WO2009092129A1 - Delayed release pharmaceutical composition of duloxetine - Google Patents
Delayed release pharmaceutical composition of duloxetine Download PDFInfo
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- WO2009092129A1 WO2009092129A1 PCT/AU2009/000028 AU2009000028W WO2009092129A1 WO 2009092129 A1 WO2009092129 A1 WO 2009092129A1 AU 2009000028 W AU2009000028 W AU 2009000028W WO 2009092129 A1 WO2009092129 A1 WO 2009092129A1
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- duloxetine
- particle size
- composition according
- pharmaceutically acceptable
- enteric
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- 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
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to pharmaceutical compositions comprising duloxetine or pharmaceutically acceptable salts thereof having a defined particle size, methods of manufacturing said compositions and use of said compositions in therapy.
- the invention is further directed towards duloxetine or any of its pharmaceutically acceptable salts having a defined particle size.
- Duloxetine chemical name (+) -W-methyl-3- (1- naphthalenyloxy) -3 - (2-thienyl) propanamine, having the structure (I) as shown below, is a dual serotonin and norepinephrine reuptake inhibitor (SNRI) . It is marketed as the hydrochloride salt under the tradename Cymbalta ® by Eli Lilly & Co for the treatment of major depressive episodes, stress urinary incontinence and diabetic peripheral neuropathic pain.
- SNRI norepinephrine reuptake inhibitor
- duloxetine to its hydrochloride salt is described in U.S. Pat. No. 5,491,243 and in Wheeler W. J., et al, J. Label. Cpds. Radiopharm, 1995, 36, 312. In both cases the reactions are performed in ethyl acetate.
- Duloxetine is an example of an acid labile compound and thus is unstable in the acidic environment of the stomach.
- duloxetine is formulated as an enteric-coated composition to delay drug release for two to three hours and thereby protect it from acidic degradation.
- Enteric coatings have been used for many years to arrest the release of the drug from orally ingestible dosage forms. Depending upon the composition and/or thickness, the enteric coatings are resistant to stomach acid for the required periods of time before they begin to dissolve or disintegrate and .permit release of the drug in the lower stomach or upper part of the small intestines .
- Duloxetine is slightly soluble in water, according to the definition in the European Pharmacopoeia 6 th ed, publ 16.07.2007, vol 1. Such compounds very often are micronised to reduce the particle size in an attempt to increase the rate of aqueous dissolution and consequently the effective bioavailability of the compound. Indeed micronisation is the easiest and most common technique available to the skilled person to enhance the dissolution rate and bioavailability of the compound. It is well known that active ingredients which are soluble in water or have been micronised to increase the rate of dissolution are susceptible, when formulated into controlled-release compositions, to a phenomenon known as ⁇ dose-dumping'. That is, release of the active ingredient is delayed for a time, but once release begins to occur the rate of release is very high.
- U.S. Pat. No. 5,508,276 relates to an enteric duloxetine pellet comprising: a) a core consisting of duloxetine and a pharmaceutically acceptable excipient; b) an optional separating layer; c) an enteric layer comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; and d) an optional finishing layer.
- HPMCAS hydroxypropyl methylcellulose acetate succinate
- duloxetine was found to react with many enteric coatings to form a slowly dissolving/eroding or even insoluble coating. Because of this unexpected cross-reactivity, formulations in pellet form were found to have a disadvantageous drug-releasing profile and low bioavailability.
- duloxetine having a micronised particle size, for example, of less than 60 ⁇ m, and thus an increased effective surface area. Further, it was found to be particularly difficult to prepare an enteric formulation with higher levels of drug loading which did not allow some release of duloxetine in acid environments, thus creating a possibility or probability that the drug would be released in the stomach, contrary to the desired method of administration.
- a pharmaceutical composition comprising duloxetine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) characterised in that the duloxetine has a D 90 particle size of about 2-40 ⁇ m.
- the duloxetine is present in a core.
- an enteric layer surrounds the core .
