CA2199778C

CA2199778C - Extended release formulation of venlafaxine

Info

Publication number: CA2199778C
Application number: CA 2199778
Authority: CA
Inventors: Deborah Marie Sherman; John C. Clark; John U. Lamer; Stephen A. White
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 1996-03-25
Filing date: 1997-03-12
Publication date: 2005-12-20
Anticipated expiration: 2017-03-12
Also published as: SV1997000015A; EP0797991B1; JP2008156374A; EP0797991A1; ES2210454T3; AU1640097A; PL318954A1; HU224617B1; IL120382A; CN1403077A; CY2442B1; EG24198A; RU2176912C2; HUP9700589A3; UA44904C2; DK0797991T3; IN187337B; UY24613A1; HUP9700589A2; MX9701873A

Abstract

This invention relates to a 24 hour extended release dosage formulation and unit dosage form thereof of venlafaxine hydrochloride, an antidepressant, which provides better control of blood plasma levels than conventional tablet formulations which must be administered two or more times a day and further provides a lower incidence of nausea and vomiting than the conventional tablets.

Description

EXTENDED RELEASE FORMULATION OF VENLAFAXINE
Background of the invention Extended release drug formulations are conventionally produced as compressed tablets by hydrogel tablet technology. To produce these sustained release tablet drug dosage forms, the active ingredient. is conventionally compounded with cellulose ethers such as methyl cellulose, ethyl cellulose or hydroxypropylniethylcellulose with or without other excipients and the resulting mixture is pressed into tablets. When the tablets are orally administered, the cellulose ethers im the tablets swell upon hydration from moisture in the digestivc system, thereby limiting exposure of the active ingredient to moisture. As the cellulose ethers are gradually leached away by moisture, water more deeply penetrates the gel matrix and the active ingredient slowly dissolves and diffuses through .the gel, making it available for absorption by the body. An example of such a sustained release dosage form of the analgesic/antiinflammatory drug etodolac (Lodine~) appears in US patent 4,966,768. .
Where the production of tablets is not feasible, it is conventional in the drug industry to prepare encapsulated drug formulations which provide extended or sustained release properties. In this situation, the extended release capsule dosage fortes may be 2o formulated by mixing the drug with one or more binding agents to form a uniform mixture which is then moistened with water or a solvent such as ethanol to form an-extrudable plastic mass from which small diameter, typically 1 mm, cylinders of drug/matrix are extruded, chopped into appropriate lengths and transformed into spheroids using standard spheronization equipment. The spheroids, after drying, may then be film-coated to retard z5 dissolution. Gelatin capsules are filled with the film-coated spheroids in the quantity needed to obtain the desired therapeutic effect. Spheroids releasing the drug at different rates may be combined in a gelatin capsule to obtain desired release rates and blood levels.
US patent 4,138,4?5 discloses a sustained release pharmaceutical composition consisting of a hard gelatin capsule filled with film-coated spheroids comprised of propanolol in 3o admixture with rnicrocrystalline cellulose wherein the film coating is composed of ethyl cellulose, optionally with hydroxypropylmethylcellulose and/or a plasticizer.
Venlafaxine, 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol, is an important drug in the neuropharmacological arsenal used for treatment of depression.
Venlafaxine and the acid addition salts thereof are disclosed in US patent 4,535,186.
35 Venlafaxine hydrochloride is presently administered to adults in compressed tablet form in doses ranging from 75 to,350 mg/day , in divided doses two or three times a day. In therapeutic dosing with venlafaxine hydrochloride tablets, rapid dissolution results in a rapid increase in blood plasma levels of the active compound shortly after administration followed by a decrease in blood plasma levels over several hours as the active compound is eliminated or metabolized, until sub-therapeutic plasma levels are approached after about twelve hours following administration, thus requiring additional dosing with the drug.
With the plural daily dosing regimen, the most common side effect is nausea, experienced by about forty five percent of patients under treatment with venlafaxine hydrochloride.
