Abstract:
A water-dispersible tablet comprises acyclovir and a dispersing agent. The dispersing agent is a swellable clay such as a smectite e.g., Veegum F or bentonite, and is present within the granules of the tablet to provide a tablet which is capable of dispersing in water within 3 minutes to provide a dispersion which will pass through a 710 μm sieve. The tablet also includes a cellulostic excipient. The tablet can be optionally film-coated, in which case the dispersion time is less than 5 minutes.

Description:
This application is a continuation-in-part of U.S. Ser. No. 041,126 filed Mar. 30, 1993, now abandoned, which is a continuation of U.S. Ser. No. 827,655 filed Jan. 29, 1992 (now abandoned). 
    
    
     The present invention relates to a water-dispersible tablet formulation containing acyclovir. 
     BACKGROUND OF THE INVENTION 
     Acyclovir (UK Patent Specification No. 1523865; U.S. Pat. No. 4,199,574) 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 simplex virus, or chicken pox or shingles, caused by the varicella zoster virus. 
     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 800 mg five times per day. A tablet formulation containing 800 mg 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. 
     We have now been able to prepare water-dispersible tablets containing acyclovir which can readily be dispersed in water to form a dispersion which can easily and conveniently be drunk by e.g. an elderly patient. More particularly the tablets of the invention meet the criteria for dispersible tablets set out in the British Pharmacopoeia (B.P. 1988, page 895, volume II) in that they disperse in water within 3 minutes to form a dispersion that will pass through a 710 μm sieve. 
     Furthermore, at a high drug loading, the overall size of a tablet containing 800 mg acyclovir (for shingles) is still small enough to swallow. The patient, depending on his capability, thus has the choice of swallowing or dispersing the tablet. 
     SUMMARY OF THE INVENTION 
     According to the present invention a water-dispersible tablet having 200 to 800 mg acyclovir, preferably about 200 mg, or about 400 mg, or about 800 mg acyclovir, is provided as follows: 
     
         __________________________________________________________________________intragranular:Acyclovir                 65% w/w to 95% w/w, preferably 70% w/w to 90%                     w/w, more preferably 75 to 85% w/w, most                     preferably                     about 80% w/wPovidone                  0.25% w/w to 5% w/w, preferably 0.5 w/w to 2%                     w/w(e.g. Povidone K30)Swellable clay(s)         0.5% w/w to 30% w/w, preferably 0.5% w/w to                     10%                     w/wexcipient selected from   1% w/w to 25% w/w, preferably 1% w/w to 15%                     w/wsubstituted hydroxyalkyl  such as 1% to 8% w/w, (e.g. 1% to 5% w/w)cellulosticdisintegrating agentpreferably substitutedhydroxypropyl cellulose (e.g. LHPC) andhydroxypropymethyl cellulose (e.g. LHPMC),orSodium starch             1% w/w to 8% w/w, preferably 2% to 6% w/wglycollate (e.g. explotab and primojel):or a combination of said excipientsextragranular:Lubricant,The tablet can be optionally film coated, suitably using:Opadry                    0.1% w/w to 2% w/w, preferably 0.25% to 1.0%                     w/wPolyethylene              0.1% w/w to 0.5% w/w, preferably 0.1% to 0.2%                     w/wglycol 8000__________________________________________________________________________ 
    
     In a further aspect of the present invention a water-dispersible tablet having 200 to 800 mg acyclovir, preferably about 200 mg, or about 400 mg, or about 800 mg acyclovir, is provided as follows: 
     
