United States Patent [19J
`Carter et al.
`
`[54] VALACICLOVIR TABLETS CONTAINING
`COLLOIDAL SILICON DIOXIDE
`
`[75]
`
`Inventors: Barry Howard Carter, Kinston, N.C.;
`Lloyd Gary Tillman, Carlsbad, Calif.
`
`[73] Assignee: Glaxo Wellcome Inc., Research
`Triangle Park, N.C.
`
`[21] Appl. No.:
`
`875,172
`
`[22] PCT Filed:
`
`Jan. 19, 1996
`
`[86] PCT No.:
`
`PCT/GB96/00111
`
`§ 371 Date:
`
`Aug. 29, 1997
`
`§ 102(e) Date: Aug. 29, 1997
`
`[87] PCT Pub. No.: W096/22082
`
`PCT Pub. Date: Jul. 25, 1996
`
`[30]
`
`Foreign Application Priority Data
`
`Jan. 20, 1995
`
`[GB]
`
`United Kingdom ................... 9501127
`
`Int. Cl.6
`....................................................... A61K 9/28
`[51]
`[52] U.S. Cl. .......................... 424/464; 424/465; 424/474;
`514/770; 514/772; 514/772.3; 514/781;
`514/934
`[58] Field of Search ..................................... 424/464, 465,
`424/474, 441, 480
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,556,639
`
`9/1996 Fielden .................................... 424/480
`
`FOREIGN PATENT DOCUMENTS
`
`B-16498/92
`0 196 546 Bl
`0 308 065
`0 349 103
`WO 92/19227
`
`12/1992
`10/1986
`3/1989
`1/1990
`11/1992
`
`Australia.
`European Pat. Off ..
`European Pat. Off ..
`European Pat. Off ..
`WIPO.
`
`OIBER PUBLICATIONS
`
`Chemical Abstracts, vol. 118, No. 10, Mar. 1993 Abstract
`No. 87553 & Zhongguo vol. 23, No. 8, 1992 p. 350--1 Yuan
`"Improved Preparation of Ibuprofen Tablets".
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US005879706A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,879,706
`Mar. 9, 1999
`
`Chemical Abstracts vol. 69, No. 4, Jul. 1968 Abstract No.
`11048 & SB. TR., VSes. Nauch.-Issled, Inst. Nov. Strait.
`Mater. vol. 15, 1967 pp. 15-21 Edell'man, "Effect of the
`nataure and particles size of fillers and methods etc.".
`
`Chemical Abstracts, vol. 95, No. 2, Jul. 1981 Abstract No.
`12656 & Pharmazie vol. 36, No. 1, 1981 p. 32-4 lonchev,
`KH., Velikova, E "Optimization of the composition of a
`multicomponent pharmaceutical form etc.".
`
`Chemical Abstracts, vol. 102, No. 18, May 1985 Abstract
`No. 154736 & J. Pharm. Pharmacol. vol. 37, No. 3, 1985 p.
`193-5 Esezobo "The effect of some excipients on the
`physical properties of a paracetamol tablet formulation".
`
`Farmatsiya, vol. 35, No. 4, 1986 p. 25-8 "Study of the
`Possibility of Producing Celanide Tablets etc.".
`
`J. Pharm. Pharmacol 1986 36:51-54 Johansson et al Inves(cid:173)
`tigation of the film formation of Magnesium etc.
`
`Drug Development and Industrial Pharmacy 6(6) 573-89
`(1980) Bossert et al "Effect of Mixing on the Lubrication of
`Crystlaline Lactose by Magnesium Stearate".
`
`Pharm. Acta Helv. 52 No. 3 (1977) p. 33-9 Lerk et al
`"Interaction of lubricants and colloidal silica during etc.".
`
`Pharm. Acta Helv. 52 No. 3 (1977) pp. 39-44 Lerk et al
`"Interaction of lubricants and colloidal silica during etc".
`
`(List continued on next page.)
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-James M. Spear
`Attorney, Agent, or Firm-Nixon & Vanderhye
`
`[57]
`
`ABSTRACT
`
`A tablet comprising at least 50% w/w valaciclovir and 0.05
`to 3% w/w colloidal silicon dioxide in which the valaciclovir
`is present within granules of the tablets and the silicon
`dioxide, a lubricant and a microcrystalline cellulose filler are
`present extragranularly has excellent hardness and friability
`properties while still maintaining lubrication of the tablet
`granules.
