MXPA97005459A - Valaciclovir tablets containing silicon dioxide color - Google Patents

Abstract

A tablet comprising at least 50% w / w of Valaciclovir, and 0.05 to 3% w / w of colloidal silicon dioxide, which has excellent hardness and friability properties while retaining good lubrication is provided the granules of the table

Description

VAIACICLOVIR TABLETS CONTAINING COLOIDAL SILICON DIOXIDE This invention relates to a tablet of the antiviral drug valaciclovir. The compound 9 - [(2-hydroxyethoxy) methyl] guanine, in other circumstances known as acyclovir possesses potent antiviral activity and is widely used in the treatment and prophylaxis of viral infections in humans, particularly infections caused by the group of the virus of the herpes (see for example, Schaeffer et al, Nature, 272, 583-585 (1978), British Patent 1523865, US Patent No. 4,199,574). However, acyclovir is poorly absorbed from the intact gastrointestinal tract after oral administration and this low bioavailability means that multiple high doses of the oral drug need to be administered, especially for treatment due to less sensitive infections or viruses to achieve and maintain effective antiviral levels. in the plasma. The L-valine ester of acyclovir L-valinate from (2- [2-amino-l, 6-dihydro-6-oxo-purin-9-yl) methoxy] ethyl (referred to herein as valaciclovir) has been shown to have a much better bioavailability and to retain antiviral properties for a long time of acyclovir. A preferred form of this compound is its hydrochloride salt, which is referred to herein as REF hydrochloride: 25263 valaciclovir. Valaciclovir and its salts including the hydrochloride salt are described in U.S. Patent No. 4,957,924 (see particular example IB), European Patent No. 0308065 (see particularly example IB) and Beauchamp et al, Antiviral Chemistry and Che otherapy, 3 (3), 157-164 (1992) (see particularly page 162, column 1). Valaciclovir tablets are also generally described in U.S. Patent No. 4,957,924 and European Patent No. 0308065. During the development of a tablet formulation containing a high proportion of valaciclovir, there are often difficulties in obtaining tablets. sufficient hardness and friability for pharmaceutical handling and for film coating. If the tablet is very friable, it will flake or break during packing or transport. The American Pharmacopoeia (USP) no. 23, 1995, pl981 in monograph 1216 requires that the pharmaceutical tablets have a friability not exceeding 1%. If the tablet is too bright, it will disintegrate during drumming in the film coating drum. In the reference manual "Problem Solver" (compiled by FMC Corporation) on pages 8 and 9, remedies are given for low tablet hardness inter alia such as increasing the compression force applied to form the tablet or decreasing the proportion of lubricant in the tablet. the formulation of the tablet. Attempts were made to increase the hardness and friability of the valaciclovir tablets by increasing the compression force, decreasing the proportion of lubricant and increasing the proportion of binder, but it was found in each case that a sufficiently hard and non-friable tablet could not be produced in a form practice. In addition, "cracks" in some tablets were introduced as a result of the increase in compressive strength.In addition, valaciclovir has "adhesive" properties since it adheres to the punches of the tableting machine, and therefore needs to be lubricated. Therefore, it is difficult to reduce the proportion of lubricant without causing the tablet to stick.In addition, the disintegration time of the valaciclovir tablet is also very long, and therefore, any possible solution to the problem of hardness , and friability may not have a substantial deleterious effect on either the disintegration time or the lubrication (measured by the ejection force) of the tablet formulation.Therefore, an object of the invention is to provide a formulation of valaciclovir tablet and salts thereof in this one, which is capable of being coated with C a film and consistently provide tablets having a friability qu e does not exceed 1%, a hardness of at L minus 9kP and an ejection force not exceeding 1000 Newtons (1 kN). The hardness of the tablet should be such that not only does it have an acceptable grinding force (measured by the value of kP), but also that the tablet does not break during drumming. A further preferred object of the invention is to provide a robust formulation that is capable of consistently providing tablets substantially free of cracks or fractures. An affective method has now been found to overcome both the problem of friability and previous hardness, which involves the use of colloidal silicon dioxide, in the formulation of the tablet. The Pharmaceutical Excipients Manual of 1994 at p 253-256 does not mention colloidal silicon dioxide as an agent to improve tablet hardness. Neither the theory and practice of the industrial pharmacy (third edition) by Lachman, Lleberman and Kanig, mention the colloidal silicon dioxide for such use. Accordingly, in a first aspect of the invention, there is provided a tablet comprising at least about 50% w / w of valaciclovir or a salt thereof present within the granules of the tablet, a filler, a binding agent, a lubricant, and about 0.05% up to about 3% w / w of colloidal silicon dioxide, the lubricant and the colloidal silicon dioxide are present extragranularly, where the friability of the tablet does not exceed 1%, the hardness is at minus 9 kP and the ejection force does not exceed 1000 Newtons. A tablet of this formulation containing 0.05% to 3% weight / weight of colloidal silicon dioxide is robust, and has substantially improved friability and hardness. Furthermore, such improved properties are achieved while retaining a satisfactory disintegration time and lubricating properties, even when the formulation is mixed under a high cut. Thus, an excellent tablet providing acyclovir is provided in a highly available form by virtue of the invention. Preferably, the disintegration time of the tablet is not greater than about 30 minutes, preferably not more than about 25 minutes, and more preferably not more than about 20 minutes. The ejection force should not be greater than about 1000 N, preferably not more than about 800 N, more preferably not more than about 500 N for compressed tablets at about 10 to 30 kN, preferably 10 to 20 kN Valaciclovir or a salt thereof is hereinafter generally referred to as the "active ingredient". The 1994 American Pharmacopoeia describes colloidal silicon dioxide (in its monograph) as: a submicroscopic fuming silica prepared by the hydrolysis of the vapor phase of a silicon compound. Preferably, the colloidal silicon dioxide is present in amounts of about 0.05% to about 1% w / w of the total formulation, more preferably, about 0.1% to about 1% w / w, and most preferably from about 0.1% to about 0.5% weight / weight. It has been found that Aerosil (registered trademark) and Cabo-sil (registered trademark) are very suitable. The drug content in the tablet is at least about 50% w / w, preferably about 60% w / w, up to about 90% w / w, more preferably still about 65% w / w / weight up to about 85% weight / weight and more preferably 80% weight / weight. Preferably, the apparent density (derivative) of the drug is from about 0.1 to 0.9 g / cc, preferably from 0.3 to 0.7 g / cc, more preferably from 0.34 to 0.66 g / cc, and more preferably from 0.34 to 0.66 g / cc, and more preferably from 0.34 to 0.66 g / cc, and preferable from 0.4 to 0.6 g / cc. Suitably the valaciclovir hydrochloride drug, preferably it is of an anhydrous crystalline form that substantially includes a separation d pattern (derived from powder diffraction with X-rays) as follows: separation pattern d (in Angstroms): 10.20 ± 0.08, 8.10 ± 0.06 , 7.27 ± 0.06, 6.08 ± 0.05, 5.83 ± 0.03, 5.37 ± 0.02, 5.23 ± 0.02, 4.89 ± 0.02, 4.42 ± 0.02, 4.06 ± 0.02, 3.71 ± 0.02, 3.39 ± 0.02, 3.32 ± 0.02, 2.91 ± 0.02, 2.77 ± 0.02. Here "anhydrous crystalline form" according to the invention, means a crystalline form having substantially the same X-ray powder diffraction pattern as that shown in Figures 1 to 3, or having substantially the same pattern of separation d as defined above. Preferably the purity of the crystalline form in any batch of such anhydrous crystalline valaciclovir hydrochloride drug used for the valaciclovir tablets is at least 70%, more preferably at least 80%, more preferably still at least 90% and more preferably at least 90% anhydrous crystalline valaciclovir hydrochloride (as characterized above).

