NZ241441A - Water-dispersible tablet formulation comprising acyclovir and a swellable clay excipient - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £41441 24 1 441 Priority Date(s):.

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•-Si No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION WATER DISPERSIBLE TABLETS We, THE WELLCOME FOUNDATION LIMITED of Unicorn House, 160 Euston Road, London NW1 2BP, England, a British Company, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by page la) PA121!Z414 41 W ATKR-DI SPERSIBLE TABLETS The present invention relates to a water-dispersible tablet formulation containing acyclovir (UK no. 1523865).

Therapeutically active compounds or drugs are frequently administered to patients in tablet form where the drug is intended for oral administration since tablets are an especially convenient pharmaceutical form for manufacture, storage and generally usage. However, problems, may arise with the administration of such tablets to patients who have difficulty in swallowing the tablets (for example, children or more seriously ill patients) especially if the tablets are large in size arising from the amount of drug required in each tablet. A solution to such problems is to formulate the tablets in a form whereby they can be dispersed in water to form a dispersion containing the drug which can then be drunk by the patient.

Known water-dispersible tablets include effervescent formulations which rely on the formation of a gas to quickly break up the tablet, but these involve expensive methods of manufacture and strict regulations for such manufacture. Other known water-dispersible tablets use disintegrating agents such as microcrystalline cellulose used in Feldene (™) dispersible tablets. We have tested well-known disintegrating agents (incorporated both internally and externally to the preformed granules) such as sodium starch glycollate (e.g. Primogel (™), Explotab (™)), cross-linked povidone (e.g. Kollidon CL(™)), and a cross-linked sodium carboxymethylcellulose (e.g. Starch, and Ac-Di-Sol(™)) in an acyclovir tablet, but found that they did not provide a satisfactory commercial water-dispersible tablet. We furthermore tested an ion exchange resin (Amberlite 1RP88) as a disintegrating agent and incorporated surface active agents (e.g. sodium lauryl sulphate and sodium docusate) in an attempt to improve tablet wetting and penetration of water during dispersion, but in all cases the disintegration time was high.

Acyclovir is a compound which has been found to have potent activity against viruses of the herpes family, particularly herpes simplex and herpes varicella zoster. Such activity has been demonstrated by the outstanding success of acyclovir in the therapeutic treatment of clinical conditions such as genital herpes caused by the herpes varicella zoster virus. UK patent no. 1523865, which is incorporated herein by reference teaches how to make acyclovir and the infectious or medical condit' WPM\JT\22nd June 1994 PA1219NZ 241441 which can be treated by it.

In the treatment of certain conditions, it may be necessary to administer acyclovir to the patient in relatively large dosages to achieve the effective therapeutic levels of drug in the plasma, particularly when oral administration is desired. For example, in the treatment of shingles, it is recommended to administer acyclovir at a dosage regime of 800mg five times per day. A tablet formulation containing 800mg of acyclovir is currently available but its relatively large size sometimes renders it difficult to swallow by elderly patients, such patients being particularly susceptible to shingles. This problem is obviated by the water-dispersible tablets according to the invention which enable relatively high doses of acyclovir to be administered in a drinkable dispersion by the oral route.

The advantageous water-dispersibility of tablets according to the invention containing acyclovir as the active compound is especially surprising in view of the poor water-dispersibility demonstrated by tablets containing conventional disintegrating agents alone such as sodium starch glycollate, cross-linked povidone and cross-linked sodium carboxymethylcellulose.

According to a first aspect of the invention there is provided a water dispersible tablet having 200mg to 800mg acyclovir comprising at least 60% w/w acyclovir, 0.25 to 40% of a pharmaceutical^ acceptable swellable clay which is present within the granules of the tablet, and an effective amount of an additional pharmaceutically acceptable disintegrating agent which is present within the granules of the tablet to provide a tablet which is capable of dispersing in water within a period of 3 minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710pm in accordance with the test for dispersible tablets defined in the British Pharmacopoea 1988, volume II, page 895.

Swellable clays such as Veegum(™) and other magnesium aluminium silicates have previously been studied and proposed for use as disintegrating agents, binders and lubricants in the manufacture of tablets, but such studies and proposals were exclusively with respect to tablets intended for swallowing and not for water-dispersible tablets (Rubenstein, Pharmaceutics - The Science of Dosage Form Design (1990) for disintegrants see p 312 and 314). Moreover, there has never bee PA12 £>41441 suggestion that a clay would be suitable to meet the more stringent requirements for dispersible tablets. Tablets for swallowing need only have a disintegration time in water of less 15 minutes and be able to form particles on disintegration in water that can pass through a 2.00mm mesh aperture (British Pharmacopia test for swallowable tablets). Such long disintegration times and large particle uizes are entirely unsuitable for a dispersible tablet.

Even when swellable clays have been proposed as disintegrating agents for swallowable tablets, they are not regarded as very suitable for such use because their off-white appearance can often discolour the tablet and because they ate not as effective as other disintegrating agents (Banker and Anderson - Theory and Practice of Industrial Pharmacy p 328 (1986) and Bhargava eial - Drug Development and Industrial Pharmacy, 17(15), 2093-2102(1991)). In fact, bentonite is identified in Marshall and Rudnic, Modern Pharmaceutics (1990) p 374, as the least swellable of the ten disintegrants listed. There is no mention in the above text-book references of how the swellable clay should be incorporated - i.e. by intra-granular addition or by extra-granular addition. In the former case, the clay would be included in the mixture from which the granulate is formed; in the latter case the clay would be added to the preformed granulate.

In J. Pharm. Sci, 55, 1244 (1966), Wai slal. reviewed the following papers relating to swellable clays such as Veegum and bentonite as disintegrating agents: Wai stal., J.Pharm.Sci, 55, 1215(1966); Granberg fitfll-, J.Am.Pharm.Assoc.Sci, 38, 648(1949); Gross st si., J.Am.Pharm.Assoc.Sci, 41, 157(1952); Firouzabadian stal-> J.Am.Pharm.Assoc.Sci, 43, 248(1954); Ward elaL, Drag Cosmetic Ind, 91, 35(1962); Nair el al-, J.Am.Pharm.Assoc.Sci, 46, 131(1957); and Patel st at, Indian J.Pharm., 19, Jan. 1957. Wai slal-, then compared three grades of Veegum evalulating both extra-granular and intra-granular addition and concluded that "the clays were not good disintegrating agents when wet granulated" (i.e. intra-granular addition), and then went on to recommend extra-granular addition. Furthermore R.T.Vanderbilt and Co. (Manufacturers of Veegum) in their publication "Veegum - The Versatile Ingredient for Pharmaceutical Formulations" at p 19 describe a tablet formulation in which Veegum is added after granulation (tablet No.2). There is no reference in the publication to a formulation of a tablet in which Veegum is added during granulation.

In contrast to the above recommendations, we have found that a swellable claj ,asf 1'r cX WPM\JT\22nd June 1994 PA12 Veegum must be added during granulation to meet the British Pharmacopoeia (B.P.) standard for dispersible tablets (presently set at a dispersion time of 3 minutes or less). If the swellable clay is added only after granulation the dispersion time is too high to meet the above standard.

By using Veegum and other swellable clays in the manner described above, we have been able to prepare water-dispersible tablets containing a variety of therapeutically active compounds. The resulting tablets can readily be dispersed in water to form a dispersion which can be drunk by a patient.

