WO2009155488A2 - Nouveau sel oxalate et nouveau cristal de o-desméthylvenlafaxine - Google Patents

Nouveau sel oxalate et nouveau cristal de o-desméthylvenlafaxine Download PDF

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Publication number
WO2009155488A2
WO2009155488A2 PCT/US2009/047907 US2009047907W WO2009155488A2 WO 2009155488 A2 WO2009155488 A2 WO 2009155488A2 US 2009047907 W US2009047907 W US 2009047907W WO 2009155488 A2 WO2009155488 A2 WO 2009155488A2
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WIPO (PCT)
Prior art keywords
crystal
exhibits
desmethylvenlafaxine
monohydrate
oxalate
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PCT/US2009/047907
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WO2009155488A3 (fr
Inventor
Dario Braga
Stefano Luca Giaffreda
Marco Curzi
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POLYCRYSTALLINE Srl
SEGRUB LLC
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POLYCRYSTALLINE Srl
SEGRUB LLC
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Publication of WO2009155488A3 publication Critical patent/WO2009155488A3/fr
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    • 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
    • C07C217/64—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 amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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

  • APIs have been known to exist as amorphous forms, crystalline forms, polymorphs, hydrates and solvates. The forms for every API are different. While one particular API may be known to exist as a polymorph or a solvate, another API may be known to only exist in amorphous form. This form diversity is important because each different polymorph, solvate, hydrate or amorphous form may have different properties such as bioavailability, stability, solubility, and hygroscopicity.
  • Some forms of an API can be formulated into an FDA appro vable formulation, while other forms lack the required properties to meet the high regulatory standards of the FDA. Even if a particular API can exist in more than one form suitable for formulation, different properties of an API form can affect the manufacturing process, shelf stability, route of administration, bioavailability and other important product characteristics. For example, the ability to improve or modulate stability or hygroscopicity can decrease manufacturing costs by reducing the need for humidity controlled chambers or reducing the need to package an API in humidity resistant packaging. In addition these same changes can increase product shelf stability thereby improving product distribution possibilities and affecting cost. In another example, one form of an API may have greater bioavailability than another form. Choosing the higher bioavailability form allows for a lower drug dose to be administered to a patient.
  • O-Desmethylvenlafaxine is a selective serotonin and norepinephrine reuptake inhibitor useful for the treatment of depression.
  • the fumarate salt of O- Desmethylvenlafaxine is known and has poor physiochemical and permeability characteristics (See US Patent 7,291 ,347).
  • US Patent 7,291 ,347 discloses that the succinate salt of O-Desmethylvenlafaxine has much improved solubility as compared to the fumarate salt and thus has improved bioavailability.
  • Applicant's unexpectedly discovered a new salt and crystal of O-Desmethylvenlafaxine with similar stability characteristics but significantly improved solubility as compared to the fumarate and succinate salt of O- Desmethylvenlafaxine.
  • this new salt possesses distinct physical properties and a distinct crystal structure that is different than any previously known forms of O- Desmethylvenlafaxine.
  • FIGURE 1 is a representative PXRD pattern for the ⁇ crystal of O-
  • FIGURE 2 is a representative DSC measurement for the ⁇ crystal of O- Desmethylvenlafaxine oxalate.
  • FIGURE 3 is a representative TGA measurement for the ⁇ crystal of O- Desmethylvenlafaxine oxalate.
  • FIGURE 4 is a representative FT-IR spectra for the ⁇ crystal of O- Desmethylvenlafaxine oxalate.
  • FIGURE 5 is a representative PXRD pattern for the ⁇ crystal of O- Desmethylvenlafaxine oxalate.
  • FIGURE 6 is a representative DSC measurement for the ⁇ crystal of O-
  • FIGURE 7 is a representative TGA measurement for the ⁇ crystal of O- Desmethylvenlafaxine oxalate.
  • FIGURE 8 is an FT-IR spectra for the ⁇ crystal of O-Desmethylvenlafaxine oxalate.
  • FIGURE 9 is a representative PXRD pattern for O-Desmethylvenlafaxine oxalate monohydrate.
  • FIGURE 10 is a representative TGA/DSC - Netzsch measurement for O- Desmethylvenlafaxine oxalate monohydrate.
