Title of Invention

PROCESS TO MANUFACTURE DISPERSIBLE TABLET

Abstract

A process for the manufacture of a dispersible tablet comprising the following steps:(i) admixing together intragranular component withgranules of pharmaceutically acceptable excipients to prepare granules in presence of a suitable binder. (ii) blending the above granules so obtained with extragranular components and a disintegrant. (iii) Compressing the granules obtained from above step into tablets.

Full Text

205370 29.6.07 FORM - 2 THE PATENTS ACT, 1970 [39 of 1970] COMPLETE SPECIFICATION [SECTION 10 rule 13] PROCESS TO MANUFACTURE DISPERSIBLE TABLET Applicant: (a) L. M. COLLEGE OF PHARMACY, Run by Ahmedabad Education Society, a Registered trust at (b) P.O. BOX NO. 4011, Navrangpura, Ahmedabad-380 009. Gujarat, India. (c) INDIA. The following specification particularly describes the nature of the invention and the manner in which it is to be performed. GARNTED 17/5/2004 ORIGINAL 925/MUMNP/203 8/9/2003 This invention relates to A NOVEL METHOD OF PREPARATION OF DISPERSIBLE HERBAL SWEETENER TABLET PREPARED USING UNIQUE BINDER. BACKGROUND OF INVENTION Liquorice consists of dried roots of Glycyrrhiza glabra. It possesses potent demulcent, expectorant and anti¬inflammatory properties and these properties are attributed to the presence of glycyrrhizin. Glycyrrhizin is 50 times sweeter than sucrose (Indian Herbal Pharmacopoeia, Volume-!, page-89). In the present era of pharmaceutics, it is really difficult to appreciate active pharmaceutical ingredient (API) dispensed as crude powder, weighed by hand and packed in newspaper pieces. There is a changing trend of using more acceptable forms such as tablets and capsules rather than the traditional formulations ('churna', 'vati', 'gutika', etc). The rational development of herbal formulations is much more complicated and tedious process, as compared to synthetic active pharmaceutical ingredient. Among various solid dosage forms, dispersible dosage forms are simple and effective alternatives to oral mixtures, suspensions and conventional compressed tablets. Dispersible tablets are easier to administer or swallow than capsules for dysphagic patients. Dispersible dosage forms disintegrate at a faster rate and hence the medicament is readily available to elicit desired pharmacological action. In a number of studies, it has been reported that the bioavailability of dispersible dosage forms is more than that of oral tablets or capsules. (Chowdary K. P. R. and Rama Rao. N, Indian drugs, 298, 1997; Muir N., Nichols. J. D., Clifford J. M., Stillings M. R., Hoare R. C, Current Medical Research and Opinion, 13, 547, 1997; Chogle P., Gudsoorkar V. R., Shete J. S., Eastern Pharmacist, 39, 121, 1996; Bayer A. J., Day J. J., Finucane P. and Pathy M. S., Journal of Clinical Pharmacology and therapeutics, 13,191, 1988). Major challenges in preparing herbal tablets are: 1) Poor flow, 2) Poor compressibility and 3) Poor disintegration quality. Poor flow may be attributed to the presence of fine particles, moisture, and/or fibers. Poor flow ultimately results in weight variation or content uniformity. The major reasons for poor compressibility seem to be presence of fibers and heterogeneous nature of the herbal drug. Poor disintegrating quality may be attributed to poor water uptake by the tablets that meet the standards of hardness and friability. Poor flow and compressibility can be improved by granulation, which can be prepared by slugging or wet granulation. Slugging is not possible in the present invention because of the nature of the drug; therefore wet granulation is carried out. For wet granulation, aqueous binder of natural or synthetic origin or organic solvent containing natural or synthetic binders can be used. The major problem of using aqueous binder solution in herbal formulation is the problems of stickiness during wet sieving. The other option is the use of organic solvents. Materials commonly used as binders include starch, gelatin, and sugars such as sucrose, glucose, dextrose, molasses, and lactose. Natural synthetic gums