WO2009066181A2 - Oral delayed-release duloxentine hydrochloride pellets - Google Patents
Oral delayed-release duloxentine hydrochloride pellets Download PDFInfo
- Publication number
- WO2009066181A2 WO2009066181A2 PCT/IB2008/003741 IB2008003741W WO2009066181A2 WO 2009066181 A2 WO2009066181 A2 WO 2009066181A2 IB 2008003741 W IB2008003741 W IB 2008003741W WO 2009066181 A2 WO2009066181 A2 WO 2009066181A2
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- WIPO (PCT)
- Prior art keywords
- duloxetine hydrochloride
- delayed
- layer
- release
- pharmaceutically acceptable
- 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
- A61K9/48—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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- the invention relates to oral delayed-release pellets of duloxetine hydrochloride.
- the invention further includes processes for their preparation and utilization.
- Duloxetine hydrochloride (chemical name: (+)-(5)-N-methyl- ⁇ -(l-naphthyloxy)-2- thiophenepropylamine hydrochloride) is a selective serotonin and norepinephrine reuptake inhibitor (SS ⁇ RI) for oral administration.
- Duloxetine hydrochloride has the following formula:
- duloxetine hydrochloride can exist in two enantiomeric forms (R and S), with the S form being the more commercially desirable enantiomer due to its pharmacological activity.
- the term "duloxetine hydrochloride” as used herein will refer to the S enantiomeric form unless otherwise specified.
- CymbaltaTM as capsules containing delayed-release pellets for oral administration for the treatment of major depressive disorder (MDD), for the management of neuropathic pain associated with diabetic peripheral neuropathy and for the treatment of generalized anxiety disorder (GAD).
- MDD major depressive disorder
- GAD generalized anxiety disorder
- duloxetine hydrochloride has been approved by EMEA as hard gastroresistant capsules under the name AriclaimTM and YentreveTM for the treatment of moderate to severe Stress Urinary Incontinence (SUI) for women and under the name Cymbalta M and Xeristar for the treatment of major depressive episodes and for treatment of diabetic peripheral neuropathic pain in adults.
- United States Patent No. 5,508,276 encompasses an enteric duloxetine pellet which necessarily contains a core that includes duloxetine hydrochloride and an enteric layer that includes hydroxypropylmethylcellulose acetate succinate (HPMCAS). Due to the fact that duloxetine hydrochloride exhibits instability in acidic conditions and that the HPMCAS enteric polymer has free acidic groups in the final composition, these pellets require a separating layer between duloxetine hydrochloride- containing core and the enteric layer in order to avoid the degradation of duloxetine hydrochloride. Therefore, the separating layer serves to avoid direct contact between duloxetine hydrochloride and the enteric layer, and consequently to avoid the undesired reaction between each other. Indeed, no additional functionality of this separating layer in the release of the drug is recognized.
- HPMCAS hydroxypropylmethylcellulose acetate succinate
- the invention provides new delayed-release duloxetine hydrochloride pellets containing: i. an inert core; ii. a first layer including duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients; iii. an intermediate layer including at least one cellulosic derivative polymer and optionally one or more pharmaceutically acceptable excipients; and iv. an enteric layer including an enteric polymer and optionally one or more pharmaceutically acceptable excipients.
- the invention provides a process for preparing the above- described delayed-release pellets of duloxetine hydrochloride.
- the process includes: i. applying to inert cores a first layer including duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients; ii. applying to the obtained duloxetine hydrochloride-containing cores an intermediate layer including at least one cellulosic derivative polymer and optionally one or more pharmaceutically acceptable excipients; and iii. applying an enteric layer including an enteric polymer and optionally one or more pharmaceutically acceptable excipients.
- the invention includes the use of above-described capsules containing the enteric pellets of duloxetine hydrochloride according to the invention for the treatment of major depressive disorder (MDD), for the management of neuropathic pain associated with diabetic peripheral neuropathy, for the treatment of generalized anxiety disorder (GAD) and for the treatment of moderate to severe Stress Urinary Incontinence (SUI) for women.
- MDD major depressive disorder
- GAD generalized anxiety disorder
- SUI moderate to severe Stress Urinary Incontinence
- Inert cores are known and commonly used in pharmaceutical compositions and are also commercially available. These inert cores can be made from microcrystalline cellulose, mannitol or a mixture of sucrose and starch (commonly known as sugar spheres). The size range of these inert cores depends on the desired size of the final pellet.
- Preferred inert cores are sugar spheres with a size from approximately 355 to approximately 500 micrometers.
- the inert core is covered by a first layer containing duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients.
- a preferred pharmaceutically acceptable excipient is a polymer which allows the duloxetine hydrochloride to stick to the inert cores.
- Preferred polymers include hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, polyvinylpirrolidone, xanthan gum acacia or gelatin.
- a more preferred polymer is hydroxypropylmethylcellulose.
- a preferred manner of coating the inert cores with the duloxetine hydrochloride is spraying a slurry suspension of duloxetine hydrochloride and the appropriate excipients in water.
