WO2004037226A2 - Compositions pharmaceutiques renfermant de la venlafaxine - Google Patents

Compositions pharmaceutiques renfermant de la venlafaxine Download PDF

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Publication number
WO2004037226A2
WO2004037226A2 PCT/IL2003/000862 IL0300862W WO2004037226A2 WO 2004037226 A2 WO2004037226 A2 WO 2004037226A2 IL 0300862 W IL0300862 W IL 0300862W WO 2004037226 A2 WO2004037226 A2 WO 2004037226A2
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WO
WIPO (PCT)
Prior art keywords
formulation
water insoluble
linked
cross
venlafaxine
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Application number
PCT/IL2003/000862
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English (en)
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WO2004037226B1 (fr
WO2004037226A3 (fr
Inventor
Adel Penhasi
Mila Gomberg
Avi Avramoff
Original Assignee
Dexcel Pharma Technologies Ltd.
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Filing date
Publication date
Priority claimed from US10/280,084 external-priority patent/US6703044B1/en
Application filed by Dexcel Pharma Technologies Ltd. filed Critical Dexcel Pharma Technologies Ltd.
Priority to EP03758627A priority Critical patent/EP1558222A2/fr
Priority to US10/532,407 priority patent/US20060057204A1/en
Priority to CA002503380A priority patent/CA2503380A1/fr
Priority to AU2003274655A priority patent/AU2003274655A1/en
Publication of WO2004037226A2 publication Critical patent/WO2004037226A2/fr
Publication of WO2004037226A3 publication Critical patent/WO2004037226A3/fr
Publication of WO2004037226B1 publication Critical patent/WO2004037226B1/fr

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a formulation and method for the delayed burst release of venlafaxine.
  • Venlafaxine 1 -[(2-dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol, is an important drug for the treatment of depression.
  • Venlafaxine and the acid salts thereof are disclosed in U.S. Patent No. 4,535,186, which is hereby incorporated by reference as if fully set forth herein.
  • Venlafaxine hydrochloride is presently administered to adults in compressed tablet form in doses ranging from 75 to 350 mg/day, in divided doses two or three times a day.
  • US Patent No. 6,274,171 issued on August 14, 2001 , describes one attempted solution to the problem of frequent administration of venlafaxine.
  • the disclosure teaches a formulation of spheroids, which is characterized by an outer film coating over a core which contains venlafaxine, and in which both are placed in a hard gelatine capsule.
  • administration of this formulation results in blood concentration levels having a distinct peak 4-8 hours after administration.
  • venlafaxine the ability to provide a more even plateau of blood concentration of venlafaxine, and therefore presumably to reduce the occurrence and/or severity of side effects, or even to eliminate such side effects altogether, as well as decreasing the frequency of administration of venlafaxine, would be desirable.
  • location of release of venlafaxine may also be problematic, as the above taught formulations clearly result in release occurring to a significant degree in the small intestine, and possibly also in the stomach. Since one of the most significant side effects of venlafaxine is nausea and/or vomiting, indicating gastric distress, clearly release of this active ingredient should not occur in the stomach and/or small intestine.
  • Extended release drug formulations are conventionally produced as compressed tablets by hydrogel tablet technology.
  • the active ingredient is conventionally compounded with cellulose ethers such as methyl cellulose, ethyl cellulose or hydroxypropylmethylcellulose with or without other excipients and the resulting mixture is pressed into tablets.
  • cellulose ethers such as methyl cellulose, ethyl cellulose or hydroxypropylmethylcellulose with or without other excipients
  • sustained release dosage form of the analgesic/anti-inflammatory drug etodolac appears in US Pat. No. 4,966,768.
  • US Pat. No. 4,389,393 discloses sustained release therapeutic compressed solid unit dose forms of an active ingredient plus a carrier base comprised of a high molecular weight hydroxypropylmethylcellulose, methyl cellulose, sodium carboxymethylcelluslose and or other cellulose ether.”
  • the extended release capsule dosage forms may be formulated by mixing the drug with one or more binding agents to form a uniform mixture which is then moistened with water or a solvent such as ethanol to form an extrudable plastic mass from which small diameter, typically of 1 mm, cylinders of drug/matrix are extruded, broken into appropriate lengths and transformed into spheroids using standard spheronization equipment. The spheroids, after drying, may then be film-coated to retard dissolution.
  • the film- coated spheroids may then be placed in pharmaceutically acceptable capsules, such as starch or gelatin capsules, in the quantity needed to obtain the desired therapeutic effect. Spheroids releasing the drug at different rates may be combined in a capsule to obtain desired release rates and blood levels.
  • US Pat. No. 4,138,475 discloses a sustained release pharmaceutical composition consisting of a hard gelatin capsule filled with film-coated spheroids comprised of propanolol in admixture with microcrystalline cellulose wherein the film coating is composed of ethyl cellulose, optionally, with hydroxypropylmethylcellulose and/or a plasticizer.”
