WO2011148380A1 - Oral pharmaceutical composition of duloxetine - Google Patents
Oral pharmaceutical composition of duloxetine Download PDFInfo
- Publication number
- WO2011148380A1 WO2011148380A1 PCT/IN2010/000353 IN2010000353W WO2011148380A1 WO 2011148380 A1 WO2011148380 A1 WO 2011148380A1 IN 2010000353 W IN2010000353 W IN 2010000353W WO 2011148380 A1 WO2011148380 A1 WO 2011148380A1
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- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- delayed release
- release pharmaceutical
- duloxetine
- cellulose
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
Definitions
- the present invention relates to an oral pharmaceutical composition of duloxetine or pharmaceutically acceptable salts thereof.
- the invention also relates to a delayed release composition of duloxetine comprising a core containing duloxetine, an optional separating layer, an enteric layer and an optional finishing layer.
- Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), effective for major depressive disorder and it is as effective as venlafaxine in generalized anxiety disorder.
- SSNRI serotonin and norepinephrine reuptake inhibitor
- Duloxetine is chemically (+)-(S)-N-methyl-y-(l-naphthyloxy)-2-thiophene propylamine, and commonly used as its hydrochloride salt.
- duloxetine will refer to the hydrochloride salt of the S-enantiomer unless otherwise specified.
- Duloxetine hydrochloride has the following formula.
- Duloxetine is commercially available as capsules containing delayed release pellets under the trade name CYMBALTATM in the United States. It has been approved by the FDA for the treatment of major depressive disorder, treatment of generalized anxiety disorder, management of neuropathic pain associated with diabetic peripheral neuropathy and management of fibromyalgia. Duloxetine is also commercially available as hard gastro-resistant capsules under the trade names CYMBALTATM and YENTREVETM in Europe. It has been approved by EMEA for the treatment of major depressive disorder, treatment of diabetic peripheral neuropathic pain in adults and treatment of generalized anxiety disorder under the brand name CYMBALTATM and for the treatment of moderate to severe stress urinary incontinence in woman under the trade name YENTREVETM.
- duloxetine being an acid-labile substance is very much susceptible to degradation in the acidic environment of the stomach. Therefore duloxetine is formulated as an enteric coated dosage form to protect it from acid degradation.
- US Patent No. 5,508,276 discloses an enteric duloxetine pellet comprising hydroxypropylmethyl cellulose acetate succinate (HPMCAS) as an enteric coating polymer.
- HPMCAS hydroxypropylmethyl cellulose acetate succinate
- the '276 patent also discloses that the HPMCAS should be neutralized, for example, with ammonia to facilitate its dissolution.
- duloxetine was found to react with many enteric coatings to form a slowly soluble or insoluble coating. This may lead to a disadvantageous drug-releasing profile and/or low bioavailability.
- US patent application no. 2006/0165776 describes an oral pharmaceutical composition comprising a core comprising duloxetine or its pharmaceutically acceptable derivative thereof and the said core comprised of pharmaceutically inert nuclei and duloxetine or its pharmaceutically acceptable derivative thereof mixed and compressed together, an intermediate layer and an enteric layer comprising one or more enteric polymers; wherein the said composition is free of alkaline reacting compounds.
- US patent application no. 2007/0292511 discloses a duloxetine hydrochloride delayed release formulation, comprising an inert core, a drug layer comprising duloxetine hydrochloride, a separating layer and an enteric layer comprising at least one of methacrylic acid copolymer and hydroxypropyl methyl cellulose phthalate.
- US patent application no. 2008/0226711 discloses a delayed release pharmaceutical composition
- a core comprising an inert core coated 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 hydroxypropyl methylcellulose phthalate (HPMCP) or cellulose acetate phthalate (CAP) or polyvinyl acetate phthalate (PVAP).
- HPMCP hydroxypropyl methylcellulose phthalate
- CAP cellulose acetate phthalate
- PVAP polyvinyl acetate phthalate
- the present invention provides a delayed release composition
- a delayed release composition comprising; inert core, a drug layer comprising duloxetine, an optional separating layer, an enteric layer comprising carboxymethyl ethyl cellulose and an optional finishing layer.
