WO2021126098A1

WO2021126098A1 - Gastro-resistant pellet comprising duloxetine

Info

Publication number: WO2021126098A1
Application number: PCT/TR2019/051105
Authority: WO
Inventors: Ersin Yildirim; Bayram Kanik; Fatma ÖZTÜRK
Original assignee: Santa Farma Ilac Sanayi AS
Current assignee: Santa Farma Ilac Sanayi AS
Priority date: 2019-12-18
Filing date: 2019-12-18
Publication date: 2021-06-24
Anticipated expiration: 2022-06-18

Abstract

The present invention relates to a gastro-resistant pellet or an oral pharmaceutical composition comprising one or more pellets, for use in the treatment of major depressive disorder, peripheral diabetic neuropathy, generalized anxiety disorders and moderate to severe stress urinary incontinence in women to provide additional advantages to the relevant technique.

Description

GASTRO-RESISTANT PELLET COMPRISING DULOXETINE

Field of the Invention The present invention relates to a gastro-resistant pellet or an oral pharmaceutical composition comprising one or more pellets, for use in the treatment of major depressive disorder, peripheral diabetic neuropathy, generalized anxiety disorders and moderate to severe stress urinary incontinence in women to provide additional advantages to the relevant technique.

Background of the Invention Duloxetine is classified as a serotonin norepinephrine reuptake inhibitor (SNRI). The mechanism of action for Duloxetine is based on is the specific inhibition of both serotonin and norepinephrine reuptake, while it weakly inhibits dopamine reuptake besides, it has no significant affinity for histaminergic, dopaminergic, cholinergic or adrenergic receptors.

Chemical name of Duloxetine is (+)-(S)-N-methyl-gamma-(l-naphthyloxy)-2- thiophenepropylamine, and is commonly used as its hydrochloride salt. Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water, its solubility is not pH dependent. The empirical formula is CigHigNOS, which corresponds to a molecular weight of 297.42 as is base and 333.88 as its hydrochloride salt. The structural formula of duloxetine is:

Formula I

The chemical structure of duloxetine hydrochloride is well characterised. It is an optically active molecule, which presents 1 asymmetric carbon, therefore two enantiomers are possible. The S enantiomer has been selected based on both in vitro and in vivo studies. Duloxetine is extensively metabolised by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of duloxetine demonstrate large inter-subject variability (generally 50-60%).

Duloxetine is well absorbed after oral administration with a maximum concentration occurring 6 hours post dose. The absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11 %). Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 hours).

As being a member of selective serotonin reuptake inhibitors (SNRI) which inhibits specifically the reuptake of both serotonin and norepinephrine, duloxetine is used to treat depression particularly major depressive disorder.

Major depressive disorder is reported to be the most common mood disorder, with a lifetime prevalence of about 15% and as high as 25% in women. Despite the availability of effective treatments, many persons with depressive disorders are disabled, and risk of suicide is considerable. It tends to be chronic and both relapse and recurrence are seen frequently.

In addition, duloxetine is also used in the treatment of peripheral diabetic neuropathy, generalized anxiety disorders, as well as the treatment of stress urinary incontinence in women.

The original medicinal product currently marketed in the form of capsule containing enteric- coated pellets under the name YENTREVE^® in the strength of 20 mg and 40 mg was commercially authorized by the European Medicines Agency in August 2004 for moderate to severe stress urinary incontinence (SUI) in women.

YENTREVE^® is in the form of hard gastro-resistant capsule contains duloxetine in the form of the hydrochloride salt that is equivalent to 20 and 40 mg of duloxetine and hypromellose, hydroxypropyl methylcellulose acetate succinate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, sodium lauryl sulphate, gelatine, propylene glycol and shellac. As an another original medicinal product, it is currently marketed in the form of capsule under the name of CYMBALTA^® in the strengths of 30 mg and 60 mg, wherein product contains duloxetine in the form of the hydrochloride salt. Moreover, duloxetine was commercially authorized once again by the European Medicines Agency in December 2004 for the treatment of major depression, diabetic peripheral neuropathy, generalised anxiety disorder.

CYMBALTA^® is in the form of hard gastro-resistant capsule contains enteric coated pellets. CYMBALTA^® enteric coated pellets contain duloxetine hydrochloride, gelatine, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulphate, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate.

