MXPA06008933A - Multiparticulate o-desmethylvenlafaxine salts and uses thereof - Google Patents

Abstract

A multiparticulate O-desmethylvenlafaxine (ODV) succinate or formate is described. Methods of treating depression and reducing the gastrointestinal side-effects of ODV are also described.

Description

SALTS OF O-DESMETILVENLAFAXINA IN MULTI PARTÍ CU THE AND USES OF THE SAME ANTECEDENTS OF THE APPLICATION O-demethylvenlafaxine (ODV), the main metabolite of venlafaxine, selectively blocks the reuptake of serotonin and norepinephrine. Klamerus, K. J. et al., "Introduction of the Composite Parameter to the Pharmacokineticsof Venlafaxine and its Active O-Desmethyl Metabolite", J. Clin Pharmacol. 32: 716-724 (1992). O-demethyl-venlafaxine, chemically named as 1- [2- (dimethylamino) -1- (4-phenol) ethyl] -cyclohexanol, was exemplified as a fumarate salt in the U.S. patent. No. 4,535,186. However, the fumarate salt of O-demethyl-venlafaxine has inadequate physicochemical and permeability characteristics. O-demethyl-venlafaxine is also exemplified as a free base in International Patent Publication No. WO 00/32555. The succinate form of ODV has been described [patent of E.U.A. 6,673,838]. The ODV monohydrate succinate form has been incorporated into an extended release hydrogel gel, which reduces adverse effects such as nausea, vomiting, diarrhea, and abdominal pain. Formulations describing the use of hydroxypropylmethylcellulose (HPMC) as the hydrogel matrix have been described [WO 02/064543 A2].

However, it has been observed that the effects of the hydrogel formulation are variable when the ODV hydrogel tablet is given with food.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a multi-particle form of ODV that reduces the undesirable characteristics related to ODV and the hydrogel formulation thereof. These ODV multiparticles are composed of ODV succinate, ODV formate, or combinations thereof. Advantageously, this formulation also allows a more convenient dose for patients who have difficulty in swallowing solid foods.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a multiparticulate formulation of an O-desmethylvenlafaxine (ODV) containing a multiparticulate form of ODV succinate (DVS), ODV formate (DVF), or combination thereof. The use of a multiparticulate formulation facilitates the dose in pediatric patients, geriatric patients, and patients who have problems swallowing, by supplying the spheroids in a liquid in suspension or by spraying / dispersing in a low pH liquid such as apple puree. , before the administration. The smallest size of the multiparticles, in a capsule or small sac or any other container, also allows the dose through a nasogastric or gastrostomy tube. Suitably, the multiparticulate ODV is a spheroid, bead, or pellet, which is generally on the scale of about 0.6 mm to about 1 mm in size. However, this may vary in size, without departing from the present invention. The multi-particle ODV of the invention is composed, at a minimum, of a core composed of DVS, DVF or a combination thereof, and one or more diluents, binders, fillers, glidants, anti-adherents, a pH adjuster and / or an adjuvant. The DVS is prepared as described in the US patent. 6,673,383, which is incorporated by reference herein. ODV formate salt (DVF), described in the patent application of E.U.A. published Publication No. US 2003/0236309, which is incorporated by reference herein, may be prepared using similar techniques by substitution of the appropriate salt. The multiparticulate core contains from about 3% w / w to about 70% w / w DVS and / or DVF. In other embodiments, the DVS or DVF can range from about 5% w / w to about 60% w / w, from about 10% w / w to about 50% w / w, from about 20% w / w to about 40%. % p / p, or from about 25% w / w about 35% w / w, from about 30% w / w about 45% w / w, or from about 32% to about 44% w / w, based on 100% by weight of the uncoated do form. Suitably, the total amount of diluent, binders, fillers, glidants, anti-adherents, and adjuvants present in the core is an amount from about 30% w / w to about 97% w / w of the multiparticulate core. For example, when present, a binder, diluent and / or filler each may be present in an amount of about 15% w / w about 80% w / w, or about 20% w / w about 70% p / p, or about 25% w / w about 45% w / w, or about 30% w / w about 42% w / w of the uncoated do form. The total amount of a pH adjuster in the formulation can range from about 0.1% w / w to about 10% w / w of the core, or from about 1% w / w to about 8% w / w, or from about 3% p / pa approximately 7% p / p. However, these percentages may be adjusted as necessary or desired by one skilled in the art. The binder can be selected from other known binders, including, for example, cellulose, and povidone, among others. In one embodiment, the binder is selected from microcrystalline cellulose, crospovidone and mixtures thereof. Suitable pH adjusters include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium carbonate, among others. Even other suitable components will be readily apparent to one skilled in the art. In one embodiment, the DVS and / or DVF is a sustained release formulation containing speed control components. Typically, said speed control components are speed control polymers selected from hydrophilic polymers and inert plasticized polymers. Suitable hydrophilic rate control polymers include, without limitation, polyvinyl alcohol (PVA), hypomellose, and mixtures thereof. Examples of suitable inert or insoluble "plastic" polymers include, without limitation, one or more polymethacrylates (ie, Eudragit® polymer). Other speed control polymer materials include, for example, hydroxyalkyl celluloses, polyethylene oxides, alkyl celluloses, carboxymethyl celluloses, hydrophilic cellulose derivatives, and polyethylene glycol. In one embodiment, an ODV multiparticulate of the invention contains about 5% w / w about 75% w / w microcrystalline cellulose (MCC), from about 10% w / w to about 70% w / w MCC, about 20% w / w about 60% w / w, or about 30% w / w about 50% w / w, based on the weight of the uncoated dose unit. In one embodiment, the core containing DVS or DVF in multiparticles is not coated. The multiparticles can be placed in a suitable capsule shell or compressed into tablets, using techniques known to those skilled in the art. Suitably, the resulting capsule or tablet shell contain 10 mg to 400 mg of ODV. In other embodiments, the multiparticulate ODV contains one or more coatings on the core. In still other embodiments, the multiparticulate consists of a pellet core and a non-functional sealing layer and a second functional coating. In one embodiment, an initial sealing layer can be applied directly to the core. Although the components of this sealing layer may be modified by one skilled in the art, the sealing layer may be selected from suitable polymers such as hydroxypropylmethylcellulose (HPMC), ethylcellulose, polyvinyl alcohol, and combinations thereof, optionally containing plasticizers, and other desirable components. A particularly suitable sealing layer contains HPMC. For example, a suitable sealing layer can be applied as a HPMC solution in a concentration of about 3% w / w to 25% w / w, and preferably 5% w / w to about 7.5% w / w. After drying, under suitable conditions, the initial sealing layer is on the scale of about 1% w / w to about 3% w / w, or about 2% w / w, of the uncoated multiparticulate. In another embodiment, a commercially available sealing layer containing HPMC is used, among other inert components. Said commercially available sealing layer is Opadry® Clear (Colorcon, Inc.).