`
`28 Claims, 3 Drawing Sheets
`
`17.66 B.838
`
`5.901
`
`n (A)
`4.436 3.559 2.976 2.562 2.252
`
`2 013
`
`1823%
`100
`
`-70
`
`- 90
`-80 ~
`tr1
`r
`;t>
`...,i
`H
`<!
`tr1
`
`CPS
`1.9t •. O
`
`'·44.6·
`
`395.2-
`
`345.8·
`
`296.4·
`
`21.7.0-
`
`197.6-
`
`11,n.2-
`
`98.8·
`
`1.9.1,.
`
`:><
`E-<
`.....
`(I) z
`w
`E-< z
`.....
`
`-60
`
`-50
`
`--40
`
`7.
`...,i
`M
`7.
`"'
`::J
`~
`
`30
`
`-20
`
`·10
`
`so
`
`2e (Degrees)
`
`1
`
`EX 1006
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`5,879,706
`Page 2
`
`OIBER PUBLICATIONS
`
`Ahmed et al Int. J. Pharm. 41 (1953) 223-6 Tablet re
`Toughening effects of Colloidal Silica etc.
`Ragnarsson et al Int J. Pharmaceutics 1979 pp. 127-131 The
`Influence of Mixing Time and Colloidal Silica etc.
`Antiviral Chemistry & Chemotherapy (1992) 3 (3) 157-164
`Beauchamp et al "Amino acid ester prodrugs of acyclovir".
`
`Handbook of Pharmaceutical Excipients 1994 p. 253-6
`Colloidal Silicon Dioxide.
`USP (1995) p. 1840 (911 Viscosity/Physical Tests p. 2300
`Colloidal Silicon Dioxide (1216) Tablet Friability.
`Pharmaceutical Dosage Forms: Tablets vol. 1 pp. 183-185
`Lieberman Compressed Tablets Jan. 1995.
`Silver Platter v 2.12 IPA 1970--Sep. 1994.
`
`2
`
`

`
`FI G.1.
`CPS
`494.0
`1,44_6J
`
`17.66 8.838
`
`I
`
`I
`
`5.901
`
`I
`
`0
`
`J) (A)
`
`4.436 3. 559 2.976 2.562 2.252
`
`I
`
`I
`
`I
`
`2.013
`
`I
`
`I
`
`I I
`
`395.2-l
`
`y
`
`~ 345.8·
`~
`......
`296.4-
`en
`z
`ril
`t-c
`z
`
`21.1.0-
`
`197.6-
`
`~
`
`11.0.2-
`
`l
`
`98.B-I J
`
`, 023°10 I
`tlOO
`90
`Lao I~
`t-4
`-70 >
`~
`-60 ~
`-50
`
`~
`
`1-4
`
`I .
`I
`" II I
`4:.:·1 ~~~~.~~v: ~.~,~ ~,,, .·.-::~ .-.v.~~-1~ I~
`I
`
`I
`I
`'
`111 .I 'I I II 1 ll I l •I -I l n fl_ • ,
`
`'
`
`-40
`
`·30
`
`1-70
`
`5
`
`10
`
`15
`
`20
`25
`30
`28 (Degrees)
`
`35
`
`40
`
`45
`
`50
`
`1-j
`t'rj
`
`z
`:z
`I~
`1-j
`
`d •
`\JJ.
`•
`~
`~ ......
`~ =
`......
`
`~
`~
`!"'l
`~~
`"'"" ~
`
`~
`~
`
`'Jl
`
`~
`~
`
`=-
`.....
`"'""
`.....,
`0
`~
`
`Ul
`....
`00
`.....::.
`\C
`....
`
`.....::. = 0--,
`
`3
`
`

`
`U.S. Patent
`
`Mar. 9, 1999
`
`Sheet 2 of 3
`
`5,879,706
`
`N
`.
`(9
`-
`LL
`
`~
`0
`....t
`
`0
`N
`
`Vl
`\..:.J
`Ll..J
`0::
`L:J
`0
`Ll..J
`0
`m 0
`z
`\..:.J
`....J
`
`L:J z
`<:
`z
`0
`I-
`0
`0 u
`<:t:
`0::
`u..
`LL
`0
`
`N
`
`....t 0
`s;?o
`x.-
`
`0
`°'
`0
`
`0
`co
`0
`
`.