In an alternative method for measuring the purity of the crystalline form, since the anhydrous crystalline form of valaciclovir hydrochloride does not substantially contain water of hydration, the level of other hybrid forms of valaciclovir hydrochloride in any batch of drug used for the tablets should measured by the water content of hydration. Preferably any batch of such anhydrous crystalline valaciclovir hydrochloride drug should not contain more than 3% w / w, more preferably not more than 2% w / w, more preferably not more than 1% in weight / weight and even more preferably, no more than 0.5% in weight / weight of water of hydration. This water hydration content is measured by the Karl Fischer method which is well known in the art and is described in the American Pharmacopoeia of 1990 on pages 1619 and 1621, and the European Pharmacopoeia, second edition (1992), part 2, sixteenth fascicle in v. 3.5.6-1. Advantageously the filler is a cellulosic filler and is at least partially present extragranularly, which mitigates the stress fracturing the tablet. A tabLeta formulation of the invention that includes colloidal silicon dioxide and extragranular cellulosic filler (such as microcrystalline cellulose) appears to have a synergistic effect and is particularly good? robust since the valaciclovir tablets can be made consistently at an acceptable hardness without introducing stress fractures even under a high compression force. According to a preferred aspect of the invention, there is provided a tablet comprising at least 50% w / w of valaciclovir or a salt thereof, a binding agent, a lubricant, 0.05 to 3% w / w dioxide colloidal silicon, and from 3 to 30% of a cellulosic filler; wherein the valaciclovir or salt thereof is present within the granules of the tablet, the lubricant, colloidal silicon dioxide, and at least a portion of the cellulosic filler is present extragranularly; wherein the friability of the tablet does not exceed 1%, the hardness is at least 9 kP, and the ejection force does not exceed 1000 N. Preferably the cellulosic filler is microcrystalline cellulose (for example Avicel); and is preferably present from 5 to 15% w / w, more preferably 10% w / w. The particle size of the cellulosic filler is preferably 20 to 300 μ, more preferably 30 to 200 μ, and most preferably 50 to 100 μ. According to a further aspect of the invention there is provided a ta "eta comprising at least 50% w / w of valaciclovir or a salt thereof, a binding agent, a lubricant, and approximately 3% to 30% w / w weight of a cellulosic filler, valaciclovir or its salt is present within the granules of the tablet and the lubricant and cellulosic filler are present extragranularly.The binding agent serves, for example, to bind the primary and secondary particles together and improve the hardness of the tablet Preferably the binding agent is present in an amount of from about 1% to about 5% w / w, more preferably from about 2% to about 4% w / w, and is suitably, a binder not based on starch such as methyl cellulose or more preferably povidone The degree of povidone is advantageously K30 and most preferably K90. binder such as povidone, can be dissolved in the granulation solvent (such as water) before adding it to the drug, but preferably (at least partially) dry is added to the drug and other excipient and then the solution is added. granulation (such as povidone in water). The lubricant is suitably present in an amount from about 0.1% to about 2.0% w / w, preferably from about 0.1% to about 1.0% weight / weight. Although lubricants such as talc or sodium lauryl sulfate are suitable, preferably the lubricant is a stearate derivative, more preferably an alkali metal stearate, such as magnesium stearate. The above amounts are applied to stearate, and are ideally present in an amount of from about 0.3% to about 0.6% weight / weight. Although valaciclovir is very soluble, especially in its salt form, it is preferable if a disintegrating agent is present in the tablet formulation, suitably in an amount of from about 0.5 to about 20% w / w, more preferably. preferable to about 0.5% to 7.0% weight / weight. The disintegrating agent is present advantageously within the granules of the tablet and can be added before or after the binder. Clays such as kaolin, bentonite or veegum (trademark), and celluloses such as microcrystalline cellulose or croscarmellose sodium, for example Ac-Di-Sol (trademark), can be used as disintegrants. Preferably, a nonionic disintegrant such as crospovidone is used. Preferably, crospovidone is present at from about 0.5% to about 7.0% w / w, more preferably from about 2 to about 5% w / w. weight, and preferably a portion is present intragranularly. A further aspect of the invention provides a process for preparing a tablet comprising at least about 50% w / w of valaciclovir or a salt thereof, a binding agent, a filler, a lubricant, and about 0.05 to 3.0% by weight / weight of colloidal silicon dioxide; wherein the hardness of the tablet is at least 9 kp, the friability is not greater than 1%, and the ejection force is not greater than 1000N; the process comprises forming granules which include valaciclovir or a salt thereof and then mixing the lubricant and the colloidal silicon dioxide with the granules. Preferably the process comprises forming the granules by mixing the valaciclovir or the salt, optionally a binding agent or a portion thereof, and optionally the filler or a portion thereof; granulating with a granulation solution to form granules or dissolving the binder or a portion in the granulation solution before adding to valaciclovir; drying the granules; mix the granules with the lubricant, colloidal silicon dioxide, and the optional filler or a portion thereof; and then compressing the combined mixture to form a tablet.

