WO2009049648A2

WO2009049648A2 - Improved pharmaceutical composition containing antiviral agent and method for the preparation thereof

Info

Publication number: WO2009049648A2
Application number: PCT/EP2007/008998
Authority: WO
Inventors: Evangelos Karavas; Efthimios Koutris; Dimitrios Bikiaris; Vicky Samara; Anastasia Kalaskani; Eleni Stathaki
Original assignee: Pharmathen S.A.
Priority date: 2007-10-17
Filing date: 2007-10-17
Publication date: 2009-04-23
Also published as: EP2197424A2; WO2009049648A3

Abstract

The present invention relates to a pharmaceutical formulation of solid dosage forms comprising a therapeutically effective amount of an antiviral agent, and in particular Valaciclovir or a pharmaceutical acceptable salt or derivative thereof, in combination with an effective diluent, such as Dibasic Calcium Phosphate Dihydrate, and a process for the preparation thereof by wet granulation.

Description

IMPROVED PHARMACEUTICAL COMPOSITION CONTAINING ANTIVIRAL AGENT AND METHOD FOR THE PREPARATION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to improved pharmaceutical formulations for oral administration and in particular to a pharmaceutical formulation for oral administration comprising a therapeutically effective quantity of an antiviral agent, and more particularly Valaciclovir or pharmaceutical acceptable salt or derivative thereof, in combination with an effective amount of Dibasic Calcium Phosphate Dihydrate and a method for the preparation thereof.

BACKGROUND OF THE INVENTION

Acyclovir is a known compound widely used for the treatment of viral infections, particularly infections caused by the herpes virus. Pharmacokinetic studies have shown that acyclovir is poorly water soluble and presents poor oral bioavailability, therefore intravenous administration is required in order to achieve high concentrations in the plasma.

Valaciclovir or L-valyl acyclovir is a prodrug of acyclovir, and has been shown to posses antiviral properties and used for the treatment of the same types of infections as acyclovir.

A preferred form of Valacyclovir is the Valaciclovir hydrochloride salt. After oral administration, Valaciclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L -valine by first-pass intestinal and/or hepatic metabolism by enzymatic hydrolysis. It has been shown that Valaciclovir provides a high bioavailability of acyclovir, 3- to 5- fold higher than that obtained with oral acyclovir, and it is equivalent to plasma levels achieved with doses of intravenous acyclovir.

Various methods are already known for the industrial preparation of oral dosage forms comprising the antiviral agent Valaciclovir or salts thereof, as an active ingredient due to its useful therapeutical properties. However, the prior art has encountered substantial difficulties in the production of the oral solid dosage form formulations containing high proportion of the active ingredient with sufficient hardness and friability. If a tablet is too friable, it will chip or break during packaging and transport. According EP Pharmacopoeia, pharmaceutical tablets should have a friability not exceeding 1% with a Carr Index from 1 - 25. In several studies, it has been tried to increase the hardness and friability of Valaciclovir tablets by increasing the compression force, decreasing the proportion of lubricant and increasing the proportion of binder, but found in each case that a sufficiently hard and non-friable tablet could not be produced in a practical way.

Furthermore, cracks were found in some tablets as a result of increasing the compression force. In addition, Valaciclovir has adhesive properties in that it can stick to tablet dies and therefore needs to be efficiently lubricated. However, elevated levels of hydrophobic lubricants can impact the mechanical strength of the tablets and disintegration/dissolution performance. It is difficult therefore to reduce the proportion of lubricant without causing the tablets to stick.

Furthermore, the disintegration performance 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 of the tablet. The formulation of Valaciclovir granules was also found to be problematic due to the adhesive properties of Valaciclovir and also to problems relating to the pH dependent dissolution rate and discolouration of the granules. Granules of Valaciclovir itself tend to be fragile and have a low coating efficacy. Furthermore, there is a need to mask the bitter taste of Valaciclovir.

EP 0 806 943 discloses a pharmaceutical composition which comprises Valaciclovir within the granules and colloidal silicon dioxide and microcrystalline cellulose extragranularly.

EP 1 541 133 discloses a pharmaceutical formulation comprising Valaciclovir and titanium dioxide.

Furthermore, in EP 1 278 515 is disclosed a composition comprising beads with a layer of Valaciclovir.

