WO2007138301A2

WO2007138301A2 - Novel formulation

Info

Publication number: WO2007138301A2
Application number: PCT/GB2007/001975
Authority: WO
Inventors: Antonia Sandric; Maja Mihoci; Anita Bevetek; Snjezana Miric; Maja Devcic; Ernest Mestrovic; Stjepan Hegedic; Nicholas Alistair Maxwell Mcleish
Original assignee: Pliva Hrvatska D.O.O.
Priority date: 2006-05-27
Filing date: 2007-05-29
Publication date: 2007-12-06
Also published as: GB0610570D0; WO2007138301A3

Abstract

The present invention relates to novel formulations of venlafaxine, their composition, preparation and use in the treatment of depression and related disorders.

Description

Novel Formulation

Field of invention

The present invention relates to novel formulations of venlafaxine hydrochloride anhydrate Form I and their use in the treatment of depression and related disorders. The formulations are preferably made by direct compression, in the absence of water, so as to preserve the venlafaxine hydrochloride anhydrate Form I from conversion into other forms. In addition disclosed is a preferred range of particle size and morphology o1 venlafaxine hydrochloride anhydrate Form I

Background of the invention Depression is a very common mental health disorder associated with feelings of sadness, worthlessness, disrupted sleep patterns, low appetite, low libido and low energy levels, and in severe cases of self harm and suicide. Depressive illness may be characterised for example as major depression, dysthymic disorder (low to moderate depression that persists and is resistant to treatment) or bipolar disorder (depression with manic episodes).

Common treatments for depression include administration of tricyclic anti-depressants (which however are commonly associated with undesired sedative effects), selective serotonin reuptake inhibitors and monoamino oxidase inhibitors. More recently serotonin noradrenalin reuptake inhibitors have been introduced which by virtue of having effect on noradrenalin as well as serotonin reuptake appear to have a broader spectrum of effect, for example being useful in the treatment of anxiety disorders, obsessive compulsive disorder, attention deficit hyperactivity disorder as well as depression.

Venlafaxine, chemical name 1~[(1 RS)-2-(dimethylamino)-1-(4- methoxyphenyl)ethyl]cyclohexanol, its synthesis, and its use in the treatment of depression are described in US4535186 (Husbands et al, see Example 3, Compound A). The hydrochloride salt is specifically described. This compound is a serotonin noradrenalin reuptake inhibitor which in the form of its hydrochloride salt (eg under the brand name Effexor™) is indicated for the treatment of moderate to severe major depressive disorder including depression accompanied by anxiety. The substance is considered safer than earlier treatments by virtue of its selectivity for reuptake of serotonin and noradrenaline with no affinity for the histaminergic, adrenergic and cholinergic receptors which are associated with toxicity in the traditional antidepressants, especially at high doses. A review of the pharmacology and clinical efficacy of venlafaxine has been reported in Montgomery (1994) J Clin Psychiatry 54, 119-126 and a clinical trial in general anxiety disorder was reported in Gelenberg et al (2000) J Am Med Assoc 283, 3082. Venlafaxine may also be useful in the treatment of obesity, panic disorder, pre-menstrual syndrome, post traumatic stress disorder, Tourette's syndrome, bulimia nervosa and Shy Drager syndrome (see eg EP639374).

Racemic venlafaxine hydrochloride anhydrate is a white to off white crystalline solid having a melting point of 215-217⁰C (source: Merck Index). A number of polymorphic forms of crystalline venlafaxine hydrochloride anhydrate have been reported. For example, Forms I and Il and solvated Forms III and IV have been described in WO02/45658. Form I was first described in Acta Crystallographica (2000) C56 1009- 1010. A monohydrate form of venlafaxine hydrochloride has been described in

WO03/050076. As pointed out in this document, the monohydrate form of venlafaxine hydrochloride is more stable than the anhydrate in manufacturing processes that involve use of water, for example in wet granulation processes. According to the findings of the present inventors, use of a wet granulation method with venlafaxine hydrochloride anhydrate Form I employing water or even ethanol leads to partial conversion of the active ingredient into venlafaxine hydrochloride monohydrate. Evidently this is very undesirable, since a uniform physical form must be maintained during the manufacture of a pharmaceutical product.