- the main objective of the invention is to provide a delayed release composition of duloxetine or its pharmaceutically acceptable salts comprising; inert core, a drug layer comprising duloxetine, an optional separating layer, an enteric layer comprising carboxy methyl ethyl cellulose and an optional finishing layer.
- the main aspect of the present invention is to provide a delayed release formulation comprising:
- a delayed release pharmaceutical composition of duloxetine or its pharmaceutically acceptable salts comprising:
- duloxetine is in the form of its hydrochloride salt.
- the inert core comprises sugar spheres or pellets of microcrystalline cellulose and more preferably, the inert core comprises sugar spheres.
- the drug layer further comprises one or more pharmaceutically acceptable excipients that do not react adversely with duloxetine.
- the pharmaceutically acceptable excipients are selected from diluents, binders and disintegrants.
- the preferable diluent is selected from the group consisting of mannitol, sucrose, sorbitol, starch, modified starches, xylitol, lactose, microcrystalline cellulose, magnesium carbonate, starch, calcium carbonate, dicalcium phosphate, tribasic calcium phosphate, and calcium sulphate.
- the preferable binder is selected from L-hydroxy propyl cellulose, corn starch, polyvinyl pyrrolidine, hydroxyl propyl methyl cellulose, hydroxyl ethyl cellulose and pre-gelatinized starch.
- the disintegrant may be preferably selected from croscarmellose sodium, crospovidone, sodium starch glycolate and low substituted hydroxyl propyl cellulose.
- the pharmaceutically acceptable excipients are selected from sucrose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, crospovidone, talc and mixtures thereof.
- the drug layer comprises duloxetine, sugar spheres, hydroxy propyl methyl cellulose, hydroxy propyl cellulose, sucrose extra fine, crospovidone and talc.
- the drug layer comprises about 15% to about 40% duloxetine, about 30-80% sugar spheres, about 2-10% hydroxy propyl methyl cellulose, about 0-10% hydroxy propyl cellulose, about 0-10% sucrose extra fine, about 1-10% crospovidone and about 1-10% talc, wherein the percentages are by weight of the drug layer.
- the separating layer between drug layer and enteric layer is optional.
- the functions of the separating layer, if applied, are to provide a smooth base for the application of the enteric layer, to prolong the pellet's resistance to acid conditions and to improve stability.
- the preferable separating layer comprises sucrose, hydroxy propyl methyl cellulose and talc.
- the separating layer is present in an amount of about 5-30% based on the total weight of the formulation.
- the separating layer is present in an amount of about 10-25% based on the total weight of the formulation.
- the enteric layer may preferably comprise carboxymethyl ethyl cellulose and povidone.
- the enteric layer is present in an amount of about 5-30% based on the total weight of the formulation.
- the enteric layer is present in an amount of about 10-20% based on the total weight of the formulation.
- the solvent used to make the enteric coating solution is selected from isopropanol, water and mixtures thereof.
- the preferable solvent is a mixture of isopropanol and water.
- the preferable ratio of isopropanol and water used in the enteric coating solution is 1:9 to 9:1.
- a finishing layer is present over the enteric coating layer.
- the optional finishing layer comprises hydroxypropyl methyl cellulose, talc, polyethylene glycol 400 (PEG-400) and titanium dioxide.
- the delayed release pharmaceutical composition of duloxetine is in the form of pellets.
- the film coated duloxetine pellets were then filled into hard gelatin capsules.
- Duloxetine hydrochloride and other inactive ingredients were dispersed in purified water. This dispersion was coated on the sugar spheres in a fluid bed processor.
- Sucrose and hydroxypropyl methyl cellulose were dissolved in purified water and talc dispersed in to this solution under stirring. This dispersion was coated on the drug loaded spheres in a fluid bed processor.
- Hydroxypropyl methyl cellulose, polyethylene glycol, titanium dioxide and talc were added in purified water and this dispersion was coated on the enteric coated pellets in a fluid bed processor.
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- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
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Abstract
The present invention relates to an oral pharmaceutical composition of duloxetine or pharmaceutically acceptable salts thereof. Preferably, the invention relates to a delayed release composition of duloxetine comprising a core containing duloxetine, an optional separating layer, an enteric layer and an optional finishing layer.
