Field Of Invention

The present invention relates to a extended release pharmaceutical formulation comprising desvenlafaxine, methods for preparing such a formulation and to its use to treat depression and related disorders and diseases.

Background of Invention:

Desvenlafaxine (O-desmethylvenlafaxine) chemically named as l-[2-(dimethylamino)-l-(4-phenol) ethyl]-cyclohexanol, is the major active metabolite of the antidepressant venlafaxine. The chemical structure of desvenlafaxine is given below.

Desvenlafaxine acts as a selective serotonin and norepinephrine reuptake inhibitor in the treatment of depression and other related central nervous system disorders and/or diseases . It has been suggested from in vitro studies, that desvenlafaxine is a more potent inhibitor of norepinephrine and dopamine uptake than the parent compound, racemic venlafaxine (Muth, E. A. et al, Drug Develop. Res, 23: 191-199, 1991). It has also been reported that desvenlafaxine has a half-life of about 10 hours, which is approximately 2.5 times longer that thehalf-life of venlafaxine (Klamerus, K.J. et al, Clin. Pharmacol., 32: 716-724, 1992).

Desvenlafaxine has been exemplified as a free base in WO 00/32555. It has also been exemplified as the fumarate salt in US Pat. No. 4,535,186. However, the fumarate salt of O-desmethyl-venlafaxine has unsuitable physicochemical and permeability characteristics.

The Succinate salt form of O-desmethylvenlafaxine (ODV) described in U.S. pat. No 6,673,838 have properties suitable for use as a drug, including improved solubility, permeability, and bioavailability. Furthermore, oral administration of ODV succinate results in a lower incidence of nausea, vomiting, diarrhea, abdominal pain, headache, vaso-vagal malaise, and/or trismus than oral administration of venlafaxine, O-desmethylvenlafaxine, and salts of O-desmethylvenlafaxine other than ODV succinate. Additionally, sustained release oral formulations of ODV succinate result in a lower incidence of nausea, vomiting, diarrhea, abdominal pain, headache, vaso¬vagal malaise, and/or trismus than oral administration of venlafaxine, O-desmethylvenlafaxine, and salts of O-desmethylvenlafaxine (other than sustained release oral formulations of ODV succinate). Presently desvenlafaxine succinate is marketed in United States as extended release tablets under proprietary name Pristiq™.

U.S. patent publication 20050175698 describes a multiparticulate form of O-desmethylvenlafaxine (ODV) succinate or formate that reduces undesirable characteristics associated with ODV and the hydrogel formulation thereof.

U.S. patent publication 20070014859 describes an oral, highly bioavailable unit dosage form of O-desmethylvenlafaxine succinate (DVS) having a delayed release of at least about one hour and a sustained release over multiple hours to provide a total release of greater than about 85% within about 12 to about 14 hours is described. In one embodiment, the superbioavailable desvenlafaxine composition has a delayed release of about two hours and a total release of greater than about 95% within about 12 to about 14 hours. Use of the formulation in treating depression and reducing the gastrointestinal side effects of O-desmethylvenlafaxine (ODV) is also described.

U.S. patent publication 20050175698 and U.S. patent publication 20070014859 discloses that desvenlafaxine extended release formulation based on hydrogel technology shows food effect.

WO2009049354 relates to a pharmaceutical formulation comprising desvenlafaxine having an mass mean diameter of between about 5jun and about l00um, or a pharmaceutically acceptable salt thereof, and at least one matrix rate-controlling pharmaceutically acceptable polymer, solid unit dosage form containing it, methods for preparing such a formulation and for its use to treat depression and related disorders and diseases.

Although various extended release formulations are known. There is a need to provide a less complicated dosage form that nonetheless provides extended release of desvenlafaxine, wherein the matrix (i.e core) and/or the coating is solely based on hydrophilic matrix materials and further the core is free of water insoluble fillers.

Description of invention:

This present invention relates to simple hydrogel matrix formulation for extended release of desvenlafaxine succinate (O-desmethylvenlafaxine succinate) comprises a core comprising desvenlafaxine succinate, water soluble filler and a matrix forming agent wherein the core if required is coated with a functional and/or non-functional coating.

The extended release formulation of present invention will have a dissolution profile comparable with that of commercially available formulation (Pristiq™).

In one embodiment of this invention water-soluble filler used generally consist of but not limited to oligosaccharides such as lactose, sucrose, mannitol and sorbitol polysaccharides such as dextrin, dextran and pullulan or combinations thereof.

In preferred embodiment water-soluble filler used herein may be lactose; different grades of lactose can be used. One non-limiting example of such different grades of lactose is Pharmatose-DCL-11.

In another embodiment matrix forming agents may be hydrophilic polymer, that swells or gels upon contact with water to thereby slow the diffusion release of the active ingredient. The hydrophilic matrix material is selected from celluloses such as methylcelluloses (i.e. having a viscosity of 400 cP to 4000 cP), hydroxy ethylcellulose, Hydroxy propyl methylcelluloses (HPMC) with varying degrees of substitution and/or varying molecular weights corresponding to varying viscosity levels (i.e. having a viscosity of 4000 to 100000 cP), polysaccharides such as galactomannans, potassium alginates, sodium alginates, agar-agar, carrageen, Arabic gum and sterculia gum and other water soluble polymers such as polyvinylpyrollidone, polyethylene oxide and combinations thereof. Generally hydroxy propyl methylcellulose is preferred.

