Stable pharmaceutical compositions comprising duloxetine hydrochloride

Abstract

The present invention relates to stable delayed-release enteric-coated pharmaceutical compositions comprising duloxetine hydrochloride which are composed of a pellet core and multiple coating layers such as drug layer, separating layer and enteric layer presenting suitable in-vitro release and nitrosamine impurity profile.

Description

[0001] DESCRIPTION

[0002] STABLE PHARMACEUTICAL COMPOSITIONS COMPRISING DULOXETINE

[0003] HYDROCHLORIDE

[0004] Field of the Invention

[0005] The present invention relates to stable delayed-release enteric-coated pharmaceutical compositions comprising duloxetine hydrochloride which are composed of a pellet core and multiple coating layers such as drug layer, separating layer and enteric layer presenting suitable in-vitro release and nitrosamine impurity profile.

[0006] Background of the Invention

[0007] 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.

[0008] 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 CisHwNOS, 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:

[0009] Formula I

[0010] 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%).

[0011] 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).

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] As an original medicinal product, 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.

[0018] Prior art documents describe many enteric compositions of duloxetine and its pharmaceutically acceptable salt thereof.

[0019] EP0693282 relates a duloxetine containing enteric-coated pellet formulation comprising an enteric layer including hydroxypropylmethylcellulose acetate succinate (HPMCAS) as enteric polymer.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] EP2018860 relates to a pharmaceiutical composition comprising a core inwhich the active substance is duloxetine hydrochloride, and a separating layer. The stability of the composition is provided by avoiding duloxetine hydrochloride active substance to be exposed to acidic conditions by designing an enteric coating on drug layer.

[0026] W02009087657 relates to stable pharmaceiutical compositions of duloxetine in an enteric coated formulation composed of multiple layers of film forming polymers.

[0027] In the prior arts of the technical field, no composition comprising duloxetine hydrochloride is developed and / or investigated considering nitrosamine impurity levels in duloxetine compositions. Nitrosamine impurity levels in duloxetine compositions should be monitored as per the most updated international guidelines with very low acceptance limit 1.67 ppm.

[0028] The present invention relates to stable delayed-release enteric-coated pharmaceutical compositions comprising duloxetine hydrochloride with a suitable nitrosamine impurity profile under a very low acceptance limit with a high potent risky nature.

[0029] Summary of the Invention

[0030] The object of the invention is to develop stable enteric-coated pharmaceutical compositions comprising one or more pellets presenting delayed-release profile, for use in the treatment of a various diseases such as major depressive disorder, peripheral diabetic neuropathy, generalized anxiety disorders and moderate to severe stress urinary incontinence in women.

[0031] Another object of the invention is to provide a pellet dosage form that prevents the generation of nitrosamine impurities, which are commonly identified and monitored in pharmaceutical products regardless of the ingredients. These nitrosamine impurities may originate from the chemical structure and / or the synthesis route of the active substance.

[0032] Further object of the invention is to provide an enteric-coated pellet comprising a pellet core, drug layer with duloxetine hydrochloride, a separating layer and an enteric layer. The present invention also relates to an oral pharmaceutical composition comprises one or more pellets according to the invention.

[0033] In the object of the invention, an enteric-coated pellet comprises duloxetine hydrochloride equivalent to 20 mg to 60 mg duloxetine as active substance.

[0034] In the present invention, the release profile of duloxetine hydrochloride in three different gastrointestinal pH media is achieved by employing the enteric polymer in amounts between 35 mg - 50 mg in enteric coating layer.

[0035] The present invention also relates to stable pharmaceutical compositions of duloxetine hydrochloride designed in the enteric-coated pellet dosage by employing HPMCAS-MF as enteric polymer between 35 mg - 50 mg in enteric layer with proper neutralization actions.

[0036] The present invention also relates to stable pharmaceutical compositions of duloxetine hydrochloride designed in the enteric-coated pellet dosage form by employing HPMCAS-MF as enteric polymer between 35 mg - 50 mg in enteric layer with performing neutralization in 100%.

[0037] The present invention also relates to stable pharmaceutical compositions of duloxetine hydrochloride designed in the enteric-coated pellet dosage form by employing HPMCAS-MF as enteric polymer between 35 mg - 50 mg in enteric layer with performing neutralization in 100%, the product temperature during neutralization process is between 40°C - 50°C.