The present invention further provides a process for the preparation of a water-dispersible tablet having 200mg to 800mg of acyclovir comprising at least 60% w/w acyclovir, 0.25 to 40% w/w of a pharmaceutically acceptable swellable clay and an additional pharmaceutically acceptable disintegrating, said process comprising bringing acyclovir into association with said swellable clay and additional disintegrating agent to form granules, and then compressing the granules to form a tablet which is capable of dispersing in water within a period of 3 minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710|a.m in accordance with the test for dispersible tablets defined in the British Pharmacopoeia, 1988, volume II, page 895.

Preferably said process comprises the steps of: a) admixing in dry, finely-divided form acyclovir, the swellable clay and the additional disintegrating agent, optionally with the addition of one or more other pharmaceutical carriers or excipients; b) addition of a quantity of a pharmaceutically acceptable liquid sufficient to moisten the dry mixture; c) granulation of the resulting moist mixture with a granulating fluid to form d) drying the granules and optionally blending the granules with other optional carriers or excipients such as lubricant: glidants, and flavouring agents; and'^ v * *r o> granules; WPM\JT\22nd June 1994 14 41 e) compression of the granules to form a tablet which is capable of dispersing in water within a period of 3 minutes to provide a dispersion which will pass through a sieve screen with a mesh aperture of 710jam in accordance with the above-defined British Pharmacopoeia test for dispersible tablets.

A tablet according to the invention, as well as being quickly dispersible in water, has the added advantage that it meets the British Pharmacopoeia (B.P.) test for dispersible tablets in respect of dispersion times and dispersion quality (i.e. passage through a 710 (j.m sieve).

Preferably the dispersion time of a tablet according to the invention is less than 2 minutes, more preferably less than 1.50 minutes and most preferably less than 1 minute.

A further advantage of the tablets according to invention is that because a relatively fine dispersion is formed the tablet will have a lower dissolution time and thus the drug may be absorbed into the blood stream much faster. Furthermore the fast dispersion times and relatively fine dispersions obtained with tablets according to the invention are also advantageous for swallowable tablets. Thus tablets according to the invention can be presented both for dispersion in water and also for directly swallowing. Those tablets according to the invention that are intended for swelling are preferably film-coated to aid swallowing. Such film-coating however increases the dispersion time up to 5 minutes determined in accordance with the above-mentioned B.P. test.

The references herein to tablets according to the invention include both film-coated and non-film-coated tablets.

After the dispersion has passed through the 710jam mesh screen, there should be substantially no residue, except fragments of undissolved tablet coating or shell, remaining on the screen or adhering to the lower surface of the disc, if a disc optionally has been used; and if any residue remains, it should consist of a soft mass having no palpably firm, unmoistened core.

The particle size distribution of the dispersion particularly are set out in the following ' o v^ WPM\JT\22nd June 1994 f4£4Z1 441 table with the increasingly preferred values being quoted from left to right.

Particle Size BP Standard Preferably More Preferably Most Preferably <710 <100% 100% 100% 100% <300 >50% >70% >80% <200 >50% >70% <150 >50% * (equivalent spherical volume diameter) It will be appreciated that reference to acyclovir also includes any pharmaceutically acceptable salts thereof.

The term "swellable clay" as used herein includes layered clays (such as smectites), porous fibrous clay minerals, and synthetic clay materials related in structure to layered clays and porous fibrous clays.

The term "layered clays" as used herein includes substantially homogeneous layered clays and mixtures thereof, and interstratified or mixed layered clays. Substantially homogeneous layered clays includes the smectite group for example dioctahedral and trioctahedral types. Examples of dioctahedral smectites are the montmorillonite group (montmorillonoids); magnesium and other (e.g. calcium) aluminium silicates such as Veegum in its various grades e.g. Veegum, Veegum HV, Veegum F, and Veegum WG); almasilate; fullers earth (e.g. Surrey finest); American fullers earth; bentonite; beidellite; cheto montmorillonite, Wyoming montmorillonite, Utah montmorillonite; Tatalia and Chambers montmorillonites; and iron rich smectites such as nontrite (e.g. Garfield nontronite) and ferrian smectites.

Examples of triocatahedral smectites (also known as saponites) are Swinefordite, hectorite, stevensite. Examples of smectites containing more unusual elements are . . . Volkhonsite, Medmontite, Sauconite, nickel smectites and vanadium smectites. As - PA1 well as the montmorillonite group, related smectites such as vermiculites may also have application.

The term "interstratified or mixed layer clays", as used herein includes clays involving different layers arranged in a regular or irregular structure. The most common examples of such clays have generally two components in substantially equal proportions and have been given mineral names such as rectorite (mica-smectite), hydrobiotite (biotite-vermiculite), corrensiten (chlorite-smectite) allettite (talc-saponite). More irregular arrangements include illite-smectite, chlorite-smectite, and kaolinite-smectite. Further examples of interstratified clays are tosudite, tarasovite, allevardite, Japanese bentonite ("acid clays"), AWAZU acid clay, and kaolinite-smectite. Other mixed layer clays may include one or more of the following minerals: clinchlore, chamosite, nimite, thuringite, sudoite, and cookeite. Mixed layer smectities are also known e.g. interdispersed montmorillonite and beidellite layers. The layers of mixed layer clays may be homogeneous or non-homogeneous.

The term "porous fibrous clays" includes palygorskite and sepiolite such as, for example attapulgite and American fuller's earth.

The term "synthetic clay materials" as used herein includes materials related in structure to layered clays and porous fibrous clay^such as synthetic hectorite (lithium magnesium sodium silicate) for example laponite .

It will be appreciated that within the scope of the invention the following classes of clays have application alone or in combination and in mixed layer clays: kaolinites, serpentines, pyrophyllites, talc, micas and brittle micas, chlorites, smectites and vermiculites, palygorskites and sepiolites. Other phyllosilicates (clay minerals) which may be employed in the tablets according to the invention are allophane and imogolite.

The following references describe the characterisation of clays of the above types: Chemistry of Clay and Clay Minerals. Edited by A.C.D. Newman. Mineralogical Society Monograph No. 6, 1987, Chapter 1; S.W. Bailey; Summary of recommendations of AIPEA Nomenclature Committee, Clay Minerals 15, 85-93; and A Handbook of Determinative Methods in Mineralogy, 1987, Chapter 1 by P.L J ...

WPM\JT\22nd June 1994 '■m • ... 441 Suitably the swellable clay is a pharmaceutically acceptable crystalline mineral clay having a lattice structure which expands upon hydration, preferably a pharmaceutically acceptable smectite or attapulgite clay, especially a montmorillonoid, more preferably yet a montmorillonoid chosen from the group consisting of montmorillonite, sauconite, vermiculite, bentonite and hectorite^still more preferably an aluminium magnesium silicate and most preferably Veegum .

The term "smectite" as used herein in relation to tablets of the present invention includes the smectites as exemplified herein and with reference to O'Brian P. and Williamson C.J., in "Clays and Clay Minerals vol. 38 No. 3 pp322-326, 1990" and the other clay nomenclature references set out hereinbefore.

