AU2003259586B2

AU2003259586B2 - Extended release formulation

Info

Publication number: AU2003259586B2
Application number: AU2003259586A
Authority: AU
Inventors: Deborah Marie Sherman
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 1996-03-25
Filing date: 2003-10-30
Publication date: 2007-01-25
Anticipated expiration: 2017-03-20
Also published as: AU2003259586A1; AU2010214740A1; AU6544200A; AU2007201828A1

Description

EXTENDED RELEASE FORMULATION The present application is a divisional application from Australian Patent Application 65442/00 which in turn is a divisional of Australian Patent Application 16400/97, the entire disclosure of both these earlier applications is incorporated herein by reference.

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 hydroxypropylmethylcellulose with or without other excipients and the resulting mixture is pressed into tablets. When the tablets are orally administered, the cellulose ethers in the tablets swell upon hydration from moisture in the digestive 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 forms may be 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 W:AcWSkankEpedeDIv of 65442-00.doc 1'' lb appropriate lengths and transformed into spheroids using standard spheronization equipment. The spheroids, after drying, may then be film-coated to retard 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 4,138,475 discloses a sustained release pharmaceutical composition consisting of a hard gelatin capsule filled with film-coated spheroids comprised of propanolol in admixture with microcrystalline cellulose wherein the film coating is composed of ethyl cellulose, optionally with hydroxypropylmethylcellulose and/or a plasticizer.

Venlafaxine, 1-[2-(dimethylamino)-l-(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. 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 WAdska~nk\spedeSkDIv of 65442-OO.doc

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c rapid increase in blood plasma levels of the active compound shortly after

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Sadministration followed by a decrease in blood plasma levels over several hours as the active compound is eliminated or metabolized, until sub-therapeutic c- 5 plasma level:s are approached after about twelve hours following administration, thus requiring additional dosing with the drug. With the plural daily dosing

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00regimen, the most common side effect is nausea, experienced by about 45% of patients under treatment with venlafaxine hydrochloride. Vomiting also occurs c in about 170/c% of the patients.

c-I The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in Australia as at the priority date of any of the claims.

Brief Description of the Invention In accordance with this invention, there is provided a method for providing a therapeutic: blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.

In a further embodiment, there is provided a method for moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilization of multiple daily dosing with venlafaxine hydrochloride, which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.

In a further embodiment, there is provided a method of reducing the level of nausea and the incidence of emesis in a patient in need of venlafaxine by W:.BA\7061\08O iP2-4D doc

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0 administering orally to said patient, a single daily dosing formulation of c- venlafaxine hydrochloride that provides a therapeutic blood plasma aU concentration of venlafaxine over a 24 hour period and a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration.

<C In a further embodiment, there is provided a method for treating 00 depression in a patient in need of such treatment, said method including the 01 steps of administering orally to said patient, a single daily dosing formulation of cN venlafaxine hydrochloride over a 24 hour period with a peak blood plasma level 0 10 of venlafaxine in from about 4 to 8 hours after administration.

In a further embodiment, there is provided a method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over the 24 hour period with a peak blood plasma concentration of no more than 150 ng/ml.

In a further embodiment, there is provided a method of moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilisation of multiple daily dosing with venlafaxine hydrochloride, which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of no more than 150 ng/ml.

In a further embodiment, there is provided a method of reducing the level of nausea and the incidence of emesis in a patient in need of venlafaxine by administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of no more than 150 ng/ml.

WABA\706611170611 P2-4C.doc 11, JAN. 2007 9:50 PHILLIPS ORMOND ,NO. 593 P. 4 In a further embodiment, there is provided a method for treating depression in a patient in need of such treatment, said method including the steps of administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of no more than 150 ng/ml.

