WO2011087765A2 - Procédés de production de compositions pharmaceutiques galéniques solides stabilisées contenant des morphinanes - Google Patents

Procédés de production de compositions pharmaceutiques galéniques solides stabilisées contenant des morphinanes Download PDF

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Publication number
WO2011087765A2
WO2011087765A2 PCT/US2010/061400 US2010061400W WO2011087765A2 WO 2011087765 A2 WO2011087765 A2 WO 2011087765A2 US 2010061400 W US2010061400 W US 2010061400W WO 2011087765 A2 WO2011087765 A2 WO 2011087765A2
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WO
WIPO (PCT)
Prior art keywords
morphinan
oxycodone
granules
granule
protected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2010/061400
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English (en)
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WO2011087765A3 (fr
Inventor
Jae Han Park
Tiffani Eisenhauer
Anish Dhanarajan
Vishal K. Gupta
Stephen Overholt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mallinckrodt Inc
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Mallinckrodt Inc
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Publication date
Application filed by Mallinckrodt Inc filed Critical Mallinckrodt Inc
Priority to RU2013132138/15A priority Critical patent/RU2013132138A/ru
Priority to BR112013015622A priority patent/BR112013015622A2/pt
Priority to JP2013546107A priority patent/JP5897036B2/ja
Priority to AU2011345329A priority patent/AU2011345329B2/en
Priority to US13/166,770 priority patent/US8597681B2/en
Priority to EP11731589.5A priority patent/EP2654727A1/fr
Priority to MX2013007057A priority patent/MX2013007057A/es
Priority to CN201180068100.2A priority patent/CN103402499B/zh
Priority to US13/995,810 priority patent/US9198861B2/en
Priority to CA2822553A priority patent/CA2822553A1/fr
Priority to KR1020137019037A priority patent/KR101748906B1/ko
Priority to PCT/US2011/041533 priority patent/WO2012087377A1/fr
Publication of WO2011087765A2 publication Critical patent/WO2011087765A2/fr
Publication of WO2011087765A3 publication Critical patent/WO2011087765A3/fr
Anticipated expiration legal-status Critical
Priority to ZA2013/03988A priority patent/ZA201303988B/en
Priority to US14/092,375 priority patent/US8980319B2/en
Priority to JP2015154715A priority patent/JP2015193668A/ja
Priority to US14/921,188 priority patent/US20160184232A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • APIs active pharmaceutical ingredients
  • Oxidation is a common mechanism of API degradation in pharmaceutical compositions.
  • the process of oxidative degradation may occur via various mechanisms such as autooxidation, nucleophilic addition, electrophilic addition, or electron transfer. Regardless of the mechanism, degradant compounds formed by the degradation of an API in a pharmaceutical composition may impart potentially harmful properties to the composition.
  • degradants are present in a pharmaceutical composition above the levels prescribed by ICH Guidelines Q3A and Q3B, the degradants must undergo a qualification procedure as part of the approval process required before the use and sale of the composition is allowed. Qualification of impurities typically involves costly studies using multiple animal models, and introduces considerable risk into the development process. If degradants of a pharmaceutical composition are found to be carcinogenic or teratogenic, the composition will not gain FDA approval, diminishing the opportunity for commercialization of the API.
  • a functional pharmaceutical carrier is typically selected primarily to impart desired performance characteristics to the composition such as an extended release profile.
  • the formulation of a solid dosage form of an API may incorporate a release-modifying pharmaceutical carrier in order to achieve a desired release profile after administration of the compound.
  • Polymer carriers such as a polyethylene oxide (PEO) polymer may be incorporated into a pharmaceutical composition to impart an extended release profile to the composition.
  • PEO polymers are produced by a process of radical polymerization process followed by oxidative degradation of the polymer to achieve the desired molecular weight. The resulting PEO polymer carriers may retain residual peroxides and other oxidative species from the production process that may cause the oxidation of the API molecules in any
  • composition that incorporates PEO polymers.
  • other excipients such as antioxidants or pH-lowering excipients may be incorporated into the API composition to minimize the degradation of the API in the presence of incompatible carriers such as PEO polymers in the pharmaceutical composition.