Description
ORAL PHARMACEUTICAL COMPOSITION OF DULOXETINE
Field of the invention
The present invention relates to an oral pharmaceutical composition of duloxetine or pharmaceutically acceptable salts thereof. The invention also relates to a delayed release composition of duloxetine comprising a core containing duloxetine, an optional separating layer, an enteric layer and an optional finishing layer.
Background of the Invention
Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), effective for major depressive disorder and it is as effective as venlafaxine in generalized anxiety disorder.
Duloxetine is chemically (+)-(S)-N-methyl-y-(l-naphthyloxy)-2-thiophene propylamine, and commonly used as its hydrochloride salt. In this document, the term "duloxetine" will refer to the hydrochloride salt of the S-enantiomer unless otherwise specified. Duloxetine hydrochloride has the following formula.
Duloxetine is commercially available as capsules containing delayed release pellets under the trade name CYMBALTA™ in the United States. It has been approved by the FDA for the treatment of major depressive disorder, treatment of generalized anxiety disorder, management of neuropathic pain associated with diabetic peripheral neuropathy and management of fibromyalgia. Duloxetine is also commercially available as hard gastro-resistant capsules under the trade names CYMBALTA™ and YENTREVE™ in Europe. It has been approved by EMEA for the treatment of major
depressive disorder, treatment of diabetic peripheral neuropathic pain in adults and treatment of generalized anxiety disorder under the brand name CYMBALTA™ and for the treatment of moderate to severe stress urinary incontinence in woman under the trade name YENTREVE™.
Duloxetine, being an acid-labile substance is very much susceptible to degradation in the acidic environment of the stomach. Therefore duloxetine is formulated as an enteric coated dosage form to protect it from acid degradation.
US Patent No. 5,508,276 discloses an enteric duloxetine pellet comprising hydroxypropylmethyl cellulose acetate succinate (HPMCAS) as an enteric coating polymer. The '276 patent also discloses that the HPMCAS should be neutralized, for example, with ammonia to facilitate its dissolution. The '276 patent also discloses that duloxetine was found to react with many enteric coatings to form a slowly soluble or insoluble coating. This may lead to a disadvantageous drug-releasing profile and/or low bioavailability.
US patent application no. 2006/0165776 describes an oral pharmaceutical composition comprising a core comprising duloxetine or its pharmaceutically acceptable derivative thereof and the said core comprised of pharmaceutically inert nuclei and duloxetine or its pharmaceutically acceptable derivative thereof mixed and compressed together, an intermediate layer and an enteric layer comprising one or more enteric polymers; wherein the said composition is free of alkaline reacting compounds.
US patent application no. 2007/0292511 discloses a duloxetine hydrochloride delayed release formulation, comprising an inert core, a drug layer comprising duloxetine hydrochloride, a separating layer and an enteric layer comprising at least one of methacrylic acid copolymer and hydroxypropyl methyl cellulose phthalate.
US patent application no. 2008/0226711 discloses a delayed release pharmaceutical composition comprising a core comprising an inert core coated 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 hydroxypropyl methylcellulose phthalate (HPMCP) or cellulose acetate phthalate (CAP) or polyvinyl acetate phthalate (PVAP).
Jansen et al, J Pharm Sci, 87 (I), 1998: 81-85 discloses that duloxetine reacts with degradation products or residual free acids present in the enteric polymer such as hydroxypropyl methylcellulose phthalate to form impurities such as phthalamide impurities.
None of the above said prior art discloses the use of carboxymethyl ethyl cellulose as an enteric coating material in the delayed release pharmaceutical composition of duloxetine. The present invention overcomes the above commonly faced stability problems with the enteric coated formulations of duloxetine.
Accordingly, the present invention provides a delayed release composition comprising; inert core, a drug layer comprising duloxetine, an optional separating layer, an enteric layer comprising carboxymethyl ethyl cellulose and an optional finishing layer.
Objective of the Invention
Accordingly, the main objective of the invention is to provide a delayed release composition of duloxetine or its pharmaceutically acceptable salts comprising; inert core, a drug layer comprising duloxetine, an optional separating layer, an enteric layer comprising carboxy methyl ethyl cellulose and an optional finishing layer.
Summary of the Invention
Accordingly, the main aspect of the present invention is to provide a delayed release formulation comprising:
a) an inert core loaded with duloxetine or its pharmaceutically acceptable salts.
b) an optional separating layer.
c) an enteric coating over the sub coating with carboxymethyl ethyl cellulose; and d) an optional finishing layer.