  • FIGURE 1 1 is an FT-IR spectra of O-Desmethylvenlafaxine oxalate monohydrate.
  • FIGURE 12 is a representative PXRD pattern for the gamma crystal of O- Desmethylvenlafaxine oxalate.
  • the invention comprises an oxalate salt of O- Desmethylvenlafaxine with an improved thermodynamic solubility.
  • the invention comprises an oxalate salt of O-Desmethylvenlafaxine with a thermodynamic solubility of between 100g/L to 200g/L.
  • the invention comprises an oxalate salt of O-Desmethylvenlafaxine with a thermodynamic solubility of about 142g/L.
  • the invention comprises O-Desmethylvenlafaxine oxalate.
  • the invention comprises crystalline O-Desmethylvenlafaxine oxalate.
  • the invention comprises anhydrous O-Desmethylvenlafaxine oxalate. In an additional embodiment, the invention comprises an ⁇ crystal of O-
  • the invention comprises an ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a powder x-ray diffraction pattern (PXRD) pattern comprising a peaks at 5.3, 9.6, and 10.5 degrees 2-theta.
  • PXRD powder x-ray diffraction pattern
  • the invention comprises an ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a PXRD pattern comprising a peaks at 5.3, 9.6, 10.5, 11.6, andl3.1 degrees 2-theta.
  • the invention comprises an ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a PXRD pattern comprising a peaks at 5.3, 9.6, 10.5, 11.6, 13.1, 14.9, 21.1, and 24.6 degrees 2-theta.
  • the invention comprises an ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a PXRD pattern substantially similar to Figure 1.
  • the invention comprises an ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a Differential scanning calorimetry (DSC) pattern comprising an endothermic transition at about 79 degrees C.
  • DSC Differential scanning calorimetry
  • the invention comprises an ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a Differential scanning calorimetry (DSC) pattern substantially similar to Figure 2.
  • DSC Differential scanning calorimetry
  • the invention comprises an ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a thermogravimetric analysis (TGA) pattern substantially similar to Figure 3.
  • TGA thermogravimetric analysis
  • the invention comprises an ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a Fourier transform infrared spectroscopy sis (FT-IR) pattern substantially similar to Figure 4.
  • FT-IR Fourier transform infrared spectroscopy sis
  • the invention comprises a ⁇ crystal of O- Desmethylvenlafaxine oxalate.
  • the invention comprises a ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a powder x-ray diffraction pattern (PXRD) pattern comprising peaks at 5.3, 7.3, and 8.6 degrees 2-theta.
  • PXRD powder x-ray diffraction pattern
  • the invention comprises a ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a PXRD pattern comprising a peaks at 5.3, 7.3, 8.6, 9.2, and 12.8 degrees 2-theta.
  • the invention comprises a ⁇ crystal of O- Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a PXRD pattern comprising a peaks at 5.3, 7.3, 8.6, 9.2, 12.8, 20.0 and 27.9 degrees 2-theta.
  • the invention comprises a ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a PXRD pattern substantially similar to Figure 5.
  • the invention comprises a ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a Differential scanning calorimetry (DSC) pattern comprising an endothermic transition at about 74 degrees C.
  • DSC Differential scanning calorimetry
  • the invention comprises a ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a Differential scanning calorimetry (DSC) pattern substantially similar to Figure 6.
  • DSC Differential scanning calorimetry
  • the invention comprises a ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a thermogravimetric analysis (TGA) pattern substantially similar to Figure 7.
  • TGA thermogravimetric analysis
  • the invention comprises a ⁇ crystal of O-Desmethylvenlafaxine oxalate, wherein said ⁇ crystal exhibits a Fourier transform infrared spectroscopy sis (FT-IR) pattern substantially similar to Figure 8.
  • FT-IR Fourier transform infrared spectroscopy sis
  • the invention comprises a hydrate of O-Desmethylvenlafaxine oxalate. In another embodiment, the invention comprises O-Desmethylvenlafaxine oxalate monohydrate. In another embodiment, the invention comprises O-Desmethylvenlafaxine oxalate monohydrate, wherein said O-Desmethylvenlafaxine oxalate monohydrate exhibits a powder x-ray diffraction pattern (PXRD) pattern comprising peaks at 5.3, 9.7, and 10.5 degrees 2-theta.