In a further embodiment there is provided a method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period whish comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride formulation having a dissolution profile in USP Apparatus 1 (basket) at 100 rpm in purified water at 37°C as follows: Time Average Venlafaxine HCI released (hours) 2 Less than 4 30-55 8 55-80 12 65-90 24 Greater than In a further embodiment there is provided a method for moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilisation of multiple daily dosing with venlafaxine hydrochloride, which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma, concentration of venlafaxine over a 24 hour period, having a dissolution profile in USP Apparatus 1 (basket) at 100 rpm in purified water at 37PC as follows: W:BAWOet\TOGil Amded Pagesdoo COMS ID No: SBMI-05883500 Received by IP Australia: Time 10:51 Date 2007-01-11 11, JAN. 2007 9:50 PHILLIPS ORMOND NO. 593 P. Time Average Venlafaxine HCi released (hours) 2 Less than 4 30-55 8 56-80 12 65-90 24 Greater than In a further embodiment there is provided a method of reducing the level of nausea and the incidence of emesis in a patient in need of venlafaxine by administering orally to said patent a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period, having a dissolution profile in USP Apparatus I (basket) at 100 rpm in purified water at 37 0 C as follows: Time Average Venlafaxine HC! released (hours) 2 Less than 4 30-55 8 55-80 12 65-90 24 Greater than In a further embodiment there is provided a method for treating depression in a patient in need of such treatment, which comprises administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hours period, having a dissolution profile in USP Apparatus I (basket) at 100 rpm in purified water at 37C as follows: 4A COMS ID No: SBMI-05883500 Received by IP Australia: Time 10:51 Date 2007-01-11

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Time Average Venlafaxine HCI released (hours) 2 Less than 4 30-55 8 55-80 12 65-90 24 Greater than In an example of the invention, the formulation of venlafaxine hydrochloride is an extended release formulation that is administered as a single daily dosing formulation. In one embodiment, the single daily dosing formulation when used in the method of the invention will provide a peak blood plasma level of venlafaxine from 5-8 hours after administration, most preferably, about 6 hours after administration.

In one embodiment, the venlafaxine hydrochloride formulation for use in the methods of this invention is comprised of venlafaxine hydrochloride, (or 1- [2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexamol hydrochloride), in admixture with microcrystalline cellulose and hydroxypropylmethylcellulose.

As an example, the extended release formulations are formed as coated beads or spheroids. In one embodiment, the drug containing formulation is coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose to provide the desired level of coating. The coating generally comprises from about 2% to about 12% on a weight/weight basis of final product or more preferably from about 5% to about 10% with best results obtained at from about 6% to about 8 More specifically, the coated spheroid core of the extended release formulation preferably comprises from about 30% to 40% venlafaxine hydrochloride, from about 50% to about 70% microcrystalline cellulose, from about 0.25% to about 1% hydroxypropylmethylcellulose, and from about 5% to W:\BA\7068117006611 P2-4C.dOC

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O about 10% film coating, all on a weight/weight basis. As a further example, the CI coated spheroid core preferably contains about 35 venlafaxine hydrochloride, aU about 55% to 60% microcrystalline cellulose, about one half percent hydroxypropylmethylcellulose, and from about 6% to 8% film coating. The C 5 microcrystalline cellulose may be, for example, microcrystalline cellulose NF such as Avicel® PH101 and the hydroxypropylmethylcellulose may be, for 00 example, 2910 USP or 2208 USP such as K3, Dow, which has a viscosity of 01 3cps for aqueous solution, a methoxy content of 19% to 24% and a cN hydroxypropoxy content of 4% to 13%.

0 c The film coating may, for example, be comprised of 80% to 90% of ethyl cellulose, more preferably 85% to 90%, and 10% to 20 hydroxypropylmethylcellulose and most preferably 10% to 15%, on a weight/weight basis.

The ethyl cellulose is ethyl cellulose may, for example, be NF having a ethoxy content of 44% to 51% and a viscosity of 50 cps for a 5% aqueous solution and the hydroxypropylmethylcellulose is USP 2910 having a viscosity of 6 cps at 2% aqueous solution with a methoxy content of 28% to 30% and a hydroxypropoxy content of 7% to 12%. The ethyl cellulose used is preferably Aqualon 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 the inventive concept.

