FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 43)
TITLE OF THE INVENTION:
"NOVEL ACID RESISTANT DULOXETINE COMPOSITION"
APPLICANT:
(a) NAME: TITAN LABORATORIES PRIVATE LIMITED
(b) NATIONALITY: An Indian Company Incorporated Under The Companies Act, 1956
(c) ADDRESS: 102, Titan House, 60 Feet Road, Ghatkopar (E),
Mumbai: 400077, Maharashtra, India.
PREAMBLE TO THE DESCRIPTION: COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of Invention:
The present invention relates to a novel acid resistant pharmaceutical composition of Duloxetine. More specifically, the present invention relates to a novel stable acid resistant enteric coated composition of Duloxetine is devoid of a separating layer or a seal coat further comprising Hydroxypropylmethyl Cellulose Trimellitate (HPMCT) as enteric polymer and process for manufacturing thereof.
Background of Invention:
Duloxetine Hydrochloride belongs to the class of drugs categorized as selective serotonin / norepinephrine reuptake inhibitor (SNRIs) and used in the treatment of major depressive disorders and generalized anxiety disorders. The first publication on the discovery of the racemic form of duloxetine known as LY227942, was made in 1988. Duloxetine is specifically claimed in the US patent US5023269 assigned to El Lily and Company.
Duloxetine hydrochloride is designated chemically as (+)-(S)-N-methyl-γ-(l-naphthyloxy)-2thiophenepropylamine hydrochloride. The empirical formula is C18H16NOS.HCl, which corresponds to a molecular weight of 333.88. The structural formula is:


Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. The antidepressant and pain inhibitory actions of duloxetine are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.
Duloxetine Hydrochloride is well absorbed when administered orally. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. The major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine (Drug Bank).
Duloxetine is currently manufactured and marketed under the brand names Cymbalta, Ariclaim, Xeristar, Yentreve, and Duzela by El Lily.

Stress degradation studies conducted on Duloxetine Hydrochloride (Journal of Chromatographic Science, Vol. 47, August 2009) exhibited that the drug was found susceptible to hydrolytic stress , light (in solution form), and heat (in solution form).The drug was however stable to the oxidative stress (in solution form), and heat (in solution form).
Duloxetine Hydrochloride is an acid labile drug hence it should be protected from the acidic environment of the gastric sac. Acid catalyzed hydrolysis of Duloxetine is attributable to its chemical structure and results in 1-napthol formation which is highly toxic.
As known from prior art dosage forms comprising drugs susceptible to degradation in the acidic environment are generally enteric coated or formulated such that the drug is not released in the acidic environment of the stomach. Enteric coated technology is a modified release technology and Gastro resistant dosage form aim release of the drug in the intestine. This is achieved by either coating the dosage form such that it is protected from the acidic environment or a matrix approach wherein the drug is embedded along with the gastro resistant polymer to serve the purpose. Enteric coated modified release dosage form restricts the drug release in the stomach and thus prevents the irritation or ulceration that may be exhibited by the drug if unprotected. Moreover it also prevents the drug degradation in the acidic environment.

Commonly used polymers in an enteric coating formulation are Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS), Hydroxypropyl Methylcellulose Phthalate (HPMCP) and Methyl acrylate -methacrylic acid copolymers.
Several enteric coating polymers known to resist degradation by stomach acid are disclosed and claimed in prior art to achieve the gastro resistant characteristics for Duloxetine dosage form. To list amongst them are Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS), Hydroxypropyl methylcellulose phthalate (HPMCP), methacrylic acid copolymers, combination of methacrylic acid copolymer and hydroxypropyl methylcellulose phthalate.
US patent US5508276 referring to the innovator (Eli Lily & Company) formulation of CYMBALTA relates to a duloxetine enteric formulation in the form of enteric pellets wherein the enteric layer comprises hydroxypropylmethylcellulose acetate succinate (HPMCAS).
Delayed release formulations of Duloxetine Hydrochloride comprising combination of methacrylic acid copolymer and hydroxypropyl niethylcellulose phthalate in the enteric layer are claimed in WO2007/139886A2 (Teva).
Torrent in its PCT application WO2008020286A2 claims methacrylic acid copolymer as enteric coating polymer to coat solid oral compositions of Duloxetine.