Venlafaxine is typically prescribed at a dose of 75mg/day up to 350 mg/day for the most severely affected patients. Conventionally patients start on the lowest dose and increase (or reduce the dose) in steps of no more than 75mg (allowing at least a week between steps). The dose may be divided so at to be administered up to 3 times per day. Effexor™, the branded version of venlafaxine hydrochloride, is available as an immediate release (IR) oral tablet in dosages of 25, 37.5, 50, 75 and 100mg (based on venlafaxine base) to be administered up to 3 times per day. It is also available as an extended release (XR) oral capsule formulation in dosages of 37.5, 75 and 150mg (based on venlafaxine base) to be administered once per day. The drug is normally taken with food.

In therapeutic dosing with venlafaxine hydrochloride IR oral tablets, rapid dissolution results in a rapid increase in plasma levels of the active agent shortly after administration followed by a decrease in blood plasma levels over several hours as the active agent is metabolised or eliminated. Sub-therapeutic plasma levels are approached after about twelve hours following administration, thus administration of the IR tablets should be at least twice and typically three times per day.

Common oral presentations of pharmaceutical products include capsules and tablets. So far as tablets are concerned these are commonly manufactured using three main technologies: "direct compression", "dry granulation" and "wet granulation". According to the direct compression method, a compressible carrier is blended with the active ingredient, together if necessary with a lubricant and a disintegrant, and the blend is then compressed using a tableting machine. According to the dry granulation method, the ingredients of the formulation are intimately mixed and compressed using a tableting machine. The slug which is so formed is ground to a uniform size and re-compressed to form the finished tablet. The wet granulation method has more operational manipulations than either of the other two methods. Initially the powdered ingredients (excluding the "granulating components") are blended. Separately, a granulating solution is prepared. The powder blend and the granulating solution are kneaded to a proper consistency and the wet mass is forced through a screen or wet granulator. The wet granules are dried in an oven or fluidised bed drier. The dried granules are screened to a suitable size for compression, these are, if desired, mixed with a lubricant and disintegrant, and the granular mix is compressed into the finished tablet. Of the three methods, although the direct compression method has the advantage that it employs the least amount of operational manipulation, the key running powder requirements (blend homogeneity, consistent bulk density, flow and compressibility) must be met by the dry blend of active agent with excipients as there is no chemical or physical modification before tableting. Accordingly the physical and functional properties of the excipients are very important and must be carefully balanced. In particular failure to correctly select and balance ingredients can lead to problems during tableting such as lamination, capping and segregation (inhomogeneity). When capping occurs, the cap of the tablet breaks off leading to accretions on the tableting head and low weight tablets. When laminating occurs, the tablet breaks up into a number of layers, generally in the middle of the tablet. Most commonly capping and laminating are caused by air entrapment in the formulation to be compressed. When segregation occurs the content of active ingredients and other components of is inhomogeneous within the batch of formulation. This may, for example, be caused by poor balancing of particle sizes within the formulation.

According to the summary of product characteristics (SmPC) for Effexor™ IR tablets (Wyeth), this product contains venlafaxine hydrochloride together with microcrystalline cellulose, lactose, sodium starch glycolate, magnesium stearate and yellow and brown iron oxide as excipients.

According to the SmPC for Effexor™ XR capsules (Wyeth), this product contains venlafaxine hydrochloride together with microcrystalline cellulose, ethylcellulose, hydroxypropylmethylcellulose, gelatine, red and yellow iron oxides (E172), titanium dioxide (E171) and printing ink as excipients.

Extended release formulations of venlafaxine suitable for administration in direct compression tablets which are free of cellulose or cellulose derivatives and contain a carboxyvinyl polymer eg a Carbopol™ are described in WO2005/039555.

Description of the invention

An object of the present invention is to provide a tablet formulation of venlafaxine hydrochloride having immediate release properties. It is a further object of the present invention to provide a tablet formulation of venlafaxine hydrochloride anhydrate Form I in which the anhydrate Form I is stable and does not convert to other polymorphic forms (eg Form II) or to any solvated form eg a hydrate during formulation. It is a further object of the present invention to provide a tablet formulation of venlafaxine hydrochloride Form I having a content of water of less than 6% by weight (determined by Karl- Fischer). It is a further object of the present invention to provide a tablet formulation of venlafaxine hydrochloride Form I in which the tablet may readily be manufactured and does not demonstrate manufacturing problems such as capping, lamination, segregation (inhomogeneity) and poor flow characteristics. It is a further object of the present invention to provide a tablet formulation of venlafaxine hydrochloride Form I having pharmacodynamic properties (eg as exemplified by its dissolution profile following standard testing) which closely matches that of a reference product (eg Effexor™ IR tablets). It is a further object of the invention to provide a robust pharmaceutical presentation of venlafaxine hydrochloride.

These and others objectives are met by the formulations and tablets according to the present invention.

