FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
A STABLE PHARMACEUTICAL COMPOSITION OF
ATOMOXETINE
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED
UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT MAHALAXMI CHAMBERS, 2nd
FLOOR,
22, BHULABHAI DESAI ROAD, MUMBAI-400 026. MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

A STABLE PHARMACEUTICAL COMPOSITION OF ATOMOXETINE
TECHNICAL FIELD
The present invention relates to a stable pharmaceutical composition of Atomoxetine More particularly, the present invention relates to a stable pharmaceutical composition comprising Atomoxetine or its pharmaceutically acceptable salt, solvates, enantiomers or mixtures thereof and its method of preparation.
BACKGROUND OF THE INVENTION
Atomoxetine hydrochloride is chemically described as (-)-7V-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride. Its molecular formula is C17H21NO.HCI and its molecular weight is 291.82. It has the following structure.

Atomoxetine is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).
According to the American Psychiatric Association, about 3 to 7 % of children have Attention Deficit Hyperactivity Disorder (ADHD). It is estimated that about 4 % of adults have ADHD. Although the disorder is not well defined in adults include a lack of organization, daydreaming, irritability and lack of motivation.
Atomoxetine, the first drug developed for Attention Deficit Hyperactivity Disorder (ADHD), approved by USFDA has a different mechanism of action from the stimulantlike drugs such as methylphenidate, currently used to that ADHD. Unlike stimulant-like


drugs, Atomoxetine doesn't appear to have a potential for abuse, and henceforth it is not classified as a Controlled Substance.
Strattera®, Eli Lilly's product containing Atomoxetine has been studied in children, adolescents and adults and has been found safe and effective. Atomoxetine is rapidly absorbed after oral administration with an absolute bioavailability of 63 % in EMs (Extensive Metabolizers) and 94 % in PMs (Poor Metabolizers). Maximal plasma concentrations are reached approximately 1 to 2 hours after dosing with an estimated elimination half-life of about 5 hours. In these trials (including open-label and long term studies), 5 % EM patients and 7 % of PM patients discontinued for adverse events. Typical adverse events included abdominal pain, constipation, dyspepsia, nausea and vomiting. A standard high-fat meal typically decreases the rate of absorption without affecting the extent of absorption, resulting in a 10 - 37 % lower Cmax and delayed Tmax by 3 hours.
Atomoxetine is administered of with a daily dose of approximately 0.5 mg / Kg and increased after a 3-day period to a target daily dose of approximately 1.2 mg /Kg either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon / early evening. It is estimated that more than 26 % of total patient population lead problems in swallowing tablets (Tidsskr Nor Laegeforen, 1995 Mar 20; 115(8): 947-97709385). It is hard to medicate children who have difficulty in swallowing tablets. This leads to poor compliance, even non-compliance, with the treatment and this has a negative impact on the efficacy of the treatment. ADHD patients are frequently advised to take Atomoxetine but it has an extremely caustic and bitter taste. The bitter taste of Atomoxetine precludes the medication from being easily sprinkled onto foods such as applesauce, a commonly used method of administering medications to children. Hence administration of Atomoxetine as a tablet in pediatric patients is especially challenging for several reasons. Tablet dosage forms when wetted by saliva, and if the patient experiences difficulty in swallowing on the first attempt, it results in a very unpleasant taste that can result in difficulty to persuade the child begin his or her school day, incidences of nausea can be partially debilitating.


An ideal dosage form as a capsule would minimize the occurrence of adverse events and
improve patient compliance, thus encouraging patient's adherence to the prescribed
dosing regimen.
In treatment of ADHD, Methylphenidate was used which is stimulant drug.
But Atomoxetine is a Non Scheduled drug & Non Stimulant drug which is used for
treating ADHD.
The non stimulants Clonidine & Guanfacine have shown efficacy in ADHD, but rebound
hypertension and sedation are among their limitations.
Atomoxetine is a valuable new treatment option for adults with ADHD and is particularly
useful in patients who are at risk for substance abuse or who do not wish to take a
Controlled substance.
Atomoxetine is a selective norepinephrine reuptake inhibitor and nonstimulant that has shown greater efficacy than placebo in attention deficit hyperactivity disorder (ADHD) in adults. In two large, well controlled, 10-week trials adults with ADHD, improvements in ADHD symptoms, as assessed by investigator and patient- related scores, were greater with oral Atomoxetine than with placebo. Mean reductions in the total ADHD symptom score on the investigator-rated Conners' Adult ADHD Rating Scale (CAARS) in Atomoxetine versus placebo recipients were 28.3% versus 18.1% and 30.1% versus 19.6% respectively. Mean reductions in the scores on the Clinician Global Impression Of severity scale, patient-rated CAARS and Wender - Reimherr Adult Attention Deficient Disorder Scale were also significantly greater with Atomoxetine than with placebo.
Atomoxetine, the (R) - (-) enantiomer of tomoxetine, is an aryl oxyphenyl propylamine. US4018895 (1977, Bryan B. et al) discloses that 3-aryloxy-3-phenylpropylamines have antidepressant properties. Indeed, in '895 patent there is described the racemic form of the compound of the invention.
The (R)-(-) enantiomer of tomoxetine is twice as effective as the racemic mixture and about nine times more effective than the (+) - enantiomer, as disclosed in EP 0052492 (1981, Foster, B. et al and EP 0721777 (1996, Heiligenstein J. et al). The patent application US20060057199 (2006, Gopi M. et al) discloses a coated multi-particulate