  • this approach is less effective than in other dosage forms such as solutions or suspensions.
  • Morphinans a widespread class of analgesic APIs, are particularly vulnerable to oxidative degradation, especially in compositions that incorporate PEO po!ymer carriers or other pharmaceutical carriers that contain residual peroxides or other oxidative species. Because the physiological effects of morphinans are notoriously sensitive to small changes in chemical structure, the formation of degradants may introduce undesirable properties to a pharmaceutical composition in which a morphinan is vulnerable to degradation. For solid dosage forms of morphinan compositions, the introduction of additional antioxidant excipients or pH-lowering excipients to prevent the degradation of the morphinan, particularly when formulated in a solid dosage form, has been relatively ineffective to date.
  • one aspect of the disclosure provides a method for the preparation of a solid dosage form pharmaceutical composition comprising a morphian and at least one other active pharmaceutical ingredient.
  • the method comprises two steps.
  • a mixture comprising the morphinan and at least one excipient is granulated in a manner such that the amount of morphinan exposed on the surface of the granule is substantially reduced thereby forming a morphinan-protected granule.
  • a mixture comprising the morphinan-protected granule, the active pharmaceutical agent, and a release-controlling polymer comprising a polyethylene oxide polymer is granulated to form the solid dosage form pharmaceutical composition comprising a sustained release layer.
  • a mixture comprising the oxycodone-protected granule, the acetaminophen, and a release-controlling polymer comprising a polyethylene oxide polymer is granulated to form the solid dosage form pharmaceutical composition comprising a sustained release layer.
  • An additional aspect of the disclosure provides a method for the
  • a mixture comprising oxycodone or hydrocodone and at least one excipient is granulated in a manner such that the amount of oxycodone or hydrocodone exposed on the surface of granule is substantially reduced thereby forming a morphinan-protected granule.
  • a mixture comprising the morphinan-protected granule, the acetaminophen, and a release-controlling polymer comprising a polyethylene oxide polymer is granulated to form a sustained release layer.
  • a mixture comprising the morphinan- protected granule, the acetaminophen, and at least one excipient is granulated to form the immediate release layer.
  • the invention provides methods of preparing morphinan-protected granules by combining a morphinan with at least one excipient to form a mixture, and granulating the mixture.
  • the resulting morphinan-protected granules have a physical structure that minimizes the amount of morphinan that is exposed on the surface of the granule.
  • the morphian-protected granules may stabilize the morphinan against various mechanisms of degradation such as oxidation by substantially decreasing the amount of morphinan exposed on the surface of the granule thereby reducing the degree of contact between the morphinan and the oxidative species in the environment
  • surrounding the granules including but not limited to carriers and residual water in the composition, and atmospheric oxygen and moisture.
  • the morphinan-protected granules may be prepared using any device known in the art, including but not limited to a high-shear wet granulator.
  • the particular device used for granulation may affect the physical properties of the resulting granules, including but not limited to granule size, granule density, and granule porosity, all of which may influence the protective properties of the granule against degradation of the morphinan.
  • the distribution of morphinan and excipients within the granules is influenced by at least several factors including but not limited to the size of the morphinan particles relative to the excipient particles in the mixture prior to granulation, the chemical properties of the morphinan and excipients including but not limited to hydrophobicity and ionic charge, and the presence of excipients dissolved in the granulation solution used to prepare the granules.
  • the morphinan-protected granules prepared by the methods of the invention may be incorporated into a solid dose form of a pharmaceutical composition, including but not limited to tablet and capsule formulations.
  • a pharmaceutical composition including but not limited to tablet and capsule formulations.
  • the inclusion of the morphinan in the form of granules imparts several other advantageous aspects to the resulting composition.
  • the choice of carrier may be selected to satisfy constraints other than compatibility with the morphinan.
  • Carriers in the composition may instead be selected based on factors including but not limited to the cost of the carrier, the desirable modified-release properties imparted by a particular carrier.