- coated cores can be made following this technique in a fluid bed dryer equipped with a
- the preferred equipment is a fluid bed dryer equipped with a Wurster column.
- this first layer can also be obtained by a "powder coating” process where the inert cores are moistened with a binder, duloxetine hydrochloride is added and mixed until homogeneous distribution, and the obtained cores are dried.
- These coated cores could be made following this technique in a high shear granulator, in a non- perforated coating pan or in a fluidized bed dryer equipped with a rotary processor or with a rotating plate.
- the intermediate layer includes a polymeric material.
- the polymer used must be neutral.
- the intermediate layer may also contain one or more pharmaceutically acceptable excipients.
- a preferred neutral polymer is a cellulosic derivative polymer.
- Preferred pharmaceutically acceptable excipients for the intermediate layer are sucrose and talc.
- a preferred intermediate layer weight is from approximately 3% to approximately 60% of the weight of duloxetine hydrochloride-containing core (sugar spheres and duloxetine hydrochloride first layer).
- a more preferred intermediate layer weight is from approximately 5% to approximately 6% of the weight of duloxetine hydrochloride- containing core (sugar spheres and duloxetine hydrochloride first layer).
- the intermediate layer may be applied by spraying aqueous mixtures of the polymeric material with one or more pharmaceutically acceptable excipients.
- a preferred method for applying this intermediate layer uses the fluidized bed dryer equipped with a Wurster column. Alternatively, a fluidized bed dryer equipped with a non-perforated coating pan could be used for applying this intermediate layer.
- the enteric layer controls the place where the dissolution must be produced, i.e., the enteric formulation passes unchanged through the stomach of the patient, and the enteric layer is dissolved and allows delivery of the duloxetine hydrochloride when it leaves the stomach and enters into the small intestine.
- an enteric layer includes a polymeric material.
- the enteric layer also contains one or more pharmaceutically acceptable excipients.
- a preferred enteric polymer is a vinyl derivative polymer, more preferred is a polyvinyl acetate phthalate (tradename SuretericTM).
- a preferred pharmaceutically acceptable excipient with this enteric polymer is an antifoam excipient.
- a preferred antifoam excipient is silicone, more preferred is simethicone (tradename SuretericTM antifoam emulsion).
- enteric polymers include eudragit polymers.
- a preferred eudragit polymer is an ethyl acrylate/methacrylic acid copolymer (1 :1) (tradename EudragitTM L30D55).
- Preferred pharmaceutically acceptable excipients with this enteric polymer are triethyl citrate, talc and titanium dioxide. Further, it has been observed that if titanium dioxide is not used as at least one of the pharmaceutically acceptable excipients with this enteric polymer (i.e. EudragitTM L30D55), the resultant duloxetine pellets show a lower dissolution profile as compared to the pellets contained in the commercially available duloxetine capsules (i.e., Cymbalta®).
- talc as a pharmaceutically acceptable excipient with this enteric polymer can be optional, since the resultant duloxetine pellets show a dissolution profile very similar to the pellets contained in the commercially available duloxetine capsules (i.e., Cymbalta®).
- a preferred enteric layer weight is when there is from approximately 5% to approximately 55% in weight with respect to the total weight of the duloxetine hydrochloride containing core and the intermediate layer (sugar spheres, duloxetine first layer and second layer).
- a more preferred enteric layer weight is when there is from approximately 38% to approximately 46% in weight with respect to the total weight of the duloxetine hydrochloride containing core and the intermediate layer (sugar spheres, duloxetine first layer and second layer).
- the enteric layer may be obtained by spraying a suspension from enteric polymer with water, preferably, or organic solvents.
- a preferred method for applying this layer uses a fluidized bed dryer equipped with a Wurster column.
- a fluidized bed dryer equipped with a non- perforated coating pan could be used for applying this enteric layer.
- the intermediate layer weight is from approximately 5% to approximately 6% in weight with respect to the duloxetine hydrochloride-containing core (sugar spheres and duloxetine hydrochloride first layer)
- the enteric layer weight is from approximately 38% to approximately 46% in weight with respect to the duloxetine hydrochloride containing core and the intermediate layer (sugar spheres, duloxetine first layer and second layer)
- the resultant duloxetine pellets show a dissolution profile very similar to the pellets contained in the commercially available duloxetine capsules (i.e.,
- Example I purified water used during preparation and was then removed. As such, it is not present in the final pellets and is not included in the above list. [0030] The product of Example 1 was made by the following process: A. First Layer (Duloxetine Hydrochloride-Containing Cores)
- step 3a Incorporate the duloxetine hydrochloride into the solution of step 2a with a helix stirrer and vortex formation. Stir until there is a homogeneous dispersion;
- step 5b Coat the product of step 6a until final weight.