  • PXRD powder x-ray diffraction pattern
  • the invention comprises O-Desmethylvenlafaxine oxalate monohydrate, wherein said O-Desmethylvenlafaxine oxalate monohydrate exhibits a PXRD pattern comprising peaks at 5.3, 9.7, 10.5, 11.7, and 12.8 degrees 2-theta.
  • the invention comprises O-Desmethylvenlafaxine oxalate monohydrate, wherein said O-Desmethylvenlafaxine oxalate monohydrate exhibits a PXRD pattern comprising peaks at 5.3, 9.7, 10.5, 11.7, 12.8, 14.5, and 14.8 degrees 2-theta.
  • the invention comprises O-Desmcthylvenlafaxine oxalate monohydrate, wherein said O-Desmethylvenlafaxine oxalate monohydrate exhibits a PXRD pattern comprising peaks at 5.3, 9.7, 10.5, 11.7, 12.8, 14.5, 14.8, 16.8, 21.1, and 26.6 degrees 2-theta.
  • the invention comprises O-Desmethylvenlafaxine oxalate monohydrate, wherein said O-Desmethylvenlafaxine oxalate monohydrate exhibits a PXRD pattern substantially similar to Figure 9.
  • the invention comprises O- Desmethylvenlafaxine oxalate monohydrate, wherein said O-Desmethylvenlafaxine oxalate monohydrate exhibits a TGA/DSC - Netzsch pattern substantially similar to Figure 10.
  • the invention comprises O-Desmethylvenlafaxine oxalate monohydrate, wherein said O-Desmethylvenlafaxine oxalate monohydrate exhibits a Fourier transform infrared spectroscopy sis (FT-IR) pattern substantially similar to Figure 11.
  • FT-IR Fourier transform infrared spectroscopy sis
  • the invention comprises a gamma crystal of O- Desmethylvenlafaxine oxalate. In another embodiment, the invention comprises a gamma crystal of O-Desmethylvenlafaxine oxalate, wherein said gamma crystal exhibits a PXRD pattern substantially similar to Figure 1. 35. In one embodiment, the invention comprises a gamma crystal wherein said gamma crystal exhibits a PXRD pattern comprising peaks at 5.3, 9.7, 10.5, 11.8, 14.7 and 15.5degrees 2-theta.
  • the invention comprises a gamma crystal wherein said gamma crystal exhibits a PXRD pattern comprising peaks at 5.3, 9.7, 10.5, 11.8, 14.7, 15.5, and 17.4degrees 2-theta.
  • the invention comprises a gamma crystal wherein said gamma crystal exhibits a PXRD pattern comprising peaks at 5.3, 9.7, 10.5, 11.8, 14.7, 15.5, 17.4, 25.3, and 26.6 degrees 2- theta.
  • an oxalate salt of this invention is crystalline.
  • the invention comprises amorphous O-Desmethylvenlafaxine oxalate.
  • the invention comprises a stable amorphous composition of O- Desmethylvenlafaxine oxalate.
  • the invention comprises an oxalate salt of an isomer of O- Desmethylvenlafaxine.
  • the invention comprises (-) O- Desmethylvenlafaxine oxalate.
  • the invention comprises crystalline (-) O-Desmethylvenlafaxine oxalate.
  • the invention comprises a pharmaceutical composition comprising O-Desmethylvenlafaxine oxalate.
  • the invention comprises a pharmaceutical composition comprising anhydrous O-Desmethylvenlafaxine oxalate. In a further embodiment, the invention comprises a pharmaceutical composition comprising an ⁇ crystal of O-Desmethylvenlafaxine oxalate. In a further embodiment, the invention comprises a pharmaceutical composition comprising a ⁇ crystal of O-
  • the invention comprises a pharmaceutical composition comprising O-Desmethylvenlafaxine oxalate monohydrate. In a still further embodiment, the invention comprises a controlled release composition comprising O-Desmethylvenlafaxine oxalate. In an additional embodiment, the invention comprises a modified release composition comprising O-Desmethylvenlafaxine oxalate. In a still further embodiment, the invention comprises a pharmaceutical composition comprising 67mg of O-Desmethylvenlafaxine oxalate. In a still further embodiment, the invention comprises a pharmaceutical composition comprising 133mg of O-Desmethylvenlafaxine oxalate.