Vomiting also occurs in about seventeen percent of the patients.
t o Brief Description of the Invention In accordance with this invention, there is provided an extended release (ER), encapsulated formulation containing venlafaxine hydrochloride as the active drug component, which provides in a single dose, a therapeutic blood serum level over a twenty 15 four hour period.
Through administration of the venlafaxine formulation of this invention, there is provided a method for obtaining a flattened drug plasma concentration to time profile, thereby affording a tighter plasma therapeutic range control than can be obtained with multiple daily dosing. In other words, this invention provides a method for eliminating the zo sharp peaks and troughs (hills and valleys) in blood plasma drug levels induced by multiple daily dosing with conventional immediate release venlafaxine hydrochloride tablets. In essence, the plasma levels of venlafaxine hydrochloride rise, after administration of the extended release formulations of this invention, for between about five to about eight hours ( optimally about six hours) and then begin to fall through a protracted, substantially linear zs decrease from the peak plasma level for the remainder of the twenty four hour period, maintaining at least a threshold therapeutic level of the dmg during the entire twenty-four period. In contrast, the conventional immediate release venlafaxine hydrochloride tablets give peak blood plasma levels in 2 to 4 hours. Hence, in accordance with the use aspect of this invention, there is provided a method for moderating the plural blood plasma peaks and 3o valleys attending the pharmacokinetic utilization of multiple daily tablet dosing with venlafaxine hydrochloride which comprises administering to a patient in need of treatment with venlafaxine hydrochloride, a one-a-day, extended release formulation of venlafaxine hydrochloride.
The use of the one-a-day venlafaxine hydrochloride formulations of this invention 35 reduces by adaptation, the level of nausea and incidence of emesis that attend the administration of multiple daily dosing. In clinical trials of venlafaxine hydrochloride ER, the probability of developing nausea in the course of the trials was greatly reduced after the first week. Venlafaxine ER showed a statistically significant improvement over conventional venlafaxine hydrochloride tablets in two eight-week and one 12 week clinical studies. Thus, in accordance with this use aspect of the invention there is provided a method for reducing the level of nausea and incidence of emesis attending the administration of venlafaxine hydrochloride which comprises dosing a patient in need of treatment with venlafaxine hydro-chloride with an extended release formulation of venlafaxine hydrochloride once a day in a therapeutically effective amount.
In accordance with one aspect, the present invention provides an extended release formulation of venlafaxine hydrochloride comprising a composition containing a thera-peutically effective amount of spheroids comprised of venlafaxine hydrochloride, micro-crystalline cellulose and hydroxypropylmethylcellulose, the spheroids being coated with a film coating comprising ethyl cellulose and hydroxypropylmethylcellulose.
Preferably, the extended release formulation of venlafaxine hydrochloride is for a once daily administration, and comprises spheroids containing 37.3% venlafaxine hydrochloride, 6:?.17%
microcrystal-line cellulose and 0.5% hydroxypropylmethylcellulose. The spheroids are coated with a quantity of a mixture comprised of 85% ethyl cellulose type and 15%
hydroxypropylmethyl-cellulose sufficient to give coated spheroids having a dissolution profile 'which gives the desired release rate over a 24 hour period.
In accordance with another aspect, the invention provides for a use of a formulation containing venlafaxine hydrochloride as the active ingredient for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with diminished incidences of nausea and emesis. The use comprises administering orally an extended release formula-tion that provides a peak blood plasma level of venlafaxine hydrochloride in from about 4 to about 8 hours.
In accordance with yet another aspect, the invention provides a film coating composi-tion which is composed of ethyl cellulose and hydroxypropylmethylcellulose.
Preferable, the film coating contains about 85% by weight of ethyl cellulose and about 15%
by weight of hydroxypropylmethylcellulose.