Thus, according to the invention we provide a pharmaceutical formulation comprising: (i) 20-40% w/w venlafaxine hydrochloride anhydrate Form I as active ingredient; (ii) 57- 79.75% w/w filling and binding component comprising lactose, starch and a vinylpyrrolidone containing polymer; and (iii) 0.25-3% w/w lubricant.

As a further aspect we provide a tablet formed from a direct compression process, for oral administration and having immediate release characteristics, comprising a formulation as just described.

Immediate release presentations according to the invention typically release at least about 80% of the active ingredient from a direct compression tablet within about 30 minutes when an amount of the dosage form equivalent to 25, 37.5, 50, 75 or 100mg of venlafaxine is tested as set out in standard tests, and in particular in the Dissolution Test, preferably in all three pH, 1.2, 4.5 and 6.8.

The Dissolution Test for venlafaxine hydrochloride tablets is the test essentially as set out in USP paragraph 711 (see US Pharmacopoeia XXII p1578-1579). Dissolution testing is performed in a USP-2 dissolution apparatus under conditions at least as stringent as the following: 900ml approx. of deionised water at 37+ 0.5⁰C₁ with three different samples at different pH of 1.2, 4.5 and 6.8, with paddles turning at 50 rpm. Tablets which release the active ingredient within the above specified time under conditions of greater stringency (lower volume of buffer, greater amount of dosage form, lower temperature, lower paddle speed) are also embraced by the above mentioned typical definition of an immediate release presentation. Whilst the Dissolution test being an in vitro test is an artificial test, it is nevertheless believed from the experience of persons skilled in the art that performance in the Dissolution test is an acceptable correlate for in vivo behaviour.

Preferably the concentration of the venlafaxine hydrochloride anhydrate Form I in the formulation is 25-30% w/w, preferably around 28% w/w.

The formulation will contain 57-79.75% w/w of filling and binding component comprising lactose, starch and a vinylpyrrolidone containing polymer. The lactose may be in the form of lactose monohydrate or lactose anhydrate, but will preferably be lactose monohydrate. The lactose may be crystalline or amorphous. Suitably the lactose may be spray-dried (e.g. spray dried lactose monohydrate, such as Pharmatose™ DCL 11). Suitably the lactose is present in the final formulation at a concentration of 29-65.75%, preferably 45-50% w/w. Starch may for example be corn starch (e.g. unmodified corn starch or alternatively pre-gelatinised corn starch). The starch may also convey some disintegrant properties to the formulation. Suitably the starch is present in the final formulation at a concentration of 10-20%, preferably around 15% w/w. Vinylpyrrolidone containing polymers may for example be selected from polyvinylpyrrolidone (e.g. Kollidon™ 30) and co-polymers of vinylpyrrolidone and vinyl acetate (e.g. Kollidon™ VA 64). The vinylpyrrolidone containing polymer may for example be polyvinylpyrrolidone alone or a mixture of polyvinylpyrrolidone and a co-polymer of vinylpyrrolidone and vinyl acetate or a co-polymer of vinylpyrrolidone and vinyl acetate alone. In addition the vinylpyrrolidone polymer may be cross linked. It will be understood that a mixture of polymers may be used. Suitably the vinylpyrrolidone containing polymer is present in the final formulation at a concentration of 4-8%, preferably around 6% w/w. Preferably the vinylpyrrolidone containing polymer is a mixture of polyvinylpyrrolidone and a co- polymer of vinylpyrrolidone and vinyl acetate employed at a ratio of between 1 :3 and 1:5, preferably around 1 :4 w/w.

The filling and binding component, and in particular the lactose, will typically be of a particle size having a D90 as determined by standard sieve analysis of less than around 450 microns, preferably less than around 400 microns. Examples of lubricants preferred in the present invention include stearic acid and metal salt stearates such magnesium stearate, zinc stearate and calcium stearate. The preferred lubricant is magnesium stearate. Further examples include sodium stearyl fumarate, sodium lauryl sulphate, sodium benzoate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, polyethylene glycol, hydrogenated vegetable oil and talc. Typically the lubricant will be included in an amount of 0.25-3% w/w, preferably 0.5-1.5% w/w, especially around 1% w/w.

If desired an anti-adherent can be added to the formulation in order to improve the flow and packing properties of the formulation prior to compression. An exemplary anti- adherent is colloidal silicon dioxide (e.g. Aerosil™ 200). Further examples include talc and magnesium trisilicate. A suitable amount of anti-adherent if added is 0.2-1% eg 0.5- 1 % such as around 0.7% w/w.