Optionally, the multiparticle may contain an additional coating layer on the initial seal layer, if present, or directly to the uncoated multiparticulate ODV core, to provide a delayed release formulation. These formulations can also decrease the incidence of side effects, including nausea, vomiting, and irritable bowel syndrome. Without wishing to be limited by theory, it is believed that these side effects are avoided by diverting the release into the upper Gl tract and providing release in the lower Gl tract. An enteric coating (speed control film) can be applied to the multiparticulates and can include, but is not limited to polymethacrylates, hypomellose, and ethylcellulose, or a combination thereof. The modified release multiparticulate formulation may contain from about 3% w / w to about 70% w / w DVS, DVF, or a combination thereof, and from about 5% w / w to about 75% w / w of microcrystalline cellulose, based on the weight of an uncoated dosage form. In one embodiment, the enteric coating contains a product that is a copolymer of methacrylic acid and methacrylates, such as commercially available Eudragit® L 30 K55 (Rohm GmbH &Co. KG). Suitably, this enteric coating is applied so as to review the multiparticulate in an amount of about 15 to 45% w / w, or about 20% w / w to about 30% w / w, or about 25%. % p / pa approximately 30% w / w of the multiparticulate not coated or initially coated. In one embodiment, the enteric coating is composed of a co-polymer of Eudragit® L30D-55 (Rohm, GmbH &Co. KG), talc, triethyl citrate, and water. More particularly, the enteric coating may contain about 30% w / w of a 30% by weight dispersion of Eudragit® L 30 D55 coating; about 15% w / w of talc, about 3% of triethyl citrate, a pH adjuster such as sodium hydroxide and water. In another embodiment, the enteric coating contains an ethylcellulose-based product, such as the commercially available aqueous Surelease® ethylcellulose dispersion product (25% solids) (Colorcon, Inc.). In one embodiment, a solution of the Surelease® dispersion of about 3% w / w about 25% w / w, and preferably from about 3% to about 7%, or about 5% w / w, is applied to the multiparticle. After drying under suitable conditions, the enteric coating is in the range of about 2% to about 5%, or from about 3% to about 4% w / w of the multiparticulate initially coated or uncoated. In one embodiment, the enteric coated multiparticulate is further coated with a final sealing layer. Suitably, this final sealing layer is composed of HPMC and water, after drying, is less than about 1% by weight of the total coated multiparticulate.

