CHEWABLE SOFT GELATIN CAPSULE DOSAGE FORM OF

MUCOLYTIC AGENTS

FIELD OF THE INVENTION

The present invention relates to chewable soft gelatin capsule dosage form of mucolytic agents. More particularly the present invention relates to chewable soft gelatin capsule dosage form of Carbocisteine. Further, the present invention also relates to process for preparing chewable soft gelatin capsule dosage form.

BACKGROUND OF THE INVENTION

Mucolytics are the agents which designed to help loosen and clear the mucus from the airways by breaking up the sputum. The most common type of mucolytic is N-Acetylcysteine. The various other mucolytic agents which are currently available in the market are Erdosteine, Bromheksin, Carbocisteine and Guiafenesin. All these products are available as capsules, tablets or liquid dosage forms. Carbocisteine is marketed in United Kingdom under the brand name of Mucodyne® and is available as capsules and syrup formulations. Chemically Carbocisteine is (i?)-2-Amino-3-(carboxymethylsulfanyl)propanoic acid and the chemical structure is as follows:

Carbocisteine is indicated for the treatment of respiratory tract disorders characterized by excessive, viscous mucus, including chronic obstructive airways disease.

US 7,101,572 patent discloses liquid pharmaceutical composition for unpleasant tasting drugs. The composition which comprises at least one unpleasant tasting drug about 0.02-15%, polyethylene glycol of molecular weight at least 900 about 0.05-10% and polyvinyl pyrrolidone or copolyvidone about 0.1-30%. The final composition was administered to a patient in the form a liquid having non-bitter taste and pH from about 2.5 to about 8. The unpleasant tasting drug is selected from the group consisting of an analgesic, an anti-inflammatory drug, an antihistamine, a decongestant, anti-infective, a mucolytic, an antitussive, an expectorant, and combinations thereof.

US 5,616,621 & 5,563,177 patents discloses pharmaceutically acceptable taste masking liquid excipient base consisting of water and polyethylene glycol having molecular weight of about 950-2200 and a cellulosic compound. The weight ratio of polyethylene glycol and cellulosic compound being between 100:1 to 20:1 and viscosity of liquid excipient base between 150-1000 centipoises at 50RPM and 150-1200 centipoises at 10RPM and antihistamines, decongestants, antitussives, expectorants, non-steroidal anti-inflammatory drugs (NSAIDs) and analgesic drugs, said pharmaceutically active compound being dissolved in the liquid excipient base.

US 5,763,449 & US 5,962,461 patents discloses liquid pharmaceutical composition comprising bitter tasting drug dissolved or dispersed in aqueous medium that is free of ethanol and consisting of water, 5-30% of polyvinylpyrrolidone, 0.01-0.5% of ammonium glycyrrhizinate and one or more flavorants. The bitter tasting drug is selected from the group consisting of acetaminophen, terfenadine, guaifenesin, trimethoprim, prednisolone, ibuprofen, prednisolone sodium phosphate, methacholine, neostigmine, epinephrine, albuterol, pseudoephedrine hydrochloride, diphenhydramine, chlorpheniramine maleate, phenothiazine, chlorpromazine, chlordiazepoxide, amitriptyline, barbiturates, diphenylhydantoin, caffeine, morphine, demerol, codeine, lomotil, lidocaine, salicylic acid, sulfonamides, chloroquine and penicillins.

US 4,935,243 patent discloses a chewable, edible soft gelatin capsule which comprises a shell comprising 15-30% of water, 20-45% of gelatin, 17.5-35% of plasticizer and 5- 25% of hydrogenated starch hydrolysate effective to render said shell dispersible and soluble in the mouth of the user; and a soft gelatin capsule fill material in which an active ingredient preferably a biologically-active agents such as vitamins, minerals, antacids and their mixtures are dispersed or dissolved. The fill substance is in the form of solid tablets or pellets or gels or semisolids.

US 5,200,191 patent discloses a process for producing a plurality of gelatin shells encapsulating a fill, wherein the fill is first encapsulated in a shell and then the shells containing the fill are dried at a given temperature so that the water content of each shell ranges from 6-10%, the improvement comprising subsequently heating the filled shells to a temperature above the given temperature and in a range of 32°C-43°C and at 35-60% relative humidity whereby dimples and bubbles are removed from the filled shells.

