Title of Invention

A MANUFACTURING PROCESS FOR THE PREPARATION OF MOUTH DISPERSIBLE TABLETS USING ACTIVE PHARMACEUTICAL SUBSTANCE ALPRAZOLAM

Abstract

A manufacturing process for the preparation of mouth dispersible tablet using active pharmaceutical substance Alprazolam. The said tablet disperses very fast and rapidly once it placed on tongue and dissolves in saliva and circulated through blood in body. The tablet prepared using the process, gives synergistic effect against anxiety disorder, depression and panic disorder. The process comprises preparing granules containing active ingredient and other pharmaceutical exccpients. Microcrystalline Cellulose granules, Manitol granules, Alprazolam granules are prepared separately. Mixture powder of Aspartame, sodium saccharine and dry flavorants is prepared. Alprazolam granules are flavoured and mixed with manitol granules and microcrystalline cellulose granules. And finally Magnesium stearate. Talcum and Sodium Starch Glycolate are added into the mixture of above prepared granules. Its fast onset of action in mouth without water gives better patient compliance in severe conditions like anxiety disorder, anti depressant effect.

Full Text

FORM - 2 THE PATENTS ACT, 1970 (39 of 3 970) COMPLETE SPECIFICATION [SECTION 10] 1. A MANUFACTURING PROCESS FOR THE PREPARATION OF MOUTH DISPERSIBLE TABLETS USING ACTIVE PHARMACEUTICAL SUBSTANCE ALPRAZOLAM. 2. (a) SKYMAX LABORATORIES PVT LTD., (b) Plot No. G/1445-46, Lodhika G.I.D.C., Metoda-360035, Dist. Rajkot. Gujarat State, India. (c) An Indian Company. The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed. The present invention relates to a manufacturing process for the preparation of mouth dispersible tablets using active pharmaceutical substance Alprazolam. The present invention provides the process by which mouth dispersible tablets of Alprazolam is prepared for oral administration. For oral administration mouth dispersible tablet is more suitable way than swallowing tablets. Generally formulations for oral administration are tablets/lozenges, hard & soft capsules, granules, powders, solutions, syrups etc. Alprazolam mouth dispersible tablets arc formulated for oral administration, is effective against anxiety disorder, depression and various panic disorders. In the preparation of Alprazolam tablet, using Alprazolam as active ingredient, exhibit its good efficacy, less toxic. Active pharmaceutical substance Alprazolam exerts its pharmacological effect by potentiation of neural inhibition in central nervous system (CNS), which is mediated by GABA. Drug Alprazolam is safer, most powerful Anxiolytic drug with built in 2 anti depressant effect, widely accepted, used and prescribed by medical professionals. At present Alprazolam tablet is available in market as uncoated form, film coated form, in sustain release form of tablet for oral use and for parental use it is not available in injectable form. This form of tablet shows clinical response after 1 to 2 hours from intake of dose. Patient finds discomfort with intake of Alprazolam in the form of uncoated tablet. Film coated swallowable tablet is swallowed as it is, film of the tablet breaks in stomach and tablet get dispersed/dissolved in gastric secretion and then absorption of drug will start. Which lakes more time to onset of action of drug. Therefore in certain critical conditions like acute anxiety disorders and massive depression, these tablets will not serve or solve the problems. Generally uncoated Alprazolam tablets available in the market are swallowable tablets. Children, Senior Citizens & other patients, because of bitter taste, do not like uncoated form of Alprazolam tablet. To overcome the discomforts raised due to uncoated and sustain release tablet of Alprazolam, an improved process is developed to prepare Alprazolam mouth dispersible tablets. To avoid the drawback of uncoated and sustain release tablet and comparatively its slow onset of action, mouth dispersible tablet of Alprazolam and its process of preparation have confronted with two problems-suppression of bitter taste of tablet and the rapid dissolution of tablet in saliva of oral cavity, fast onset of action thereof. Considering the need of the medical profession and ailing patients, Alprazolam mouth dispersible tablet is developed using novel process, for faster & rapid clinical action of the drug. Alprazolam dose in the form of mouth dispersible tablet is given to the patient in 0.25 to 2.0 mg/unit dose, as per the severity of the disease. Mouth dispersible tablet of Alprazolam gives fast disintegration in mouth without intake of water for ease in oral administration. Manufacturing process of Alprazolam mouth dispersible tablet contains active ingredient Alprazolam; inactive 4 ingredients: microcrystalline cellulose powder (MCCP), sweeteners aspartame, manitol crystal, sodium saccharine, dry flavourants to mask the bitter taste of the drug; lubricants magnesium stearate, fast disintegrating agent Sodium Starch Glycolate for faster and easy dispersion of tablet in saliva of mouth cavity. In the manufacturing process of preparation of mouth dispersible tablet of Alprazolam, the use of microcrystalline cellulose powder (MCCP) with active ingredient Alprazolam during granulation produces swelled granules in presence of water with resulting in high compressibility and dispersion of tablet. Due to high compressibility and dispersion of the tablet in saliva, the tablet absorbs at the faster rate from oral mucosa and faster circulation of it in oral submucosa. Alprazolam tablet prepared by using novel process gives relief against acute psychotic condition. Tablet prepared by using novel process, is the most preferred & provide fixed dose for patient who find difficulty in swallowing tablets. 