- the enteric layer comprises one or more polymer coat(s) at least one of which is an enteric coat.
- the or at least one of the enteric coat(s) is selected from the group comprising hydroxypropyl methylcellulose phthalate (HPMCP) , methacrylic acid copolymer Type A, methacrylic acid copolymer Type B, methacrylic acid copolymer Type C, hydroxypropyl methylcellulose acetate succinate and mixtures thereof .
- the enteric coating comprises hydroxypropyl methylcellulose phthalate.
- the or at least one of the enteric coat(s) further comprises sodium lauryl sulphate and purified talc.
- the or at least one of the enteric coat(s) further comprise a plasticiser.
- the plasticiser is selected from the group consisting of polyethylene glycol, triethyl citrate and diethyl phthalate .
- compositions comprising one or more sub-coat layers separating the core from the enteric layer.
- the composition further comprises a finishing layer.
- the sub-coat layer and/or finishing layer can comprise hydroxypropyl methylcellulose.
- the sub-coat layer and/or the finishing layer can additionally comprise one or both of purified talc and polyethylene glycol.
- the duloxetine has a D 90 particle size of about 10-35 ⁇ m.
- the duloxetine has a D 90 particle size of about 25-35 ⁇ m.
- duloxetine is present as the hydrochloride salt.
- a composition comprising a unit dosage form selected from the group comprising: tablets, pellets, beads or mini-tablets.
- a delayed- release capsule comprising one or more unit dosage form(s) comprising duloxetine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients characterised in that the duloxetine has a D 90 particle size of about 2-40 ⁇ m.
- a pharmaceutical composition comprising: a) a core consisting of duloxetine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients; and b) an enteric layer characterised in that the duloxetine has a D 90 particle size of about 2- 40 ⁇ m.
- composition further comprises a sub-coat layer surrounding the core.
- composition further comprises a finishing layer surrounding the enteric layer.
- a pharmaceutical composition comprising a core in the form of a tablet, pellet, beadlet or mini-tablet, surrounded by an enteric layer, said core comprising: a) 10-50% duloxetine or a pharmaceutically acceptable salt thereof having a D 90 particle size of 2-40 ⁇ m; b) 10-45% of a filler/diluent; c) 0.5-20% of a binder; d) 0.5-10% of a lubricant; e) 0.5-15% of a disintegrant; and f) 0.1-3% of a glidant.
- a composition wherein the duloxetine has a D 90 particle size of about 10-35 ⁇ m. In an embodiment the duloxetine has a D 90 particle size of about 25-35 ⁇ m. In another preferred embodiment the duloxetine is present as the hydrochloride salt.
- a composition wherein the core comprises: a) Duloxetine HCl 67.38mg b) Microcrystalline Cellulose 101 54mg c) Crospovidone 6mg d) Colloidal Anhydrous Silica 1.62mg e) Hypromellose E3 6mg f) Water qs g) Crospovidone 12mg h) Magnesium Stearate 3mg wherein the duloxetine HCl has a D 90 particle size of 2-40 ⁇ m. In an embodiment the duloxetine HCl has a D 90 particle size of 10-35 ⁇ m. In an embodiment the duloxetine has a D 90 particle size of 25-35 ⁇ m.
- a method of preparing an enteric-coated composition comprising: a) providing a core consisting of duloxetine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients b) applying an enteric layer characterised in that the duloxetine has a D 90 particle size of about 2-40 ⁇ m.
- the duloxetine has a Dg 0 particle size of about 10-35 ⁇ m. In an embodiment the duloxetine has a D 90 particle size of about 25-35 ⁇ m.
- the method further comprises surrounding the core with a sub-coat layer.
- Another embodiment of a method according to the invention comprises surrounding the enteric layer with a finishing layer.
- the enteric layer comprises one or more coat(s) comprising hydroxypropyl methylcellulose phthalate and optionally one or more pharmaceutically acceptable excipients.