  • the present invention provides a delayed burst release formulation comprising a core formed as a compressed tablet and an outer coating that surrounds the core; said core comprising venlafaxine, or a pharmaceutically acceptable salt thereof, at least one burst controlling agent and a disintegrant; and said outer coating comprising a water insoluble hydrophobic carrier and water-insoluble but hydrophilic particulate matter.
  • Preferably said water-insoluble hydrophobic carrier is relatively rigid.
  • a formulation which releases substantially no venlafaxine in vitro for at least about two hours.
  • said in vitro delayed burst release occurs after at least about 2 hours.
  • a formulation wherein at least about 60% of the venlafaxine is released in vitro about one hour after said delayed burst release occurs.
  • said formulations are characterized in that substantially no venlafaxine is released in vivo until said delayed burst release occurs.
  • said in vivo release occurs after at least about 2 hours and in especially preferred embodiments of the present invention said in vivo release occurs after at least about 3 hours and in further formulations of the present invention, said in vivo release occurs after at least about 4 hours.
  • the invention is preferably further characterized in that it provides a method for treating a subject with venlafaxine, comprising administering to the subject a formulation having a therapeutically effective amount of venlafaxine or a pharmaceutically acceptable salt thereof, wherein said formulation provides a delayed burst release after at least three hours resulting in dispersion of the active ingredient mainly through the colon into the blood stream as a result of colon absorption over a period of at least 24 hours.
  • the delivery system of the present invention also advantageously uses the unique continuous absorption characterizing the colon, which results in more flat, consistent concentration levels of the drug in blood.
  • Such an absorption can significantly contribute to reduce the fluctuations in blood drug concentration thus to prevent the side effects which may appear significantly upon using either immediate or conventional controlled release formulations, thereby improving compliance.
  • the formulation preferably features a core, over which an outer coating is layered.
  • the core is formed as a compressed tablet and comprises a burst controlling agent and a disintegrant.
  • the outer coating features a water insoluble, hydrophobic polymer, in which particles of a water insoluble but hydrophilic material are embedded. These particles preferably form channels upon contact with water or an aqueous medium, thereby enabling the active ingredient to be released upon the burst of the film coat.
  • the formulation of the present invention provides a delayed burst release of venlafaxine resulting in a substantially even plasma concentration level of venlafaxine for a period extending over four hours, and a higher AUC (area under the blood concentration - time curve) when compared with the extended release formulations of venlafaxine presently available on the market and said patent neither teaches nor suggests the surprising characteristics of the venlafaxine formulations of the present invention as demonstrated in said example, table and figure.
  • the formulations of the present invention allow for the use of lower dosages since a formulation comprising about 60 mg according to the present invention provides bioequivalence of Efexor XR 75 mg and provides similar bioavailability in the area under the concentration-time curve to Efexor XR 75 mg while formulations comprising about 120 mg according to the present invention provides bioequivalence of Efexor XR 150 mg and provides similar bioavailability in the area under the concentration-time curve to Efexor XR 150 mg.
  • venlafaxine includes venlafaxine and pharmaceutically acceptable salts thereof, as disclosed for example in U.S. Patent No. 4,535,186, which was previously incorporated by reference.
  • hydrophobic when applied to a film means, besides its common definition, that the film is relatively non-permeable to water and to water-insoluble compounds.
  • hydrophilic when applied to a film means, besides its common definition, that the film is relatively permeable to water and to water-soluble compounds.
  • substantially sustained plateau of blood concentration levels refers to a period of time during which the concentration of venlafaxine in the blood exhibits relatively low variability.
  • the substantially sustained plateau preferably occurs for at least about four hours, but more preferably occurs for a longer period of time of at least about eight hours.
  • relatively low variability it is meant that on average, variability is preferably less than about 20% of the blood concentration, and more preferably is less than about 10% of the blood concentration.
  • even blood concentration level also refers to blood concentrations having relatively low variability as previously described.
  • the dosage levels of the active ingredient venlafaxine could easily be determined by one of ordinary skill in the art.
  • effective dosages for venlafaxine are well known in the art.
  • a delayed burst formulation as defined, wherein said formulation preferably provides a substantially sustained plateau of blood concentration level of venlafaxine in the subject, wherein said substantially sustained plateau is present for at least four hours.
  • the formulation comprises
  • a core comprising the venlafaxine, wherein said core includes at least one burst controlling agent and a disintegrant, and wherein said core is formed as a compressed tablet; and (b) an outer coating over said core, said outer coating comprising a water insoluble hydrophobic carrier and water-insoluble but hydrophilic particulate matter, contained in the carrier, that forms channels in the outer coating, upon contact with water or an aqueous medium wherein said channels imbibe liquid and cause said at least one burst controlling agent to burst said coating, thereby enabling the delayed burst release of venlafaxine through these channels after at least three hours followed by dispersion of venlafaxine into the blood stream mainly through the colon over a period extending over at least twenty-four hours.
  • the burst controlling agent comprises a water insoluble polymer for swelling upon contact with liquid, wherein the polymer does not form a hydrogel.
  • the water insoluble polymer is selected from the group consisting of cross-linked polysaccharide, water insoluble starch, microcrystalline cellulose, water insoluble cross- ' nked peptide, water insoluble cross-linked protein, water insoluble cross-linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross-linked collagen modified cellulose, and cross-linked polyacrylic acid.