         __________________________________________________________________________intragranular:Acyclovir                           65% w/w to 95% w/w, preferably 70%                               w/w to 90%                               w/w, more preferably 75% to 85% w/w,                               most preferably                               about 80% w/wPovidone                            0.25% w/w to 5% w/w, preferably 0.5%                               to 2% w/w(e.g. Povidone K30)Swellable clay selected from        0.5% w/w to 30% w/w, preferably 0.5%                               w/w to 10%sepiolite such as attapulgite, or   w/w, more preferably 3% to 10% w/w,                               still moreselected from smectite wherein the  preferably about 5% w/wsmectite is preferably montmorillonite,such as magnesiumaluminiumsilicate(e.g. Veegum F) orbentonite; or a combinationthereofCellulostic excipient selected from 5% w/w to 25% w/w, preferably 5% to                               15% w/wmicrocrystallinecellulose(e.g. Avicel)substituted hydroxypropyl cellulosee.g. low substituted hydroxypropyl cellulose (LHPC) andsubstituted hydroxypropymethyl cellulose (e.g. LHPMC)e.g. low substituted hydroxypropylmethyl cellulose (LHPMC); or acombination thereofSodium starch                       1% w/w to 8% w/w, preferably 2% w/w                               to 6% w/wglycollate (e.g. explotab and primojel)extragranular:lubricant, preferably               0.25% w/w to 2% w/w, preferably 0.25%                               to 1.0% w/wmagnesiumstearateThe tablet can be optionally film coated, suitably using:Opadry                              0.1% w/w to 2% w/w, preferably 0.25%                               to 1.0% w/wPolyethylene                        0.1% w/w to 0.5% w/w, preferably 0.1%                               to 0.2% w/wglycol 8000__________________________________________________________________________ 
    
     In yet a further aspect of the present invention a water-dispersible tablet having 200 to 800 mg acyclovir, preferably about 200 mg or about 400 mg or about 800 mg acyclovir, is provided as follows: 
     
         __________________________________________________________________________intragranular:Acyclovir                 65% w/w to 95% w/w, preferably 70% w/w to 90%                     w/w, more preferably 75% w/w to 85% w/w, most                     preferably about 80% w/wPovidone                  0.25% w/w to 5% w/w, preferably 0.5% to 2% w/w(Povidone K30)Swellable clay selected from sepiolite                     0.5% w/w to 30% w/w, preferably 0.5 w/w to 10%such as attapulgite, or selected from                     w/w, more preferably 3% to 10% w/w, still moresmectite wherein the smectite is                     preferably about 5% w/wpreferably montmorillonite,such as magnesiumaluminiumsilicate(e.g. Veegum F) orbentonite; or a combination thereofsubstituted hydroxypropyl 1% w/w to 25% w/w, preferably 1% to 15% w/w                     suchcellulose (e.g. LHPC)     as 1% to 8% w/w (e.g. 1% to 5% w/w)orsubstituted hydroxypropymethylcellulose (e.g. LHPMC); or a combination thereof(optionally) microcrystalline                     5% to 25% w/w preferably 5% to 15% w/wcellulose(e.g. Avicel)extragranular:lubricant, preferably     0.25% w/w to 2% w/w, preferably 0.25% to 1.0%                     w/wmagnesiumstearateThe tablet can be optionally film coated, suitably using:Opadry                    0.1% w/w to 2% w/w, preferably 0.25-1.0% w/wPolyethylene              0.1% w/w to 0.5% w/w, preferably 0.1-0.2% w/wglycol 8000__________________________________________________________________________ 
    
     In yet a further aspect of the present invention a water dispersible tablet having 200 to 800 mg acyclovir, preferably about 200 mg, or about 400 mg or about 800 mg acyclovir, is provided as follows: 
     
         __________________________________________________________________________intragranular:Acyclovir           65% w/w to 95% w/w, preferably 70% w/w to 90%               w/w, more preferably 75% to 85% w/w, most preferably               about 80% w/wPovidone            0.25% w/w to 5% w/w, preferably 0.5% to 2% w/w(e.g. Povidone K30)Swellable clay preferably selected from               0.5% w/w to 30% w/w, preferably 0.5% to 10% w/w,sepiolite such as attapulgite, or selected               more preferably 3% to 10% w/w, still more preferably               aboutfrom smectite wherein the smectite is               5% w/wpreferably montmorillonite,such as magnesiumaluminiumsilicate(e.g. Veegum F) orbentonite; or a combination thereof               1% w/w to 25% w/w, preferably 1% to 15% w/w suchsubstituted hydroxypropymethyl cellulose               as 1% to 8% (e.g. 1% to 5% w/w)(e.g. LHPMC)(optionally)Sodium starch       1% w/w to 8% w/w preferably 2% w/w to 6% w/wglycollate (e.g. explotab and primojel)(optionally)microcrystalline cellulose               5% w/w to 25% w/w, preferably 5% to 15% w/w(e.g. Avicel)extragranular:lubricant, preferably               0.25% w/w to 2% w/w, preferably 0.25% to 1.0% w/wMagnesiumstearate__________________________________________________________________________ 
    