pharmaceutical dosage form such as an orally disintegrating tablet (ODT) presentation for delivering atomoxetine or a pharmaceutically acceptable salt.
OBJECT OF THE INVENTION
An object of the present invention is to provide an immediate release, stable pharmaceutical composition of Atomoxetine.
Another object of the present invention is to provide an industrially scalable process for immediate release pharmaceutical composition of Atomoxetine.
Yet another objective of the present invention is to provide a stable pharmaceutical composition of Atomoxetine using R- (-) enantiomers.
Yet another object of the present inventions is to provide pharmaceutical composition wherein the active ingredient Atomoxetine or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof has particle size less than 200 microns.
Yet another object of the present inventions is to provide immediate release stable Pharmaceutical composition wherein the dosage form has a release of drug more than about 75% in 15mins as measured in 0. IN HC1, 50RPM using USP type II apparatus, at 37± 2°C.
Yet another object of the present inventions is to provide immediate release stable immediate release stable pharmaceutical composition dosage form suitable for oral administration
Yet another object of the present invention is to provide an ideal dosage form, which would minimize the occurrence of adverse events and improve patient compliance, thus encouraging patient's adherence to the prescribed dosing regimen.

SUMMARY OF THE INVENTION
According to the present invention there is provided an immediate release stable pharmaceutical composition, which comprises an active ingredient and one or more of pharmaceutically acceptable excipients
Also, according to the present invention there is provided a process for the preparation of immediate release pharmaceutical composition comprises:
a. Sift all the materials.
b. Mix all the materials of step (a) to prepare a blend.
c. Fill the blend of step (b) into capsules.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention there is provided an immediate release stable pharmaceutical composition, which comprises an active ingredient and one or more of pharmaceutically acceptable excipients
The formulation employed in the present invention is of immediate-release dosage form. An immediate-release dosage form is one in which the release properties of the drug from the dosage form are essentially unmodified. Immediate-Release dosage forms generally also have dissolution profiles in any given media that are unmodified from those of Atomoxetine alone in the same media. An immediate-release dosage form preferably results in delivery of greater than or equal to about 75 % Atomoxetine within about 2 hours of administration, preferably within 1hour of administration. An immediate-release dosage form may contain optional excipients so long as the excipients do not significantly extend the release of the drug.
The term "Atomoxetine" includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof.
The active ingredient Atomoxetine or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof has particle size less than 200 microns.

Pharmaceutical composition means solid oral formulations, which includes capsules or
powder in sachets..
The Pharmaceutical Compositions are prepared in a manner well known in the
pharmaceutical art. The carrier or the pharmaceutical^ acceptable excipient may include
diluents, disintegrants and lubricants.
The term pharmaceutically acceptable excipient as used herein, refers to ingredients of
the composition excluding the active drug substances.
The diluent may be one or more of Microcrystalline Cellulose, Starch, Lactose.
The disintegrant may be selected from the group consisting of Crospovidone (Cross
linked PVP) Sodium Starch Glycolate, Cross linked Sodium Carboxy methyl cellulose,
Calcium silicate, low substituted Hydroxy propyl cellulose and mixtures thereof.
The lubricants may be of Magnesium stearate or Calcium stearate used for the
formulation.
The formulation may contain 5 % to 50 % of the active ingredient, preferably from 7.5 %
to 47.5 % (WAV) based on the total weight of the pharmaceutical composition.
The formulation may contain 40 % to 95 % (WAV) of the diluent, preferably from 45 % to 92 % (WAV) based on total weight of the pharmaceutical composition.
The formulation may contain 1 % to 5 % (WAV) of the disintegrant, preferably from 2.5 % to 4 % (WAV) based on total weight of the pharmaceutical composition.
The formulation may contain 0.5 % to 2.5 % (WAV) of the lubricant, preferably from 0.5 % to 2 % (WAV) based on total weight of the pharmaceutical composition.
In a preferred embodiment, there is also provided a process of making stable pharmaceutical composition as herein above described comprising the steps of:
a) Sifting of active ingredient and pharmaceutically acceptable additives through 60- mesh sieve.
b) Dry mix of step (a) is mixed in a rapid mixer granulator to prepare a blend, c) Filling the blend of step (b) into empty hard gelatin capsule.

Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example 1:
A formulation useful for the administration of Atomoxetine hydrochloride comprises a dry mixture of Atomoxetine hydrochloride with a diluent and disintegrant. Microcrystalline Cellulose is a suitable diluent and Crospovidone a suitable disintegrant used in this formulation. The composition of Empty Hard Gelatin Capsule includes gelatin, titanium dioxide and sodium lauryl sulfate. The following table illustrates particularly preferred formulations:

Ingredient in % 10mg 18mg 25mg 40mg 60mg 80mg 100mg
Atomoxetine hydrochloride 9.142 16.456 22.856 36.570 36.570 36.570 45.712
Crospovidone 3.000 3.000 3.000 3.000 3.000 3.000 3.000
Microcrystalline Cellulose 87.858 80.544 74.144 60.430 60.430 60.430 51.288

Ingredient in mg 10mg 18mg 25mg 40mg 60mg 80mg 100mg
Atomoxetine hydrochloride 11.428 20.570 28.570 45.712 68.568 91.424 114.280
Crospovidone 3.750 3.750 3.750 3.750 5.625 7.500 7.500
Microcrystalline Cellulose 109.822 100.680 92.680 75.538 113.307 151.076 128 220
Capsule fill weight 125.000 125.000 125.000 125.000 187.500 250.000 250.000
Capsule size 3 3 3 3 2 1 1
Procedure:
Atomoxetine hydrochloride, Crospovidone and Microcrystalline Cellulose were passed through 60-mesh sieve. Dry mix comprising of Atomoxetine hydrochloride, Crospovidone and Microcrystalline Cellulose was mixed in Rapid Mixer Granulator (High Shear Granulator). The mixed blend was filled into Empty Hard Gelatin Capsules.
The above formulations were subjected to dissolution in 0.1N HC1, 50RPM using USP type II apparatus, at 37± 2°C. Following result were obtained for the different Strength is as follows

Strength Release at 15 min (mean of 6 values)
10 mg 99.60%
60 mg 94.20 %

100 mg

91.40%

Example 2:
The present invention provides one more composition comprising of Atomoxetine hydrochloride - the active, Macrocrystalline Cellulose - a suitable diluent and Magnesium stearate - a suitable lubricant used in this formulation. The composition of Empty Hard Gelatin Capsule includes gelatin, titanium dioxide and sodium lauryl sulfate.
The following table illustrates particularly preferred formulations:

Ingredient (%) 10mg 18mg 25mg 40mg 60mg 80mg 100mg
Atomoxetine hydrochloride 8.163 14.693 20.407 32.651 32.651 32.651 40.814
Microcrystalline Cellulose 90.837 84.307 78.593 66.349 66.349 66.349 58.186
Magnesium Stearate 1.000 1.000 1.000 1.000 1.000 1.000 1.000

Ingredient (mg / capsule) 10mg 18mg 25mg 40mg 60mg 80mg 100mg
Atomoxetine hydrochloride 11.428 20.570 28.570 45.712 68.568 91.424 114.280
Microcrystalline Cellulose 127.172 118.030 110.030 92.888 139.332 185.776 162.920
Magnesium Stearate 1.400 1.400 1.400 1.400 2.100 2.800 2.800

Capsule All weight 140.000 140.000 140.000 140.000 210.000 280.000 280.000
Capsule size 3 3 3 3 2 1 1
Procedure:
Atomoxetine hydrochloride, Microcrystalline Cellulose and Magnesium Stearate were
passed through 60-mesh sieve. Dry mix comprising of Atomoxetine hydrochloride,
Microcrystalline Cellulose and Magnesium Stearate was mixed in Rapid Mixer
Granulator (High Shear Granulator). The mixed blend was filled into Empty Hard Gelatin
Capsules.
The above formulation was subjected to dissolution in 0. IN HC1, 50RPM using USP
type II apparatus, at 37± 2°C. The result obtained is as follows.

Strength Release at 15 min (mean of 6 values)
100 mg 93.10%
Example 3:
A formulation useful for the administration of Atomoxetine hydrochloride comprises a dry mixture of Atomoxetine hydrochloride with a diluent, lubricating agent and disintegrant. Microcrystalline Cellulose is a suitable diluent, Magnesium stearate as a suitable lubricant and Crospovidone a suitable disintegrant used in this formulation. The composition of Empty Hard Gelatin Capsule includes gelatin, titanium dioxide and sodium lauryl sulfate. The following table illustrates particularly preferred formulations:

Ingredient in % 10mg 18mg 25mg 40mg 60mg 80mg 100mg
Atomoxetine hydrochloride 9.142 16.456 22.856 36.570 36.570 36.570 45.712
Crospovidone 3.000 3.000 3.000 3.000 3.000 3.000 3.000
Microcrystalline Cellulose 86.858 79.544 73.140 59.430 59.430 59.430 50.288
Magnesium Stearate 1.000 1.000 1.000 1.000 1.000 1.000 1.000

Ingredient in mg 10mg 18 nig 25mg 40mg 60mg 80mg 100mg
Atomoxetine hydrochloride 11.428 20.570 28.570 45.712 68.568 91.424 114.280
Crospovidone 3.75 3.75 3.75 3.75 5.625 7.50 7.50
Microcrystalline Cellulose 108.572 99.43 91.43 74.288 111.432 148.576 125.72
Magnesium Stearate 1.25 1.25 1.25 1.25 1.875 2.50 2.50
Capsule fill weight 125 125 125 125 187.5 250 250
Capsule size 3 3 3 3 2 1 1
Procedure:
Atomoxetine hydrochloride, Crospovidone, Microcrystalline Cellulose & Magnesium Stearate were passed through 60-mesh sieve. Dry mix comprising of Atomoxetine

hydrochloride, Crospovidone, Microcrystalline Cellulose & Magnesium Stearate was mixed in Rapid Mixer Granulator (High Shear Granulator). The mixed blend was filled into Empty Hard Gelatin Capsules.
The above formulations were subjected to dissolution in 0.1N HCl, 50RPM using USP type II apparatus, at 37± 2°C. The result obtained is as follows.

Strength Release at 15 min (mean of 6 values)
100 mg 91.60%

We Claim:
1. An immediate release stable pharmaceutical composition, which comprises an active ingredient and one or more of pharmaceutically acceptable excipients.
2. The pharmaceutical composition according to claim 1, wherein the active ingredient comprises Atomoxetine or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
3. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients comprises one or more of diluents, disintegrants and lubricants.
4. The pharmaceutical composition according to claim 1, wherein the diluents comprises one or more of Microcrystalline Cellulose, Starch and Lactose.
5. The pharmaceutical composition according to claim 1, wherein the disintegrants comprises one or more of Crospovidone (Cross linked PVP), Sodium Starch Glycolate, Calcium silicate , Cross linked Sodium Carboxy methyl cellulose, low substituted Hydroxy propyl cellulose and mixtures thereof.
6. The pharmaceutical composition according to claim 1, wherein the lubricants comprises Magnesium stearate or calcium stearate or combination thereof
7. The pharmaceutical composition according to claim 1, wherein the active ingredient ranges from 5 % to 50 % preferably 7.5% to 47.5% (WAV) based on the total weight of the pharmaceutical composition.

8. The pharmaceutical composition according to claim 1, wherein the diluent ranges from 40 % to 95 % preferably 45 % to 92% (WAV) based on the total weight of the pharmaceutical composition
9. The pharmaceutical composition according to claim 1, wherein the disintegrants ranges from 1 % to 5.0% preferably 2.5% to 4% (WAV) based on the total weight of the pharmaceutical composition
10. The pharmaceutical composition according to claim 1, wherein the lubricant ranges from 0.5 % to 2.5 % preferably 0.5 % to 2 % (WAV) based on the total weight of the pharmaceutical composition

11. The immediate release stable pharmaceutical composition according to claim 1, wherein the atomoxetine or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof ranges between 7.5% to 47.5% (WAV), Macrocrystalline cellulose ranges between about 45 % to 92 % (WAV), Crospovidone ranges between 2.5 % to 4 %(WAV) , and Magnesium Stearate ranges between 0.5 % to 2 %(WAV) based on the total weight of the pharmaceutical composition.
12. The immediate release stable pharmaceutical composition according to claim 1, wherein the dosage form comprises capsules, powder in sachets preferably capsules for oral administration.
13. A pharmaceutical composition according to claim 1, wherein the active ingredient Atomoxetine or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof has particle size less than 200 microns.
14. The process for the preparation of immediate release pharamaceutical composition comprises:
a. Sift all the materials.
b. Mix all the materials of step (a) to prepare a blend.
c. Fill the blend of step (b) into capsules.
15. The immediate release stable pharmaceutical composition according to claim 1, wherein the dosage form has a release of drug more than about 75% in 15mins as measured in 0.1N HC1, 50RPM using USP type II apparatus, at 37± 2°C.
16. The immediate release stable pharmaceutical composition according to claim 1, wherein the dosage form suitable for oral administration.
17. The immediate release stable pharmaceutical composition substantially as herein described and illustrated with reference to the accompanying examples

ABSTRACT
The present invention relates to a immediate release stable pharmaceutical composition containing Atomoxetine or a pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof and its method of preparation suitable for oral administration for the treatment of symptoms of Attention Deficit Hyperactivity Disorder (ADHD), which includes inattention, hyperactivity and impulsiveness.