TITLE:

Novel Pharmaceutical Process for Chewable formulation

FIELD OF THE INVENTION:

The present invention relates to a novel process for chewable solid oral formulation in the form of tablet comprising therapeutic compositions containing iron for oral use, and usually administered to people suffering from iron deficiency. The oral administration of therapeutic ferrous iron as the sulfate, citrate and Fumarate.etc, for use in treating iron deficiency anemia is well known. Of the various forms of ferrous salts, ferrous calcium citrate is generally preferred and well-tolerated. Chewable tablets are widely preferred for patients who have difficulty in swallowing conventional tablets or capsules. This invention pertains to a process and steps involving coating the active ingredients with suitable polymers for taste masking purpose and targeted release of the medicament.

OBJECTIVE OF THE INVENTION

Powders for reconstitution, suspensions, syrups, elixir solutions, along with conventional tablets are considered to be suitable dosage forms which satisfy the therapeutic need of the patients.
It is worth mentioning, though, that some patients still find inconvenience in taking the liquid dosage forms, in measuring the exact dose accurately or in carrying the package along while traveling. The same problem is encountered with conventional tablets. All the mentioned reasons make chewable tablets one of the excellent alternative choices as an easy method of drug administration for these patients. Iron plays an important role in oxygen and electron transport. Symptoms of iron deficiency are fatigability; other symptoms of anemia include pallor, dyspnea on exertion, palpitation and a feeling of exhaustion. When it comes to the needs of the anemic patients, Ferrous Calcium Citrate which is ferrous calcium salt of citric acid is a well-tolerated compound, and a hematinic used in treating iron deficiency anemia is a well-known compound having a chemical structure Folic acid (also known as folate, vitamin M, vitamin B9) chemically called as (2S)-2-[(4-{[(2-amino-4-hydroxypteridin-6-yl) methyl] amino} phenyl) formamido] pentanedioic acid, is a compound having the chemical structure It is especially important in aiding rapid cell division and growth, such as in infancy and pregnancy, and also protects against a number of congenital malformations, including neural tube defects.

Ferrous calcium citrate is a tasteless drug, however giving a mild unpleasant metallic odor and folic acid is naturally a drug with that of bitter or unpleasant taste in mouth, Several patents propose several optimized process approaches, in the prior art which help in formulating an effective solid oral chewable formulation which is taste-masked in the form of tablet All the methods in the patents of the prior art focus mainly on the process for developing an effective solid oral chewable tablets and for effective taste masking, but yet are complicated process and does not display or display characteristics of mild palatability and mouth feel. Objectionable taste and/or mouth feel continues to be a problem and make it less likely to obtain dosage compliance by the user. Palatability and "mouth feel" are among the most important characteristics to be considered in providing an effective chewable tablet formulation for an active medicament or nutritional supplement. Many bitter drugs give unpleasant taste and unacceptable mouth feels due to the grittiness or chalkiness of the active moiety or their chemical nature. Despite these disclosures there is an ongoing need for a chewable tablet delivery system, that is pleasant tasting and provides improved mouth feel qualities. There is also an ongoing need for a chewable tablet delivery system that is pleasant tasting has acceptable mouth feel, and that is suitable for administration to persons having diabetes or hypoglycemia, and does not promote tooth decay or dental caries. Hence there arises a need for developing a process which is reasonably economical for the formulation of oral solid chewable tablets of especially which are taste-masking, gastro-resistant and provide palatability and effective mouth-feel.

In the present embodiment, the objective of invention is to provide a novel process for producing a formulation of Chewable dosage form in the form of tablet with effective taste masking of bitter drugs such as ferrous calcium salt of citric acid and Folic acid. The formulation comprising multilayer polymer coating with an anionic Co-polymer preferably with Methacrylic acid – Ethyl acrylate copolymer and an cationic Copolymer preferably Basic Butylated Methacrylate Copolymer in the form of dispersion or solution using a suitable solvent system. It is another objective of the invention to provide a novel process for formulating a chewable tablet which provides effective taste-masking, along with good palatability and mouth feel, comprising a combination of Mannitol, Maltodextrin and sorbitol. It is yet another objective of the invention to provide a process for formulating stable tasteless therapeutic compound containing chemically bound calcium and iron in the ferrous state which upon oral administration are utilized normally without mutual interference between the calcium and iron and without gastro-intestinal disturbances, constipation or diarrhea. In addition to the foregoing, chewable tablets have several advantages that make them the method of choice in delivering certain types of therapeutic agents or actives to an even greater population. One such advantage is that certain types of tablets, because of the large size of the dosage, must be unusually large and, therefore, difficult to swallow. Furthermore, patient compliance with the prescribed therapy, such as antacid treatment, is enhanced by the use of smaller, more convenient tablets that may be consumed when it may be inconvenient to swallow pills.

Excipients when added to chewable tablets must not only be inert in respect of the active moiety, but also preferably provide pleasant mouth feel and/or prevent tooth packing, grittiness, and the like, without imparting any unpleasant characteristics to the tablets as they are chewed.
The use of polyols such as mannitol, sorbitol, xylitol and lycasin, Nutritive sweeteners such as maltodextrin and maltose and non-saccharide sweetener such as aspartame, does not promote tooth decay and prevents dental caries, as they tend to maintain proper mineralization of tooth. Polyols such as mannitol and sorbitol are sugar alcohols derived from monosaccharides, and are not metabolized by cavity producing bacteria and hence they are non-cariogenic and maintain tooth mineralization./EFS/\ Journal 2011 ;9(4):2076)]. Sorbitol can sweeten saliva without causing a drop in the critical salivary pH, which is usually altered by the bacterial fermentation. Maltodextrin, an oligosaccharide is found to have no potential for dental caries [Riva Touger-Decker and Cor van Loveren; Sugars and dental caries; Amen Jour. Clin. Nutr. October 2003 vol. 78 no. 4 881S-892S] Aspertame, non-saccharide sweetener does not cause dental caries and effectively safe for use. Aspertame, in a study on rat pups, inoculated with Streptococcus and fed basal diet with varying concentrations of sucrose and aspartame and aspartame alone. The results displayed that sucrose with aspartame decreased caries formation, whereas the aspartame alone did not cause any caries formation [Sumitra Das, DDS, MS Arup K. Das, DDS, MD et. al; Aspartame and dental caries in the rat; Pediatr Dent 13:217-20, 1991] The process in the present invention details about formulating an effective taste-masked chewable solid oral dosage form, in the form of tablet comprising active ingredients which are metallic drug such as Ferrous Calcium Citrate and Folic acid, which impart an objectionable and unpleasant taste to the dosage form.