     The tablet can be optionally film coated, suitably using: 
     
         ______________________________________Opadry   0.1% w/w to 2% w/w, preferably 0.25% to 1.0%    w/wPolyethylene    0.1% w/w to 0.5% w/w, preferably 0.1% to 0.2%glycol 8000    w/w______________________________________ 
    
     Preferably acyclovir is present in a 2/3 hydrate form (i.e. a ratio 3 acyclovir:2 water molecules). 
     Yet a further aspect of the invention is granules for a water dispersible tablet as defined herein. 
     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 may 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 swallowing 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 as required for disintegration of film-coated tablets. According to a further feature of the present invention therefore we provide a water-dispersible film-coated tablet wherein the dispersion time can be up to 5 minutes. 
     The particle size distribution of the dispersion is set out in the following table with the increasingly preferred values being quoted form left to right. 
     
         ______________________________________Particle   BP                  More    MostSize (μm)*   Standard Preferably Preferably                               Preferably______________________________________&lt;710    &lt;100%     100%       100%    100%&lt;300    --       &gt;50%       &gt;70%    &gt;80%&lt;200    --       --         &gt;50%    &gt;70%&lt;150    --       --         --      &gt;50%______________________________________ *(equivalent spherical volume diameter) 
    
     The term &#34;swellable clay&#34; 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 &#34;layered clays&#34; 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 well as the montmorillonite group, related smectites such as vermiculites may also have application. 
     The term &#34;interstratified or mixed layer clays&#34;, 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 (&#34;acid clays&#34;), 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 smectites are also known e.g. interdispersed montmorillonite and beidellite layers. The layers of mixed layer clays may be homogeneous or non-homogeneous. 
     The term &#34;porous fibrous clays&#34; includes polygorskite and sepiolite such as, for example attapulgite and American fuller&#39;s earth. 
     The term &#34;synthetic clay materials&#34; as used herein includes materials related in structure to layered clays and porous fibrous clays 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 with one another 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 type: 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. Hall. 
     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 (also termed magnesium aluminum silicates) and most preferably Veegum® (e.g. Veegum F) Veegum® is a complex colloidal magnesium aluminium silicate described and characterised in Technical Booklet No. 97, R. T. Vanderbilt Company, Inc., Industrial Minerals and Chemicals, 30 Winfield Street, Norwalk, Conn. 06855, U.S.A: an especially preferred such material is Veegum F (loc. cit.). 
     The term &#34;smectite&#34; as used herein in relation to tablets of the present invention includes the smectites as exemplified herein and with reference to O&#39;Brian P. and Williamson C. J., in &#34;Clays and Clay Minerals vol. 38 No. 3 pp322-326, 1990&#34; and the other clay nomenclature references set out hereinbefore. 
     The term &#34;magnesium aluminium silicate&#34; 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 form 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 &amp; 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. 
     For a dispersible tablet according to the present invention, 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 0.5 to 30% w/w, more preferably 0.5 to 10% w/w, still more preferably 3 to 10% w/w, and most preferably 5 to 10%, most desirably about 5% 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 200 to 800 mg, such about 200 mg, about 400 mg and about 800 mg of acyclovir. 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 1200 mg and containing about 750 to 850 mg 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 65 to 95% w/w preferably 70-90% w/w, preferably 75 to 85% w/w and most preferably about 80% w/w of acyclovir. 
     There are presently on the markets tablets containing an equivalent (unfactorized amount) of about 200 mg, about 400 mg and about 800 mg of acyclovir which is equivalent to about 80% w/w of the tablet. 
     Preliminary experimentation suggests that when acyclovir is present in an amount of at least 65% w/w in tablets according to the invention, 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. 
     Excipients suitable for inclusion in the tablets according to the invention include the following: 
     a) Lubricants: 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%. 
     b) 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. 
     c) 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 0 to 0.5% w/w. 
     d) 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. 
     e) Sweetening agents: for example sodium saccharin 0 to 10% w/w, preferably, 0.5 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). 