  • O-Desmethylvenlafaxine Methods of making O-Desmethylvenlafaxine are known in the art. Examples of some references disclosing methods of making O-Desmethylvenlafaxine are US patent application publication numbers 2008/0139849, 2008/0033051, 2008/0015259, US2007/0225525 and US patent 7291347.
  • the invention comprises a method of treating a patient for depression comprising providing O-Desmethylvenlafaxine oxalate. In another embodiment, the invention comprises a method of treating a patient for depression comprising providing a once daily dose of O-Desmethylvenlafaxine oxalate. In a further embodiment, the invention comprises a method of treating a patient for a major depressive disorder comprising providing O-Desmethylvenlafaxine oxalate. In another embodiment, the invention comprises a method of treating a patient for a major depressive disorder depression comprising providing a once daily dose of O-Desmethylvenlafaxine oxalate.
  • the invention comprises a method of treating a patient for neuropathic pain comprising providing O-Desmethylvenlafaxine oxalate. In a still further embodiment, the invention comprises a method of treating a patient for fibromyalgia comprising providing O-Desmethylvenlafaxine oxalate. In an additional embodiment, the invention comprises a method of treating a patient for menopausal vasomotor symptoms comprising providing O-Desmethylvenlafaxine oxalate. In one embodiment, the invention comprises a method of treating a patient for generalized anxiety disorder comprising providing O-Desmethylvenlafaxine oxalate.
  • the invention comprises a method of treating a patient for social anxiety disorder comprising providing O-Desmethylvenlafaxine oxalate.
  • the invention comprises a method of treating a patient for panic disorder comprising providing O-Desmethylvenlafaxine oxalate.
  • O-Desmethylvenlafaxine oxalate may be readily incorporated into a pharmaceutical composition (or medicament) by conventional means.
  • Pharmaceutical compositions and medicaments may further comprise a pharmaceutically-acceptable diluent, excipient or carrier.
  • formulations comprising O-Desmethylvenlafaxine oxalate are suitably stable for pharmaceutical use.
  • O-Desmethylvenlafaxine oxalate may be used in combination with other drugs such as O-Desmethylvenlafaxine succinate, venlafaxine, eszopiclone, apeledoxifine, buproprion, nefazodone, trazodone, mirtazapinc, monoamine oxidase inhibitors, Tricyclic antidepressant, and selective serotonin reuptake inhibitors.
  • invention provides oral delayed release dosage units composed of O-Desmethylvenlafaxine oxalate, and an enteric coat in the range of about 10 to 20 wt % of the dosage unit.
  • These oral delayed release dosage units enhance bioavailability, reduce undesirable side effects, and reduce variability in plasma.
  • the compositions of the invention enhance the bioavailability of O-Desmethylvenlafaxine oxalate by deferring release of most of the O-Desmethylvenlafaxine oxalate until such time as the formulation is in the ileum and small intestine, while minimizing colonic release.
  • compositions described herein may provide sustained release over a period of at least 8 hours, while providing at least about 85% total release within 12 hours of the oral dosage unit being taken orally.
  • the O-Desmethylvenlafaxine oxalate oral dosing units of the invention are composed, at a minimum, of a core containing O-Desmethylvenlafaxine oxalate, and one or more pharmaceutically acceptable excipients.
  • the core contains about 40 wt % to about 60 wt % DVS, about 45 to 55 wt %, or about 47 to 52 wt %, of the total oral dosing unit.
  • the core containing the O-Desmethylvenlafaxine oxalate may be in a sustained release formulation or other suitable cores as are described in greater detail below may be selected.
  • a delay release coat and/or an enteric coat are provided over the core.
  • the delay release coat and/or an enteric coat can be applied to the O-Desmethylvenlafaxine oxalate core directly, or there may be intermediate coating layers located between the DVS core and any over coats.
  • a further seal or top coat may be located outside the enteric coat.
  • the O-Desmethylvenlafaxine oxalate can range from about 20% w/w to about 75 wt % w/w, 25 wt % to about 50 wt %, from about 30 wt % to about 45 wt %, or from about 35 wt % to about 55 wt %, based upon 100% weight of the core.