The dosage form is being coated with a composition involving the combination of anionic copolymer and a cationic copolymer for effective taste masking& gastro resistance. Further the formulation incorporates the use of combination of diluents such as Mannitol, Maltodextrin and Sorbitol in various stages of granulation process for providing good palatability, enhanced taste and better mouth feel. Finally the dosage form is being seal-coated with Opaglos for moisture barrier over the tablet followed by film coating, comprising a sweetening agent and a flavoring agent. The granulation in the present invention is being carried out by the method of wet granulation separately for Ferrous calcium citrate and Folic acid along with selected suitable excipients before subjecting to Prelubrication by combining both the granulates, followed by the lubrication process, and subsequent seal coating and coating process The overcoming of complexities in the present embodiment of the invention in the granulation stage for various parameters such as bulk density, tapped density, compressibility index, Hausner's ratio, and Loss on drying are optimized by subsequent changes in the excipient quantities during various stages of formulation to provide effective dosage unit of chewable tablet. The process parameters in the present invention such as temperature, air pressure, drying time, pump rotations, flap positions, granulation time, mixing time and drying time, The dosage unit parameters like weight variation, uniformity of weight, thickness, length, width, hardness, friability, The coating parameters such as drying time, spraying rate, Pan RPM, air flow, pressure and distance between spray gun and tablet bed were overcome by monitoring and optimization of the above mentioned parameters.

The technicality of the process in the present invention for the manufacturing of the chewable tablet for effective taste masking, and good palatability and mouth feel involves the coating of core granules of active drug by anionic and cationic copolymers which are pH dependent by multi-layer coating technology followed by addition of combination of diluents with ability to impart effective palatability and mouth feel, and other suitable excipients and subjecting to compression into tablet, further followed by seal coating and film coating comprising a sweetening and a flavoring agent . The steps involved in the said technical process are as follows:

a) First active ingredient Ferrous calcium citrate is being coated with Anionic copolymer preferably with Methacrylic acid - Ethyl acrylate copolymer and suitable chosen excipients for gastro-resistant activity

b) The active drug gastro-resistant granulates are then coated with Cationic polymer preferably with Basic Butylated Methacrylate Copolymer giving a granules with taste masking and acid resistant activity.

c) The second active ingredient Folic acid being granulated with chosen suitable excipients preferably Shellac as binder to promote stability of folic acid as moisture barrier

d) Folic acid granulates and Granulates with Ferrous calcium citrate having gastro-resistant and taste masking effect blended with other suitable excipients such as combination of diluents like mannitol, sorbitol and maltodextrin for palatability and mouth feel effect, and preferably with other excipients such as disintegrant, Acidulating agent, alkalizer, sweetening agent, flavoring agents and glidant.

e) Lubricating the granule mass with Magnesium Stearate.

f) Compressing the granulate lubricated mass into suitable chewabie tablets

g) Seal coating of the tablets with moisture barrier coating polymer such as Opaglos NA 7150.

h) Film coating of seal coated tablets, the film coat comprising of a sweetening agent and a flavoring agent.

In the present embodiment of the invention, the taste of the chewabie tablet is dominated by the active ingredients preferably Ferrous calcium citrate imparting a metallic odor due to the chemical nature of the salt of citric acid, which is further made disagreeable and objectionable by the addition of Folic acid, which has a natural bitter or unpleasant taste in mouth. In the present embodiment of the invention, though the taste of the Ferrous calcium citrate is being masked by coating with Cationic polymer, Folic acid added in the later stages of granulation imparts an unpleasant taste. In the present invention, in order to avoid the unpleasant folic acid taste, the combined granulate mass of gastro-resistant taste-masking Ferrous calcium citrate granules and Folic acid granules are blended with suitable combination of diluents such as sorbitol, mannitol and maltodextrinfor mouth feel and palatability along with a sweetening agent such as Aspartame and combination of flavoring agents such as Mango Green flavor and Spearmint flavor in combination with a disintegrant such as sodium starch glycollate.
Other excipients such as acidulating agents, alkalizer, glidant and lubricant are added.
The tablet is than seal coated to be moisture proof, followed by film coating with a sweetening agent and a flavoring agent.

NOVELTY:

The process in the present embodiment of the invention provides a reasonable novel approach for formulating a chewabie tablet, especially imparting good palatability and mouth feel along with effective taste masking nature of the dosage unit. The process in the present embodiment of the invention in which the granules and particles of active substance being coated first with coating composition containing a gastro-resistant coat of a pH dependent anionic polymer preferably Methacrylic acid - Ethyl acrylate copolymer along with suitable excipients followed by coating with a pH dependent Cationic polymer preferably Basic Butylated Methacrylate Copolymer, which imparts taste-masking effect. The process in the present invention which involves manufacturing the tablet core with a novel combination of various diluents, such as sorbitol and mannitol in combination with other excipients such as acidulating agent, alkalizer, sweetening agent, flavoring agent, glidant and a lubricant followed by moisture barrier coating and a water soluble film coating with an oligosaccharide, sweetener and a flavor. The process in the present embodiment of the invention relates to a dosage form involving multi-layer coating of the granules and particles which on disintegration from the said chewable tablet does not impart unpleasant taste or does not release the drug in the buccal cavity and is taste-masked, which is followed by the release of the active moiety in the duodenum enhancing the iron absorption.