The term "magnesium aluminium silicate" as used herein in relation to tablets of the present invention should be understood to include the Aluminium Magnesium Silicate defined in the British Pharmacopoeia, volume 1, pages 27-28, 1988 and the Magnesium Aluminium Silicate defined in the United States Pharmacopoeia. National Formulary XVI. pages 1943-1944, 1990. Advantageously, said silicate is in the fonn of a microfine powder having a No. 325 US Standard mesh particle size, a viscosity of 250 cps (± 25%) for a 5.5% (w/v) aqueous dispersion and an acid demand (the volume in ml. of O.IN hydrochloric acid required to reduce the pH of one gram to 4) of 6-8: such a material is available as VEEGUM F (R.T. Vanderbilt Co., New York, N.Y., U.S.A.; K & K-Greeff Chemicals Ltd., Croydon, Surrey CR9 3QL, England).

The amount of swellable clay employed in the tablet according to the invention generally depends on the weight of the tablet. Experiments with acyclovir indicate for a lOOmg tablet, amounts as low as 0.25% w/w of tablet can be used. In our experiments up to 40% w/w of swellable clay was used for a tablet having a total weight of 11 OOmg and gave fine dispersions and fast dispersion times.

Thus for a dispersible tablet defined hereinbefore, the intra-granular amount of swellable clay such as a crystalline mineral clay for example, magnesium aluminium silicate is suitably present in the following general ranges 0.25 to 40% w/w, preferably 0.5 to 40% w/w, more preferably still 1 to 40% w/w, more preferably still 2 to 20% w/w, more preferably still 2.5 to 20% w/w, still more preferably 1 to 10% w/w. more preferably 3 to 10% w/w, and most preferably 5 to 10%, most desirably alj WPM\JT\22nd June 1994 rMJ 4 A1 w/w.

The tablets according to the invention will generally contain a pre-determined amount of acyclovir, depending on the desired dosage and the total weight of the tablet.

The tablets generally contain 100 to lOOOmg, preferably 200 to 800mg, such as 400 to 800mg of the compound. Such dosage units may be administered one or more times, for example up to five times, per day, at the discretion of the physician, according to the age and condition of the patient and the particular condition being treated. For an acyclovir tablet having a total weight about 1000 to 1200mg and containing about 750 to 850mg of acyclovir, the swellable clay e.g. Veegum F, is preferably present in an amount of 40 to 120 mg intragranularly.

In general the tablets according to the invention contain acyclovir in the following percentage proportions: 20 to 90% w/w, preferably 45 to 85% w/w.

When acyclovir is present in an amount of at least 60% w/w in tablets according to the invention, we have suprisingly found that the dispersion time remains substantially constant over a range of tablet hardnesses. This is a considerable quality control advantage since in industrial manufacture it is essential to maintain a constant tablet hardness. Tablets according to the invention can thus be produced with sufficient hardness and friability so that they can easily be film-coated. A tablet according to the invention should desirably have a friability of about 2% or less, preferably 0.5% or less.

Based on experiments that we have carried out, it has been found that in addition to the amount of swellable clay present within the granules of the tablet, a further amount of swellable clay may be present outside the granules. At very low intra-granular amounts (such as 1% w/w or below), higher extra-granular amounts (such as about 10% w/w or more) may decrease the dispersion time, but in general extra-granular addition has little or no effect on the dispersion time. The maximum percentage(s) of the clay present within the granules and, optionally outside the granules, may be limited by other practical considerations such as poor flow and compression properties.

Examples of suitable disintegrating agents which can be incorporated intc s, WPM\JT\22nd June 1994 l ??. Mk -m A o m -10- PAm91 according to the invention are: microcrystalline cellulose (e.g. Avicel R) 0 to 30% w/w, preferably 5 to 10% w/w, Sodium carboxymethyl cellulose (e.g. Nymcel R) 0 to 5% w/w, preferably 1 to 2% w/w, calcium carboxymethyl cellulose 0 to 20% w/w, preferably 1 to 5% w/w, modified cellulose gum (e.g. Ac-Di-Sol R) 0 to 10% w/w, preferably 1 to 5% w/w, cross-linked povidone 0 to 10% w/w, preferably 2 to 6% w/w, alginic acid and alginates 0 to 10% w/w, 2 to 5% w/w, pregelatinised starch 0 to 10% w/w, preferably 0.5 to 5% w/w, sodium starch glycollate (e.g. Explotab R, Primojel R) 0 to 10% w/w, preferably 0.5 to 5% w/w, modified corn starch (e.g. starch 1500 R) 0 to 20% w/w, preferably 1 to 10% w/w, starch (e.g. potato/maize starch ) 0 to 15% w/w, preferably 0.2 to 10% w/w, ion exchange resin such as polacrin potassium (e.g. Amberlite IRP-88) up to 5% w/w, preferably 0.5 to 2.0% w/w.

Work with lamotrigine and other active compounds is supportive of the view that if lowhydroxypropylcellulose (LHPC) is used a suitable dispersion can be obtained without the need for a separate wetting agent/surfactant.

Other excipients suitable for inclusion in the tablets according to the invention include the following: a) Binders and Adhesives: we have found that if there is sufficient amount of swellable clay such as Veegum F present within the granules, then a separate binder is not required (i.e. the clay also acts as a binder). Preferably .iowever a separate binder is present in a sufficient amount to provide a tablet having a satisfactory tablet hardness and satisfactory dispersion characterstics. The amount of binder will vary depending on the overall tablet formulation and type of binder used but general functional limits for most tablets of the invention are 0 to 25% w/w. The following binders and amounts are suitable for inclusion in a tablet according to the invention. The concentration of the binder in the granulation fluid (% w/v) is given (% w/w in tablet will vary according to the volume of granulating solution used to form a satisfactory tablet): Examples of binders are: acacia mucilage 0 to 25% w/v, preferably 1 to 5% w/v, alginic acid 0 to 20.0% w/v, preferably 1 to 5% w/v, polyvinylpyrrolidone (povidone) 0 to 15.0% w/v, preferably 0.5 to 5% w/v, gelatin 0 to 20.0% w/v, preferably 1 to 5.0% w/v, sucrose 0 to 70.0% w/v, preferably 2.0 to 20.0% w/v, starch mucilage.,..;-^ 0 to 10.0% w/v, preferably 0.5 to 5.0% w/v, pregelatinised starch 0 to 10:0% WPM\JTY22nd June 1994 pai^4 4441 w/v, preferably 0.5 to 5.0% w/v, starch paste 0 to 10.0% w/v, preferably 5.0 to 10.0% w/v, sodium alginate 0 to 5.0% w/v, preferably 1.0 to 3.0% w/v, sorbitol 0 to 10.0% w/v, preferably 3.0 to 10.0% w/v, tragacanth 0 to 20% w/v, preferably 5.0 to 10.0% w/v, glucose 0 to 50%, preferably 5 to 25% w/v, hydroxypropylmethyl cellulose (HPMC) 0 to 10% w/v, preferably 1.0 to 5.0% w/v, magnesium aluminium silicate 0 to 40% w/v, preferably 2 to 10% w/v, starch paste 0 to 25% w/v, preferably 5 to 15% w/v, polyvinylpyrrolidone 0 to 15% w/v, preferably 3 to 10% w/v, carboxymethylcellulose sodium 0 to 10% w/v, preferably 1 to 6% w/v, dextrin 0 to 50% w/v, preferably 5 to 25% w/v, ethyl cellulose 0 to 10% w/v, preferably 1 to 6% w/v, polyethylene glycol 0 to 5% w/v, guar gum 0 to 10% w/v, preferably 1 to 5% w/v, zein 0 to 30% w/v, preferably 1 to 10% w/v, hydroxyethyl cellulose 0 to 5% w/v, preferably 2 to 4% w/v, hydroxypropyl cellulose up to 5% w/v, preferably 2 to 4% w/v, methyl cellulose up to 20% w/v, preferably 1 to 10% w/v, polymethacrylates up to 25% w/v, preferably 5 to 10% w/v, carboxymethylcellulose calcium 0 to 20% w/v, preferably 5 to 10% w/v. b) Fillers: These serve the purpose of bulking up the tablet to a suitable size and aiding compressibility especially in lower dosage tablets. The amount of filler depends on its type, size of tablet and amount of active compound. When the concentration of active compound is below 60% w/w, more preferably 45% w/w and most preferably below 30% w/w, an inorganic water-insoluble filler is advantageously used. Examples of water-soluble fillers (which can be used in general quantities of 0 to 95% w/w) are: soluble lactose, compressible sugar, confectioners sugar, dextrose, mannitol, sodium chloride, sorbitol, xylitol, sodium chloride F. Examples of water-insoluble fillers (which can be used in general quantities of 0 to 93% w/w) are: calcium carbonate, magnesium carbonate, calcium phosphate (e.g. di and tri basic calcium phosphate), calcium sulphate, kaolin, microcrystalline cellulose, powdered cellulose, pregelatinized starch 5 to 75%, starch, barium sulphate, magnesium tri silicate, aluminium hydroxide.