Prior art documents describe many enteric compositions of duloxetine and its pharmaceutically acceptable salt thereof.

EP0693282 relates a duloxetine containing enteric-coated pellet formulation comprising an enteric layer including hydroxypropylmethylcellulose acetate succinate (HPMCAS) as enteric polymer.

W02008077939 relates a pharmaceutical pellet composition comprising a duloxetine core and a separating layer in which a sodium chloride salt is used in the form of crystals.

EP2377525 relates pellet composition comprising a core with duloxetine, an intermediate non-porous layer including one or more film forming water-soluble polymers, an enteric layer and an optional finishing layer. In this invention, the methacrylic acid copolymer is used as enteric coating polymer which increases the enteric coating layer’s solubility at a pH value of 6.

EP1919467 relates a duloxetine hydrochloride delayed release formulation comprising an inert core, a drug layer, a separating layer and an enteric layer including at least one methacrylic acid copolymer and hydroxypropyl methyl cellulose phthalate.

W02008020286 relates a delayed release pharmaceutical composition comprising; a core with duloxetine, optionally a separating coat on the core and an enteric coat on the core or on the separating coat wherein the enteric coat comprises methacrylic acid copolymer. EP3035919 relates an enteric-coated tablet consisting of a core comprising duloxetine hydrochloride which is blended uniformly without the use of any liquid with the amount of said compressible sugar being 60-85% by weight calculated on the total weight of the core, and optionally with one or more pharmaceutically acceptable excipients, and an enteric coating layer which is applied directly on the core and comprises methacrylic acid-ethyl acrylate copolymer (1:1) as the only polymer resistant to gastric acid and one or more pharmaceutically acceptable excipients.

EP2453880 relates an enteric duloxetine hydrochloride formulation in pellet form comprising a duloxetine containing core, particularly an inner protective layer coating the duloxetine core, further a separating layer and an enteric layer are applied respectively.

W02010078878 relates to a pharmaceutical dosage form consisting of of plurality of pellets comprise a pellet core with a diameter of 600-1000 micrometer, a drug layer covering the pellet core including duloxetine and binder which layer preferably constitutes 25-40 wt% of the total weight of the pellet, a seperating layer covering the drug layer including a binder and a pore forming component which layer preferably constitutes 3-10wt% of the total weight of the pellet, and enteric coating layer covering the seprating layer including acid resistant polymer, which layer preferably constitutes 10-40 wt% of the total weight of the pellet.

EP2240173 relates to a pharmaceutical compositions comprising a core obtainable by wet granulation including an intimate mixture of duloxetine or pharmaceutically acceptable salts thereof having a micronized particle size wherein the core is covered with an enteric layer including hydroxypropyl methylcellulose phthalate and optionally one or more pharmaceutically acceptable excipients.

W02010037849 relates to enteric pellet comprising; a core including duloxetine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients; an intermediate non-porous layer including one or more film forming water-soluble polymers; an enteric coating layer including polyvinyl acetate phthalate as the enteric polymer, and an optional finishing layer.

EP2170297 relates to a pharmaceutical formulation comprising; a core including an amount of duloxetine, an enteric coating including hydroxypropyl methylcellulose phthalate and a separating layer including polyvinyl alcohol or optionally a cellulose polymer. In particular, with the present invention, suitable dissolution and impurity profiles are targeted for a formulation containing duloxetine hydrochloride and enteric polymer with acidic functional groups. Although, it is already known duloxetine is labile in solution at pH values less than 2.5 due to degradation in the gastric environment. This gastric environment can be generated with the acidic groups in enteric polymer structure and the natural environment of stomach after oral administration. Therefore, enteric coated dosage forms are preferred, which pass through the stomach unchanged and do not release the active substance until they have reached the small intestine.

The present invention relates to a gastro-resistant oral pharmaceutical composition in enteric pellet form comprising Duloxetine hydrochloride with a suitable dissolution and impurity profiles although also comprising enteric polymer having acidic functional groups.

Summary of the Invention

The object of the invention is to develop a gastro-resistant pellet or an oral pharmaceutical composition comprising one or more pellets, for use in the treatment of major depressive disorder, peripheral diabetic neuropathy, generalized anxiety disorders and moderate to severe stress urinary incontinence in women to provide additional advantages to the relevant technique.