  • variation in the characteristics of the morphinan-protected granules including granule size, excipients included in the granules, and the physical structure of the granules may be used to control the release profile or other pharmacokinetic characteristics of pharmaceutical compositions.
  • the granules prepared by the methods of the invention stabilize the morphinan contained within the granules by substantially reducing the amount of morphinan exposed on the surface of the granule.
  • significantly less of the morphinan is in contact with any oxidative species in the environment outside of the granule, and may additionally provide chemical protection of the morphinan against degradation by surrounding the morphinan with chemically protective excipients including but not limited to antioxidants that are contained within the morphinan- protected granule.
  • the physical structure of the morphinan-protected granule may influence the protective efficacy of the granule against degradation of the morphinan, and further influences the suitability of the granules for inclusion in various solid dose forms of pharmaceutical compositions, including but not limited to tablets and capsules.
  • the physical structure of the granule includes the morphinan dispersed within the excipient mixture and granulated in a manner such that the amount of morphinan exposed on the surface of the granule is substantially reduced.
  • the particular physical structure of any embodiment of a morphinan-protected granule is influenced by at least several factors related to the method of preparing the granules and the particular morphinan and excipients included in the granule. The influence of these factors on the physical structure of the granules is described in detail below.
  • the physical structure of the granules may vary from an essentially random spatial distribution of the morphinan and excipients throughout the granules to a highly ordered distribution in which essentially ail of the morphinan is contained within a sharply delineated interior region that is surrounded by an exterior region that contains essentially all of the excipients.
  • the amount of morphinan that is exposed at the surface of the granules is less than about 100% of the total weight of the morphinan in the granules.
  • the amount of morphinan that is exposed at the surface of the granules is less than about 95%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, and less than about 5% of the total weight of morphinan in the granule.
  • Excipients contained within the granule may provide additional protection against degradation of the morphinan by chemically interacting with degradative compounds surrounding or within the granule.
  • the effectiveness of the excipients at protecting the morphinans in the granule may be enhanced if at least one of the excipients includes but is not limited to an antioxidant, a chelating agent, or a pH- adjusting agent.
  • the excipients included in the granule are described in detail below.
  • the density and porosity of the exterior regions of the granules may influence the effectiveness of the exterior regions at protecting the morphinans in the granules from degradation. Exterior regions having higher densities and lower porosities may be more resistant to penetration by degradative compounds from outside the granule.
  • the densities and porosities of the exterior regions of the granules may be influenced by at least several factors including but not limited to the particular
  • a granule prepared using a high-shear wet granulator may have a higher density and lower porosity compared to a granule with a similar composition prepared using a fluid bed granulator.
  • the dso of the granules in various embodiments may be selected based on the intended use of the granules, in particular the particular solid dosage form in which the granules are to be incorporated.
  • the particular dg 0 of the granule may be influenced by a variety of factors including but not limited to the composition of the granule and the granulation device used to prepare the granules.
  • the d 90 of the granules may be larger for granule compositions having a higher proportion of excipients including but not limited to binders and fillers relative to other types of excipients.
  • the granules may have an average d 90 of less than about 2000 pm. In other embodiments, the granules may have an average d9o of less than about 1800 pm, less than about 1500 pm, less than about 1000 pm, less than about 900 pm, less than about 800 pm, less than about 700 pm, less than about 600 pm, less than about 500 pm, less than about 400 pm, less than about 300 pm, less than about 200 pm, less than about 150 ⁇ , and less than about 100 pm. In one exemplary embodiment in which the granules are to be incorporated in a solid dosage form including but not limited to a capsule, the granules may be less than about 1000 pm in average dg 0 .
  • the granules may be less than about 800 pm in average d ⁇ o- In yet another embodiment, the granules may range from about 150 pm to about 200 pm in average d 90 .
  • composition of the granules prepared using the methods of the invention include a morphinan and at least one excipient.
  • the particular composition of the granules may influence a variety of properties of the granules including but not limited to the physical structure of the granules, the stability of the morphinan contained within the granule, and the suitability of the granules for incorporation into a particular dry dosage form of a pharmaceutical composition.