Inclusion of a filler having a negative heat of solution in water, for example mannitol, sorbitol and xylitol, provides tablets which, in addition to being water-dispersible, are especially suitable for chewing in the mouth, the dissolving of ! o > WPM\JTA22nd June 1994 Zk44 41 such an excipient in the saliva producing a cool, pleasant sensation. c) Lubricants: Generally lubricants are used in as low an amount as possible. Examples of lubricants with percentage weights which are suitable for a tablet are: stearates (e.g. magnesium or calcium stearate) 0.2 to 5% w/w, preferably 0.25 to 1% w/w, talc 0.19 to 5% w/w, preferably 1 to 2% w/w, polyethylene glycol 0.19 to 5% w/w, preferably 2 to. 5% w/w, liquid paraffin 0.18 to 5% w/w, preferably 2 to 5% w/w, sodium lauryl sulphate 0.19 to 5% w/w, preferably 0.5 to 2% w/w, magnesium lauryl sulphate 0.12 to 5% w/w, preferably 1 to 2% w/w, colloidal silicon dioxide 0.1 to 5% w/w, preferably 0.1 to 1.0% w/w, palmitostearate 0.01 to 5% w/w, preferably 1 to 3% w/w, stearic acid 0.01 to 5% w/w, preferably 1 to 3% w/w, zinc stearate 0.01 to 2% w/w, 0.5 to 1.5% w/w, hydrogenated vegetable oil 0.5 to 5% w/w, preferably 1 to 3% w/w. More suitably the lower value is 0.25%. d) Wetting agents/surfactants: examples with suitable amounts are: sodium dodecyl sulphate 0 to 10% w/w, preferably 0.5 to 2% w/w, sodium lauryl sulphate 0 to 10% w/w, preferably 0.1 to 3.0% w/w, polyoxyethylene sorbitan fatty acid esters (Tweens) 0 to 3% w/w, preferably 0.05 to 1.0% w/w, polyoxyethylene stearates 0 to 2% w/w, preferably 0.05 to 1.0% w/w, sorbitan fatty acid esters (Spans) 0 to 3% w/w, preferably 0.05 to 1.0% w/w. e) Glidants: for example, talc 0 to 5% w/w, preferably 1 to 2% w/w, starch 0 to 15% w/w, preferably 2 to 10% w/w, magnesium stearate up to 5%, preferably 0 -2.0% w/w, silica derivatives generally 0 to 1% w/w, preferably 0.2 to 0.5% w/w, such as colloidal silica (e.g. Aerosil) 0 to 0-5% w/w, preferably 0.25 to 3% w/w, pyrogenic silica 0 to 2% w/w, preferably 0.25 to 1% w/w, hydrated sodium silicoaluminate 0 to 2% w/w, preferably 0.5 to 1% w/w, colloidal silicon dioxide Oto 0.5% w/w. f) Flavouring agents: are used in for example approximate quantities of 0 to 5% w/w, preferably 0.25 to 2% w/w, orange, cherry and strawberry, raspberry, grape and passion fruit. g) Sweetening agents: for example sodium saccharin 0 to 10% w/w, prefe WPM\JT\22nd June 1994 PA1 to 5.0% w/w, aspartame 0 to 10% w/w, preferably 0.25 to 5.0% w/w, confectioners sugar 0 to 30% w/w, preferably 5 to 20% w/w, sorbitol 25 to 90% w/w, preferably 0.5 to 10% w/w, sucrose 0 to 85% w/w, preferably 0.5 to 20% w/w, xylitol 0 - 20% w/w, preferably 0.5 to 10% w/w.

Such materials may be incorporated at the appropriate stage(s) of the manufacturing process together with any other agents (e.g. colourants).

Other aspects of the tablet preparation will now be discussed.

Suitably the dry mixing is effected with a mixing time of 5 minutes to 25 minutes preferably about 10 minutes.

The swellable clay can be dry mixed with acyclovir and other excipients and then granulating solution added, or the clay and other excipients can be dispersed firstly in the granulating solution and then added to acyclovir and any other excipients prior to granulation.

The liquid employed to moisten the dry mixture, prior to the granulation step, is preferably aqueous, for example water or a mixture of water and a suitable alcohol such as ethanol or isopropanol.

Wet mixing or granulating times which are suitable (depending on the type of mixer used) are 5 to 20 minutes.

Suitable granule drying times and conditions (which will vary according to the type of o equipment used and batch size of granules) are about 50 to 80 C, (using a dryer such as with a tray or fluid bed dryer) to obtain a moisture content generally below about Generally suitable compression weights and final tablet hardness will vary according to the size of tablet, but generally suitable values are as follows: 4%. pa 2,4^4 41 Approximate Tablet weight (nig) Approximate Tablet diameter (mm) Approximate Target tablet hardness (Kp) 60 5.6 1-2 80 6.4 3-4 125 7.4 4-5 250 8.6 5-6 330 9.4 6-8 500 11.0 10-12 600 11.8 10-14 1000 14.0 12-16 The tablets may optionally be film-coated, for example with hydroxypropylmethyl cellulose, polyethylene glycol or titanium dioxide, and/or may be scored and/or may be polished, for example with polyethylene glycol 8000. If the tablets are film-coated, this makes them easier to swallow or chew (i.e. the tablets are suitable for either dispersion in water or for direct swallowing or chewing), but the dispersion time is increased.