SUMMARY

In one embodiment, the present invention provides a process for formulating chewable tablets, comprising coating with an pH dependent anionic copolymer and a cationic copolymer which are preferably to impart gastro-resistant activity and effective taste masking effect. In another embodiment of present invention relates to a novel process for formulating chewable tablet with improved taste-masking effect and better palatability and mouth-feel property. More particularly the present invention provides a process for the formulation of novel excipient base for a chewable tablet comprising excipients such as diluents like sorbitol, mannitol and Maltodextrin in combination with acidulating agent, alkalizer, sweetening agent, flavoring agent, glidant and a lubricant, wherein the novel excipient base provides for an improved taste, stabilization and effective mouth feel qualities. At the outset of the description that follows it is to be understood that ensuring description illustrate only the particular form of this invention. However such particular form is only a exemplary embodiment without intending to imply any limitation on the scope of the invention. Accordingly the description is to be understood as an exemplary embodiment and reading of the invention is not to be taken restrictively.
The forgoing description outlined is rather broadly preferred and alternative future of the present invention, so that those skilled in the art may better understand the detailed description of the invention that follows.

Additional feature of the invention will be described hereinafter that form the subject of claims of the invention. Those skilled in the art should appreciate that they can readily use the disclosed consumption and specific embodiment as a basic for designing and modifying other structure for carrying out the same purposes of the present invention. Those skilled in the art should realize such equivalent consumption do not depart from the spirit and scope of the invention in its broadest form. Now the invention will be described in detail in the following description.
The nature of the invention and the manner in which the invention is to be performed are clearly described in the following description. The diagram of the process of the invention and the processing steps involved in the said invention is shown in the diagram accompanying the specification.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for an oral pharmaceutical formulation of chewable tablet, comprising coating of active ingredients with a pH dependent anionic polymer and a pH dependent cationic polymer, preferably to impart gastro-resistant activity and effective taste masking effect. In an embodiment of the present invention relates to a novel process for formulating chewable tablets with improved taste-masking effect and better mouth palatability and mouth-feel property. More particularly the present invention provides a process for the formulation of novel excipient base for a chewable tablet comprising excipients such as diluents like sorbitol, mannitol and Maltodextrin in combination with acidulating agent, alkalizer, sweetening agent, flavoring agent, glidant and a lubricant, wherein the novel excipient base provides for an improved taste, stabilization and effective mouth feel qualities. It is yet another objective of the invention to provide a process stable tasteless therapeutic compound containing chemically bound calcium and iron in the ferrous state which upon oral administration are utilized normally without mutual interference between the calcium and iron and without gastro-intestinal disturbances, constipation or diarrhea.

As used herein the term "Palatability" refers to the property of the chewable tablet being acceptable in relation to taste and odor in the buccal cavity As used herein the term "Mouth-feel" refers to the interaction of the dosage unit with the mouth usually evaluated by perception through mastication and after-taste Palatability and mouth-feel of a dosage unit, especially of a chewable tablet are provided usually by effective taste masking of bitter active ingredients by various pharmaceutical techniques, employed in the prior art such as addition of taste-masking excipients, microencapsulation, particle coating, film coating with suitable polymer, coated liquiflash particles and shear-form floss particles, coated roto-granules, use of sweeteners and flavors, ion-exchange resins and use of alternative metallic salts. Employed in the art, in the present embodiment of the invention is process relating to the use of Multilayer particle coating technology, comprising coating with Methacrylic acid Copolymer and a Methacrylate Copolymer, which is a derivative of dimethylaminoethyl methacrylate and neutral methacrylic acid esters, involving the use of Fluid Bed Processor. It is yet another objective of the invention to provide a process for formulating stable tasteless therapeutic compound containing chemically bound calcium and iron in the ferrous state which upon oral administration are utilized normally without mutual interference between the calcium and iron and without gastro-intestinal disturbances, constipation or diarrhea.

The present invention also relates to the process of formulating chewable tablet with effective taste masking of bitter active ingredients which are selected to be an iron supplement mostly hematinic and a nutritional supplement. Preferably the bitter active ingredients are Ferrous calcium citrate (Hematinic) and Folic acid (Nutritional supplement) The present invention relates to the process for use of other excipients such as diluents, binders, Acidulating agent, alkalizer, sweetening agent, flavoring agent, coloring agent, glidant and a lubricant. The present invention also relates to a process of barrier coating of the chewable tablets with a suitable seal coat for moisture barrier, and a film coating comprising a coating polymer, an oligosaccharide, a sweetener, a flavor, an opacifier, colorant and a glidant dispersed in a mixture of suitable solvents. The polymers for multi-layer coating of the chewable tablets of the present invention are selected to be a combination of pH dependent Methacrylic acid Copolymer and a Methacrylate Copolymer, which is a derivative of dimethylaminoethyl methacrylate and neutral methacrylic acid esters, Methacrylic acid Copolymer for the present invention is selected from a group of anionic copolymers, preferably based on Methyl acrylic acid and ethyl acrylate, intended to be preferably dispersible in water so as to take advantage of aqueous formulation techniques and has a rapid rate of dissolution at a pH of about 5.5. Methacrylic acid Copolymer most preferably used here is Methacrylic acid - Ethyl Acrylate Copolymer, commercially available as Eudragit L Grade, insoluble at a pH rage of 3-5, providing immediate release upon reaching the duodenum that have solubility above pH 5 and showing gastric - resistance in the stomach.

Methacrylic acid Copolymer based on Methyl acrylic acid and ethyl acrylate, may have a structural formula such as Methacrylate Copolymer, for the present invention is selected from a group of cationic copolymers, which are derivatives of dimethylaminoethyl methacrylate and neutral methacrylic acid esters, and which are based on butylated methacrylate group intended to be water soluble via salt formation with acids, thus providing gastro-soluble film coatings, and providing taste masking effect in the neutral pH of saliva in the buccal cavity. Methacrylate Copolymer, most preferably used here is basic butylated Methacrylate Copolymer, commercially available as Eudragit E Grade, swells and is permeable in water and buffer solutions above pH 5. It is soluble in gastric fluid below a pH of 5. The Cationic Methacrylate copolymer with a dimethylaminoethyl group preferably with butylated Methacrylate may have the following structural formula such as where: R1 = R3 = CH3 R2 - CH2CH2N(CH3)2 R = CH3, C4H9.
The diluents used for the present invention is selected from a group of polyols such as sorbitol, mannitol, xylitol and lycasin which are sugar alcohols derived from monosaccharides and Nutritive sweeteners such as maltodextrin,maltose, maltilol dextrose and glucosesuch as sorbitol, mannitol, xylitol and lycasin which are sugar alcohols derived from monosaccharides, Most preferred polyols used here is Sorbitol and Mannitol. Sorbitol, also known as can sweeten saliva without causing a drop in the critical salivary pH, which is usually altered by the bacterial fermentation. Mannitol, a sugar alcohol derived from mannose by reduction, does not cause dental caries and enhances the mouth-feel.