Another object of the invention is to provide a pellet dosage form in order to prevent degradation of the Duloxetine hydrochloride in case of contact with the gastric environment in the stomach. Thus, an gastro-resistant oral pharmaceutical composition in enteric pellet form comprising Duloxetine hydrochloride with suitable dissolution and impurity profiles is provided.

The present invention relates to a gastro-resistant pellet comprising a pellet core, drug layer with duloxetine hydrochloride, a separating layer, an enteric layer and a finishing layer, wherein the amount of the enteric layer is from 14.0% to 19.0% (w/w) of the total weight of the composition.

The present invention also relates to an oral pharmaceutical composition comprises one or more pellets according to the invention.

The present invention also relates to the use of a gastro-resistant pellet or oral pharmaceutical compositions comprises one or more pellets according to the invention for the treatment of major depressive disorder, peripheral diabetic neuropathy, generalized anxiety disorders and moderate to severe stress urinary incontinence in women. The present invention also relates to an enteric coating process for preparing a gastro-resistant pellet according to the invention comprises the following steps: i) Hydroxypropyl methylcellulose acetate succinate is dispersed in water during stirring to obtain suspension, ii) Aqueous solution of ammonium hydroxide is added to dispersed hydroxypropyl methylcellulose acetate succinate in water in Step (i), iii) Triethyl citrate and talc are added subsequently to the prepared solution in Step (ii) under stirring, iv) The prepared solution in Step (iii) is sprayed on the pellets that had coated with separating layer previously.

Detailed Description of the Invention

The present invention provides a gastro-resistant pellet comprising a gastro-resistant pellet core, drug layer with duloxetine hydrochloride, a separating layer, an enteric layer and optionally a finishing layer, wherein the amount of the enteric layer is from 14.0% to 19.0% (w/w) of the total weight of the pellet composition.

In the present invention the term “gastro-resistant” refers to a pharmaceutical dosage form which is designed to pass unchanged in acid environment, such as stomach, and dissolves when it leaves the stomach and enters the near neutral environments such as the small intestine. The core of the pellet can be a spherical core that may be made by pelletizing of pharmaceutically acceptable water soluble materials such as sugars or starches or mixtures thereof in a manner know by a skilled person in the art. Preferably the pellet core is a sugar sphere.

In the present invention, gastro-resistant pellet or pellets comprises a pellet core, drug layer, seperating layer, an enteric layer, and a finishing layer.

In a preferred embodiment, pellet core is covered by a drug layer. Drug layer comprises duloxetine hydrochloride, optionally with other excipients. Drug layer is covered by a separating layer. Seperating layer is covered by an enteric layer. Finally, enteric layer is covered by a finishing layer.

In a preffered embodiment, a gastro-resistant pellet comprises duloxetine hydrochloride equivalent to 20 mg to 60 mg duloxetine.

In a further embodiment, pharmaceutical excipients can be added to the drug layer with duloxetine in order to facilitating the coating process which is needed to aid flow, reduce static charge, aid bulk buildup and form a smooth surface. Thus, filler can be selected among the group of talc, kaolin, and titanium dioxide. Preferably, the filler is talc in drug layer composition.

Morever, the duloxetine can be made to adhere to the beads by spraying a pharmaceutical excipient such as coating polymer wherein the coating polymer can be selected among the group comprising gelatin, hydroxypropyl methylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone. Preferably, the coating polymer is hydroxypropyl methylcellulose in drug layer composition.

Solvent can be used to obtain a dispersion solution containing hydroxypropyl methylcellulose, duloxetine hydrochloride and talc. Preferably, the solvent is water.

In another embodiment, the enteric layer comprises at least one excipient selected from the group consisting of enteric cellulosic polymers, fillers, neutralization agents, solvents and plasticizers.

Preferably, the enteric cellulosic polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS). More preferably, the acetyl content of hydroxypropyl methylcellulose acetate succinate is between 7-ll%(w/w) and the succionayl content of hydroxypropyl methylcellulose acetate succinate is between 10-14% (w/w), by weight of the total hydroxypropyl methylcellulose acetate succinate

In another embodiment, the amount of hydroxypropyl methylcellulose acetate succinate is between 30 mg to 45 mg in the total pellet composition.