In further embodiment core optionally may contain other excipients well known in the art and include without limitation such as surfactants, lubricants, disintegrants, glidants, colorants, plasticizers etc. The excipients are selected based in part on the dosage form, the intended mode of administration, the intended release rate and manufacturing reliability.

Further core may optionally coated with functional and/or non-functional coating. Suitable materials for coating without limitation may include hydrophilic film forming polymers selected from the groups of cellulose derivatives such as soluble alkyl- or hydroxyalkylcellulose derivatives such as methylcellulose, hydroxy methylcellulose, hydroxy ethylcellulose, hydroxy propylcellulose, hydroxy propyl methylcellulose, dextrins, soluble starches and starch derivatives, natural gums such as gum arabic, xanthans, alginates; and other water soluble film forming polymers such as polyvinylpyrollidone, polyethylene oxide and the like.

Preferably hydroxy propyl methylcellulose with varying degrees of substitution and/or varying molecular weights corresponding to varying viscosity levels of the aqueous solutions may be used as suitable film-forming agents.

The coating composition in addition to hydrophilic film forming polymers may also contain classical excipients such as plasticizers selected from but not limited to polyethylene glycol, triethyl citrate, glycerol, 1,2 propylene glycol; colorants, opacifiers (usually titanium oxide), adhesive agents (such as low viscous HPMC, hydroxypropyl cellulose and polyvinylpyrrolidone). Ethanol, acetone, water-isopropyl alcohol, methylene chloride, chloroform or any other suitable solvents may be used as well as mixtures of the solvents as long as they can dissolve or uniformly disperse the constituents of the coating mixture. Alternatively the aqueous coating dispersions may also be used.

Pharmaceutical composition of this present invention consist of about 15% to 35% w/w of desvenfaxine succinate, 10% to 70%w/w of water-soluble filler, 15% to 75%w/w of matrix forming agent and 0.5% to 15%w/w of other excipients of total uncoated oral dosage form.

Preferably consist of about 20% to 30% w/w of desvenlafaxine, 20% to 50%w/w of water-soluble filler, 25% to 55%w/w of matrix forming agent and 1% to 3%w/w of other excipient of total uncoated oral dosage form.

More preferably of about 24% to 26% w/w of desvenlafaxine succinate, 22% to 45% w/w of water-soluble filler, 29% to 51%w/w of matrix forming agent and about 1% to 1.5%w/w of other excipients of total uncoated oral dosage form.

This present invention of hydrogel matrix formulation may be produced by any of the standard techniques known to person skilled in art; examples of such techniques without limitation may include wet granulation, dry granulation or direct compression. Preferably wet granulation technique is used.

The present invention can conveniently be formulated in to different solid oral dosage forms; such as the core comprising desvenfaxine succinate, water soluble fillers, matrix forming agent and acceptable excipients can be compressed into a single monolithic tablet and if required followed by functional and/or non-functional coating and used as such or can be filled in to hard gelatin capsule to represent a unit dosage form. Alternatively the core can be compressed in to multiple mini tablets, which if required are then coated with functional and/or non-functional coating then required number of mini tablets are filled in hard gelatin capsule to represent a unit dosage form.

In another embodiment of this invention functional and/or non-functional coating optionally used can be applied on to the core directly or there may be intermediate coating layers located between the core and the functional and/or non functional coating. Further seal coat or topcoat may be applied outside the functional and/or non-functional coating.

In further embodiment percentage release of desvenlafaxine succinate at about 20 hours is not less than 75% in a USP apparatus type I (basket type) at 100 rpm in 0.9% of NaCl in water at 37° C.

A unit dose, (i.e. one tablet or capsule) of the pharmaceutical composition of present invention in general contains 76mg or 152 mg of desvenlafaxine succinate equivalent to 50 or 100 mg of desvenlafaxine, respectively.

The Extended -release formulation of the present invention may be used for any type of treatment for which acceptable salts is recommended and/or is suitable; which are known in the art (U.S. Pat No 6,673,838 discloses the use of desvenlafaxine succinate or polymorphs or mixtures thereof)

The following non-limiting examples illustrate the following invention.

General Procedure for the Preparation of Extended Release Formulations:

Manufacturing procedure for Desvenlafaxine ER tablets by wet granulation method.

(i) The intragranular portion comprising desvenlafaxine and other ingredients such as water-soluble filler and matrix forming agents are mixed using a suitable blender, (ii) The blended mass is granulated with a solution of isopropyl alcohol and the granulated mass is dried and the dried granules are resized, (iii) The resulting granules are lubricated with extragranular portion, (iv) The lubricated granules are compressed either into a single monolithic tablet, if required the tablet is coated with functional and/or non-functional coating which is used as such or as a single monolithic tablet is filled in hard gelatin capsule, (i) Alternatively the lubricated granules are compressed into multiple mini tablets, if required the mini tablets are coated and required number of mini tablets is filled in hard gelatin capsule.