Although each of the above patents represents an attempt to overcome the hardness and friability problems associated with pharmaceuticals compositions comprising an antiviral agent such as Valaciclovir, there still exists a need for improving the mechanical strength of such pharmaceutical compositions.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide an improved solid dosage formulation for oral administration containing a high portion of an antiviral agent, and in particular Valaciclovir or pharmaceutical acceptable salts thereof as an active ingredient, which overcomes the deficiencies of the prior art.

It is another object of the present invention is to provide a solid dosage formulation for oral administration containing an antiviral agent, and in particular Valaciclovir or a pharmaceutical acceptable salt or derivative thereof as an active ingredient, which has a sufficient hardness and friability with satisfactory disintegration time, lubrication properties, flow properties and good pharmacotechnical properties.

Moreover, it is another object of the present invention to provide a solid dosage formulation for oral administration containing an antiviral agent at a high concentration, and in particular Valaciclovir or a pharmaceutical acceptable salt or derivative thereof as an active ingredient, which can be prepared in dosage forms of different strength by proportionally adjusting the quantities of the excipients and the active ingredient, thereby providing excellent pharmacotechnical and physicochemical characteristics, regarding its storage and manufacturing procedure stability, without affecting the dissolution profile and bioavailability of the active ingredient. A further aspect of the present invention is to provide a method for the preparation of a stable solid dosage formulation for oral administration containing a high portion of an antiviral agent, and in particular Valaciclovir or a pharmaceutical acceptable salt or derivative thereof as an active ingredient, thereby improving the friability, hardness, flow properties and the pharmacotechnical characteristics of the composition.

In accordance with the above objects of the present invention, a pharmaceutical composition for oral administration is provided comprising a high proportion of an antiviral agent or a pharmaceutical acceptable salt or derivative thereof as an active ingredient, and an effective quantity of Dibasic Calcium Phosphate Dihydrate to improve friability, hardness and flow properties of the composition. According to another embodiment of the present invention, a process for the preparation of solid dosage forms for oral administration such as tablets, capsules and sachets, containing an antiviral agent such as Valaciclovir or a pharmaceutical acceptable salt or derivative thereof as an active ingredient and an effective amount of Dibasic Calcium Phosphate Dihydrate to improve friability, hardness and flow properties of the composition is provided, which comprises:

- Forming a granulating solution by agitating ethyl alcohol and purified water with a portion of the total quantity of a binder such as HPC;

- Forming a homogenous mixture by mixing the total quantity of said active ingredient with a portion of the total quantity of Dibasic Calcium Phosphate Dihydrate, and optionally at least a disintegrant such as Sodium Starch Glycolate, and the remaining portion of the binder;

- Kneading the above mixture with the granulating solution;

- Sieving the wetted mass through a sieve and forming granules

- Drying the granules; - Sieving the dried granules through a sieve to achieve the desired granule size;

- forming a second blend by mixing the remaining quantity of Dibasic Calcium Phosphate Dihydrate and at least one optional excipient such as a binder, disintegrant, lubricant, a colorant, and/or a glidant until uniform,

- blending the above formed granules with the second blend, and - Formulating the resulting mixture in a solid dosage form either by compressing it into a desired tablet form or by filling capsules or sachets.

Further preferred embodiments of the present invention are defined in dependent claims 2 to 10 and 12 to 13.

Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, the term "pharmaceutically acceptable salt" refers to a salt that is not toxic at the specific therapeutic dosage and to a salt that does not independently possess significant pharmacological activity.

An excipient is considered to be "incompatible" with an active ingredient (an antiviral agent such as Valaciclovir or a pharmaceutical acceptable salt or derivative thereof) if it inhibits the dissolution rate of said active ingredient, that is to say, if said active ingredient (an antiviral agent such as Valaciclovir or a pharmaceutical acceptable salt or derivative thereof) dissolves less or slower in the presence of said excipient when compared with the dissolution rate of said active ingredient on its own. The terms "incompatibility", "compatible" and "compatibility" are defined accordingly. The active ingredient (Valaciclovir or a pharmaceutical acceptable salt or derivative thereof) contained in a dosage form is "bioavailable", if when administered in a dosage form is released from the dosage form, absorbed and reaches, at least the same, concentration levels in plasma as any of the marketed products containing the same quantity of the same active ingredient and intended for the same use.