Detailed Description of the Invention 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride is polymorphic. Of the forms isolated and characterized to date, Form I is considered to be the kinetic product of crystallization which can be converted to Form II upon heating in the crystallization solvent. Forms I and II cannot be distinguished by their melting points but do exhibit some differences in their infrared spectra and X-ray diffraction patterns. Any of the polymorphic forms such as Form I or Form II may be used in the formulations of the present invention.
The extended release formulations of this invention are comprised of 1-[2-(dimethyl-amino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride in admixture with micro-crystalline cellulose and hydroxypropylmethylcellulose. Formed as beads or spheroids, the drug containing formulation is coated with a mixture of ethyl cellulose and hydroxypropyl-methylcellulose to provide the desired level of coating, generally from about two to about twelve percent on a weight/weight basis of final product or more preferably from about five to about ten percent (w/w), with best results obtained at from about 6 to about 8 percent (w/w). More specifically, the extended release spheroid formulations of this invention com-prise from about 30 to 40 percent venlafaxine hydrochloride, from about 50 to about 70 percent microcrystalline cellulose NF, from about 0.25 to about 1 percent hydroxypropyl-methylcellulose, USP, and from about 5 to about 10 percent film coating, all on a weight/
weight basis. And preferably, the spheroid formulations contain about 35 percent venlafaxine hydrochloride, about 55 to 60 percent microcrystalline cellulose NF (Avicel~
PH101), about one half percent hydroxypropylmethylcellulose 2208 USP (K3, Dow, which has a viscosity of 3 cps for 2% aqueous solutions, a methoxy content of 19-24% and a hydroxypropoxy content of 4-13%), and from about 6 to 8 percent film coating.
-3a-The film coating is comprised of 80 to 90 percent of ethyl cellulose, NF and 10 to 20 percent hydroxypropyl methylcellulose (2910), USP on a weightlweight basis.
Preferably the ethyl cellulose has a ethoxy content of 44.0-51 % and a viscosity of 50 cps for a 5% aqueous solution and the hydroxypropylmethylcellulose is USP 2910 having a s viscosity of 6 cps at 2% aqueous solution with a methoxy content of 28-30%
and a hydroxypropoxy content of 7-12%. The ethyl cellulose used herein is Aqualor~'HG 2834.
Other equivalents of the hydroxypropylmethylcelluloses 2208 and 2910 USP and ethyl cellulose, NF, having the same chemical and physical characteristics as the proprietary products named above may be substituted in the formulation without changing t o the inventive concept.
It was completely unexpected that an extended release formulation containing venlafaxine hydrochloride could be obtained because the hydrochloride of venlafaxine proved to be extremely water soluble. Numerous attempts to produce extended release tablets by hydrogel technology proved to be fruitless because the compressed tablets were ~s either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies. Typically, the tablets prepared as hydrogel sustained release formulations gave 40-50% dissolution at 2 hrs, 60-70% dissolution at 4 hrs and 85-100%
dissolution at 8 hrs.
Numerous spheroid formulations were prepared using different grades of 2o microcrystalline cellulose and hydroxypropyl methylcellulose, different ratios of venlafaxine hydrochloride and filler, different binders such as polyvinylpyrrolidone, methylcellulose, water, and polyethylene glycol of different molecular weight ranges in order to find a formulation which would provide a suitable granulation mix which could be extruded properly. In the extrusion process, heat buildup occurred which dried out the 2s extrudate so much that it was difficult to convert the extruded cylinders into spheroids.
Addition of hydroxypropylmethylcellulose 2208 to the venlafaxine hydrochloride-microcrystalline cellulose mix made production of spheroids practical.
The following examples are presented to illustrate applicant's solution to the problem of preparation of the extended release drug containing formulations of this 3o invention.
* trade-mark Example 1.
VENLAFAXINE HYDROCHLORIDE EXTENDED RELEASE AP UI E
A mixture of 44.8 parts ( 88.4 % free base) of venlafaxine hydrochloride, 74.6 parts of the microcrystalline cellulose, NF, and 0.60 parts of hydroxypropylmethyl cellulose 2208, USP, are blended with the addition of 41.0 parts water. The plastic mass of material is extruded, spheronized and dried to provide uncoated drug containing spheroids.