HPMCAS is a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethyl cellulose. It has three grades extent of substitution of acetyl and succinoyl groups which is defined as containing not less than 4% and not more than 28% of succinoyl groups, and not less than 5% and not more than 14% acetyl groups which are L, M, H. Each grade is available in different particle sizes, F (fine) and G (granular).

The preferred HPMCAS used in the enteric layer has 7-11% acetyl content and 10-14% succionayl content due to having medium succinyl group content, which is called HPMCAS - MF. The solubility HPMCAS-MF is at pH 6.0. D90 value of particle size of HPMCAS-MF is measured by using laser diffraction method is lower than 20 micrometers.

Preferably, filler can be selected from talc, silicon dioxide and alike is added to build up the thickness of the layer, to strengthen it, to reduce static charge, and to reduce particle cohesion. More preferably, the filler used in the enteric layer is talc.

Preferably, plasticizer can be selected from propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate and the like is used to increase the flexibility and strength of the layer. More preferably, plasticizer used in the enteric layer is triethyl citrate.

The solvent can be used to obtain a dispersion containing triethyl citrate, the preferred HPMCAS as mentioned, talc and aqueous ammonium hydroxide. Preferably, the solvent is water.

Preferably, neutralization agent is aqueous solution of ammonia which is in the form of aqueous ammonium hydroxide. Use of neutralizing agent to the polymer provides to facilitate the dissolution of the polymer in the solvent.

In a preffered embodiment, the neutralization agent used in enteric layer is aqueous ammonium hydroxide at 25% concentration.

The present invention also provides oral pharmaceutical compositions comprises one or more pellets, wherein pellet/s comprising a gastro-resistant pellet core, drug layer with duloxetine hydrochloride, a separating layer, an enteric layer and a finishing layer, wherein the amount of the enteric layer is from 14.0% to 19.0% (w/w) of the total weight of the pellet composition. This gastro-resistant oral pharmaceutical compositions also provides suitable dissolution and impurity profiles.

In a further embodiment, the oral pharmaceutical composition according to the invention is in capsule form.

The present invention further provides a gastro-resistant pellet according to the invention or an oral pharmaceutical composition comrising one or more pellet according to invention for use in the treatment of major depressive disorder, peripheral diabetic neuropathy, generalized anxiety disorders and moderate to severe stress urinary incontinence in women.

The present invention also provides an enteric coating process for preparing a gastro-resistant pellet according to the invention, wherein the process comprises the following steps: i) Hydroxypropyl methylcellulose acetate succinate is dispersed in water during stirring to obtain suspension, ii) Aqueous solution of ammonium hydroxide is added to dispersed hydroxypropyl methylcellulose acetate succinate in water in Step (i), iii) Triethyl citrate and talc are added subsequently to the prepared solution in Step (ii) under stirring, iv) The prepared solution in Step (iii) is sprayed on the pellets that had coated with separating layer previously.

The pellets can be filled into capsules to obtain an oral pharmaceutical composition comprising one or more pellets according to the invention. Preferably, the acetyl content of hydroxypropyl methylcellulose acetate succinate is between 7-ll%(w/w) and the succionayl content of hydroxypropyl methylcellulose acetate succinate is between 10-14% (w/w), by weight of the total hydroxypropyl methylcellulose acetate succinate.

The present invention also provides a process for preparing a pellet core coated with drug layer comprising the following steps: i) Hydroxypropyl methylcellulose was dispersed in water during stirring until obtained homogenous distribution, ii) Duloxetine hydrochloride was added to the prepared dispersion is Step (i) under stirring, iii) Talc was added to the prepared dispersion is Step (ii) under stirring, iv) The pellet cores were coated by spraying the prepared dispersion in Step (iii) with fluid bed drier, v) The obtained cores in Step (iv) were dried.

The pellet core comprising the drug layer is coated by a separating layer that is essential to provide a smooth base for the application of the enteric layer, prolonging the formulation's resistance to the acidic environment of the stomach, improving stability of the formulation by inhibiting interaction between the duloxetine hydrochloride and the enteric layer, or improving storage stability of the formulation by protecting the duloxetine hydrochloride from exposure to light.

In a preffered embodiment, the separating layer comprises sucrose as a derivative of sugar with the advantage of its incompatible and sticky properties which holds the excipients together used in separating layer.