If desired a disintegrant can be added to the formulation to enhance the disintegrating properties of the formulation and thereby to accelerate dissolution. An exemplary disintegrant is crospovidone (cross linked polyvinylpyrrollidone). Further examples include sodium starch glycolate and croscarmellose sodium. Other examples include powdered cellulose and microcrystalline cellulose.

A suitable amount of disintegrant, if added, is 0.25-3%, preferably. 0.5-1.5%, such as around 1.2% w/w.

If desired a colouring agent can be added to the formulation to provide a distinguishing colour to the eventual tablet. An exemplary colouring agent is iron oxide. A suitable amount of colouring agent, if added, is 0.02-0.15%, preferably 0.02-0.1%, such as around 0.07% w/w.

If desired further filler components may include mannitol, cellulose (such as microcrystalline cellulose) or cellulose derivatives (such as hydroxypropylmethyl cellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose), or mixtures of any thereof, may be included within the formulation (of up to 20% w/w). However the preferred formulations according to the invention avoid use of cellulose or cellulose derivatives. Furthermore they avoid the use of mannitol.

As a further aspect of the invention we also provide a method of treating a disorder susceptible to serotonin noradrenalin reuptake inhibitor therapy which comprises administering to a patient a formulation according to the invention.

As a further aspect of the invention we also provide use of a formulation according to the invention in the manufacture of a medicament for the treatment of a disorder susceptible to serotonin noradrenalin reuptake inhibitor therapy.

Disorders susceptible to serotonin noradrenalin reuptake inhibitor therapy include depression, anxiety disorders, obsessive compulsive disorder, attention deficit hyperactivity disorder, obesity, panic disorder, pre-menstrual syndrome, post traumatic stress disorder, Tourette's syndrome, bulimia nervosa and Shy Drager syndrome, and especially depression eg moderate to severe major depressive disorder including depression accompanied by anxiety.

Venlafaxine hydrochloride may be prepared following the method described in US4,535,186 the disclosure of which is herein incorporated in its entirety.

Venlafaxine hydrochloride anhydrate Form I may be prepared following the method described in WO02/45658 the disclosure of which is herein incorporated in its entirety. For example venlafaxine hydrochloride anhydrate Form I may be prepared by dissolving venlafaxine hydrochloride in water and precipitating solid by treatment with dimethylformamide or methylethylketone.

Alternatively, it may be prepared by crystallisation from a solution of venlafaxine base in an appropriate organic solvent by the addition of hydrogen chloride. Suitably, the addition takes place with intensive stirring at elevated temperature and, following nucleation, is gradually cooled.

The venlafaxine hydrochloride anhydrate Form I will be substantially free of venlafaxine hydrochloride anhydrate Form Il and venlafaxine hydrochloride monohydrate (i.e. venlafaxine hydrochloride anhydrate Form I forms at least 98% w/w of the venlafaxine component, preferably at least 99% w/w and, for example, venlafaxine hydrochloride anhydrate Form Il and venlafaxine hydrochloride monohydrate are each present at less than 1% w/w of the venlafaxine component). Preferably the venlafaxine hydrochloride anhydrate Form I will be free of venlafaxine hydrochloride anhydrate Form Il or venlafaxine hydrochloride monohydrate (i.e. venlafaxine hydrochloride anhydrate Form I forms at least 99.8% w/w of the venlafaxine component, preferably at least 99.9% w/w and, for example, venlafaxine hydrochloride anhydrate Form Il and venlafaxine hydrochloride monohydrate are each essentially undetectable in the formulation).

Venlafaxine hydrochloride anhydrate Form I may be characterised by a XRPD profile substantially resembling that shown in Figure 4 middle trace or bottom trace (typically the bottom trace). Venlafaxine hydrochloride anhydrate Form Il may be characterised by a XRPD profile substantially resembling that shown in Figure 4 top trace, and in particular by a peak at 2 Theta 8.40° which is absent in Form I. Venlafaxine hydrochloride monohydrate may be characterised by a XRPD profile substantially resembling that shown in Figure 6 bottom trace, and in particular by a peak at 2Theta 7.45° which is absent in Form I.

In order for the active ingredient to be in a form which has ideal dissolution characteristics and is also suitable for direct compression we have undertaken significant efforts to optimise the form of the active ingredient itself.