`,,.,
`0
`0
`0
`0
`0
`..::J
`N
`IJ"\
`...j'
`c:i
`ci
`0
`0
`0
`(31\-/Ci lNnOJ l J-11SN31NI ~V'3d
`
`0
`r-
`C>
`
`0
`ci
`
`'
`
`0
`~
`0
`
`4
`
`

`
`U.S. Patent
`
`Mar. 9, 1999
`
`Sheet 3 of 3
`
`5,879,706
`
`0
`0
`....::
`
`0
`N
`
`0
`0
`m
`
`0
`0
`N
`
`(./")
`w
`w
`c::
`1.:1
`w
`0
`z
`L.U _,
`l..:J z
`<
`z
`0
`I-
`
`LJ <
`
`0::
`LL
`LL
`0
`
`M .
`~ -
`LL
`
`(31VCJ lNnOJJ AllSN31NI >iV3d
`
`5
`
`

`
`1
`VALACICLOVIR TABLETS CONTAINING
`COLLOIDAL SILICON DIOXIDE
`
`5,879,706
`
`2
`which is capable of being film coated and consistently
`providing tablets having a friability not exceeding 1 %, a
`hardness of at least 9 kP and an ejection force not exceeding
`1000 Newtons (1 kN).
`The hardness of the tablet should be such that it not only
`has an acceptable crushing force (as measured by the kP
`value), but also that the tablet does not break during tum(cid:173)
`bling.
`It is a further preferred object of the invention to provide
`10 a robust formulation which is capable of consistently pro(cid:173)
`viding tablets substantially free of cracks.
`We have now found an effective method of overcoming
`both of the above friability and hardness problems which
`involves the extragranular use of colloidal silicon dioxide
`15 and microcrystalline cellulose in the tablet formulation.
`The Handbook of Pharmaceutical Excipients 1994 at
`p253-256 does not mention colloidal silicon dioxide as an
`agent to improve the hardness of tablets. Neither does The
`Theory and Practice of Industrial Pharmacy (third edition)
`20 by Lachman, Lleberman and Kanig, mention colloidal sili(cid:173)
`con dioxide for such a use.
`Accordingly in a first aspect of the invention there is
`provided a tablet comprising at least about 50% w/w val(cid:173)
`aciclovir or a salt thereof present within the granules of the
`25 tablet, a microcrystalline cellulose filler, a binding agent, a
`lubricant selected from talc, sodium lauryl sulphate and
`alkaline earth metal stearates, and about 0.05% to about 3%
`w/w colloidal silicon dioxide, the lubricant, colloidal silicon
`dioxide and at least a portion of the filler being present
`30 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 Newtons.
`A tablet of this formulation containing 0.05% to 3% w/w
`colloidal silicon dioxide and microcrystalline cellulose is
`35 robust, and has a substantially improved friability and hard(cid:173)
`ness. Furthermore such improved properties is achieved
`while still retaining a satisfactory disintegration time and
`lubrication properties, even when the formulation is blended
`under high shear. An excellent tablet providing acyclovir in
`40 a highly bioavailable form is thus provided by virtue of the
`invention.
`Preferably the disintegration time of the tablet is not
`more than about 30 minutes, more preferably not more than
`about 25 minutes, and most preferably not more than about
`20 minutes.
`The ejection force should not be more than about 1000 N,
`preferably not more than about 800 N, more preferably still
`not more than about 500 N for tablets compressed at about
`10 to 30 kN, preferably 10 to 20 kN.
`Valaciclovir or a salt thereof are hereinafter referred to
`generally as the 'active ingredient' or 'drug'.
`The 1994 U.S. Pharmacopoeia describes colloidal silicon
`dioxide (in its monograph) as: a submicroscopic fumed
`silica prepared by the vapour phase hydrolysis of a silica
`compound.
`Preferably the colloidal silicon dioxide is present in
`amounts of about 0.05% to about 1 % of the total
`formulation, more preferably at about 0.1 % to about 1 %
`w/w, and most preferably about 0.1 % to about 0.5% w/w. We
`have found Aerosil (trade mark) and Cab-o-sil (trade mark)
`to be very suitable.
`
`5
`
`This application is a 371 of PCT/GB96/00111 filed Jan.
`19, 1996.
`This invention relates to a tablet of the antiviral drug
`valaciclovir.