- step 5c Pass the dispersion of step 3c through a 0.25mm sieve and maintain with agitation throughout the coating process;
- Example 2 purified water used during preparation and was then removed. As such, it is not present in the final pellets and is not included in the above list. [0032] The product of Example 2 was made by the following process: A. First Layer (Duloxetine Hydrochloride-Containing Cores)
- step 3a Incorporate the duloxetine hydrochloride into the solution of step 2a with a helix stirrer and vortex formation. Stir until homogeneous dispersion;
- step 4a Introduce the sugar spheres into the Wurster column; 5a. Pass the dispersion of step 3a through a 0.5 mm sieve and maintain the dispersion with agitation throughout the coating process; and 6a. Coat the sugar spheres until final weight.
- step 3b Dissolve the sucrose in the solution of step 2b.
- step 4b Incorporate the talc into the solution of step 2b with a helix stirrer and vortex formation. Stir until there is a homogeneous dispersion and maintain the dispersion with agitation throughout the coating process;
- step 5b Coat the product of step 6a until final weight.
- step 3c Maintain the dispersion of step 2c under agitation with a helix stirrer for 15 minutes;
- step 4c Pass the dispersion of step 3c through a 0.25 mm sieve;
- step 5c Add the dispersion of step 4c onto the EudragitTM L30-D55. Maintain the solution with agitation for a minimum of 30 minutes and maintain with agitation throughout the coating process;
- Example 3 **Added as EudragitTM L30D55 In Example 3, purified water used during the preparation and was removed. As such, it is not present in the final pellets and is not included in the above list.
- the product of Example 3 was made by the following process:
- step 3a Incorporate the duloxetine hydrochloride into the solution of step 2a with a helix stirrer and vortex formation. Stir until homogeneous dispersion;
- step 5a Pass the dispersion of step 3a through a 0.5 mm sieve and maintain the dispersion with agitation throughout the coating process;
- step 3b Dissolve the sucrose in the solution of step 2b.
- step 4b Incorporate the talc into the solution of step 3b with a helix stirrer and vortex formation. Stir until homogeneous dispersion and maintain the dispersion with agitation throughout the coating process;
- step 6a Coat the product of step 6a by means of spry-drying until final weight.
- step 3c Pass the dispersion of step 2c through ultraturrax during 15 min;
- step 4c Pass the dispersion of step 3c through a 0.25mm sieve; 5c. Add the dispersion of step 4c onto the EudragitTM L30-D55.
- step 6c Coat the product of step 5b by means of spry-drying until final weight.
- Example 3 The capsules of Example 3 and commercially available Duloxetine capsules (i.e., Cymbalta ® 60mg) were tested for in vitro drug release in 750 mL of HCl 0.1 N and 250 mL OfNa 3 PO 4 0.2 M, having a pH of approximately 6.8 [see USP ⁇ 724> Delayed-Release (Enteric coated) Articles-General Drug Release Standard (Method A) ; current edition]. A USP-I apparatus with baskets speed at 100 rpm was used for the study. The dissolution results are reported in Table 1 (below) and illustrated in Graph 1 (below):
Abstract
The invention relates to oral delay ed-re lease pellets of duloxetine hydrochloride. The invention further includes processes for their preparation and utilization.
Description
ORAL DELAYED-RELEASE DULOXETINE HYDROCHLORIDE PELLETS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to United States Provisional Application No. 60/929,697, filed on July 9, 2007, which application is expressly incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0001] The invention relates to oral delayed-release pellets of duloxetine hydrochloride. The invention further includes processes for their preparation and utilization.
2. Discussion of the Related Art
[0002] Duloxetine hydrochloride (chemical name: (+)-(5)-N-methyl-γ-(l-naphthyloxy)-2- thiophenepropylamine hydrochloride) is a selective serotonin and norepinephrine reuptake inhibitor (SSΝRI) for oral administration. Duloxetine hydrochloride has the following formula:
[0003] Notably, duloxetine hydrochloride can exist in two enantiomeric forms (R and S), with the S form being the more commercially desirable enantiomer due to its pharmacological activity. As such, the term "duloxetine hydrochloride" as used herein will refer to the S enantiomeric form unless otherwise specified.
[0004] Presently, duloxetine hydrochloride has been approved by the FDA under the name
Cymbalta™ as capsules containing delayed-release pellets for oral administration for the treatment of major depressive disorder (MDD), for the management of neuropathic pain associated with diabetic peripheral neuropathy and for the treatment of generalized anxiety disorder (GAD).
[0005] Also, duloxetine hydrochloride has been approved by EMEA as hard gastroresistant capsules under the name Ariclaim™ and Yentreve™ for the treatment of moderate to severe
Stress Urinary Incontinence (SUI) for women and under the name Cymbalta M and Xeristar for the treatment of major depressive episodes and for treatment of diabetic peripheral neuropathic pain in adults.