It was completely unexpected that a single daily dosing formulation containing venlafaxine hydrochloride for use in the methods of the invention could be obtained because the hydrochloride of venlafaxine proved to be extremely water soluble. Numerous attempts to produce single daily dosing, extended release or tablets by hydrogel technology proved to be fruitless because the compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution W:\BA\70661170811 P2-4DdDoc

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0 studies. Typically, the tablets prepared as hydrogel sustained release 0 CN formulations gave 40% to 50% dissolution at 2 hrs, 60% to 70% dissolution at 4 0 hrs and 85% to 100% dissolution at 8 hrs.

c 5 Numerous spheroid formulations were prepared using different grades of microcrystalline cellulose and hydroxypropylmethylcellulose, different ratios of oo venlafaxine hydrochloride and filler, different binders such as Spolyvinylpyrrolidone, methylcellulose, water, and polyethylene glycol of different N molecular weight ranges in order to find a formulation which would provide a O 10 suitable granulation mix which could be extruded properly. In the extrusion CN process, heat buildup occurred which dried out the extrudate so much that it was difficult to convert the extruded cylinders into spheroids. Addition of hydroxypropylmethylcellulose 2208 to the venlafaxine hydrochloridemicrocrystalline cellulose mix made production of spheroids practical which proved to be practical for a single daily dosing formulation useful in the methods of the invention.

The following examples are presented to illustrate applicant's solution to the problem of preparation of the extended release drug containing formulations of this invention.

W \BA\70B611 \706I61 P2-4.o Example 1.

VENLAFAXINE HYDROCHLORIDE EXTENDED RELEASE CAPSULES 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 inethylcellulose 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 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 uncoated spheroids is applied to obtain a coating level of 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%.

Example 4.

Same as for Example 1 except that 1.55 pars of the film coating solution is applied to 1 part of uncoated spheroids. to obtain a coating level of 7%.

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 drug component of the extended release capsules of this 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 Snheroid Dissolution Rates Time (hours) Average Venlafaxine HCL released to 2. 4 30-55 8 55-80 12 65-90 24 Batches of the coated venlafaxine hydrochloride containing spheroids which have a dissolution rate corresponding to that of Table 1 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 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 ir 100 rpm on 0.9 L of water. A filtered sample of the dissolution medium is taken at h!e 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 nn 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 venlafaxine hydrochloride spheroids and measured for dissolution. Standard samples consist of venlafaxine hydrochloride standard solutions plus a gelatin capsule correcton solution. The percentage of venlafaxine released is determined from the equation )(0.888)(100) Venlafaxine hydrochloride released (Ar)(V2)(C) where As is absorbance of sample preparation, Wr is weight of reference standard, mg; S is strength of the reference standard, decimal; VI 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 io 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.

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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)capsules 1 x 150 mg (IR)tablet (ER)capsules (q 12 h) (q24hr) (q 24 h) 0 62.3 55.0 55.8 76.3 S 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 0o release 75 mg tablets of venlafaxine hydrochloride administered at 12 hour intervals.

SFurther, 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 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 The peak plasma level of venlafaxine, somewhat over 200 ng/ml, following administration of (IR) is reached in two hours and falls rapidly thereafter.

Table 3 shows venlafaxine blood plasma levels in male human subjects having a zero initial blood plasma level. Again, a peak blood plasma concentradon of venlafaxine is seen at about 6 hours after dosing with venlafaxine, hydrochloride extended release capsules in the quanities 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 plasma levels of venlafaxine for subjects receiving the conventional formulated tablet can be o1 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 Venlafaxine Blood Level Time (Hours) 1 x 50 mg IR tablet 2 x 75 mg ER capsules 0 1 2 4 6 8 12 14 16 24 28 36 48 .0 27.87 44.12 54.83 66.38 49.36 30.06 21.84 15.91 13.73 10.67 5.52 3.56 2.53 1.44 0.66 0 1.3 6.0 20.6 77.0 96.5 93.3 73.2 61.3 52.9 47.5 35.2 29.3 23.4 11.9 5.8 No Prior 1 x 150 mg ER capsule 0 0 2.2 12.8 81.0 94.4 86.9 72.8 61.4 51.9 41.1 34.0.