`The compound 9-[(2-hydroxyethoxy)methyl]guanine,
`otherwise 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 herpes group in humans (see, for example, Schaeffer
`et al, Nature, 272, 583-585 (1978), UK Patent No. 1523865,
`U.S. Pat. No. 4,199,574). However, acyclovir is poorly
`absorbed from the gastrointestinal tract upon oral adminis(cid:173)
`tration and this low bioavailability means that multiple high
`doses or oral drug may need to be administered, especially
`for the treatment of less sensitive viruses or infections in
`order to achieve and maintain effective anti-viral levels in
`the plasma.
`The L-valine ester of acyclovir (2-[2-amino-l,6-dihydro-
`6-oxo-9H-Purin-9yl)methoxy ]ethyl L-valinate (herein
`referred to as valaciclovir) has been shown to possess much
`improved bioavailability whilst retaining the anti-viral prop(cid:173)
`erties of acyclovir. A preferred form of this compound is its
`hydrochloride salt which is herein referred to as valaciclovir
`hydrochloride. Valaciclovir and its salts including the hydro(cid:173)
`chloride salt are disclosed in U.S. Pat. No. 4,957,924 (see
`particular example lB), European Patent No. 0308065 (see
`particularly example IB) and Beauchamp et al, Antiviral
`Chemistry and Chemotherapy, 3(3), 157-164 (1992) (see
`particularly page 162 column 1). Tablets of valaciclovir are
`also generally disclosed in the U.S. Pat. No. 4,957,924 and
`European Patent No. 0308065.
`During development of a tablet formulation containing a
`high proportion of valaciclovir, we often encountered diffi(cid:173)
`culties in obtaining tablets of sufficient hardness and friabil(cid:173)
`ity for pharmaceutical handling and for film coating.
`If the tablet is too friable, it will chip or break during
`packaging and transport. The US Pharmacopoeia (USP) no.
`23, 1995, p1981 at monograph 1216 requires that pharma(cid:173)
`ceutical tablets have a friability not exceeding 1 %. If the
`tablet is too soft, it will crumble during, tumbling in the film
`coating pan.
`In the reference manual 'Problem Solver' (compiles by
`FMC Corporation) at pages 8 and 9, the remedies for low 45
`tablet hardness are given inter alia as increasing the com(cid:173)
`pression force applied to form the tablet, or decreasing the
`proportion of lubricant in the tablet formulation.
`We tried to increase the hardness and friability of val(cid:173)
`aciclovir tablets by increasing the compression force, by 50
`decreasing the proportion of lubricant and increasing the
`proportion of biner, but found in each case that a sufficiently
`hard and non-friable tablet could not be produced m a
`practical way.
`Furthermore, cracks were found in some tablets as a 55
`result of increasing the compression force. Additionally,
`valaciclovir has 'adhesive' properties in that it can stick to
`tablet dies and therefore needs to be efficiently lubricated. It
`is difficult therefore to reduce the proportion of lubricant
`without causing the tablets to stick. Furthermore, the disin- 60
`tegration time of the valaciclovir tablet is also quite long and
`therefore any possible solution to the hardness and friability
`problem should not have a substantial deleterious effect on
`either the disintegration time or lubrication (as measured by
`the ejection force) of the table formulation.
`It is therefore an object of the invention to provide a
`robust tablet formulation of valaciclovir and salts thereof
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIGS. 1-3, show X-ray powder diffraction patterns of the
`65 product of examples lB and 2B.
`The content of drug in the tablet is at least about 50% w/w,
`preferably about 60% w/w to about 90% w/w, more pref-
`
`6
`
`

`
`5,879,706
`
`25
`
`30
`
`3
`erably still about 65% w/w to about 85% w/w and most
`preferably about 80% w/w/. Preferably the (tapped) bulk
`density of the drug is about 0.1 to 0.9 glee, more preferably
`0.3 to 0.7 glee, more preferably still 0.34 to 0.66 glee, and
`most preferably 0.4 to 0.6 glee. Suitably the drug is valaci(cid:173)
`clovir hydrochloride, preferably being of an anhydrous
`crystalline form including substantially a d-spacing pattern
`(derived from X-ray powder diffraction) as follows:
`d spacing pattern (in Angstroms):
`10.20±0.08, 8.10±0.06, 7.27±0.06, 6.08±0.05, 5.83±0.03, 10
`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±0.01, 2.77±0.02.