II. Method for Producing Multiparticle Formulations of the Invention The multiparticle formulations of the invention can be prepared using techniques described herein, as well as methods known to those skilled in the art. In one embodiment, the uncoated ODV multiparticles are prepared in the following manner. The dry components, including at least the DVS and / or DVF and the binder, are dry mixed in a suitable mixer, for example, a Hobart mixer. Optionally, HPMC and a pH adjuster can be included in this step. Subsequently, the liquid components, for example, the surfactant and water, are mixed to produce a granulated product. The granulation is then extruded and spheronized through a suitable device (e.g., a Nica extruder / spheronizer) and the resulting spheroids are dried, filtered, and optionally mixed before storage. In another embodiment, the uncoated ODV multiparticles are prepared in the following manner. The DVS and the binder are combined and granulated with water in a planetary mixer, such as a Hobart mixer. Subsequently using the Nica® system the resulting wet mass is extruded through a 1 mm sieve. The extruded products are then transferred to a spheronizer and rotated until spherical pellets are obtained (approximately 2 to 3 minutes). The wet pellets are then dried in an Aeromatic Strea ™ fluid bed dryer at a moisture level of 2% to 5%. The dried pellets are then passed through a mesh screen to remove the larger pellets. Optionally, an initial sealing layer can be applied to the uncoated multiparticulates. For example, an initial seal layer may be applied in a fluid bed coater, for example, by spraying. In one embodiment, an Aeromatic Strea ™ fluid bed apparatus is fitted with a Wurster column and a lower spray nozzle system. Approximately 200 grams of dry pelleted cores are loaded into the unit. The Opadry® Clear sealing layer is applied with an inlet temperature of approximately 50 ° C to 60 ° C, a coating solution spray speed of 5 to 10 grams / minute, spray pressure of 1 to 2 bar. The desired temperature of the product is 35 ° C to 45 ° C, and preferably 38 ° C to 43 ° C. The enteric coating can be applied directly to the uncoated spheroid, i.e., the uncoated multiparticulate, or it can be applied over an initial sealing layer. The enteric coating, as described above, is typically applied in a fluid bed coater. In one embodiment, the Surelease® aqueous ethylcellulose dispersion (25% solids) is applied in a similar manner as the sealing layer. After the ethyl cellulose coating is applied, the pellets are dried for an additional 5 to 10 minutes. Subsequently, they are removed and sieved through a mesh screen to remove agglomerates and larger particles.