28.5 22.9 13.5 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 cenrifuged at 2500 rpm for 15 minutes. The plasma was pipetted into plastic tubes and stored at -20'C until analysis could be completed.

To I mL of each plasma sample in a plastic tube was added 150 IL of a stock internal standard solution (150 ag/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 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 50p.L portion of the mobile phase (23:77 acetonicrile:0.1M monobasic armmuonium phosphate buffer, pH 4.4) was added to each tube, vortexed, and 50 p.L samples were injected on a Supelco Supelcoil LC-8-DB, 5 cm x 4.6 mm, 5 l. 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 hydrochloride, impossible to achieve with hydrogel tablet technology, has been achieved with the film-coated spheroid compositons of this invention.

Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, integers or process steps.

Claims

11. JAN. 2007 9:51 PHILLIPS ORMOND NO. 593 P. 6 0 0 STHE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a 6, patient in need of venlafaxine a single daily dosing formulation of venlafaxine O hydrochloride that provides a peak blood plasma level of venlafaxine in from I/n about 4 to 8 hours after administration. n 2. A method for moderating the plural blood plasma peaks and valleys attending o 10 the pharmacokinetic utilization of multiple daily dosing with venlafaxine hydrochloride, which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration. 3. A method of reducing the level of nausea and the incidence of emesis in a patient in need of venlafaxine which comprises administering orally to said patient, a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period and a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration. 4. A method for treating depression in a patient in need of such treatment, which comprises administering orally to said patient, a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration. 5. A method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of 11 COMS ID No: SBMI-05883500 Received by IP Australia: Time 10:51 Date 2007-01-11 IND O venlafaxine hydrochloride that provides a therapeutic blood plasma CI concentration of venlafaxine over the 24 hour period with a peak blood a, plasma level of no more than 150 ng/ml. 6. A method of moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilisation of multiple daily dosing with oo venlafaxine hydrochloride, which comprises administering orally to a o patient in need of venlafaxine a single daily dosing formulation of r venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood c plasma level of no more than 150 ng/ml. 7. A method of reducing the level of nausea and the incidence of emesis in a patient in need of venlafaxine by administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of no more than 150 ng/ml. 8. A method for treating depression in a patient in need of such treatment, said method including the steps of administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period with a peak blood plasma level of no more than 150 ng/ml. 9. A method according to any one of claims 1 to 4 wherein the formulation provides a peak blood plasma level of venlafaxine of no more than 150 ng/ml. A method according to any one of claims 5 to 7 wherein the formulation provides peak blood plasma level of venlafaxine in from about 4 to 8 hours after administration. W:\BA\70611 \706f11_Claim: doc 11. JAN. 2007 9:51 PHILLIPS ORMOND NO. 5901 P. 7 11. A method for providing a therapeutic blood plasma concentration of venlafaxine over a 24 hour period whish comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride formulation having a dissolution profile in USP Apparatus 1 (basket) at 100 rpm in purified water at 37'C as follows: Time Average Venlafaxine HCI released (hours) 2 Less than 4 30-55 8 55-80 12 65-90 24 Greater than

12. A method for moderating the plural blood plasma peaks and valleys attending the pharmacokinetic utilisation of multiple daily dosing with venlafaxine hydrochloride, which comprises administering orally to a patient in need of venlafaxine a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period, having a dissolution profile in USP Apparatus 1 (basket) at 100 rpm in purified water at 37*C as follows: Time Average Venlafaxine HCI released (hours) 2 Less than 4 30-55 8 55-80 12 65-90 24 Greater than