     A process for the preparation of a water-dispersible tablet according to the invention comprises the steps of: 
     a) admixing in dry finely divided form 200 to 800 mg e.g. about 200 mg or about 400 mg or about 800 mg acyclovir (65 to 95% w/w), 0.25 to 5% w/w povidone optionally dissolved in a pharmaceutically acceptable liquid, 0.5 to 30% w/w of a swellable clay, an excipient selected from the group consisting of 5 to 25% w/w substituted hydroxyalkyl cellulostic disintegrating agent and 1 to 8% w/w sodium starch glycollate, or a combination thereof; 
     b) addition of a quantity of a pharmaceutically acceptable liquid sufficient to moisten the dry mixture; 
     c) granulation of the resulting moist mixture to form granules; 
     d) drying the granules and blending the granules with a lubricant; and 
     e) compression of the granules to form a tablet 
     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 the 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 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 4%. 
     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. 
     The above-mentioned test for dispersion time is carried out using the following apparatus and method, which is extracted from the British Pharmacopoeia 1988, page 895, volume II. 
     Apparatus 
     (a) A rigid basket-rack assembly supporting six cylindrical glass tubes 75.0 to 80.0 mm long, 21.5 mm in internal diameter and with a wall thickness of about 2 mm. 
     (b) A cylindrical disc for each tube, each 20.55 to 20.85 mm in diameter and 9.35 to 9.65 mm thick, made of transparent plastic with a relative density of 1.18 to 1.20, pierced with five holes, each 2 mm in diameter, one in the centre and the other four spaced equally on a circle of radius 6 mm from the centre of the disc. Four equally spaced grooves are cut in the lateral surface of the disc in such a way that at the upper surface of the disc they are 9.5 mm wide and 2.55 mm deep and at the lower surface 1.6 mm square. 
     (c) The tubes are held vertically by two superimposed transparent plastic plates 90 mm in diameter and 6 mm thick, perforated by six holes having the same diameter as the tubes. The holes are equidistant from the centre of the plate and are equally spaced from one another. Attached to the underside of the lower plate is a piece of woven gauze made from stainless steel wire 0.635 mm in diameter and having nominal mesh apertures of 2.00 mm. 
     (d) The plates are held rigidly in position and 77.5 mm apart by vertical metal rods at the periphery and a metal rod is also fixed to the centre of the upper plate to enable the assembly to be attached to a mechanical device capable of raising and lowering it smoothly through a distance of 50 to 60 mm at a constant frequency of between 28 and 32 cycles per minute. 
     (e) The assembly is suspended in the liquid medium in a suitable vessel, preferably a 1000-ml beaker. The volume of liquid is such that when the assembly is in the highest position the wire mesh is at least 15 mm below the surface of the liquid and when the assembly is in the lowest position the wire mesh is at least 25 mm above the bottom of the beaker and the upper open ends of the tubes remain above the surface of the liquid. 
     (f) A suitable device maintains the temperature of the liquid at 19° C. to 21° C. 
     The design of the basket-rack assembly may be varied provided that the specifications for the glass tubes and wire mesh are maintained. 
     Method 
     Introduce one tablet into each tube, optionally adding a disc to each tube. Suspend the assembly in the beaker containing the specified liquid and operate the apparatus for a maximum period of three minutes. Remove the assembly from the liquid. The tablets pass the test if all six have dispersed within a period of three minutes, five minutes for film-coated tablets. 
     The test for dispersion quality (i.e. uniformity of dispersion) is carried out as follows: 
     Place two tablets in 100 ml of water and stir until completely dispersed. A smooth dispersion is produced which passes through a sieve screen with a nominal mesh aperture of 710 μm. 
     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 710 μm 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. 
     Generally suitable compression weights and final table hardness will vary according to the size of tablet, but generally suitable values are as follows: 
     
         ______________________________________         Approximate                    ApproximateApproximate   Tablet     Target tabletTablet weight diameter   hardness(mg)          (mm)       (Kp)______________________________________ 60           5.6        1-2 80           6.4        3-4125           7.4        4-5250           8.6        5-6330           9.4        6-8500           11.0       10-12600           11.8       10-141000          14.0       12-16______________________________________ 
    
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The following Examples illustrate the present invention. 
     Examples 1 to 6 and 29 are comparative examples while examples 7-28, 30 to 33 describe the preparation of tablets according to the invention 
     