- duloxetine or a pharmaceutically acceptable salt thereof having a D 90 particle size of about 2-40 ⁇ m for the treatment of a disorder selected from the group comprising major depressive episode and diabetic peripheral neuropathic pain.
- a method for the treatment of a disorder selected from the group consisting of major depressive episode and diabetic peripheral neuropathic pain comprising administering duloxetine or a pharmaceutically acceptable salt thereof having a D 90 particle size of about 2-40 ⁇ m to a patient in need of such treatment .
- the duloxetine has a D 90 particle size of about 10-35 ⁇ m. In an embodiment the duloxetine has a D 90 particle size of about 25-35 ⁇ m. In a ninth aspect there is provided duloxetine or a pharmaceutically acceptable salt thereof having a D 90 particle size of about 2-40 ⁇ m. In an embodiment the duloxetine has a D 90 particle size of between about 10-35 ⁇ m. In an embodiment the duloxetine has a D 90 particle size of about 25-35 ⁇ m.
- Particle size is often reduced to aid in the formulation of active pharmaceutical compounds .
- Pharmaceutics The Science of Dosage Form Design ed. ME Aulton; ch 10-11 discloses that the function of particle size reduction may be to aid efficient processing of solid particles by facilitating powder mixing, extraction or reducing the bulk volume of a material to improve transportation efficiency. Thus, reduced particle size is sometimes a desirable property for an active pharmaceutical ingredient. Problems can arise however when reducing the particle size of an active pharmaceutical compound to increase aqueous solubility.
- WO2007058593 Al discloses that when formulated in a controlled-release composition, water soluble compounds are susceptible to dose-dumping.
- duloxetine compositions having the advantageous properties provided by duloxetine having a D 90 particle size of micronised proportions and which surprisingly do not suffer from the dose-dumping phenomenon or react to any greater extent with any coating material or excipient that might be present, than the prior art compositions. This is particularly surprising as the skilled person would expect the increase surface area of micronised duloxetine to in fact show increased reactivity with any enteric coating or other susceptible excipient.
- a pharmaceutical composition comprising duloxetine and one or more pharmaceutically acceptable excipient (s) characterised in that the duloxetine has a D 90 particle size of about 2-40 ⁇ m, and optionally comprising an enteric layer surrounding the core.
- the duloxetine has a D 90 particle size of about 10-35 ⁇ m and about 25-35 ⁇ m.
- the core composition may be prepared by any means known in the art.
- the cores can be produced using direct compression or by conventional granulation methods, for example wet or dry granulation, with optional comminution of the granules and with subsequent compression and coating. Granulation methods are described, for example, in Voigt, loc. cit., pages 156-169. The inventors have found that an intimate mixture of duloxetine having the claimed particle sizes and one or more pharmaceutically acceptable tabletting excipients prepared by wet granulation to be particularly advantageous.
- a composition wherein the core comprises : a) 10-50% duloxetine or a pharmaceutically acceptable salt thereof having a D 90 particle size of between 2-40 ⁇ m,- b) 10-45% of a filler/diluent; c) 0.5-20% of a binder; d) 0.5-10% of a lubricant; e) 0.5-15% of a disintegrant; and f) 0.1-3% of a glidant.
- the duloxetine has a D 90 particle size of about 10-35 ⁇ m, or about 25-35 ⁇ m. In another embodiment the duloxetine is present as the hydrochloride salt.
- compositions wherein the core comprises: a) Duloxetine HCl 67.38mg b) Microcrystalline Cellulose 101 54mg c) Crospovidone 6mg d) Colloidal Anhydrous Silica 1.62mg e) Hypromellose E3 6mg f) Water qs g) Crospovidone 12mg h) Magnesium Sterate 3mg wherein the duloxetine HCl has a D 90 particle size of between 2-40 ⁇ m or, in embodiments, between 10-35 ⁇ m or between 25-35 ⁇ m.