`Hereinafter by "anhydrous crystalline form" according to
`the invention, we mean a crystalline form having substan(cid:173)
`tially the same X-ray powder diffraction pattern as shown in
`FIGS. 1 to 3, or having substantially the same d pattern a
`defined above.
`Preferably the crystal form purity in any such drug lot of
`anhydrous crystalline valaciclovir hydrochloride used for
`valaciclovir tablets is at least 70%, more preferably at least 20
`80%, more preferably still at least 90% and most preferably
`at least 95% anhydrous crystalline valaciclovir hydrochlo(cid:173)
`ride (as characterised above).
`In an alternative method for measuring crystal form
`purity, since the anhydrous crystalline form of valaciclovir
`hydrochloride contains substantially no water of hydration,
`the level of other hydrated forms of valaciclovir hydrochlo(cid:173)
`ride in any drug lot used for tablets can be measured by the
`water of hydration content. Preferably any such drug lot of
`anhydrous crystalline, valaciclovir hydrochloride contain no
`more than 3% w/w, more preferably no more than 2% w/w,
`more preferably still not more than 1 % w/w and most
`preferably not more than 0.5% w/w water of hydration.
`This water of hydration content is measured by the Keri 35
`Fischer method which is well known in the art and is
`described in the 1990 U.S. Pharmacopoeia at pages
`1619-1621, and the European Pharmacopoeia, second edi(cid:173)
`tion (1992), part 2, sixteenth fasicule at v. 3.5.6-1.
`The filler is microcrystalline cellulose and is at least partly 40
`present extragranularly, which mitigates stress cracking of
`the tablet. A tablet formulation of the invention including
`colloidal silicon dioxide and extragranular microcrystalline
`cellulose appears to have a synergistic effect and is particu(cid:173)
`larly good and robust in that tablets of valaciclovir can 45
`consistently be made to an acceptable hardness without
`introducing stress cracks 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 valaciclovir 50
`or a salt thereof, a binding agent, a lubricant selected from
`talc, sodium lauryl sulphate and alkaline earth metal
`stearates, 0.05 to 3% w/w colloidal silicon dioxide, and 3 to
`30% of microcrystalline cellulose; wherein the valaciclovir
`or salt thereof is present within the granules of the tablet, the 55
`lubricant, colloidal silicon dioxide, and at least a portion of
`microcrystalline cellulose 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 microcrystalline cellulose (e.g. Avicel)
`present at 5 to 15% w/w, most preferably about 10% w/w.
`The particle size of the microcrystalline cellulose is prefer(cid:173)
`ably 20 to 300µ, more preferably 30 to 200µ, and most
`preferably 50 to 100µ.
`The binding agent serves, for example, to bind the pri(cid:173)
`mary and secondary particles together and improve tablet
`
`4
`hardness. Preferably the binding agent is present in an
`amount of about 1 % to about 5% w/w, more preferably at
`about 2% to about 4% w/w, and is suitably a non-starch
`based binder such as methylcellulose or most preferably
`5 povidone. The grade of povidone is advantageously K30 and
`most preferably K90.
`The binding agent such as the povidone, can be dissolved
`in the granulating solvent (such as water) before adding to
`the drug, but preferably it is added (at least partly) dry to the
`drug and other excipients and then the granulating solution
`(such as povidone in water) added.
`The lubricant is suitably present in an amount of about
`0.1 % to about 2.0% w/w, preferably about 0.1 % to about
`1.0% w/w. Although talc or sodium lauryl sulphate are
`15 suitable, preferably the lubricant is an alkaline earth metal
`stearate, such as magnesium stearate. The above amounts
`apply to the stearate, and they are ideally present in amount
`of at about 0.3% to about 0.6% w/w.
`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 about 0.5 to
`about 20% w/w, more preferably at about 0.5% to 7.0% w/w.
`The disintegrating agent is advantageously present within
`the granules of the tablet and can be added before or after the
`binding agent. Clays such as kaolin, bentonite or veegum
`(trademark), and celluloses such as microcrystalline cellu(cid:173)
`lose or croscarmellose sodium e.g., Ac-Di-Sol (trademark)
`maybe used as disintegrants. Preferably a non-ionic disin(cid:173)
`tegrant such as crospovidone is used. Preferably, the
`crospovidone is present at about 0.5% to about 7.0% w/w,
`more preferably about 2 to about 5% w/w, 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
`valaciclovir or a salt thereof, a binding agent, microcrystal(cid:173)
`line cellulose filler, a lubricant selected from talc, sodium
`lauryl sulphate and alkaline earth metal stearates, and about
`0.05 to 3.0% w/w colloidal silicon dioxide, wherein the
`hardness of the tablet is at least 9 kP, the friability is not
`more than 1 %, and the ejection force is not more than 1000
`N; said process comprising forming granules which include
`valaciclovir or a salt thereof and then blending the lubricant,
`colloidal silicon dioxide and at least a portion of the filler
`with said granules.