PCT Application WO2008/129501 (Wockhardt) claims a number of enteric polymers in the main claim for coating the capsule composition comprising Duloxetine. The claimed acceptable enteric polymers comprises one or more of gelatin , shellac , methacrylic acid copolymer type C NF ,cellulose butyrate phthalate , cellulose hydrogen phthalate , cellulose propionate phthalate, polyvinyl acetate phthalate , cellulose acetate phthalate , cellulose acetate trimellitate , hydroxypropyl methylcellulose phthalate , hydroxypropyl methylcellulose acetate , dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose and acrylic acid polymers /copolymers.
WO2009/001043A2 (Arrow) claims an enteric coat comprising Hydroxypropyl methylcellulose phthalate (HPMCP) as an enteric polymer for a Duloxetine pellet formulation.
EP2018860 reveals that polymethacrylates are not appropriate polymers for duloxetine formulation since they have a tendency to form complexes with duloxetine, this result in inadequate dissolution of duloxetine hydrochloride from pellets hence considering the dissolution fact the claimed formulation uses a water soluble salt typically an inorganic salt in the separating layer.
Duloxetine Enteric pellets as claimed in the PCT application WO2010/037849A1 (Laboratories Del Dr. Esteve, S.A.) comprise an enteric layer comprising polyvinylacetate phthalate (PVAP).

Formulations of Duloxetine as claimed and disclosed in the PCT application WO2010/078878A1 (Synthon) comprise hydroxypropylmethylcellulose acetate succinate polymer and /or hydroxypropyl methylcellulose phthalate polymer.
As disclosed in EP693282 (Lilly Co Eli) certain difficulties arose in preparation of conventional enteric formulations of Duloxetine. It further reveals that Duloxetine was found to react with many enteric coatings to form a slowly - or even insoluble coating. Because of this unexpected cross-reactivity, formulations in pellet form were found to have a disadvantageous drug-releasing profile and low bioavailability.
As revealed from literature the free acids present in the polymers HPMCAS and HPMCP may accelerate the degradation of Duloxetine.
Prior art disclose use of enteric polymers have an acidic pH which could react with the active ingredient leading to its degradation hence it is necessary to supersede a seal coat over the drug layer. However the additional seal coating would attribute to lengthy processes and processing time and in addition would add to the process cost.
Also insufficient enteric coating may result in the failure of the design of the enteric coated dosage form. Hence a defined percentage of enteric coating polymers and an enteric coat of required thickness are generally the prime requisites and requirements while designing enteric coating formulations.

Increased quantity of the enteric polymers to achieve the desired result would ultimately add to the extra processing time and steps and would affect the economic factor of the overall formulation.
To emphasize on the enteric coating polymers as utilized in prior art the trimeliitate salt of Hydroxypropyl cellulose has not yet been explored in the enteric coating of Duloxetine compositions. Though the acetate trimeliitate salt of Hydroxypropylmethyl cellulose (HPMCAT) and the cellulose acetate trimeliitate (CAT) polymers have been disclosed and claimed generically and have been listed in the enteric polymers claimed, the physicochemical characteristics of Hydroxypropyl methylcellulose trimeliitate (HPMCT) have not been reconnoitered specifically for enteric coating of Duloxetine formulations.
Hydroxypropyl methylcellulose trimeliitate (HPMCT) is a novel enteric coating polymer for acid protection which can dissolve at pH of around 4. Hydroxypropyl methylcellulose trimeliitate (HPMCT) showed good acid resistance, and the pH at which it dissolves can be controlled in the range of pH 3.5 to 4.S by varying the content of trimellityl groups and the methoxyl substitution of the base polymer. (Chemical & Pharmaceutical Bulletin [1997, 45(8): 1350-1353])
As claimed Hydroxypropyl methylcellulose trimeliitate (HPMCT) generically finds a large number of applications as an enteric coating polymer in a variety of class of actives the categories include NSAIDs , gastrointestinal agents , antiplatelet agents, HMG Co -A reductase preparations and actives which are highly or poorly water