- the particle size of the duloxetine may be prepared by any means known in the art for example conventional comminution and de-agglomeration techniques may be used, for example grinding in an air-jet mill, impact mill, a ball mill, vibration mill, mortar mill or pin mill.
- Measurement of the resultant particles may be performed to ensure the duloxetine is within the scope of the invention.
- the known particle size analysis methods are suitable for determining the particle size, for example particle size measurement using light; light- scattering methods or turbidimetric methods, sedimentation methods; for example pipette analysis using an Andreassen pipette, sedimentation scales, photosedimentometers or sedimentation in a centrifugal force field, pulse methods, for example using a Coulter counter, or sorting by means of gravitational or centrifugal force.
- Those methods are described, inter alia, in Voigt, loc. cit. , pages 64-79.
- Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
- Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. AViCeI*) , microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulphate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit 0 ) , potassium chloride, powdered cellulose, sodium chloride, sorbitol, talc or combinations thereof.
- Solid pharmaceutical compositions that are compacted into a dosage form may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
- Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol ), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel*) , hydroxypropyl methylcellulose
- Methocel ⁇ methylcellulose, liquid glucose, magnesium aluminium silicate, maltodextrin, polymeth- acrylates, povidone (e.g. Kollidon ® , Plasdone ® ) , pregelatinized starch, sodium alginate, starch or combinations thereof .
- povidone e.g. Kollidon ® , Plasdone ®
- the dissolution rate and subsequent bioavailability of a compacted solid pharmaceutical composition in the patient ⁇ s intestine may be increased by the addition of a disintegrant to the composition in order to break apart the compacted solid pharmaceutical dosage form.
- Disintegrants include alginic acid, carboxymethylcellulose
- carboxymethylcellulose sodium e.g. Ac-Di-SoI ,
- Primellose colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon CL, Polyplasdone 0 ) , guar gum, magnesium aluminium silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium: , powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ® ) , starch or combinations thereof .
- Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate or combinations thereof.
- a dosage form such as a tablet, minitablet or pellet is made by the compaction of a powdered composition
- the composition is subjected to pressure from a punch and dye.
- Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
- a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
- Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl dihydrogen phosphate, stearic acid, talc, zinc stearate or combinations thereof .
- a core composition comprising duloxetine, microcrystalline cellulose 101, colloidal anhydrous silica, crospovidone, hydrodroxypropyl methylcellulose (e.g. hypromellose E3) and magnesium stearate prepared by a standard wet granulation technique to be particularly advantageous .
- Sub- coat layer comprising duloxetine, microcrystalline cellulose 101, colloidal anhydrous silica, crospovidone, hydrodroxypropyl methylcellulose (e.g. hypromellose E3) and magnesium stearate prepared by a standard wet granulation technique to be particularly advantageous .
- Sub- coat layer comprising duloxetine, microcrystalline cellulose 101, colloidal anhydrous silica, crospovidone, hydrodroxypropyl methylcellulose (e.g. hypromellose E3) and magnesium stearate prepared by a standard wet granulation technique to be particularly advantageous .
- the sub-coat layer between the duloxetine-containing core and the enteric layer is not required, but is a preferred feature of the formulation.
- the functions of the sub-coat layer are to provide a smooth base for the application of the enteric layer, to prolong the pellet's resistance to acid conditions, to improve stability by inhibiting any interaction between the drug and the enteric polymer in the enteric layer, and to improve shelf-life by protecting the drug from light exposure .
- the smoothing function of the sub-coat layer is purely mechanical, the objective of which is to improve the coverage of the enteric layer and to avoid thin spots in it, caused by bumps and irregularities on the core surface. Accordingly, the more uniform the core surface can be made, the less material is needed in the sub-coat layer, and the need for the smoothing characteristic of the sub-coat layer may be avoided entirely when the duloxetine is of extremely fine particle size and the core is made as close as possible to truly spherical.
- the sub-coat layer is composed of coherent or polymeric materials, and finely powdered solid excipients which constitute fillers.
