FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITION OF VALACYCLOVIR OR SALT THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to pharmaceutical composition of valacyclovir or salt thereof wherein the composition comprises granules of valacyclovir or salt thereof in admixture with pharmaceutically acceptable excipients wherein the granules are prepared using a mixture of aqueous and non-aqueous vehicle.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention relates to pharmaceutical composition of valacyclovir or salt thereof wherein the composition comprises granules of valacyclovir or salt thereof in admixture with pharmaceutically acceptable excipients wherein the granules are prepared using a mixture of aqueous and non-aqueous vehicle.
Valacyclovir is chemically, L-valyl ester of acyclovir designated as 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valyl ester. It is commercially available in form of its hydrochloride salt (FORMULA I) as Valtrex® Tablets. Valacyclovir hydrochloride is indicated for the treatment of Herpes Zoster, Genital Herpes and Herpes labialis.
##STR(

N

k

NH2

° . HCI
FORMULA I
)##
US Patent No 4,957,924 provides ester of acyclovir i.e. valacyclovir having antiviral property. Also provides pharmaceutical composition comprising valacyclovir or salt thereof.
US Patent No 5,879,706 provides tablet formulation of valacyclovir hydrochloride wherein colloidal silicon dioxide and microcrystalline cellulose is present extragranularly to overcome hardness and friability problems.
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US Application No 20060147519 relates to tablet formulation of valacyclovir hydrochloride. Also provides process of preparing tablet formulation of valacyclovir and improving friability and hardness by reducing the particle size of hydrated form of valacyclovir hydrochloride.
US Application No 20050123607 relates to pharmaceutical formulation of valacyclovir containing titanium dioxide.
US Application No 2003108615 relates to pharmaceutical formulation of valaciclovir comprising carrier beads coated with one or more layers of pharmaceutically acceptable substances, wherein, at least one layer is a drug coat layer comprising valaciclovir, or a pharmaceutically acceptable derivative thereof. The invention also relates to a process for the preparation of such a formulation.
Several other pharmaceutical composition containing valacyclovir are known in the art such as US Patent No 6,117,453, US Patent No 6,048,547, US Application No 2005059684.
It was surprisingly found by the present inventors that when valacyclovir in admixture with pharmaceutically acceptable excipients is granulated using water, the obtained granules have following problems such as formation of hard lumps, non-uniform binder distribution, local wetting and poor compressibility. The present inventors have surprisingly found that when valacyclovir in admixture with pharmaceutically acceptable excipients is granulated using a mixture of water and isopropyl alcohol, all the above problems are sorted out in addition granules have better flow property and the tablets prepared using these granules showed better hardness and friability.
In one of the aspects of the present invention there is provided a pharmaceutical composition of valacyclovir or salt thereof wherein the said composition comprises granules of valacyclovir or salt thereof in admixture with pharmaceutically
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acceptable excipients prepared by using a mixture of aqueous and non-aqueous vehicle.
In yet another aspect of the present invention there is provided a process of preparing a pharmaceutical composition of valacyclovir or salt thereof comprising the steps of:
a) granulating valacyclovir or salt thereof and pharmaceutically acceptable excipients using a mixture of aqueous and non- aqueous vehicle.
b) blending the granules of step a) with pharmaceutically acceptable excipients.
The pharmaceutical composition comprises of valacyclovir or salt thereof as an active ingredient wherein valacyclovir can be present in the form of valacyclovir hydrochloride in immediate release form, sustained release form, extended release form or controlled release form.
The pharmaceutical composition of valacyclovir or salt thereof comprises of two parts namely intragranular part and extragranular part. The Intragranular part is prepared by sifting individually through a suitable mesh Valacyclovir Hydrochloride, suitable filler & portion of suitable binding agent followed by mixing and then granulating with solution of suitable binding agent (remaining portion) in water or mixture of aqueous and non-aqueous vehicle. The obtained granules are dried and then mixed with presifted extragranular part comprising suitable disintegrant, suitable glidant and suitable lubricant. The obtained blend can be compressed to form a tablet using suitable tooling and can be optionally coated for aesthetic appeal (such as film coating) or to provide enteric or sustained release properties.
The dosage form includes solid oral dosage forms such as granules, sachets, tablets, mini tablets, capsule or powder.
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The term 'mixture of aqueous and non-aqueous vehicle' as used herein refers to mixture of aqueous solvent selected from water and the like with non-aqueous solvents selected from a group comprising one or more of chloroform, acetone, isopropyl alcohol, ethanol, methanol and the like in a particular ratio wherein the ratio varies between 1:100 to 1: 0.001
Pharmaceutically acceptable excipients can be filler, binding agent, disintegrant, lubricant, glidant and the like.
Suitable filler may be one or more of calcium hydrogen phosphate, lactose, microcrystalline cellulose and the like.
The binding agent may be any suitable binding agent commonly known in the art, including one or more of cellulose ethers (e.g., hydroxypropyl methylcellulose and hydroxypropyl cellulose) and polyvinyl pyrrolidone, such as the pyrrolidone that is sold under the trade name povidone K30 and povidone K90.
Suitable disintegrants include those commonly known in the art, including clays such as bentonite, kaolin or veegum; celluloses such as microcrystalline cellulose or croscarmellose sodium; and non-ionic disintegrants such as cross-linked polyvinyl pyrrolidone sold under the trade name of crospovidone.
Suitable lubricants may be selected from those commonly known pharmaceutically acceptable lubricants, e.g. one or more of talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate.
Suitable glidant may be selected from those commonly known pharmaceutically acceptable glidant e.g. one or more of colloidal silicon dioxide, talc or magnesium stearate.
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Granules comprising valacyclovir or salt thereof in admixture with pharmaceutically acceptable excipients prepared using a mixture of water and isopropyl alcohol showed better flow property when compared to granules prepared using water as is depicted from the values of angle of repose and compressibility index shown in Table 1
Table 1: Angle of repose and compressibility index of granules of Valacyclovir hydrochloride having the formula given in Table 3.