Most preferred Nutritive sweetener used here is maltodextrin, which is an easily digestible non-sweet oligosaccharide, consisting of D-glucose units, have no effect on dental caries provides soft mouth-feel for the chewable tablet Binders used for the present invention is selected from a group of excipients such as Microcrystalline cellulose, Hydroxypropyl cellulose, Hydroxyethyl cellulose, Hydroxy proyl Methyl cellulose and Polyvinylpyrrolidone. Most preferred binder used here is Polyvinyl Pyrolidone, (Povidone - K 30), preferably as drybinder and preferably in combination with Shellac, which is used for providing moisture barrier, preferably with a suitable solvent such as Isopropyl Alcohol. Acidulants used for the present invention is selected from a group of excipients such as citricacid, lactic acid, malic acid, adipic acid, benzoic acid, fumaric acid, preferably citric acid known for its pH-lowering nature and to impart flavor and preservative action. Alkalizer used for the present invention is selected from the group of excipients such as sodium bicarbonate, sodium citrate, potassium citrate, calcium carbonate and calcium acetate, preferably sodium citrate, for raising the pH of saliva facilitating the taste masking nature of Cationic Methacrylate copolymer (Eudragit E grade). Disintegrants used for the present invention is selected from a group of excipients such as maize starch, sodium Carboxymethylcellulose, Calcium Carboxymethylcellulose, sodium starch glycollate, crospovidone, preferably sodium starch glycollate for swelling and breakdown of the chewable tablet into multiple large particles on mastication in mouth.

Sweeteners used for the present invention are Non-saccharides such as Sucralose, Aspartame, Saccharin and Neotame. They are non-cariogenic and maintain tooth mineralization preventing dental caries, and are not metabolized by cavity producing bacteria, which usually produce acid by fermentable sugars. Preferred for the present invention is Aspartame, flavor. Aspartame, a methylester of the aspartic acid/phenylalanine dipeptide is a non-saccharide sweetener, which helps in maintaining tooth mineralization preventing dental caries. The flavoring agent for the present invention are selected from a group of flavors such as citrus flavor, banana flavor, mango flavor, mint flavor, spearmint flavor, and mint flavor, preferably spearmint flavor and mango flavor used in combination or individually to impart flavor to the chewable tablet for better mouth-feel and palatability, in combination with menthol, for inducing minimal cooling effect. Coloring agents used for the present invention are selected from a group of excipients such as Tartrazine Yellow, Brilliant Blue, red iron oxide, yellow iron oxide, Titanium dioxide, preferably tartrazine yellow, brilliant blue and titanium dioxide individually or in combination thereof.The glidants used for the present invention are selected from a group of excipients such as sodium steryl fumerate, magnesium trisilicate, powdered cellulose, talc, starch, colloidal silicon dioside, preferably colloidal silicon dioxide, individually or in combination thereof.

The lubricants used for the invention are selected from magnesium Stearate and stearic acid, preferably magnesium Stearate. In the present embodiment of the invention, the process for formulating the chewable tablet which is taste masked and provides effective mouth feel, technically comprises the following steps such as:

a) First granules of active ingredient Ferrous calcium citrate is being coated with Anionic copolymer preferably with Methacrylic acid - Ethyl acrylate copolymer and suitable chosen excipients for gastro-resistant activity

b) The active drug gastro-resistant granulates are then coated with Cationic polymer preferably with Basic Butylated Methacrylate Copolymer giving a granules with taste masking effect.

c) The second active ingredient Folic acid being granulated with chosen suitable excipients preferably Shellac as binder to promote stability of folic acid as moisture barrier

d) Folic acid granulates and Granulates with Ferrous calcium citrate having gastro-resistant and taste masking effect blended with other suitable excipients such as combination of diluents like mannitol, sorbitol and maltodextrin for palatability and mouth feel effect, and preferably with other excipients such as disintegrant, Acidulating agent, alkalizer, sweetening agent, flavoring agents and glidant.

e) Lubricating the granule mass with Magnesium Stearate.

f) Compressing the granulate lubricated mass into suitable chewable tablets

g) Seal coating of the tablets with moisture barrier coating polymer such as Opaglos NA 7150.

h) Film coating of seal coated tablets, the film coat comprising of a sweetening agent and a flavoring agent.

Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, parameters, or reaction conditions used herein are to be understood as modified in all instances by the term "about". In an embodiment, the invention provides a process for the preparation of Gastro-resistant granulation of chewable tablet of the active ingredient from herein referred to as "Active moiety 1 ".preferably ferrous calcium Citrate, with Methacrylic acid copolymer and suitable chosen excipients for gastro-resistant activity. The steps are as follows:

a) Accurately weighing and dispensing "active Moiety 1" with a diluent (Maltodextrin)and shifting it through Sieve no 30 to 80# (preferably 40#), made of Stainless Steel., from hereto referred as 'S.S',

b) Dissolving accurately weighed colorants (Tartrazine Yellow and Brilliant Blue) in water, followed by Methacrylic acid copolymer (anionic copolymer) of Eudragit L Grade slowly into the above solution and stir for approximately 5-20 minutes.

c) The polymer powder of Methacrylic acid copolymer is thoroughly wetted and lump or foam formation is avoided, the above dispersion used as the binder solution.

d) Charging the above shifted material of "active moiety 1" and Maltodextrin into a fluid bed processor referred here to as "FBP"and mix for 5-20 minutes, with flap positions being around 10 - 50% without heater.

e) Spraying of the above binder solution of Methacrylic acid copolymer on to the mixed blend by monitoring the process parameters such as inlet temperature, product temperature, exhaust temperature, atomization air pressure, RPM flap positions, specified as below

f) Inlet Temperature is maintained about 35-70° C, and the product temperature is maintained about 25-40° C, and exhaust temperature is maintained about 25-45° C.

g) The atomization air pressure is maintained about 1.5 to 4 Bar, and peristaltic pump is maintained at about 20 - 80 RPM, and the flap position is maintained about 20 - 70%.