- a polymeric material may also be used in the sub-coat layer.
- substances such as hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and the like may be used in small amounts to increase the adherence and coherence of the sub-coat layer. It is further advisable to use a filler excipient in the sub-coat layer to increase the smoothness and solidity of the layer.
- Substances such as finely powdered talc, silicon dioxide and the like are universally accepted as pharmaceutical excipients and may be added as is convenient in the circumstances to fill and smooth the sub-coat layer.
- the amount of polymeric or coherent material may be in the range of from about 0.1 to about 10%.
- the amount of filler, such as talc, should be in the range of from about 0.1 to about 10%, based on final product weight.
- the sub-coat layer may further comprise a plasticiser to improve the elastic qualities of the sub- coat layer.
- any of the pharmaceutically acceptable plasticisers on the market may be utilised in the compositions according to the invention.
- the inventors have found however that one of polyethylene glycol, triethyl citrate and diethyl phthalate to be advantageous . Polyethylene glycol is particularly advantageous .
- the sub-coat layer may be applied by spraying aqueous solutions of the polymeric material, and dusting in the filler.
- the smoothness and homogeneity of the sub-coat layer can be improved, however, if the filler is thoroughly dispersed as a suspension in the solution or polymeric material, and the suspension is sprayed on the core and dried, using standard equipment.
- the enteric layer is comprised of one or more coats of polymeric material and generally comprises between about 5-30% of the composition as a whole and more preferably between about 10-15%. At least one of the coats must be an enteric polymer, which must be chosen for compatibility with duloxetine as discussed above.
- the preferred enteric polymer is hydroxypropyl methylcellulose phthalate (HPMCP) and generally comprises between about 10-90% of the enteric coat and more preferably between about 50-90%, most preferably between about 70-90%.
- HPMCP hydroxypropyl methylcellulose phthalate
- Enteric polymers may be applied as coatings from aqueous suspensions or from solutions in aqueous or organic solvents.
- Application from organic solvents is presently not at all favoured in the pharmaceutical industry, because of the cost of the solvent and the difficulty in either disposing of solvent vapours or recovering the evaporated solvent. Accordingly, no detailed discussion of application of the enteric layer from organic solvents will be given here, but the pharmaceutical scientist will recognize that such application is entirely possible if circumstances favour it.
- the enteric polymer When the enteric polymer is applied as an aqueous suspension, a problem in obtaining a uniform, coherent film often results. It is very advisable, accordingly, to purchase a fine particle grade or grind the particles of polymer to an extremely small size before application. It is possible either to grind the dry polymer, as in an air- impaction mill or to prepare the suspension and grind the polymer in slurry form. Slurry grinding is generally preferable, particularly since it can be used also to grind the filler portion of the enteric layer in the same step. It is advisable to reduce the average particle size of the enteric polymer to the range from about l ⁇ m to about 5 ⁇ m, preferably no larger than 3 ⁇ m.
- the enteric polymer When the enteric polymer is applied in the form of a suspension, it is important to assure that the suspension remains homogeneous, and that conditions which favour the agglomeration of the polymer do not occur. Such precautions include maintaining the suspension in a gently stirred condition, but not stirring so vigorously as to create foam, and assuring that the suspension does not stand still in eddies in nozzle bodies, for example, or in over-large delivery tubing. It is preferred in the present invention, to apply the enteric polymer as an aqueous solution.
- the preferred polymer is HPMCP and the preferred plasticiser is chosen from the group comprising triethyl citrate, polyethylene glycol and diethyl phthalate. Most preferably the plasticiser is triethyl citrate that is used in an amount of between about 0-30% of the amount of enteric polymer in aqueous suspension application. When a neutralized HPMCAS is employed, lower levels or no plasticiser may be required. Minor ingredients, such as antifoam, suspending agents when the polymer is in suspended form, and surfactants to assist in smoothing the film are also commonly used.