soluble but Hydroxypropyl methylcellulose trimellitate (HPMCT) has not found its applicability specifically for Duloxetine.
Amongst the prior art patents /patent applications claiming the listed class of drugs in combination with Hydroxypropylmethylcellulose Trimellitate (HPMCT) in a generic way are US2004/0228916 Al, EP1886673B1, EP0069259B1, US6015577 , US4367217 , US2010/0080846 and WO2010/036975.
US5700929 (Shin Etsu Chemical Co. Ltd) discloses and claims a base for coating enteric pharmaceutical preparations having a dissolution pH ranging from 3.5 to 4.5 essentially consisting of Hydroxypropyl Methyl Cellulose Trimellitate (HPMCT) obtained by substituting water -soluble Hydroxypropylmethyl Cellulose having 1.1 to 1.6 methoxy group per glucose ring thereof, with 0.2 to 1.0 trimellitate group per glucose ring.
US6258799 (Shinetsu Chemical Co.) discloses and claims an aqueous coating composition comprising Hydroxypropyl methyl cellulose trimellitate (HPMCT) typically having a mean particle size of up to 10 μm and a plasticizer is applied to a solid pharmaceutical preparation to form a coating film having acid resistance and solubility at about pH 4.
As disclosed and claimed in US6258799 the aqueous coating composition of HPMCT though claimed broadly for solid pharmaceutical preparations would not be feasible for Duloxetine compositions specifically because of the aqueous nature of the coating composition .Since as disclosed in the scientific literature of the FDA for

the New Dosage form of Cymbalta NDA 21-427 it is revealed that Duloxetine is prone to hydrolysis and would degrade in an aqueous environment.
WO2008/129501 A2 (Wockhardt) relating to the pharmaceutical compositions of Duloxetine lists cellulose acetate trimellitate (CAT) as one of the acceptable enteric coating polymer either alone or in combination to coat the capsule composition comprising Duloxetine. Here again the invention is not specific to the use of the trimellitate polymer CAT but is claimed in a generic way.
US2005/0244365 (Novaflux Biosciences Inc) relates to a method for treating, or decreasing the frequency of transmission of a virus, or bacterial infection in a host comprising administering to the host a therapeutically effective amount of at least one compound either alone or in combination with a pharmaceutically acceptable carrier, emulsifier, salt, or diluent, or other pharmaceutically active agent wherein the therapeutic agent is Hydroxypropyl Methylcellulose Trimellitate (HPMCT).
The stomach is divided into four sections namely Cardia, Fundus, Body or Corpus and Pylorus. The pH of gastric acid is 1.35 to 3.5 in the human stomach lumen, the proton pump H+/K+ ATPase maintain the acidity in the stomach. In the duodenum, gastric acid is neutralized by sodium bicarbonate. The gastric enzymes having their optima in the acidic pH range are also blocked. The secretion of sodium bicarbonate from the pancreas is stimulated by secretin. This polypeptide hormone gets activated and secreted from so-called S cells in the mucosa of the duodenum and jejunum when the pH in duodenum falls below 4.5 to 5.0.

Hence an enteric coated dosage form is normally expected to dissolve or release the active in alkaline environment to avoid untimely disintegration in the stomach and, to guarantee the desired release of the active ingredient at the expected site of action i.e. the intestinal tract.
However, heretofore there has been no disclosure or teaching in the art of Duloxetine enteric coated composition comprising specifically of Hydroxypropylmethyl Cellulose Trimellitate as an enteric coating polymer. Also there remains a need to produce formulations of APIs that are bioequivalent to commercially available dosage forms. In view of the existing prior art and to explore the unexplored concepts of the prior art the inventor have designed a novel acid resistant pharmaceutical formulation of Duloxetine comprising Hydroxypropylmethyl Cellulose Trimellitate as the enteric polymer, devoid of the separating or seal coat and exhibiting a dissolution with zero release in 1.2 acidic buffer and a:further drug release of NLT 80% in acetate buffer of pH 4.5 or further a 100% drug release when dissolution is followed further in phosphate buffer of pH 6.8. The designed formula has a definitive economic significance over existing prior art. The enteric coating polymer solution comprises of non-aqueous solvents.
Further it is proved experimentally by the inventor that HPMCT alone exhibits a drug dissolution profile similar to that exhibited by the innovator CYMBALTA especially in the Acetate buffer 4.5.