[0038] Detailed Description of the Invention

[0039] The present invention relates to a stable delayed-release enteric-coated pharmaceutical pellet composition composed of a pellet core, a drug layer with duloxetine hydrochloride, a separating layer, an enteric layer wherein the process parameters of enteric-coating layer mainly affects nitrosamine impurity levels in the formulation.

[0040] In the present invention the term “enteric-coated” refers to a pharmaceutical dosage form in which the product to pass unchanged through the stomach of the patient, and dissolves and the release the active substance when it leaves the stomach and enters the near neutral environments such as the small intestine. In the present invention, the developed pharmaceutical composition in capsule form comprising duloxetine hydrochloride is an administered orally in the enteric-coated dosage form. Preferably, it is in the enteric-coated pellet dosage form.

[0041] In the present invention, gastro-resistant pellet or pellets comprises a pellet core, drug layer, separating layer, an enteric layer, and optionally finishing layer.

[0042] The preferred pellet core is spherical inert beads conventionally used in the pharmaceutical technology. The most preferred one is prepared from water-soluble materials such as sugars or starches or mixtures thereof in a manner know by a skilled person in the art. In the embodiment of the present invention, the pellet core is preferably a sugar sphere.

[0043] In a preferred embodiment, drug layer comprising duloxetine hydrochloride and at least one pharmaceutical acceptable excipients in function of glidant, binder, disintegrant and granulation solvent is applied on the pellet core.

[0044] In the drug layer of the preferred embodiment, talc is used as glidant, hydroxypropyl methylcellulose is used as binder, polyplasone is used as superdisintegrant and water is used granulation solvent.

[0045] In a preferred embodiment, an enteric-coated pellet comprises duloxetine hydrochloride equivalent to 20 mg to 60 mg duloxetine.

[0046] In one of the embodiment, process of preparing drug layer is composed of preparing homogenous distribution of hydroxypropyl methylcellulose in the water, adding the duloxetine hydrochloride and talc to the prepared homogenous distribution under stirring, respectively, the coating of the pellet cores by spraying the prepared dispersion and further, drying the obtained cores.

[0047] The separating layer between the drug layer comprising duloxetine hydrochloride and the enteric layer is not required, but it is preferred to prevent the duloxetine’ s reaction with many enteric coatings including polymers with acidic groups to form a slowly or even insoluble coating.

[0048] In a preferred embodiment, a separating layer comprising at least one pharmaceutical acceptable excipients in function of talc as glidant, hydroxypropyl methylcellulose as binder, sucrose as pore forming component and water as granulation solvent is applied on the prepared drug layer.

[0049] In one of the embodiment, process of preparing separating layer is composed of preparing the dispersion of sucrose, talc and hydroxypropyl methylcellulose in the water under stirring, coating of the pellets that had coated with drug layer at the previous process by spraying the prepared dispersion, and further, drying the obtained pellets.

[0050] 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.

[0051] In a preferred embodiment, the enteric layer is the final layer of the enteric-coated pellet composition that is comprised of an enteric polymer and at least one pharmaceutical excipients in function of neutralization agent, glidant, plasticizer and granulation solvent.

[0052] In a preferred embodiment, the enteric layer is the final layer of the enteric-coated pellet composition is manufactured by using wet granulation method.

[0053] In a preferred embodiment, the enteric polymer must be chosen by depending on the compatibility with desired release of duloxetine from the pharmaceutical composition. Preferably, hydroxypropyl methylcellulose acetate succinate (HPMCAS) is selected as an enteric polymer. More preferably, HPMCAS-MF is selected an enteric polymer that has 7-11% acetyl content and 10-14% succionayl content.

[0054] HPMCAS is a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethyl cellulose. Thus, it is an acidic polymer and used in enteric-coated compositions as enteric polymer which prevents the drug to expose gastric conditions pathway environment in the stomach. Therefore, this polymer control the release rate to obtain delayed-release duloxetine compositions.

[0055] In a preferred embodiment, aqueous ammonium hydroxide at 25% concentration is used as neutralization agent, talc is used as glidant, triethyl citrate is used as plasticizer and water is used granulation solvent.