US 5,569,466 patent discloses dosage unit form comprising a biologically active agent dissolved or suspended in a carrier liquid encapsulated in a soft elastic gel capsule, wherein the carrier liquid comprises at least about 20% maltilol syrup. The biologically active compound is selected from the group of pharmaceuticals, nutritional supplements, diagnostics, cosmetics and confectionary products. The pharmaceuticals is selected from the group of analgesic formulations, antihistamine formulations, antibiotics, antacid formulations, breath freshener formulations, allergy/sinus formulations, expectorants, sedatives, sore throat soothers, local anesthetics, laxative formulations, steroids, bronchodilators, prophylactic dental products, cough suppressants, vitamins, herbal extracts, motion sickness preventatives, antifungal formulations, anti-yeast formulations and diet aids.

US 5,637,313 patent discloses a soft, chewable dosage form, including a matrix of hydrogenated starch hydrolysate, a water soluble bulking agent, and a water insoluble bulking agent. This invention includes a method of preparing a soft, chewable dosage form, including the steps of mixing under high shear force, a hydrogenated starch hydrolysate, a water soluble bulking agent, and a water insoluble bulking agent until a uniformly blended matrix is obtained. The active ingredient is selected from the group consisting of magnesium hydroxide, aluminum hydroxide, caffeine, simethicone, vitamin A, vitamin B.sub.12, vitamin D.sub.3 and mixtures are incorporated in the matrix and the dosage form is selected from the group of tablets, caplets and pills.

US 5,641,512 patent discloses a soft gelatin capsule comprising a outer gelatin shell comprising a xanthene derivative and a concentrated liquid core is encapsulated in a outer gelatin shell with at least one solubilized analgesic pharmaceutical active agent in the encapsulated shell. The analgesic active is selected from the group consisting of acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, fenoprofen, flurbiprofen, indomethacin, naproxen, pharmaceutically-acceptable salts thereof and mixtures thereof and additional pharmaceutical active selected from the group consisting of decongestants, expectorants, antitussives, and antihistamines and mixtures thereof.

US 6,258,380 patent discloses a chewable, soft gelatin capsules having a sheath formed of a mixture of a low bloom and a medium bloom gelatins, a plasticizer, water, and preferably a moisture retention agent to enhance the machinability and integrity of the sheath composition; and a fill of an active material in a carrier liquid. The active material is selected from the group consisting of medicaments, vitamins, minerals, fruits, and herbals.

EP 1458367 patent discloses a drug delivery composition comprising a flowable at least water soluble or water swellable film forming matrix, a particular bioeffecting agent uniformly stationed there in and taste masking agent is coated and selected from the group of cellulosic polymers having a particle size of 200 microns or less. The bioeffecting agent is selected from mucolytics, anti tussives, decongestants and anti histamines and combinations there of.

WO 1997/033621 patent discloses a taste masked pharmaceutical composition including one pharmaceutical ingredient and an effective amount of polyhydric alcohol based carrier sufficient to taste mask the pharmaceutically active ingredient and is selected from antacids including aluminium hydroxide and magnesium hydroxide, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, anti-invectives, psychotropic, anti-maniacs, stimulants, anti-histamines, laxatives, decongestants, vitamins, gastro-intestinal sedatives, anti-diarrhoeal preparations, anti-anginal drugs, vasodilators, anti-arrhythmic, anti-hypertensive drugs, vasoconstrictors and migraine treatments, anti-coagulants and anti-thrombotic drugs, analgesics, anti-pyrites, hypnotics, sedatives, anti-emetics, anti-nauseates, anti-convulsants, neuromuscular drugs, hyper-and hypoglycaemic agents, thyroid and anti¬thyroid preparations, diuretics, anti-spasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, anti¬asthmatics, bronchodilators, expectorants, cough suppressants, mucolytics and anti-uricemic drugs.. The pharmaceutical unit is in a particulate form having a particle size of from approximately 0.1-250microns.

WO 2004/052345 patent discloses a taste masking coating composition comprising a copolymer of acrylate and methacrylate with a quaternary ammonium group in combination with sodium carboxy methyl cellulose and a polyvinyl alcohol-polyethylene glycol copolymer. The ratio of acrylate and methacrylate to the polyvinyl alcohol-polyethylene glycol is about 1:2 to 1:3. the active agent is selected from the antitussives, cough suppressants, expectorants, mucolytics and vitamins.

US 2007/0292501 patent discloses a chewable soft gelatin capsule, comprising; a chewable soft gelatin shell comprising: gelatin; a plasticizer that is not xylitol; xylitol; water; and a fill material encapsulated within said chewable soft gelatin shell, comprising an active agent and, optionally, an acceptable carrier. Where in active agent is selected from mixed tocopherols and carrier is selected from rice bran oil or bees wax.