`Preferably said process comprises forming granules by
`mixing said valaciclovir or salt, optionally a binding agent
`or a portion thereof, and optionally a portion of the filler;
`granulating with a granulating solution to form granules or
`dissolving the binding agent or a portion in the granulating
`solution before adding to valaciclovir; drying the granules;
`blending the granules with the lubricant, colloidal silicon
`dioxide, and filler or a portion thereof; and then compressing
`the blended mixture to form a tablet.
`A preferred aspect of the invention provides a process for
`preparing a tablet comprising at least 50% w/w valaciclovir
`or a salt thereof, a binding agent, a lubricant selected from
`talc, sodium lauryl sulphate and alkaline earth metal
`stearates, 0.05 to 3% w/w colloidal silicon dioxide and 3 to
`60 30% w/w of microcrystalline cellulose filler; wherein the
`hardness of the tablet is at least 9 kP, the friability is not
`more than 1 %, and the ejection force is not more than 1000
`N; said process comprising forming granules by mixing the
`valaciclovir or salt, optional binding agent or a portion
`65 thereof, and optionally a portion of microcrystalline cellu(cid:173)
`lose filler; granulating with a granulating solution to form
`granules or dissolving the binding agent or a portion thereof
`
`7
`
`

`
`5,879,706
`
`5
`
`10
`
`5
`in the granulating solution before adding to valaciclovir;
`drying the granules; blending the granules with the
`lubricant, colloidal silicon dioxide, and at least a portion of
`the filler; and then compressing the blended mixture to form
`a tablet.
`the colloidal silicon dioxide can be first blended with the
`lubricant, preferably a stearate derivative (e.g. magnesium
`stearate) before blending with the granules or it can be added
`separately from the lubricant. When the lubricant is a
`stearate, preferably the ratio or stearate to colloidal silicon
`dioxide is about 1:1 to 10:1, more preferable about 1:1 to
`about 3:1.
`The present invention also provides a tablet (as described
`above) for use in medical therapy, e.g. in the treatment of a
`viral disease in an animal, e.g. 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 simlex 1 and 2, varicella
`zoster, cytomegalovirus, Epstein-Barr viruses or human her(cid:173)
`pes virus-6 (HHV-6) as well as diseases caused by hepatitis 20
`B. The active compound can also be used for the treatment
`of papilloma or wart virus infections and, may furthermore
`be administered in combination with other therapeutic
`agents, for example with zidovudine, to treat retroviral
`associated infections in particular HIV infections.
`In addition to its use in human medical therapy, the active
`compound can be administered to other animals for treat(cid:173)
`ment of viral diseases, e.g. to other mammals. The present
`tablet also provides a method for the treatment of a viral
`infection, particularly a herpes viral infection, in an animal, 30
`e.g. a mammal such as a human, which comprises admin(cid:173)
`istering to the host one or more tablets of the invention to
`provide an effective antiviral amount of the active com(cid:173)
`pound.
`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 may be administered by any
`route appropriate to the condition to be treated, but the
`preferred route of administration is oral. Although tablets
`generally are included within the scope of the invention, for
`example a dispersible tablet or chewable tablet, preferably
`the tablet is a swallowable tablet, most preferably a film(cid:173)
`coated swallowable tablet. It will be appreciated however,
`that the preferred route may vary with, for example, the
`condition of the recipient.
`For each of the above-indicated utilities and indications
`the amounts required of the active ingredient (as above
`defined) will depend upon 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
`attendant physician or veterinarian. In general however, for
`each of these utilities and indications, a suitable effective
`dose will be in the range 1 to 150 mg per kilogram
`bodyweight of recipient per day, preferably in the range 5 to
`120 mg per kilogram bodyweight per day (Unless otherwise
`indicated, all weights of the active ingredients are calculated
`with respect to the free base valaciclovir). The desired dose
`is preferably presented as one, two, three or four or more
`sub-doses administered at appropriate intervals throughout
`the day. These sub-doses may be administered in unit dosage
`forms, for example, containing about 50 to 2000 mg, pref(cid:173)
`erably about 250, 500, 1000 or 2000 mg of active ingredients
`per unit dose form.