A preferred aspect of the invention provides a process for preparing a tablet comprising at least 50% w / w of valaciclovir or a salt thereof, a binding agent, a lubricant, 0.05 to 3% w / w dioxide colloidal silicon, and 3 to 30% w / w of a celuxosic filler; wherein the hardness of the tablet is at least 9kP, the friability is not greater than 1%, and the ejection force is not 1000N; the process comprises forming granules by mixing the valaciclovir or the salt, optionally binding agent or a portion thereof, and optionally a portion of the cellulosic filler; granulating with a granulation solution to form the granules or dissolving the binder or a portion thereof in the granulation solution before adding to valaciclovir; drying the granules; mix the granules with the lubricant, colloidal silicon dioxide, and at least a portion of the cellulose filler; and then compressing the combined mixture to form a tablet. The colloidal silicon dioxide can first be mixed with the lubricant, preferably a stearate derivative (eg, magnesium stearate) before blending with the granules or it can be added separately from the lubricant. When the lubricant is a stearate derivative, preferably the ratio of stearate to colloidal silicon dioxide is from about 1: 1 to 10: 1, more preferably from about 1: 1 to about 3: 1. The present invention it also provides a tablet (as described above) for use in medical therapy, for example in the treatment of a viral disease in an animal, for example, or a mammal such as a human. The compound is especially useful for the treatment of diseases caused by various DNA viruses, such as herpes infections, for example, herpes simplex 1 and 2, varicella zoster, cytomegalovirus, Epstein-Barr virus or human herpes virus 6 (HHV). -6) as well as diseases caused by hepatitis B. The active compound can also be used for the treatment of infections with papilloma virus or wart and, in addition, can be administered in combination with other therapeutic agents, for example as zidovudine, to treat retroviral infections associated in particular with HIV infections. In addition to its use in human medical therapy, the active compound can be administered to other animals for the treatment of viral diseases, for example to other mammals. The tablet herein also provides a method for the treatment of a viral infection, particularly a viral infection with herpes, in an animal, for example a mammal such as a human, which comprises administering to the host one or more tablets of the invention. to provide an effective antiviral amount of the active compound. The present invention also provides the use of the active compound in the preparation of a tablet of the invention for the treatment of a viral infection. A tablet of the invention can be administered by any route appropriate to the condition to be treated, although the preferred route of administration is oral. Although tablets are generally included within the scope of the invention, for example, a dispersible tablet or chewable tablet, preferably the tablet is a swallowable tablet, more preferably a swallowable tablet coated with film. It should be appreciated, however, that the preferred route may vary with, for example, the condition of the receiver. For each of the utilities and indications made above the required amounts of the active ingredient (as defined above) will depend on a number of factors, including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the physician. or veterinarian who presents the care. In general, however, for each of those purposes and indications, an adequate effective dose will be in the range of 1 to 150 mg per kilogram of body weight of the receptor per day, preferably in the range of 5 to 120 mg per kilogram of body weight per day (A r. otherwise, all weights of the active ingredient were calculated with respect to valaciclovir on free base). The desired dose is preferably presented as one, two, three or four or more sub-doses administered at appropriate intervals during the day. These sub-doses may be administered in unit dosage forms, for example, containing approximately 50 to 2000 mg, preferably approximately 250, 500, 1000 or 2000 mg of the active ingredient per unit dosage form. The following dosing regimens are given as a guide: treatment of infection with herpes simplex virus types 1 and 2: total daily dose of approximately 1 or 2g administered at 500 mg twice a day or twice daily for 5 to 10 days; suppression of infections with herpes simplex virus types 1 and 2: total daily dose of approximately 250 mg to lg for approximately one to ten years (depending on the patient); treatment of infections with varicella zoster virus (eg zonal): daily dose of approximately 3g administered to lg three times a day for seven days; suppression of infections with cytomegalovirus: total daily dose of approximately 8g administered at 2g 4 times a day. For transplant patients this daily dose is administered for three to six months during the period at risk; and for HIV positive patients such a daily dose is administered as usually indicated to improve the quality of life, for example for two years or more. The first results now indicate that valaciclovir can be used in the effective suppression of recurrent genital herpes at a daily dose of about 200 mg to about 1000 mg during an effective treatment period. The most likely daily doses are 250 mg, 500 mg or 1000 mg. Valacyclovir hydrochloride was made as described below: Example 1 A. L-Valinate of 2 - [(2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) m toyl-tyl-N- [(benzoloxy) carbonylol CBZ-L-valine (170 g) was dissolved in dimethylformamide (DMF) (750 ml) and cooled. A cold solution of N, N-dichlohexylcarbodiimide (DCC) (156.7 g) in DMF (266 ml) was added and stirred with cooling. Acyclovir (10.1 g) was added in a single portion, and then 4- (dimethylamino) -pyridine (9.4 g) was added while maintaining cooling. The mixture was stirred cold overnight. A white precipitate of the by-product was then removed by filtration. The filtrate was reduced in volume by vacuum distillation and the concentrate was treated with water (663 ml) then heated to 70 ° C. The suspension was cooled to 20 ° C, filtered and the solid was washed with water. The wet, crude material was then purified by recrystallization of the denaturing alcohol (1.2 liters) to obtain the title compound as a wet white crystalline solid (281.5 g).