  • d 90 of the morphinan particles relative to the d 90 of the excipient particles in the mixture that used to form the granules.
  • d 90 represents the particle diameter at which 90% of the individual particles of a compound are smaller than the specified diameter.
  • a granulation device including but not limited to a low-shear wet granulator, a high-shear wet granulator, or a fluid bed granulator is used to granulate the mixture of the morphinan and at least one excipient
  • the compounds having a smaller d 90 relative to the other compounds in the mixture tend to aggregate near the interior regions of the granules
  • the compounds having larger d 90 tend to aggregate near the exterior regions of the granules, regardless of whether the compound is a morphinan or an excipient.
  • compositions in which the morphinan accounts for an extremely low proportion of the total mass of the granule the size of the morphinan particles relative to the excipient particles may not exert the same influence on the physical structure of the resulting granules as described previously.
  • the relative scarcity of the morphinan particles may result in a granule in which the individual morphinan particles are surrounded by excipient particles, and the morphinan particles may be located in both the interior region and the exterior region of the granule.
  • the d 90 of the morphinan is smaller than the d 90 of the excipients. In another embodiment, the d 90 of the morphinan is less than about 80% of the d 90 of the excipients. In yet other embodiments, the d 90 of the morphinan is less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, or less than about 50% of the d 90 of the excipients.
  • the d 90 values of the morphinan and the excipients may also be influenced by the capabilities of the particular device used to prepare the granules. Without being bound to any particular theory, when a granulation device including but not limited to a low-shear wet granu!ator, a high-shear wet granulator, or a fluid bed granulator is used to granulate the mixture of the morphinan and at least one excipient, if the d 90 of a particular compound falls below a threshold d 90 , the particles of that compound tend to aggregate before they are granulated, resulting in granules that have a non-homogenous distribution of the compound from granule to granule.
  • a granulation device including but not limited to a low-shear wet granu!ator, a high-shear wet granulator, or a fluid bed granulator is used to granulate the mixture of the morphinan and
  • other properties of the morphinan and excipients may influence the physical structure of the granule including but not limited to the hydrophobicity and ionic charge of the morphinan relative to the one or more excipients.
  • the morphinan is hydrophobic relative to the excipients and if a polar granulation fluid is used in the granulation process,
  • hydrophobic repulsive forces may tend to situate the morphinan within the interior region of the granules.
  • the composition of the granules includes one morphinan compound, in other embodiments, the composition of the granules may further include one or more additional morphinan compounds within each granule. Any number of different morphinans may be included in the composition of the granules, so long as ail morphinans that are included in the granule are physically and chemically compatible.
  • An acid refers to the acid and any pharmaceutically acceptable salt of the acid.
  • compositions of various embodiments of the granules include a morphinan.
  • the morphinan may be included in the granules in an amount of up to about 90% of the total weight of the granules.
  • the morphinan may be included in the granules in an amount ranging up to about 80%, up to about 70%, up to about 60%, up to about 50%, up to about 40%, up to about 30%, up to about 20%, up to about 10%, up to about 1 %, and up to about 0.5% of the total weight of the granules.
  • the morphinan included in various embodiments of the granules may be selected from opium, natural opium derivatives, semi-synthetic opium derivatives, and synthetic opium derivatives.
  • suitable morphinans for various embodiments of the granules include adulmine, al!ocryptopine, aporphine,
  • epiporphyroxine ethylmorphine, eupaverine, fagarine, fentanyl, g!aucine
  • the morphinan included in the granules may be selected from oxycodone, oxymorphone, hydrocodone, hydromorphone, nalbuphine, naloxone, buprenorphine, and naltrexone.
  • the morphinan in the granules is oxycodone or hydrocodone.
  • any of the morphinans included in the embodiments of the granules may have a (-) or (+) orientation with respect to the rotation of polarized light, depending upon whether the starting substrate has ⁇ -) or (+) optical activity, and are referred to herein as (-)-morphinans and (+)-morphinans respectively. More specifically, each chiral center may independently have an R or an S configuration.
  • an embodiment of the granules may include a morphinan compound possessing a fused carbon ring structure.