  • the O-Desmethylvenlafaxine oxalate can range from about 10% w/w to about 70% w/w of the total oral dosage unit, and preferably, about 40 to about 60 wt %, and more preferably, about 50 to about 55 wt % of the total weight of the oral dosage unit.
  • the core contains about 25 wt % to about 30 wt % microcrystalline cellulose.
  • the core may contain another binder or additional binders, or further excipients such as diluents, fillers, glidants, anti-adherents, and adjuvants to provide a total amount of excipients in the core of about 25 wt % to about 80 wt % w/w of the core.
  • excipients such as diluents, fillers, glidants, anti-adherents, and adjuvants to provide a total amount of excipients in the core of about 25 wt % to about 80 wt % w/w of the core.
  • one or more binder/fillers and/or diluents can each be present in an amount of about 15% w/w to about 80% w/w, or about 20% w/w to about 70% w/w, or about 25% w/w to about 45% w/w, or about 30% w/w to about 42% w/w of the uncoated dosage form.
  • the total amount of a pH adjuster in the formulation can range from about 0.1% w/w to about 10% w/w of the core, or about 1% w/w to about 8% w/w, or about 3% w/w to about 7% w/w. However, these percentages can be adjusted as needed or desired by one of skill in the art.
  • the filler/binder is water insoluble.
  • the filler/binder may be selected from among known fillers/binders, including, e.g., cellulose, and povidone, among others.
  • the filler/binder is selected from among microcrystalline cellulose, crospovidone, and mixtures thereof.
  • Other suitable fillers/binders including those that are water soluble or partially water soluble may be used in combination with water insoluble fillers/binders, as needed.
  • Suitable pH adjusters include, e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, lithium carbonate, among others. Still other suitable components will be readily apparent to one of skill in the art.
  • the O-Desmethylvenlafaxine oxalate core is provided with further layers that provide a sustained release formulation which contains rate-controlling components.
  • rate controlling components are rate controlling polymers selected from among hydrophilic polymers and inert plasticized polymers.
  • Suitable rate controlling hydrophilic polymers include, without limitation, polyvinyl alcohol (PVA), hypomellose and mixtures thereof.
  • suitable insoluble or inert "plastic" polymers include, without limitation, one or more polymethacrylates (i.e., Eudragit® polymer).
  • Other suitable rate-controlling polymer materials include, e.g., hydroxyalkyl celluloses, poly(ethylene) oxides, alkyl celluloses, carboxymethyl celluloses, hydrophilic cellulose derivatives, and polyethylene glycol.
  • the formulation of the invention contains one or more coatings over the O-Desmethylvenlafaxine oxalate core.
  • the core can contain a non-functional seal coating (i.e., a coat which does not affect release rate) and a functional second coating.
  • an initial seal coat can be applied directly to the core.
  • the seal coat may be selected from among suitable polymers such as hydroxypropyl methylcellulose (HPMC), ethylcellulose, polyvinyl alcohol, and combinations thereof, optionally containing plasticizers and other desirable components.
  • HPMC hydroxypropyl methylcellulose
  • ethylcellulose ethylcellulose
  • polyvinyl alcohol polyvinyl alcohol
  • a particularly suitable seal coat contains HPMC.
  • a suitable seal coat can be applied as a HPMC solution at a concentration of about 3% w/w to 25% w/w, and preferably 5% w/w to about 7.5% w/w.
  • the initial seal coat can be applied on a fluid bed coater, e.g., by spraying.
  • an Aeromatic Strea® fluid bed apparatus is fitted with a Wurster column and bottom spray nozzle system. Approximately 200 grams of the dried pellet cores are charged into the unit.
  • the Opadry® Clear seal coat is applied with an inlet temperature of approximately 50° C. to 60° C 5 a coating solution spray rate of 5 to 10 grams/minute, atomization pressure of 1 to 2 bar.
  • the desired product temperature is 35° C. to 45° C, and preferably 38° C. to 43° C.
  • the initial seal coat Upon drying, under suitable conditions, the initial seal coat is in the range of about 1% w/w to about 3% w/w, or about 2% w/w, of the uncoated core.
  • a commercially available seal coat containing HPMC, among other inert components is utilized.
  • One such commercially available seal coat is Opadry® Clear (Colorcon, Inc.).
  • the oral dosage unit contains a further release or "delay” coating layer.
  • This release coating layer may be applied over an initial seal coat or directly over a core.