S.No. Granule Characterization Granules prepared usingmixture of water and isopropylalcohol Granulesprepared usingwater
1. Angle of repose (°) 22 31
2. Compressibility Index (%) 18.9 26.6
The Granules comprising valacyclovir or salt thereof in admixture with pharmaceutically acceptable excipients prepared using a mixture of water and isopropyl alcohol were compressed to form a tablet, the resulting tablets showed better hardness and friability as compared to tablets of valacyclovir prepared by compressing granules of valacyclovir prepared using water as shown in Table 2.
Table2: Hardness and Friability data of Valacyclovir Tablets prepared as per the formula given in Table3.

S.No. Tablet Characterization Valacyclovir tabletcomprising granulesprepared using mixture ofwater and isopropyl alcohol Valacyclovir tablet comprising granules prepared using water
500 mg tab 1 gm tab 500 mg tab 1 gm tab
1. Hardness (N) 160-170 272-295 165-175 238-253
2. Friability (% w/w) Nil Nil 0.12 0.30
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While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES 1-4
Table 3: Composition of Valacyclovir Tablets

Example 4 Qty/tab (mg)
1206.7 86.80
1206.7 101.14
603.35 43.40
603.35 50.57
60.00 q.s

Name of Ingredients Example 1 Qty/tab (mg) Example 2 Qty/tab (mg) Example 3 Qty/tab (mg)
Intragranular Part:
60.00
qs qs
30.00
qs
30.00
qs qs
Valacyclovir HCI Microcrystalline Cellulose Povidone K-90 Water
IPA
Extragranular Part:

14.00
Croscarmellose
Sodium
Talc
14.00
Magnesium Stearate 5.25
Total Weight (mg) 717.17
Hardness (Newton) 160-170
Friability (% w/w)

28.00
28.00
10.50
1434.34
272-295

14.00
14.00
5.25
710.00
165-175
0.12

28.00
28.00
10.50
1420.00
238-253
0.30

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Procedure: The valacyclovir tablet composition as mentioned in Examples 1-4 comprises of intragranular and extragranular parts. The Intragranular part is prepared by sifting individually through a suitable mesh Valacyclovir Hydrochloride, Microcrystalline Cellulose & portion of Povidone K-90 followed by mixing and then granulating with solution of Povidone K-90 (remaining portion) in water or mixture of water and isopropyl alcohol. The obtained granules are dried and then mixed with presifted extragranular part comprising Croscarmellose Sodium, Talc and Magnesium Stearate. The obtained blend is compressed to form a tablet using suitable tooling and is optionally coated with opadry coating.
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We Claim:
1. A pharmaceutical composition of valacyclovir or salt thereof wherein the said composition comprises granules of valacyclovir or salt thereof in admixture with pharmaceutically acceptable excipients prepared by using a mixture of aqueous and non-aqueous vehicle.
2. A process of preparing a pharmaceutical composition of valacyclovir or salt thereof comprising the steps of:

a) granulating valacyclovir or salt thereof and pharmaceutically acceptable excipients using a mixture of aqueous and non- aqueous vehicle.
b) blending the granules of step a) with pharmaceutically acceptable excipients.

3. A pharmaceutical composition and a process as per claim 1 and 2 wherein aqueous vehicle is water.
4. A pharmaceutical composition and a process as per claim 1 and 2 wherein non-aqueous vehicle is selected from a group comprising one or more of chloroform, acetone, isopropyl alcohol, ethanol, methanol
5. A pharmaceutical composition and a process as per claim 1 and 2 wherein the ratio of aqueous to non-aqueous vehicle varies between 1:100 to 1:0.001
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6. A pharmaceutical composition and a process as per claim 1 and 2 wherein pharmaceutically acceptable excipients is selected from a group comprising one or more of filler, binding agent, disintegrant, lubricant, glidant.
7. A pharmaceutical composition as per claim 1 wherein the dosage form is tablet, capsule, granule, powder, sachet or pellet
Dated this 1 st day of November 2006.
For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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