  • said cross-linked polysaccharide is selected from the group consisting of insoluble metal salts or cross-linked derivatives of alginate, pectin, xantham gum, guar gum, tragacanth gum, and locust bean gum, carrageenan, metal salts thereof, and covalently cross-linked derivatives thereof.
  • said modified cellulose is selected from the group consisting of cross-linked derivatives of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, and metal salts of carboxymethylcellulose.
  • the water insoluble polymer is calcium pectinate or microcrystalline cellulose.
  • the core further comprises at least one of an absorption enhancer, a binder, a disintegrant, a hardness enhancing agent, and another excipient.
  • the binder is selected from the group consisting of starch, PVP (polyvinyl pyrrolidone), low molecular weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxy methylcellulose, ethylcellulose, gelatin polyethylene oxide, acacia, dextrin, magnesium aluminum silicate, and polymethacrylates.
  • the hardness enhancing agent is microcrystalline cellulose.
  • the disintegrant is selected from the group consisting of crospovidone (cross-linked PVP) sodium carboxymethyl starch (sodium starch glycolate), cross-linked sodium carboxymethyl cellulose (Croscarmellose), pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate and a combination thereof.
  • crospovidone cross-linked PVP
  • sodium carboxymethyl starch sodium starch glycolate
  • Cross-linked sodium carboxymethyl cellulose Cross-linked sodium carboxymethyl cellulose (Croscarmellose)
  • pregelatinized starch starch 1500
  • microcrystalline starch water insoluble starch
  • calcium carboxymethyl cellulose calcium carboxymethyl cellulose
  • magnesium aluminum silicate and a combination thereof.
  • the core further comprises a buffering agent.
  • the buffering agent is selected from the group consisting of an inorganic or organic alkaline salt compound.
  • the core further comprises a filler.
  • the filler is selected from the group consisting of microcrystalline cellulose, starch, lactitol, lactose, a suitable inorganic calcium salt, sucrose, or a combination thereof.
  • the core further comprises a flow regulating agent.
  • the flow regulating agent includes at least one of colloidal silicon dioxide and aluminum silicate.
  • the core further comprises a lubricant.
  • the lubricant is selected from the group consisting of stearate salts; stearic acid, talc, sodium stearyl fumarate, and compritol (glycerol behenate), or a combination thereof.
  • the water insoluble polymer being used in the film coating composition is relatively rigid.
  • the water insoluble polymer is selected from the group consisting of a dimethylaminoethylacrylate/ethylmethacrylate copolymer, the copolymer being based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is approximately 1 :20, the polymer corresponding to USP/NF "Ammonio Methacrylate Copolymer Type A", an ethylmethacrylate/chlorotrimethylammoniumethyl methacrylate copolymer, the copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is 1 :40
  • the water insoluble particulate matter in the film coating composition is selected from the group consisting of a water insoluble polysaccharide, a water insoluble cross-linked polysaccharide, a water insoluble polysaccharide metal salt including calcium pectinate, a water insoluble cross-linked protein, a water insoluble cross-linked peptide, water insoluble cross-linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross-linked collagen, a water insoluble cross linked polyacrylic acid, a water insoluble cross-linked cellulose derivatives, water insoluble cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, insoluble starch, microcrystalline starch and a combination thereof.
  • said particulate matter is microcrystalline cellulose.
  • the outer coating further comprises a plasticizer.
  • the plasticizer includes at least one of dibutyl sebacate, polyethylene glycol and polypropylene glycol, dibutyl phthalate, diethyl phthalate, triethyl citrate, tributyl citrate, acetylated monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl benzoate, butyl and/or glycol esters of fatty acids, refined mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol and sorbitol or a combination thereof.
  • the outer coating further comprises a stiffening agent.
  • the stiffening agent is cetyl alcohol.
  • the outer coating further comprises at least one of a wetting agent, a suspending agent, and a dispersing agent, or a combination thereof.
  • the wetting agent is selected from the group consisting of poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, and docusate sodium.
  • the suspending agent is selected from the group consisting of alginic acid, bentonite, carbomer, carboxymethylcellulose, carboxymethylcellulose calcium, hydroxyethylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin, gelatin, guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol, medium chain triglycerides, methylcellulose, polyoxyethylene sorbitan fatty acid esters (polysorbates), povidone (PVP), propylene glycol alginate, sodium alginate, sorbitan fatty acid esters, and tragacanth.
  • the dispersing agent is selected from the group consisting of poloxamer, polyoxyethylene sorbitan fatty acid esters (polysorbates) and sorbitan fatty acid esters.
  • a method for providing a therapeutically effective amount of venlafaxine to a subject comprising: administering orally to the subject a delayed burst release formulation comprising a core and an outer coating that surrounds the core; said core comprising venlafaxine, or a pharmaceutically acceptable salt thereof, a burst controlling agent and a disintegrant; and said coating comprising a water-insoluble hydrophobic carrier and a hydrophilic particulate matter.