B. L-Valinate Hydrochloride of 2- \ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) m-toxylethyl L-Valinate from 2- [(2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl-N- [(benzyloxy) carbonyl] (175 g) was charged to alcohol denatured aqueous (335 ml / 795 ml) and heated to reflux. The solution was then cooled to 40 ° C. The suspension was treated with 5% palladium on carbon catalyst (25 g wet weight 50% wet with water) then formic acid (30.6 ml 90% w / w) was added for 1 hour. The reaction mixture was stirred for an additional 1 hour and then a second charge of formic acid (19.5 ml) was made and the mixture was filtered to remove the catalyst. The filter cake was washed with denatured alcohol and the combined filtrates were treated with concentrated hydrochloric acid (33.7 ml) and the resulting mixture was concentrated by vacuum distillation. Then acetone (1295 ml) was added over 15 minutes and the suspension was stirred for 1 hour before filtering the product. The solid was then suspended with acetone (circa 530 ml), filtered again and dried at 60 ° C in vacuo to give the title compound (1123 g: 81.6%). A sample of 15 g of this material was combined with denatured alcohol (circa 7 ml), to be moistened and heated with agitation at 60 ° C overnight in a closed flask to prevent the loss of alcohol and maintain moisture in the mixture. The mixture was then dried at 60 ° C in vacuo to give the product as the desired morphic form.

Physical data : Karl Fischer value: 0.9% weight / weight of water. The X-ray powder diffraction patterns of the product of Example IB are shown in Figure 1 of the accompanying drawings. The separation d's and the additional X-ray diffraction data are shown in Table 1.

Table 1 Peak No: Peak Angle Error Pattern in I / Imax (degrees) (counts) d of separation d (± A) (o) (A) 1 3.56 680 24.8 0.5 24 2 8.62 1151 10.25 0.08 39 3 9.42 87 9.38 0.07 3 4 10.85 1438 8.14 0.05 49 12.10 835 7.31 0.06 28 6 13.22 198 5.69 0.05 6 7 14.49 2172 6.11 0.05 75 8 15.12 455 5.85 0.03 15 9 15.90 352 5.57 0.02 12 6.45 1969 5.38 0.02 68 11 15.90 744 5.24 0.02 25 12 17.33 119 5.11 0.02 4 13 18.12 1013 4.89 0.02 35 14 22.71 1429 4.43 0.02 49 20.55 255 4.32 0.02 8 16 21.21 370 4.19 0.02 12 17 21.83 753 4.07 0.02 26 18 22.71 95 3.91 0.02 3 19 23.95 2893 3.71 0.02 100 25.10 171 3.54 0.02 5 Peak No: Peak Angle Error Pattern in I / Imax (degrees) (counts) d of separation d (± Á) () (Á) 21 26.21 1784 3.40 0.02 61 22. 26.89 428 3.31 0.02 14 23 27.08 373 3.29 0.02 12 24 28.02 158 3.18 0.02 5 28.27 161 3.15 0.02 5 26 28.91 391 3.09 0.02 13 27 29.68 191 3.01 0.02 6 28 30.55 502 2.92 0.02 17 29 31.34 110 2.85 0.02 3 31.58 98 2.83 0.02 3 31 32.13 597 2.78 0.02 20 32 32.96 260 2.72 0.02 8 33 33.99 344 2.64 0.02 11 'A 34.38 374 2.61 0.02 12 35.12 141 2.55 0.02 4 36 36.78 408 2.44 0.02 14 37 38.71 101 2.32 0.02 3 I / Imax = (peak height / peak peak height) x 100 The powder sample used to produce the previous X-ray diffraction data was prepared by a method equivalent to that of the powder sample used to produce the data from X-ray diffraction of table 2 (described hereinafter) except that for the above data the following preparation was used to prepare the powder sample. The sample was prepared 1 g of sample in a plastic container using two acrylic spheres during minutes with a Chemplex Spectromill. The samples were again packed against a glass slide at a depth of 2 mm. The X-ray diffraction scan was obtained using a Scintag PADV diffractometer in the gradual scan mode at 0.02 ° per step and an account of 10 seconds per step. The sample retention device was centrifuged at 1 rotation per second during the scan. The additional adjustments are described below.

