ORALLY DISINTEGRATING PHARMACEUTICAL COMPOSITIONS OF ESCITALOPRAM AND SALTS THEREOF

FIELD OF THE INVENTION

The present invention relates to orally disintegrating pharmaceutical compositions of Escitalopram and salts thereof and methods for the manufacture of such orally disintegrating pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Escitalopram is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor. It is marketed as Lexapro® tablets in the United States for the treatment of Major depressive disorder and Generalized anxiety disorder.

Escitalopram was first disclosed in U.S. Pat. No. 4,943,590.

Orally disintegrating pharmaceutical compositions including granules, tablets are convenient oral delivery systems designed to disintegrate rapidly upon contact with aqueous fluids, e.g. water or saliva, to form a dispersion, which can be swallowed easily. Orally disintegrating pharmaceutical compositions are particularly advantageous for patients e.g. pediatric or geriatric patients, having difficulty in swallowing conventional tablets or capsules, or for individuals who may not have difficulty in swallowing but may have an aversion to swallowing conventional tablets or capsules. Orally disintegrating pharmaceutical compositions are also convenient under circumstances in which taking an oral dosage form with water may be inconvenient (e.g. while working or traveling).

Conventional orally disintegrating tablets are typically formed by compression (e.g., in a tablet press). It is desirable for such tablets to have sufficiently high hardness and sufficiently low friability to provide structural stability for transportation and storage. Low friability (which is measured based on the percent tablet weight loss after a certain number of revolutions in a friabilator) is desirable in that it is generally indicative of high tablet strength. High porosity of the tablet structure also is desirable in that it allows fluids (e.g., aqueous or bodily fluids, e.g.; water or saliva) to be drawn or "wicked" from the external

environment and into the interstices of the tablet structure, thereby promoting rapid and effective disintegration.

Various methods have been used to manufacture orally disintegrating tablets. Many of these methods use unconventional equipment and complicated processing techniques such as lyophilization and foam techniques. These methods result in fast disintegrating tablets with poor tablet strength and low friability. This may prevent the use of conventional packaging material and conventional packaging procedures.

US 2007/0021499 Al discloses orodispersible tablets prepared by mixing water soluble filler and active pharmaceutical ingredient at a temperature above, around or slightly below the melting point of the active pharmaceutical ingredient followed by cooling to a temperature below 40° C and mixing cooled mass with other excipients and compressing it into tablets with a hardness of at least 22 N.

US 2007/0092564 Al discloses orally disintegrating tablets prepared with pullalan as binder and glycine as disintegrant comprising quickly freeze-drying soluble composition, useful for providing oral-drug delivery of various drugs in disease treatment.

US 2002/0142034 Al discloses an orally disintegrable tablet comprising (i) fine granules composition coated by an enteric coating layer and (ii) an additive, having a superior disintegrability or dissolution in the oral cavity.

Above mentioned patent applications discloses costly and time-consuming methods of manufacturing of an orally disintegrating dosage forms which further require special technology, equipments etc.

As such, there exists a need for a conventional orally disintegrating pharmaceutical compositions having sufficiently low friability and sufficiently high hardness, while maintaining high porosity of the pharmaceutical compositions structure by using economic and conventional equipments and techniques.

The invention provides such orally disintegrating pharmaceutical compositions.

OBJECT OF THE INVENTION The present invention provides orally disintegrating pharmaceutical compositions of a)

Escitalopram or salts thereof as an active ingredient; b) diluent(s) selected from the group consisting of cellulose derivatives such as macrocrystalline cellulose and the like, mannitol, lactose, dextrose, sorbitol, starch, xylitol, maltose, dicalcium phosphate and their derivatives thereof; c) disintegrating agent(s) and d) optionally one or more suitable pharmaceutically acceptable excipient(s).

Yet another object of the present invention provides orally disintegrating pharmaceutical compositions comprising Escitalopram and salts thereof, as an active ingredient in an amount from about 1% to about 25% by total weight of the composition.

Yet another object of the present invention provides orally disintegrating pharmaceutical compositions comprising Escitalopram and/or salts thereof, wherein orally disintegrating pharmaceutical composition is a tablet.

Yet another object of the present invention provides orally disintegrating tablet comprising Escitalopram and/or salts thereof having low friability not more than 0.5%.