Stir 38.25 parts of ethyl cellulose, NF, HG2834 and 6.75 parts of hydroxypropyl methylcellulose 2910, USP in a 1:1 v/v mixture of methylene chloride and anhydrous to methanol until solution of the film coating material is complete.
To a fluidized bed of the uncoated spheroids is applied 0.667 parts of coating solution per part of uncoated spheroids to obtain extended release, film coated spheroids having a coating level of 3%.
The spheroids are sieved to retain the coated spheroids of a particle size between t5 0.85 mm to 1.76 mm diameter. These selected film coated spheroids are filled into hard gelatin capsules conventionally.
Example 2.
Same as for Example 1 except that 1.11 parts of the film coating solution per part of 2o uncoated spheroids is applied to obtain a coating level of 5%.
Example 3.
Same as for Example 1 except that 1.33 parts of the film coating solution is applied to 1 part of uncoated spheroids to obtain a coating level of 6%.
2s Example 4.
Same as for Example 1 except that 1.55 parts of the film coating solution is applied to 1 part of uncoated spheroids to obtain a coating level of 7%.
so The test for acceptability of the coating level is determined by analysis of the dissolution rate of the finished coated spheroids prior the encapsulation. The dissolution procedure followed uses USP Apparatus 1 (basket) at 100 rpm in purified water at 37°C.
Conformance with the dissolution rate given in Table 1 provides the twenty-four hour therapeutic blood levels for the dmg component of the extended release capsules of this 35 invention in capsule form. Where a given batch of coated spheroids releases drug too slowly to comply with the desired dissolution rate study, a portion of uncoated spheroids or spheroids with a lower coating level may be added to the batch to provide, after thorough mixing, a loading dose for rapid increase of blood drug levels. A
batch of coated spheroids that releases the drug too rapidly can receive additional film-coating to give the desired dissolution profile.
Table 1 Acceptable Coated Spheroid Dissolution Rates Time (hours) Average % Venlafaxine HCL released to 2 <30 24 >80 is Batches of the coated venlafaxine hydra;hloride containing spheroids which have a dissolution rate corresponding to that of Table I are filled into hard gelatin capsules in an amount needed to provide the unit dosage level desired. The standard unit dosage immediate release (IR) tablet used presently provides amounts of venlafaxine hydrochloride 2o equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg and 100 mg venlafaxine. The capsules of this invention are filled to provide an amount of venlafaxine hydrochloride equivalent to that presently used in tablet form and also up to about 150 mg venlafaxine hydrochloride.
Dissolution of the venlafaxine hydrochloride ER capsules is determined as directed in the U. S. Pharmacopoeia (USP) using apparatus 1 at 100 rpm on 0.9 L of water. A
25 filtered sample of the dissolution medium is taken at the times specified.
The absorbance of the clear solution is determined from 240 to 450 nanometers (nm) against the dissolution medium. A baseline is drawn from 450 nm through 400 nm and extended to 240 nm.
The absorbance at the wavelength of maximum absorbance (about 274 nm) is determined with respect to this baseline. Six hard gelatin capsules are filled with the theoretical amount of 3o venlafaxine hydrochloride spheroids and measured for dissolution. Standard samples consist of venlafaxine hydrochloride standard solutions plus a gelatin capsule correction solution. The percentage of venlafaxine released is determined from the equation % Venlafaxine hydrochloride released - (As)(Wr)(S)(V 1)(0.888)(100) (Ar)(V2)(C) Z ~ y ~~ ~ % U AHP-95011 where As is absorbance of sample preparation, Wr is weight of reference standard, mg; S
is strength of the reference standard, decimal; V 1 is the volume of dissolution medium used to dissolve the dosage form, mL; 0.884 is the percent free base, Ar is the absorbance of the standard preparation, V2 is the volume of reference standard solution, mL; and C is the capsule claim in mg.
Table 2 shows the plasma level of venlafaxine versus time for one 75 mg conventional Immediate Release (IR) tablet administered every 12 hours, two 75 mg extended release (ER) capsules administered simultaneously every 24 hours, and one 150 mg extended release (ER) capsule administered once every 24 hours in human male t o subjects. The subjects were already receiving venlafaxine hydrochloride according to the dosage protocol, thus the plasma blood level at zero time when dosages were administered is not zero.