  • the present invention also provides a method for a treating a subject with venlafaxine, comprising: administering to the subject a formulation having a therapeutically effective amount of venlafaxine or a pharmaceutically acceptable salt thereof,
  • the formulation comprises: (a) a core containing the venlafaxine, the core comprising a water insoluble, swellable polymer, and a disintegrant; and (b) a coating comprising a water insoluble, hydrophobic polymer and water-insoluble but hydrophilic particulate matter embedded in the polymer, for forming channels in the outer coating, upon contact with water or an aqueous medium wherein said channels imbibe liquid and cause at least one burst controlling agent to burst the coating, thereby releasing venlafaxine; wherein an amount of the disintegrant and the water insoluble swellable polymer is selected such that the core releases venlafaxine in a manner providing a substantially even blood concentration level of venlafaxine for a period extending over at least
  • a method for providing enhanced bioavailability of venlafaxine in a subject comprising: administering to the subject a formulation having a therapeutically effective amount of venlafaxine or a pharmaceutically acceptable salt thereof, wherein the formulation provides a substantially sustained plateau of blood concentration level of venlafaxine in the subject, the combination of preferential release in the colon and substantially sustained plateau of blood concentration level resulting in enhanced bioavailability of venlafaxine.
  • a formulation for release of venlafaxine in the colon of a subject comprising: (a) a core that comprises the venlafaxine, wherein the core includes at least one burst controlling agent and a disintegrant, and wherein the core is formed as a compressed tablet; and (b) an outer coating over the core, the outer coating comprising a water insoluble hydrophobic carrier and water-insoluble but hydrophilic particulate matter, contained in the carrier, for forming channels in the outer coating, upon contact with water or an aqueous medium, wherein said channels imbibe liquid and cause the at least one burst controlling agent to burst the coating, thereby releasing venlafaxine in a delayed burst release after at least three hours followed by dispersion of venlafaxine through the colon into the blood stream over a period extending over at least twenty-four hours.
  • FIGS. 1-10 are graphic representations of in vitro release profiles of venlafaxine from the formulations as described in the following examples and according to the present invention.
  • FIG. 11 shows the in vivo release profile of venlafaxine in a bioavailability study.
  • FIGS. 12 and 13 are graphical representations of a bioequivalence study of two formulations of 60 mg according to the present invention, compared to a 75 mg formulation of the prior art, showing mean plasma venlafaxine concentration-time curves and mean plasma ODV concentration-time curves.
  • FIG. 14a is a tabular representation and
  • FIG. 14b is a graphical representation of the burst time release and percentage release of 60 mg formulations of the present invention.
  • FIG. 15a is a tabular representation and FIG. 15b is a graphical representation of the burst time release and percentage release of 120 mg formulations of the present invention.
  • FIGS. 16a is a tabular representation and FIG. 16b is a graphical representation of the burst time release and percentage release of a 60 mg core burst formulation of the present invention, without its outer coating. DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • the present invention is of a formulation for delayed burst release of an active ingredient at least 2 hours after ingestion and mainly in the colon in order to produce a more stable and less variable plateau of the concentration of the active ingredient in the body of the subject.
  • delayed burst release of the active ingredient from the formulation also increases the bioavailability of the active ingredient, although such an increase in bioavailability is not necessary in order to receive the benefit of the formulation according to the present invention.
  • the formulation preferably releases the active ingredient, such as venlafaxine, in the colon.
  • the core is in the form of a compressed tablet and features a burst controlling agent.
  • the burst controlling agent is preferably a water insoluble polymer that swells considerably but preferably does not form a hydrogel or any other type of strong gel.
  • polymers include but are not limited to, an the group consisting of cross-linked polysaccharide, water insoluble starch, microcrystalline cellulose, water insoluble cross-linked peptide, water insoluble cross-linked protein, water insoluble cross-linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross-linked collagen modified cellulose, and cross-linked polyacrylic acid.
  • the water insoluble polymer at least includes calcium pectinate or microcrystalline cellulose or a combination thereof.
  • the core preferably also optionally contains one or more of an absorption enhancer, a binder, a disintegrant, another excipient or a combination thereof.
  • a binder include but are not limited to starch, PVP (polyvinyl pyrrolidone), low molecular weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethyl cellulose, ethylcellulose, gelatin, polyethylene oxide, acacia, dextrin, magnesium aluminum silicate, and polymethacrylates.
  • Preferred examples of a disintegrant include but are not limited to, Crospovidone (cross-linked PVP), sodium carboxymethyl starch (sodium starch glycolate), cross-linked sodium carboxymethyl cellulose (Croscarmellose), pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum) or a combination thereof.
  • the cores also contain a buffering agent such as magnesium stearate, sodium stearate, or any other inorganic or organic alkaline salt compound.
  • a buffering agent such as magnesium stearate, sodium stearate, or any other inorganic or organic alkaline salt compound.
  • Such a buffering agent may optionally at least assist in the maintenance of the pH of the environment of the core, and is more preferably used as needed for the stability of the active ingredient itself.