In one embodiment, a final seal layer is applied over the enteric coating and, optionally, talc is used as a final step before filling the multiparticulates into a suitable packing unit. lll. Formulations / equipment / delivery methods In another embodiment, the present invention provides products that contain the ODV multiparticles of the invention. In one modality, ODV mutliparticles are packaged for use by the patient or their health professional. For example, the multiparticles can be packaged in a thin sheet or other suitable package and are suitable for mixing in a food product (eg, applesauce or the like) or in a beverage for consumption to be consumed by the patient. In another embodiment, the ODV multiparticles are suspended in a physiologically compatible suspension liquid. For oral liquid pharmaceutical compositions, pharmaceutical carriers and excipients may include, but are not limited to water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like. In yet another embodiment, the ODV multiparticles are filled into capsules, tablets or the like for oral delivery. In another embodiment, the present invention provides the use of multiparticulate formulations of the invention in the preparation of medicaments, including but not limited to drugs useful in the treatment of depression, gastrointestinal side effects of venlafaxine in a subject undergoing treatment therewith. , and irritable bowel syndrome. In another embodiment, the present invention provides the use of multiparticle formulations of the invention in the preparation of medicaments for delivery to a pediatric or geriatric patient. In other embodiments, the present invention provides the use of multiparticulate formulations of the invention in the preparation of dosage units, including but not limited to dosage units for oral, transdermal or mucosal administration. Also encompassed by the invention are pharmaceutical packages and equipment comprising a container, such as a thin film package or other suitable container, having a formulation of the invention in a unit dosage form. In even a further embodiment, the invention provides a method for treating a subject in need thereof by administering an effective dose of ODV multiparticles of the invention. The formulations of the invention are useful in the treatment of depression, anxiety, panic disorder, generalized anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, fibromyalgia, agoraphobia, attention deficit disorder, obsessive-compulsive disorder, of social anxiety, autism, schizophrenia, obesity, anorexia nervosa, bulimia nervosa, Gilles de la Tourette syndrome, vasomotor tension, addition to cocaine and alcohol, sexual dysfunction, borderline personality disorder, chronic fatigue syndrome, urinary incontinence, pain, Shy Drager syndrome, Raynaud's syndrome, Parkinson's disease and epilepsy. These formulations are also useful for improving the sensation or treating cognitive impairment in a patient, for quitting smoking or other uses of tobacco in a patient, treating hypothalamic amenorrhea in a depressed or non-depressed woman, decreasing the incidence of nausea, vomiting, diarrhea, abdominal pain, headache, or vasovagal discomfort or trismus that results from the oral administration of O-desmethylvenlafaxine succinate. Suitably, the multiparticulate ODV of the invention can reduce the gastrointestinal side effects of venlafaxine in a subject undergoing treatment therewith which comprises administering to the patient a formulation of the invention. An effective amount of the multiparticle of the invention is an amount sufficient to prevent, inhibit or alleviate one or more symptoms of the aforementioned conditions. The amount of dose useful to treat, avoid, inhibit or alleviate each of the aforementioned conditions will vary with the severity of the condition to be treated and the route of administration. The dose, and dose frequency will also vary according to the age, body weight, response and past medical history of the individual human patient. In general, the recommended daily dose scale for the conditions described herein are within the range of 10 mg to about 1000 mg of DVS or DVF per day and more preferably within the range of about 15 mg to about 350. mg / day and even more preferably from about 15 mg to about 140 mg / day. In other embodiments of the invention, the dose will range from about 30 mg to about 90 mg / day. The dose is described in terms of the free base and is also adjusted for the succinate salt. To treat the patient, it is generally preferred that the therapy be started at a lower dose and increased if necessary. Doses for non-human patients can also be adjusted by one skilled in the art. The DVS or DVF multiparticles can also be provided in combination with other active agents including, for example, venlafaxine. The dose of venlafaxine is preferably from about 75 mg to about 350 mg / day and more preferably from about 75 mg to about 225 mg / day. Even more preferably the dose of venlafaxine is from about 75 mg to about 150 mg / day. The ratio of DVS and / or DVF multiparticles will vary from patient to patient depending on the speed of response of the patient, but will generally be at least 6: 1 salt of ODV to venlafaxine. Venlafaxine or another active agent delivered in a regimen with the multiparticle of the invention can be formulated together with the multiparticle of the invention, or be supplied separately. Any suitable route of administration can be used to provide the patient with an effective amount of ODV multiparticle. For example, oral, mucosal (eg, nasal, sublingual, buccal, rectal or vaginal), parenteral (eg, intravenous or intramuscular), transdermal or subcutaneous routes can be employed. Preferred routes of administration include oral, transdermal and mucosal. The DVS and / or multiparticulate ODF can be combined with a pharmaceutical carrier or excipient (eg, acceptable pharmaceutical carriers and excipients) according to a conventional pharmaceutical compounding technique to form a pharmaceutical composition or dosage form. Suitable pharmaceutically acceptable carriers and excipients include, but are not limited to, those described in Remington's, The Science and Practice of Pharmacy, (Gennaro, AR, ed., 19th edition, 1995, Mack Pub. Co.) which are incorporated herein by reference. the present by reference. The phrase "pharmaceutically acceptable" refers to additives or compositions that are physiologically tolerable and do not typically produce a similar adverse or allergic reaction, such as gastric disturbance, vertigo and the like, when administered to an animal, such as a mammal (e.g. , a human). Oral solid pharmaceutical compositions may include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents. The pharmaceutical composition and dosage form may also include venlafaxine or a salt thereof as discussed above.

The following examples illustrate exemplary dosage forms of the multiparticulate ODV of the invention, and the use thereof. These examples are not a limitation of the present invention.