[0006] United States Patent No. 5,508,276 (equivalent to EP 0 693 282) encompasses an enteric duloxetine pellet which necessarily contains a core that includes duloxetine hydrochloride and an enteric layer that includes hydroxypropylmethylcellulose acetate succinate (HPMCAS). Due to the fact that duloxetine hydrochloride exhibits instability in acidic conditions and that the HPMCAS enteric polymer has free acidic groups in the final composition, these pellets require a separating layer between duloxetine hydrochloride- containing core and the enteric layer in order to avoid the degradation of duloxetine hydrochloride. Therefore, the separating layer serves to avoid direct contact between duloxetine hydrochloride and the enteric layer, and consequently to avoid the undesired reaction between each other. Indeed, no additional functionality of this separating layer in the release of the drug is recognized.
3. Summary of the Invention
[0007] In one aspect, the invention provides new delayed-release duloxetine hydrochloride pellets containing: i. an inert core; ii. a first layer including duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients; iii. an intermediate layer including at least one cellulosic derivative polymer and optionally one or more pharmaceutically acceptable excipients; and iv. an enteric layer including an enteric polymer and optionally one or more pharmaceutically acceptable excipients.
[0008] In another aspect, the invention provides a process for preparing the above- described delayed-release pellets of duloxetine hydrochloride. The process includes: i. applying to inert cores a first layer including duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients; ii. applying to the obtained duloxetine hydrochloride-containing cores an intermediate layer including at least one cellulosic derivative polymer and optionally one or more pharmaceutically acceptable excipients; and
iii. applying an enteric layer including an enteric polymer and optionally one or more pharmaceutically acceptable excipients.
[0009] In another aspect, the invention includes the use of above-described capsules containing the enteric pellets of duloxetine hydrochloride according to the invention for the treatment of major depressive disorder (MDD), for the management of neuropathic pain associated with diabetic peripheral neuropathy, for the treatment of generalized anxiety disorder (GAD) and for the treatment of moderate to severe Stress Urinary Incontinence (SUI) for women.
4. Detailed Description of the Invention
Inert Core
[0010] Inert cores are known and commonly used in pharmaceutical compositions and are also commercially available. These inert cores can be made from microcrystalline cellulose, mannitol or a mixture of sucrose and starch (commonly known as sugar spheres). The size range of these inert cores depends on the desired size of the final pellet.
Preferred inert cores are sugar spheres with a size from approximately 355 to approximately 500 micrometers.
First Layer (Duloxetine Hydrochloride-Containing Cores)
[0011] The inert core is covered by a first layer containing duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients.
[0012] A preferred pharmaceutically acceptable excipient is a polymer which allows the duloxetine hydrochloride to stick to the inert cores. Preferred polymers include hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, polyvinylpirrolidone, xanthan gum acacia or gelatin. A more preferred polymer is hydroxypropylmethylcellulose.
[0013] A preferred manner of coating the inert cores with the duloxetine hydrochloride is spraying a slurry suspension of duloxetine hydrochloride and the appropriate excipients in water.
These coated cores can be made following this technique in a fluid bed dryer equipped with a
Wurster column or a non-perforated coating pan. The preferred equipment is a fluid bed dryer equipped with a Wurster column.
[0014] Alternatively, this first layer can also be obtained by a "powder coating" process where the inert cores are moistened with a binder, duloxetine hydrochloride is added and mixed until homogeneous distribution, and the obtained cores are dried. These coated
cores could be made following this technique in a high shear granulator, in a non- perforated coating pan or in a fluidized bed dryer equipped with a rotary processor or with a rotating plate. In order to reduce static charge, it may be appropriate or convenient to add some inert powders to the duloxetine hydrochloride, such as talc or magnesium stearate.
Intermediate (Second) Layer
[0015] The intermediate layer includes a polymeric material. In order to guarantee the stability of duloxetine hydrochloride, the polymer used must be neutral. Optionally, the intermediate layer may also contain one or more pharmaceutically acceptable excipients. [0016] A preferred neutral polymer is a cellulosic derivative polymer. A preferred cellulosic derivative polymer is methylcellulose, hydroxypropylmethylcellulose or mixtures thereof. The viscosity of these cellulosic derivative polymers can be between approximately 3 to approximately 400 cps (cps = centipoises).
[0017] Preferred pharmaceutically acceptable excipients for the intermediate layer are sucrose and talc.
[0018] A preferred intermediate layer weight is from approximately 3% to approximately 60% of the weight of duloxetine hydrochloride-containing core (sugar spheres and duloxetine hydrochloride first layer). A more preferred intermediate layer weight is from approximately 5% to approximately 6% of the weight of duloxetine hydrochloride- containing core (sugar spheres and duloxetine hydrochloride first layer). [0019] The intermediate layer may be applied by spraying aqueous mixtures of the polymeric material with one or more pharmaceutically acceptable excipients. [0020] A preferred method for applying this intermediate layer uses the fluidized bed dryer equipped with a Wurster column. Alternatively, a fluidized bed dryer equipped with a non-perforated coating pan could be used for applying this intermediate layer.
Enteric Layer
[0021] The enteric layer controls the place where the dissolution must be produced, i.e., the enteric formulation passes unchanged through the stomach of the patient, and the enteric layer is dissolved and allows delivery of the duloxetine hydrochloride when it leaves the stomach and enters into the small intestine. In general, an enteric layer includes a polymeric
material. Optionally, the enteric layer also contains one or more pharmaceutically acceptable excipients.