  • a filler examples include but are not limited to, microcrystalline cellulose (AvicelTM), starch, lactitol, lactose, dibasic calcium phosphate or any other type of suitable inorganic calcium salt and sucrose, or a combination thereof.
  • suitable lubricants include but are not limited to, stearate salts such as magnesium stearate, calcium stearate, and sodium stearate; stearic acid, talc, sodium stearyl fumarate, and compritol (glycerol behenate), or a combi ⁇ stion thereof.
  • suitable flow regulating agents include but are not limited to, colloidal silicon dioxide and aluminum silicate.
  • the cores are coated with an outer coating, which includes at least one water insoluble hydrophobic carrier and at least one type of water insoluble but hydrophilic particles or particulate matter embedded in the water insoluble polymer.
  • the coating is preferably designed so that when the formulation enters the gastrointestinal tract, the particles absorb liquid, thus forming channels that interconnect the core with the outer surface of the coating.
  • the water insoluble polymer is more preferably relatively rigid, and is optionally and more preferably selected from the group consisting of a dimethylaminoethylacrylate/ethylmethacrylate copolymer, the copolymer being based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is approximately 1 :20, said polymer corresponding to USP/NF "Ammonio Methacrylate Copolymer Type A", an ethylmethacrylate/chlorotrimethylammoniumethyl methacrylate copolymer, the copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is 1 :40, the polymer corresponding to USP/NF "Ammonio Meth
  • the water insoluble particulate matter is more preferably selected from the group consisting of a water insoluble cross-linked polysaccharide, a water insoluble cross-linked protein, a water insoluble cross-linked peptide, water insoluble cross- linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross- linked collagen, water insoluble cross linked polyacrylic acid, water insoluble cross- linked cellulose derivatives, water insoluble cross-linked polyvinyl pyrrolidone, micro crystalline cellulose, insoluble starch, micro crystalline starch and a combination thereof.
  • the outer coating preferably includes at least one plasticizer.
  • suitable plasticizers include but are not limited to, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetylated monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl benzoate, butyl and/or glycol esters of fatty acids, refined mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol, polyethylene glycol, propylene glycol and sorbitol.
  • the amount of plasticizer is optionally and more preferably in a range of from about 0 to about 50% weight per weight of the water insoluble polymer in the film coat.
  • a stiffening agent such as cetyl alcohol could optionally be used.
  • the outer coating may also optionally contain at least one of a wetting agent, suspending agent, surfactant, and dispersing agent, or a combination thereof, in addition to the plasticizer.
  • wetting agents include, but are not limited to, poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, docusate sodium.
  • suspending agents include but are not limited to, alginic acid, bentonite, carbomer, carboxymethylcellulose, carboxymethylcellulose calcium, hydroxyethylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin, gelatin, guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol, medium chain triglycerides, methylcellulose, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyvinyl pyrrolidone (PVP), propylene glycol alginate, sodium alginate, sorbitan fatty acid esters, and tragacanth.
  • surfactants include but are not limited to, anionic surfactants such as docusate sodium and sodium lauryl sulfate; cationic, such as cetrimide; nonionic, such as polyoxyethylene sorbitan fatty acid esters (polysorbates) and sorbitan fatty acid esters.
  • Suitable dispersing agents include but are not limited to, poloxamer, polyoxyethylene sorbitan fatty acid esters (polysorbates) and sorbitan fatty acid esters.
  • the content of the wetting agent, surfactant, dispersing agent and suspending agent may optionally be in an amount of from about 0 to about 30% of the weight of the film coat of the Tormulation.
  • a particularly preferred embodiment of the present invention features crospovidone (cross-linked PVP), calcium pectinate, microcrystalline cellulose, ethylcellulose, polyvinyl pyrrolidone (PVP), colloidal silicon dioxide, and magnesium stearate in the core.
  • the coating for this embodiment preferably features ethyl cellulose, cetyl alcohol, microcrystalline cellulose or calcium pectinate (CaP).
  • an enteric coating may be applied to these coated cores.
  • the enteric coating contains Eudragit L or cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose acetate succinate. This embodiment is particularly preferred for the administration of venlafaxine.
  • release of the drug is optionally possible through any type of mechanism, including but not limited to, disintegration, burst release, diffusion, permeation (release through pores or channels), or erosion, or a combination thereof.
  • the type of mechanism may be destructive to the outer layer or non-destructive; the continuity and/or structure of the outer layer may be maintained, or altered and/or destroyed.
  • both the outer layer and the core preferably permit the drug to be released through some type of destructive process, including but not limited to, burst release, erosion and disintegration of the core, or a combination thereof.
  • a mixture of mechanisms is also possible.
  • Burst release is the preferred mechanism for release of the active ingredient.
  • the preferred embodiment of the formulation according to the present invention preferably features a core, which contains a swellable material, covered by a coating, which includes a water insoluble hydrophobic carrier.
  • the coating also includes water insoluble but hydrophilic particulate matter. When this particulate matter comes into contact with water or an aqueous medium, the particulate matter imbibes water and swells, thereby forming channels, which enable the water to enter the core.