IN 511/MUM/2008 patent discloses a chewable/or twist-off soft gelatin capsule which comprises: a) a soft gelatin shell composition which comprises about 20-40% gelatin; about 25-45% water; about 15 to 35% plasticizer and about 5 to 20% of starch; and wherein said shell encloses b) a soft gelatin capsule fill material.

WO/2004/066925A3 patents discloses a dispersion of crystals or granules of active substance in a lipophilic vehicle, said crystals or granules being coated by a coating for taste masking purposes. The invention also it concerns unit dosage forms and preferentially chewable or fast dissolving soft gelatin capsules filled with said dispersion as well as process for manufacturing same and the active substance is selected from dextromethorphan hydrobromide and Ibuprofen.

US 7,763,276 patent discloses a method of chewable soft capsule comprising a chocolate base comprising cacao butter to produce a fill material and hardness of not more than 47kgs and producing a shell. Shell was filled with material drying at a temperature of 30-40°C for 5-64 hours and finally fill material are homogenized with each other to produce the soft capsule. The drug is selected from the group consisting of an antipyretic analgesic drug component, a rhinitis drug component, an antitussive expectorant drug component and a vitamin component as well as a combination thereof.

IN 240638 patent discloses a 'twist off chewable soft gelatin capsule defined by a shell-wall enclosing a medicament, said shell-wall having at least one neck region and bulbous region extending from the neck region and said shell-wall being made of a composition comprising water being 8 to 13% in the final composition, gelatin of bloom strength 120 to 250 and a plasticizer formulation comprising glycerin and sorbitol, the ratio of the quantity of plasticizer to the quantity of gelatin being in the range of 1:1.8 to 1:2.1 and the ratio of quantity of sorbitol to glycerin being in the range of 0:17 to 1:2.5, the composition including sweeter being 0.01 to 0.25% and a preservative being 0.2 to 0.3% of the composition.

The above prior arts disclose various technologies and formulations of liquid formulations of taste masking drugs. None of the above prior-arts did not disclose about chewable softgel capsule dosage form of mucolytic agents. The current available dosage forms of mucolytic agents i.e Capsules & solutions/syrup, the capsule dosage form have a difficulty for geriatric people and in case of syrup formulations have a difficulty of carrying the bottle along with them during traveling and need of water for every consumption of dose. So there is need to develop chewable soft gelatin capsule dosage forms for mucolytic agents, where the dosage form can be taken by geriatric people as well can carry easily without requirement of water for consumption. The present inventors have developed chewable soft gelatin dosage form by filling unpleasant drug along with other excipients.

Chewable gelatin capsules offer excellent mouth feel and chewing experience as compared with other chewable dosage forms. Chewable soft gels are suitable for pediatrics and also convenient for adults because they can be taken easily on the run without the need of water and also suitable for people who really can't swallow the tablets and capsules.

SUMMARY OF THE INVENTION

The present invention provides soft gelatin capsule dosage form of mucolytic agents.

The present invention also provides process for preparing soft gelatin capsule dosage form of mucolytic agents.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of the present invention is soft gelatin capsule dosage form of mucolytic agent.

Soft gelatin capsule dosage form of mucolytic agent of the present invention comprises at least one mucolytic agent, one or more pharmaceutically acceptable excipients.

Mucolytic agents according to the present invention may be selected from acetylcysteine, Erdosteine, Bromheksin, Carbocisteine and Guiafenesin or pharmaceutically acceptable salts thereof.

One or more pharmaceutically acceptable excipients selected from acidulants, flavoring agents, suspending agents, diluents and sweetening agents and combinations thereof.

Acidulants are additives that give a sharp taste to foods and also assist in the settling of gels and act as preservative. Suitable acidulants according to the present invention are selected from citric acid anhydrous, acetic acid, fumaric acid, malic acid, lactic acid and combinations thereof.

Suitable flavoring agents used according to the present invention may be selected from essential oils and oils derived from plants and fruits such as citrus oils, forest fruit flavor, fruit essences, peppermint oil, spear mint oil, clove oil, orange oil, anise oil and combinations thereof.

Suitable suspending agents used according to the present invention may be selected from Lecithin-alcolec, alginates, methyl cellulose, xanthan gum, acacia, carageenan and combinations thereof.

Suitable diluents used according to the present invention may be selected from coconut oil, sunflower oil, Hydrogenated vegetable oil and combinations thereof.

Sweetening agents used according to the present invention may be selected from sucralose, xylitol, sweefil, sweegel, saccharine, sorbitol, maltilol, aspartame and combinations thereof.