[0022] A preferred enteric polymer is a vinyl derivative polymer, more preferred is a polyvinyl acetate phthalate (tradename Sureteric™). A preferred pharmaceutically acceptable excipient with this enteric polymer is an antifoam excipient. A preferred antifoam excipient is silicone, more preferred is simethicone (tradename Sureteric™ antifoam emulsion).
[0023] Other preferred enteric polymers include eudragit polymers. A preferred eudragit polymer is an ethyl acrylate/methacrylic acid copolymer (1 :1) (tradename Eudragit™ L30D55). Preferred pharmaceutically acceptable excipients with this enteric polymer are triethyl citrate, talc and titanium dioxide. Further, it has been observed that if titanium dioxide is not used as at least one of the pharmaceutically acceptable excipients with this enteric polymer (i.e. Eudragit™ L30D55), the resultant duloxetine pellets show a lower dissolution profile as compared to the pellets contained in the commercially available duloxetine capsules (i.e., Cymbalta®). Conversely, the use of talc as a pharmaceutically acceptable excipient with this enteric polymer can be optional, since the resultant duloxetine pellets show a dissolution profile very similar to the pellets contained in the commercially available duloxetine capsules (i.e., Cymbalta®).
[0024] A preferred enteric layer weight is when there is from approximately 5% to approximately 55% in weight with respect to the total weight of the duloxetine hydrochloride containing core and the intermediate layer (sugar spheres, duloxetine first layer and second layer). A more preferred enteric layer weight is when there is from approximately 38% to approximately 46% in weight with respect to the total weight of the duloxetine hydrochloride containing core and the intermediate layer (sugar spheres, duloxetine first layer and second layer).
[0025] The enteric layer may be obtained by spraying a suspension from enteric polymer with water, preferably, or organic solvents.
[0026] A preferred method for applying this layer uses a fluidized bed dryer equipped with a Wurster column. Alternatively, a fluidized bed dryer equipped with a non- perforated coating pan could be used for applying this enteric layer. In one embodiment of the invention, when the intermediate layer weight is from approximately 5% to approximately 6% in weight with respect to the duloxetine hydrochloride-containing core (sugar spheres and duloxetine hydrochloride first layer), and the enteric layer weight is
from approximately 38% to approximately 46% in weight with respect to the duloxetine hydrochloride containing core and the intermediate layer (sugar spheres, duloxetine first layer and second layer), the resultant duloxetine pellets show a dissolution profile very similar to the pellets contained in the commercially available duloxetine capsules (i.e.,
Cymbalta®).
[0027] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
[0028] The following examples are for illustrative purposes only and are not intended, nor should they be interpreted, to limit the scope of the invention.
EXAMPLE 1:
Intermediate Layer with Cellulosic Polymer and Enteric Layer with Sureteric™.
[0029] In Example I, purified water used during preparation and was then removed. As such, it is not present in the final pellets and is not included in the above list. [0030] The product of Example 1 was made by the following process:
A. First Layer (Duloxetine Hydrochloride-Containing Cores)
Ia. Weigh sugar spheres, HPMC 6 cps and duloxetine hydrochloride;
2a. Dissolve the HPMC 6 cps in purified water with a helix stirrer. Stir until total dissolution and allow the solution to rest until it becomes clear;
3a. Incorporate the duloxetine hydrochloride into the solution of step 2a with a helix stirrer and vortex formation. Stir until there is a homogeneous dispersion;
4a. Introduce the sugar spheres in the Wurster column;
5a. Pass the dispersion 3a through a 0.5 mm sieve, while maintaining the dispersion with agitation all the coating process; and
6a. Coat sugar spheres until final weight.
B. Intermediate Layer
Ib. Weigh sucrose, HPMC 6 cps and talc;
2b. Dissolve the HPMC 6 cps in purified water, with a helix stirrer. Stir until total dissolution and allow the solution to rest until it becomes clear;
3b. Dissolve the sucrose in the solution of 2b;
4b. Incorporate talc in the solution of 3b with a helix stirrer and vortex formation. Stir until there is a homogeneous dispersion and maintain the dispersion with agitation throughout the coating process; and
5b. Coat the product of step 6a until final weight.
C. Enteric Layer
Ic. Weigh Sureteric™ antifoam emulsion and Sureteric™;
2c. Add Sureteric™ antifoam emulsion into water under agitation by helix stirrer;
3c. Add Sureteric™ into the solution of 2c under agitation by a helix stirrer;
4c. Maintain the solution with agitation for a minimum of 30 minutes;
5c. Pass the dispersion of step 3c through a 0.25mm sieve and maintain with agitation throughout the coating process; and
6c. Coat the product of step 5b until final weight.
D. Capsulation
Id. Capsulate the final product.
EXAMPLE 2:
Intermediate Layer with Cellulosic Polymer and Enteric Layer with Eudragit™.
