Title of Invention

A PROCESS FOR PREPARING AN ENCAPSULATED EXTENDED RELEASE FORMULATION OF VENLAFAXINE HYDROCHLORIDE

Abstract A process for preparing an encapsulated, extended release formulation of venlafaxine hydrochloride comprising incorporation of a therapeutically effective amount of spheroids comprised of venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropyl methylcellulose coated with ethyl cellulose and hydroxypropylmethylcellulose into a hard gelatin capsule.
Full Text BACKGROUND OF THE INVENTION
This invention relates to a process for preparing an encapsulated extended release formulation of venlafaxine hydrochloride.
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/anti-inflammatory drug etodolac (LodineR) 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 dosage forms may be formulated by mixing the drug with one or more
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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 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 microcystalline 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. 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
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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. BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparing an encapsulated, extended release formulation of venlafaxine hydrochloride comprising incorporation of a therapeutically effective amount of spheroids comprised of venlafaxine hydrochloride, microcrystalline cellulose hydroxypropyl methylcellulose coated with a coating composition comprising ethyl cellulose and hydroxypropylmethylcellulose, into a hard gelatin capsule.
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 four hour period.
Through administration of the venlafaxine formulation of
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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 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 (optionally about six hours) and then begin to fall through a protracted, substantially linear decrease from the peak plasma level for the remainder of the twenty four hour period, maintaining at least a threshold therapeutic level of the drug during the entire twenty-four hour 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 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.
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The use of the one-a-day venlafaxine hydrochloride formulations of this invention reduces by adaptation, the level of nausea and incidence of ernesis that attend the administration of multiple daily dosing. In clinical trials of venlafaxine hydrochloride ER,
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the probability of developing nausea in the couisc of the trials was greatly reduced alter the first week. Venlafaxinc 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 hydrochloride with an extended release formulation of venlafaxinc hydrochloride once a day in a therapeuucally effective amount.
Detailed Description of the Invention
l-[2-(dimeihyIamino)-l-(4-methoxyphenyl)e[hyI]cycIohexanoi 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 convened 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 Fonn II may be. used in the formulations of the present invention.
The extended release formulations of this invention are comprised of 1-|2-(dimethylamino)-l-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride in admixture with microcrystalline cellulose and hydroxypropylmethylcellulose. Formed as beads or spheroids, the drug containing formulation is coated with a mixture of ethyl cellulose and hydroxypropy 1 methyl cellulose 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 comprise from about 30 to 40 percent venlafaxine hydrochloride, from about 50 to about 70 percent macrocrystalline cellulose, NT7, from about 0.25 to about 1 percent hydroxypropylmethylcellulose, USP, and from about 5 to about 10 peicent 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 (AvicelĀ® PH101), about one half percent hydroxypropyl methylcellulose 2208 USP (K3, Dow, which has a viscosity of 3 cps for 2% aqueous solutions, a methoxy content of 19-24% and a hydroxypiopoxy content of 4-13%), and from about 6 to 8 percent film coating.
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Hydroxypropyl Methylcellulose is a derivative of cellulose in which some hydroxy groups of cellulose are replaced by methoxy (- O - CH3) and some hydroxy groups of cellulose are replaced by 2-hydroxypropoxy (- O - CH2 - CHOH - CH3). It is available in several grades that vary in viscosity and extent of substitution. The US Pharmacopeia (USP) identifies the substitution type of the product by appending a four digit number to the chemical (i.e. nonproprietary) name. The first two digits refer to the approximate percentage content of the methoxy group (- O - CH3). The second two
digits refer to the approximate percentage content of the hydroxypropoxy group (- O -CH2-CHOH-CH3). The percentages are calculated on a dry basis. The USP specifications are

TYPE
Type 1828 Type 2208 Type 2906 Type 2910

METHOXY CONTENT HYDROXYPROPOXY CONTENT
23.0-32.0% 4.0-12.0% 4.0-7.5% 7.0-12.0%"
16.5-20.0% 19.0-24.0% 27.0-30.0% 28.0-30.0%