Suitably, for optimal suitability in a direct compression method of preparing tablets, we have found that active ingredient in the form of a needle crystalline shape (i.e. wherein the particles of venlafaxine hydrochloride anhydrate Form I having an aspect ratio of greater than 1 :5, or even greater than 1 :6 and especially those with an aspect ratio greater than 1 :8, are to be avoided). More particularly an ideal form of venlafaxine hydrochloride anhydrate Form I is one in which the crystalline shape has an aspect ratio of between 1 :1 and 1 :4, which are where the particles have crystals in the shape of plates or prisms. Tablet formulations containing such shaped particles surprisingly seem to be less susceptible to lamination than tablets containing the aforementioned needle shape. Suitably, the particle size of the population of venlafaxine hydrochloride anhydrate Form I particles employed in the invention is such that the D90, as determined by a standard laser scattering method, is not more than around 450 microns, and is not more than around 400 microns. Suitably the particle size of the venlafaxine hydrochloride anhydrate Form I employed in the invention is such that the D10, as determined by a standard laser scattering method, is not more than around 20 microns, and is not more than around 10 microns.

Thus as a specific aspect of the invention we provide particles of venlafaxine hydrochloride anhydrate Form I having an aspect ratio of between 1:1 and 1:4, and in particular a population of particles of venlafaxine hydrochloride anhydrate Form I in which more than 50% of particles especially more than 75% particularly more than 90% of particles by number have an aspect ratio of between 1 :1 and 1 :4. We also provide a pharmaceutical formulation comprising such a population of particles of venlafaxine hydrochloride anhydrate Form I together with one or more pharmaceutically acceptable diluents or carriers.

By aspect ratio in this context particles will have three major dimensions (width, length and thickness) and it is meant that the ratio of the second largest dimension of a particle (i.e. its width) to the largest dimension (i.e. its length).

Such particles may be prepared by a methods disclosed herein.

Particle size reduction, if desired, may be achieved by conventional means, such as milling. As noted above, particles having an aspect ratio of between 1 :1 and 1 :4 are particularly suitable for direct compression. Particles having this aspect ratio before milling will tend to have this aspect ratio after milling.

Excipients may be obtained from commercial sources (e.g. Degussa, BASF etc). Suitably the excipients are categorised as "direct compression grade", where applicable.

Formulations according to the invention suitable for use in direct compression tablets may be prepared by intimate mixing of the ingredients using apparatus known to persons skilled in the art. Tablets prepared according to the invention will typically be of conventional shape, such as biconvex.

As a further aspect of the invention we provide a process for preparing an oral immediate release pharmaceutical formulation for use in a direct compression tablet according to the invention which comprises intimately mixing the ingredients in a water free environment.

As a further aspect of the invention we also provide a process for preparing a direct compression tablet which comprises directly compressing a formulation according to the invention. Tablet compression apparatus will be known to a person skilled in the art.

If desired, tablets may be coated using conventional coating excipients.

It will be understood by the skilled person that "pharmaceutical" includes veterinary applications.

All % concentrations stated herein are expressed as w/w based on total weight of formulation.

Examples

Preparative Example 1

Method for preparation of particles of venlafaxine hydrochloride anhvdrate Form I Synthesised venlafaxine base was extracted from reaction mixture in appropriate organic solvent. The solution was warmed to elevated temperature and then a solution of hydrogen chloride in organic solvent was added with intensive stirring. Following nucleation, the solution was gradually cooled.

Whether the crystals had a habit to form plates or prisms or needles mostly depended upon the stirring rate used at the moment when the nucleation process took place. The stirring rate to be used may vary with the vessel size and by simple trial and error the appropriate rate may be found to create the desired crystal shape. The crystals obtained were then isolated, washed and dried. Example 1

A formulation was prepared as follows:

prepared essentially according to the method of Preparative Example 1 ^* polyvinylpyrrolidone *^* cross-linked polyvinylpyrrolidone

*^**particles containing α-lactose monohydrate crystals with some amorphous lactose ^****copolyrner of vinylpyrrolidone and vinyl acetate

Tablets corresponding to 25, 37.5, 50, 75 and 100mg of venlafaxine were prepared by directly compressing, respectively, 100, 150, 200, 300 and 400 mg of the above described formulation.

The manufacturing process involves the following steps:

1. Milling phase (optional)

- if necessary, milling of active substance to reduce the particle size

2. Homogenisation of active substance with excipients

3. Compression of the tabletting blend into tablets Homogenisation of active substance with excipients is a phase that has been divided into separate steps with specified order, to assure optimal quality of a finished product: 1. Preparation of a coloring agent-corn starch triturate in order to assure uniform colour distribution and uniform appearance of tablets 2. Preparation of a mixture of Kollidon™ VA 64 with Aerosil™ 200, unpressed

3. Addition of substances in a blender is performed in a specified order:

Ludipress™,

Venlafaxine hydrochloride,

Mixture of colour and com starch, Corn starch,

Pharmatose™ DCL 11

Mixture of Kollidon™ VA 64 and Aerosil™ 200

Substances are mixed in a blender for 5 minutes, followed by the sieving of the prepared mixture (in order to remove possibly present agglomerates that would enable a proper homogenisation and blend uniformity) and additional mixing for 10 more minutes.