that have been used include acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapholol husk, carboxymethylcellulose, methylcellulose, veegum, polyvinylpyrrolidone,, and larch arabogalactan. Other agents that may be considered as binders under certain circumstances are polyethylene glycol, ethylcellulose, waxes, water and alcohol. (Remington "The Science and Practice of Pharmacy" 20 th edition-2000, pg-860, Lippincott, Williams and Wilkins.) PRIOR ART Ogasawara reported preparation of taste masked tablets containing sweeteners and sugar alcohol. A formulation of acetaminophen tablets containing corn starch, microcrystalline cellulose, dipotasium glycyrrhizinate, erythritol and hydrogenated castor oil is presented (Ogasawara Hideo, Kizu Norio et al., Jpn. Kokai Tokkyo Koho JP11 35,486 [99 35,486] application no. 97/212611 published on 09/02/1999) Tezuka Takahiro and Kato Yoshiteru reported an invention on solid oral composition containing chlorophyllin and sweetener. The sweetener was selected from the group consisting of dipotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, erythritol, stevia , xylitol and D- mannitol (Tezuka Takahiro and Kato Yoshiteru, Jpn. Kokai Tokkyo Koho JP 2003, 26576). Burges et al., filed a patent on a composition comprising of paroxitine and ammonium glycyrrhizinate (Burges Causert Nathalie Claude Marianne, Marzolini, Nicola Lisa Anna, Meneaud Padma PCT Int. Appl. WO 0313470). Pharmaceutical formulations of fluoxetine or an acid addition salt of thereof, suitable for manufacturing dispersible tablets by direct compression and comprising, in addition to the active ingredient, the appropriate excipients and coadjuvants, selected from among disintegrants, diluents, lubricants, anti-adherents, sweeteners, flavorings and, optionally, colorants. Said formulations are suitable for manufacturing dispersible tablets which disintegrate in less than three minutes in water at 19 to 21° C, and are appropriate for treatment of depression. In this formulation ammonium glyciricinate is used as a sweetener between 0.5% and 1% by weight in relation to total weight of the formulation. (US patent 5,747,068) The above mentioned inventions make use of pure salt of glycyrrhizinate as a sweetener. However, we have used the whole powder of liqourice as a sweetener for the development of dispersible tablets. None of the invention mentioned above have reported a method of preparation of dispersible tablet. The above mentioned inventions make use of drug containing pharmaceutical products while we have reported the preparation of drug free dispersible sweetener tablet. In light of the prior art, it would be useful to prepare herbal dispersible tablets using novel approach of using the extract of a drug, i.e. liquorice, for obtaining binding. It has not been reported in the prior art that extract of herbal drug is used as a binder. We have explored the use of a novel binder i.e. alcoholic extract of liquorice containing Cab-O-Sil for the preparation of granules. OBJECT AND SUMMARY OF INVENTION: It is an object of the present invention to prepare herbal dispersible tablets. It is another object of the present invention to use liquid extract of a herbal drug to bind the same powdered herbal drug. It is still another object of the present invention to achieve the dispersing quality in a tablet using disintegrant. A still further object is to provide a safe sweetener for use in food, pharmaceutical or neutraceutical. DETAILED DESCRIPTION OF INVENTION: In accordance with the present invention, a process is disclosed herein for the manufacturing of herbal dispersible sweetener tablets containing liquorice. For the reasons mentioned below, wet granulation tablet manufacturing procedure is the one which has been chosen. The parameters defining dispersible tablets are as follows: (i) Their high speed of disintegration in water and (ii) The uniformity of the particles into which they disintegrate. The properties and quality of the finished tablet depend largely upon the type and the quantity of the adjuvants incorporated in the tablet. The