X-ray generator: 45 kV, 40 mA Radiation: Copper K alpha radiation Fixed divergent slot: 1 mm Incisive dispersion slot: 2 mm Diffracted scattering slot: 0.5 mm Reception slot: 0.3 mm Goniometer radius: 235 mm Detector: Scintillation with a graphite monochromator.

The peak intensities were reported as absolute counts of the top of the peak. The intensity units on the X-ray diffraction graph are count / sec. The absolute counts = count / sec x count time = counts / sec x 10 sec. The peak intensities in the table have been corrected for the background noise and the contribution of the wave length of the Copper K alpha II X-ray.

Example 2 A. L-Valinate from 2- [(2-amino-l, 6-dihydro-6-oxo-9H-purin-9-yl) methoxyl-N- [(benzyloxy)] carbonyl] CBZ-L-valine (167 g) was dissolved in dimethylformamide (DMF) (750 ml) and cooled to 0.5 ° C. A cold solution of N, N-dicyclohexylcarbodiimide (DCC) (153.5 g) in DMF (266 ml) was added followed by acyclovir (111.7 g) in a single portion. Then 4 (Dimethylamino) pyridine (9.4 g) was added and the mixture was stirred cold overnight. A white precipitate of the by-product was then removed by filtration. The solvent was partially removed by vacuum distillation and the water-treated concentrate (663 ml) was then heated to 70 ° C. The suspension was cooled to 20 ° C, filtered and the solid was washed with water. The wet, crude material was then purified by recrystallization from denatured alcohol (1.2 liters) for the title compound as a pale white crystalline solid (215.3 g).

B. L-valinate hydrochloride of 2- [(2-amino-1, β-dihydro-6-oxo-9H-purin-9-yl) methoxy-ethyl) L-Valinate from 2- [(2-amino-l, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl-N- [(benzyloxy) carbonyl] (200 g) was charged. to aqueous denatured alcohol (282 ml / 908 ml) and heated to reflux to dissolve the solids. The solution was cooled to 40 ° C. The solution was treated with a 50% w / w paste of 5% palladium on carbon catalyst and water (40 g) and then formic acid (96% w / w: 32.8 ml) was added over 1 hour. The reaction mixture was stirred for an additional 1 hour and then a second charge of formic acid (20.88 ml) was made and the mixture was filtered to remove the catalyst. The filtrate was treated with concentrated hydrochloric acid (38.56 ml) and the resulting mixture was concentrated under vacuum.

Then acetone (1480 ml) was added over 15 minutes and the suspension was stirred for 1 hour before filtering the product. The solid was then suspended in acetone (ca. 500 ml), filtered again and dried at 60 ° C in vacuo to give the title compound (137.75 g: 87.6%). A 10 g sample of this material was combined with denatured alcohol (3.5 ml), heated at 60 ° C for several hours and the solvent was then stirred in vacuo to give the product as the desired morphic form. Purity of the Crystalline Form: the sample of Example 2 (B) contained more than 90% of valaciclovir in anhydrous crystalline form. The X-ray powder diffraction patterns of the product of example 2 (B) are shown in Figures 2 and 3 of the accompanying drawings in which: Figure 2 is a line graph of the X-ray diffractogram; and Figure 3 is a graph of the square network of the X-ray diffractogram. The separation d's and the additional X-ray data are shown in Table 2.

Table 2 Peak No: Peak angle Pattern of d I / Imax (Degrees) (counts) of separation (A) (%) 1 3.62 2673 24.40 5 2 7.21 119 12.26 2 3 8.64 1910 10.22 25 4 9.43 180 9.37 2 10.86 2652 8.14 35 6 12.12 734 7.30 10 7 13.24 615 6.68 8 8 13.77 106 6.42 1 9 14.50 2333 6.11 31 15.14 635 5.85 8 11 15.89 511 5.57 7 12 16.44 2652 5.39 35 13 16.90 1267 5.24 17 14 17.33 475 5.11 6 18.13 1648 4.89 22 16 20.05 2172 4.43 28 17 20.56 640 4.32 8 18 21.20 1C96 4.19 14 19 21.78 2034 4.08 27 21.90 1384 4.06 18 21 22.66 729 3.92 what 22 23.94 7621 3.71 100 Peak No: Peak angle Pattern of d I / Imax (Degrees) (counts) of separation (Á) (%) 23 24.39 1624 3.65 21 24 25.11 967 3.54 13 25.86 2450 3.44 32 26 26.21 5127 3.40 67 27 25.82 1892 3.32 25 28 26.89 1927 3.31 25 29 27.19 1429 3.28 19 27.99 1156 3.18 15 31 28.35 1076 3.15 14 32 28.87 1722 3.09 23 33 28.94 1529 3.08 20 34 29.62 1274 3.01 17 30.56 1673 2.92 22 36 31.30 999 2.86 13 37 32.25 2570 2.77 34 38 33.04 1376 2.71 18 39 34.00 1805 2.63 24 40 34.45 1225 2.60 15 41 35.13 1149 2.55 15 42 36.77 1600 2.44 21 43 38.01 576 2.37 8 44 38.76 729 2.32 10 45 39.52 524 2.28 7 Peak No: Peak angle Pattern of d I / Imax (Degrees) (counts) of separation (%) (Á) 46 40.70 751 2.22 10 47 41.28 870 2.19 11 48 41.88 686 2.16 9 49 42.47 718 2.13 9 50 43.40 548 2.08 7 51 44.53 729 2.03 10 The diffraction patterns of the example product 2B were generated in a D '"X-ray Powder ractometer Automatic Phillips PW1800 using a scan from 2 to 45 2? with gradual intervals of 0.02 degrees and an integration time of 4 seconds per step. Generator parameters: 40 KV, 45 mA, 1.2 alpha wavelength of Cu: 1.54060, 1.54439 A; step size, sampling time: 0.020 degrees, 4.00 s, 0.005 degrees / s; monochromator used: yes; divergence slot: automatic (irradiated sample length: 10.0 mm); peak angle interval: 2.00-45,000 degrees; interval in the separation D: 44.1372 - 2.01289 A; Peak position criterion: top of the flattened data; interval of the width of the peak of the crystal: 0.00 - 2.00 degrees; Significance of minimum peak: maximum intensity 0.75: 7621 cts, 1905.3 cps.