  • the ring atoms of the morphinan compound may be numbered as diagrammed in Formula (I) below.
  • Morphinan compounds have asymmetric centers and the core morphinan compound may have at least four chiral carbons including but not limited to C-5, C-13, C-14, and C-9.
  • the configuration of the chiral carbons C-5, C-13, C-14, and C-9 may be RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, or SSSS, provided that the C-15 and the C-16 carbons are both oriented either on the alpha face or the beta face of the morphinan molecule.
  • the morphinan may be provided in any solid form including but not limited to a finely divided solid, a crystal, a particle, a powder, or any other finely divided solid form known in the art. Any finely divided solid form of the morphinan may be used so long as the d 90 of the morphinan particles are smaller than the d 90 of the one or more excipients as described above.
  • the granules include one or more excipients in addition to the morphinan.
  • the one or more excipients are selected to impart at least one or more desired physical or chemical properties to the granules, including but not limtted to adhesion of the particles of the morphinan and excipient compounds in the mixture to facilitate the formation of granules, formation of physical barriers around the morphinans in the granules, and chemical inhibition of various mechanisms of degradation of the morphinans including but not limited to oxidation.
  • the one or more excipients include binders, fillers, antioxidants, pH- adjusting agents, chelating agents, and antimicrobial agents.
  • the one or more excipients may be introduced into the mixture to be granulated in a solid form including but not limited to a crystal, a particle, a powder, or any other finely divided solid form known in the art.
  • the one or more excipients may be dissolved or suspended in a solvent and sprayed onto the mixture in a granulation device as a binder fluid during granulation.
  • binders are excipients included in various embodiments of the granule to impart structural integrity to the granules by binding together the particles making up each granule.
  • binders suitable for the formulations of various embodiments include starches, pregelatinized starches, gelatin,
  • the binder may be introduced into the mixture to be granulated in a solid form including but not limited to a crystal, a particle, a powder, or any other finely divided solid form known in the art.
  • the binder may be dissolved or suspended in a solvent and sprayed onto the mixture in a granulation device as a binder fluid during granulation.
  • Fillers may be included in various embodiments of the granule
  • composition as an excipient to increase the bulk volume of the granules and to impart suitable compressibility characteristics to the granules for subsequent inclusion in solid dosage forms of pharmaceutical compositions including but not limited to tablets.
  • fillers include carbohydrates, inorganic compounds, and
  • Antioxidants are excipients included in various embodiments of the granules to prevent the oxidation of the morphinan in the granules.
  • Suitable antioxidants include, but are not limited to anoxomer, N-acetylcysteine, benzyl isothiocyanate, m- aminobenzoic acid, o-aminobenzoic acid, p-aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, alpha-carotene, beta-carotene, beta-caraotene, beta-apo-carotenoic acid, carnosol, carvacroi, catechins, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p-coumaric acid, 3,4-dihydroxybenzoic acid, ⁇ , ⁇ '-diphenyl-p-
  • thtodipropionic acid trihydroxy butyrophenone, tryptamine, tyramine, uric acid, vitamin K and derivates, vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof.
  • an antioxidant agent may be subjected to a particle size reduction process including but not limited to grinding, milling, sonication, or hammer milling in order to reduce the dgo of the antioxidant agent to a value less than the d 90 of the morphinan (or other API included in the formulation) prior to granulation.
  • the reduced d 90 of the antioxidant agent may result in a distribution of antioxidant agent that is clustered around the morphinan particles, rather than near the outer surface of the granule.
  • a pH-adjusting agent may be included as an excipient to raise or lower the pH of the granule in order to prevent the oxidation of the morphinan in the granules.
  • a pH-adjusting agent including but not limited to citric acid may be incorporated into the composition granule in order to lower the pH of the granule.
  • a lower pH prevents the oxidation of the granule by various oxidative compounds associated with release- modifying polymer incorporated into a sold dosage form, including but not limited to peroxides.
  • a pH-adjusting agent may be subjected to a particle size reduction process including but not limited to grinding, milling, sonication, or hammer milling in order to reduce the d 90 of the pH-adjusting agent to a value less than the d 90 of the morphinan prior to granulation.