manufacturing process is also equally important in controlling the quality of the tablets. The new pharmaceutical formulation of liquorice, suitable for the manufacture of herbal dispersible tablets as provided by this invention take the foregoing considerations into account and contain in addition to liquorice suitable quantities of disintegrant, diluent, lubricant and antiadherent. The main ingredient of the formulation in this invention is liquorice. Granulation is carried out to improve flow. The term "granulation" refers as a process of putting particles together by creating bonds between them. For granulation, wet granulation technique is carried out. The term "wet granulation" refers to a process of adding a liquid solution to powders for granulating. In this invention, the term "diluents/ dummy granules" includes excipients which facilitate the compression of powder and give the tablets the required strength. A mixture of starch, microcrystalline cellulose, talc, sodium starch glycolate, croscarmellose sodium, Cab-O-Sil and magnesium stearate is suitable. For the preparation of granules, granulating agent is used. In the present invention alcoholic extract of liquorice along with 5% Cab-O-Sil is used as granulating agent. Liquorice is mixed with dummy granules in various proportions. The mixture is then granulated. Wet granulation technique helps in preparing granules which in turn improves the flow and compressibility of the powder. To the dried granules, other adjuvants are added. Because the dispersible tablets critical parameter is its rate of disintegration in water, the selection of appropriate disintegrant is one of the most important phases. In the present invention, the term "disintegrant" refers to an agent which disrupts the bonds between the particles so that the tablets disintegrate quickly. Low-substituted hydroxypropylcellulose, crospovidone, sodium starch glycolate and croscarmellose sodium are suitable disintegrants for the formulation in this invention. Low-substituted hydroxypropylcellulose may be used in concentration of 5%w/w. Sodium starch glycolate may be used in the concentration of 5% w/w. Croscarmellose sodium may be used in. the. concentration of 5% w/w. Crospovidone may be used.in concentration of 5%. w/w.. For the preparation of tablets, lubricant is added.. The. term. '"lubricant" as used. in this description includes excipients which reduce the friction during compression on a tablet machine. Magnesium stearate (1%) and. talc (2%) are used as lubricant, in this invention.. The term "antiadherent" as used, in this description. includes excipients which prevent adhesion on the punch faces Cab-O-Sil is used in the present invention.. This co adj uvant. can be incorporated, at a percentage of between 1%. and. 2%. w/w,. preferably 1%. w/w.. Dispersible tablets of liquorice provided, by this invention are solid, of uniform appearance, and. with sufficient mechanical strength to bear possible stress during storage and.transport.. Crushing strength The crushing strength of the tablets was determined, after 24. hr (time for stress relaxation) of compression, using a. Monsanto hardness tester (Shital Scientific Industries,. Bombay, India).. Friability Friability was evaluated as the percentage weight loss of 20 tablets tumbled in.a.friabilator (model EF2. Electrolab. Bombay) for 4 min at 25 rpm. The tablets were than dedusted. and the loss in weight caused bv fracture or abrasion was recorded as percentage friability.. Disintegration Dispersible tablets disintegrate within 3 minute when examined bv the disintegration test. for. tablets. using water at 24 to 26 ° C (Indian Pharmacopoeia. Vol. - I.I. pg-73.5.. 1.996.. published bv The. Controller of Publications. Delhi). The dispersible tablets also confine the. test for uniformity of dispersion. Two tablets are. placed in 100 ml water and stirred until, completely dispersed. The. dispersion.passed through a screen with a nominal mesh aperture of 710 nm (Indian Pharmacopoeia. Vol.- II. A-80. 