  • the swellable material in the core then swells and bursts the coating, after which the core more preferably disintegrates slowly or otherwise releases the active ingredient.
  • Table 1 Different formulations of the core containing VLF, and CaP- containing TCDS coating
  • Example 1 (560-9)
  • the cores were manufactured by dry mixing. Venlafaxine HCI (34g) was mixed with colloidal silicon dioxide (2.4g). The obtained mixture was sieved by sieve 600 microns and blended with crospovidone (16.6g), microcrystalline cellulose (66.4g) and polyvinyl pyrrolidone (6g). Magnesium stearate (0.12g) was passed through mechanical sieve equipped with 600 micron screen into the mixture and blended. Tabletting
  • the tablets' blend was ccmpressed with WICK single punch tabletting press equipped with suitable punches for providing sufficient active material and hardness sufficient for subsequent coating.
  • the formed cores were then coated with a TCDS coating containing calcium pectinate. (Ingredients and concentrations given in the tables above.)
  • the coating process was prepared and performed as follows. A weighed quantity of ethyl cellulose 20 (0.30kg) was dissolved in ethanol (6.06 kg) to obtain clear solution, to which a weighed quantity of plasticizer (cetyl alcohol-0.03kg) was added and mixed with mechanical stirrer to complete dissolution. Microcrystalline Cellulose (0.3kg) was added and stirred to obtain a homogeneous suspension, which was stirred during the whole coating process. The TCDS coating was performed in a perforated pan coater, with an applied spraying pressure of 2.5 Bar. Tine suspension was coated until the weight of the coating was about 40-50mg. The tablets were dried.
  • Figure 1 shows the results for the release of venlafaxine from formulation 560-9. As shown, release is delayed until 3 hours after being placed in the more basic medium, which is sufficient to demonstrate that venlafaxine would be preferentially released at the colon.
  • Example 2 (560-11)
  • Venlafaxine HCI(50 g) was mixed with disintegrator (cross-linked polyvinyl pyrrolidone-2.5g ) and binder-polyvinyl pyrrolidone and the granulation solution (water purified) was added. The blend was mixed until sufficient consistency was achieved. The granulated blend was dried.
  • the dried granulation blend was milled to obtain the desired particle size distribution of the final granulation blend.
  • colloidal silicon dioxide (3.2 g) was mixed with an additional amount of crospovidone (18.5g) and sieved by a mechanical sieve equipped with a 600 micron screen into the previously obtained granulation blend. The obtained mixture was blended. Microcrystalline cellulose (84.7 g) was added into the mixture and the entirety was blended.
  • the tabletting mixture was then compressed with a WICK single punch tabletting press equipped with suitable punches, as previously described.
  • the formed cores were then coated with TCDS coating that was prepared as follows.
  • a weighed quantity of Ethylcellulose 20 (10g) was dissolved in ethanol (200g) to obtain a clear solution, to which a weighed quantity of plasticizer (cetyl alcohol-1.0g) was added and mixed with the mechanical stirrer to complete dissolution.
  • Sieved calcium pectinate (10 g) was added and stirred to obtain a homogeneous suspension, which was stirred during the whole coating process.
  • the coating was performed in a perforated pan coater, with the temperature of the incoming air kept to 28-32°C and with an applied spraying pressure of 0.4 Bar. The tablets were dried in the oven at 35°C overnight.
  • Figure 2 shows the results for the release of venlafaxine from formulation 560-12. As shown, release is sufficiently delayed after being placed in the more basic medium to demonstrate that venlafaxine would be preferentially released at the colon.
  • Example 3 (560-15)
  • Venlafaxine HCI (42.5g) was mixed with calcium pectinate (023.5g) and disintegrator (cross-linked polyvinyl pyrrolidone-3.5g), and the granulation solution (polyvinyl pyrrolidone 3g dissolved in 30g Ethanol) was added. The blend was mixed until sufficient consistency was achieved. The granulated blend was dried.
  • the dried granulation blend was milled to obtain the desired particle size distribution of the final granulation blend.
  • the tabletting mixture was then compressed with a WICK single punch tabletting press equipped with suitable punches, as previously described.
  • the TCDS coating was prepared and added as previously described in Examples 1 and 2, containing calcium pectinate.
  • Figure 3 shows the results for the release of venlafaxine from formulation 560-16. As shown, release is sufficiently delayed after being placed in the more basic medium to demonstrate that venlafaxine would be preferentially released at the colon.
  • Table 2 Different formulations of the core containing VLF, and microcristalline cellulose-containing TCDS coating
  • Venlafaxine HCI(50 g) was mixed with disintegrator (cross-linked polyvinylpyrrolidone-2.5g ) and binder-polyvinyl pyrrolidone (1g) and the granulation solution (water purified) was added. Colloidal silicon dioxide (0.6g) was added for improvement porosity of granulate. The blend was mixed until sufficient consistency was achieved. The granulated blend was dried.