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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 weight/weight basis. Preferably the ethyl cellulose has a ethoxy content of 4-1.0-51% 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 28-30% and a hydroxypropoxy content of 7-12%. The ethyl cellulose used herein is 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 an extended release formulation containing venlafaxine hydrochloride could be obtained because the hydrochloride of venlafaxine proved to be extremely water soluble. Numeious attempts to produce extended release 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 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 microcrystalline cellulose and hydroxypropyl methylcellulose, different ratios of venlafaxine hydrochloride and filler, different hinders 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 occuncd which dried out the extrudate so much that it was difficult to convert the extruded cylinders into spheroids. Addition of hydroxypropylmethyleellulose 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 invention.
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Example 1.
VENLAFAXINE HYDROCHLORIDE EXTENDED RELEASE CAPSULES
A mixture of 44.8 pans ( 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 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 pan 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 panicle 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 pans of the film coating solution per part of uncoated spheroids is applied to obtain a coating level of 5%.
Example 3.
Same as for Example 1 except that 1.33 pans of the film coating solution is applied to 1 pan of uncoated spheroids to obtain a coating level of 6%.
Example 4.
Same as for Example 1 except that 1.55 pans of the film coating solution is applied to 1 pan 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 ponion of uncoated spheroids
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or spheroids with a lower coaling 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
Acceptable Coated Spherold Dissolution Rates
Time (hours) Average % Venlafaxine HCL released
2 4 30-55
8 55-80
12 65-90
24 >80
Batches of the coared venlafaxine hydroclor ide 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 (it/sited. The standard unit dosage immediate release (IR) tablet used presently provides amounts of venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 rng, 75 mg and 100 mg venlafaxine. The capsules of this invention are filled to provide an amount of venhfaxine hydrochloride equivalent to that presently used in tablet form and also up to about 150 mg venlafaxine hydrochloride.
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Dissolution of the venlafaxine hydrochloride ER capsules is determined as directed in the U. S. Pharmacopoeia (USP) using appai.mis 1 at 100 ipm on 0.9 L of water. A filtered sample of the dissolution medium is taken at the times specified. The absorbance of the clear solution is determined from 2-10 to 150 nanomcieis (mn) 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 venlafaxine hydrochloride spheroids and measured for dissolution. Standard samples consist of venlafaxine hydrochloride stand and solutions plus a gelatin capsule correction solution. The percentage of venlafaxine released is determined from the equation


where As is absorbnnce of sample prepaiation, Wi is weight of reference standard, mg; S is strength of the reference standard, decimal; V] is the volume of dissolution medium used
to dissolve the dosage form, mL; 0.884 is the peiccnt 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 venlafaxinc 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 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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'I able 2
Plasma venlafaxine level (ng/mL) versus lime, conventional tablet (not extended release) versus ER capsule

Time (hours) 75 mg 2 x 75 mg (ER)capsules 1 x 150 mg
(IR)tablet (HR)capsules
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
10 1 18.4 1 14.4
12 51.9 105.1 105.8
12.5 74.7
13 127.5
14 161.3 , 90.5 91.3
16 13-1.6 78.2 78.5
18 106.2
'20 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 HR 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 release 75 mg tablets of veniafaxinc 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 below 150 ng/ml, is reached in about six hours, plus or minus two hours, based upon this
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specific dose when administered to patients prcscnily under tretmemt with venlafaxinc hydrochloride (IR). The peak plasma level of vcnlafaxine, somewhat over 200 ng/ml, following administration of (IR) is reached in two homs and falls rapidly thereafrer.
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 vcnlafaxine is seen at about 6 hours afier dosing with vcnlafaxine 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 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 Venlafaxine blood Level
Time (Hours) 1 x 50 mg IR tablet 2 x 75 mg ER 1 x 150 mg ER
capsules capsule
0 0 0 0
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
10 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
20 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
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tubes and the tubes were inverted gently several times. As quickly as possible, the tubes were eentrifuged 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 L of a stock internal standard solution (150 ng/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 lube. A 0.3 mL portion of 0.01 N HC1 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 discanlcd. A 50 L portion of the mobile phase (23:77 acetonitrile:0.1M monobasic ammonium phosphate buffer, pH 4.4) was added to each tube, vortexed, and 50 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 concenuations were used as standards.
Thus, the desired dissolution rare of a sustained release dosage form of venlafaxine hydrochloride, impossible to achieve with hydrogel tablet technology, has been achieved with the film coated spherold omposinons of this invention.
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WE CLAIM :
1. A process for preparing an encapsulated, extended
release formulation of venlafaxine hydrochloride comprising
incorporation of a therapeutically effective amount of
spheroids comprised of venlafaxine hydrochloride/ micro-
crystalline cellulose and hydroxypropyl methylcellulose
coated with a coating composition comprising ethyl cellulose
and hydroxypropylmethylcellulose, into a hard gelatin
capsule.
2. A process as claimed in claim 1 wherein the spheroids
are composed of 37.3% by weight of venlafaxine hydrochloride
0.5% by weight of hydroxypropylmethylcellulose having a
methoxy content of 19.0% to 24.0 % and a hydroxypropoxy
content of 4.0% to 12.0%, and 62.17% by weight of
microcrystalline cellulose.
3. A process as claimed in claim 1 or 2, wherein the
coating composition is comprised of ethyl cellulose (4.81% of
the weight of the formulation) and hydroxypropylmethyl
cellulose (0.85% of the weight of the formulation).
4. A process as claimed in claim 1 or 2, wherein the
coating composition is comprised of ethyl cellulose (4.04% of
the weight of the formulation) and hydroxypropylmethyl
cellulose (0.714% of the weight of the formulation).
5. A process as claimed in claim 1 or 2, wherein the
coating composition is comprised of ethyl cellulose (2.48% of
the weight of the formulation) and hydroxypropylmethyl
cellulose (0.437% of the weight of the formulation).
6. A process as claimed in claim 1 or 2, wherein the
coating composition comprises a mixture of ethyl cellulose
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(85% of total weight of the coating composition), having a 44.0-51.0% content of ethoxy groups, and hydroxypropylmethyl-cellulose (15% of total weight of the coating composition), wherein the hydroxypropylmethylcellulose has a methoxy content of 28.0-30.0% and a hydroxypropoxy group content of
7.0-12.0%.
>
7. 'A process as claimed in any of the preceding claims, wherein the extended release formulation is for once daily administration and the spheroids contain 37.3% by weight, calculated on the spheroids, of venlafaxine, 62.17% by weight, calculated on the spheroids, of microcrystalline cellulose and 0.5% by weight, calculated on the spheroids, of hydroxypropylmethylcellulose whose methoxy content is 19.0% to 24.0% and hydroxypropoxy content is 4.0% to 12.0%, and are coated with a quantity of a mixture comprised of 85% by weight of ethyl cellulose and 15% by weight of hydroxypropylmethylcellulose whose methoxy content is 28.0% to 30.0% and a hydroxypropoxy content is 7.0% to 12%, the said quantity being sufficient to give coated spheroids having a dissolution profile which gives the desired release rate over a 24 hour period.
8. A process for preparing an encapsulated, extended release formulation of venlafaxine hydrochloride, substantially as herein described, particularly with reference to the forgoing examples.
A process for preparing an encapsulated, extended release formulation of venlafaxine hydrochloride comprising incorporation of a therapeutically effective amount of spheroids comprised of venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropyl methylcellulose coated with ethyl cellulose and hydroxypropylmethylcellulose into a hard gelatin capsule.