Yet further aspects of the invention with respect to acyclovir are as follows: a) A granulate comprising acyclovir, a pharmaceutically acceptable magnesium aluminium silicate compound and an additional pharmaceutically WPM\JT\22nd June 1994 acceptable ■SET- /, >» T 1441 disintegrating agent; b) Use of a granulate according to a) above for the manufacture of a water-dispersible tablet formulation. c) A water-dispersible pharmaceutical tablet formulation comprising acyclovir, a pharmaceutically acceptable magnesium aluminium silicate compound, and an additional pharmaceutically acceptable disintegrating agent; d) A process for the preparation of a water-dispersible tablet having 200mg to 800mg acyclovir comprising at least 60% w/w/ acyclovir, 0.25 to 40% w/w of a magnesium aluminium silicate, and an additional pharmaceutically acceptable disintegrating agent, said process comprising admixing acyclovir with a magnesium aluminium silicate compound and the additional disintegrating agent, optionally also admixing one or more further pharmaceutical carriers or excipients, granulating the resulting mixture with a pharmaceutically acceptable liquid, drying the resulting granulate, optionally mixing the dried granulate with one or more further pharmaceutical carriers or excipients, and subsequendy compressing the dried granulate to form tablets which conform with the B.P. test given herebefore. The liquid employed in the above granulation step is advantageously aqueous, for example, an aqueous ethanol mixture. The resulting tablets may be subsequently film coated for example with hydroxypropylmethyl cellulose, titanium dioxide or polyethylene glycol and, if desired, polished for example with polyethylene glycol 8000.

Tablets according to the invention containing acyclovir advantageously include a magnesium aluminium silicate such as Veegum F as the swellable clay.

In such tablets the ingredients are advantageously present in the following proportions: acyclovir 40 to 98% w/w, preferably 75 to 85% w/w, swellable clay 0.5 to 40% w/w, preferably 0.5 to 10% w/w.

A suitable formulation of an acyclovir dispersible tablet containing from 200mg- 800mg acyclovir would be: « /«■> ' * WPM\JT\22nd June 1994 b \ n r o 24*1441 -16- PA1219NZ Acyclovir 70% w/w to 90% w/w, preferably 75-85% w/w Povidone or pregelled starch 0.25% w/w to 5% w/w, preferably 0.5-2% w/w Magnesium aluminium silicate Veegum F or bentonite 0.5% w/w to 30% w/w, preferably 0.5-10% w/w Microcrystalline cellulose Avicel PHI 01 or LHPC-LH11 % w/w to 25% w/w, preferably 5-15% w/w Sodium starch glycollate 0% w/w to 8% w/w, preferably 0-5% w/w Magnesium stearate 0.25% w/w to 2% w/w, preferably 0.25-1.0% w/w and if optionally film coated: Opadry 0.1 % w/w to 2% w/w, preferably 0.25-1.0% w/w Polyethylene glycol 8000 0.1% w/w to 0.5% w/w, preferably 0.1-0.2% w/w The following Examples illustrate the present invention.

Examples 1 to 6 and 29 are comparative examples while examples^7-28, 30 and 31 describe the preparation of tablets according to the invention in which the active compound is acyclovir. /r^ % K f 'X WPM\JT\22nd June 1994 17- 2M441 Example 1 Number me/tablet 2 mg/tablet 3 mg/tablet 4 mg/tab Acyclovir * 848.0 848.0 844.0 844.0 Avicel PH101 60.0 NIL 101 NIL Lactose 120.0 NIL NIL NIL Starch (maize) NIL NIL 50 NIL Explotab NIL 75.0 50 NIL Primogel NIL NIL NIL 75.0 Ac-Di-Sol 83.0 NIL 23 NIL Kollidon CL starch NIL NIL NIL NIL Saccharin sodium .0 .0 NIL NIL Sodium lauryl .0 NIL 3.0 NIL sulphate Sodium docusate NIL 1.0 NIL 0.5 Dicalc.phosph.dihyr. NIL NIL NIL 200.0 Povidone K30 NIL .0 22 11.2 Extra-granular: Ac-Di-Sol 40.0 NIL NIL NIL Avicel PHI02 60.0 94 NIL NIL Amberlite 1RP88 NIL NIL NIL 50.0 Kollidon CL NIL NIL 60.1 NIL Mg stearate 12.0 .0 .1 11.0 Tablet weight (mg) 1248.0 1048.0 1163.2 1191.7 * In the following examples except examples 13, 14 and 15, the actual quantity of acyclovir used is calculated from a factor so as to provide 800mg of acyclovir per tablet. (The factor for acyclovir is typically 105.5 equivalent to 100 acyclovir). In examples 13, 14 and 15, the actual quantity of acyclovir used was adjusted from the factor so as to provide 800mg of acyclovir per tablet.

WPM\JT\22nd June 1994 ry n r,; : ■irjQJi e. '■ .J:H w-t:' Vs.' -18- TR1219; Example 6 7 8 9 Number mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet Acyclovir 844.0 848.0 844.0 848.0 848.0 Avicel PH 101 101.0 83.46 100.0 89.0 89.0 Veegum F NIL NIL 53.0 53.0 53.0 Sodium starch 90.0 39.37 42.0 42.0 42.0 glycollate (Explotab) Povidone K30 11.0 .27 NIL 11.0 11.0 Magnesium 9.5 8.85 9.4 9.4 9.4 stearate Film coat composite 1: Opadry NIL NIL NIL NIL 7.86 Film coat composite 2: Polyethylene glycol 8000 NIL NIL NIL NIL 2.097 Tablet weight 1055.5 989.95 1048.4 1052.4 1062.4 (mg) In accordance with the invention, to illustrate that the disintegration time remains substantially constant at different tablet hardnesses, the formulation of Example 7 was compressed at approximately 8 kp (7a), 12 kp (7b) and 18 kp (7c) and the results noted hereafter.

WPM\JT\22nd June 1994 Z«441 Example 10 11 12 Number mg/tablet mg/tablet mg/tablet Acyclovir 848.0 848.0 848.00 Avicel PH 101 118.5 71.1 86.8 Veegum F 26.5 * 53.0 53.0 Primojel 42.0 42.0 42.0 Po*ddone K30 NIL 20.9 5.2 Magnesium 9.4 9.4 9.4 stearate Tablet weight 1044.4 1044.4 1044.4 (mg) * Veegum added as a paste - example contains no PVP-K30 as a binder.

WPM\JT\22nd June 1994 / ■tv- /•' • (,...