The improved solid pharmaceutical composition of the present invention is characterized by physicochemical properties suitable for the tablet formulation by wet granulation, the adequate release rate of the active ingredient (an antiviral agent such as Valaciclovir or a pharmaceutical acceptable salt or derivative thereof) and the storage stability, by employing suitable pharmaceutically acceptable excipients. The pharmacotechnical properties of pharmaceutical tablets include friability, hardness and flowability of the granules. Some of the problems that are encountered when producing tablets comprising high dose active ingredients are friction and shock that most often cause tablets to chip or break. Generally, the mechanical strength of a tablet formulation provides a measure of the bonding potential of the tablet contents and this information depends upon the selection of suitable excipients.

Tablet friability is defined as the percentage value of weight loss due to abrasion. A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable.

The friability test is closely related to the tablet hardness and is designed to evaluate the ability of the tablet to withstand abrasion during packaging and handling. Tablet hardness constitutes another important pharmacotechnical property during tablet manufacture. Tablet hardness is associated with several tablet properties, including density and porosity. Hardness generally increases with normal storage of tablets, and depends on the shape, chemical properties, binding agent, as well as pressure applied during compression. If a tablet is too hard, then it may not disintegrate in the required period of time to meet the dissolution specifications, hi contrast, if a tablet is too soft, then it may not be able to withstand the handling during subsequent processing, such as coating or packaging.

Another significant important property determining the mechanical strength of tablets is the flow property or fluidity. Flow property or fluidity is a characteristic required in order to produce tablets of a consistent weight and uniform strength. This means that good flowability is desirable for content uniformity and less weight variation in final tablets. In addition to that, compressibility is required to form a stable, intact compact mass when pressure is applied. Pharmaceutical formulations with acceptable flow property and compressibility characteristics for granules can be obtained by incorporating suitable excipients. Flow property of tablet granules is defined via the known term "Carr's Compressibility Index".

Furthermore, another property of significant importance during the evaluation of tablets is tablet dissolution. The dissolution rate of the drug from the primary particles of the tablet constitutes the important factor in drug absorption and for many formulations is the rate- limiting step. Therefore, the dissolution rate is an indication of the availability of the active ingredient from the tablet.

As already mentioned tablets containing a high proportion of Valaciclovir or salts thereof are susceptible to degradation / oxidation and their tendency gets stronger when they are formulated and mixed with excipients or other active substances.

It has been surprisingly found that the object of the present invention is achieved by employing Dibasic Calcium Phosphate Dihydrate, as an effective diluent in order to improve friability, hardness and flow properties of the composition. Dibasic calcium phosphate dehydrate constitutes a diluent with excellent flowability and compressibility properties resolving the flow and hardness problems associated with high dose active ingredient formulations. It is practically insoluble in ethanol, ether, and water, and soluble in dilute acids. It is widely used in tablet formulations because of its compaction properties, and the good flow properties. It is also non hygroscopic and stable at room temperature. However, under certain conditions of temperature and humidity, it tends to lose water of crystallization below 100°C.

Additionally, two main particle-size grades of dibasic calcium phosphate dihydrate are used in the pharmaceutical industry. The milled material is typically used in wet- granulated, roller-compacted or slugged formulations, whereas the 'unmilled' or coarse- grade material is typically used in direct-compression formulations.

Dibasic calcium phosphate is a white, odorless, tasteless crystalline powder. It is not consisted of individual crystals but aggregates of crystallites that undergo fragmentation caused by brittle fracture upon compaction and thus promoting inter-particulate interaction by creating numerous clean surfaces for bonding.

Moreover, any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with the poor flow properties and unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability and the dissolution rate of the finished dosage form, and provide a product exhibiting excellent bioavailability.

Furthermore, sodium starch glycolate is incorporated into the composition of the present invention by internal addition (intragranular) and by external addition (extragranular). During the internal addition, the disintegrating agent is mixed with other powders prior to wetting the powder mixture with the granulating fluid. The result of this method is that the super disintegrant becomes incorporated within the granules of the composition, resulting to a more effective disintegration process. During the external addition, the disintegrating agent is added to the granulate composition prior to compression. Thus the tablet can be disrupted into the previously compressed granules. Sodium starch glycolate also presents the tendency to absorb water rapidly, so it swells in a significant amount. Therefore, this rapid water absorption by sodium starch glycolate molecules has as a result a significant increase in the volume of granules resulting to rapid and uniform disintegration

Another pharmaceutical excipient used in the tablet formulation of the present invention is Hydroxypropyl cellulose (HPC) as a binder, in order to improve tablet hardness. This improvement in tablet hardness is proved from the pharmacotechnical tests performed.