The powder sample was prepared as follows: A 1 gram portion of valaciclovir hydrochloride was transferred to a 10 ml polystyrol container from Retsch, reference 762, containing 2 acrylic spheres, reference 26-253, and then milled to a very fine powder using a modest Retsch MM2 mill set at 100% powder for five minutes. The ground powder was charged again in a Phillips PW1811 / 10 sample retainer which had been placed inverted on a perfectly smooth surface (eg as produced by a glass plate or a highly polished metal sheet). The powder was then packed in the retention device and additional powder was added and packaged until the retention device was filled. The bottom plate of the Phillips PW 1811 00 was then attached to the retainer and the entire assembly was then inverted before removing the glass / metal plate in an upward direction to reveal the smooth surface of the sample which was leveled with the one of the retention device. The invention is illustrated below in the following examples and the properties of the tablets are shown in Table 3 below.

* Apparent density 0.6g / cc after 50 strokes (anhydrous crystalline form): water content of Karl Fischer = 0.4. 1. Weight of the core per batch: 0.5575 kg for examples 3, 4 and 5; 0.4900 kg for examples 6 and 7. 2. Factor 1.153 = 100 3. Average particle size of approximately 50 μ * apparent density 0.45 g / cc after 50 strokes (anhydrous crystalline form) 1. Average particle size of approximately 50 μ anhydrous crystalline) 1. Average particle size of approximately 50 μ The tablets of the examples were made as described below.

Examples 3 to 7 Step 1. Core ingredients were screened with a 20 mesh manual screen, and then mixed in a V-frame mixer of appropriate size for 10 minutes. Step 2. The mixed powders from Step 1 were then granulated in a 10 liter high cut mixer (model SP1) by adding pure water while mixing. Then approximately 11-14% water, weight / weight of the core ingredients were added and the mixture was kneaded for 3 to 4 ^ minutes. Step 3. The granule from Step 2 was dried in a tray (examples 5, 6 and 7) or a vacuum dryer (examples 3 and 4) (model SP1) at a temperature of 50 ° C at an acceptable moisture content of approximately 1.0 to 2.0% LOD Step 4. The remaining ingredients were sifted through a 20-mesh screen and added to the core ingredients of step 3, and then the mixture was sieved using an I-197 AS-equipped Cornil with a 0.062"screen.

Step 5. The mixture is then mixed in a V-frame mixer of appropriate size for 5 minutes. Step 6. The mixed granule from Step 5 was compressed into a Net Press Manesty equipped with capsule-shaped tools, 18.25 mm x 7.14 mm, at a compression weight of about 700 mg and a compression force of about 14.5 to 18 kN. Step 7. The tablets can then optionally be film coated using standard methods such as using white concentrate, methylhydroxypropylcellulose, titanium dioxide, polyethylene glycol and polysorbate.

The hardness (crushing force across the longitudinal axis) was measured using a Key hardness tester, Model HT-300. The friability (percent of weight loss after 100 falls of six inches) was measured according to the USP no. 23, 1995, pl981 in monograph 1216, using a Erweka friability tester, Model TA-3. The physical properties were measured at comparable compression forces. The disintegration time was measured according to the monograph of USP 23 (1995) on page 1790.

Examples 8 and 9 Step 1. The ingredients, as shown, were sifted with a manual sieve. Mesh 30 valaciclovir hydrochloride 5,289 kg lactose 1,763 kg microcrystalline cellulose 0.6450 kg povidone K30 0.1548 kg crospovidone 0.1548 kg Mesh 60 magnesium stearate 0.03096 kg colloidal silicon dioxide (CSD) 0.002598 kg Step 2. The sieve ingredients with 30 mesh from Step I were then mixed, excluding povidone, in a V-frame mixer of 1 cubic foot for 10 minutes.