         __________________________________________________________________________Example    1     2        3     4Number     mg/tablet            mg/tablet                     mg/tablet                           mg/tablet__________________________________________________________________________Intra-granular:Acyclovir* 848.0 848.0    844.0 844.0Avicel PH101      60.0  NIL      101   NILLactose    120.0 NIL      NIL   NILStarch     NIL   NIL      50    NIL(maize)Explotab   NIL   75.0     50    NILPrimogel   NIL   NIL      NIL   75.0Ac-Di-Sol  83.0  NIL      23    NILKollidon CL      NIL   NIL      NIL   NILSaccharin  20.0  10.0     NIL   NILsodiumSodium     5.0   NIL      3.0   NILlaurylsulphateSodium     NIL   1.0      NIL   0.5docusateDicalc.    NIL   NIL      NIL   200.0phosph.dihyr.Povidone   NIL   10.0     22    11.2K30Extra-granular:Ac-Di-Sol  40.0  NIL      NIL   NILAvicel PH102      60.0  94       NIL   NILAmberlite  NIL   NIL      NIL   50.0IRP88Kollidon CL      NIL   NIL      60.1  NILMg stearate      12.0  10.0     10.1  11.0Tablet weight      1248.0            1048.0   1163.2                           1191.7(mg)__________________________________________________________________________*In the following examples 13, 14 and 15, the actual quantity ofacyclovir used is calculated from a factor so as to provide 800 mg ofacyclovir pertablet. (The factor for acyclovir is typically 105.5 equivalent to 100acyclovir).In examples 13, 14 and 15, the actual quantity of acyclovir used wasadjustedfrom the factor so as to provide 800 mg of acyclovir per__________________________________________________________________________tablet.Example    5     6     7     8*    9Number     mg/tablet            mg/tablet                  mg/tablet                        mg/tablet                              mg/tablet__________________________________________________________________________Acyclovir  844.0 848.0 844.0 848.0 848.0Avicel PH101      101.0 83.46 100.0 89.0  89.0Veegum F   NIL   NIL   53.0  53.0  53.0Sodium starch      90.0  39.37 42.0  42.0  42.0glycollate(Explotab)Povidone K30      11.0  10.27 NIL   11.0  11.0Magnesium  9.5   8.85  9.4   9.4   9.4stearateFilm coat composite 1:      NIL   NIL   NIL   NIL   7.86OpadryFilm coat composite 2:      NIL   NIL   NIL   NIL   2.097Polyethylene glycol8000Tablet weight      1055.5            989.95                  1048.4                        1052.4                              1062.4(mg)__________________________________________________________________________ *Tablets containing either a 200 mg or 400 mg (unfactorized) dose of acyclovir were also made using the granule of Example 8, with the following compression weights: 200 mg acyclovir tablet: 263.1 mg 400 mg acyclovir tablet: 526.2 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. 
     
         ______________________________________Example     10         11        12Number      mg/tablet  mg/tablet mg/tablet______________________________________Acyclovir   848.0      848.0     848.00Avicel PH 101       118.5      71.1      86.8Veegum F    26.5*      53.0      53.0Primojel    42.0       42.0      42.0Povidone K30       NIL        20.9      5.2Magnesium   9.4        9.4       9.4stearateTablet weight       1044.4     1044.4    1044.4(mg)______________________________________ *Veegum added as a pasteexample contains no PVPK30 as a binder. 
    