Detailed description of the Invention
According to the present invention there is provided a delayed release pharmaceutical composition of duloxetine or its pharmaceutically acceptable salts comprising:
a) an inert core loaded with duloxetine or its pharmaceutically acceptable salts.
b) an optional separating layer.
c) an enteric coating over the sub coating with carboxy methyl ethyl cellulose; and d) an optional finishing layer.
Preferably, duloxetine is in the form of its hydrochloride salt.
Preferably, the inert core comprises sugar spheres or pellets of microcrystalline cellulose and more preferably, the inert core comprises sugar spheres.
The drug layer further comprises one or more pharmaceutically acceptable excipients that do not react adversely with duloxetine.
Preferably, the pharmaceutically acceptable excipients are selected from diluents, binders and disintegrants.
The preferable diluent is selected from the group consisting of mannitol, sucrose, sorbitol, starch, modified starches, xylitol, lactose, microcrystalline cellulose, magnesium carbonate, starch, calcium carbonate, dicalcium phosphate, tribasic calcium phosphate, and calcium sulphate.
The preferable binder is selected from L-hydroxy propyl cellulose, corn starch, polyvinyl pyrrolidine, hydroxyl propyl methyl cellulose, hydroxyl ethyl cellulose and pre-gelatinized starch.
The disintegrant may be preferably selected from croscarmellose sodium, crospovidone, sodium starch glycolate and low substituted hydroxyl propyl cellulose.
More preferably, the pharmaceutically acceptable excipients are selected from sucrose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, crospovidone, talc and mixtures thereof.
Preferably, the drug layer comprises duloxetine, sugar spheres, hydroxy propyl methyl cellulose, hydroxy propyl cellulose, sucrose extra fine, crospovidone and talc.
More preferably, the drug layer comprises about 15% to about 40% duloxetine, about 30-80% sugar spheres, about 2-10% hydroxy propyl methyl cellulose, about 0-10% hydroxy propyl cellulose, about 0-10% sucrose extra fine, about 1-10% crospovidone and about 1-10% talc, wherein the percentages are by weight of the drug layer.
The separating layer between drug layer and enteric layer is optional. The functions of the separating layer, if applied, are to provide a smooth base for the
application of the enteric layer, to prolong the pellet's resistance to acid conditions and to improve stability.
The preferable separating layer comprises sucrose, hydroxy propyl methyl cellulose and talc.
Preferably, the separating layer is present in an amount of about 5-30% based on the total weight of the formulation.
More preferably, the separating layer is present in an amount of about 10-25% based on the total weight of the formulation.
The enteric layer may preferably comprise carboxymethyl ethyl cellulose and povidone.
The enteric layer is present in an amount of about 5-30% based on the total weight of the formulation.
More preferably, the enteric layer is present in an amount of about 10-20% based on the total weight of the formulation.
The solvent used to make the enteric coating solution is selected from isopropanol, water and mixtures thereof. The preferable solvent is a mixture of isopropanol and water.
The preferable ratio of isopropanol and water used in the enteric coating solution is 1:9 to 9:1.
Optionally, a finishing layer is present over the enteric coating layer.
Preferably, the optional finishing layer comprises hydroxypropyl methyl cellulose, talc, polyethylene glycol 400 (PEG-400) and titanium dioxide.
Preferably, the delayed release pharmaceutical composition of duloxetine is in the form of pellets.
The film coated duloxetine pellets were then filled into hard gelatin capsules.
The following examples further exemplify the invention and are not intended to limit the scope of the invention.