h) After completion of spraying, wet mass is raked and subjected to drying in Fluidized Bed Processor. Inlet temperature is maintained about 40 to 70°C, Product temperature is maintained about 30 to 45°C, Exhaust temperature is maintained about 30 to 50°C.

i) The flap position at about 20 to 70 % for about 20-60 minutes. LOD Limit is maintained about 1.5 to 3.0 %w/w.

j) Shifting the dried granules through S.S Sieve No. 16 to 30# (preferably 20 #), using vibratory shifter.

k) Passing the granule retains through multi-mill, fitted with S. S. 1.0 mm to 2.5mm (preferably 1.5mm)Screen, with knives forward at low to moderate speed, followed by milled granules passed through S.S Sieve No 16 to 30# (preferably 20 #), finally obtaining the Gastro-resistant granulates. The invention further provides a process for the preparation of taste masking granules of the chewable tablet of the "active moiety 1" by using the gastro-resistant granulates of the "active moiety 1", comprising coating the gastro-resistant granules of "active moiety 1" with Methacrylate copolymer and suitable chosen excipients for taste-masking activity. The steps are as follows:

a) Dissolving accurately weighed Methacrylate copolymer (cationic copolymer) of Eudragit E Grade in a suitable solution. The binder solution preferably being suitable non-aqueous solvent, more preferably Ethanol.

b) Charging the Gastro-resistant granules of "active moiety 1" into the 'FBP' followed by spraying of the Ethanolic solution of Methacrylate copolymer (cationic copolymer) on to the Gastro-resistant granules of "active moiety 1" by monitoring the process parameters such as inlet temperature, product temperature, exhaust temperature, atomization air pressure, RPM, flap positions, as specified below

c) Inlet Temperature is maintained about 25-40° C, and the product temperature is maintained about 20-30° C, and exhaust temperature is maintained about 20-35° C.

d) The atomization air pressure is maintained about 1.5 to 4 Bar, and peristaltic pump is maintained at about 20 - 80 RPM, and the flap position is maintained about 20 - 70%.

e) Raking the wet mass and drying in 'FBP'. By monitoring process parameters as specified below

f) Inlet temperature is maintained about 30-40°C, Product temperature is maintained about 20-30°C, Exhaust temperature is maintained about 20-35°C

g) The flap position at about 20 to 70 % for about 20-60 minutes. LOD Limit is maintained about 1.5 to 3.0 %w/w.

h) Shifting the dried granules through S.S Sieve No. 16 to 30# (preferably 20 #), using vibratory shifter.

i) Passing of Granule retains through multi-mill, fitted with S. S. 1.5mm Screen, with knives forward at low to moderate speed, followed by milled granules passed through S.S Sieve No 16 to 30# (preferably 20 #), finally obtaining the Taste - masking layer above gastro-resistant granulates giving taste-masked granulates.

The invention of present embodiment provides a process for granulation for the said chewable tablet with another active ingredient, preferably folic acid, from here in referred to as "Active Moiety 2", comprising suitable excipients and a binder solution made to provide moisture barrier, preferably made with shellac, the steps are as follows:

a) Accurately weighing and dispensing "active moiety 2" with diluent and a dry binder such as Mannitol and Povidone K-30, followed by shifting through S. S. Sieve No. 30 to 60# (preferably 40#).

b) Dispensing moisture barrier excipient (Shellac) and adding to a suitable solvent. The suitable solvent preferably being Isopropyl Alcohol. Followed by soaking for about 6 to 24 hours, and after used as a binder solution.

c) Charging the above shifted material of "active moiety 2" into rapid mixer granulator referred hereto as "RMG", followed by granulation by monitoring process parameters such as Mixing time, Binder addition, Speed rate,as specified below

d) Initial Mixing time for about 5 to 20 minutes at slow speed. Followed by addition of 50-80 % of the binder to dry mix present in RMG, under slow speed for 2 to 5 minutes.

e) Raking the wet mass in RMG, if necessary. Adding remaining quantity of binder, continue mixing for 4 - 8 minutes with impeller at slow and chopper slow until desired wet mass obtained.

f) Discharging the wet mass of into FBP bowl by opening the discharge port and operating the impeller at slow rate.

g) Drying the granules comprising 'Cycle 1' and 'Cycle 2'

h) Cycle - 1: Air drying the granules in FBP bowl, without application of heat for about 10-30 Minutes followed by Cycle - 2.

i) Cycle - 2: Raking the wet mass and continuing drying in FBP by monitoring the process parameters such as inlet temperature, drying time and LOD

j) Inlet temperature maintained of about 40 - 70°C for about 20-60 minutes, with in the LOD limit of about 1.0-3.0%

I) Shifting the dried granules through S.S Sieve No. 20 to 60#(preferably 40#), using vibratory shifter.

k) Passing of Granule retains through multi-mill, fitted with S. S. 0.5 to 2.0mm (preferably 1.0 mm) Screen, with knives forward at low to moderate speed, followed by milled granules passed through S.S Sieve No 20 to 60#(preferably 40#), The obtained granules of Active Moiety 2 are subjected to pre-lubrication with suitable excipients.

The invention further provides a process of combined pre-lubrication and lubrication of the Taste-masked gastro-resistant granules of active ingredients preferably being Ferrous Calcium Citrate, and Folic acid Granules comprising moisture barrier, comprising suitable excipients such as Diluents, disintegrant, Sweeteners, Flavors, acidifiers, alkalizers, a glidant and a lubricant. The processes in the steps are as follows:

a) Accurately weighing and dispensing diluents (Mannitol, sorbitol), disintegrant (Sodium starch glycollate), sweetener (aspartame) and Flavors (Mango and Spearmint flavor), followed by shifting through S.S Sieve. No30 to 100# (preferably 40 #).

b) Accurately weighing and dispensing Acidifier (Citric acid), Alkalizer (Sodium citrate), and a flavor/cooling agent (Menthol), followed by shifting using S.S. Sieve. No. 40 to 120# (preferably80#).

c) Transfer the above sifted materials into the blender containing dried and milled granules of Gastro-resistant, Taste-masked granules of 'Active moiety 1' and Moisture barrier granules of Active moiety 2.

d) Blending for 10 to 30 minutes (preferably 20 minutes) at slow rate. The pre-lubricated blend obtained for lubrication process.