  • the release coat is a controlled release coating layer which contains an ethylcellulose-based product.
  • An example of one suitable ethylcellulose-based product is an aqueous ethylcellulose dispersion (25% solids).
  • the controlled release coat contains both an ethylcellulose-based product and hypomellose.
  • hypomellose e.g., in an amount of about 5 to 15% by weight, and preferably, about 10% by weight
  • the ethylcellulose may be about 85% to about 95%, by weight, or in embodiment, about 90% by weight, of the coat solution.
  • the total controlled release coat is in the range of about 2% to about 5%, or about 3% to about 4% w/w of the uncoated or initially-coated core.
  • the oral dosage unit contains an enteric coat, which can provide an initial "delay".
  • the enteric coat may delay release for as much as about 30 minutes to two hours.
  • the enteric coat may be applied over the controlled release coat, over an initial seal coat, or directly over a core.
  • the enteric coat may contain, e.g., polymethacrylates, hypomellose, and ethylcellulose, or a combination thereof.
  • the enteric coat contains a product which is a copolymer of methacrylic acid and methacrylates, such as the commercially available Eudragit® L 30 K55 (Roehm GmbH & Co. KG).
  • this enteric coat is applied such that it coats the core in an amount of about 10 wt % to 20 wt %, or about 12 wt % to about 17 wt % , or about 15.5 wt % to 16.5 wt % of the uncoated or initially-coated core.
  • the enteric coat is composed of a Eudragit® L30D-55 copolymer (Roehm GmbH & Co. KG), talc, tri ethyl citrate, and water. More particularly, the enteric coating may contain about 7 wt % to about 9 wt % of a 30 wt % dispersion of Eudragit® L 30 D55 coating; about 4 wt % to about 5 wt % /w talc, about 0.7 wt % to about 1 wt % triethyl citrate; a pH adjuster such as sodium hydroxide and water.
  • a pH adjuster such as sodium hydroxide and water.
  • the enteric coat can be applied directly to the uncoated spheroid core, i e., the uncoated core, or may be applied over an initial seal coat.
  • the enteric coat as described above, is typically applied on a fluid bed coater.
  • Surelease® aqueous ethylcellulose dispersion (25% solids) is applied in a similar fashion as the seal coat. After the ethylcellulose coat is applied, the pellets are dried for an additional 5 to 10 minutes. They are then removed and screened through a mesh screen to remove agglomerates and oversize particles.
  • a final seal coat is applied over the enteric coat and, optionally, talc is utilized as a final step prior to filling the O-Desmethylvenlafaxine oxalate formulations into a suitable packaging unit.
  • this final seal coat is composed of HPMC and water, upon drying, is less than about 1 wt % of the total, coated oral dosage unit.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), The Science and Practice of Pharmacy, 20.sup.th Edition, Lippincott Williams & Wilkins, Baltimore, Md., (2000).
  • Liquid form preparations include solutions, suspensions and emulsions. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
  • Specific dosage and treatment regimens for any particular patient may be varied and will depend upon a variety of factors, the age, body weight, general health status, sex and diet of the patient, the time of administration, the rate of excretion, the specific drug combination, the severity and course of the symptoms being treated, the patient's disposition to the condition being treated and the judgment of the treating physician. Determination of the proper dosage regimen for a particular situation is within the skill of the art.
  • the amount and frequency of the administration of the compositions of this invention, or the pharmaceutical compositions thereof, may be regulated according to the judgment of the attending clinician, based on the factors recited above. As a skilled artisan will appreciate, lower or higher doses than those recited above may be required.
  • the relative intensity of peaks in a diffractogram is not necessarily a limitation of the
  • PXRD pattern because peak intensity can vary from sample to sample, e.g., due to crystalline impurities. All reported PXRD peaks in the Figures, Examples, and elsewhere herein are reported with an error of about .+-.0.2 degrees 2-theta.
  • Example 1 The material from Example 1 was dissolved in 4 ml of either methanol, ethanol, or dichloromethane under stirring. After 1 hour, the solution was filtered with a Whatman 0.45um filter and left to evaporate at room temperature for three days.
  • B The material from Example 1 was dissolved in 4 ml of either methanol, ethanol, or dichloromethane under stirring. After 1 hour, the solution was filtered with a Whatman 0.45um filter and left to evaporate at 5 degrees C for 1 week.