5 Attempt is made to prepare a mouth dispersible tablet of Alprazolam giving synergistic effect against anxiety, panic disorder and depression due to unfavourable circumstances. The manufacturing process for the preparation of mouth dispersible tablet using active pharmaceutical substance Alprazolam is given below. Step 1: Preparation of granules of Microcrystalline Cellulose Powder (MCCP) Powder of Microcrystalline Cellulose 88.34 mg/unil dose is passed through 40# sieve and the prepared fine powder is transferred in the mixer. The fine powder is added with purified water and mixed it thoroughly in mixer. The wet mass obtained is passed through 16# sieve and the granules obtained are collected in tray. The granules are dried in tray at 55 C for 5 to 6 hours. The granules are dried in tray till they get completely dry. The granules are further passed through 30# sieve and collected in plastic bag. 6 Step-2: Separate preparation of Manitol granules and powder mixture of sweeteners and dry flavourants. 88.34 mg/unit dose of Manitol crystals are passed through 30# sieve and uniform manitol granules are prepared. Sweeteners 6 mg/unit dose aspartame & 4 mg/unit dose sodium saccharine are mixed with 0.80 mg/unit dose dry flavour. The said powder mixture is passed through 60# sieve. Manitol is highly soluble in water and also impart its sweeter taste to the tablet. Using manitol during granulation process of tablet, imparts fast dissolution of tablet in mouth water and also give it's sweeter taste immediately once the tablet put in mouth. Step-3: Preparation of granules of active ingredient Alprazolam: 0.2-2.0 mg/unit dose of Alprazolam is passed through 60# sieve for the preparation of fine granules. Active drug containing Alprazolam granules are admixed with the powder mixture of sweetener and dry llavour prepared as in step-2. These flavoured and sweet Alprazolam granules are further passed through 100# mesh sieve. Accordingly fine Alprazolam granules are prepared. 7 Fine sweet and flavored Alprazolam granules are mixed with the Microcrystalline Cellulose granules prepared in step-1 and with manitol granules prepared in step-2. Step-4: Preparation of granules adding lubricants and disintcgrant: After mixing thoroughly the granules of Alprazolam, Microcrystalline Cellulose and manitol; lubricants 3.0 mg/unit dose Magnesium Stearate & 3.0 mg/unit dose Talcum, disintegrant 0.5 mg/unit dose sodium starch Glycolate are mixed with it. The whole mixture is kept for 5 minutes for better mixing. Finally, prepared granules are packed in bag. Step-5: Preparation of tablet: Final granules obtained from step-4 are compressed into tablet form as per the standard method used. Tablets are packed in blister or Aluminium strip under controlled temperature and humidity. For the manufacturing of Alprazolam mouth dispersible tablet according to the present invention requires active and other pharmaceutical excipients, conventional to the art such as binders, 8 lubricants, disintegrating agents, sweetening agents and flavourants. Sweetening agents Manitol, Aspartame and Sodium Saccharine are used in the present invention to impart its delicious taste into tablet and mask bitter taste of active ingredient Alprazolam. Lubricants magnesium stearate, talcum are used to give smoothness to tablets. Dry flavourant is to impart its taste and flavour. Fast disintegrating agent sodium starch Giycolate gives easy and faster dispersion of tablet in saliva of mouth cavity. Microcrystalline Cellulose powder used in granulation process exerts higher compressibility and faster dissolution of the tablet in saliva without intake of water. All these ingredients are added as per the stability of the tablet & taste requirement. It is important that the final product should have a high degree of stability. Manufacturing of Alprazolam mouth dispersible tablet using a novel process, rapidly disperse in mouth giving sweeter taste and fast onset of action on the disease. 