Summary of Invention:
Accordingly, one general aspect of the present invention relates to a novel acid-resistant pharmaceutical composition of Duloxetine comprising Hydroxypropyl Methylcellulose Trimellitate (HPMCT) essentially as enteric coating agent which is devoid of a separating layer or a seal coat.
Further compositions may comprise pharmaceutically acceptable excipients eg. Diluents, disintegrants, binders, lubricants, formulation processing aids or excipients as required for formulating the respective dosage forms.
The general aspect of the invention also encompasses Duloxetine Hydrochloride which has been provided enteric protection with HPMCT in a form such that it is feasible to be filled in final dosage form of a capsule.
In an aspect of the invention Hydroxypropylmethyl Cellulose Trimellitate (HPMCT) functions as an enteric coating polymer for Duloxetine Hydrochloride and also prevents the intimate contact of the active ingredient with the gastric environment thus preventing drug degradation and further preventing the possible gastric irritation.
In an aspect, the invention provides pellets comprising; a) Inert core seeds;

b) the said seeds are coated with a layer of binder solution comprising HPMC and Polysorbate 80 which are further powder layered with Duloxetine and Talc to yield the drug loaded pellets.
c) The drug loaded pellets are finally coated with a non-aqueous enteric coating solution, comprising HPMC Trimellitate, Triethy] Citrate and Talc.
In a further aspect of the invention the drug loaded Duloxetine cores are further coated with a non-aqueous enteric coating dispersion comprising a combination of non-aqueous solvents Ethanol and Acetone.
In yet another aspect of the invention the combination of the non-aqueous solvents for the enteric coating dispersion are taken in a defined ratio of Ethanol: Acetone of 1:8.
Another aspect relates to a process for preparing Enteric coated Duloxetine Capsules.
Further aspect of the invention relates to the pharmaceutical composition of Duloxetine in the form of spherules, beads, pellets, tablets which are feasible to be filled in empty hard capsules shells to portray the final dosage form.
Specific aspect of the invention relate to inert sugar spheres which are powder layered with Duloxetine and required excipients and protected with the enteric coating polymer HPMCT.

In still further aspect, the formulation of Duloxetine which has been enteric coated with HPMCT exhibits a dissolution similar to that of the innovator with a zero release in acidic buffer of pH 1.2 followed by a further drug release of NLT 80% in acetate buffer of pH 4.5 or further a 100% drug release when dissolution is followed further in phosphate buffer of pH 6.8 unlike other polymers like HPMCP HP50, HPMCP HP55 , Ethyl Cellulose and their combinations which had been tried to achieve and match the desired innovator drug release in the desired dissolution media.
In yet another aspect, the enteric coated Duloxetine pellets are further filled into empty hard gelatin capsule shells or the feasible processed form can be further formulated in the form of tablets, suspensions etc. as required.
Still further aspect of the invention provides a linear formulation of Enteric coated Duloxetine pellets for both 30 mg and 60 mg doses thus economizing the scale up stability and bio study cost.
An aspect of the invention provides Enteric coated Duloxetine capsules coated with an additional coat of HPMCT to prevent the accidental opening of the capsule when being consumed by the consumer.
Brief Description of Drawings:

Fig. 1 - Graphical representation of the Drug release versus time in 4.5 pH Acetate
buffer media with reference to the different polymers used to achieve the desired
drug release.
Fig 2 - Graphical representation of the Drug release versus time in 6.8 pH Phosphate
buffer media with reference to the different polymers used to achieve the desired
drug release.
Fig 3 - Comparative Graphical representation of the Drug release versus time in 4.5
pH Acetate buffer media with reference to Cymbalta (Innovator) and Duloxetine
formulation comprising HPMCT. _ _
Fig 4 - Comparative Graphical representation of the Drug release versus time in 6.8
pH Phosphate buffer media with reference to Cymbalta (Innovator) and Duloxetine
formulation comprising HPMCT.
Detailed description:
Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (Cmax) of approximately 47ng/mL (40 mg twice-daily dosing) to HOng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10—12 hours and the volume of distribution is approximately 1640L. (Clinical Pharmacokinetics: 1 May 2011 - Volume 50 - Issue 5 -pp 281-294).