`The following dosage regimes are given for guidance:
`treatment of herpes simplex virus types 1 and 2 infection:-
`
`6
`total daily dose of about 1 or 2 g administered at 500 mg
`twice a day or 1 g twice a day for 5 to 10 days; suppression
`of herpes simplex virus types 1 and 2 infections:- total daily
`dose about 250 mg to 1 g for about one to ten years
`(depending on the patient);
`treatment of varicella zoster virus infections (for example
`shingles):- daily dose about 3 g administered at 1 g three
`times a day for seven days; suppression of cytomegalovirus
`infections:- total daily dose about 8 g administered at 2 g 4
`times a day. For transplant patients this daily dose is
`administered for three to six months for the period at risk;
`and for HIV positive patients said daily dose is administered
`as usually indicated for improving quality of life, for
`example for two years or more.
`Early results now indicate that valaciclovir can be used in
`15 the effective suppression of recurrent genital herpes at a once
`daily dose of from about 200 mg to about 1000 mg for an
`effective treatment period. The most likely daily dosages are
`250 mg, 500 mg or 1000 mg.
`Valaciclovir hydrochloride was made as described below:
`EXAMPLE 1
`A. 2-[ (2-amino-l ,6-dihydro-6-oxo-9H-purine-9-y 1)
`methoxy ]ethyl-N-[(benzyloxy)]-L-valinate
`CBZ-L-value (170 g) was dissolved in dimethylformamide
`(DMF) (750 ml) and cooled. A cold solution of N,N-
`25 dicyclohexyl-carbodiimide (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 concen-
`trate treated with water ( 663 ml) then heated to 70° C. The
`suspension was cooled to 20° C., filtered and the solid
`washed with water.
`The damp, crude material was then purified by recrystal-
`lisation from denatured alcohol (1.2 liters) to afford the title
`compound as a damp white crystalline solid (281.5 g).
`B. 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl) methoxy]
`ethyl-L-valinate hydrochloride
`2-[ (2-amino- l ,6-dihydro-6-oxo-9H-purin-9-y l)methoxy]
`40 ethyl-N-[(benzyloxy)carbonyl]-L-valinate (175 g) was
`charged to aqueous denatured alcohol (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 cata(cid:173)
`lyst (35 g wet weight 50% wet with water) then formic acid
`45 (30.6 ml of 90% w/w) added over 1 hour. The reaction
`mixture was stirred for a further 1 hour then a second charge
`of formic acid made (19.5 ml) and the mixture filtered to
`remove the catalyst. The filter cake was washed with dena(cid:173)
`tured alcohol and the combined filtrates were treated with
`50 concentrated hydrochlorid acid (33.7 ml) and the resultant
`mixture was concentrated by vacuum distillation.
`Acetone (1295 ml) was then added over 15 minutes and
`the suspension stirred for 1 hour before filtering off the
`product. The solid was then slurried with acetone (circa. 530
`55 ml), refiltered and dried at 60° C. in vacuo to give the title
`compound (1123 g:Sl.6%).
`A 15 g sample of this material was combined with
`denatured alcohol (circa. 7 ml), to moisten and was heated
`with agitation at 60° C. overnight in a closed flask to avoid
`60 loss of alcohol and maintain the dampness of the mixture.
`The mixture was then dried at 60° C. in vacuo to afford the
`product as the desired morphic form.
`Physical Data:
`Karl Fischer value: 0.9% w/w water.
`The X-ray powder diffraction patterns of the product of
`example lB are shown in FIG. 1 of the accompanying
`drawings.
`
`35
`
`65
`
`8
`
`

`
`5,879,706
`
`7
`The d spacings and further X-ray diffraction data are
`shown in Table 1.