The separating layer may further comprise a coating polymer, filler and solvent. Coating polymers such as hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and others may be used in small amounts to increase the adherence and coherence of the separating layer. Preferably, coating polymer is hydroxypropyl methylcellulose in separating layer composition. Fillers such as talc, silicon dioxide and the like are added as is convenient in the circumstances to fill and smooth the separating layer. Preferably, filler is talc in separating layer composition. Solvents can be used to obtain a dispersion containing sucrose, hydroxypropyl methylcellulose and talc. Preferably, the solvent is water.

Pellet core which is covered by the drug layer, can be coated with a seperating layer by spraying the aqueous dispersion of the sucrose, talc and hydroxypropyl methylcellulose. The present invention also provides a coating process of separating layer for the pellet core coated with drug layer previously that comprises the following steps: i) Sucrose, talc and hydroxypropyl methylcellulose were dispersed in water under stirring, ii) The prepared dispersion in Step (i) was sprayed on the pellets that had coated with drug layer at the previous process and dried.

In a preffered embodiment, a pellet comprising a pellet core, drug layer and separating layer is coated with an enteric layer. Enteric pharmaceutical formulations are those which remain unchanged in the stomach, but dissolve and release the active ingredient after it reachs the small intestine. Since duloxetine is known to have poor stability and be incompatible with gastric juice that causes to decompase easily in an acidic environment, enteric layer must be applied on separating layer.

In a preffered embodiment, the enteric layer comprises at least one excipient selected from the group consisting of enteric cellulosic polymers, fillers, neutralization agents, solvents and plasticizers.

In a preffered embodiment, a plasticizer such as propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate and others is used to increase the flexibility and strength of the layer. Preferably, plasticizer used in the enteric layer is triethyl citrate.

In a preffered embodiment, a filler such as talc, silicon dioxide and others is added to build up the thickness of the layer, to strengthen it, to reduce static charge, and to reduce particle cohesion. Preferably, filler used in the enteric layer is talc.

In a preffered embodiment, an enteric cellulosic polymer must be chosen by considering its compatibility with duloxetine. Hydroxypropylmethyl cellulose acetate succinate (HMPCAS) polymer can be selected in the enteric layer due to small number of carboxylic acid groups per unit weight or repeating unit of the polymer.

In a preffered embodiment, the neutalization agent used in enteric layer is aqueous solution of ammonia which is in the form of aqueous ammonium hydroxide. Use of neutralizing agent to the polymer provides to facilitate the dissolution of the polymer in the solvent.

In a preffered embodiment, the neutalization agent used in enteric layer is aqueous ammonium hydroxide at 25% concentration.

Solvent is used to obtain a dispersion containing triethyl citrate, HPMCAS, talc and aqueous ammonium hydroxide. Preferably, the solvent is water. In a preffered embodiment, the amount of the HPMCAS used in the total pellet composition is between 30 mg - 45 mg. In the present invention, the amount range of the preferred HPMCAS is also affecting the amount of enteric layer in the total pellet composition since the amount of other pharmaceutically acceptable excipients are kept constant.

Table 1: Amount of the HPMCAS (preferably HPMCAS -MF) and enteric layer in the gastro- resistant oral formulation comprising duloxetine hydrochloride.

In the present invention, the solubility of gastro-resistant pellets or oral pharmaceutical compositions comprising one or more pellets are dependent on the amount of enteric layer on the pellet. The enteric layer applied on pellet core previously coated with drug layer and separating layer, prevents duloxetine hydrochloride dissolution require additional time for gastric emptying.

The dissolution profile of the gastro-resistant pellet or an oral pharmaceutical composition comprising one or more pellets are determined by the following procedure:

The dissolution test is carried out at 0.1N HCI solution for 2 hours. After 2 hours, test continues at pH 6.8 phosphate buffer, USP apparatus I (basket) at 37°C±0.5°C, 100 rpm rotation speed. Volume of dissolution medium is 1000 ml.

Amounts of dissolved active ingredients over time were determined by HPLC. Almost no dissolution of duloxetine is observed after 2-hour duration in 0.1N HCI solution. Further, performing dissolution test was continued at pH 6.8 phosphate buffer. Table 2: Results of dissolution test at pH 6.8 phosphate buffer for the gastro-resistant oral pellets comprising duloxetine hydrochloride

According to the present invention, the targetted dissolution profile is provided for the gastro- resistant oral pellet comprising in amounts between 14.0% to 19.0% enteric layer by weight of total pellet composition. More specifically, the targetted dissolution profile is provided by means of certain quantities of enteric layer having different quantities of HPMCAS, preferably HPMCAS -MF.

