LEVETIRACETAM FORMULATIONS AND METHODS FOR THEIR
MANUFACTURE
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Patent Application No.
60/762,103 filed January 24,2006, hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to stable substantially glidant free levetiracetam
compositions, to pharmaceutical compositions and pharmaceuticals comprising the substantially glidant free levetiracetam compositions of the invention as the active ingredient, and to methods of preparing the compositions of the invention.
BACKGROUND OF THE INVENTION
[0003] Levetiracetam is reported to be an antiepileptic drug. Apparently, only one
enantiomer of levetiracetam, (-)-(S)-(alpha)-ethy]-2-oxo-l-pyrroh'dine acetamide, is active. Levetiracetam is reported to be represented by the structural formula

(Formula Removed)

[0004] Levetiracetam tablets are commercially available under the trade name
KEPPRA®, and, typically, comprise colloidal silicon dioxide as a glidant, as well as com starch, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol 4000, povidone, talc, titanium dioxide, and coloring agents.
[0005] Glidant materials are generally added to pharmaceutical compositions
following granulation and drying of the particles to facilitate the flow of the dried granules. Therefore, for use as a glidant, such materials are extra-granular materials. Glidant materials, especially colloidal silicon dioxide, are typically extremely fluffy and bulky, and often require a sieving stage. During sieving, a significant amount of airborne particles is often produced. Such airborne particles are a potential safety hazard, and, thus, require the use of safety equipment and other safety precautions by workers handling the materials.
[0006] Moreover, because particles of glidant materials, such as colloidal silicon
dioxide, are extremely small, the total surface area of a sample of-such a material is extremely large, relative to the volume of the sample. It is believed that the small size and high surface area are possible sources of instability of the active ingredients of a formulation comprising such a glidant. The instability may be caused by a direct interaction between the glidant particles and the active ingredient, or the glidant may act as a catalyst, facilitating interactions that result in the instability of the active ingredient.
[0007] Therefore, to reduce hazards to workers and improve the stability of
levetiracetam. in pharmaceutical compositions, a need exists for substantially glidant free levetiracetam formulations and methods of preparing such formulations. The present invention provides such formulations and methods.
SUMMARY OF THE INVENTION
[0008] The present invention is directed to stable levetiracetam tablet formulations
that are preferably substantially free of glidants and to methods of preparing substantially glidant free levetiracetam formulations and pharmaceutical compositions comprising substantially glidant free levetiracetam formulations. The substantially ghdant free levetiracetam formulations of the invention may be formed into tablets that are stable and easily handled.
[0009] The present invention provides robust, high concentration, substantially
glidant free levetiracetam pharmaceutical compositions, preferably, comprising at least about 60 percent levetiracetam, more preferably, at least about 70 percent levetiracetam, and, most preferably, from about 70 to about 95 percent levetiracetam. Substantially ghdant free levetiracetam compositions of the invention may comprise one or more other pharmaceutically acceptable excipients, such as com starch, povidone, croscarmellose sodium, sodium starch glycolate, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, coloring agents, and mixtures thereof. Where an excipient used in a formulation in accordance with the invention is a substance that can function as a glidant if mixed with granules of the substantially glidant free levetiracetam compositions of the invention, the substance is either incorporated into the granules of the composition, where it cannot function as a glidant, and, thus, is not a glidant, or is not present in an amount that allows the excipient to function as a glidant. Substantially ghdant free
levetiracetam formulations in accordance with the present invention are preferably formulated into phaimaceutical formulations, such as conventional dosage forms, e.g., tablets and capsules. The preferred substantially glidant free levetiracetam dosage form is a tablet.
[00010] Substantially glidant free levetiracetam formulations for use in tablets may be
dry-granulated or wet-granulated before tableting, or the tablet blends may be directly compressed. For pharmaceutical's, the type of processing utilized often depends upon the properties of the drag, the chosen excipients, and the dosage form, e.g., particle size, blending compatibility, density, and flowability. For levetiracetam tablets, granulation is preferred, and wet granulation is most preferred. Tablets in accordance with the invention may be coated to facilitate swallowing and/or to enhance the appearance of the tablet.
DETAILED DESCRIPTION OF THE INVENTION
,[00011] As used herein, the term "glidant" refers to a material mat, when added to a
dried granulated pharmaceutical composition in a sufficient amount, facilitates the flow of the granules during processing. As glidants are generally added to dried, granulated compositions, glidants may be referred to as extra-granular materials.
[00012] As used here in the term "substantially glidant free levetiracetam" refers to a
levetiracetam formulation of composition that is free of all but trace amounts of any extra-granular material that can function as a glidant. That is, extra-granular materials that can function as. a glidant are not present in the substantially glidant free levetiracetam compositions of the invention in an amount that will function as a glidant for a granulated composition. Glidants are typically added to pharmaceutical compositions to improve the flowability of a non-compacted solid composition, and to improve the accuracy of dosing. The addition of glidants is not necessary in the substantially glidant free levetiracetam compositions of the invention to improve flowability.