Sucralose is used as sweetening agent in pharmaceuticals, food and beverages. It has a sweetening power of approximately 300-1000 times that of sucrose and relatively stable material. Xylitol is a naturally occurring polyol substitute and acts as a bulk sweetening agent. Xylitol is widely used in pharmaceuticals, food products and others like chewing gums.

Suitable encapsulation materials used for capsule shell according to the present invention may be selected from gelatin, hydroxy propyl methyl cellulose, alginates and combinations thereof.

Suitable film forming materials used for capsule shell according to the present invention may be selected from glycerol, propylene glycol, polyvinyl pyrrolidone, acrylates, zein, shellac and acrylamides. Glycerol is a simple polyol compound and widely used in medicinal, pharmaceutical and personal formulations mainly as a means of improving smoothness, providing lubrication and as a humectant. Mainly glycerin is used as a plasticizer of gelatin in the production of soft gelatin capsules.

Suitable disintegrating agents used for capsule shell according to the present invention may be selected from starch potato, pre gelatinized starch, Povidone, crospovidone, sodium starch glycolate, croscarmellose sodium and combinations thereof.

Suitable coloring agents used for capsule shell according to the present invention may be selected from titanium dioxide, iron oxide red, caramel coloring, chlorophyllin, saffron, brilliant blue, tartrazine, sunset yellow and combinations thereof.

Suitable solubilizing agents used for capsule shell used according to the present invention may be selected from water, polyethylene glycol, glycerin, polyprylene glycol and combinations thereof.

In another embodiment of the present invention is process for preparing chewable soft gelatin capsule dosage form of mucolytic agent.

The process for the preparation of chewable soft gelatin capsule dosage form of mucolytic agent comprises optionally sifting of all materials, mixing in blender, and then the mixture is homogenized to form smooth paste and finally homogenized product is filled into capsules.

The present invention is further illustrated by the following non limiting examples:



Brief Method of preparation: Preparation of fill material:

i) Sifted Sucralose, Xylitol, Citric Acid anhydrous, and Carbocisteine through 300 mesh and collected poly bag separately.

ii) Melted Hydrogenated Vegetable oil at 50°C and cool down to room temperature

iii) Added Lecithin, coconut oil and above Melted Hydrogenated Vegetable oil in mixing tank and mixed at 100 RPM for 10 minutes. Further added all the above sifted materials to mixing tank and further mixed at 200 RPM for 10 minutes. Finally added Forest fruit flavor and Orange oil to mixing tank and mixed at 100 RPM for 10 minutes.

iv) Finally the fill mass is passed through 80 mesh and collected separately.

Capsule shell material preparation:
i) Taken Glycerol, sucralose and gelatin in melting tank and added sufficient water and mixed well for 10 minutes ii) Added potato starch, sucralose and sweegel to above tank and mixed for 10 minutes

iii) Switched on the stirrer and stirred till to attain temperature 75°C - 85°C and continued stirring till gelatin completely melted iv) Added Iron oxide red and titanium dioxide to the above gelatin solution and mixed well till uniform distribution of colors and finally maintain temperature between 55°C and 65°C. Filling:

The above fill material is filled into above capsule shell material using soft gelatin capsule machine.

We Claim:

1. Chewable soft gelatin capsule dosage form of mucolytic agents.

2. Chewable soft gelatin capsule dosage form as claimed in claim 1, wherein mucolytic agents are selected from Acetylcysteine, Erdosteine, Bromheksin, Carbocisteine and Guiafenesin or pharmaceutically acceptable salts thereof.

3. Chewable soft gelatin capsule dosage form as claimed in claim 1, wherein the dosage form comprises acidulants, flavoring agents, suspending agents, diluents and sweetening agents and combinations thereof.

4. Acidulants as claimed in claim 3, wherein acidulants are selected from citric acid anhydrous, acetic acid, fumaric acid, malic acid, lactic acid and combinations thereof.

5. Flavoring agents as claimed in claim 3, wherein flavoring agents are selected from essential oils and oils derived from plants and fruits such as citrus oils, forest fruit flavor, fruit essences, peppermint oil, spear mint oil, clove oil, orange oil, anise oil and combinations thereof.

6. Suspending agents as claimed in claim 3, wherein suspending agents are selected from Lecithin, alginates, methyl cellulose, xanthan gum, acacia, carageenan and combinations thereof.

7. Diluents as claimed in claim 3, wherein diluents are selected from coconut oil, sunflower oil, Hydrogenated vegetable oil and combinations thereof.

8. Sweetening agents as claimed in claim 3, wherein sweetening agents are selected from sucralose, xylitol, sweefil, sweegel, saccharine, sorbitol, maltilol, aspartame and combinations thereof.