e) Accurately weighing and dispensing lubricant (Magnesium Stearate), followed by shifting through S.S. Sieve No 40 to 100# (preferably 60 #).

f) Transferring into blender containing Pre-lubricated blend and blending for 2-5 minutes

The process of invention in the present embodiment further provides the appropriate limits for the monitoring of blend parameters such as bulk density, tapped density, Carr's compressibility Index, hausner's ratio and Sieve Analysis, the appropriate limits are as follows:

a) Bulk density should be about 0.40 to 0.60 g/cc; Tapped density should be about 0.50 to 0.80 g/cc.

b) Carr's compressibility index should be about 11-20 %, Hausner's ratio should be about 1.12 -1.25

c) On sieve analysis, maximum % retained obtained by retains of granules on S.S. Sieve no 30# NMT 15.0%, and for of S. S. Sieve no 100# NLT 40.0%

In the present embodiment of the invention there is selected a specific shape and size of the upper and lower punches for compression of taste-masked chewable tablets with good palatability and mouth-feel and for commercial and attractive purposes. In the present invention, the Upper Punch dimensions10x8mm to 20x18mm, having preferably 13.21 x 10.88 mm, preferably Mango shaped, punches plain on surface. And Lower Punch dimension10x8mm to 20x18mm, having preferably 13.21 x 10.88 mm, preferably Mango shaped, punches plain on surface, with the speed of compression maintained about 15-30 RPM. The invention of the present embodiment further provides a process of barrier coating of the said chewable tablet for purpose of moisture barrier protection and preventing oxidation, comprising coating with a suitable moisture barrier coat, by using conventional method of coating. In the present invention, the moisture barrier coat is selected from a suitable list of excipients, preferably being shellac, preferably in esterified form, dispersed or dissolved in a suitable solvent, preferably Isopropyl Alcohol.

In the present invention, the moisture barrier coat, preferably shellac is dissolved or dispersed in Isopropyl Alcohol, followed by continuous stirring during the process of coating, on maintaining the process parameters such as:

a) Inlet temperature is about 30-45°C, outlet temperature is about 30-40°C

b) Pan RPM is about 2-6 RPM, with spray rate of about 80-160ml/min.

c) Atomization pressure is about 4-6Kg/cm2, and the distance between tablet bed and spray gun is maintained about 15-25 cm.

d) The final percentage weight build-up on coating may be maintained about 0.2 -2.0%.

In the present embodiment, it is an objective of the invention to provide a process for the film coating of Chewable tablets comprising two active ingredients, further the coating comprising a sweetening agent and a flavoring agent along with other suitable excipients for effective taste-masking, good palatability and enhanced mouth feel properties. In one embodiment, the invention relates to the process for film coating of the said chewable tablets comprising excipients such as coating polymer, plasticizer, sweetening agent, flavoring agent, colorant, glidant and opacifier, in alone or in combinations of the same type, dispersed or dissolved in a suitable solvent or a mixture of solvents The coating polymer for the present invention is selected from a group of cellulose based derivatives such as Hydroxypropyl Cellulose (HPC), Hydroxyethyl Cellulose (HEC), Hydroxy Propyl Methyl Cellulose (HPMC), preferably chosen is HPMC, for its effective film forming properties and solubility in water The plasticizer for the present invention is selected from a group of excipients such as triethyl citrate, acetyl triethyl citrate, polyethylene glycol and propylene glycol. Preferably chosen is polyethylene glycol and most preferably chosen does PEG 6000, due to its high molecular weight and effective plasticization of the film comprise other excipients.

Sweeteners used for the present invention are Non-saccharides such as Sucralose, Aspartame, Saccharin and Neotame. They are non-cariogenic and maintain tooth mineralization Preferred for the present invention is Aspartame, flavor. Aspartame, a methylester of the aspartic acid/phenylalaninedipeptide is a non-saccharide sweetener, which helps in effective taste-masking and to induce mouth-feel property. The flavoring agent for the present invention are selected from a group of flavors such as citrus flavor, banana flavor, mango flavor, mint flavor, spearmint flavor, and mint flavor, preferably spearmint flavor to impart flavor to the chewable tablet for better mouth-feel and palatability, Coloring agents used for the present invention are selected from a group of excipients such as Tartrazine Yellow, Brilliant Blue, red iron oxide, yellow iron oxide, Titanium dioxide, preferably tartrazine yellow, Brilliant blue and titanium dioxide (used as an opacifier) individually or in combination thereof, In the present embodiment of the invention, the process for taste-masking film coating for said chewable tablet involves the use of a suitable hydro-alcoholic preparation, preferably the ratio of Isopropyl alcohol: Water of 1:1, to 1:4, most preferably in the ratio of 1:2.5

In the present embodiment of the invention, the process for taste-masking film coating is performed based on monitoring of process parameters such as:

a) Inlet temperature is about 35-50°C, outlet temperature is about 35-40°C

b) Pan RPM is about 2-6 RPM, with spray rate of about 80-160ml/min.

c) Atomization pressure is about 4-6Kg/cm2, and the distance between tablet bed and spray gun is maintained about 15-25 cm.

d) The final percentage weight build-up on coating may be maintained about 1-5%.

In the present invention, there is provided the appropriate limits of the dosage unit physical parameters, which may be maintained within the final product obtained as the effective taste-masking gastro-resistant chewable tablet with good payability and mouth feel properties.