4. Magnesium stearate is blended with the mixture for 5 minutes.

Compression of the tabletting blend is performed on a rotary tablet press using suitable tooling, and tablets of all dosage strengths are round, biconvex, with specific marking.

With the formulation presented in the table above, tablets with satisfactory quality were obtained. No lamination or capping was experienced. The manufacturing process used for production of these tablets proved to yield consistently Form I of venlafaxine hydrochloride anhydrate. Example 2

prepared essentially according to the method of Preparative Example 1

Tablets (25, 37.5, 50, 75 and 100mg) were prepared by directly compressing the formulation above, following the process given in Example 1.

With the formulation presented in the table above, tablets with satisfactory quality were obtained. No lamination or capping was experienced. The manufacturing process used for production of these tablets proved to yield consistently Form I of venlafaxine hydrochloride anhydrate.

Analytical Example 1

In order to determine the stability of the anhydrate Form I in the tablet formulation, samples of the finished tablet were compared with standards for Form I and Form I venlafaxine anhydrate.

The following samples were tested:

1. WOBMUV -X-ray powder diffraction pattern is generated from data taken from Cambridge Structural Database (CSDB, Version 5.26), D.Vega at al, Acta Cryst. Section C56 (2000) 1009-1010. Generated pattern corresponds to measured pattern of venlafaxine hydrochloride anhydrate Form I. 2. WOBMUV01 - X-ray powder diffraction pattern is generated from data taken from Cambridge Structural Database (CSDB, Version 5.26), A. Sivalakshmidevi at al, Acta Cryst. Section E58 (2002) o1072. Generated pattern corresponds to measured pattern of venlafaxine hydrochloride anhydrate Form II. 3. RS1794 Ser.02- working standard for venlafaxine hydrochloride anhydrate Form

I.

4. VEN32/M PLACEBO - placebo formulation (this formulation is as per Example 1 but without active ingredient)

5. VEN 32/M/50 - tablets of venlafaxine hydrochloride according to the invention (Example 1) (ground and prepared for XRPD)

6. T50 Kbr. 4835036 START - tablets of venlafaxine hydrochloride according to the invention (Example 1) (ground and prepared for XRPD) (different batch to sample 5)

7. Venlafaxine hydrochloride monohydrate reference standard

The results are shown in Figures 1-6.

Figure 1 shows the X-ray powder diffraction pattern for sample 3 (RS1794 Ser.02)

Figure 2 shows the X-ray powder diffraction pattern for sample 5 (VEN 32/M/50)

Figure 3 shows the X-ray powder diffraction pattern for sample 6 (T50 Kbr. 4835036 START)

Figure 4 shows a comparison of the X-ray powder diffraction patterns for samples 2

(WOBMUV01) (top trace), 1 (WOBMUV) (middle trace) and 3 (RS1794 Ser.02) (bottom trace).

Figure 5 shows a comparison of the X-ray powder diffraction patterns for samples 2 (WOBMUV01) (top trace), 1 (WOBMUV) (second trace from top), 3 (RS1794 Ser.02)

(third trace from top), 5 (VEN 32/M/50) (fourth trace from top) and 4 (VEN32/M

PLACEBO) (bottom trace).

Figure 6 shows a comparison of the X-ray powder diffraction patterns for samples 4

(VEN32/M PLACEBO) (top trace), 5 (VEN 32/M/50) (second trace from top), -2 (WOBMUV01 ) (third trace from top), 3 (RS1794 Ser.02) (fourth trace from top), and 7

(venlafaxine hydrochloride monohydrate reference standard) (bottom trace).

In comparing the X-ray powder diffraction patterns of venlafaxine hydrochloride anhydrate Form I RS1794 Ser.02 with the X-ray powder diffraction pattern of venlafaxine hydrochloride anhydrate Form Il (WOBMUV01), it was concluded that the working standard venlafaxine hydrochloride corresponds to venlafaxine hydrochloride anhydrate Form I without presence of venlafaxine hydrochloride anhydrate Form Il (Fig.

4.)