     
         __________________________________________________________________________Examples of Acyclovir formulations__________________________________________________________________________Example   13            14    15Number    mg/tablet     mg/tablet                         mg/tablet__________________________________________________________________________Component(mg/tablet)Acyclovir 800.0         800.0 800.0Avicel PH 101     100.0         89.0  89.0Veegum F  53.0          53.0  110.0Sodium starch     42.0          42.0  42.0glycollatePovidone K30     NIL           11.0  11.0Magnesium stearate     9.4           9.4   9.9Tablet weight     1004.4        1004.4                         1061.9(mg)__________________________________________________________________________        16       17       18       19Example      mg/      mg/      mg/      mg/Number  % w/w        tablet            % w/w                 tablet                     % w/w                          tablet                              % w/w                                   tablet__________________________________________________________________________Acyclovir   79.95        848.0            75.54                 795.00                     65.47                          689.00                              55.00                                   583.00Avicel PH 101   8.86 89.0            8.86 89.00                     8.86 89.00                              8.86 89.00Veegum F   5.28 53.0            10.00                 106.00                     20.00                          212.00                              30.00                                   318.00Explotab   4.18 42.0            4.18 42.00                     41.8 42.00                              4.18 42.00Povidone K30   1.09 11.0            1.09 11.00                     1.09 11.00                              1.09 11.00Magnesium   0.94 9.4 0.94 9.40                     0.94 9.40                              0.94 9.40stearateTablet weight   100.0        1052.4            100.0                 1052.4                     100.0                          1052.4                              100.0                                   1052.4(mg)__________________________________________________________________________Example         20         21         22Number     % w/w           mg/tablet                 % w/w                      mg/tablet                            % w/w                                 mg/tablet__________________________________________________________________________Acyclovir  45.32           477.00                 84.3 890.00                            44.93                                 39 848.00Avicel PH 101      8.86 89.00 8.86 89.00 8.86 157.76Veegum F   40.00           424.00                 1.00 10.60 40.00                                 712.22Explotab   4.18 42.00 4.18 42.00 4.18 74.43Povidone K30      1.09 11.00 1.09 11.00 1.09 19.41Magnesium stearate      0.94 9.40  0.94 9.40  0.94 16.74Tablet weight      100.00           1052.4                 100.00                      1052.4                            100.00                                 1828.56(mg)__________________________________________________________________________        23       24       25       26Example      mg/      mg/      mg/      mg/Number  % w/w        tablet            % w/w                 tablet                     % w/w                          tablet                              % w/w                                   tablet__________________________________________________________________________Acyclovir   65.47        689.00            55.00                 583.00                     45.32                          477.00                              79.65                                   848.00Avicel PH 101   8.86 89.00            8.86 89.00                     8.86 89.00                              8.86 89.0Veegum F   *20.00        (106.00            *30.00                 (159.00                     *40.00                          (212.00                              5.28 53.0        (106.00  (159.00  (212.00Explotab   4.18 42.00            4.18 42.00                     4.18 42.00                              4.18 42.0Povidone K30   1.09 11.00            1.09 11.00                     1.09 11.00                              1.09 11.0Magnesium   0.94 9.40            0.94 9.40                     0.94 9.40                              0.94 9.4stearateTablet weight   100.00        1052.4            100.00                 1052.4                     100.00                          1052.4                              100.00                                   1052.4(mg)__________________________________________________________________________ *In these examples the Veegum is distributed equally both intragranularly and extragranularly. 
    
     
         __________________________________________________________________________        27       28       29  30  31Example      mg/      mg/      mg/ mg/ mg/Number  % w/w        tablet            % w/w                 tablet                     % w/w                          tablet                              tablet                                  tablet__________________________________________________________________________Acyclovir   84.43        848.00            84.68                 848.00                     84.93                          848.00                              848.0                                  840.0Avicel PH101   8.86 83.95            8.86 83.70                     8.86 83.46                              89.0                                  89.0Veegum F   0.50 4.74            0.25 2.36                     0.00 0.00                              --  --Bentonite   --   --  --   --  --   --  53.0                                  NILAttapulgite   --   --  --   --  --   --  NIL 53.0Explotab   4.18 39.60            4.18 39.49                     4.18 39.37                              42.0                                  42.0Povidone K30   1.09 10.32            1.09 10.30                     1.09 10.27                              11.0                                  11.0Magnesium   0.94 8.91            0.94 8.88                     0.94 8.85                              9.1 9.1stearateTablet weight   100.00        995.53            100.00                 992.73                     100.00                          989.95                              1052.1                                  1044.1(mg)__________________________________________________________________________Example                  32    33Number                   mg/tablet                          mg/tablet__________________________________________________________________________Acyclovir                848.0 848.0Avicel PH 101            89.0  89.0Veegum F                 53.0  53.0low substituted hydroxypropyl cellulose LH-11                    42.0  NIL(LHPC LH-11)low substituted hydroxypropyl methyl cellulose                    NIL   42.0Povidone K30             11.0  11.0Magnesium stearate       9.4   9.4Film coat composite 1:   NIL   NILOpadryFilm coat composite 2:   NIL   NILPolyethylene glycol 8000Tablet weight            1052.4                          1052.4(mg)__________________________________________________________________________ 
    