  • the reduced d 90 of the pH-adjusting agent may result in a distribution of pH-adjusting agent that is clustered around the morphinan particles, rather than near the outer surface of the granule.
  • pH-adjusting agents include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate and sodium bicarbonate.
  • a chelating agent may be included as an excipient to immobilize oxidative species including but not limited to metal ions in order to inhibit the oxidative degradation of the morphinan by these oxidative species.
  • chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamate, aspartate, and Na 2 EDTA.
  • an antimicrobial agent may be included as an excipient to minimize the degradation of the morphinan by microbial agents including but not limited to bacteria and fungi.
  • microbial agents including but not limited to bacteria and fungi.
  • antimicrobials include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na 2 EDTA and sulfites including but not limited to sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite.
  • the morphinan in the granule is substantially resistant to degradation due to interactions of the morphinan with degradative compounds or conditions present in the environment or in the carriers surrounding the granules in a solid dosage form of a pharmaceutical composition
  • the morphinan in the granules is substantially resistant to the formation of degradants resulting from a chemical change in the morphinan brought about during the production and/or storage of the pharmaceutical composition containing the morphinan by the effect of factors including but not limited to light, temperature, pH, water, or reaction with an excipient or carrier included in the
  • the particular degradants formed in a pharmaceutical composition depend on the particular morphinan and the at least one excipient within the granule, as well as the particular carriers included in the pharmaceutical
  • composition along with the granules.
  • degradants must be reported and subjected to the qualification process described above. According to ICH Guideline Q3B, the amount of any individual degradant must be reported if the amount of degradant exceeds 0.10% of the total API weight for maximum daily doses of 1000 mg of API or below. For APIs having average daily doses of above 1000 mg, degradants in excess of 0.05% of the total API mass must be reported.
  • the ICH guidelines apply throughout the effective shelf life of the
  • any one degradant in the composition may be limited to less than about 0.5% of the total mass of the morphinan after about six months of storage at a temperature of about 40° C and a relative humidity of about 75%.
  • the granules contain less than about 0.5% w/w of a degradant selected from 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide after being stored for 6 months at 40° C and 75% relative humidity.
  • the granules contain less than about 0.5% w/w of each of one or more degradants selected from 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide after being stored for 6 months at 40° C and 75% relative humidity.
  • the granules may be prepared by combining the morphinan with at least one excipient to form a mixture and granulating the mixture in a manner such that the amount of morphinan exposed on the surface of the granules is minimized (thereby forming a morphinan-protected granule).
  • Suitable morphinans for the granule embodiments are described in detail in Section (lla) above, and suitable excipients are described in Section (lib) above.
  • the mixture may be formed using any suitable method known in the art including but not limited to stirring, shaking, vibrating, and blending.
  • the morphinan and dry excipients may be charged into a granulation device and mixed prior to the addition of the granulation fluid.
  • Any suitable granulation device known in the art may be used to prepare the granules. As previously discussed, the particular granulation device selected for the preparation of the granules may influence the physical properties of the resulting granules.
  • Non-limiting examples of suitable devices for the preparation of the granules include a low-shear wet granulator, a high-shear wet granulator, a fluid-bed granulator, a roller compactor, a vertical granulator, an oscillating granulator, a gelatinizer, a pelletizer, and a spheronizer.
  • the granulation device may be selected in order to prepare granules having the desired granule physical characteristics described in Section (II) above.
  • a high-shear wet granulator is used to prepare the granules.
  • the high-shear wet granulator may be capable of preparing granules having properties that enhance the protective effect of the granule, including but not limited to higher granule densities and lower granule porosities relative to granules prepared by other devices. Further, the high-shear wet granulator is capable of preparing granules with a dg 0 that is larger than other granulation devices, resulting in granules suitable for inclusion in a wider variety of solid dosage forms of morphinan compositions.
  • the morphinan and the excipients in dry form of the composition are introduced into the wet high shear granulator in order to form the mixture. After the morphinan and the dry excipients are essentially
  • a granulation fluid is sprayed into the granulator.