  • a suspension was made by dissolving 0.05Og of the material from Example 1 in 2ml of either acetonitrile or di ethyl ether. The suspensions were stirred for one day at room temperature, and filtered on a Whatman filter. PXRD analysis of the crystal resulted in the following data.
  • Example 2 The material from Example 1 was dissolved in 4 ml of 1-propanol under stirring. After 1 hour, the solution was filtered with a Whatman 0.45um filter and left to evaporate at 5 degrees C for 1 week.
  • Example 1 The material from Example 1 was dissolved in 4 ml of 1 ,2-dimethoxy ethane or water under stirring. After 1 hour, the solution was filtered with a Whatman 0.45um filter and left to evaporate at 60 degrees C for two days.
  • the crystals were prepared by dissolving 0.050 g of solid from Example 1 in 2 niL of water. The solution was heated until complete dissolution and then cooled at RT. A representative PXRD pattern that was obtained is shown in Figure 12. PXRD analysis of the crystal (by calculation from the single crystal data) resulted in the following data.
  • the kinetic dissolution of the ⁇ crystal of O-Desmethylvenlafaxine oxalate was found to be 0.017 g/min as compared to the kinetic dissolution of O-Desmethylvenlafaxine succinate at 0.014 g/min.
  • the thermodynamic solubility of the ⁇ crystal of O-Desmethylvenlafaxine oxalate was found to be 142 g/L as compared to the thermodynamic solubility of O- Desmethylvenlafaxine succinate at 70 g/L.
  • EXAMPLE 9 PROPHETIC FORMULATION The following exemplary formulation could be used to formulate O-
  • EXAMPLE 10 PROPHETIC FORMULATION The following exemplary formulation could be used to formulate O- Desmethylvenlafaxine oxalate.
  • % are in w/w.
  • a coating could also be added to the tablet formulation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un nouveau sel et un nouveau cristal de l'ingrédient pharmaceutique actif, O-Desméthylvenlafaxine, et concerne des procédés de préparation du sel et du cristal, des compositions pharmaceutiques comprenant le sel et le cristal ainsi que des méthodes de traitement d'un patient avec le sel et le cristal.
PCT/US2009/047907 2008-06-19 2009-06-19 Nouveau sel oxalate et nouveau cristal de o-desméthylvenlafaxine Ceased WO2009155488A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010088865A3 (fr) * 2009-02-06 2010-12-02 Zentiva, K.S. Nouveaux sels de la desvenlafaxine et un de leurs procédés de préparation
WO2018097733A3 (fr) * 2016-11-23 2018-08-02 Bohne Askøy As Prévention et/ou traitement du syndrome de fatigue chronique

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR0311693A (pt) * 2002-06-10 2005-03-22 Wyeth Corp Sal de formato de o-desmetil-venlafaxina
IN2003MU00504A (fr) * 2003-06-05 2005-05-13 Alembic Ltd
GT200600397A (es) * 2005-09-07 2007-08-28 Formulas topicas conteniendo o-desmetil venlafaxina (odv) o sus sales
GT200600396A (es) * 2005-09-07 2007-04-23 Dispositivos para la aplicacion de medicamentos transdermicos conteniendo o-desmetil venlafaxina (odv) o sus sales
KR20100132069A (ko) * 2008-06-16 2010-12-16 테바 파마슈티컬 인더스트리즈 리미티드 Ｏ-데스메틸벤라팍신염의 고체 상태

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010088865A3 (fr) * 2009-02-06 2010-12-02 Zentiva, K.S. Nouveaux sels de la desvenlafaxine et un de leurs procédés de préparation
US20120041227A1 (en) * 2009-02-06 2012-02-16 Ludek Ridvan New salts of desvenlafaxine and a method of their preparation
EA019449B1 (ru) * 2009-02-06 2014-03-31 Зентива, К.С. Новые соли десвенлафаксина и способ их получения
US8779005B2 (en) 2009-02-06 2014-07-15 Zentiva K.S. Salts of desvenlafaxine and a method of their preparation
WO2018097733A3 (fr) * 2016-11-23 2018-08-02 Bohne Askøy As Prévention et/ou traitement du syndrome de fatigue chronique

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