Documents:

00507-cal-1997 abstract.pdf

00507-cal-1997 assignment.pdf

00507-cal-1997 claims.pdf

00507-cal-1997 correspondence.pdf

00507-cal-1997 description(complete).pdf

00507-cal-1997 form-1.pdf

00507-cal-1997 form-2.pdf

00507-cal-1997 form-3.pdf

00507-cal-1997 form-5.pdf

00507-cal-1997 letters patent.pdf

00507-cal-1997 p.a.pdf

00507-cal-1997 priority document.pdf

00507-cal-1997 reply f.e.r.pdf

507-cal-1997-abstract.pdf

507-cal-1997-assignment.pdf

507-cal-1997-claims.pdf

507-CAL-1997-CORRESPONDENCE-1.1.pdf

507-cal-1997-correspondence.pdf

507-cal-1997-description (complete).pdf

507-cal-1997-examination report.pdf

507-CAL-1997-FOR ALTERATION OF ENTRY.pdf

507-cal-1997-form 1.pdf

507-cal-1997-form 2.pdf

507-CAL-1997-FORM 27.pdf

507-cal-1997-form 3.pdf

507-cal-1997-form 5.pdf

507-CAL-1997-FORM-27.pdf

507-cal-1997-gpa.pdf

507-CAL-1997-PA-1.1.pdf

507-cal-1997-pa.pdf

507-cal-1997-petition under rule 124.pdf

507-cal-1997-reply to examination report.pdf

507-cal-1997-specification.pdf

507-cal-1997-translated copy of priority document.pdf


Patent Number 187337
Indian Patent Application Number 507/CAL/1997
PG Journal Number 25/2007
Publication Date 22-Jun-2007
Grant Date 22-Jun-2007
Date of Filing 21-Mar-1997
Name of Patentee WYETH
Applicant Address DELAWARE, FIVE GIRALDA FARMS, MADISON, NEW JERSEY 07940 0874, U.S.A.
Inventors:
# Inventor's Name Inventor's Address
1 DEBORAH MARIE SHERMAN 5, BELMONT AVENUE, PLATTSBURGH, NEW YORK 12901, U.S.A.
PCT International Classification Number A 61 K 9/32,9/54
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/014, 006 1996-03-25 U.S.A.