In the present invention, the tablet parameters for the final seal/film coated chewable tablets with appropriate limits, for an optimized product are as follows:

a) The appearance may be as green color tablet, almost as a mango shape, or any other shape with commercial advantage, and as biconvex film coated tablet on both sides

b) The uniformity of the weight may be as per pharmacopoeial limits, not exceeding ± 5%, as the average weight of tablets may be with deviation about ±2 %.

c) The thickness may be about 6.40-7.00mm, and the length is maintained about 12.90 -13.50mm, whereas the width may be about 10.50-11.10mm.

d) The hardness may be about not more than 300N

BRIEF PROCESS

In one particular aspect of the invention, relating to the process of the said chewable tablet dosage form is described in the Example below detailing the various steps, involved in the process for manufacturing of the said dosage unit the accompanying drawings are intended to provide further understanding of invention and are incorporated in and constitute a part of invention. The drawings illustrate an embodiment of invention and together with the description illustrate principle of invention. The drawings should not be taken as implying any necessary limitation on the essential scope of invention. The drawings are given by way of non-limitative example to explain the nature of the invention. For a more complete understanding of the instant invention reference is now made to the following description taken in conjunction with accompanying drawings. The foregoing description is outlined rather broadly preferred and alternative feature of the present invention so that those skilled in the art may better understand the detailed description of the invention that follows. Additional features of the invention will be described hereinafter that form the subject of claims of the invention. Those skilled in the art should appreciated that they can readily use the disclosed conception and specific embodiment as a basis for designing and modifying other structure for carrying out the same purposes of the present invention. Those skilled in the art should realize such equivalent conception do not depart from the spirit and scope of the inventing in its broadest form.

EXAMPLE:

STAGE I: GRANULATION:

PART I: (API GASTRO RESISTANT GRANULATION)

STEP 1. DISPENSING & SIFTING:

Accurately weigh and sieve Ferrous calcium citrate complex, Maltodextrin using 30 to 80# (preferably 40#) S.S. Sieve and collect in the S.S. bin.

STEP 2. BINDER PREPARATION:

Dissolve accurately weighed Tatrazine yellow, Brilliant blue in Purified water. Add the Methacrylic acid copolymer (anionic copolymer) slowly into the above solution and stir for approximately 5 to 20 minutes. Make sure that the powder is thoroughly wetted and lump or foam formation is avoided, the above dispersion used as the binder.

STEP 3. DRY MIXING & GRANULATION:

Charge the above sifted material in the Fluidized Bed Processor. Mix total for 5 to 20 minutes in the Fluidized Bed Processor with the Flap position at 10 to 50% (Target -20%) without heater.
i 1 1 1

STEP 4. DRYING THE GRANULES:

After completion of spraying, rake the wet mass and continue drying the wet granules in Fluidized Bed Processor. Inlet temperature of 40 to 70°C, Product temperature- 30 to 45°C, Exhaust temperature- 30 to 50°C & flap position at 20 to 70 % for 20 to 60 minutes. LOD Limit: 1.5to3.0%w/w.

STEP 5. DRY SIFTING & MILLING:

Pass the dried granules through 16 to 30# (preferably 20 #)Vibro sifter & collect the retains, Pass the retains through Multimill fitted with 1.0mm to 2.5mm (preferably 1.5mm screen) with knives forward at slow speed & Collect in a poly bag. Pass the milled granules through 16 to 30# (preferably 20 #), Ensure that all the granules are passed through 16 to 30# (preferably 20 #). Charge the above sifted material in the Fluidized Bed Processor.

PART II: (API TASTE MASKING GRANULATION):

STEP 1. GRANULATION VEHICLE PREPARATION:

Dissolve accurately weighed Methacrylate copolymer (cationic copolymer) in Ethanol used as the taste maskinggranulation vehicle.

STEP 2. GRANULATION Charge the above sifted material in the Fluidized Bed Processor.

STEP 4. DRYING THE GRANULES:

After completion of spraying, rake the wet mass and continue drying the wet granules in Fluidized Bed Processor. Dry the wet mass without application of heat for 1 hour, followed by Inlet temperature of 30 to 45°C, Product temperature- 20 - 30°C, Exhaust temperature- 20 to 35°C & flap position at 20 to 70 % for 20 to 60minutes. LOD Limit: 1.5 to 3.0 %w/w.

STEP 5. DRY SIFTING & MILLING:

Pass the dried granules through 16 to 30# (preferably 20 #)Vibro sifter & collect the retains, Pass the retains through Multimill fitted with 1.0 mm to 2.5mm (preferably 1.5mm screen) with knives forward & Collect in a poly bag. Pass the milled granules through 16 to 30# (preferably 20 #), Ensure that all the granules are passed through 16 to 30# (preferably 20 #). Charge the above sifted material in the blender.

PART III: FOLIC ACID GRANULATION:

STEP 1. DISPENSING & SIFTING:

Accurately weigh and sieve Folic acid, Mannitol, Povidone K30 using 30 to 60# (preferably 40#) S.S. Sieve and collect in the S.S. bin.

STEP 2. BINDER PREPARATION:

Dispense and take Isopropyl alcohol in a stainless steel vessel and add Shellac under stirring. Allow the solution to soak for 6 to 24 hours. This solution is to be used as binder.

STEP 3. DRY MIXING & GRANULATION:

Charge the above sifted material in the Rapid Mixer Granulator. Mix total for 5 to 20 minutes at slow or fast speed.(preferably slow). Add 50 to 80% % of binder to dry mix present in Rapid Mixer Granulator under slow speed for 2 to 5 minutes. Rake the mass in Rapid Mixer Granulator, if necessary. Add remaining quantity of binder, continue mixing for 4 - 8 minutes with impeller at slow or fast and chopper slow or fast until desired wet mass obtained. Discharge the wet mass into Fluidized Bed Processor bowl by opening the discharge port and operating the impeller at slow or fast.

STEP 4. DRYING THE GRANULES:

CYCLE I: Distribute the material uniformly in the Fluidized Bed Processor bowl using S.S. paddle. Start the Fluidized Bed Processor and air dry the wet mass without application of heat for 10 to 30 minutes.

CYCLE II: Rake the wet mass and continue drying the wet granules in Fluidized Bed Processor at an inlet temperature of 40 - 70°C for 20 to 60 minutes. LOD Limit: Between 1.0 - 3.0 % w/w.

STEP 5. DRY SIFTING & MILLING:

Sift the dried granules through 20 to 60#(preferably 40#) SS sieve using vibratory sifter. Collect the retention in a poly bag. Pass the retention granules through multimill fitted with 0.5 to 2.0mm (preferably 1.0 mm) screen. Collect the milled granules in a double lined polythene bag. Charge the above sifted material in the blender. STAGE-II PRE-LUBRICATION: Accurately weigh and sieve Mannitol SD 200, Sorbitol crystalline, Colloidal silicon dioxide, Sodium starch glycollate, Aspartame, Mango green flavor, Spearmint flavor using 30 to 100# (preferably 40 #) S.S. Sieve and collect in the S.S. bin. Accurately weigh and sieve Citric acid anhydrous, Sodium citrate, Menthol using 40 to 120#(preferably 80 #) S.S. Sieve and collect in the S.S. bin. Transfer the above sifted materials into the blender containing dried and milled granules of Ferrous calcium citrate & Folic acid. Blend for 10 to 30 minutes (preferably 20 minutes) at slow.