Example 1:
Ingredient Quantity (mg)
Core
Sugar spheres 155.70
Duloxetine hydrochloride 67.30
Hydroxypropyl methyl cellulose 10.00
Hydroxy propyl cellulose 3.00
Sucrose extra fine 3.00
Crospovidone 5.00
Talc 6.00
Purified water q.s
Separating layer
Sucrose 31.00
Hydroxypropyl methyl cellulose 11.00
Talc 11.00
Purified water q.s
Enteric Coating
Carboxy methyl ethyl cellulose 39.00
Povidone 3.00
Isopropanol /Water (7:3) q.s
Total weight 345.00
Example 2:
Ingredient Ouantitv fmg)
Core
Sugar spheres 155.70
Duloxetine hydrochloride 67.30
Hydroxypropyl methyl cellulose 10.00
Sucrose extra fine 3.00
Crospovidone 5.00
Talc 6.00
Purified water q.s
Separating layer
Sucrose 31.00
Hydroxypropyl methyl cellulose 11.00
Talc 11.00
Purified water q.s
Enteric Coating
Carboxy methyl ethyl cellulose 39.00
Povidone 3.00
Isopropanol/Water (8:2) q.s
Total weight 342.00
Example 3:
Ingredient Quantity (mg)
Core
Sugar spheres 155.70
Duloxetine hydrochloride 67.30
Hydroxypropyl methyl cellulose 10.00
Sucrose extra fine 3.00
Crospovidone 5.00
Talc 6.00
Purified water q.s
Separating layer
Sucrose 22.00
Hydroxypropyl methyl cellulose 5.00
Talc 10.00
Purified water q.s
Enteric Coating
Carboxy methyl ethyl cellulose 41.00
Povidone 3.10
Isopropanol /Water (7:3) q.s
Total weight 328.10
Example 4:
Ingredient Quantity (mz)
Core
Sugar spheres 155.70
Duloxetine hydrochloride 67.30
Hydroxypropyl methyl cellulose 13.00
Hydroxypropyl cellulose 3.00
Crospovidone 5.00
Talc 6.00
Purified water q.s
Separating layer
Sucrose 42.40
Hydroxypropyl methyl cellulose 6.60
Talc 13.00
Purified water q.s
Enteric Coating
Carboxy methyl ethyl cellulose 41.80
Povidone 3.20
Isopropanol/Water (7:3) q.s
Total weight 357.00
Example 5:
Ingredient Quantity (me)
Core
Sugar spheres 155.70
Duloxetine hydrochloride 67.30
Hydroxypropyl methyl cellulose 10.00
Sucrose extra fine 3.00
Crospovidone 5.00
Talc 6.00
Purified water q.s
Separating layer
Sucrose 32.00
Hydroxypropyl methyl cellulose 5.00
Talc 10.00
Purified water q.s
Enteric Coating
Carboxy methyl ethyl cellulose 41.00
Povidone 3.10
Isopropanol/Water (7:3) q.s
Total weight 338.10
Preparation process:
The process for preparation of formulations of examples 1-5 as given below.
Core
Duloxetine hydrochloride and other inactive ingredients were dispersed in purified water. This dispersion was coated on the sugar spheres in a fluid bed processor.
Separating Layer
Sucrose and hydroxypropyl methyl cellulose were dissolved in purified water and talc dispersed in to this solution under stirring. This dispersion was coated on the drug loaded spheres in a fluid bed processor.
Enteric Layer
In order to provide enteric coated duloxetine pellets,' the above coated particles were then coated in fluid bed processor with a solution of carboxymefhyl cellulose, povidone in purified water and isopropanol.
Finishing layer
Hydroxypropyl methyl cellulose, polyethylene glycol, titanium dioxide and talc were added in purified water and this dispersion was coated on the enteric coated pellets in a fluid bed processor.
Capsule filling
The above coated pellets were then filled into hard gelatin capsules.
Claims
We claim:
■ 1. A delayed release pharmaceutical composition of duloxetine or its pharmaceutically acceptable salts comprising:
a) an inert core loaded with duloxetine or its pharmaceutically acceptable salts.
b) an optional separating layer.
c) an enteric coating over the sub coating with carboxymethyl ethyl cellulose; and d) an optional finishing layer.
2. The delayed release pharmaceutical composition of claim 1, wherein the duloxetine is in the form of its hydrochloride salt.
3. The delayed release pharmaceutical composition of claim 1, wherein the inert core comprises sugar spheres or pellets of microcrystalline cellulose.
4. The delayed release pharmaceutical composition of claim 3, wherein the inert core comprises sugar spheres.
5.. The delayed release pharmaceutical composition of claim 1, wherein the drug layer comprises one or more pharmaceutically acceptable excipients that do not react adversely with duloxetine.
6. The delayed release pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable excipient is selected from diluents, binders and disintegrants.