  • Venlafaxine HCI(30.3 g) was mixed with calcium pectinate (16.8g), and disintegrant (cross-linked polyvinylpyrrolidone-2.5g ) and the granulation solution (1.1 g Ethocel 7 in 15g Ethanol)) was added. The blend was mixed until sufficient consistency was achieved. The granulated blend was dried. The remainder of the process was performed as previously described.
  • the coating again contained microcrystalline cellulose, to form formulation 560-24/B. Again, as shown in Figure 5 release is sufficiently delayed after being placed in the more basic medium to demonstrate that venlafaxine would be preferentially released at the colon.
  • the formulation 560-23 was performed as for 560-22 but polyvinyl pyrrolidone was used as a binder instead of ethyl cellulose.
  • the coating again contained microcrystalline cellulose, to form formulation 560-24/C.
  • Figure 6 shows the release profile of the formulation 560-24C. As shown, the release is sufficiently delayed after being placed in the more basic medium to demonstrate that venlafaxine would be preferentially released at the colon.
  • Venlafaxine HCI (1.697 kg) was granulated with binder (Povidone K-30- 0.054kg) and disintegrant (cros linked polyvinyl pyrrolidone-0.093kg), and water purified (0.275kg) was added.
  • binder Povidone K-30- 0.054kg
  • disintegrant cros linked polyvinyl pyrrolidone-0.093kg
  • Figure 7 shows the results of the release profile for 241201.
  • Figure 8 shows the results of the in vitro release for the formulation 241201 E, which has a TCDS coating that contains microcrystalline cellulose, over which an enteric coat has been added. As shown, release is sufficiently delayed after being placed in the more basic medium to demonstrate that venlafaxine would be preferentially released at the colon.
  • Venlafaxine HCI (0.848kg) was granulated with calcium pectinate (0.700kg) and disintegrant (cross-linked polyvinyl pyrrolidone-0.070kg). Binder solution (Povidone K-30-0.0085kg) and purified water (0.350kg) was added.
  • Figure 9 shows the results, for the formulation 180502, which has a TCDS coating that contains microcrystalline cellulose. This formulation shows a slightly delayed release, sufficient to show that release would preferentially occur in the colon.
  • Example 10 (560-74)
  • Venlafaxine HCI (0.5kg) was granulated with binder (Povidone K-30 - 0.0162kg), and disintegrant (cross-linked polyvinyl pyrrolidone - 0.0274 kg) and purified water (0.081 kg).
  • Figure 10 shows the in vitro release of venlafaxine of the formulation 560-74, which has a TCDS coating that contains microcrystalline cellulose. This formulation shows a delayed release, sufficient to show that release would preferentially occur in the colon.
  • Example 11 Pilot Study of Bioavailability (Venlafaxine)
  • the formulation according to the present invention was administered to fasting volunteers and blood samples were withdrawn pre-dose and at: 1 , 2, 3, 4, 5, 6, 7, 7.5, 8, 8.5, 9, 10, 12, 15, 24, 36, 48 and 60 hours post-dose.
  • Plasma concentrations of venlafaxine were determined using an HPLC analytical method with UV detection. Table 3: Venlafaxine Formulations
  • Crospovidone 39 12.2 39 12.2 77.4 12.9 39 13
  • Figure 11 shows the blood concentration values for the venlafaxine DR formulation according to the present invention vs. Effexor ER after administration.
  • Table 4 PHARMACOKINETIC PARAMETERS Venlafaxine Test versus Efexor Reference
  • FIGS. 12 and 13 there is shown a bioequivalence study of two formulations of 60 mg according to the present invention as compared to two 75 mg reference formulations, which were Efexor XR 75 mg. These graphs show the result of single dose administration in ten healthy men volunteers.
  • the mean plasma venlafaxine concentration in the area under the concentration-time curve is substantially equivalent for the 60 mg formulation of the present invention and the 75 mg reference formulation.
  • the ODV plasma concentration over time is also substantially equivalent for the 60 mg formulation of the present invention and the 75 mg reference formulation.
  • FIGS. 14a and 14b there are shown the dissolution in vitro of six 60 mg delayed burst release formulation tablets according to the present invention from which it can be seen that the tablets, according to the present invention, release substantially no venlafaxine for at least about 2 hours and that within about 1 hour after said delayed burst release occurs, over 70% of the venlafaxine was released from each of the tested tablets.
  • FIGS 15a and 15b there are shown the dissolution in vitro of six 120 mg delayed burst release formulation tablets according to the present invention from which it can be seen that the tablets, according to the present invention, release substantially no venlafaxine for at least about 2 hours and that within about 1 hour after said delayed burst release occurs, over 80% of the venlafaxine was released from each of the tested tablets.
  • FIGS 16a and 16b there are shown the dissolution in vitro of three 60 mg burst release formulation tablets using only the uncoated core according to the present invention for comparative purposes, from which it can be seen that the burst core of the present invention when uncoated, releases more than 75% and an average of more than 85% of the venlafaxine within half a minute of burst release and that within ⁇ bout 1 minute after said burst release occurs, over 95% of the venlafaxine was released from each of the tested tablets.
  • This indicates that the core has a fast and an immediate release characteristic and no extended and sustained release nature is related to the uncoated core.