Dissolution Method and Specification:

For all examples, the compositions were tested for dissolution of desvenlafaxine succinate in 900 ml of 0.9% NaCl in water as dissolution media at 37°C using USP type I dissolution apparatus rotated at 100 rpm. The sampling was done at 1, 2, 4, 8, 12, 16, 18,20 and 24 hours. The dissolution data presented is the mean of at least 3 tablets or capsules.

Dissolution of Pristiq™ 100 mg tablets were carried out at same media and sampling were done 1, 2, 4, 8, 12, 16, 18, 20 and 24 hours, the dissolution profiles of the composition prepared by present invention were compared with that of Pristiq™.

Example: 1

TABLEI

S.No Ingredients Qty/tablets %w/w
Intragranular Portion
1 Desvenlafaxine succinate monohydrate 152* 25.33
2 Spray dried Lactose (Pharmatose-DCL-11) 262 43.67
3 Hydroxypropyl methylcellulose (Methocel-K-4 MCR) 180 30 Extragranular Portion
4 Silicon dioxide (Aerosil-200) 3 0.50
5 Magnesium stearate 3 0.50
6 Total 600 1(H)
* Desvenlafaxine succinate monohydrate eq to desvenlafaxine –l00mg

Brief manufacturing procedure:

1. The intragranular ingredients are mixed and granulated with isopropyl alcohol.

2. Granulated mass is dried and resized.

3. Granules formed are mixed with extragranular ingredients and compressed into tablets

Example: 2

TABLED

S.No Ingredients Qty/tablets %wAv

Intragranular Portion
1 Desvenlafaxine succinate monohydrate 152* 25.33
2 Spray dried Lactose (Pharmatose-DCL-11) 142 23.67
3 Hydroxypropyl methylcellulose (Methocel-K-4 MCR) 300 50.00 Extragranular Portion
4 Silicon dioxide (Aerosil-200) 3 0.50
5 Magnesium stearate 3 0.50
6 Total 600 100
* Desvenlafaxine succinate monohydrate eq to desvenlafaxine -l00mg

Brief manufacturing procedure:

1. The intragranular ingredients are mixed and granulated with isopropyl alcohol.

2. Granulated mass is dried and resized.

3. Granules formed are mixed with extragranular ingredients and compressed into tablets.

Example: 3 Dissolution profile;

The tablets prepared in accordance with Examples 1 & 2 and commercially available Pristiq ™ were dissolution tested in USP dissolution Apparatus type I, with media of 0.9% NaCl in water at an agitation of 100 rpm. The volume and temperature of the media were 900ml and 37°C respectively. The tablets were tested at 1, 2, 4, 6, 8, 12,16, 18, 20 and 24 hour time points. The dissolution results are listed in Table III below

TABLE III; Dissolution data of Pristia ™and Example 1 & 2

The dissolution data of desvenlafaxine succinate extended release tablets of Example 1 & 2 of the present invention is comparable with that of Pristiq™ . Graphical representation comparing the dissolution data of Pristiq™ with Examples 1 & 2 is depicted as Figure 1.

We claim:

1. An extended release formulation comprising a therapeutically effective amount of desvenlafaxine succinate, a water soluble filler, a matrix forming agent and optionally other pharmaceutically acceptable excipients.

2. The extended release formulation according to claim 1, wherein not more than 35% desvenlafaxine succinate is released during the first two hours in USP Apparatus I (basket) at 100 rpm in 0.9% NaCl in water at 37° C.

3. The extended release formulation according to claim 1, wherein the said desvenlafaxine succinate is about 15% to about 35% by weight of the formulation.

4. The extended release formulation according to claim 1, wherein the water soluble filler is about 10% to about 70% by weight of the formulation.

5. The extended release formulation according to claim 1 or 4, wherein said water soluble filler is an oligosaccharide such as lactose, sucrose, mannitol and sorbitol or a polysaccharide such as dextrin, dextran and pullulan and combinations thereof.

6. The extended release formulation according to claim 1, wherein the matrix forming agent is about 15% to about 75% by weight of the formulation.

7. The extended release formulation according to claim 1 or 6 , wherein said matrix forming agent is an hydrophilic matrix material which is a cellulose polymer such as methylcellulose, hydroxy ethylcellulose, hydroxy propyl cellulose, hydroxy propyl methylcellulose , polysaccharide such as galactomannans, alginates, agar-agar, carrageen, arabic gum and sterculia gum and combinations thereof and other water soluble polymers such as polyvinylpyrrolidone, polyethylene oxide, and combinations thereof.

8. A process for preparing the extended release formulation comprising steps: a) forming mixture of desvenlafaxine succinate, water soluble filler, matrix forming agent and pharmaceutically acceptable excipients. b) processing the mixture into desired dosage form.