The present invention can be applied in the formulation of tablets, capsules, caplets, sachets or other solid dosage forms for oral administration of an active ingredient having friability, hardness and flow properties problems.

Furthermore, it is possible to prepare dosage forms of different strength using appropriate quantity of the same composition, thereby limiting the cost of production and minimizing the number, and consequently the cost, of clinical studies required for the approval of the product by the authorities.

Therefore, in a first embodiment, the present invention provides a pharmaceutical composition comprising from about 40% to 90% by weight of Valaciclovir or salt thereof and from about 0.5% to 20% by weight of Dibasic Calcium Phosphate Dihydrate. The weight ratio of Valaciclovir or salt thereof to Dibasic Calcium Phosphate Dihydrate is preferably 2:1 to 180:1.

More preferred pharmaceutical compositions according to the present invention comprise approximately 0.5% to 20%, more preferably 0.75% to 15% and most preferably 1% to 15% by weight of Dibasic Calcium Phosphate Dihydrate. The preferred pharmaceutical compositions are in the form of solid dosage forms for oral administration such as tablets, capsules, caplets, troches, pastilles, pills, lozenges and the like, in all shapes and sizes, coated or uncoated.

Although the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, capsules and caplets.

All percentages stated herein are weight percentages based on total composition weight, unless otherwise stated. Another embodiment of the present invention is the use of the wet granulation process for the preparation of solid dosage forms for oral administration such as tablets, capsules and sachets containing an antiviral agent such as Valaciclovir or a pharmaceutical acceptable salt or derivative thereof as an active ingredient, which comprises:

- Forming a granulating solution by dissolving a portion of the total quantity of a binder such as HPC into ethyl alcohol and purified water;

- Forming a first homogenous blend by mixing the total quantity of said active ingredient with a portion of the total quantity of Dibasic Calcium Phosphate Dihydrate to improve friability, hardness and flow properties of the composition, and optionally at least a disintegrant such as Sodium Starch Glycolate, and the remaining portion of the binder; - Kneading the above mixture with the granulating solution; - Sieving the wetted mass through a sieve and forming granules

- forming a second blend by mixing the remaining quantity of Dibasic Calcium Phosphate Dihydrate, and at least one optional excipient such as binder, surfactant, disintegrant, lubricant, colorant, and/or glidant until uniform,

- blending the above formed granules with the second blend, and - Formulating the resulting mixture in a solid dosage form either by compressing it into a desired tablet form or by filling capsules or sachets. The tablets are optionally coated by water soluble coating agents.

According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form composition.

Such ingredients include, but are not limited to, diluents, binders, compression aids, disintegrants, surfactants, wetting agents, glidants, lubricants, flavours, water scavengers, colorants, sweetener, coating agents and preservatives.

The optional excipients must be compatible with the selective estrogen receptor modulator or the salt thereof so that it does not interfere with it in the composition. Diluents may be, for example, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose D dehydrate, lactose trihydrate, mannitol sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin, maltitol. Binders may be, for example, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, and sucrose.

Disintegrants may be, for example, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, sodium docusate, guar gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, starch, pregelatinized starch.

Surfactants may be, for example, poloxamer, pluronic, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, as well as sodium docusate or sodium lauryl sulphate.

Glidants may be, for example, calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.

Lubricants may be e.g. magnesium stearate, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, starch, talc. The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention:

EXAMPLES

As already mentioned the selection of the excipients is critical in order to fulfill the objects of the present invention. First of all the preferred excipients should provide to the granule good compressibility and flowability. Then those excipients should be compatible with the active ingredient.

Valaciclovir was tested for its compatibility with several pharmaceutically acceptable excipients comprising the above mentioned properties.

The following examples represent attempts on the bases of the current invention using excipients that are compatible with Valaciclovir.

Example 1 : Tablet of 500mg Valaciclovir (composition 1)

Tablets of the above formulation were prepared according to the following manufacturing process: Valaciclovir, a portion of the total quantity of HPC, a portion of the total quantity of Dibasic Calcium Phosphate Dihydrate as diluent and a portion of the total quantity of Sodium Starch Glycolate as a disintegrant were admixed to complete homogeneity. The remaining quantity of HPC as a binder was dissolved in a mixture of ethanol and water and stirred for an adequate period of time till it was completely dissolved. The first blend was kneaded with the granulating solution described above until it becomes homogenous. Sieving the resulting mixture through a sieve and forming the granules. Drying the granules and sieving. Subsequently, the excipients of the external phase, namely the remaining quantity of Dibasic Calcium Phosphate Dihydrate, the remaining quantity of Sodium Starch Glycolate, and the total amount of Talc and Mg stearate were added in the above formed granules and mixed.

