Field of the invention

The invention relates to a pharmaceutical formulation and in particular to a pharmaceutical formulation comprising Sembragiline or a salt thereof.

Background of the invention Sembragiline (N-[(3S)- l-[4-[(3-fluorophenyl)methoxy]phenyl]-5-oxo-pyrrolidin-3- yl]acetamide has previously been described in the art. WO 2004/026825 WO 2006/097197 ² and WO 2006/097270 relate to methods for preparing enantiomerically pure 4- pyrrolidinophenylbenzyl ether derivatives. Sembragiline is a Monoamine oxidase-B type (MAO- B) inhibitor. Alzheimer's Disease is a brain disease that slowly destroys memory and thinking skills, up to loss of the ability to carry out the simplest tasks. It is the most common cause of dementia among older people. Mild Alzheimer's Disease manifests itself in memory loss and small changes in other cognitive abilities, e.g. getting lost, trouble handling money and managing daily tasks, having some mood and personality changes, etc. In the stage of Moderate Alzheimer ^' s Disease, the control of language, reasoning, sensory processing, and conscious thought are impacted. Memory loss and confusion grow worse, e.g. patients have problems recognizing family and friends and become unable to learn new things, etc. hallucinations, delusions, and paranoia may occur. Severe Alzheimer ^' s Disease is the final stage. Patients cannot communicate anymore and are completely dependent. MAO-B is involved in Alzheimer's Disease etiology. MAO-B activity is increased in several regions of the brain from an early stage and this is maintained throughout the course of the disease. MAO-B activity is believed to be involved in the production of toxic reactive oxygen species, which are thought to contribute to the pathogenesis of Alzheimer ^' s Disease.

Object of the present invention is to provide stable tablet formulations of different strengths suitable for oral administration of Sembragiline and methods to prepare the same. These formulations have a better manufacturability and performance as previously described formulations.

Definitions The following definitions of the general terms used in the present description apply irrespectively of whether the terms in question appear alone or in combination with other groups.

Detailed Description of the Invention

Present invention provides stable tablet formulations of different strengths suitable for oral administration of sembragiline.

In particular, sembragiline has been formulated as 1 mg and 5 mg film-coated, immediate- release tablets for oral administration. The 1 mg and 5 mg tablets are manufactured by aqueous fluid bed granulation, mixing, tableting, and coating.

Present film-coated tablets use a 4: 1 ratio of lactose monohydrate: microcrystalline cellulose (MCC) in the internal phase to reach optimal granule particle sizes and therewith optimal flow properties. Present tablets contain 4% povidone K30 as binder and 9.33% MCC in the external phase as filler. The level of sodium starch glycolate in present tablets is 2.5% that leads to satisfactory dissolution rates of the tablets. The level of magnesium stearate in present tablets is 0.67% (film-coated tablets) that leads to a satisfactory lubrication level. Sembragiline (CAS RN 676479-06-4) has the following structure

The term "disintegrant" refers to excipients that expand and dissolve when wet causing the tablet to break apart in the body and release the active ingredient for absorption. Examples include cross-linked polymers like crospovidone, croscarmellose sodium etc. and modified starches like sodium starch glycolate. A specific example is Primojel.

The term "filler" refers to excipients that fill out the size of a tablet by increasing the bulk volume. Fillers make it possible for the final product to have the proper volume for patient handling. Examples of fillers are plant cellulose, lactose, starch, mannitol, etc. Specific examples are lactose monohydrate like Pharmatose 200M and microcrystalline cellulose (MCC) like Avicel PH 101 , Avicel PH 102 and the like.

The term "binder" refers to excipients that hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength. Examples of binders are, polyvinlypyrrolidon (PV), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), cellulose, etc., sugar alcohols like sorbitol, proteins like gelatin and polymers like PVP, e.g. copovidone (PVP/VA 64)., PEG, etc. A specific example is Povidone K30.

The term "lubricant" refers to excipients that prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low fraction between active ingredient and wall. Examples of lubricants are minerals like talc or silica and fats like stearin, magnesium stearate, etc. A specific example is magnesium stearate.