_7_ Table 2 Plasma venlafaxine level (ng/mL) versus time, conventional tablet (not extended release) versus ER capsule Time (hours)75 mg 2 x 75 mg (ER)capsules1 x 150 mg (IR)tablet (ER)capsules (q 12 h) (q 24 hr) (q 24 h) 0 62.3 55.0 55.8 0.5 76.3 1 135.6 53.3 53.2 2 212.1 69.8 70.9 4 162.0 138.6 133.3 6 114.6 149.0 143.5 8 86.7 129.3 129.5 118.4 114.4 12 51.9 105.1 105.8 12.5 74.7 13 127.5 14 161.3 90.5 91.3 16 134.6 78.2 78.5 18 106.2 83.6 62.7 63.3 24 57.6 56.0 57.3 Table 2 shows that the plasma levels of two 75 mg/capsule venlafaxine hydrochloride ER capsules and one 150 mg/capsule venlafaxine hydrochloride ER
capsule provide very similar blood levels. The data also show that the plasma level after 24 hours for either extended release regimen is very similar to that provided by two immediate t o release 75 mg tablets of venlafaxine hydrochloride administered at 12 hour intervals.
Further, the plasma levels of venlafaxine obtained with the extended release formulation do not increase to the peak levels obtained with the conventional immediate release tablets given 12 hours apart. The peak level of venlafaxine from (ER) , somewhat _g_ G ~ 9 ~ I ~ U AHP_95011 below 150 ng/ml, is reached in about six hours, plus or minus two hours, based upon this specific dose when administered to patients presently under treatment with venlafaxine hydrochloride (IR). The peak plasma level of venlafaxine, somewhat over 200 ng/ml, following administration of (IR) is reached in two hours and falls rapidly thereafter.
s Table 3 shows venlafaxine blood plasma levels in male human subjects having a zero initial blood plasma level. Again, a peak blood plasma concentration of venlafaxine is seen at about 6 hours after dosing with venlafaxine hydrochloride extended release capsules in the quantities indicated. The subjects receiving the single 50 mg immediate release tablet showed a peak plasma level occurring at about 4 hours. For comparative purposes, the to plasma levels of venlafaxine for subjects receiving the conventional formulated tablet can be multiplied by a factor of three to approximate the plasma levels expected for a single dose of 150 mg. conventional formulation.
Table 3. Plasma Blood Levels in Human Males Having No Prior is Venlafaxine Blood Level Time (Hours) 1 x 50 mg IR tablet 2 x 75 mg ER 1 x 150 mg ER
capsules capsule 1 27.87 1.3 0 1.5 44.12 6.0 2.2 2 54.83 20.6 12.8 4 66.38 77.0 81.0 6 49.36 96.5 94.4 8 30.06 93.3 86.9 21.84 73.2 72.8 12 15.91 61.3 61.4 14 13.73 52.9 51.9 16 10.67 47.5 41.1 5.52 35.2 34.0 24 3.56 29.3 28.5 28 2.53 23.4 22.9 36 1.44 11.9 13.5 48 0.66 5.8 5.2 The blood plasma levels of venlafaxine were measured according to the following procedure. Blood samples from the subjects were collected in heparinized evacuated blood tubes and the tubes were inverted gently several times. As quickly as possible, the tubes were centrifuged at 2500 rpm for 15 minutes. The plasma was pipetted into plastic tubes and stored at -20°C until analysis could be completed.
To 1 mL of each plasma sample in a plastic tube was added 150 ItL of a stock internal standard solution (150 ltg/ml). Saturated sodium borate (0.2 mL) solution was added to each tube and vortexed. Five mL of ethyl ether was added to each tube which were then capped and shaken for 10 minutes at high speed. The tubes were centrifuged at to 3000 rpm for 5 minutes. The aqueous layer was frozen in dry ice and the organic layer transferred to a clean screw cap tube. A 0.3 mL portion of 0.01 N HCI solution was added to each tube and shaken for 10 minutes at high speed. The aqueous layer was frozen and the organic layer removed and discarded. A 501tL portion of the mobile phase (23:77 acetonitrile:0.lM monobasic ammonium phosphate buffer, pH 4.4) was added to each is tube, vortexed, and 50 p.L samples were injected on a Supelco Supelcoil LC-8-DB, 5 cm x 4.6 mm, 5 p column in a high pressure liquid chromatography apparatus equipped with a Waters Lambda Max 481 detector or equivalent at 229 nm. Solutions of venlafaxine hydrochloride at various concentrations were used as standards.
Thus, the desired dissolution rate of a sustained release dosage form of venlafaxine zo hydrochloride, impossible to achieve with hydrogel tablet technology, has been achieved with the film-coated spheroid compositons of this invention.