EXAMPLE 1 ODV succinate (DVS) formulations in multiparticles Form A of multiparticulate dose Ingredient mg / 300 mg% w / w DVS 151.75 (100 as free base of 50.58 ODV) Microcrystalline cellulose 148.25 49.42 Total 300 100.00 Form B of multiparticulate dose Ingredient mg / 300 mg% p / p DVS 151.75 (100 as free base of 50.58 ODV) Hypomellose 75.0 25.00 Microcrystalline cellulose 73.25 24.42 Total 300 100.00 EXAMPLE 2 Formulations of ODV formate (DVF) in multiparticles Form A dose for DVF Ingredient mg / 300 mg% p / p DVF 118.3 (100 as free base of 39.43 ODV) Microcrystalline cellulose 181.7 60.57 Total 300 100.00 Form B of multiparticulate dose for DVF Ingredient mg / 300 mg% w / w DVF 118.3 (100 as free base of 39.43 ODV) Hypomellose 90.85 30.28 Microcrystalline cellulose 90.85 30.28 Total 300 100.00 The multiparticulate formulation is anticipated to provide a therapeutically effective plasma level sustained for at least a period of 16 to 20 hours. Similar to the hypomellose tablet model (see, U.S. Patent 6,673,838 and E.U.A. 6,274,171), the time to reach the maximum plasma levels (Tmax) is expected to be generally three to ten hours, more preferably 6 to 9 hours. The Tmax is critical for the reduction in adverse effects such as nausea and vomiting when deriving receptors in the upper Gl tract, which are responsible for these effects adverse. In addition, increases in the Cmax (peak concentration) and AUC (total area under the concentration-time curve) observed with the hypomellose picture in the fed state will not be observed in the multiparticle formulation due to the faster elimination from the stomach accompanied by a smaller amount of dissolved drug that passes from the stomach to the upper Gl tract. The multiparticulate formulation will also demonstrate a reduction in patient-to-patient variability as well as a dose-to-dose variability due to the fact that they can easily pass through the pylorus while a hypomelous picture can be difficult, especially after it has occurred the intake of a tablet. The modified release pellet formula also demonstrates a reduction in nausea, vomiting, diarrhea, abdominal pain, headache, and vaso-vaginal discomfort, and / or trismus.

EXAMPLE 3 Preparation of a multiparticulate formulation of coated desvenlafaxine succinate (DVS) The manufacture of the multiparticle core was as follows. The desvenlafaxine succinate (DVS) is combined with microcrystalline cellulose and granulated with water in a planetary mixer. Subsequently using the Nica® system, the resulting moisture mass is extruded through a 1 mm sieve. The extruded DVS products are then transferred to the spheronizer and rotated at about 700 rpm until spherical pellets are obtained (2-3 minutes). The wet pellets are then dried in an Aeromatic Strea ™ fluid bed dryer at a moisture level of 2% to 5%. The dried pellets are passed through an 18 mesh screen to remove the larger pellets. The pellets are now ready for the coating procedure.

Coating Sealing layer The Aeromatic Strea ™ fluid bed apparatus is fitted with a Wurster column and a lower sprinkler nozzle system. Approximately 200 grams of dry pelleted cores are loaded into the unit. The Opadry® sealing layer is applied with an inlet temperature of approximately 60 ° C, a coating solution spray rate of 5-10 grams / minute, atomization pressure of 1 -2 bar. The desired product temperature is 38 ° C-43 ° C. After approximately 2% by weight gain of the sealing layer is achieved, the ethylcellulose coating can be applied.

Coating of ethylcellulose The ethylcellulose is applied in a similar manner as the sealing layer at a weight gain of 3-4%. After the ethyl cellulose coating is applied, the pellets are dried for an additional 5-10 minutes. They are removed and sieved through an 18 mesh screen to remove agglomerates and larger particles.

Dissolving test of coated DVS multiparticles The resulting coated multiparticulates were tested in vitro for the release rate of DVS-233. Pellets containing DVS multiparticles having an active amount equivalent to 150 mg of desvenlafaxine were tested using an I USP apparatus, the baskets at 10 rpm. The dissolution medium was 0.9% NaCl at 37 ° C. The results show that the product in multiparticles of Uncoated DVS provides immediate release (<1 hour) that was sustained for at least 24 hours. The coated DVS multiparticulate product had liberation released [50% release after 2 hours, < 70% release after 4 hours, and > 90% release after 8 hours] with maximum levels of sustained release achieved after 20 hours.