13. A method of reducing the level of nausea and the incidence of emesis in a patient in need of venlafaxine by administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour DGo nenc COMS ID No: SBMI-05883500 Received by IP Australia: Time 10:51 Date 2007-01-11 11.JAN, 200 9:51 PHILLIPS ORMOND NO. 593 P. 8 period, having a dissolution profile in USP Apparatus 1 (basket) at 100 rpm in purified water at 370C as follows: Time Average Venlafaxine HC released (hours) 2 Less than 4 30-55 8 55-80 12 65-90 24 Greater than

14. A method for treating depression in a patient in need of such treatment, which comprises administering orally to said patient a single daily dosing formulation of venlafaxine hydrochloride that provides a therapeutic blood plasma concentration of venlafaxine over a 24 hour period, having a dissolution profile in USP Apparatus I (basket) at 100 rpm in purified water at 37°C as follows: Time Average Venlafaxine HCI released (hours) 2 Less than 4 30-55 8 55-80 12 65-90 24 Greater than A method according to any one of the preceding claims, wherein the formulation of venlafaxine hydrochloride is an extended release formulation that is administered as a single daily dosing formulation.

16. A method according to any one of the preceding claims wherein the formulation provides a peak blood plasma level of venlafaxine from 5-8 hours after administration. flOCM2 14 COMS ID No: SBMI-05883500 Received by IP Australia: Time 10:51 Date 2007-01-11 11. JAN. 2007 9:51 PHILLIPS ORMOND NO. 593 P. 9 r- 0 17. A method according to any one of the preceding claims wherein the formulation C- provides a peak blood plasma level of venlafaxine at about 6 hours.

18. A method according to any one of the preceding claims wherein the formulation of venlafaxine hydrochioride contains a therapeutically effective amount of spheroid core comprising venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropylmethylcellulose, the spheroid core being coated with a coating 00 comprising ethyl cellulose and hydroxypropylmethylcellulose.

19. A method according to claim 18 wherein the coated spheroid core comprises M 30%-40% venlafaxine hydrochloride, 50%-70% microcrystalline cellulose, 0.25%- 0 hydroxypropylmethylcellulose and 5%-10% of a film coating comprising ethyl cellulose and hydroxypropylmethylcellulose, all on a weight to weight basis.

20. A method according to claim 18 or 19 wherein the coated spheroid core comprises about 35% venlafaxine hydrochloride, 55%-60% microcrystalline cellulose, about 0.5% hydroxypropylmethylcellulose and from about of the film coating.

21. A method according to any one of claims 18 to 20 wherein the film coating the spheroids comprises 80-90% by weight of ethyl cellulose and 10-20% by weight of hydroxypropylmethylcellulose.

22. A method according to any one of claims 18 to 21 wherein the film coating comprises 85-90% by weight of ethyl cellulose and 10-15% by weight of hydroxypropylmethylcellulose.

23. A method according to any one of claims 18 to 22 wherein the ethyl cellulose is ethyl cellulose NF and includes 44%-51% ethoxy content, and the hydroxypropylmethylcellulose includes 28%-30% methoxy content and 7%-12% hydroxypropoxy content. COMS ID No: SBMI-05883500 Received by IP Australia: Time 10:51 Date 2007-01-11 O 24. A method according to any one of claims 18 to 23 wherein the ethyl cl cellulose is Aqualon HG 2834 and the hydroxypropylmethylcellulose is 0 type 2208 or 2910 USP. C l 5 25. A method according to any one of claims 18 to 24 wherein the microcrystalline cellulose is microcrystalline cellulose NF. 00 O0\ 26. A method according to any one of claims 18 to 25 wherein the Nc hydroxymethylcellulose has a viscosity of 3cps for 2% aqueous solution, a O 10 methoxy content of 19% to 24% and a hydroxypropoxy content of 4% to cl 13%.

27. A method according to any one of the preceding claims wherein the formulation is an encapsulated formulation.

28. A method according to any one of claims 1 to 14 substantially as hereinbefore described with reference to any one of the Examples. WBA\7006 11\706611 Claim;.oc