Duloxetine undergoes degradation in acidic environment and hence it has to be protected form the gastric acid. Protection of Duloxetine in the gastric sac has been achieved by the use of enteric coating polymers.
A number of enteric coating polymers have been used in prior art but after thorough experimentation it has been found that though these polymers provide protection form stomach acid none of the polymers except Hydroxy propyl methylcellulose Trimellitate (HPMCT) provides a release similar to the innovator product Cymbalta
When analyzed Cymbalta exhibits no drug release in 1.2 pH acidic buffer (which mimics the gastric environment) but does exhibit a drug release of NLT 80% in 4.5 pH buffer. Enteric polymers which failed to exhibit such release in different concentration and combinations are Hydroxypropyl methylcellulose phthalate HP55, Ethyl Cellulose, Eudragit L-30-D~55:rHence it was gathered that these polymers would not match the innovator dissolution profile in 4.5 pH acetate buffer.
Novel enteric coating polymers were used to match the innovator dissolution profile in acetate buffer and it was found that Hydroxypropyl methyl cellulose trimellitate (HPMCT) when used as enteric coating polymer in Duloxetine enteric coated formulations exhibited a dissolution profile similar to the dissolution profile of the innovator Cymbalta especially drug release of NLT 80% in Acetate buffer of pH 4.5 in addition to the dissolution profile matching in acidic and phosphate buffer.

Hydroxypropyl methylcellulose trimellitate (HPMCT) provides protection from gastric acid when the dosage form traverses through the gastric zone. Hydroxypropyl methylcellulose trimelliltate (HPMCT) dissolves at a pH of around 4. The pH range of dissolution can be varied by varying the content of trimellityl groups and the methoxyl substitution of the base polymer such that the drug is released in the alkaline environment of the intestine thus preventing the untimely burst of the drug in the stomach.
Duloxetine is powder layered over inert cores and the cores are further coated with the enteric coating dispersion of Hydroxypropyl methylcellulose trimelHtate (HPMCT), the HPMCT enteric coating dispersion comprises HPMCT dispersed in a solvent combination of Ethanol and Acetone in a defined ratio of 1:8.
The inert cores referred to here for drug layering refer to different inert cores such as sugar spheres (non pareil), Microcrystalline cellulose spheres (Cellets), starch beads or spheres containing waxes , gums etc. which are commercially available or which could be manufactured utilizing inert ingredients by manufacturing processes known in art. Cores of the desired physicochemical characteristics specifically the size and the core ingredients may be used.
Drug layering over the inert cores may be carried out either by Pan layering or coating drums equipment or the Fluidization technology may be utilized to achieve the purpose.

The active ingredient along with a processing aid like a lubricating or bulking agent may be thoroughly blended and thereafter layered over the inert cores which are wetted previously with the binder solution maintaining the desired layering conditions. The additional excipients added along with the active agent not only facilitates the flow and lubricity during the layering process but also enables the final smoothing of the drug core which if further subjected to the enteric coating of HPMCT (Hydroxypropyl methyl cellulose trimellitate) to achieve the drug release which is hindered in the gastric environment but is released in the intestine..
The above objective may also be achieved by use of drug loaded matrix cores which are then coated with the enteric coat of HPMCT (Hydroxypropyl methyl cellulose trimellitate).
The invention is specific to the enteric polymer which is used for enteric coating the drug loaded cores. Special emphasis is laid on the use of HPMCT (Hydroxypropyl methyl cellulose trimellitate) dispersed in a non-aqueous solvent combination of Ethanol and Acetone in a fixed ratio of 1:8.
HPMCT is slowly dispersed in ethanol to form dispersion; acetone is further added to this dispersion which is utilized for enteric coating.
HPMCT (Hydroxypropyl methyl cellulose trimellitate) in the range of 30 to 50 % by weight of the drug loaded dosage form is the preferred enteric polymer of the invention since this was found to be the only polymer exhibiting the drug release