[0056] In one of the embodiment, process of preparing enteric layer is composed of preparing a dispersion of HPMCAS-MF in the water, performing of neutralization process of HPMCAS- MF acidic groups with an aqueous ammonium hydroxide as the neutralization agent, adding the talc and triethyl citrate to the dispersion under stirring, respectively, coating of the pellets that had coated with separated layer at the previous process by spraying the prepared dispersion, and further, drying the obtained pellets.

[0057] Nitrosamine impurities are triggered under acidic conditions in the presence of any nitrite material. Therefore, any source of acid is to be neutralized by using ammonia solution as neutralizing agent.

[0058] Embodiments in accordance with the present invention were designed with determined quantitative composition composed of pharmaceutically acceptable ingredients mentioned above. The prepared enteric-coated pellet dosage form comprising one pellet core and three layers. Moreover, the amount of neutralization agent in the total enteric layer is also used in the specified range in all excipient due to being effected by the amount of the HPMCAS-MF during performing neutralization process.

[0059] The amount of rest of pharmaceutically acceptable excipients were kept constant. The amounts of HPMCAS were between 35 mg to 50 mg in the enteric coating layer.

[0060] It is also challenging to design a delayed-release formulation to achieve dissolution profiles in three physiological media along with stability. The asidic nature of HPMCAS is critical and upon the used amount range it can present negative effect on stability. Thus, amount and process parameters of HPMCAS in enteric coating layer was designed to obtain both in-vitro releases and nitrosamine impurity levels within the acceptable international specifications. Thus, neutralization of acidic environment was also studied during the process.

[0061] The common nitrosamine impurities identified in international guidelines are listed on below: N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), Nnitrosomethylphenylamine (NMPA), N-nitrosodiisopropylamine (NDIPA), Nnitrosoisophenylethylamine (NIPEA), N-nitrosodibutylamine (NDBA), and N-nitroso-N-methyl-4-aminobutyric acid (NMBA). The nitrosamine impurities related to chemical structure and route of synthesis of duloxetine hydrochloride active substance is listed on below:

[0062] N-Nitroso Duloxetine

[0063] The generation pathway of a nitrosamine impurity is described in many literature and scientific guidelines. It is reported that a nitrosamine impurity is formed in the presence of nitrite source which exposed to acidic conditions. As a result, HNO2 formed and HNO2 can react with any chemical structure comprising primary, secondary, tertiary and quarternary amine groups.

[0064] First of all, an amine is a type of compound that is derived from ammonia (NH3) as derivatives of ammonia. Primary amines are formed when one hydrogen atom in ammonia is substituted by an alkyl or aromatic group. Secondary amines are those amines that have two organic substituents either alkyl or aryl ones or both. They are bound to the nitrogen together with one hydrogen. Tertiary amines are those where the nitrogen consists of three organic substituents. Quaternary amines are those where the nitrogen consists of four organic substituents.

[0065] Duloxetine represents a chemical structure that contains secondary amine group. Secondary amine groups have the highest potential nature to be the source of nitrosamine impurity formation.

[0066] On the other hand, the embodiments of the present invention designed as an enteric coated pellet composition according to get highest efficacy with the optimal drug amount by guarantee of the lowest adverse effects.

[0067] The enteric coating layer of the embodiments of the present invention improved to get an enteric coated pellet composition according to obtain the highest efficacy with the optimal drug amount by guarantee of the lowest adverse effects considering another trigger effect - product temperature. The product temperature is critical regarding to perform complete and convenient coatin process of enteric layer avoiding any layer capping. However, it can cause an increase in the composition regarding sensitive - easily degraded - nature of duloxetine.

[0068] The present invention also relates to an enteric coating process according to the invention comprises the following steps: a) Hydroxypropyl methylcellulose acetate succinate is dispersed in water during stirring to obtain suspension, b) Aqueous solution of ammonium hydroxide is added to dispersed hydroxypropyl methylcellulose acetate succinate in water in Step (i), c) Triethyl citrate and talc are added subsequently to the prepared solution in Step (ii) under stirring to perform 100% neutralization, d) The prepared solution in Step (iii) is sprayed on the pellets that had coated with separating layer previously. e) The product temperature is maintained between 40°C-50°C during throughout the entire enteric coating process.