Claims

1. An extended release formulation of venlafaxine hydrochloride comprising a composi-tion containing spheroids comprised of venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropylmethylcellulose, the spheroids being coated with a film coating comprising ethyl cellulose and hydroxypropylmethylcellulose.

2. The extended release formulation according to claim 1, wherein the spheroids are composed of from about 30 to about 40% by weight of venlafaxine hydrochloride, from about 50 to about 70% by weight of microcrystalline cellulose, and from about 0.25 to about 1% by weight of hydroxypropylmethylcellulose.

3. The extended release formulation according to claim 1, wherein the spheroids are composed of about 35% venlafaxine hydrochloride, from about 55 to about 60%
microcrystalline cellulose, and about 0.5% hydroxypropylmethylcellulose.

4. The extended release formulation according to claim 1, wherein the spheroids are composed of about 37.3% by weight of venlafaxine hydrochloride, about 62.17%
by weight of microcrystalline cellulose, and about 0.5% by weight of hydroxypropyl-methylcellulose.

5. The extended release formulation according to claim 1, wherein the spheroids are coated at a level of coating of from about 2 to about 12% by weight of the coated spheroids.

6. The extended release formulation according to claim 5, wherein said level of coating is from about 6 to about 8% by weight of the coated spheroids.

7. The extended release formulation according to claim 1, wherein the film coating is comprised of from about 80 to about 90% by weight of ethyl cellulose and from about to about 20% by weight of hydroxypropylmethylcellulose.

8. The extended release formulation of venlafaxine hydrochloride according to claim 1, wherein the film coating is comprised of ethyl cellulose (4.81% of total weight) and hydroxypropylmethylcellulose (0.85% of total weight).

9. The extended release formulation of venlafaxine hydrochloride according to claim 1, wherein the film coating is comprised of ethyl cellulose (4.04% of total weight) and hydroxypropylmethylcellulose (0.714% of total weight).

10. The extended release formulation of venlafaxine hydrochloride according to claim 1, wherein the film coating is comprised of ethyl cellulose (2.48% of total weight) and hydroxypropylmethylcellulose (0.437% of total weight).

11. The extended release formulation according to claim 1, wherein ethyl cellulose has an ethoxy content of from about 44 to about 51%.

12. The extended release formulation according to claim 1, wherein hydroxypropyl-methylcellulose has a methoxy content of from about 28 to about 30%.

13. The extended release formulation according to claim 1, wherein hydroxypropyl-methylcellulose has a hydroxypropoxy content of from about 7 to about 12%.

14. The extended release formulation according to claim 1, wherein ethylcellulose has a viscosity of about 50 cps for a 5% aqueous solution.