`
`TABLE 1
`
`Peak No:
`
`Angle
`(degrees)
`
`Peak
`(counts)
`
`d Spacing
`pattern
`(A)
`
`Error in
`d (±A)
`
`!/!max
`(%)
`
`2
`3
`4
`5
`
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`
`3.56
`8.62
`9.42
`10.86
`12.10
`13.22
`14.49
`15.12
`15.90
`16.45
`16.90
`17.33
`18.12
`22.71
`20.55
`21.21
`21.83
`22.71
`23.95
`25.10
`26.21
`26.89
`27.08
`28.02
`28.27
`28.91
`29.68
`30.55
`31.34
`31.58
`32.13
`32.96
`33.99
`34.38
`35.12
`36.78
`38.71
`
`680
`1151
`87
`1438
`835
`198
`2172
`455
`352
`1969
`744
`119
`1013
`1429
`256
`370
`753
`95
`2893
`171
`1784
`428
`373
`158
`161
`391
`191
`502
`110
`98
`597
`260
`344
`374
`141
`408
`101
`
`24.8
`10.25
`9.38
`8.14
`7.31
`6.69
`6.11
`5.85
`5.57
`5.38
`5.24
`5.11
`4.89
`4.43
`4.32
`4.19
`4.07
`3.91
`3.71
`3.54
`3.40
`3.31
`3.29
`3.18
`3.15
`3.09
`3.01
`2.92
`2.85
`2.83
`2.78
`2.72
`2.64
`2.61
`2.55
`2.44
`2.32
`
`0.5
`0.08
`0.07
`0.06
`0.06
`0.05
`0.05
`0.03
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`0.02
`
`24
`39
`3
`49
`28
`6
`75
`15
`12
`68
`25
`4
`35
`49
`8
`12
`26
`3
`100
`5
`61
`14
`12
`5
`5
`13
`
`17
`3
`3
`20
`8
`11
`12
`4
`14
`3
`
`!/!max ~ (peak height/max. peak ht) x 100
`
`15
`
`20
`
`8
`EXAMPLE 2
`A. 2-[ (2-amino-l ,6-dihydro-6-oxo-9H-purin-9-y 1)
`methoxylethyl-N-[(benzyloxy)carbonyl]-L-valinate
`CBZ-L-valine (167 g) was dissolved in dimethylforma-
`5 mide (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. 4(Dimethylamino)pyridine (9.4 g) was then
`added and the mixture stirred cold overnight. A white
`10 precipitate of the by-product was then removed by filtration.
`The solvent was partially removed by vacuum distillation
`and the concentrate treated with water (663 ml) then heated
`to 70° C. The suspension was cooled to 20° C., filtered and
`the solid washed with water.
`The damp, crude material was then purified by recrystal-
`lisation from denatured alcohol (1.2 liters) to afford the title
`compound as a damp white crystalline solid (215.3 g).
`B. 2-[(2-amino-l ,6-dihydro-6-oxo-9H-purin-9-yl)
`methoxylethyl-L-valinate hydrochloride
`2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]
`ethyl-N-[(benzyloxy)carbonyl]-L-valinate (200 g) was
`charged to aqueous denatured alcohol (382 ml/908 ml) and
`heated to reflux to dissolve solids. The solution was cooled
`to 40° C. The suspension was treated with a 50% w/w paste
`25 of 5% palladium on carbon catalyst and water ( 40 g) then
`formic acid (96% w/w:32.8 ml) added over 1 hour. The
`reaction mixture was stirred for a further 1 hour then a
`second charge of formic acid made (20.88 ml) and the
`mixture filtered to remove the catalyst. The filtrate was
`30 treated with concentrated hydrochloric acid (38.56 ml) and
`the resultant mixture was concentrated under vacuum.
`Acetone (1480 ml) was then added over 15 minutes and
`the suspension stirred for 1 hour before filtering off the
`product. The solid was then slurried with acetone (ca. 500
`35 ml), refiltered 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 then removed in vacuo to afford the product
`40 as the desired morphic form.
`Crystal From Purity: the sample of example 2(B) con(cid:173)
`tained above 90% of the anhydrous crystalline form valaci(cid:173)
`clovir.
`The X-ray powder diffraction patterns of the product of
`45 example 2(B) are shown in FIGS. 2 and 3 of the accompa-
`nying drawings in which:
`FIG. 2 is a linear plot X-ray diffractogram; and
`FIG. 3 is a square root plot X-ray diffractogram.
`The d spacings and further X-ray diffraction data are
`50 shown in Table 2.
`
`The powder sample used to produce the above X-ray
`diffraction data was prepared by an equivalent method as the
`powder sample used to produce the X-ray diffraction data of
`table 2 (described hereinafter) except that for the above data
`the following preparation was u