[0031] In Example 2, purified water used during preparation and was then removed. As such, it is not present in the final pellets and is not included in the above list. [0032] The product of Example 2 was made by the following process: A. First Layer (Duloxetine Hydrochloride-Containing Cores)
Ia. Weigh sugar spheres, HPMC 6 cps and duloxetine hydrochloride;
2a. Dissolve the HPMC 6 cps in purified water with a helix stirrer. Stir until total dissolution and allow the solution to rest until it becomes clear;
3a. Incorporate the duloxetine hydrochloride into the solution of step 2a with a helix stirrer and vortex formation. Stir until homogeneous dispersion;
4a. Introduce the sugar spheres into the Wurster column;
5a. Pass the dispersion of step 3a through a 0.5 mm sieve and maintain the dispersion with agitation throughout the coating process; and 6a. Coat the sugar spheres until final weight.
B. Intermediate layer
Ib. Weigh sucrose, HPMC 6 cps and talc;
2b. Dissolve the HPMC 6 cps in purified water with helix a stirrer. Stir until total dissolution and allow the solution to rest until it becomes clear;
3b. Dissolve the sucrose in the solution of step 2b.
4b. Incorporate the talc into the solution of step 2b with a helix stirrer and vortex formation. Stir until there is a homogeneous dispersion and maintain the dispersion with agitation throughout the coating process; and
5b. Coat the product of step 6a until final weight.
C. Enteric layer
Ic. Weigh Eudragit™ L30D55, triethyl citrate, talc and titanium dioxide;
2c. Incorporate the following in order: triethyl citrate, titanium dioxide, and talc in purified water with a helix stirrer;
3c. Maintain the dispersion of step 2c under agitation with a helix stirrer for 15 minutes;
4c. Pass the dispersion of step 3c through a 0.25 mm sieve;
5c. Add the dispersion of step 4c onto the Eudragit™ L30-D55. Maintain the solution with agitation for a minimum of 30 minutes and maintain with agitation throughout the coating process; and
6c. Coat the product of step 5b until final weight.
D. Capsulation
Id. Capsulate the final product.
[0033] Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the disclosure has been made only by way of example, and that numerous changes in the conditions and order of steps can be resorted to by those skilled in the art without departing from the spirit and scope of the invention.
EXAMPLE 3:
[0034] Intermediate Layer with Cellulosic Polymer (5.5% of the weight of the total of inert core and first layer) and Enteric Layer with Eudragit™ (40.0% of the weight of total of inert core, first, and intermediate layers).
* 67.30 mg/capsule of Duloxetine hydrochloride is equivalent to 60 mg/capsule of
Duloxetine
**Added as Eudragit™ L30D55
In Example 3, purified water used during the preparation and was removed. As such, it is not present in the final pellets and is not included in the above list. The product of Example 3 was made by the following process:
A. First layer (duloxetine hydrochloride-containing cores)
Ia. Weight sugar spheres, HPMC 6 cps and duloxetine hydrochloride;
2a. Dissolve the HPMC 6 cps in purified water with a helix stirrer. Stir until total dissolution and allow the dissolution to rest until it becomes clear;
3a. Incorporate the duloxetine hydrochloride into the solution of step 2a with a helix stirrer and vortex formation. Stir until homogeneous dispersion;
4a. Introduce the sugar spheres into the Wurster column;
5a. Pass the dispersion of step 3a through a 0.5 mm sieve and maintain the dispersion with agitation throughout the coating process; and
6a. Coat the sugar spheres by means of spry-drying until final weight.
B. Intermediate layer
Ib. Weigh sucrose, HPMC 6 cps and talc;
2b. Dissolve the HPMC 6 cps in purified water with a helix stirrer. Stir until total dissolution and allow the dissolution to rest until it becomes clear;
3b. Dissolve the sucrose in the solution of step 2b.
4b. Incorporate the talc into the solution of step 3b with a helix stirrer and vortex formation. Stir until homogeneous dispersion and maintain the dispersion with agitation throughout the coating process; and
5b. Coat the product of step 6a by means of spry-drying until final weight.
C. Enteric layer
Ic. Weigh Eudragit™ L30D55, triethyl citrate, talc and titanium dioxide;
2c. Incorporate the following in order: triethyl citrate, talc and titanium dioxide in purified water with a helix stirrer.
3c. Pass the dispersion of step 2c through ultraturrax during 15 min;
4c. Pass the dispersion of step 3c through a 0.25mm sieve;
5c. Add the dispersion of step 4c onto the Eudragit™ L30-D55.
Maintain the dispersion with agitation throughout the coating process; and
6c. Coat the product of step 5b by means of spry-drying until final weight.
D. Capsulation
Id. Capsulate the final product.
The spry-drying of the coating processes of steps A to C was carried out by means of a fluidized bed dryer equipped with a Wurster column.