9 Examples: Example 1: Preparation of Alprazolam-0.25 MD: A mouth dispersible tablet is prepared using the following components of which the active ingredient is Alprazolam. The other components are physiologically acceptable excepients. Tablet is prepared by using the granulation process known to those skilled in the art. Separate granules of microcrystalline cellulose powder (MCCP) is prepared by passing it through 40# sieve, 16# sieve after adding purified water, tray drying granules at 55° C for 5-6 hours, preparing fine granules passing through 30# sieve. Separate granules of manitol are prepared after passing through 30# sieve. Separate powder mixture of sweeteners aspartame & sodium saccharine with dry flavourant is prepared on passing through 30# sieve. Separate granules of active substance Alprazolam is prepared on passing it through 60# sieve and admixed with powder mixture of sweeteners and dry flavouranls. Flavoured Alprazolam granules arc admixed with MCCP granules and manitol granules. Finally above prepared granules are admixed with lubricants magnesium stearate, talcum and fast disintegrant sodium starch 10 Glycolate. After 5 minutes the granules are compressed into tablet form by process known to those skilled in the art. The relative proportion of active ingredient and other pharmaceutical excepients is used lo prepare tablet during granulation: Ingredients Volume (mg/unit dose) Alprazolam 0.25 Microcrystalline Cellulose powder (MCCP) 88.34 Manitol 88.34 Magnesium Stearate 3.00 Talcum 3.00 Sodium Starch Glycolate 0.50 Aspartame 6.00 Sodium Saccharine 4.00 Dry flavour powder 0.80 Example 2: Preparation of AIprazoIam-0-50 MD: A mouth dispersible tablet is prepared using the following components of which the active ingredient is Alprazolam. The other components are physiologically acceptable excepients. Tablet is prepared by using the granulation process known to those skilled in the art. Separate granules of microcrystalline cellulose powder (MCCP) is prepared by passing it through 40# sieve, 16# sieve after adding purified water, tray drying granules at 55 C for 5-6 hours,preparingfinegranualspassingitthrough30#sieve.Separate granules of manitol are prepared after passing through 30# sieve. Separate powder mixture of sweeteners aspartame & sodium saccharine with dry flavourant is prepared on passing through 30# sieve. Separate granules of active substance Alprazolam is prepared on passing through 60# sieve and admixed with powder mixture of sweeteners and dry llavourants- Mavoured Alprazolam granules are admixed with MCCP granules and manitol granules; in finally prepared granules lubricants magnesium stearate, talcum and fast disintegrant sodium starch Glycolate is admixed. After 5 12 minutes the granules are compressed into tablet form by process known to those skilled in the art. The relative proportion of active ingredient and other pharmaceutical excepients is used to prepare tablet during granulation: * Ingredients Volume (mg/unit dose) Alprazolam 0.50 Microcrystalline Cellulose powder (MCC?) 88.34 Manitol 88.34 Magnesium Stearate 3.00 Talcum 3.00 Sodium Starch Glycolate 0.50 Aspartame 6.00 Sodium Saccharine 4.00 Dry flavour powder 0.80 13 We Claim, 1. A manufacturing process for the preparation of mouth dispersible tablets of active pharmaceutical substance Alprazolam gives synergistic effect in the treatment of anxiety disorder, panic disorder, depression is comprising the steps of: (a) passing 88.34 mg/190 mg of tablet microcrystalline cellulose powder (MCCP) through 40# mesh sieve, thoroughly mixing it with sufficient purified water in mixer, passing the wet mass of MCCP through 16# sieve, drying the wet mass in tray at 55° C for 5 to 6 hours or till complete dry, passing the dry granules through 30# mesh sieve; (b) (i) preparing mannitol granules on passing 88.34 mg/190 mg tablet mannitol crystal through 30# mesh sieve, (ii) preparing granules on passing the mixture containing 6 mg/190 mg tablet aspartame, 4 mg/190 14 mg tablet sodium saccharine, 0.80 mg/190 mg tablet dry flavour through 60# mesh sieve; (c) preparing granules on passing 0.2 - 2.0 mg/190 mg tablet Alprazolam through 60# mesh sieve, mixing the Alprazolam granules with the granules obtained from step (b)-(i) & (ii), further passing these flavoured Alprazolam granules through 200# mesh sieve, finally mixing the Alprazolam granules with granules obtained from step-(a); (d) fine flavoured granules obtained from step (c) are mixing with 3.0 mg/190 mg tablet magnesium stearate, 3.0 mg/190 mg tablet talcum and 0.5 mg/190 mg tablet sodium starch glycolate, finally mixed granules are keeping for 5 min; (e) granules obtained from step-fU) are compressed into tablet form as per standard method. 2. A manufacturing process for the preparation of mouth dispersible tablets of active pharmaceutical substance Alprazolam gives synergistic effect in the treatment of 15

Documents:

1243-mum-2003-abstract.doc

1243-mum-2003-abstract.pdf

1243-mum-2003-claims(cancelled).pdf

1243-mum-2003-claims.doc

1243-mum-2003-claims.pdf

1243-mum-2003-correspondence.pdf

1243-mum-2003-declaration.pdf

1243-mum-2003-description(granted).doc

1243-mum-2003-description(granted).pdf

1243-mum-2003-form 1.pdf

1243-mum-2003-form 19.pdf

1243-mum-2003-form 2 (cancelled).pdf

1243-mum-2003-form 2(granted).pdf

1243-mum-2003-form 2(title page).pdf

1243-mum-2003-form 3.pdf

1243-mum-2003-form 5.pdf

1243-mum-2003-form-2(granted).doc

1243-mum-2003-power of attorney.pdf