- silicone anti-foams such as polysorbate 80, sodium lauryl sulfate and the like and suspending agents such as carboxymethylcellulose, vegetable gums and the like may commonly be used at amounts in the general range up to about 5% of the product.
- the enteric layer is filled with a powdered excipient such as talc or hydrated silicon dioxide to build up the thickness of the layer, to strengthen it, to reduce static charge, and to reduce interparticle cohesion.
- a powdered excipient such as talc or hydrated silicon dioxide to build up the thickness of the layer, to strengthen it, to reduce static charge, and to reduce interparticle cohesion.
- Amounts of such solids in the range of from about 5% to about 30% of the final product may be added to the enteric polymer mixture, while the amount of enteric polymer itself is usually in the range from about 10% to about 30%, more preferably, from about 15% to about 25%.
- enteric layer to the core follows the same general procedure previously discussed, using fluid bed type equipment with simultaneous spraying of enteric polymer solution or suspension and warm air drying . Temperature of the drying air and the temperature of the circulating mass of pellets should be kept in the ranges advised by the manufacturer of the enteric polymer.
- opacifying agent in the enteric layer, in the present case, to protect the duloxetine from light.
- opacifiers in pharmaceutical science are the finely powdered oxides of titanium and iron. Amounts of opacifier range up to as much as 5% of the composition weight. Finishing Layer
- a finishing layer over the enteric layer is not necessary in every case, but frequently improves the handling, storage and processability and may provide further benefits as well.
- the finishing layer comprises between about 0.5-3% of the composition as a whole.
- the simplest finishing layer is a small amount, about less than 1% of an anti-static ingredient such as talc or silicon dioxide, simply dusted on the surface of the pellets, mini-tablets or tablets.
- Another simple finishing layer is a small amount, about 1%, of a wax such as beeswax melted onto the circulating mass of tablets, mini-tablets or pellets to further smooth the composition, reduce static charge, prevent any tendency for the tablets, mini-tablets or pellets to stick together, and increase the hydrophobicity of the surface.
- More complex finishing layers may constitute a final sprayed-on layer of ingredients.
- a thin layer of polymeric material such as hydroxypropyl methylcellulose, the inventors have found that hypromellose E3 is particularly suitable in this respect, polyvinylpyrrolidone and the like, in an amount such as from about 0.1% up to about 3%, may be applied.
- the polymeric material may also include an opacifier, a bulking agent such as talc, or a colouring material, particularly an opaque finely divided colour agent such as red or yellow iron oxide.
- Such a layer quickly dissolves away in the stomach, leaving the enteric layer to protect the duloxetine, but provides an added measure of protection from mechanical damage to the product.
- the finishing layer may also comprise a plasticiser to improve the elastic qualities of the finishing layer.
- a plasticiser to improve the elastic qualities of the finishing layer.
- any of the pharmaceutically acceptable plasticisers on the market may be utilised in the compositions according to the invention.
- the inventors have found however that one of polyethylene glycol, triethyl citrate and diethyl phthalate to be advantageous .
- Polyethylene glycol has been found to be particularly advantageous .
- Finishing layers to be applied to the present product are of essentially the same types commonly used in pharmaceutical science to smooth, seal and colour enteric products, and may be formulated and applied in the usual manners .
- the dosage form of the present invention may be a capsule containing the composition within either a hard or a soft shell.
- the composition is preferably a powdered or granulated solid composition of the invention but may also be a solid unit such as a tablet, mini-tablet or pellet.
- the shell may be made from gelatin and optionally contain a plasticiser such as glycerine and sorbitol, and an opacifying agent or colourant.
- a plasticiser such as glycerine and sorbitol
- an opacifying agent or colourant such as glycerine and sorbitol
- the active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
- the following examples relate to hard gelatin capsules comprising tablet core compositions prepared by standard wet granulation techniques.
- the capsules represent a single 60mg dose of duloxetine and comprises 3 unit dosage forms, in the form of tablets compressed at 50mg each and each containing 20mg of Duloxetine in the form of the hydrochloride salt.