Finally, it was formulated in a solid dosage form by compressing it into a desired tablet form. Subsequently, the tablets were film-coated. Tablets prepared according to example 1 demonstrate good hardness (>80 Nt), very good friability (0.17%) and the granule has excellent flowability (Carr's index 11.8%). The produced tablets were tested for content uniformity, disintegration, water content and dissolution proving that they are meeting the specifications.

Example 2: Tablet of 500mg Valaciclovir (composition 2)

Tablets of the composition 2 of Example 2 were prepared according to the manufacturing process used in Example 1.

In composition 2 dibasic calcium phosphate dihydrate has been replaced by dibasic calcium phosphate anhydrous. Dibasic calcium phosphate anhydrous posses the same properties as the dihydrate, however when compacted at high pressures exhibits lamination and capping, especially when the material represents a substantial proportion of the formulation. In the current case the tablets produced had low hardness (only up to 42Nt) and high friability (0.55%). In addition, capping problems were observed.

Composition 1 and Composition 2 were also tested for their stability for a three months period in normal (25°C±2°C/60%±5% RH) and accelerated (40°C±2°C/75%±5% RH) conditions. As it can be seen from Table 1 below the composition of example 1 is more stable compared to the one of example 2.

As mentioned above dibasic calcium phosphate dihydrate is consisted of aggregates of crystallites that undergo fragmentation caused by brittle fracture upon compaction and thus promoting inter-particulate interaction by creating numerous clean surfaces for bonding. Bonds may be created with the water distributed over the surface and/or distributed through the body and/or contained in the solid crystals of Valaciclovir hydrochloride hydrated forms and thus promoting stability and better pharmacotechnical properties. TABLE 1 : Stability results for Valaciclovir compositions of examples 1 and 2 in normal and accelerated conditions

Example 3: Tablet of 500mg Valaciclovir (composition 3)

Tablets of the composition 3 of Example 3 were prepared according to the manufacturing process used in Example 1.

In composition 3 microcrystalline cellulose has been used as filler. However, the tablets produced according to example 3 had lower hardness (~63Nt), higher friability (0.82%) and worse granule flow properties (Carr's index 21.6%) in comparison with example 1. Example 4: Tablet of 500mg Valaciclovir (composition 4)

Tablets of the composition 4 of Example 4 were prepared according to the manufacturing process used in Example 1.

In composition 4 a combination of dibasic calcium phosphate dihydrate with microcrystalline cellulose as diluents has been used. The tablets produced according to example 4 had hardness (~75Nt), friability (0.33%) and granule flow properties (Carr's index 18.8%). The pharmacotechnical properties for example 4 were better than example 3 but still worse than example 1.

Example 5: Tablet of 500mg Valaciclovir (composition 5)

Tablets of the composition 5 of Example 5 were prepared according to the manufacturing process used in Example 1. In composition 5 lactose monohydrate has been used as filler. The tablets produced according to example 5 had the lower hardness (^42Nt), the higher friability (1.14%) and the worse granule flow properties (Carr's index 30.7%). One of the most critical pharmacotechnical tests is the dissolution test as it is strongly correlated with the bioavailability of the product. For the dissolution method Apparatus II (Paddles) was run at 75rpm, 37⁰C ± 0.5 °C, for 60min, while as dissolution medium 1000ml of buffer pH=4,5 was used.

Dissolution tests were performed for the compositions of examples 1, 3 and 4 since example 2 exhibits capping and stability problems and example 5 poor granule flow properties.

TABLE 2: Dissolution profiles of the compositions according to examples 1, 3 and 4

As it can be seen from Table 2 the composition of example 1 meet the specifications of the product (>65% dissolved in 30 min and >85% dissolved in 60 min) for the dissolution test in a greater degree than the other two compositions.