Step 3. Then 1.540 kg of alcohol were mixed SD3A (ethanol denatured with 5% methanol) with 0.6600 kg of purified water and the povidone sieved, 0.1548 kg, was dissolved in 0.6192 kg of the mixed solvents by shaking manually. Step 4. The mixed powders from Step 2 were then granulated in a 1 cubic foot Littleford Lodige mixer by adding the povidone dissolved while mixing. 1.315 kg of more mixed solvent was added and the mixture was kneaded for a total of seven minutes as shown below. Plows 7 minutes Trozadores 6.5 minutes Step 5. The granulate from Step 4 was then dried in a Fluidized Bed Dryer (Glatt GPCG5) with an inlet air temperature of 50 ° C at any acceptable moisture content of about 1.0 to 3.0% LOD Step 6. The granule from Step 5 was then sieved using a Fitz Mili Model M equipped with a 30 mesh screen, with front blades, operating at medium speed. Step 7. The sifted magnesium stearate from step 1 was added to the granulate from Step 6 and mixed for 5 minutes using the mixer from Step 2. This was marked as Example 10 (2.650kg). Step 8. Part of the mixed granule of Step 7 was compressed into a < Manesty Beta Press equipped with oval tools, 19.1 mm x 10.2 mm, at a compression weight of approximately 934.6 mg. Step 9. The rest of the lubricated granule, 2.650 kg (from Step 7), weighed and added the sifted CSD from step I, then manually dispersed and the mixture was mixed for 5 minutes in the mixer of Step 3. This portion was marked as Example 11. The mixture was compressed to form tablets.

Examples 10 and 11 were manufactured in a manner substantially similar to that of Examples 9 and 10 with the following exceptions. 1. All ingredients were screened through a 20 mesh screen. 2. The drug and intragranular ingredients were mixed for 10 minutes. 3. The amounts of water and alcohol SD3A were adjusted for differences in lot size. 4. The dried granule was milled using a Comil Model 197AS with a 0.062"screen 5. Example 11 was dried in a tray dryer 6. Magnesium stearate was mixed for 10 minutes after 10 minutes of pre-mixing of the granule. ground and the other ingredients.

TABLE 3 1. Heating in a forced air oven at 50 ° C to stimulate film coating. 2. Fractures of effort before and after heating. 3. One tablet broken in half (unacceptable hardness).

As can be seen from the results, the tablet of Example 4 (which lacks colloidal silicon dioxide and has extragranular microcrystalline cellulose) is broken in half during drumming, to simulate the film coating conditions. The hardness of the tablet is therefore totally unacceptable. In contrast, when colloidal silicon dioxide (Example 3) was added the tablet surprisingly did not break and further the disintegration time and ejection force increased substantially less than might be expected. The tablets of Examples 5 and 6, like that of Example 3, developed stress fractures after heating. In the tablet of Example 3, colloidal silicon dioxide and intragranular microcrystalline cellulose were present; in Example 5 the microcrystalline cellulose was also intragranular, but there was no colloidal silicon dioxide; and in Example 6 again there was no colloidal silicon dioxide, but the microcrystalline cellulose was extragranular. Surprisingly, however, when colloidal silicon dioxide is present and microcrystalline cellulose is extragranular, there seems to be a synergistic effect, which prevents stress fractures. This effect can be observed in the table of example 7, where there are no stress fractures, and also the hardness and coldness were good. As with the table of Example 3, the disintegration and ejection forces increased substantially less than might be expected. As can also be seen from comparative example 8a) the hardness value is very low and the friability falls within the 1% limit of the American Pharmacopoeia (USP). Even at the very high compression force used in example 8b), the friability still falls within the USP test. In contrast to the addition of approximately 0.1% weight / weight of colloidal silicon dioxide (in example 9a and b), the hardness and friability improved dramatically. In addition the ejection force, which was good before the addition of the colloidal silicon dioxide still good, and indeed actually improved with its addition. The disintegration time of the tablets of Example 9 is also very satisfactory. Additionally when the formulation of example 11 was repeated incorporating colloidal silicon dioxide in amounts ranging from 0.05 to 3% w / w, excellent tablets can be consistently produced having a high purity and a low friability value, substantially free of fractures of effort.

The robust tablet formulation of the invention therefore can consistently provide valacyclovir tablets which have excellent handling characteristics, which are suitable for film coating and which still have adequate lubrication and disintegration time.

It is noted that in relation to this date, the best known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (1)