EXAMPLE 4 Formulation of ODV succinate (DVS) in multiparticles Does not appear in the final product The present invention is not limited in scope by the specific embodiments described herein. Various modifications to these modalities will be obvious to a person skilled in the art from the description. Such modifications fall within the scope of the appended claims. Patents, patent applications, publications, procedures and the like are cited through the application. The descriptions of these documents are incorporated by reference herein in their entirety. To the extent that there may be a conflict between the specification and a reference, what governs is the language of the description made in the present.

Claims (29)

NOVELTY OF THE INVENTION CLAIMS

1. - A multiparticulate formulation of an O-demethylvenlafaxine (ODV) comprising a multiparticulate form of ODV succinate and / or an ODV formate.

2. The formulation according to claim 1, further characterized in that said multiparticulate formulation is a sustained release formulation or a delayed release formulation.

3. The formulation according to claim 1 or claim 2, further characterized in that said formulation comprises spheroids, beads or pellets of an ODV.

4. The formulation according to claim 3, further characterized in that the pellets are from about 0.6 mm to about 1 mm in size.

5. The formulation according to any of claims 1 to 4, further characterized in that the multiparticulates further comprise speed control polymers.

6. The formulation according to claim 5, further characterized in that the speed control polymers are selected from the group consisting of hydrophilic polymers and inert plasticized polymers.

7. - The formulation according to claim 1, further characterized in that the multiparticulates further comprise a diluent, filler, slip, non-stick, and / or adjuvant.

8. The formulation according to any of claims 1 to 7, further characterized in that the multiparticles comprise a film coating.

9. The use of a composition comprising a multiparticulate formulation of an ODV succinate or formate according to any of claims 1-8 for the preparation of a medicament for treating depression in a subject.

10. The use of a composition comprising a multiparticulate formulation of an ODV according to any of claims 1-8 for the preparation of a medicament for reducing the gastrointestinal side effects of venlafaxine in a subject.

11. A modified multiparticulate release formulation comprising from about 3% w / w to about 70% w / w succinate or O-demethylvenlafaxine formate and from about 5% w / w to about 75% w / w macrocrystalline cellulose.

12. The modified release formulation according to claim 11, further characterized in that the multiparticulate further comprises a sealing layer.

13. - The modified release formulation according to claim 12, further characterized in that the sealing layer comprises hydroxypropylmethylcellulose.

14. The modified release formulation according to any of claims 11-13, further characterized in that the multiparticulate further comprises an enteric coating selected from polymethacrylates, hypomellose, ethylcellulose and combinations thereof.

15. The modified release formulation according to claim 14, further characterized in that the enteric coating comprises ethylcellulose.

16. The use of a modified formulation according to any of claims 11-15 for the preparation of a medicament for treating depression in a subject.

17. The use of a modified formulation according to any of claims 11-15 for the preparation of a medicament for reducing the gastrointestinal side effects of ODV in a subject.

18. A modified release venlafaxine product comprising 10 mg to 400 mg of multiparticulate O-desmethylvenlafaxine (ODV) succinate or formate.

19. - The product according to claim 18, which is a capsule shell containing said multiparticulate ODV succinate or formate.

20. The product according to claim 18, which is a compressed tablet comprising said multicomponent ODV succinate or formate.

21. The use of a product according to claim 18 for the preparation of a medicament for treating depression in a subject.

22. The use claimed in any of claims 18 to 20 for the preparation of a medicament for reducing gastrointestinal side effects related to venlafaxine in a patient.

23. A product comprising multiparticulate ODV succinate and / or formate.

24.- The product in accordance with claim 23, further characterized in that it comprises a thin film package comprising the multiparticulate ODV succinate and / or formate.

25.- A multiparticulate formulation of ODV formate or succinate that can be administered to patients through naso-gastric tubes, as a suspension or dispersed over semi-solid foods.

26.- The use of ODV formate or succinate for the preparation of a delayed-release multiparticulate formulation for the treatment of irritable bowel syndrome.

27. - Use of a formulation according to any of claims 1-8, 11-15, and 25-26, wherein the medicament will be administrable as a dosage unit.

28. The use as claimed in claim 27, wherein said dose unit is orally, transdermally or mucosally administrable.

29. A pharmaceutical package comprising a container having a formulation according to any of claims 1-8, 11-15 and 25-26 in a unit dosage form.