The term "coating agent" refers functional coating agents that is a group of substances that provides a coating to provide a barrier to protect drugs from e.g. the PH environment of the stomach, and non-functional coating agents. A specific example of a non-functional coating agent is Aqua Polish P yellow (029.59).

One embodiment of present invention relates to a pharmaceutical formulation in form of a film-coating tablet comprising sembragiline or a salt thereof. A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, consisting of an internal phase that comprises sembragiline, an external phase and a coating phase.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, wherein the internal phase are granules comprising sembragiline, fillers, disintegrant and binder.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, wherein the fillers are lactose monohydrate and microcrystalline cellulose.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, wherein the disintegrant is sodium starch glycolate. A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, wherein the binder is polyvinylpyrrolidone.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, wherein the external phase comprises filler and lubricant.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, wherein the filler of the external phase is microcrystalline cellulose.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, wherein the lubricant is magnesium stearate. A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, wherein the coating agent is a non-functional coating agent.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein that is

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein that has the following dissolution profile

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein that has the following dissolution profile

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein that has the dissolution profile as shown in Figure 2. A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, for the treatment of Alzheimer's Disease.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, obtainable by the process comprising the steps of aqueous fluid bed granulation, mixing, tableting, and coating. A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, obtainable by the process as shown in Figure 1.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, obtainable by the process comprising the steps

1. Povidone is dissolved in purified water and the milled Sembragiline is then suspended in the resulting solution.

2. After screening, the lactose monohydrate, MCC, and sodium starch glycolate are mixed in a fluid bed granulator.

3. The mixed powder from step 2 is granulated with the suspension from step 1.

4. The granulate from step 3 is dried and then milled. 5. The milled granulate from step 4 is mixed with screened MCC and magnesium stearate. 6. The final blend from step 5 is compressed into tablet cores.

7. The cores from step 6 are coated with the film-coating mixture in order to obtain film- coated tablets.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, wherein the sembragiline is in crystalline form.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, wherein the pharmaceutical formulation is a tablet.

A specific embodiment of present invention relates to a tablet comprising a pharmaceutical formulation as described herein. A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, for use as medicament for the treatment of Alzheimer's Disease.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, for the treatment of Alzheimer's Disease.

A specific embodiment of present invention relates to a method for the treatment of Alzheimer's Disease, comprising the step of administering a pharmaceutical formulation as described herein to a patient in need thereof.

A specific embodiment of present invention relates to a pharmaceutical formulation as described herein, which is administered once daily.

Figures Figure 1: Manufacturing Process of film-coated tablets

Figure 2: Dissolution in Sodium Phosphat buffer pH 6.8

Experimental Part

The following experiments are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof. Manufacturing of the tablets

1. Povidone K30 is dissolved in purified water and the milled Drug Substance Sembragiline is then suspended in the resulting solution.

2. After screening, the lactose monohydrate, MCC, and sodium starch glycolate are mixed in a fluid bed granulator. 3. The mixed powder from step 2 is granulated with the suspension from step 1.

4. The granulate from step 3 is dried and then milled.

5. The milled granulate from step 4 is mixed with screened MCC and magnesium stearate.

6. The final blend from step 5 is compressed into tablet cores. 7. The cores from step 6 are coated with the film-coating mixture in order to obtain film-coated tablets.

Pharmaceutical Formulations

Abbreviation: HCI = hydrochloric acid.

Stability of tablets

Table 1 -Stabil ity Report Film-coated tab ets 1 mg in HDPE Bottles without desiccant

Table 2 -Stabil it Film-coated tablets 5 m in HDPE Bottles without desiccant

wherein degradation product X has the following structure:

After 6 months at 40°C/75%r.h. all analytical tests are well within the specifications. Sembragiline film-coated tablets are very stable.

Dissolution

Experimental Conditions:

The pharmaceutical composition has a rapid dissolution, e.g. at least 85% of the dose is dissolved within 30 min in 900 mL of pH 6.8 buffer which is consistent with an immediate release profile

¹ WO 2004/026825

² WO 2006/097197

³ WO 2006/097270