1. CLAIMS A tablet comprising at least about 50% w / w of valaciclovir or a salt thereof, a cellulose filler, a binding agent, a lubricant of from about 0.05 to about 3% w / w of colloidal silicon dioxide , characterized in that the valaciclovir or the salt thereof is present within the granules in the tablet, the lubricating silicon dioxide and at least a portion of the cellulosic filler are present extragranularly; where the friability of the tablet does not exceed 1%, the hardness is at least 8 kP, and the ejection force does not exceed 1000 Newtons. The tablet according to any of the preceding claims, characterized in that the colloidal silicon dioxide is present in an amount from about 0.1% to about 0.5% w / w. The tablet according to claim 1 or 2, characterized in that the filler is present in an amount of about 3% w / w up to about 30% w / w. The tablet according to claim 3, characterized in that the cellulosic filler is present at about 5% up to about 15% by weight / weight. The tablet according to claim 4, characterized in that the cellulosic filler is present at approximately 10% w / w. The tablet according to any one of the preceding claims, characterized in that the filler is microcrystalline cellulose. The tablet according to any of the preceding claims, characterized in that the particle size of the cellulosic filler is from about 20 to about 300 μm. The tablet according to any of the preceding claims, characterized in that the binder is present in about 1% to about 5% w / w. The tablet according to any of the preceding claims, characterized in that the binder is ethylcellulose or povidone. The tablet according to claim 9, characterized in that the binder is povidone. The tablet according to claim 10, characterized in that the povidone is povidone grade K90. The tablet according to any of the preceding claims, characterized in that the lubricant is present at about 0.1% up to about 2.0% w / w. The tablet according to claim 12, characterized in that the lubricant is a stearate derivative. The tablet according to claim 13, characterized in that the lubricant is magnesium stearate and is present at about 0.1% up to about 1.0% w / w. The tablet according to any of the preceding claims, characterized in that the valaciclovir or its salt is present in about 65% up to about 85% w / w. The tablet according to any of the preceding claims, characterized in that it comprises valaciclovir hydrochloride. The tablet according to claim 16, characterized in that valaciclovir hydrochloride is in anhydrous crystalline form including substantially a separation d pattern as follows: separation pattern d (in Angstroms): 10.20 ± 0.08, 8..10 ± 0.06, 7.27 ± 0.06, 6.08 ± 0.05, 5.83 ± 0.03, 5.37 ± 0.02, 5.23 ± 0.02, 4.89 ± 0.02, 4. 42 ± 0.02, 4.06 ± 0.02, 3.71 ± 0.02, 3.39 ± 0.02, 3.32 ± 0.02, 2.91 ± 0.02, 2.77 ± 0.02. The tablet according to any of the preceding claims, characterized in that the compacted bulk density of valaciclovir or the salt thereof is from about 0.1 to about 0.9 g / cc. 19. The tablet according to any of the preceding claims, characterized in that it further includes a disintegrating agent present in about 0.5% up to about 20% w / w. 20. The tablet 1 according to claim 19, characterized in that the disintegrating agent is a nonionic disintegrating agent. 21. The tablet according to claim 20, characterized in that the disintegrating agent is crospovindone present in about 0.5% up to about 7% w / w. 22. A tablet, characterized in that it comprises from about 65% up to about 85% w / w of anhydrous crystalline valaciclovir hydrochloride, including the separation d-diffraction pattern according to claim 16, about 0.5% up to about 5% w / w povidone weight, about 3% to about 30% w / w of a cellulosic filler, about 0.5 to about 7% w / w of a nonionic disintegrating agent, about 0.1% to about 1.0% of a stearate lubricant, and about 0.1% to about 0.5% weight / weight of colloidal silicon dioxide, wherein the valac_clovir hydrochloride is present intragranularly; and wherein the cellulosic filler, the stearate lubricant and the colloidal silicon dioxide are present extragranularly. The tablet according to any of claims 1 to 22, characterized in that it is coated with a film. The tablet according to any of the preceding claims for use in medical therapy. 5. A method of treating an infection with a herpes virus in a human, characterized in that it comprises administering to the host one or more tablets in accordance with any of the preceding claims for administering an antiviral amount against the effective herpes of valacyclovir or a salt thereof. 26. A process for preparing a tablet comprising at least about 50% w / w of valaciclovir or a salt thereof, a binding agent, cellulosic filler, a lubricant, and about 0.05 to about 3.0% colloidal silicon dioxide, wherein the friability of the tablet does not exceed 1% and the hardness is at least 9 kP and the ejection force does not exceed 1000N; the process is characterized in that it has the valaciclovir or its salt present within the granules of the tablet, and the lubricant, the colloidal silicon dioxide and at least a portion of the cellulosic filler are present extragranularly. A process for preparing a tablet comprising at least about 50% w / w of valaciclovir or a salt thereof, a binding agent, a cellulosic filler, a lubricant, and about 0.05 to 3.0% w / w of silicon dioxide colloidal; wherein the hardness of the tablet is at least 9 kP, the friability is not greater than 1% and the ejection force is not greater than 1000 N; the process is characterized in that it comprises forming granules which include valaciclovir or a salt thereof and then mixing the lubricating colloidal silicon dioxide and at least a portion of the cellulosic filler with the granules. The process according to claim 26 or 27, characterized in that it comprises forming granules by mixing the valaciclovir or the salt, optionally a binding agent or a portion thereof, and optionally a portion of the cellulosic filler; granulating with a granulation solution to form granules or dissolving the binder or a portion in the granulation solution before adding to valaciclovir; drying the granules; mixing the granules with the lubricant, colloidal silicon dioxide, and the optional cellulosic filler or a portion thereof; and then compressing the combined mixture to form a tablet. A process for preparing a tablet comprising at least about 50% w / w of valaciclovir or a salt thereof, a binding agent, a lubricant, about 0.05 to about 3% w / w of colloidal silicon dioxide, and about 3 up to about 30% w / w of a cellulosic grinder; wherein the hardness of the tablet is at least 9 kP, the friability is not greater than 1%, and the injection force is not greater than 1000N; the process is characterized in that it comprises forming granules by mixing the valaciclovir or the salt, the optional binder or a portion thereof, and optionally a portion of the cellulosic filler; granulating with a granulation solution to form granules or dissolving the binder or a portion thereof in the granulation solution before adding to valaciclovir; drying the granules; mixing the granules with the lubricant, colloidal silicon dioxide, and at least a portion of the cellulosic filler; and then compressing the combined mixture to form a tablet. 30. The use of the combination of 0.05 to 3% weight / weight of colloidal silicon dioxide and the cellulose filler r. • Assists extragranularly in a tablet that includes at least 50% w / w of intragranular ce valaciclovir hydrochloride, and extragranular lubricant to prevent stress fractures.