  • the granulation fluid may be any volatile, non-toxic granulation fluid known in the art.
  • suitable granulation fluids include water, ethanol, isopropanol, and combinations thereof.
  • one or more of the excipients may be mixed with the granulation fluid prior to spraying the granulation fluid into the granulator.
  • a binder including but not limited to pregelatinized starch may be dissolved into the granulation fluid including but not limited to water to form a granulation solution, and the granulation solution may be sprayed into the granulator in order to prepare the granules.
  • the wet granules prepared in the high shear wet granulator may be dried using a drying device, resulting in dried granules having a water content of less than about 2% of the total weight of the granules.
  • a drying device Any suitable drying device known in the art may be used to dry the wet granules, including but not limited to an oven, a vacuum oven, and a rotary drum dryer.
  • the morphinan-protected granules prepared by various embodiments may be incorporated into various solid dosage pharmaceutical compositions.
  • Non-iimiting examples of solid dosage pharmaceutical compositions incorporating embodiments of the morphinan granules include granules, tablets, and capsules.
  • embodiments of tablets include uncoated tablets, coated tablets, mini-tablets, orally disintegrating tablets, and biiayer tablets.
  • Non-limiting embodiments of capsules include hard capsules and multi-layer capsules.
  • the solid dosage pharmaceutical composition may have release
  • characteristics including but not limited to rapid release, sustained release, extended release, slow release, time release, and combinations thereof.
  • solid dosage form pharmaceutical compositions are made via a two step process. First, the morphinan-protected granule is formed. The morphinan-protected granule is then mixed with excipients and other active pharmaceutical ingredients, which are then granulated to form the solid dosage form pharmaceutical composition.
  • the solid dosage form pharmaceutical composition may include additional APIs.
  • the solid dosage form pharmaceutical composition comprises a morphinan and acetaminophen.
  • the solid dosage form pharmaceutical composition may comprise sustained release (SR) and immediate release layers (IR). Typically, the SR and IR layers both include the morphinan and acetaminophen.
  • the SR layer typically comprises a release-controlling polymer comprising a polyethylene oxide polymer.
  • compositions incorporating the morphinan-protected granules may include one or more pharmaceutically acceptable carriers in addition to the granules.
  • Pharmaceutically acceptable carriers suitable for embodiments of the solid dosage pharmaceutical compositions may include but are not limited to binders, fillers, lubricants, diluents, non- effervescent disintegrants, effervescent disintegrants, flavor-modifying agents, sweeteners, dispersants, coloring agents, taste masking agents, release-controlling polymers and combinations thereof.
  • Non-limiting examples of binders suitable for the formulations of various embodiments include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellu!ose, sodium carboxymethylcellulose, ethylcellulose,
  • polyacrylamides polyvinyloxoazolidone, polyvinylalcohols, C12-C 8 fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
  • the polypeptide may be any arrangement of amino acids ranging from about 100 to about 300,000 Daltons.
  • Non-limiting examples of fillers include carbohydrates, inorganic
  • fillers include dibasic calcium sulfate, tribasic calcium sulfate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, lactose, sucrose, mannitol, and sorbitol.
  • Non-limiting examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.
  • diluents include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.
  • Diluents suitable for use include but are not limited to pharmaceutically acceptable saccharides such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol; pofyhydric alcohols; starches; pre-manufactured direct compression diluents; and mixtures of any of the foregoing.
  • Non-limiting examples of non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth.
  • Suitable effervescent disintegrants include but are not limited to sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.
  • Suitable flavor-modifying agents include but are not limited to synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof.
  • Other non-limiting examples of flavor- modifying agents include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.
  • Non-limiting examples of sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, sylitol, hydrogenated starch hydrolysates and the synthetic sweetener 3,6- dihydro-e-methyl-I ⁇ .S-oxathiazin ⁇ -one ⁇ -dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.
  • dipeptide sweeteners such as aspartame
  • dihydrochalcone compounds glycyrrhizin
  • Stevia rebaudiana Stevia rebaudian
  • Dispersants may include but are not limited to starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.
