine HC1, Chlorpheniramine maleate and Phenylephrine HC1

The capsules were prepared according to the procedure similar to the one described in example 3.

Disintegration of the soft gelatin capsules prepared according to the present invention were carried out and the results are given in the table 1 below: Table 1

The dissolution of soft gelatin capsules prepared above were measure using USP Apparatus type II, RPM 50, in pH 1.2 Media at 45 minutes. Dissolution rate is given in the table 2 below.

Table 2

The soft gelatin capsules encapsulated with the solution is further analysed for stability. The soft gelatin capsules of the present invention were found to be stable chemically and physically on long term storage. The stability data is given in table 3.

Table 3

Phenylephrine HC1 95.2 91.9

L.O.D. of capsule (% w/w) 9.60 9.90

Noscapine 99.3 98.6

Guaiphenesin 96.93 96.9

Phenylephrine HC1 98.03 96.9

L.O.D. of capsule (% w/w) 9.40 10.0

Noscapine 99.2 95.0

Chlorpheniramine maleate 96.2 93.4

Phenylephrine HC1 96.7 92.1

L.O.D. of capsule (% w/w) 9.8 10.0

Claims

1. A soft-gelatin capsule composition comprising noscapine alone or in combination with one or more therapeutically active substances and solvent system.

2. The composition according to claim .1 , wherein noscapine is present in an amount from 0.1% to 20% by weight and the solvent system in an amount from 5% to 95% by weight.

3. The composition according to claims 1 to 2, wherein one or more therapeutically active substance is selected from chlorpheniramine, phenylephrine, guaiphenesin, acetaminophen, doxylamine, dextromethorphan, pseudoephedrine, cetirizine, diphenhydramine, loratadine and its pharmaceutically acceptable salts or solvates thereof.

4. The composition according to any one of claims 1 to 3, wherein the solvent system comprises solvent, co-solvent and crystal growth inhibitor.

5. The composition according to any one of claim 4, wherein the solvent is polyethylene glycol (PEG) having molecular weight from about 200 to about 6000 Daltons.

6. The composition according to any one of claims 1 to 5, wherein the solvent system is present in an amount from 20% to 95 % by weight.

7. The composition according to claim 6, wherein the co-solvent is selected from the group consisting of water, propylene glycol, glycerin, ethyl alcohol or mixtures thereof.

8. The composition according to claim 4, wherein the crystal growth inhibitor is selected from polyvinyl alcohol, sodium carboxymethyl cellulose and povidone or mixtures thereof.

9. A soft-gelatin capsule dosage form, comprising Noscapine HCl alone or in combination with one or more other therapeutically active substances which comprise: a) a shell of gelatin and plasticizers, and

10. The composition according to claim 9, wherein the fill composition further comprises one or more excipients selected from antioxidants, solubilizer, surfactant and hydroxide ion source.

1 1. The composition according to claim 10, wherein the hydroxide ion source is sodium hydroxide or potassium hydroxide.

12. The dosage form as claimed in claim 9, wherein the plasticizer is selected from glycerin, propylene glycol, sorbitol, sorbitan anhydrides maltitol, sugar alcohol, polyethylene glycol 200 (PEG 200).

13. The soft gelatin capsule according to any of the claims 1 to 12, wherein Noscapine or its hydrochloride salt is present in an amount from 5 to 20mg.

14. A Soft gelatin capsule comprising 5 to 20mg of Noscapine hydrochloride, 250 to 500mg of Acetaminophen (Paracetamol); 5 to 20mg of Phenylephrine hydrochloride, 2 to 20% w/w of water, 40 to 85% w/w polyethylene glycol; 0 to 10 % w/w of propylene glycol, 0.5 to 10% w/w of crystal growth inhibitor and 0.01 to 2 % w/w of antioxidants;

15. A Soft gelatin capsule comprising 5 to 20mg of Noscapine hydrochloride, 25 to lOOmg of Guaiphenesin, 5 to 20mg of Phenylephrine hydrochloride, 2 to 10% w/w of water, 70 to 85 w/w polyethylene glycol; 0 to 5 % w/w of propylene glycol, 1 to 5 % w/w of crystal growth inhibitor and 0.01 to 2 % w/w of antioxidant;

16. A Soft gelatin capsule comprising 5 to 20mg of Noscapine hydrochloride, 2 to 5 mg of Chlorpheniramine maleate, 2 to 10% w/w of water, 80 to 95 w/w polyethylene glycol; 0 to 5 % w/w of propylene glycol, 1 to 5 % w/w of crystal growth inhibitor and 0.01 to 2 % w/w of antioxidant;

17. A Soft gelatin capsule comprising 5 to 20mg of Noscapine hydrochloride, 2 to 5 mg of Chlorpheniramine maleate, 5 to 20mg of Phenylephrine hydrochloride, 2 to 10% w/w of water, 80 to 95 w/w polyethylene glycol; 0 to 5 % w/w of propylene glycol, 1 to 5 % w/w of crystal growth inhibitor and 0.01 to 2 % w/w of antioxidant.

18. A process for preparing soft-gelatin capsule comprising Noscapine alone or in combination with one or more therapeutically active substances which comprises: a) solubilization or suspension of Noscapine alone or in combination with one or more therapeutically active substances in solvent system comprising one or more of solvent, solubilizer, co-solvent, surfactant, crystal growth inhibitor, viscosity modifiers, antioxidants and aqueous alkali or acid solution and

b) encapsulation of pharmaceutical active fill in soft gelatin shell dosage form.