[00013] As used herein-, the term "high dosage levetiracetam" preferably refers to a
levetiracetam dosage form of at least about 250 mg, more preferably, at least about 500 mg, and, most preferably, at least about 750' mg. Preferably, substantially glidant free levetiracetam compositions of the invention are formed into film coated tablets, and, more preferably, comprise about 250, about 500, or about 750mg of levetiracetam per tablet.
[00014] Substantially glidant free levetiracetam tablets in accordance with the
invention can be dry-granulated or wet-granulated before tableting, or directly compressed
into tablets. Preferably, in accordance with the method of the invention, levetiracetam and, optionally, at least one excipient is wet-granulated, where the preferred granulating liquid is purified water. The granulated material is then preferably dried, milled, and, optionally, blended with one or more excipients. Most preferably, the final blend is then compressed into tablets and coated. The granulated material optionally blended with one or more additional excipients can also be placed into an ingestible capsule.
[00015] In addition to the active ingredient, levetiracetam, pharmaceutical
compositions of the substantially glidant free levetiracetam of the present invention may contain one or more' excipients or adjuvants. Selection of excipients and the amount of such excipients used may be readily determined by a formulation scientist based upon experience and consideration of standard procedures and reference works in the field. Excipients and adjuvants that may function as a glidant are not present as extra-granular materials in the formulations of the invention in an amount that allows the excipient or adjuvant to function as a glidant.
[00016] Diluents increase the bulk of a solid pharmaceutical composition, and may
make a phannaceutical dosage form containing the composition easier for the patient and/or a care giver to handle. Diluents useful in the present invention include those diluents Icnown in the art that do not function as glidants. Diluents that may function as a glidant are not present as extra-granular materials in the formulations of the invention in an amount that allows the diluent to function as a glidant
[00017] Solid pharmaceutical compositions that are compacted into a dosage form,
such as'a tablet, may include excipients that facilitate binding the active ingredient and excipients together after compression. Useful binders include those binders known in the art that do not function as glidants. Binders that may function as a glidant are not present as extra-granular materials in the formulations of the invention in an amount that allows the . binder to function as a glidant.
[00018] The dissolution rate of a compacted solid pharmaceutical composition in the
patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants useful in the invention include those disintegrants known in the art that do not function as glidants. Disintegrants that may function as a gHdant are not present as
extra-granular materials in the formulations of the invention in an amount that allows the disintegrant to function as a glidant.
[00019] Solid compositions of the substantially glidant free levetiracetam of the
. invention include powders, granulates, aggregates, and compacted compositions. The dosages may be conveniently presented in unit dosage form, and prepared by any of the methods well-known in the pharmaceutical arts. Useful dosage forms of the substantially, glidant free levetiracetam of the invention include, but are not limited to solid dosage forms, such astablets, powders, and capsules.
[00020] The dosage form of the present invention may be a capsule containing the
composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin, and optionally contain a plasticizer, such as glycerin and sorbitol, and an opacifying' agent or colorant.
[00021] Flavoring agents and flavor enhancers make the dosage form more palatable to
the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
[00022] A composition for tableting or capsule filling may be prepared by wet
granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended, and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate may be screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a lubricant
[00023] A tableting composition may be prepared conventionally by dry granulation.
For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet, and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
[00024] As an alternative to dry granulation, a blended composition may be
compressed directly into a compacted dosage form using direct compression techniques. The proper use of excipients in direct compression tableting is known to those skilled in the art of direct compressiop tableting.
[00025] When a dosage form, such as a tablet, is made by the compaction of a
powdered composition, the composition is subiected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, -which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. Lubricants that may function as a glidant are not present in the formulations of the invention in an amount that allows the lubricant to function as a glidant.
[00026] A capsule filling of the present invention may comprise any of the
aforementioned blends and granulates that were described with reference to tableting; however, they are not subjected to a final tableting step.
[00027] The following non-limiting examples are merely illustrative of the preferred
embodiments of the present invention, and are not to be construed as limiting the invention, the scope of which is defined by the appended claims.
EXAMPLES
(Table Removed)
Example 1