profile, similar to the innovator drug release specifically in pH 4.5 Acetate buffer or pH 6.8 phosphate after having passed unaffected and exhibiting a zero drug release in 1.2 pH acidic buffer mimicking the gastric environment.
Other polymers which were utilized to achieve the desired drug release profile and their dissolution profiles are as depicted below. Polymers used:
1. Ethyl Cellulose
2. Hydroxypropyl methyl cellulose E5
3. Kollicoat MEP
4. Hydroxypropyl methyl cellulose phthalate HP 55 (HPMCP HP55)
5. Hydroxypropyl methyl cellulose phthalate HP 50 (HPMCP HP50)
6. EudragitL30
and mixtures thereof. This is evident from the data as given in Table land 2 and as depicted in appended Figures l and 2
Detailed Description of Drawings:
The appended Fig. 1 and 2 illustrates drug release in 4.5 pH Acetate buffer and 6.8 pH Phosphate buffer exhibited by a Duloxetine formulation comprising the following listed polymers or their mixtures used to achieve the desired drug release profile as exhibited by Cymbalta (Innovator).
The polymers or their mixtures denoted by batch nos. P1 to P12 used for the study are as follows:

P1: Mixture of Ethyl Cellulose (2%) and HPMC E5 (0.5%)
P2: Mixture of Ethyl Cellulose (3%) and HPMC E5 (0.75%)
P3: Mixture of Ethyl Cellulose (2%) and HPMC E5 (0.5%) followed by L30D
P4: Mixture of Ethyl Cellulose (3%) and HPMC E5 (0.75%) followed by L30D
P5: Kollicoat MEP: Extra 2% (Total 8%)
P6: Kollicoat MEP: Extra 4% (Total 10%)
P7: 0.5% Ethyl Cellulose
P8: 1.0% Ethyl Cellulose
P9: SR: Ethyl Cellulose 1% followed by HPMCP HP 55: 2%
P10: EC coating by using HPMC P HP 50 & HPMC P HP 55: 8.5%
P11: HPMC PHP 55: 8%
P12: HPMC PHP 55:16%
Duloxetine HC1 EC pellets 17.0 % w/w
Table 1: Drug release in Acetate buffer pH 4.5 after being resisted in the acidic
media

Dissolution Medium: Acetate Buffer pH 4.5 Drug release (Time in Minutes)
B.No. Polymer details 10 15 30 45 60
P1 Mixture of Ethyl Cellulose (2%) and HPMC E5 (0.5%) 28.7 30.1
P2 Mixture of Ethyl Cellulose (3%) and HPMC E5 (0.75%) 40.5 45.1
P3 Mixture of Ethyl Cellulose (2%) and HPMC E5 (0.5%) followed by L30D 9.0 12.4
P4 Mixture of Ethyl Cellulose (3%) and HPMC E5 (075%) followed by L30D 9.0 12.1

P5
Kollicoat MEP: Extra 2% (Total 8%) 12.3 15.1
P6 Kollicoat MEP: Extra 4% (Total 10%) 10.3 14.6
P7 0.5% Ethyl Cellulose 0.2 0.3 0.8 0.7 1.0
P8 1.0% Ethyl Cellulose 0.5 0.3 0.4 0.7 0.9
P9 SR : Ethyl Cellulose 1% followed by HPMCP HP 55 :.2% 4.7 5.5 12.1 21.7 32.3
P10 EC coating by using HPMC P HP 50 & HPMC PHP 55: 8.5% 0.7 0.8
It is clear from above that the polymers or their mixtures in the combinations did not provide the desired drug release even over a period of 60 minutes in Acetate buffer of pH 4.5.
Table 2: Drug release in Phosphate buffer pH 6.8 after being resisted in the acidic media