STAGE- III LUBRICATION:

Accurately weigh and sieve Magnesium stearate using 40 to 100# (preferably 60 #) S.S. Sieve and collect in the S.S. bin. Transfer sifted Magnesium stearate into the blender & Blend for 2 to 5 minutes (preferably 3 minutes).

Evaluation of the Lubricated blend:

STAGE IV: COMPRESSION:

Punch specification: 10x8mm to 19x16mm, Mango shape punches (Preferably13.21 x 10.88 mm Mango shaped, punches plain on surface).

PARAMETERS FOR UNCOATED TABLETS

STAGE V: COATING:

PART I: BARRIER COATING:

Place Iso propyl alcohol in a stainless steel and slowly incorporate Opaglos (Esterified shellac) in to it. Maintain continuous stirring for 15 to 60 minutes. Maintain continuous stirring during the implementation of the coating.

PARAMETERS FOR SEAL COATED TABLETS

PART II FILM COATING:

Place purified water in a stainless steel vessel and slowly incorporate Opadry green (Hypromellose, Lactose monohydrate, Maltodextrin, PEG -6000, Talc, Titanium dioxide, Aspartame, Spearmint flavor, Tartrazine Yellow Supra& Brilliant Blue) under continuous stirring. Continue stirring till a smooth dispersion is obtained. Incorporate isopropyl alcohol to the coating dispersion, Continue stirring for 15-45 minutes. Filter the coating suspension through 100 to 200# sieve. (Preferably 100 # mesh). The compressed tablets loaded in a coating pan, coating solution sprayed over the tablet to required weight buildup.

PARAMETERS FOR SEAL COATED & FILM COATED TABLETS

STAGE VI: PACKING:

PVC/ PVDC/ALU-ALU Blister (preferably clear PVDC/Aluminum Blister)

ADVANTAGE OF THE INVENTION:

Chewable tablets are a convenient alternative to conventional tablets. They have the great advantage of not requiring water, which means that they can be taken at any time and in any place. When used in combination with other dosage forms, like effervescent tablets, chewable tablets offer additional variety for patients, improving the experience and ensuring better compliance. In the present invention, the process provided for the manufacture of the chewable tablets helps in obtaining an effective chewable dosage unit, which tend to show good palatability, pleasant tasting and enhanced acceptable mouth-feel qualities, providing over-all effective taste-masking Chewable tablets of the said invention obtained by the reasonable process of multi-layer particle (granule) coating technology is specifically designed to release the active ingredient (Hematinic) into duodenum, allowing effective iron absorption. Also providing taste-masking of the bitter nutritional supplement such as folic acid, in-turn providing moisture-barrier for folic acid as well as the whole dosage unit, in combination with taste-masking film coating. The chewable tablet designed by the process in the present invention aims at proving a dosage unit designed to provide better patient compliance of especially pregnant woman as Anti-nauseating therapeutic product.

Benefits

• A more reasonable process for user-friendly dosage form.

• Designed to eliminate the need of water intake

• Increase compliance.

• Provides gastro-resistant granules with taste masking coating.

• Provides tablets with good palatability and mouth -feel

• Provides pleasing appearance and smooth texture

• Provides dose precision

• Provides reduced risk of dental caries and tooth decay

CLAIMS:

1. A process for manufacturing oral pharmaceutical composition in the form of chewable tablet, providing good palatability, pleasant and enhanced mouth-feel qualities, effective taste- masking and a targeted release of active ingredient in the duodenum, the process comprising:

a) Enteric Coating with pH-dependent Anionic and cationic copolymers said to possess gastro-resistant and taste-masking properties of metallic tasting hematinic.

b) Incorporation of mouth-feel enhancing diluents, acidifier, alkalizer, sweetening agent and a flavoring agents by pre-lubrication process

c) Seal coating with a moisture - barrier excipient to avoid oxidation and moisture-attack

d) Film coating comprising sweetener and a flavor, in a hydro-alcoholic solvent

2. The process according to Claim 1, where the active ingredients is a hematinic, preferably Ferrous calcium citrate and a nutritional supplement, preferably folic acid.

3. The process according to Claim 1, where the anionic copolymer is Methacrylic acid Copolymer.

4. The process according to Claim 1, where the cationic copolymer is Methacrylate Copolymer.

5. The process according to Claim 1, where the Methacrylic acid Copolymer is preferably a Methacrylic acid - Ethyl Acrylate Copolymer, (Eudragit L100-55).

6. The process according to Claim 1, where the Methacrylate Copolymer is preferably a basic butylated Methacrylate Copolymer (Eudragit E100).

7. The process according to claim 1, where the solvent for Methacrylic acid copolymer is water with colorants, preferably Tartrazine yellow and brilliant blue, and with a diluents preferably maltodextrin.

8. The process according to claim 1, where the solvent for Methacrylate copolymer is Ethanol.

9. The process according to claim 1, where the cationic and anionic co-polymer coating is done through Fluid bed processor

10. The process according to claim 1, where the cationic and anionic co-polymer coating is done by binder solution through wet granulation method

11. The process according to claim 1, where the anionic polymer (Methacrylic acid Copolymer) coating is done followed by cationic co-polymer (Methacrylate copolymer)

12. The process involving moisture-barrier of folic acid, with shellac, as binder solution, by the process of wet granulation, through Rapid Mixer granulator

13. The process according to claim 1, where the mouth-feel enhancing diluents are sorbitol, mannitol and maltodextrin.

14. The process according to claim 1, where a sweetening agent, preferably aspartame, is used in combination with flavors, preferably Mango flavor, spearmint flavor and menthol.

15. The process wherein the table assumes the shape of the mango green, with biconvex and plain on both sides.

16. The process according to claim 1, where the seal coat, preferred is esterified shellac.

17. The process according to claim 1, where the film coat comprises the same sweetener, flavor and colorants as used in granulation and pre-lubrication.