Also, in comparing the X-ray powder diffraction patterns of formulations according to the invention (VEN32/M/50 and Kbr. 4835036) with patterns of PLACEBO and reference products, it was concluded that formulation according to the invention is composed of venlafaxine hydrochloride anhydrate Form I as active compound without the presence of Form Il or monohydrate (Fig. 3, 5 and 6). In particular the characteristic peaks of 2Theta 8.40° and 7.45° (corresponding to Form Il and monohydrate respectively) were missing.

Analytical Example 2

In order to compare the dissolution profile of tablets according to the invention with the reference product (Effexor™ IR), dissolution studies were performed.

Dissolution profiles of the formulation of venlafaxine hydrochloride anhydrate Form I tablets 50mg (prepared according to the method of Example 1) were tested using the Dissolution Test in media over the physiological pH range (pH 1.2, pH 4.5 and pH 6.8) of the gastrointestinal tract. The results are shown in Figures 7-9. Results of the dissolution studies performed in water as a recommended dissolution medium are presented in Figure 10.

Figure 7 shows comparative dissolution profiles of venlafaxine released from venlafaxine hydrochloride tablets 50 mg (B. No. VEN 32/M/50) and Effexor™ IR Tablets 50 mg. Method USP apparatus II, 50 rpm, 900 ml of dissolution medium at pH 1.2.

Figure 8. Comparative dissolution profiles of venlafaxine released from venlafaxine hydrochloride tablets 50 mg (B. No. VEN 32/M/50) and Effexor™ IR tablets 50 mg. Method USP apparatus II, 50 rpm, 900 ml of dissolution medium at pH 4.5. Figure 9. Comparative dissolution profiles of venlafaxine released from venlafaxine hydrochloride tablets 50 mg (B. No. VEN 32/M/50) and Effexor™ IR tablets 50 mg Method USP apparatus II, 50 rpm, 900 ml of dissolution medium at pH 6.8.

Figure 10. Comparative dissolution profiles of venlafaxine released from venlafaxine hydrochloride tablets 50 mg (B. No. VEN 32/M/50) and Effexor™ IR tablets 50 mg. Method USP apparatus II, 50 rpm, 900 ml of deionised water as the dissolution medium.

Each point in each of Figures 7-10 indicates the mean value of data obtained for 6 tablets.

Figures 7-10 demonstrate satisfying similarity in dissolution profiles of the formulation of venlafaxine hydrochloride tablets according to the invention and the reference product in all the dissolution media used. As can be see from the Figures, the formulation according to the invention and the reference released at least 80% of the active ingredient within 30 minutes under all tested conditions and are thus determined to have immediate release characteristics.

Analytical Example 3 Particles prepared essentially according to Preparative Example 1 were viewed using scanning electron microscopy.

Figure 11 shows a Scanning Electron Microscope (SEM) picture for a first sample of particles of venlafaxine hydrochloride anhydrate Form I produced essentially as per Preparative Example 1

Figure 12 shows the SEM picture for a second sample of particles of venlafaxine hydrochloride anhydrate Form I

Figure 11 shows plate like crystals having an aspect ratio of less than 1 :4.

Figure 12 shows needle like crystals having an aspect ratio of greater than 1:4. Comparative Examples

Comparative Example 1

prepared essentially according to the method of Preparative Example 1

This formulation resembles the formulation of Effexor™ IR as shown in the SmPC

(Wyeth).

Tablets were prepared by directly compressing the formulation above.

Tablets suffered from lamination problems.

This comparative example shows that use of microcrystalline cellulose as the main filler is not satisfactory in venlafaxine hydrochloride anhydrate Form I tablets.

Tablets were prepared by directly compressing the formulation above. Tablets suffered from lamination problems. This comparative example shows that use of mannitol as the filler does not solve the problem of lamination shown with cellulose as the main filler in venlafaxine hydrochloride anhydrate Form I tablets.

Addition of the binder hydroxypropyl cellulose (KLUCEL™) in the formulations presented above (2% KLUCEL used in place of 2% of the mannitol) was considered as a possible solution of laminating problem, but no improvement was observed. This shows that the use of a cellulose derivative as binder in conjunction with mannitol as filler is also inadequate.

Comparative Example 3

prepared essentially according to the method of Preparative Example 1

Tablets were prepared by directly compressing the formulation above. Again, lamination of tablets was observed. This shows that the use of cellulose in conjunction with calcium hydrogen phosphate as filler is also inadequate. Comparative Example 4

A formulation was prepared as follows:

prepared essentially according to the method of Preparative Example 1

Tablets were prepared by directly compressing the formulation above.