Dissolution Medium: Phosphate Buffer pH 6.8 Drug release (Time i n Minutes)
B.No. Polymer details 10 15 30 45 60
PI Mixture of Ethyl Cellulose (2%) and HPMC E5 (0.5%) 14.0 16.6
P2 Mixture of Ethyl Cellulose (3%) and HPMC E5 (0.75%) 17.5 21.1
P3 Mixture of Ethyl Cellulose (2%) and HPMC E5 (0.5%) followed by L30D 30.2 43.3
P4 Mixture of Ethyl Cellulose (3%) and HPMC E5 (0.7.5%) followed by L30D 27.0 41.2
P5 Kollicoat MEP: Extra 2% (Total 8%) 7.0 8.9
P6 Kollicoat MEP: Extra 4% (Total 10%) 8.1 11.4
P7 0.5% Ethyl Cellulose 11.0 26.5 52.6 65.4 74.3
P8 1.0% Ethyl Cellulose 6.2 12.8 35.7 51.2 59.6

P9 SR : Ethyl Cellulose 1% followed by HPMCP HP
55 :2% 5.2 10.5 25.9 44.6 53.4
P10 EC coating by using HPMC P HP 50 & HPMC PHP 55: 8.5% 38.2 53.4 75.7 83.8 87.4
Pll HPMC P HP 55 : 8% 20.2 60.8 87.7 93.1 92.5
P12 HPMC PHP 55: 16% 26.3 58.6 80.6 91.8 91.7
As noted from the data of drug release in 6.8 pH Phosphate buffer it was found that the polymer or their mixture combinations failed to achieve the desired drug release in 6.8 pH Phosphate buffer as well.
The further illustrated example would prove the novelty and inventive concept of the invention but should not be construed to limit the scope of the invention in any way.
Formulation: Duloxetine enteric coated formulation (Pellets)
Table 5:
Composition:

Sr.
No. Ingredients Function B.No. P13 (%)
Stage: Drug Pelle ts
1 Duloxetine HC1 (1 -30%) Active Ingredient 17.00
2 Purified Talc Anti -caking agent 2.035
3 Sugar Spheres (18-20 mesh) Inert core 47.822
4 HPMC E5 Binding agent 0.566
5 Polysorbate 80 Surfactant 0.887
6 IPA Solvent q.s.
Stage: Enteric ( Hoating
1 Drug loaded pellets 100.00
2 HPMC Trimellitate (30 % - 50%) Enteric Polymer 40.00
3 TEC Plasticizer 2.912
4 Talc Anti -caking agent 3.488
5 Ethanol Solvent 100.00
6 Acetone Solvent 800.00

Procedure:
STAGE I: Drug Pellet (DRUG LOADING)
1. Duloxetine HC1 & Purified Talc was passed through specified sieve.
2. The ingredients of step 1 were mixed to form a uniform Duloxetine HC1 Talc blend.
3. HPMC was dissolved in Isopropyl alcohol and, to this Polysorbate 80 was added and stirred to get a clear solution.
4. Sugar spheres of # 18-20 were loaded in the coating pan.
5. Binder solution was sprayed on the Sugar spheres.
6. The dry Duloxetine HC1 Talc blend of step 2 was layered over the Sugar spheres.
7. The drug loaded pellets were dried to achieve LOD of NMT 3.0%w/w.
8. The Drug pellets were stored in double lined poly bags.
STAGE II: Enteric Coating (FBC COATING)
1. Hydroxypropyl methylcellulose Trimellitate (HPMCT) was dissolved in Ethanol under continuous stirring,
2. Acetone was added to the dispersion of step I slowly to get a uniform suspension.
3. Triethyl Citrate and Talc were further added under continuous stirring to get a uniform suspension.
4. Duloxetine Drug pellets of Stage I were loaded in Fluid Bed Coater.
5. The dispersion of step 4 was sprayed on Duloxetine Drug pellets.
8. The enteric coated Duloxetine pellets were dried in Fluid Bed Coater to achieve LOD of NMT 3.0%w/w.
6. The enteric coated Duloxetine pellets were stored in double lined poly bag.
The final enteric coated drug pellets were filled into empty hard gelatin capsule shells as per required dosage or further processed as per final dosage form requirement.