Commercially available powder mix for coating comprising Hypromellose (HPMC); Titanium Dioxide; PolyEthyleneGlycol (PEG 3350); colorants
[00028] The ingredients of Part I were granulated using purified water as a granulating
liquid. The granulate was dried, milled and blended with the Part II ingredient The final blend was compressed into tablets, and coated using the Part III material suspended in.water.
Example 2
(Table Removed)

*Commercially available powder mix for coating.comprising Hypromellose (HPMC); Titanium Dioxide; PolyEthyleneGlycol (PEG 335 0); colorants
[00029] The ingredients of Part 1 were granulated using purified water as a granulating
liquid. The resulting granulate was dried, milled, and blended with the Part IT ingredients. The final blend was compressed into tablets and coated using a suspension of the PartIII material in water.
[00030] As demonstrated by Examples 1 and 2, the exemplified formulations contain
about 75 percent by weight of the active material in the tablet cores. The importance of flow properties cannot be over emphasized for such a high dose product. The flow properties of solids have an impact on encapsulation and tablering, as manufacturing processes require the flow of powder materials from a storage container to capsule filling injectors or tablet dies. The flow properties of solids also have influence on the uniformity of powders before tableting. Colloidal silicon dioxide is widely used as a glidant in capsule and tablet formulations improving the flow properties of the powders or granulates, but is not required in the substantially glidant free levetiracetam compositions of the invention. Therefore, the substantially glidant free levetiracetam compositions of the invention are substantially free of colloidal silicon dioxide.
[00031] Preferably, the formulations of the invention have good flow properties, such
that an analysis of the blend uniformity provides an assay of the blend between about 90 and "110 percent with, an associated RSD of less than about 5 percent. More preferably, the assay of the blend is between about 95 and about 105 percent with an associated RSD of less than about 2 percent. Examples 1 and 2 demonstrate that substantially glidant free levetiracetam formulations in accordance with the invention have very good flow properties, uniform final blends, such that the assay is greater than about 98 percent, and the associated RSD is less than about 1 percent, and tablet cores, having acceptable physical properties, as shown in Table 1.
(Table Removed)

*SCU = Strong Cobb Units
[00032] In order to avoid possible handling difficulties, the levetiracetam used
preferably comprises particles having a particle size distribution such that d(0.1) is Not Less Than (NLT) about 0.6 µm, d(0.5) is from about 10 to about 30 µrn, and d(0.9) is Not More Than (NMT) about 65 µm. In addition, the Bulk Density is NLT 0.2 g/cm3, and the Tapped Density is NLT 0.35g/cm3. The levetiracetam used above had a particle size of about 50 µm. To minimize the impact of particle size on the levetiracetam release rate, a disintegrant was added intra- and extra-granularly. "Although the resulting dissolution rate is somewhat slower than that of the commercial product, the product of present invention is found to be bioequivalent to the marketed product in both fasting and food bio-equivalent studies.
[00033] A stability test was performed on samples of Examples land 2 initially after
they were prepared and after storage under the accelerated conditions of a temperature of 40°C and a relative humidity (RH) of 75 percent for 3 months. The HPLC method was employed for chemical analysis. A stability test was also conducted for the marketed product. The results are shown in Table 2.