Yet another object of the present invention provides orally disintegrating tablet comprising Escitalopram and/or salts thereof having hardness not less than IO N.

Yet another object of the present invention provides orally disintegrating pharmaceutical compositions comprising Escitalopram and/or salts thereof having disintegration time not more than 120 seconds.

Yet another object of the present invention provides orally disintegrating pharmaceutical compositions comprising Escitalopram and/or salts thereof, wherein orally disintegrating pharmaceutical composition is in form of granules.

Yet another object of the present invention provides a method of producing orally disintegrating pharmaceutical compositions by conventional methods known in the art.

The method of producing orally disintegrating pharmaceutical compositions comprises direct compression, dry granulation or wet granulation.

Dry granulation method comprises mixing of Escitalopram and/or salts with diluent(s) and optionally with other suitable pharmaceutically acceptable excipients, passing this blend through roll compaction, milling this compacted mass through suitable sieves, adding disintegrant(s) and other suitable pharmaceutically acceptable excipients and finally thus obtained granules can be filled into a suitable container or can be compressed into an orally disintegrating tablet. The method of producing orally disintegrating pharmaceutical compositions preferably comprises Escitalopram and/or salts thereof, diluents, disintegrating agents; optionally other suitable pharmaceutically acceptable excipients, and solvent(s), to form a wet granulate. The wet granulate is dried, to produce a dry granulate comprising the Escitalopram and/or salts thereof. The wet granulate and/or dry granulate can be blended with other suitable pharmaceutically acceptable excipients. These granules can be filled into a suitable container or can be compressed into an orally disintegrating tablet. The most preferred method of manufacturing of an orally disintegrating pharmaceutical compositions comprising wet granulation of Escitalopram and/or salts thereof, diluents, disintegrating agents, binders, by fluidized bed processor.

DETAILED DESCRIPTION OF THE INVENTION

The orally disintegrating pharmaceutical compositions of the invention typically contain 1% to 25% w/w Escitalopram as base. The orally disintegrating pharmaceutical compositions of

the invention optionally may comprise pharmaceutically acceptable complexes, salts, polymorphs, hydrates, and solvates, of Escitalopram, preferably Escitalopram oxalate.

The present invention provides orally disintegrating pharmaceutical compositions comprising Escitalopram and salts thereof, as an active ingredient, diluent(s), a disintegrating agent(s) and optionally other suitable pharmaceutically acceptable excipient(s)

The term "orally disintegrating pharmaceutical compositions " as used herein refers to the ability of a pharmaceutical composition (e.g., granules, a tablet for oral administration) to disintegrate rapidly when contacted with a fluid, particularly an aqueous fluid (e.g., water, bodily fluids (e.g., saliva), and the like), to form a suspension, slurry or dispersion, which facilitates administration of the contents of the composition (e.g., by forming a suspension, slurry or dispersion, which is easily swallowed).

The orally disintegrating pharmaceutical compositions of the present invention can either be granules alone that can be filled into a suitable container preferably a sachet or granules can further be compressed into a tablet.

According to the present invention, oral granular formulations such as granules, powders and fine granules can also be prepared.

The term "orally" includes the region within the interior of the mouth, including, but not limited to, the buccal cavity (e.g., anterior to the teeth and gums) as well as the sublingual and supralingual spaces, and the like. .

The pharmaceutical compositions of the present invention preferably disintegrates within about 120 seconds or less, when contacted with an aqueous fluid (e.g., water, saliva, or a buffered solution), to form a slurry, a dispersion or a suspension, which can be administered

(e.g., swallowed) easily. The disintegration time of the pharmaceutical compositions of the present invention can range from within about 2 seconds to within about 120 seconds, e.g.,

from within about 2 seconds to within about 60 seconds, or from within about 2 seconds to within about 30 seconds, as measured in by the Standard USP Disintegration Test Apparatus.

The pharmaceutical compositions of the present invention more preferably disintegrates from within about 2 seconds to within about 30 seconds, and still more preferably from within about 2 seconds to within about 20 seconds, and most preferably from within about 2 seconds to within about 10 seconds, as measured in by the Standard USP Disintegration Test Apparatus.

The friability of the orally disintegrating tablet of the present invention preferably is not more than about 1 %, more preferably about 0.8 %, and most preferably about 0.5 %.