- the figures in the examples below relate to the combined values of the three tablets within the capsule. Of course it will be understood that the number of unit dosage forms and indeed the amount of active within each unit dosage form may be varied depending on dosage requirements .
- a 20mg dose of duloxetine may be formed of a capsule comprising a single unit dosage form of 20mg duloxetine or the equivalent amount as a pharmaceutically acceptable salt or two unit dosage forms comprising lOmg of duloxetine each.
- Hypromellose E3 0.634 0.708 0.708 0.69
- duloxetine HCl coated tablets prepared by standard wet granulation techniques .
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Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP20090704911 EP2240173A4 (en) | 2008-01-25 | 2009-01-09 | Delayed release pharmaceutical composition of duloxetine |
JP2010543345A JP2011510024A (en) | 2008-01-25 | 2009-01-09 | Delayed release pharmaceutical composition of duloxetine |
CA2712282A CA2712282A1 (en) | 2008-01-25 | 2009-01-09 | Delayed release pharmaceutical composition of duloxetine |
AU2009206204A AU2009206204B2 (en) | 2008-01-25 | 2009-01-09 | Delayed release pharmaceutical composition of duloxetine |
CN2009801017187A CN101939004A (en) | 2008-01-25 | 2009-01-09 | Delayed release pharmaceutical composition of duloxetine |
US12/863,882 US20110070299A1 (en) | 2008-01-25 | 2009-01-09 | Delayed release pharmaceutical composition of duloxetine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2008900332A AU2008900332A0 (en) | 2008-01-25 | Delayed Release Composition and Compound | |
AU2008900332 | 2008-01-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2009092129A1 true WO2009092129A1 (en) | 2009-07-30 |
WO2009092129A8 WO2009092129A8 (en) | 2009-10-22 |
Family
ID=40900727
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/AU2009/000028 WO2009092129A1 (en) | 2008-01-25 | 2009-01-09 | Delayed release pharmaceutical composition of duloxetine |
Country Status (7)
Country | Link |
---|---|
US (1) | US20110070299A1 (en) |
EP (1) | EP2240173A4 (en) |
JP (1) | JP2011510024A (en) |
CN (1) | CN101939004A (en) |
AU (1) | AU2009206204B2 (en) |
CA (1) | CA2712282A1 (en) |
WO (1) | WO2009092129A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102579403A (en) * | 2011-12-26 | 2012-07-18 | 天津市嵩锐医药科技有限公司 | Duloxetine hydrochloride drug composition |
US8313774B1 (en) * | 2012-06-26 | 2012-11-20 | Magnifica Inc. | Oral solid composition |
EP2567959A1 (en) | 2011-09-12 | 2013-03-13 | Sanofi | 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2014173516A1 (en) * | 2013-04-23 | 2014-10-30 | Pharmathen S.A. | Pharmaceutical composition comprising a dual reuptake inhibitor and method for the preparation thereof |
EP2633857B1 (en) | 2009-12-23 | 2015-08-12 | ratiopharm GmbH | Solid pharmaceutical dosage form of ticagrelor and acetylsalicylic acid |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102908331A (en) * | 2011-08-01 | 2013-02-06 | 浙江九洲药物科技有限公司 | Duloxetine hydrochloride enteric capsules and preparation method thereof |
CN103127023B (en) * | 2013-03-01 | 2014-08-27 | 河北天成药业股份有限公司 | Duloxetine hydrochloride enteric-coated tablet and preparation method |
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 |
CN104414993A (en) * | 2013-08-20 | 2015-03-18 | 天津药物研究院 | Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof |
JP6815109B2 (en) * | 2016-06-23 | 2021-01-20 | キョーリンリメディオ株式会社 | A pharmaceutical composition containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient. |
JP6972674B2 (en) * | 2017-06-06 | 2021-11-24 | ニプロ株式会社 | Oral pharmaceutical product |
JP7046323B2 (en) * | 2017-09-13 | 2022-04-04 | アリメント工業株式会社 | Multi-layer coating formulation |
JP2020029447A (en) * | 2018-06-25 | 2020-02-27 | 大原薬品工業株式会社 | Granule containing enteric polymer and anti-attachment agent |
WO2021126098A1 (en) * | 2019-12-18 | 2021-06-24 | Santa Farma İlaç Sanayi̇ A.Ş. | Gastro-resistant pellet comprising duloxetine |
CN116617189B (en) * | 2023-07-26 | 2023-09-26 | 四川尚锐生物医药有限公司 | Duloxetine hydrochloride sustained-release capsule and preparation method thereof |
Citations (3)
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WO2002024160A2 (en) * | 2000-09-21 | 2002-03-28 | Phase 2 Discovery, Inc. | Long acting antidepressant microparticles |
WO2003094900A1 (en) * | 2002-05-13 | 2003-11-20 | Alexza Molecular Delivery Corporation | Delivery of drug amines through an inhalation route |
WO2008077939A2 (en) * | 2006-12-27 | 2008-07-03 | Lek Pharmaceuticals D.D. | Duloxetine composition |
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-
2009
- 2009-01-09 CN CN2009801017187A patent/CN101939004A/en active Pending
- 2009-01-09 EP EP20090704911 patent/EP2240173A4/en not_active Ceased
- 2009-01-09 CA CA2712282A patent/CA2712282A1/en not_active Abandoned
- 2009-01-09 WO PCT/AU2009/000028 patent/WO2009092129A1/en active Application Filing
- 2009-01-09 US US12/863,882 patent/US20110070299A1/en not_active Abandoned
- 2009-01-09 JP JP2010543345A patent/JP2011510024A/en active Pending
- 2009-01-09 AU AU2009206204A patent/AU2009206204B2/en not_active Ceased
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WO2002024160A2 (en) * | 2000-09-21 | 2002-03-28 | Phase 2 Discovery, Inc. | Long acting antidepressant microparticles |
WO2003094900A1 (en) * | 2002-05-13 | 2003-11-20 | Alexza Molecular Delivery Corporation | Delivery of drug amines through an inhalation route |
WO2008077939A2 (en) * | 2006-12-27 | 2008-07-03 | Lek Pharmaceuticals D.D. | Duloxetine composition |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2633857B1 (en) | 2009-12-23 | 2015-08-12 | ratiopharm GmbH | Solid pharmaceutical dosage form of ticagrelor and acetylsalicylic acid |
EP2515871B1 (en) | 2009-12-23 | 2015-09-23 | ratiopharm GmbH | Solid pharmaceutical dosage form of ticagrelor |
EP2567959A1 (en) | 2011-09-12 | 2013-03-13 | Sanofi | 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
CN102579403A (en) * | 2011-12-26 | 2012-07-18 | 天津市嵩锐医药科技有限公司 | Duloxetine hydrochloride drug composition |
CN102579403B (en) * | 2011-12-26 | 2013-08-21 | 天津市嵩锐医药科技有限公司 | Duloxetine hydrochloride drug composition |
US8313774B1 (en) * | 2012-06-26 | 2012-11-20 | Magnifica Inc. | Oral solid composition |
WO2014173516A1 (en) * | 2013-04-23 | 2014-10-30 | Pharmathen S.A. | Pharmaceutical composition comprising a dual reuptake inhibitor and method for the preparation thereof |
Also Published As
Publication number | Publication date |
---|---|
JP2011510024A (en) | 2011-03-31 |
AU2009206204B2 (en) | 2015-03-19 |
CN101939004A (en) | 2011-01-05 |
EP2240173A1 (en) | 2010-10-20 |
CA2712282A1 (en) | 2009-07-30 |
WO2009092129A8 (en) | 2009-10-22 |
EP2240173A4 (en) | 2013-07-17 |
AU2009206204A1 (en) | 2009-07-30 |
US20110070299A1 (en) | 2011-03-24 |
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