\ V n T o i 241441 -20- PA1219NZ Examples of Acyclovir formulations Example Number 13 14 15 mg/tablet mg/tablet mg/tablet Component (mg/tablet) Acyclovir Avicel PH 101 Veegum F Sodium starch glycollate Povidone KL30 800.0 800.0 800.0 100.0 53.0 42.0 NIL 89.0 53.0 42.0 11.0 89.0 110.0 42.0 11.0 Magnesium stearate 9.4 9.4 9.9 Tablet weight (mg) 1004.4 1004.4 1061.9 WPM\JT\22nd June 1994 241A4t -21- PA1219NZ Example 16 17 18 19 Number % w/w rn °aw/w mg/ % w/w mg/ % w/w mg/ tablet tablet tablet tablet Acyclovir 79.95 848.0 75.54 795.00 65.47 689.00 55.00 583.00 Avicel PH101 8.86 89.0 8.86 89.00 8.86 89.00 8.86 89.00 Veegum F 5.28 53.0 10.00 106.00 20.00 212.00 30.00 318.00 Explotab 4.18 42.0 4.18 42.00 4.18 42.00 4.18 42.00 Povidone 1.09 11.0 1.09 11.00 1.09 11.00 1.09 11.00 K30 Magnesium 0.94 9.4 0.94 9.40 0.94 9.40 0.94 9.40 stearate Tablet weight 100.0 1052.4 100.0 1052.4 100.0 1052.4 100.0 1052.4 (mg) p^i4z14 41 Example Number 21 22 % w/w mg/ % w/w mg/ % w/w mg/ tablet tablet tablet Acyclovir 45.32 477.00 84.3 890.00 44.93 848.00 Avicel PHlOl 8.86 89.00 8.86 89.00 8.86 157.76 Veegum F 40.00 424.00 1.00 10.60 40.00 712.22 Explotab 4.18 42.00 4.18 42.00 4.18 74.43 Povidone K30 1.09 11.00 1.09 11.00 1.09 19.41 Magnesium stearate 0.94 9.40 0.94 9.40 0.94 16.74 Tablet weight (mg) 100.00 1052.4 100.00 1052.4 100.00 1828.56 WPM\JT\22nd June 1994 :: - >*v,. - " * ' ,»>V °X f. ?r m m m - 23 - PAl £41441 Example 23 24 25 26 Number % w/w mg/ % w/w mg/ % w/w mg/ % w/w mg/ tablet tablet tablet tablet Acyclovir 65.47 689.00 55.00 583.00 45.32 477.00 79.65 848.00 Avicel 8.86 89.00 8.86 89.00 8.86 89.00 8.86 89.0 PHlOl Veegum F *20.00(106.00*30.00 (159.00*40.00 (212.00 5.28 53.0 (106.00 (159.00 (212.00 Explotab 4.18 42.00 4.18 42.00 4.18 42.00 4.18 42.0 Povidone 1.09 11.00 1.09 11.00 1.09 11.00 1.09 11.0 K30 Magnesium 0.94 9.40 0.94 9.40 0.94 9.40 0.94 9.4 stearate Tablet weight 100.00 1052.4 100.00 1 052.4 100.00 1052.4 100.00 1052.4 (mg) * In these examples the Veegum is distributed equally both intra-granularly and extra-granularly.

I?* ^ ! WPM\JT\22nd June 1994 -24- PAl Example 27 Number % w/w mg/ % w/w tablet 28 mg/ tablet % w/w 29 mg/ tablet mg/ tablet 31 mg/ tablet Acyclovir 84.43 848.00 84.68 848.00 84.93 848.00 848.0 840.0 Avicel 8.86 83.95 8.86 PHlOl 83.70 8.86 83.46 89.0 89.0 Veegum F 0.50 4.74 0.25 2.36 0.00 0.00 - - Bentonite - - - 53.0 NIL Attapulgite - - - - NIL 53.0 Explotab 4.18 39.60 4.18 39.49 4.18 39.37 42.0 42.0 Povidone 1.09 10.32 1.09 K30 .30 1.09 .27 11.0 11.0 Magnesium 0.94 8.91 0.94 stearate 8.88 0.94 8.85 9.1 9.1 Tablet weight 100.00 995.53 100.00 992.73 100.00 989.95 (mg) 1052.1 1044.1 WPM\JT\22nd June 1994 ( A' . f V • Jo is| 1394 1 '2t\ 4 A t Method of Preparation The tablets described in Examples 1-31 above were prepared according to the following general method: (a) A dry mixture was made of all components except Povidone/PVP K30, sodium docusate (if present) and magnesium stearate; (b) The Povidone/PVP K30 and sodium docusate (if present) were dissolved in 50% v/v aqueous alcohol to form a granulation solution; (c) The granulation solution was added to the dry mixture to form granules; (d) The wet granules were dried in a fluid bed dryer; (e) The granules were then sifted through a lOOOjim diameter mesh sieve; and (f) The dried granules were blended with the magnesium stearate and compressed to form tablets.

Flavouring agents where present were added at blending step (f) above.

This general method is illustrated with respect to the following specific examples.

Example 8 : Uncoated Tablets (a) A dry mixture was made of all components except Povidone/PVP K30 and magnesium stearate using a Diosna PI00 (high shear mixer - granulator) for 3 (b) The Povidone/PVP K30 was dissolved in 50% aqueous alcohol to form a granulation solution. minutes. (c) The granulation solution was added to an approximate quantity of dry weight to the dry mixture to form granules. Wet mixing was ( WPM\JT\22nd June 1994 - 26 - PA 2414 41 approximately 5 minutes. (d) The wet granules were dried in an Aeromatic T3 fluid bed drier at a temperature of 70 C for approximately 30 minutes. The moisture content of the granules was approximately 4%. (e) The granules were then sifted through a lOOO^m diameter mesh sieve using a Jackson Crockatt No.7 sifter. (f) The dried granules were blended with the magnesium stearate using a collette mixer for approximately 10 minutes and compressed to form tablets using a Manesty D3 Rotary tablet press fitted with caplet shaped punches of approximately 19.3mm length and 9.0mm breadth. Tablets were compressed to a weight of 1052mg ± 2%.

This granule can be used to make other strengths of acyclovir dispersible tablets, e.g. 200mg and 400mg, compressing the dried granules to a weight of respectively 263mg and 526mg, using round punches with diameters of respectively 11.0mm and 8.6mm.

Example 9 : Film Coated Tablets Steps (a) to (f) described in Example 8 were repeated to form an uncoated tablet which was then film-coated by the following procedure.

The film-coating apparatus used was a Manesty Accellacota 10. The coating suspension was sprayed onto the tablet cores to a target weight increase of between 0.5 -1.0% using suitable parameters of: pan rotation speed (8.5 rpm) spray (application rate (~20g per min) o inlet temperature (-75 C) o exhaust temperature (-53 C).

A polish coat of PEG8000 was then applied to the film-coated tablets, to a further weight gain of 0.1 - 0.2%.

WPM\JT\22nd June 1994 -27- 2p4*2%4 41 Examples 13 to 15 In Example 13, Acyclovir, Avicel PHlOl, Sodium starch glycollate and Veegum F are dry mixed in a mixer. The mixture is then granulated after adding a sufficient volume of 50% aqueous alcohol (IMS). The resulting granules are dried, blended with the magnesium stearate and then compressed to form tablets.

Example 14 The procedure described in Example 13 for the preparation of the granules and formation of the tablets is employed except that granulation of the dry mixture is effected with the Povidone in a 50% aqueous alcohol solution. Film coating of the resulting tablets can be optionally effected by treating the tablets with a dispersion of Opadry white dispersion in purified water and drying the coated tablets which are subsequently polished with a solution of polyethylene glycol 8000, USNF in 50% aqueous alcohol (IMS).

For Example 15, the procedure described in Example 13 for the preparation of the granules and formation of the tablets is employed except that granulation of the dry mixture was effected with the Povidone in a 50% aqueous alcohol solution.

Further Example (a) A dry mixture was made of all components except Povidone/PVP K30 and magnesium stearate using a Z-blade Morton Mixer, mixing for 10 minutes at a slow speed. (b) The Povidone/PVP K30 was dissolved in 50% v/v aqueous alcohol to form a granulation solution; (c) The granulation solution was added to an approximate quantity of 350ml per kg dry weight to the d.y mixture to form granules; (d) Wet mixing was carried out for approximately 10 minutes. The wet granules were sieved through a 2000nm mesh sieve; (e) The wet granules were dried in an Aeromatic ^idE^ad'^i'fe^t a tem o WPMYJTV22nd June i 994 | 1 ? f f33*t B \ ?r l: o 70 C for approximately 25 minutes; (0 The granules were then sifted through a lOOOfim diameter mesh sieve; (g) The dried granules were blended with the magnesium stearate using a Rotomixer rotary blender for 5 minutes and compressed to form tablets using a Manesty D3 Rotary press fitted with 5.6mm diameter round (normal curvature) punches and dies. Tablets were compressed to a weight of 62.55mg ± 2%.