This formulation, when manufactured on a small scale, did not suffer capping or lamination problems, however the dissolution rate were a little higher than the reference product.

Comparative Example 5

A formulation was prepared as follows:

prepared essentially according to the method of Preparative Example 1 Tablets were prepared by directly compressing the formulation above. This product corresponds to Comparative Example 4 except that copolyvidone has been added. As a result the dissolution profile has been slightly retarded and closely matches that of the reference product. However whereas satisfactory tablets could be produced on a small scale, on scale-up the tablets seemed to have problems with flowability when released from the rotary press and analysis performed on the manufactured product implied that segregation of the tabletting mixture had occurred.

All references referred to in this application, including patents and patent applications, are incorporated herein by reference to the fullest extent possible.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:

Claims

1. A pharmaceutical formulation comprising: (i) 20-40% w/w venlafaxine hydrochloride anhydrate Form I as active ingredient; (ii) 57-79.75% w/w filling and binding component comprising lactose, starch and a vinylpyrrolidone containing polymer; and (iii) 0.25-3% w/w lubricant.

2. A formulation according to claim 1 wherein lactose is present in the formulation at a concentration of 29-65.75% w/w.

3. A formulation according to claim 1 or claim 2 wherein the lactose is lactose monohydrate.

4. A formulation according to any one of the preceding claims wherein the starch is present in the formulation at a concentration of 10-20% w/w.

5. A formulation according to any one of the preceding claims wherein the starch is com starch.

6. A formulation according to any one of the preceding claims wherein the vinylpyrrolidone containing polymer is present in the formulation at a concentration of 4-8% w/w.

7. A formulation according to any one of the preceding claims wherein the vinylpyrrolidone containing polymer is selected from polyvinylpyrrolidone and co-polymers of vinylpyrrolidone and vinyl acetate.

8. A formulation according to any one of the preceding claims further comprising a lubricant.

9. A formulation according to claim 8 wherein magnesium stearate is present as lubricant.

10. A formulation according to any one of the preceding claims further comprising a disintegrant.

11. A formulation according to claim 10 wherein the disintegrant is present at a concentration of 0.25-3% w/w.

12. A formulation according to claim 10 or claim 11 wherein the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, powdered cellulose and microcrystalline cellulose.

13. A formulation according to any one of the preceding claims further comprising an anti-adherent.

14. A formulation according to claim 13 wherein the anti-adherent is present at a concentration of 0.5-3% w/w.

15. A formulation according to claim 13 or claim 14 wherein the anti-adherent is selected from the group consisting of colloidal silicon dioxide, talc and magnesium trisilicate.

16. A formulation according to any one of the preceding claims further comprising a colouring agent.

17. A formulation according to any one of the preceding claims which releases at least about 80% of the active ingredient from a direct compression tablet within about 30 minutes in the Dissolution Test.

18. A formulation according to claim 1 having a composition substantially corresponding to Example 1 or Example 2.

19. A formulation, as claimed in any claim from 1 to 18, which is in the shape of a tablet and is made by a direct compression process.

20. A method of treating a disorder susceptible to serotonin noradrenalin reuptake inhibitor therapy which comprises administering to a patient a formulation according to any one of claims 1 to 19.

21. Use of a formulation according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment of a disorder susceptible to serotonin noradrenalin reuptake inhibitor therapy.

22. A process for preparing a pharmaceutical formulation according to any one of claims 1 to 18 which comprises intimately mixing the ingredients in a water free environment.

23. A process for preparing a tablet which comprises compressing a mixture of ingredients as defined in any one of claims 1 to 18.

24. Particles of venlafaxine hydrochloride anhydrate Form I having an aspect ratio of between 1 : 1 and 1 :4.

25. A population of particles of venlafaxine hydrochloride anhydrate Form I in which more than 50% of particles by number have an aspect ratio of between 1 :1 and 1 :4.

26. A population of particles according to claim 25 having a D90 of not more than around 450 microns and a D10 of not more than around 20 microns, as determined using a light scattering method.

27. A formulation comprising a population of particles of venlafaxine hydrochloride anhydrate Form I according to claim 26 together with one or more pharmaceutically acceptable diluents or carriers.

28. A formulation, as claimed in claim 27, which is in the form of a tablet and is made by a direct compression process.

29. A method of treating a disorder susceptible to serotonin noradrenalin reuptake inhibitor therapy which comprises administering to a patient a formulation according to claim 27 or claim 28.

30. Use of a formulation according to claim 27 or claim 28 in the manufacture of a medicament for the treatment of a disorder susceptible to serotonin noradrenalin reuptake inhibitor therapy.