(Table Removed)

[00034] While it is apparent that the invention disclosed herein is well calculated to
fiilfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments as falling within the true spirit and scope of the present invention.

What is claimed:
1. A substantially glidant free levetiracetam composition, comprising levetiracetam and, optionally, an excipient, wherein the composition is substantially free of any extra-granular glidant.
2. The substantially glidant free levetiracetam composition of claim 1, wherein the composition has a uniformity of blend, such that an assay of the blend is between 90 and 110 percent with an associated RSD of less than 5 percent.
3. The substantially glidant free levetiracetam composition of claim 1, wherein the composition has a uniformity of blend, such that an assay of the blend is between 95 and 105 percent with an associated RSD of less than 2 percent.
4. The substantially glidant free levetiracetam composition of claim 1, wherein the composition has a uniformity of blend, such that an assay of the blend is greater than 98 percent with an associated RSD of less than 1 percent.
5. The substantially glidant free levetiracetam composition of claim 1, wherein the levetiracetam is present in an amount of at least about 60 percent by weight, based on the total weight of the composition.
6. The substantially glidant free levetiracetam composition of claim 1, wherein the levetiracetam is present in an amount of at least about 70 percent by weight, based on the total weight df the composition.
7. The substantially glidant free levetiracetam composition of claim 1, wherein the levetiracetam is present in an amount of from about 70 to about 95 percent by weight, based on the total weight of the composition.
8. The substantially glidant free levetiracetam composition of claim 1, wherein the excipient is selected from the group consisting of corn starch, povidone, croscarrnellose sodium, sodium starch glycolate, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, a coloring agent, and mixtures thereof.
9. The substantially glidant free levetiracetam composition of claim 1, wherein particles of levetiracetam in the composition have a particle size distribution such that d(0.1)
is not less than about 0.6 µrn, d(0.5) is between about 10 and about 30 µrn, and d(0.9) is not more than about 65 µm.
10. A pharmaceutical composition, comprising levetiracetam and, optionally, an excipient, wherein the composition is substantially free of any extra-granular glidant
11. A pharmaceutical dosage form, comprising the pharmaceutical composition of claim 10.
12. The pharmaceutical dosage form of claim 11, wherein the dosage form is a tablet or capsule.
13. The pharmaceutical dosage form of claim 11, comprising at least about 25 0 mg of levetiracetam.
14. A method of preparing a substantially glidant free levetiracetam pharmaceutical composition, the method comprising granulating a levetiracetam composition, thereby forming a granulated levetiracetam composition, and, optionally, blending the levetiracetam composition with one or more excipients, wherein the resulting pharmaceutical levetiracetam composition is substantially free of any extra-granular glidant.
15. The method of claim 14, wherein the levetiracetam composition comprises at least one excipient.
16. The method of claim 14, wherein the granulating comprises wet granulation.
17. The method of claim 16, wherein the levetiracetam composition is granulated in a granulation liquid of purified water.
18. The method of claim 16, farther comprising compressing the pharmaceutical levetiracetam composition into a tablet, or placing the composition into a capsule.
19. The method of claim 16, further comprising drying, milling, and, optionally, blending the granulated composition with one or more excipients; and compressing the substantially glidant free levetiracetam composition into a tablet, or placing the substantially glidant free levetiracetam composition into a capsule.
20. The method of claim 14, wherein the granulating comprises dry granulation.
21. The method of claim 20, further comprising compressmg the levetiracetam composition into a tablet, or placing the composition into a capsule.
22. The method of claim 20, further comprising milling and, optionally, blending the'granulated composition with one or more excipients; and compressing the levetiracetam •composition into a tablet, or placing the levetiracetam composition into a capsule.
23. The method of claim 14, wherein particles of levetiracetam in the pharmaceutical composition have a-particle size distribution such that d(0.1) is not less than about 0.6µm; d(0.5) is between about 10 and about 30 urn, and d(0.9) is not more than about 65 µm.