     Method of Preparation 
     The tablets described in Examples 1-33 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% 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 1000 μm 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 P100 (high shear mixer--granulator) for 3 minutes. 
     (b) The Povidone/PVP K30 was dissolved in 50% aqueous alcohol to form a granulation solution. 
     (c) The granulation solution was added to an approximate quantity of 300 ml per kg dry weight to the dry mixture to form granules. Wet mixing was carried out for 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 1000 μm 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 19.3 mm length and 9.0 mm breadth. Tablets were compressed to a weight of 1052 mg±2%. 
     This granule can be used to make other strengths of acyclovir dispersible tablets, e.g. 200 mg and 400 mg, compressing the dried granules to a weight of respectively 263 mg and 526 mg, using round punches with diameters of respectively 8.6 mm and 11.0 mm. 
     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 Accellocota 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 (˜20 g per min) 
     inlet temperature (˜75° C.) 
     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%. 
     EXAMPLES 13 TO 15 
     In Example 13, Acyclovir, Avicel PH101, 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. 
     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-kp). 5 tablets were individually tested using a Schleuniger crushing strength tester, and the average breaking strength calculated. 
     3. Friability (% loss). 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. 
     4. Dispersion Disintegration time DT (BP 1988). 6 tablets were tested in accordance to the above-defined BP test (without discs) for dispersible tablets. This utilises water at a temperature of 19°-21° C. 
     5. 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 100 ml of water at 19°-21° C. and allowed to disperse. A smooth dispersion was produced which passed through a 710 μmesh sieve. 
     Granule Evaluation Methods 
     1. Loss on Drying (LOD). The residual moisture content of the granule (LOD) was determined on a 3-4 g sample using a Computrac moisture analyser set to 90° C. operated in accordance with the manufacturer&#39;s procedure. 
     2. Weight Median Diameter (WMD). A 10 g sample of granule was sifted for 2 minutes at suitable pulse and sift amplitudes in an Allen Bradley sonic sifter in accordance with manufacturer&#39;s instructions. Sieves of 710 μm, 500 μm, 355 μm, 250 μm, 150 μm, 106 μm and 53 μm were used. The WMD was calculated from the cumulative percentage undersize size distribution using a computer programme. 
     