EXAMPLE 4:
Dissolution of Duloxetine Capsules of Example 3
The capsules of Example 3 and commercially available Duloxetine capsules (i.e., Cymbalta® 60mg) were tested for in vitro drug release in 750 mL of HCl 0.1 N and 250 mL OfNa3PO4 0.2 M, having a pH of approximately 6.8 [see USP <724> Delayed-Release (Enteric coated) Articles-General Drug Release Standard (Method A) ; current edition]. A USP-I apparatus with baskets speed at 100 rpm was used for the study. The dissolution results are reported in Table 1 (below) and illustrated in Graph 1 (below):
Table 1
Graph 1
EXAMPLES 5-8
Intermediate Layer with Cellulosic Polymer (5-6% of the weight of the total of inert core and first layer) and Enteric Layer with Eudragit™ (38-46% of the weight of total of inert core, first, and intermediate layers).
* 67.30 mg/capsule of Duloxetine hydrochloride is equivalent to 60 mg/capsule of Duloxetine
**Added as Eudragit .T1MM L30D55
In Examples 5-8, purified water used during the preparation and was removed. As such, it is not present in the final pellets and is not included in the above list.
The product of Examples 5-8 was made by the same process as for Example 3, and was concluded at step 6c, to obtain Duloxetine pellets.
EXAMPLE 9:
Dissolution of Duloxetine Pellets of Examples 5 to 8
The pellets of Examples 5 to 8 and duloxetine pellets contained in commercially available Duloxetine capsules (i.e., Cymbalta® 60mg) were tested for in vitro drug release in 750 mL of HCl 0.1 N and 250 mL Of Na3PO4 0.2 M, having a pH of approximately 6.8 [see USP <724> Delayed-Release (Enteric coated) Articles-General Drug Release Standard (Method A) ; current edition]. A USP-I apparatus with baskets speed at 100 rpm was used for the study. The dissolution results are reported in Table 2 (below) and illustrated in Graph 2 (below):
Table 2
Graph 2
Claims
1. A delayed-release duloxetine hydrochloride pellet comprising: i. an inert core; ii. a first layer comprising duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients; iii. an intermediate layer comprising a cellulosic derivative polymer and optionally one or more pharmaceutically acceptable excipients; and iv. an enteric layer comprising an enteric polymer and optionally one or more pharmaceutically acceptable excipients.
2. The delayed-release duloxetine hydrochloride pellet of claim 1, wherein said first layer comprises a polymer that allows the duloxetine hydrochloride to stick to the inert cores.
3. The delayed-release duloxetine hydrochloride pellet of claim 2, wherein said polymer is at least one of hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, polyvinylpirrolidone, xanthan gum, acacia, gelatin and combinations thereof.
4. The delayed-release duloxetine hydrochloride pellet of claim 1, wherein said cellulosic derivative polymer is at least one of methylcellulose, hydroxypropylmethylcellulose and combinations thereof.
5. The delayed-release duloxetine hydrochloride pellet of claim 1, wherein said intermediate layer comprises at least one of sucrose and talc.
6. The delayed-release duloxetine hydrochloride pellet of claim 1, wherein the weight of said intermediate layer is from approximately 3% to approximately 50% with respect to the total weight of the inert core and the first layer.
7. The delayed-release duloxetine hydrochloride pellet of claim 1, wherein said enteric polymer is an ethyl acrylate/methacrylic acid copolymer.
8. The delayed-release duloxetine hydrochloride pellet of claim 7, wherein said ethyl acrylate/methacrylic acid copolymer is a 1 : 1 ethyl acrylate/methacrylic acid copolymer.
9. The delayed-release duloxetine hydrochloride pellet of claim 1, wherein said enteric layer comprises at least one of triethyl citrate, talc, titanium dioxide and combinations thereof.
10. The delayed-release duloxetine hydrochloride pellet of claim 1, wherein the weight of said enteric layer is from approximately 30% to approximately 55% with respect to the total weight of the inert core, the first layer and the intermediate layer.
11. A process for preparing a delayed-release duloxetine hydrochloride pellet, said process comprising the steps of: i. applying to an inert core a first layer comprising duloxetine hydrochloride and optionally one or more pharmaceutically acceptable excipients; ii. applying to the obtained duloxetine hydrochloride-containing core an intermediate layer comprising a cellulosic derivative polymer and optionally one or more pharmaceutically acceptable excipients; and iii. thereafter applying an enteric layer comprising an enteric polymer and optionally one or more pharmaceutically acceptable excipients.
12. The process of claim 11, wherein said first step comprises spray-drying to the inert core a slurry suspension of duloxetine hydrochloride and any optional pharmaceutically acceptable excipients in water.
13. The process of claim 1 1, wherein said second step comprises spray-drying an aqueous mixture of the cellulosic derivative polymer and any optional pharmaceutically acceptable excipients.
14. The process of claim 1 1, wherein said third step comprises spray-drying a suspension in water of the enteric polymer and any optional pharmaceutically acceptable excipients.