7. The delayed release pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable diluent is selected from mannitol, sorbitol, sucrose, starch, modified starches, xylitol, lactose, microcrystalline cellulose, magnesium carbonate, starch, calcium carbonate, dicalcium phosphate, tribasic calcium phosphate, and calcium sulphate.
8. The delayed release pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable binder is selected from hydroxypropyl cellulose, corn starch, polyvinyl pyrrolidine, hydroxyl propyl methyl cellulose, hydroxyethyl cellulose and pre-gelatinized starch.
9. The delayed release pharmaceutical composition of claim 6, wherein the disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate and low substituted hydroxyl propyl cellulose.
10. The delayed release pharmaceutical composition of claim 1, wherein the drug layer comprises duloxetine hydrochloride, sugar spheres, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sucrose extra fine, crospovidone and talc.
11. The delayed release pharmaceutical composition of claim 1, wherein the drug layer comprises 15% to about 40% duloxetine hydrochloride, about 30-80% sugar spheres, about 2-10% hydroxypropyl methyl cellulose, about 0-10% hydroxypropyl cellulose, about 0-10% sucrose extra fine, about 1-10% crospovidone and about 1-10% talc based on the weight of the drug layer.
12. The delayed release pharmaceutical composition of claim 1, wherein the separating layer comprises sucrose, hydroxypropyl methyl cellulose and talc.
13. The delayed release pharmaceutical composition of claim 1, wherein the separating layer is present in an amount of about 5-30% based on the total weight of the formulation.
14. The delayed release pharmaceutical composition of claim 13, wherein the separating layer is present in an amount of about 10-25% based on the total weight of the formulation.
15. The delayed release pharmaceutical composition of claim 1, wherein the enteric layer comprises carboxymethyl ethyl cellulose and povidone.
16. The delayed release pharmaceutical composition of claim 1, wherein the enteric layer is present in an amount of about 5-30% based on the total weight of the formulation.
17. The delayed release pharmaceutical composition of claim 16, wherein the enteric layer is present in an amount of about 10-20% based on the total weight of the formulation.
18. The delayed release pharmaceutical composition of claim 1, wherein the composition comprises a finishing layer over the enteric coating.
19. The delayed release pharmaceutical composition of claim 18, wherein the finishing layer comprises hydroxypropyl methyl cellulose, polyethylene glycol, titanium dioxide and talc.
20. The delayed release pharmaceutical composition of claim 18, wherein the finishing layer is present in an amount of about 2-8% based on the total weight of the formulation.
21. The delayed release pharmaceutical composition of claim 1, wherein the delayed release pharmaceutical composition of duloxetine is in the form of pellets.
22. The delayed release pharmaceutical composition of claim 21, wherein the pellets were filled in hard gelatin capsules.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2799007A CA2799007A1 (en) | 2010-05-25 | 2010-05-25 | Oral pharmaceutical composition of duloxetine |
| ES10852078.4T ES2601841T3 (en) | 2010-05-25 | 2010-05-25 | Duloxetine oral pharmaceutical composition |
| PCT/IN2010/000353 WO2011148380A1 (en) | 2010-05-25 | 2010-05-25 | Oral pharmaceutical composition of duloxetine |
| US13/699,699 US20130224290A1 (en) | 2010-05-25 | 2010-05-25 | Oral Pharmaceutical Composition of Duloxetine |
| EP10852078.4A EP2575457B1 (en) | 2010-05-25 | 2010-05-25 | Oral pharmaceutical composition of duloxetine |
| KR1020127029442A KR20130071430A (en) | 2010-05-25 | 2010-05-25 | Oral pharmaceutical composition of duloxetine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2010/000353 WO2011148380A1 (en) | 2010-05-25 | 2010-05-25 | Oral pharmaceutical composition of duloxetine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011148380A1 true WO2011148380A1 (en) | 2011-12-01 |