Flavouring agents may be added at blending step (g) above.

For a 50mg tablet, the same procedure was used, except that a die of 11.8mm diameter was used and the tablets were compressed to a weight of625.5mg ± 2%.

The lamotrigine tablets could be optionally film coated using the same procedure as described for Example 9.

The tablets prepared in accordance with the above Examples were then tested as follows.

Tablet Evaluation Methods 1. Average tablet weight. Twenty tablets were weighed on an analytical balance and the average tablet weight calculated. 2. Tablet breaking strength (kilo pond-kpl. 5 tablets were individually tested using a Schleuniger crushing strength tester, and the average breaking strength 3. Friability (% lossY 10 tablets, accurately weighed, were subjected to 10 minutes friability testing using a Roche Friabilator. The tablets were dedusted, reweighed, and the weight loss due to the friability was calculated as a percentage of the initial weight. calculated. 4. Dispersion Disintegration time DT CBP 1988V 6 tablets WPM\JT\22nd June 1994 - 29 - PA accordance to the above-defined BP test (without discs) for dispersible tablets. o This utilises water at a temperature of 19-21 C.

. Dispersion Quality. In accordance with the BP uniformity of dispersion test for dispersible tablets (BP 1988 Volume II page 895), two tablets were placed in o 100ml of water at 19-21 C and allowed to disperse. A smooth dispersion was produced which passed through a 710nm mesh sieve.

Granule Evaluation Methods 1. Loss on Drying flLQDV The residual moisture content of the granule (LOD) was o determined on a 3-4g sample using a Computrac moisture analyser set to 90 C operated in accordance with the manufacturer's procedure. 2. Weight Median Diameter (WMDV A lOg sample of granule was sifted for 2 minutes at suitable pulse and sift amplitudes in an Allen Bradley sonic sifter in accordance with manufacturer's instructions. Sieves of 710(im, 500|xm, 355fxm, 250|a, 150jim, 106|am and 53|im were used. The WMD was calculated from the cumulative percentage undersize size distribution using a computer programme.

PA1219NZ Acyclovir Granule and Tablet Evaluation Results Example Number Actual Average Tablet Weight (Kp) Target Average Tablet Thickness Weight Tablet Tablet Average Breaking Strength WMD (fim) Fria- Disintegration bility time ** First Last Granule Properties Loss on Weight Drying median (%LOD) diameter Tablet shape/ maximum diameter 1 2 3 4 6 7a 7b fr> 1176 1053 983 1022 1046 7o-/ // 1248.0 1048.0 1163.2 1191.7 1055.5 989.95 1048.4 1048.4 1048.4 .46 11.0 11.6 .7 13.7 .0 .8 7.2 12.8 17.1 12*17" 7'26" >10" 4'50" 4'21" 0.34 6'27" 7'26" 2.74 0.47 0.19 0'33" 0'42" 0'44" 1.43 1.59 2.28 1.18 1.75 1.43 1.31 1.31 1.31 186 315 233 233 233 Caplet* Caplet Round 14.0mm Round 14.0mm Round 14.0mm Caplet Caplet CapiEtS2* Caplet \ (Ai Q I 31- 8 1049 1052.4 7.0 14.6 (uncoated) 9 1053 1062.4 6.99 16.1 (coated) ** All dispersions passed through a 710 Jim sieve (BP uniformity of dispersion test).

PA1219NZ 0.18 0'35" 4.06 138 Caplet negligible 1'05" 4.06 138 Caplet 1 \ ro 4S Example Number Actual Average Tablet Weight (Kp) Target Tablet Weight Average Thickness (%) Tablet Tablet Average Breaking Strength WMD(nm) - 1044.4 - 14.4 11 - 1044.4 - .3 12 - 1044.4 - 13.3 13,14,15 *** 16 1051.24 1052.4 7.1 11.6 17 1059.54 1052.4 7.0 11.8 18 1060.79 1052.4 6.90 11.5 19 1053.4 1052.4 6.70 11.6 1057.6 1052.4 6.71 9.1 21 1048.8 1052.4 7.24 11.5 22 1743.9 1828.56 .40 11.6 23 1054.2 1052.4 6.90 11.5 ** All dispersions passed through a 710 fam sieve (BP uniformity of dispersion test).

PA1219NZ Fria- Disintegration Granule Properties Tablet bility time Loss on Weight shape/ ** Drying median maximum First Last (%LOD) diameter diameter 0.11 - 0'32" 2.65 123 Caplet 0.24 - 0'46" 1.46 196 Caplet 0.73 - 0'27" 1.76 105 Caplet 0.49 0*46" 0'49" 1.12 185 Caplet 0.46 0'28" 0'30" 2.18 125 Caplet 0.62 o'n" 0'19" 1.46 178 Caplet 0.71 0'19" 0'24M 2.00 73 Caplet 2.45 O^O" 0'23" 1.81 90 Caplet 0.85 2'18" 2'59" 1.15 341 Caplet 2.19 0'29" 0'31" 1.84 83 Caplet 0.09 0'43M 0'51" 1.84 157 Caplet ro •a* Example Actual Target Average Average Number Average Tablet Thickness Breaking Tablet Weight Strength Weight (Kp) (%) Tablet Tablet WMD (jim) 24 1059.1 1052.4 6.90 11.4 1052.6 1052.4 6.70 11.9 26a)# 130.6 131.55 2.80 4.2 26b)# 526.0 526.2 4.81 12.84 26c)# 1216.5 1215.0 8.20 11.10 27 125.7 124.4 3.68 3.68 28 29 31 124.7 982.9 1041.2 1038.6 124.1 989.95 1052,1 1044.1 2.78 5.46 3.55 .8 11.8 16.6 PA1219NZ Fria- Disintegration bility time ** First Last Granule Properties Loss on Weight Drying median (%LOD) diameter Tablet shape/ maximum diameter 0.02 0'55" roo" 0.68 142 Caplet 0.09 1'30" 1'42" 1.59 118 Caplet 0.56 025" 0*28" 1.34 296 7.4mm Round 0.79 0'26" 0'30" 1.34 296 ll.Omn Round 0.83 0'45" 0'51" 1.34 296 Caplet 0.71 0*33" 0'39" 1.21 334 7.4mm Round 0.65 0'44" 0'47" 1.90 332 7.4mm Round 0.34 6'27H 776" 1.43 315 Caplet - 130" 1'55" 1.62 227 Caplet 1.59 © 3 2'10" 1.96 150 Caplet no JS I •J**' ** Disintegration times measured in accordance with BP test for dispersible tablets. All dispersions passed through a 710 |im sieve (BP uniformity of dispersion test).

# Same granule formulation, but different compression weights giving approximately: a=100mg, b=400mg and c=925mg of acyclovir per tablet.

*** Examples 13,14 and 15 disintegrated in 0'30" to 1'30".

PA1219NZ I \ ro 4^ * < PA1219NZ A particle size analysis was carried out on the dispersion of a tablet of Example 9 in accordance with the following method.