The dissolution profile of the described formulation in 4.5 pH Acetate buffer and 6.8 pH Phosphate buffer in comparison with the innovator product Cymbalta in the same media is as given below In Table 6.
Each 100 mg Pellets contains 17mg Duloxetine HCl
1. Buffer Stage= (2hr in 900mL 0. IN HCl followed by JOOOmL Acetate Buffer pH 4.5),
2. Buffer Stage = (2hr in 750mL O.IN HCl & same solution adjust to pH 6.8 with 250 ml Tri-Sodium Phosphate Buffer 0.2M)
RPM-JOO, Apparatus - Basket
Reference: Cymbalta 60mg, Test: Duloxetine HCl EC pellets! 7 %w/w B. No. P13
Table 6

4.5 pH Acetate buffer 6.8 pH Phosphate buffer
Time in Minutes Cymbalta 60mg (CO12740) B.No.:P13 Cymbalta 60mg (CO12740) B.No.:P13
10 0.0 0.4 23.9 18.5
15 0.0 0.5 38.7 41.3
30 1.2 0.8 64.1 61.9
45 12.8 8.4 75.7 69.5
60 34.1 30.2 82.2 74.0
90 72.3 64.6 89.7 78.7
120 84.4 78.6 91.4 83.0
150' 88.2 82.0
Appended Fig 3 and 4 gives a comparative graphical representation of the drug release profile in 4.5 pH Acetate buffer and 6.8 pH Phosphate buffer media respectively with reference to Cymbalta (Innovator) and Duloxetine formulation comprising HPMCT.
We claim,
1. An acid resistant formulation of Duloxetine comprising Hydroxypropyl methyl cellulose Trimellitate (HPMCT) as the enteric coating polymer.

2. An acid resistant formulation of Duloxetine as claimed in Claim 1 essentially comprising a) an inert core b) Duloxetine coat c) Enteric coat
3. An acid resistant formulation of Duloxetine as claimed in Claim 1 and 2 which does not comprise of any seal coat or a separating layer.
4. An acid resistant formulation of Duloxetine as claimed in preceding claims wherein a blend of Duloxetine along with pharmaceutically acceptable processing aid is layered on the inert core.
5. An acid resistant formulation of Duloxetine as claimed in Claim 5 wherein the processing aid is Purified Talc.
6. An acid resistant formulation of Duloxetine as claimed in preceding claims wherein the enteric polymer Hydroxypropyl methyl cellulose Trimellitate (HPMCT) in the range of 30 % -50% of the drug loaded formulation is essentially dispersed in a defined combinatorial ratio of Ethanol and Acetone.
7. An acid resistant formulation of Duloxetine as claimed in Claim 6 wherein defined combinatorial ratio of Ethanol and Acetone is 1:8.
8. A process for manufacturing an acid resistant formulation of Duloxetine
comprising Hydroxypropyl methyl cellulose Trimellitate (HPMCT) as the
enteric coating polymer comprising the following steps:
i) Preparing the Duloxetine processing aid blend.
ii) Preparing the binder solution.
iii) Spraying the binder solution of step (ii) on the inert cores.
iv) Layering the drug blend of step (i) on the inert cores of step (iii).
v) Drying the drug loaded cores to achieve LOD of NMT 3.0%w/w.

vi) Preparing the enteric coating dispersion comprising Hydroxypropyl
methyl cellulose Trimellitate (HPMCT) vii) Coating the drug loaded cores of step (v) with the enteric coating
dispersion of step (vi). viii) Drying the enteric coated cores of step (vii) to achieve LOD of NMT
3.0%w/w. ix) Further processing the enteric coated Duloxetine cores into the
desired dosage forms.
9. An acid resistant formulation of Duloxetine comprising Hydroxypropyl methyl cellulose Trimellitate (HPMCT) as the enteric coating polymer as described and illustrated.