  • This specific release profile of the core is resulted from both lack of any release controlling agent in the formulation of the core as well as the presence of the burst controlling agent and disintegrant as well.

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Abstract

L'invention concerne une formulation retard à libération progressive comprenant un noyau présenté sous la forme d'une pastille comprimée et un enrobage externe entourant le noyau renfermant la venlafaxine ou un sel acceptable sur le plan pharmaceutique de celle-ci, au moins un agent de commande de décharge et un désintégrant; l'enrobage externe comprenant un véhicule hydrophobe insoluble dans l'eau et une matière particulaire insoluble dans l'eau mais hydrophile.
PCT/IL2003/000862 2002-10-25 2003-10-23 Compositions pharmaceutiques renfermant de la venlafaxine WO2004037226A2 (fr)

Priority Applications (4)

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EP03758627A EP1558222A2 (fr) 2002-10-25 2003-10-23 Compositions pharmaceutiques renfermant de la venlafaxine
US10/532,407 US20060057204A1 (en) 2002-10-25 2003-10-23 Pharmaceutical compositions containing venlafaxine
CA002503380A CA2503380A1 (fr) 2002-10-25 2003-10-23 Compositions pharmaceutiques renfermant de la venlafaxine
AU2003274655A AU2003274655A1 (en) 2002-10-25 2003-10-23 Pharmaceutical compositions containing venlafaxine

Applications Claiming Priority (4)

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US10/280,084 2002-10-25
US10/280,084 US6703044B1 (en) 2002-10-25 2002-10-25 Venlafaxine formulations
IL158,493 2003-10-20
IL15849303A IL158493A0 (en) 2002-10-25 2003-10-20 Pharmaceutical compositions containing venlafaxine

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005074895A1 (fr) * 2004-02-04 2005-08-18 Alembic Limited Micro-comprimes revetus a liberation prolongee de chlorhydrate de venlafaxine
WO2007102169A1 (fr) * 2006-03-08 2007-09-13 Jubilant Organosys Limited Préparation pharmaceutique de venlafaxine à libération prolongée et son procédé de fabrication
WO2007112574A1 (fr) * 2006-04-03 2007-10-11 Isa Odidi Composition de venlafaxine à libération prolongée
US20130156829A1 (en) * 2010-08-31 2013-06-20 Toray Industries, Inc. Coating agent for pharmaceutical solid preparation, pharmaceutical film formulation, and coated pharmaceutical solid preparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6274171B1 (en) * 1996-03-25 2001-08-14 American Home Products Corporation Extended release formulation of venlafaxine hydrochloride
US20010048943A1 (en) * 2000-01-13 2001-12-06 Joaquina Faour Osmotic device containing venlafaxine and an anti-psychotic agent
WO2003055475A1 (fr) * 2002-01-03 2003-07-10 Lek Pharmaceutical And Chemical Company D.D. Formulation pharmaceutique a liberation controlee contenant de la venlafaxine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6274171B1 (en) * 1996-03-25 2001-08-14 American Home Products Corporation Extended release formulation of venlafaxine hydrochloride
US20010048943A1 (en) * 2000-01-13 2001-12-06 Joaquina Faour Osmotic device containing venlafaxine and an anti-psychotic agent
WO2003055475A1 (fr) * 2002-01-03 2003-07-10 Lek Pharmaceutical And Chemical Company D.D. Formulation pharmaceutique a liberation controlee contenant de la venlafaxine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005074895A1 (fr) * 2004-02-04 2005-08-18 Alembic Limited Micro-comprimes revetus a liberation prolongee de chlorhydrate de venlafaxine
WO2007102169A1 (fr) * 2006-03-08 2007-09-13 Jubilant Organosys Limited Préparation pharmaceutique de venlafaxine à libération prolongée et son procédé de fabrication
WO2007112574A1 (fr) * 2006-04-03 2007-10-11 Isa Odidi Composition de venlafaxine à libération prolongée
US20130156829A1 (en) * 2010-08-31 2013-06-20 Toray Industries, Inc. Coating agent for pharmaceutical solid preparation, pharmaceutical film formulation, and coated pharmaceutical solid preparation
KR101483476B1 (ko) 2010-08-31 2015-01-16 도레이 카부시키가이샤 의약 고형 제제용의 코팅제, 의약용 필름 제제 및 피복 의약 고형 제제
US9381248B2 (en) * 2010-08-31 2016-07-05 Toray Industries, Inc. Coating agent for pharmaceutical solid preparation, pharmaceutical film formulation, and coated pharmaceutical solid preparation
EP2612681B1 (fr) * 2010-08-31 2019-01-30 Toray Industries, Inc. Agent de revêtement pour préparation solide pharmaceutique, formulation de film pharmaceutique, et préparation solide pharmaceutique revêtue

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CA2503380A1 (fr) 2004-05-06
EP1558222A2 (fr) 2005-08-03
WO2004037226B1 (fr) 2004-09-10
WO2004037226A3 (fr) 2004-07-08
AU2003274655A1 (en) 2004-05-13

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