15. The extended release formulation according to claim 1, wherein hydroxypropyl-methylcellulose has a viscosity of about 6 cps for a 2% aqueous solution.

16. The extended release formulation of venlafaxine hydrochloride according to any one of claims 1 to 17, wherein said extended release formulation of venlafaxine hydro-chloride is encapsulated.

17. The extended release formulation of venlafaxine hydrochloride according to claim 16, wherein said extended release formulation of venlafaxine hydrochloride is encapsu-lated in a hard gelatin capsule.

18. An extended release formulation of venlafaxine hydrochloride for once daily admini-stration which comprises spheroids containing 37.3% venlafaxine hydrochloride, 62.17% microcrystalline cellulose and 0.5% hydroxypropylmethylcellulose, the spheroids being coated with a quantity of a mixture comprised of 85% ethyl cellulose type and 15% hydroxypropylmethylcellulose sufficient to give coated spheroids.

19. The extended release formulation of venlafaxine hydrochloride according to claim 18, which provides lower peak serum levels of up to 150 ng/ml and extended therapeutic-ally effective plasma levels over a 24 hour period.

20. The extended release formulation according to claim 1, wherein ethylcellulose is selected from ethylcellulose NF and ethylcellulose HG 2834.

21. The extended release formulation according to claim 1, wherein hydroxypropyl-methylcellulose is selected from hydroxypropylmethylcellulose 2208 and hydroxy-propylmethylcellulose 2910.

22. An extended release formulation of venlafaxine hydrochloride according to claims 1-21 which provides diminished levels of nausea and incidences of emesis.

23. An extended release formulation of venlafaxine hydrochloride for use as a medicament for treating depression providing diminished levels of nausea and incidences of emesis, said medication providing a therapeutic blood plasma concentration of venlafaxine over a twenty four hour period, a peak blood plasma level of venlafaxine in from about four to about eight hours, and a peak blood plasma level of venlafaxine of no more than 150 ng/ml, wherein said formulation is characterized by having a dissolution profile in USP Apparatus 1(basket) at 100 rpm in purified water at 37°C. as follows:

Time Average % Venlafaxine HCL
released 2 < 30

24 > 80 24. An extended release formulation of venlafaxine hydrochloride according to claim 23 which provides a peak blood plasma level of venlafaxine in from about five to about eight hours.

25. An extended release formulation of venlafaxine hydrochloride according to any one of claim 23 or 24 which provides a peak blood plasma level of venlafaxine at about six hours.

26. Use of an extended release formulation of venlafaxine hydrochloride in the preparation of a medicament for treating depression with diminished levels of nausea and incidences of emesis, wherein said formulation provides a therapeutic blood plasma concentration of venlafaxine over a twenty four hour period, a peak blood plasma level of venlafaxine in from about four to about eight hours, and a peak blood plasma level of no more than about 150 ng/ml.

27. Use of venlafaxine hydrochloride according to claim 26, wherein said medicament provides a peak blood plasma level of venlafaxine in from about five to about eight hours.

28. Use of venlafaxine hydrochloride according to any one of claims 26 or 27 wherein said medicament provides a peak blood plasma level of venlafaxine at about six hours.

29. Use of an extended release formulation of venlafaxine for the treatment of depression with diminished levels of nausea and incidences of emesis, wherein, in use, the formulation provides a therapeutic blood plasma concentration of venlafaxine over a twenty four hour period and wherein the formulation eliminates the troughs and peaks of drug concentration in blood plasma which provides a peak blood plasma concentration of venlafaxine in from about 4 to about 8 hours, and a peak blood plasma level of no more than about 150 ng/ml.

30. Use of an extended release formulation of venlafaxine hydrochloride and a pharmaceutically acceptable excipient in the preparation of a medicament for treating depression with diminished levels of nausea and incidences of emesis, said medication providing a therapeutic blood plasma concentration of venlafaxine over a twenty four hour period, a peak blood plasma level of venlafaxine in from about four to about eight hours, and a peak blood plasma level of no more than about 150 ng/ml.