Family
ID=45003413
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2010/000353 WO2011148380A1 (en) | 2010-05-25 | 2010-05-25 | Oral pharmaceutical composition of duloxetine |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20130224290A1 (en) |
| EP (1) | EP2575457B1 (en) |
| KR (1) | KR20130071430A (en) |
| CA (1) | CA2799007A1 (en) |
| ES (1) | ES2601841T3 (en) |
| WO (1) | WO2011148380A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103393615A (en) * | 2013-07-24 | 2013-11-20 | 海南华益泰康药业有限公司 | Duloxetine enteric pellet and preparation method thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102242670B1 (en) * | 2014-01-09 | 2021-04-20 | 일동제약(주) | Multicoating pharmaceutical composition containing duloxetin |
| JP2019081753A (en) * | 2017-10-30 | 2019-05-30 | 大原薬品工業株式会社 | Enteric-coated preparation having improved leachability of duloxetine hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030096001A1 (en) * | 2000-06-06 | 2003-05-22 | Cherukuri S. Rao | Encapsulation products and method of controlled release of fluoxetine or mesalamine |
| US20060270731A1 (en) * | 2005-03-14 | 2006-11-30 | Santiago Ini | Pure duloxetine hydrochloride |
| US20080226711A1 (en) * | 2007-03-12 | 2008-09-18 | Torrent Pharmaceuticals Ltd. | Pharmaceutical compositions of duloxetine |
| US20090175935A1 (en) * | 2006-08-14 | 2009-07-09 | Torrent Research Ltd. | Pharmaceutical compositions of duloxetine |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3478445D1 (en) * | 1983-10-06 | 1989-07-06 | Kohjin Co | Process for preparing carboxymethyl ethyl cellulose suitable for enteric coating |
| US5508276A (en) * | 1994-07-18 | 1996-04-16 | Eli Lilly And Company | Duloxetine enteric pellets |
| EP1820800A1 (en) * | 2006-02-17 | 2007-08-22 | KRKA, tovarna zdravil, d.d., Novo mesto | Crystalline forms of duloxetine hydrochloride and processes for their preparation |
| WO2008129501A2 (en) * | 2007-04-20 | 2008-10-30 | Wockhardt Research Centre | Pharmaceutical compositions of duloxetine |
| US20090226517A1 (en) * | 2008-02-06 | 2009-09-10 | Vinita Umashankar Vyas | Pharmaceutical formulations comprising duloxetine |
| DE102009033621A1 (en) * | 2009-07-17 | 2011-01-20 | Add Technologies Ltd. | Separating layers for pharmaceutical preparations for preventing interactions between drugs and pharmaceutical-technological excipients |
-
2010
- 2010-05-25 ES ES10852078.4T patent/ES2601841T3/en active Active
- 2010-05-25 US US13/699,699 patent/US20130224290A1/en not_active Abandoned
- 2010-05-25 WO PCT/IN2010/000353 patent/WO2011148380A1/en active Application Filing
- 2010-05-25 KR KR1020127029442A patent/KR20130071430A/en active Search and Examination
- 2010-05-25 CA CA2799007A patent/CA2799007A1/en not_active Abandoned
- 2010-05-25 EP EP10852078.4A patent/EP2575457B1/en not_active Not-in-force
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030096001A1 (en) * | 2000-06-06 | 2003-05-22 | Cherukuri S. Rao | Encapsulation products and method of controlled release of fluoxetine or mesalamine |
| US20060270731A1 (en) * | 2005-03-14 | 2006-11-30 | Santiago Ini | Pure duloxetine hydrochloride |
| US20090175935A1 (en) * | 2006-08-14 | 2009-07-09 | Torrent Research Ltd. | Pharmaceutical compositions of duloxetine |
| US20080226711A1 (en) * | 2007-03-12 | 2008-09-18 | Torrent Pharmaceuticals Ltd. | Pharmaceutical compositions of duloxetine |
Non-Patent Citations (1)
| Title |
|---|
| See also references of EP2575457A4 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103393615A (en) * | 2013-07-24 | 2013-11-20 | 海南华益泰康药业有限公司 | Duloxetine enteric pellet and preparation method thereof |
| CN103393615B (en) * | 2013-07-24 | 2015-07-15 | 海南华益泰康药业有限公司 | Duloxetine enteric pellet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2575457A4 (en) | 2013-09-11 |
| ES2601841T3 (en) | 2017-02-16 |
| CA2799007A1 (en) | 2011-12-01 |
| EP2575457A1 (en) | 2013-04-10 |
| KR20130071430A (en) | 2013-06-28 |
| US20130224290A1 (en) | 2013-08-29 |
| EP2575457B1 (en) | 2016-08-17 |
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