Amounts of impurities originated from degradation due to qualitative/quantitative composition and manufacturing process were determined by HPLC.

Table 3: Impurity profile for the gastro-resistant oral pellets comprising duloxetine hydrochloride

Maximum limits for known impurities designated as Imp. B, Imp. C, Imp. D, Imp. E and Imp. F corresponding the impurities described in product monograph of duloxetine gastro-resistant oral pharmaceutical formulation are identified according to the ICH Q3B(R2) Guideline.

The impurity profile of the present invention as being a gastro-resistant pellet is well below of the maximum limit values.

The present invention also provides oral pharmaceutical composition comprises one or more pellets, wherein pellet/s comprising a gastro-resistant pellet core, drug layer with duloxetine hydrochloride, a separating layer, an enteric layer and a finishing layer, wherein the amount of the enteric layer is from 14.0% to 19.0% (w/w) of the total weight of the pellet composition. This gastro-resistant oral pharmaceutical compositions also provides suitable dissolution and impurity profiles. While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

1. A gastro-resistant pellet comprising a gastro-resistant pellet core, drug layer with duloxetine hydrochloride, a separating layer, an enteric layer and optionally a finishing layer, wherein the amount of the enteric layer is from 14.0% to 19.0% (w/w) of the total weight of the pellet composition.

2. A gastro-resistant pellet according to claim 1, wherein the enteric layer comprises at least one excipient selected from the group consisting of enteric cellulosic polymers, fillers, neutralization agents, solvents and plasticizers.

3. A gastro-resistant pellet according to claim 2, wherein the enteric cellulosic polymer is hydroxypropyl methylcellulose acetate succinate.

4. A gastro-resistant pellet according to claim 3, wherein the acetyl content of hydroxypropyl methylcellulose acetate succinate is between 7-ll%(w/w) and the succionayl content of hydroxypropyl methylcellulose acetate succinate is between 10-14% (w/w), by weight of the total hydroxypropyl methylcellulose acetate succinate.

5. A gastro-resistant pellet according to claim 4, wherein the amount of hydroxypropyl methylcellulose acetate succinate is between 30 mg to 45 mg in the total pellet composition.

6. A gastro-resistant pellet according to claim 2, wherein the filler is talc.

7. A gastro-resistant pellet according to claim 2, wherein the plasticizer is triethyl citrate.

8. A gastro-resistant pellet according to claim 2, wherein the solvent is water.

9. A gastro-resistant pellet according to claim 2, wherein the neutralization agent is aqueous solution of ammonium hydroxide.

10. A gastro-resistant pellet according to claim 1, wherein the pellet comprises duloxetine hydrochloride equivalent to 20 mg to 60 mg duloxetine.

11. An oral pharmaceutical composition comprises one or more gastro-resistant pellets according to any preceding claims.

12. An oral pharmaceutical composition according to claim 11, wherein the composition is in capsule form.

13. A gastro-resistant pellet according to claim 1-10 or an oral pharmaceutical composition according to claim 11-12 for use in the treatment of major depressive disorder, peripheral diabetic neuropathy, generalized anxiety disorders and moderate to severe stress urinary incontinence in women.

14. An enteric coating process for preparing a gastro-resistant pellet according claim 1-10, wherein the process comprises the following steps: i) Hydroxypropyl methylcellulose acetate succinate is dispersed in water during stirring to obtain suspension, ii) Aqueous solution of ammonium hydroxide is added to dispersed hydroxypropyl methylcellulose acetate succinate in water in Step (i), iii) Triethyl citrate and talc are added subsequently to the prepared solution in Step (ii) under stirring, iv) The prepared solution in Step (iii) is sprayed on the pellets that had coated with separating layer previously.

15. A process according to claim 13, wherein the acetyl content of hydroxypropyl methylcellulose acetate succinate is between 7-ll%(w/w) and the succionayl content of hydroxypropyl methylcellulose acetate succinate is between 10-14% (w/w), by weight of the total hydroxypropyl methylcellulose acetate succinate.