[0069] The embodiments of the present invention were subjected to dissolution analysis and subsequently impurity analysis.

[0070] The dissolution conditions are designated considering the gastrointestinal pathway of orally applied dosage forms by the following procedure:

[0071] The dissolution test is performed in pH 1.2 solution for 2 hours, then test continues in pH 4.5 acetate buffer for 2 hours, and then in pH 6.8 phosphate buffer for 2 hours at 37°C±0.5°C with maintaining USP apparatus I (basket) at 100 rpm rotation speed.

[0072] Besides that, the dissolution studies is also carried out in pH 1.2 for 2 hours and then in pH 4.5 acetate buffer and then in pH 6.8 phosphate buffer. These studies are performed to understand the release behavior of duloxetine hydrochloride in the duodenum and jejunum, respectively.

[0073] The amount of dissolved active ingredient over time is determined by HPLC.

[0074] Table 1: The dissolution profiles of enteric-coated duloxetine hydrochloride composition at pH 1.2 for 2 hours, following pH 4.5 for 2 hours and then pH 6.8 media for 2 hours (as transitional media exchange)

[0075] The results confirm that the complete release of duloxetine is provided with the present invention.

[0076] Following, the embodiments were subjected to impurity testing to quantify the levels of nitrosamine impurities by using LCMS / MS.

[0077] Table 2: Impurity profile for the enteric-coated duloxetine hydrochloride composition

[0078] N D. - Not detected.

[0079] The impurity profile of the present invention as being a gastro-resistant pellet is well below of the maximum nitrosamine impurity specifications.

Claims

CLAIMS1. Stable delayed-release enteric-coated pharmaceutical composition comprising duloxetine hydrochloride as active ingredient, and enteric-coating layer wherein,- the enteric coating layer comprising 35 mg to 50 mg Hydroxypropylmethyl cellulose acetate succinate, and one or more pharmaceutically acceptable excipient neutralized till to degree of 100% with an alkaline material, and- the product temperature is between 40°C-50°C during entire enteric-coating process.

2. Stable delayed-release enteric-coated pharmaceutical composition according to claim 1, wherein the composition comprises duloxetine hydrochloride equivalent to 20 mg to 60 mg duloxetine.

3. Stable delayed-release enteric-coated pharmaceutical composition according to claim 1 or 2, wherein the acetyl content of hydroxypropyl methylcellulose acetate succinate is between 7- l l%(w / w) and the succinoyl content of hydroxypropyl methylcellulose acetate succinate is between 10-14% (w / w), by weight of the total hydroxypropyl methylcellulose acetate succinate.

4. Stable delayed-release enteric-coated pharmaceutical compositions according to any preceding claims, wherein the alkaline material is aqueous ammonium hydroxide.

5. Stable delayed-release enteric-coated pharmaceutical compositions according to any preceding claims, wherein the pharmaceutically acceptable excipient is triethyl citrate as plasticizer.

6. Stable delayed-release enteric-coated pharmaceutical compositions according to any preceding claims, wherein the pharmaceutically acceptable excipient is triethyl citrate as glidant is talc.

7. Stable delayed-release enteric-coated pharmaceutical compositions composition according to any one of the preceding claims, wherein the enteric coating process comprises the following steps: a) Hydroxypropyl methylcellulose acetate succinate is dispersed in water during stirring to obtain suspension,b) Aqueous solution of ammonium hydroxide is added to dispersed hydroxypropyl methylcellulose acetate succinate in water in Step (i), c) Triethyl citrate and talc are added subsequently to the prepared solution in Step (ii) under stirring to perform 100% neutralization, d) The prepared solution in Step (iii) is sprayed on the pellets that had coated with separating layer previously. e) The product temperature is maintained between 40°C-50°C during throughout the entire enteric coating process.

8. Stable delayed-release enteric-coated pharmaceutical compositions according to any one of the preceding claims composed of pellet core, drug layer comprising duloxetine hydrochloride as active ingredient, separating layer and enteric-coating layer.

9. Stable delayed-release enteric-coated pharmaceutical compositions according to any one of the preceding claims for use in the treatment of major depressive disorder, peripheral diabetic neuropathy, generalized anxiety disorders and moderate to severe stress urinary incontinence in women.

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