Another objects of the present invention was to prepare a pharmaceutical composition that is stable, said active ingredient does not degradates and remains stable for a long period of storage time. Composition of example 1 illustrated the best performance according to the objects of the present invention (hardness, friability, flow properties, dissolution rate). Tablets of this composition were prepared in larger scale and packed in PVC/PE/PVDC aluminum blisters and exposed to normal (25°C±2°C/60%±5% RH), intermediate (30°C±2°C/65%±5% RH) and accelerated (40°C±2°C/75%±5% RH) stability studies, according to the current ICH guidelines. The stability results after 6 months for accelerated conditions are shown in the table 3 below.

The composition 1 described above was investigated for its scalability, while a process validation was performed in order to prove the repeatability and accuracy of the manufacturing process and the proposed formulation.

The validation process showed that the composition and the manufacturing process are suitable in order to provide a repeatable and high quality product. TABLE 3: Stability results for 500mg Valaciclovir film-coated tablets of composition 1 at 40°C/75 % RH

The results show a good stability of the product and compatibility between the drug substance and the excipients proposed by the present invention. The excellent results regarding the physicochemical characteristics (such as good granule flowability and tablets with excellent hardness and friability), the excellent stability of the product as well as the simple and economic manufacturing process indicate the advantages of the present invention relative to the commonly used methods and excipients for the formulation of Valacyclovir. While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

-1-CLAIMS

1. A pharmaceutical composition for oral administration comprising an antiviral agent or a pharmaceutical acceptable salt thereof, and in particular Valaciclovir, or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, and an effective quantity of a diluent such as Dibasic Calcium Phosphate Dihydrate as an agent to improve friability, hardness and flow properties of the composition.

2. The pharmaceutical composition according to claim 1, wherein said diluent is Dibasic Calcium Phosphate Dihydrate.

3. The pharmaceutical composition according to claim 2, wherein it comprises from about 40 to 90% by weight of said antiviral agent such as Valaciclovir or salt thereof, and from about 0.5 to 20 % by weight of said Dibasic Calcium Phosphate Dihydrate.

4. The pharmaceutical composition according to claim 2, wherein the weight ratio of said pyrrolidone anticonvulsant agent such as Valaciclovir or salt thereof, to Dibasic Calcium

Phosphate Dihydrate is preferably 2:1 to 180:1.

5. The pharmaceutical composition according to claim 1, wherein it comprises approximately 40% to 90%, preferably 45% to 85% and most preferably 50% to 85% by weight of said antiviral agent such as Valaciclovir or salt thereof.

6. The pharmaceutical composition according to claim 2, wherein it comprises approximately 0.5% to 20%, more preferably 0.75% to 15% and most preferably 1% to 15% by weight of Dibasic Calcium Phosphate Dihydrate.

7. The pharmaceutical composition according to any preceding claim, wherein said antiviral agent is Valaciclovir or pharmaceutical acceptable salt or derivative thereof.

8. The pharmaceutical composition according to any preceding claim, wherein it further comprises at least one optionally excipient selected from the group consisting of diluents, binders, disintegrants, lubricants, and glidants.

9. The pharmaceutical composition according to any preceding claim, wherein it further comprises a Sodium Starch Glycolate and HPC.

10. The pharmaceutical composition according to any preceding claim, wherein said composition is in a solid dosage form such as a tablet, capsule or sachet comprising an active ingredient such as Valaciclovir or salt thereof.

11. A process for the preparation of a solid dosage form for oral administration, such as a tablet, a capsule or a sachet, containing an antiviral agent such Valaciclovir or a pharmaceutical acceptable salt or derivative thereof as an active ingredient and an effective amount of Dibasic Calcium Phosphate Dihydrate to improve friability, hardness and flow properties of the composition is provided, which comprises: -2-

- Forming a granulating solution by dissolving a portion of the total quantity of a binder such as HPC in ethyl alcohol and purified water; - Forming a homogenous mixture by mixing the total quantity of said active ingredient with a portion of the total quantity of Dibasic Calcium Phosphate Dihydrate, and optionally at least a disintegrant such as Sodium Starch Glycolate, and the remaining portion of the binder;

- Kneading the above mixture with the granulating solution; - Sieving the wetted mass through a sieve and forming granules

- Drying the granules;

- Sieving the dried granules through a sieve to achieve the desired granule size;

- blending the above formed granules with the second blend, and

- Formulating the resulting mixture in a solid dosage form either by compressing it into a desired tablet form or by filling capsules or sachets.

12. The process according to claim 11, wherein said active ingredient is Valaciclovir or salt thereof.

13. The process according to claim 11, wherein said tablet is coated with a water soluble coating agent.