1.996. published by The. Controller of Publications. Delhi). They are. suitable for patients with difficulties for ingesting solid forms.They may be. used by diabetic patients since they do not. contain sucrose as a The following examples illustrate specific implementations of the invention and should not be constructed as limiting it. Example 1: Intragranular components: Liquorice (44#) : 25 gm Dummy granules (44/120#) : 25 gm Alcoholic liquorice extract : 50 ml with 5% Cab-O-Sil Preparation of Extract: Liquorice powder (40 gm) was kept in contact with 200 ml of ethanol for 1 hr at room temperature. The mixture was then boiled for 10 min. After 12 hr of storage at an ambient condition, the extract was separated by filtration through a Whatman filter paper. To 50 ml of this extract 5 % of Cab-O-Sil was added and used as a binder. Extragranular components: Crospovidone : 5 % w/w Talc : 2 % w/w Magensium stearate : 1 % w/w Cab-O-Sil : 1 % w/w Procedure The dummy granules and the liquorice powder were mixed in a ratio of 1:1. Five % of Cab-O-Sil wais added to alcoholic liquorice extract to obtain a binder. Sufficient quantity of the binder was added to granulate the blend through 44#. The granules were resifited through 44# after drying at 60 ° C. The fines were removed by tapping the granules on 120#. The extragranular components were added.The tablets were prepared on a single punch tablet machine. The results of tablet evaluatiori are shown below: Crushing strength : 3 kg Friability : 0.61 % Disintegration time Example 2: Intragranular components: Liquorice (44#) :25 gm Dummy granules (44/120#) :25 gm Alcoholic liquorice extract : 50 ml with 5% Cab-O-Sil . Extragranular components: Low-substituted hydroxypropylcellulose: 5 % w/w Talc : 2 % w/w Magnesium stearate : 1 % w/w Cab-O-Sil : 1 % w/w Procedure: The procedure is identical to that shown in example 1, except the disintegrant used. The tablets were prepared on a single punch tablet machine. The results of tablet evaluation are shown below Crushing strength : 3 kg Friability : 0.65 % Disintegration time We claim: 1. A process for the manufacture of a dispersible tablet comprising the following steps: (i) admixing together intragranular component with granules of pharmaceutically acceptable excipients to prepare granules in presence of a suitable binder. (ii) blending the above granules so obtained with extragranular components and a disintegrant. (iii) Compressing the granules obtained from above step into tablets. 2. A process as claimed in claim 1 Wherein said intragranular component is liquorice. 3. A process as claimed in claim 1 Wherein said pharmaceutical excipients are selected from a group comprising: starch, microcrystalline cellulose, talc, sodium starch glycolate, crosscarmellose sodium, Cab-O-Sil and magnesium stearate. 4. The process as claimed in 1 wherein said intragranular component & pharmaceutically acceptable excipients are processed in ratios from 0.6:0.4 to 1:4. 5. A process as claimed in claim 1 wherein said binder used is alcoholic liquorice extract. 6. A process as claimed in claim 1 wherein said pharmaceutically acceptable excipients are used in 0.1 to 2% w/w as compared to the tablets. 7. A process as claimed in claim 1 wherein the disintegrant used is selected from a group comprising: low-substituted hydroxypropylcellulose, crospovidone, sodium starch glycolate, croscarmellose sodium. 8. A process as claimed in claim 1 wherein the disintegrant used is in an amount of 5 % w/w with that of the tablet. Dated:8/sep/2003 (Dr. Mukesh C. Gohel) Applicant on behalf of L. M.College of Pharmacy To The Controller of Patents The Patent Office At Mumbai

Documents:

925-mum-2003-cancelled pages(17-05-2004).pdf

925-mum-2003-claims(granted)-(17-05-2004).doc

925-mum-2003-claims(granted)-(17-05-2004).pdf

925-mum-2003-correspondence(17-05-2004).pdf

925-mum-2003-correspondence(ipo)-(30-03-2007).pdf

925-mum-2003-form 1(08-09-2003).pdf

925-mum-2003-form 19(22-09-2003).pdf

925-mum-2003-form 2(granted)-(17-05-2004).pdf

925-mum-2003-form 3(08-09-2003).pdf

925-mum-2003-form 5(08-09-2003).pdf

925-mum-2003-formm 2(granted)-(17-05-2004).doc