15. A delayed-release duloxetine hydrochloride pellet obtained by the processes of any of claims 11 to 14.
16. A pharmaceutical formulation comprising delayed-release duloxetine hydrochloride pellets obtained by the processes of any of claims 1 1 to 14.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US92969707P | 2007-07-09 | 2007-07-09 | |
| US60/929,697 | 2007-07-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2009066181A2 true WO2009066181A2 (en) | 2009-05-28 |
| WO2009066181A3 WO2009066181A3 (en) | 2009-08-20 |
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ID=40667910
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2008/003741 WO2009066181A2 (en) | 2007-07-09 | 2008-07-09 | Oral delayed-release duloxentine hydrochloride pellets |
Country Status (2)
| Country | Link |
|---|---|
| AR (1) | AR067502A1 (en) |
| WO (1) | WO2009066181A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010037849A1 (en) * | 2008-10-02 | 2010-04-08 | Laboratorios Del Dr. Esteve, S.A. | Duloxetine enteric pellets |
| WO2011039768A3 (en) * | 2009-09-17 | 2011-09-01 | Cadila Healthcare Limited | Pharmaceutical compositions for reducing alcohol-induced dose dumping |
| WO2015025261A1 (en) | 2013-08-21 | 2015-02-26 | Adamed Sp. Z O.O. | Duloxetine enteric coated tablet |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0693282A2 (en) * | 1994-07-18 | 1996-01-24 | Eli Lilly And Company | Duloxetine enteric pellets |
| WO1997033880A1 (en) * | 1996-03-11 | 1997-09-18 | Eli Lilly And Company | Methods of treating or preventing interstitial cystitis |
| EP1640000A2 (en) * | 2002-11-27 | 2006-03-29 | Boehringer Ingelheim International GmbH | Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor |
| WO2007034503A2 (en) * | 2005-06-20 | 2007-03-29 | Cadila Healthcare Limited | Controlled release dosage formulation of duloxetine |
| WO2007139886A2 (en) * | 2006-05-22 | 2007-12-06 | Teva Pharmaceutical Industries Ltd. | Duloxetine hydrochloride delayed release formulations |
| EP1938840A1 (en) * | 2006-12-27 | 2008-07-02 | LEK Pharmaceuticals D.D. | Duloxetine composition |
| WO2008129501A2 (en) * | 2007-04-20 | 2008-10-30 | Wockhardt Research Centre | Pharmaceutical compositions of duloxetine |
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2008
- 2008-07-09 WO PCT/IB2008/003741 patent/WO2009066181A2/en active Application Filing
- 2008-07-10 AR ARP080102970A patent/AR067502A1/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0693282A2 (en) * | 1994-07-18 | 1996-01-24 | Eli Lilly And Company | Duloxetine enteric pellets |
| WO1997033880A1 (en) * | 1996-03-11 | 1997-09-18 | Eli Lilly And Company | Methods of treating or preventing interstitial cystitis |
| EP1640000A2 (en) * | 2002-11-27 | 2006-03-29 | Boehringer Ingelheim International GmbH | Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor |
| WO2007034503A2 (en) * | 2005-06-20 | 2007-03-29 | Cadila Healthcare Limited | Controlled release dosage formulation of duloxetine |
| WO2007139886A2 (en) * | 2006-05-22 | 2007-12-06 | Teva Pharmaceutical Industries Ltd. | Duloxetine hydrochloride delayed release formulations |
| EP1938840A1 (en) * | 2006-12-27 | 2008-07-02 | LEK Pharmaceuticals D.D. | Duloxetine composition |
| WO2008129501A2 (en) * | 2007-04-20 | 2008-10-30 | Wockhardt Research Centre | Pharmaceutical compositions of duloxetine |
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| Title |
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| JANSEN P J ET AL: "CHARACTERIZATION OF IMPURITIES FORMED BY INTERACTION OF DULOXETINE HCI WITH ENTERIC POLYMERS HYDROXYPROPYL METHYLCELLULOSE ACETATE SUCCINATE AND HYDROXYPROPYL METHYLCELLULOSE PHTHALATE" JOURNAL OF PHARMACEUTICAL SCIENCE, AMERICAN PHARMACEUTICAL ASSOCIATION, WASHINGTON, US, vol. 87, no. 1, 1 January 1998 (1998-01-01), pages 81-85, XP000891949 ISSN: 0022-3549 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010037849A1 (en) * | 2008-10-02 | 2010-04-08 | Laboratorios Del Dr. Esteve, S.A. | Duloxetine enteric pellets |
| WO2011039768A3 (en) * | 2009-09-17 | 2011-09-01 | Cadila Healthcare Limited | Pharmaceutical compositions for reducing alcohol-induced dose dumping |
| JP2013504562A (en) * | 2009-09-17 | 2013-02-07 | カディラ・ヘルスケア・リミテッド | Pharmaceutical composition for reducing alcohol-induced dose dumping |
| WO2015025261A1 (en) | 2013-08-21 | 2015-02-26 | Adamed Sp. Z O.O. | Duloxetine enteric coated tablet |
Also Published As
| Publication number | Publication date |
|---|---|
| AR067502A1 (en) | 2009-10-14 |
| WO2009066181A3 (en) | 2009-08-20 |
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