The particle size distribution was determined using a Malvern 2600 particle analyser as follows. The instrument was set to analyse particles in liquid with magnetic stirrer fitted. A 300mm focal length lens was used. 1. Disperse tablet in 100ml of de-ionised water. 2. Agitate solution for approximately 2 hours. 3. Filter or centrifuge solution to obtain liquor which should be saturated with all ingredients present in the tablet. 4. Disperse second tablet in 50ml of saturated liquor allowing 3 minutes to fiilly disperse. Agitate vigorously and remove a sample of the dispersion within 5 minutes adding sufficient quantity to the Malvern PIL cell containing the liquor to obtain an observation value of 0.15-0.30. Analyse sample.

The particle size distribution was as follows: Particle size: (as equivalent spherical volume) <710|im -100% <300fim - 98.7% <200^im - 86.7% <130jim - 50% (median particle size). 241441

Claims (30)

WHAT WE CLAIM IS:

1) A water dispersible tablet having 200mg to 800mg acyclovir comprising at least 60% w/w acyclovir, 0.25 to 40% w/w of a pharmaceutically acceptable swellable clay which is present within the granules of the tablet, and an effective amount of an additional pharmaceutically acceptable disintegrating agent which is present within the granules of the tablet to provide a tablet which is capable of dispersing in water within a period of 3 minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710/zm in accordance with the test for dispersible tablets defined in the British Pharmacopoeia 1988, volume II, page 895.

2) A tablet as claimed in claim 1 wherein the swellable clay is a smectite or attapulgite.

3) A tablet as claimed in claim 2 wherein the smectite is selected from the montmorillonite gronp.

4) A tablet as claimed in claim 3 wherein the montmorillonite 's magnesium aluminium silicate or bentonite.

5) A tablet as claimed in any one of the preceding claims wherein the swellable clay is present within the granules of the tablet in an amount of 1 to substantially 10% w/w.

6) A tablet as claimed in any one of the preceding claims wherein the additional pharmaceutically acceptable disintegrating agent is sodium starch glycolate or LHPC.

7) A tablet as claimed in any one of the preceding claims which further comprises a binder.

8) A tablet as claimed in claim 7 wherein the binder is povidone.

9) A tablet as claimed in any one of the preceding claims which further comprises a filler. £41441

10) A tablet as claimed in claim9 wherein the filler is microcrystalline cellulose.

11) A tablet as.claimed in any one of the preceding claims which is further film coated and wherein the dispersion time can be up to 5 minutes.

12) A tablet as claimed in any one of claims 1 to 10 which is capable of dispersing in water within a period of 2 minutes.

13) A tablet as claimed in any one of the preceding claims wherein the dispersion contains particles having a particle size distribution of 100% less than 710nm, and more than 50% less than 300{im.

14) A tablet as claimed in claim 13 wherein the dispersion contains particles having a particle size distribution of 100% less than 710|xm, more than 70% less than 300ja m, and more than 50% less than 200(xm.

15) A tablet us claimed in any one of the preceding claims wherein the tablet comprises 200 to 800mg of acyclovir and has a formulation of acyclovir 70 to 90% w/w, povidone or pregelled starch 0.25 to 5% w/w, magnesium aluminium silicate or bentonite 0.5 to 30% w/w, microcrystalline cellulose or LHPC 5 to 25% w/w, sodium starch glycollate 0 to 8% w/w, magnesium stearate 0.25 to 2% w/w, and optional film-coating composites of opadry 0.1 to 2% w/w, and polyethylene glycol 8000 0.1 to 0.5% w/w.

16) A tablet as claimed in claim 15 wherein the formulation is acyclovir 75 to 85% w/w, povidone or pregelled starch 0.5 to 2% w/w, magnesium aluminium silicate or bentonite 0.5 to 10% w/w, microcrystalline cellulose, or LHPC-LH11 5 to 15% w/w, sodium starch glycollate 0 to 5% w/w, magnesium stearate 0.25 to 2.0% w/w, and optional film-coating composites of opadry 0.25 to 1.0% w/w, and polyethylene glycol 8000 0.1 to 0.2% w/w.

17) A tablet as claimed in any one of claims 4, 15 and 16 wherein the swellable clay is Veegum F.

IS) A tablet as claimed in any one of the preceding claims wherein the amount of - 38 2A1441

19) A tablet as claimed in claim 1 wherein the acyclovir is present in substantially 750 to 850mg, the total tablet weight is substantially lOOOmg to 12u0mg, and the amount of swellable clay present is substantially 40 to 120mg.

20) A tablet as claimed in claim 16 consisting of substantially 79.95% w/w acyclovir, substantially 8.86% w/w Avicel PHlOl, substantially 5.28% w/w Veegum F, substantially 4.18% w/w Explotab, substantially 1.09% w/w povidone K30, and substantially 0.94% w/w magnesium stearate.

21) A tablet as claimed in claim 20 which consists of substantially 800mg acyclovir, substantially 89mg Avicel PHlOl, substantially 53mg Veegum F, substantially 42mg Explotab, substantially llmg povidone K30, and substantially 9.4mg magnesium stearate.

22) A process for the preparation of a water-dispersible tablet having 200mg to 800mg of acyclovir comprising at least 60% w/w acyclovir, 0.25 to 40% w/w of a pharmaceutically acceptable swellable clay and an additional pharmaceutically acceptable disintegrating agent, said process comprising bringing acyclovir into association with said swellable clay and additional disintegrating agent to form granules, and then compressing the granules to form a tablet which is capable of dispersing in water within a period of 3 minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710jxm in accordance with the test for dispersible tablets defined in the British Pharmacopaeia, 1988, volume II, page 895.

23) A process as claimed in claim 22 comprising the steps of: a) admixing in dry, finely-divided form acyclovir, the swellable clay and the additional disintegrating agent, optionally with the addition of one or more other pharmaceutical carriers or excipients; b) addition of a quantity of a pharmaceutically acceptable liquid sufficient to moisten the dry mixture; c) granulation of the resulting moist mixture with a granulating fluid to form granules; 241441 d) drying the granules and optionally blending the granules with other optional carriers or excipients such as lubricants, glidants, and flavouring agents; and e) compression of the granules to form a tablet which is capable of dispersing in water within a period of 3 minutes to provide a dispersion which will pass through a sieve screen with a mesh aperture of 710(im in accordance with the above-defined British Pharmacopoeia test for dispersible tablets.

24) A process as claimed in claim 23 wherein the granulating fluid is povidone dissolved in 50% v/v aqueous alcohol.

25) A process as claimed in any one of claims 22 to 24 wherein a filler is also admixed with acyclovir, the swellable clay and additional disintegrating agent.

26) A process as claimed in any one of claims 22 to 25 wherein a high shear mixer is used to mix the acyclovir, swellable clay and additional disintegrating agent.

27) A process as claimed in any one of claims 22 to 26 wherein the tablet is then further film coated.

28) A process as claimed in claim 22, substantially as hereinbefore described with particular reference to any one of Examples 7 to 28, 30 and 31.

29) A tablet as claimed in claim 1, substantially as hereinbefore described with particular reference to any one of Examples 7 to 28, 30 and 31.

30) A tablet as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 22 to 28. r> D THIS ^ DAY OF (T*^\ A. J. PARK & SON PER AGENTS FOR THE APPLICANTS