Hardness refers to the diametral breaking strength as measured by conventional pharmaceutical tablet hardness determination methods, which are well known in the art. A higher hardness value, sometimes measured in Newtons (N), generally is indicative of higher diametric strength. The hardness of the tablet of the present invention preferably ranges from about 35 N to about 30 N, and more preferably from about 25 N to about 20 N, and most preferably from about 15 N to about IO N.

Diluents may be for example various cellulose derivatives such as microcrystalline cellulose and the like, mannitol, lactose, dextrose, sorbitol, starch, xylitol, maltose, dicalcium phosphate and their derivatives thereof.

Disintegrants may be for example starch or its derivative like pregelatinised starch, sodium carboxymethyl starch, sodium starch glycolate and the like, various cellulose derivatives crosslinked sodium carboxy methyl cellulose, low substitute hydroxypropyl cellulose, cross carmellose calcium and the like, crosspovidone and the like, alginic acid and various ion exchange resins.

The other suitable pharmaceutically acceptable excipients of the compositions of the present invention can also include other materials such as binding agents, taste masking agents, anti- adherents, lubricants, sweeteners, flavors and co-processed excipients.

Binding agents may be, for example, various cellulose derivatives such as low molecular weight hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like, methacrylate copolymers, amino alkyl methacrylate copolymers and the like, povidone and the like, sodium alginate and the like.

Taste masking agent may be, for example, various cellulose derivatives such as low molecular weight hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like, methacrylate copolymers, amino alkyl methacrylate copolymers and the like, povidone and the like.

Antiadherents may be, for example, colloidal silicon dioxide, talc and the like.

Lubricants may be, for example, talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate and the like.

Sweeteners may be for example aspartame, acesulfam potassium, sucralose, xylitol, saccharine, saccharine potassium, sugars and the like.

Flavors may be for example mint flavors, orange flavor, lemon flavor, banana flavor, strawberry flavor, magnasweet, grape flavor and the like.

Solvents may be for example aqueous or non-aqueous or their mixtures thereof.

Nonaqueous solvents for example may be isopropyl alcohol, acetone and the like. Co-processed excipients may be for example CELLACTOSE ^® 80 (75% lactose monohydrate & 25% cellulose powder), StarLac (85% Lactose monohydrate & 15% Maize Starch), Formax™ (Calcium carbonate / Sorbitol (70:30), Ludiflash ^® (Mannitol, crospovidone, polyvinyl acetate and povidone).

Following are the non-limiting examples of the invention:

Example 1

Brief manufacturing process: 1. Sift separately Escitalopram oxalate, microcrystalline cellulose and croscarmellose sodium through 40# S. S. sieve and mix in a suitable granulator or fluid bed processor.

2. Dissolve amino methacrylate copolymer in mixture of Isopropyl alcohol and Water (70:30). Granulate the blend at step 1 with this solution.

3. Dry the wet mass at step 2 at 40°-50°C temperature till required LOD is achieved. 4. Mill and sift the dried granules through 40 # S. S. sieve.

5. Sift co-processed excipient (Mannitol, crospovidone, polyvinyl acetate and povidone), Xylitol, Sucralose and both the flavours through 40# s.s. Sieve. Mix these ingredients with the granules at step 4.

6. Sift Talc and Magnesium stearate through 40-# S. S. sieve and mix with blend of step 5.

7. Compress into tablets using suitable punch.

Example 2

Brief manufacturing process:

1. Sift Escitalopram Oxalate, Amino methacrylate copolymer, Co-processed excipient {Calcium carbonate / Sorbitol (70:30)}, xylitol and croscarmellose sodium through 40 # sieve.

2. Mix well and roll compact the step 1 blend and mill it through 30 # sieve.

3. Add microcrystalline cellulose, Croscarmellose sodium, Banana Flavor and Aspartame to blend of step 3.

4. Mix blend of step 2 and 3 and finally lubricate with talc and magnesium stearate and compress the resultant blend.

Example 3

Brief manufacturing process:

1. Sift Escitalopram Oxalate, Amino methacrylate copolymer, Co-processed excipient (Mannitol, crospovidone, polyvinyl acetate and povidone), Sucralose and crosscarmellose sodium through 40 # sieve and mix well.

2. Add microcrystalline cellulose, Mint Flavor and Aspartame to blend of step 1.

3. Mix and finally lubricate blend of step 2 with talc and magnesium stearate and compress the resultant blend.