         __________________________________________________________________________Acyclovir Granule and Tablet Evaluation ResultsActual                                  Granule PropertiesAverage    Target    Average    Disintegration                                   Loss on     TabletTablet     Tablet          Average                Breaking                     Fria- time**  Drying Weight                                               shape/Example Weight      Weight          Thickness                Strength                     bility                           First                               Last                                   (% LOD)                                          median                                               maximumNumber (mg) (mg)          (mm)  (Kp) (%)   Tablet                               Tablet                                   WMD (μm)                                          diameter                                               diameter__________________________________________________________________________ 1    --   1248.0          --    11.0 --        12&#39;17&#34;                                   1.43   --   Caplet* 2    --   1048.0          --    11.6 --        7&#39;26&#34;                                   1.59   --   Caplet 3    1176 1163.2          --    10.7 --    &gt;10&#39;                               &gt;10&#34;                                   2.28   --   Round                                               14.0 mm 4    --   1191.7          --    13.7 --        4&#39;50&#34;                                   1.18   --   Round                                               14.0 mm 5    1053 1055.5          --    15.0 --        4&#39;21&#34;                                   1.75   186  Round                                               14.0 mm 6    983  989.95          5.46  10.8 0.34  6&#39;27&#34;                               7&#39;26&#34;                                   1.43   315  Caplet 7a   1022 1048.4          --    7.2  2.74      0&#39;33&#34;                                   1.31   233  Caplet**All dispersions passed through a 710 m sieve (BP uniformity ofdispersion test) 7b   1046 1048.4          --    12.8 0.47      0&#39;42&#34;                                   1.31   233  Caplet 7c   1048 1048.4          --    17.1 0.19      0&#39;44&#34;                                   1.31   233  Caplet 8    1049 1052.4          7.0   14.6 0.18      0&#39;35&#34;                                   4.06   138  Caplet(uncoated) 9    1053 1062.4          6.99  16.1 negligible                               1&#39;05&#34;                                   4.06   138  Caplet(coated)10    --   1044.4          --    14.4 0.11  --  0&#39;32&#34;                                   2.65   123  Caplet11    --   1044.4          --    15.3 0.24  --  0&#39;46&#34;                                   1.46   196  Caplet12    --   1044.4          --    13.3 0.73  --  0&#39;27&#34;                                   1.76   105  Caplet13, 14, 15***16    1051.24      1052.4          7.1   11.6 0.49  0&#39;46&#34;                               0&#39;49&#34;                                   1.12   185  Caplet17    1059.54      1052.4          7.0   11.8 0.46  0&#39;28&#34;                               0&#39;30&#34;                                   2.18   125  Caplet18    1060.79      1052.4          6.90  11.5 0.62  0&#39;17&#34;                               0&#39;19&#34;                                   1.46   178  Caplet19    1053.4      1052.4          6.70  11.6 0.71  0&#39;19&#34;                               0&#39;24&#34;                                   2.00    73  Caplet20    1057.6      1052.4          6.71  9.1  2.45  0&#39;20&#34;                               0&#39;23&#34;                                   1.81    90  Caplet21    1048.8      1052.4          7.24  11.5 0.85  2&#39;18&#34;                               2&#39;59&#34;                                   1.15   341  Caplet22    1743.9      1828.56          10.40 11.6 2.19  0&#39;29&#34;                               0&#39;31&#34;                                   1.84    83  Caplet23    1054.2      1052.4          6.90  11.5 0.09  0&#39;43&#34;                               0&#39;51&#34;                                   1.84   157  Caplet24    1059.1      1052.4          6.90  11.4 0.02  0&#39;55&#34;                               1&#39;00&#34;                                   0.68   142  Caplet25    1052.6      1052.4          6.70  11.9 0.09  1&#39;30&#34;                               1&#39;42&#34;                                   1.59   118  Caplet26a)# 130.6      131.55          2.80  4.2  0.56  0&#39;25&#34;                               0&#39;28&#34;                                   1.34   296  7.4 mm                                               Round26b)# 526.0      426.2          4.81  12.84                     0.79  0&#39;26&#34;                               0&#39;30&#34;                                   1.34   296  11.0 mm                                               Round26c)# 1216.5      1215.0          8.20  11.10                     0.83  0&#39;45&#34;                               0&#39;51&#34;                                   1.34   296  Caplet27    125.7      124.4          3.68  3.68 0.71  0&#39;33&#34;                               0&#39;39&#34;                                   1.21   334  7.4 mm                                               Round28    124.7      124.1          2.78  3.55 0.65  0&#39;44&#34;                               0&#39;47&#34;                                   1.90   332  7.4 mm                                               Round29    982.9      989.95          5.46  10.8 0.34  6&#39;27&#34;                               7&#39;26&#34;                                   1.43   315  Caplet30    1041.2      1052.1          --    11.8 --    1&#39;30&#34;                               1&#39;55&#34;                                   1.62   227  Caplet31    1038.6      1044.1          --    16.6 1.59  1&#39;50&#34;                               2&#39;10&#34;                                   1.96   150  Caplet__________________________________________________________________________ *Approximate dimensions of caplet were: 19.3 mm long, 9.0 mm wide, 7.0 mm thick. **Disintegration times measured in accordance with BP test for dispersibl tablets. All dispersions passed through a 710 m sieve (BP uniformity of dispersion) # Same granule formulation, but different compression weights giving approximately: a = 100 mg, b = 400 mg and c = 925 mg of acyclovir per tablet. ***Examples 13, 14 and 15 disintegrated in 0&#39;30&#34; to 1&#39;30&#34;. 
    
     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 300 mm focal length lens was used. 
     1. Disperse tablet in 100 ml 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 50 ml of saturated liquor allowing 3 minutes to fully 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) 
     &lt;710 μm--100% 
     &lt;300 μm--98.7% 
     &lt;200 μm--86.7% 
     &lt;130 μm--50% (median particle size)