  • Suitable coloring agents include but are not limited to food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors or dyes, along with their corresponding lakes, and certain natural and derived colorants may be suitable for use in various
  • Taste-masking agents include but are not limited to cellulose
  • HPC hydroxypropyl ethers
  • HPMC cellulose hydroxypropyl methyl ethers
  • HPMC cellulose hydroxypropyl methyl ethers
  • Release-controlling polymers may be included in the various embodiments of the solid dosage pharmaceutical compositions incorporating the granules.
  • the release-controlling polymers may be used as a tablet coating.
  • a release-controlling polymer may be mixed with the granules and other excipients prior to the formation of a tablet by a known process including but not limited to compression in a tablet mold.
  • Suitable release-controlling polymers include but are not limited to hydrophilic polymers and hydrophobic polymers.
  • Suitable hydrophilic polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, crosslinked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitoi, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, alginate sodium carmellose, calcium carmellose, carrageenan, fucoidan, furcellaran, arabicgum, carrageensgum, ghaftigum, guargum, karayagum, locust beangum, okragum, tragacanthgum
  • polystyrene resin polystyrene resin
  • polystyrenes polystyrene resin
  • anionic and cationic hydrogels and combinations thereof.
  • Non-limiting examples of suitable hydrophobic polymers include cellulose acetate butyrate, cellulose acetate ethylcarbamate, cellulose acetate heptanoate, cellulose acetate methylcarbamate, cellulose acetate octanoate, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate succinate, cellulose acetate trimaletate, cellulose acetaldehyde dimethyl acetate, cellulose butyrate, cellulose ditnethylaminoacetate, cellulose disuccinate, cellulose dipalmitate, cellulose dicaprylate, cellulose propionate, cellulose propionate succinate, cellulose trioctanoate, cellulose tripropionate, cellulose trimellitate, cellulose tripalmitate, cellulose trivalerate, cellulose valerate palmitate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, ethyl
  • methacrylate copolymer poly(acrylate), poly(methacrylate), poly(methyl methacrylate), poly(ethylacrylate), poly(ethyl methacrylate), poly(methacrylic acid anhydride), glycidyl methacrylate copolymers, ammonio methacrylate copolymers, lecithins, aluminum monostearate, cetyialcohol, hydrogenated beef tallow, hydrogenated castor oil, hydrogentated vegetable oil, 12-hydroxystearyl alcohol, glyceryl monopalmitate, glyceryl dipalmitate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, myristyl alcohol, stearic acid, stearyl alcohol, polyethyleneglycols, zein, shellac, bee's wax, carnauba wax, glyceryl behenate, Japan wax, paraffin, spermaceti, synthetic waxes, and
  • the solid dosage pharmaceutical compositions may be produced using any suitable method known in the art. The particular production method selected may depend on the desired type of solid dosage form and the desired release profile. Production of tablet compositions [0078]
  • the pharmaceutical compositions in the form of a tabfet may be produced using any suitable method known in the art including but not limited to direct
  • the morphinan-protected granules may be combined with the one or more carriers and granulated into tablet granules using any of the known granulation devices described previously.
  • the tablet granules formed from the combination of the morphinan-protected granules and the one or more carriers may be optionally blended with one or more additional carriers including but not limited to lubricants, and the resulting tablet blend may be compressed into a tablet form.
  • one or more carriers incorporated into the tablet granules may include a release-controlling polymer to impart a modified release profile to the resulting tablet.
  • a bilayer tablet may be formed by producing a first tablet blend and a second tablet blend using a tablet granulation and blending process similar to those previously described.
  • the first tablet blend may include a disintegrant in order to impart a rapid release profile to the resulting tablet produced using the first tablet blend.
  • the second tablet blend of this embodiment may include a release-controlling polymer to impart a modified release profile to the resulting tablet produced using the second tablet blend.
  • the first tablet blend and the second tablet blend may be loaded into a tableting device including but not limited to a bi!ayer tablet press, and pressed into a bilayer tablet in which the first layer may have a rapid release profile and the second layer may have a modified release profile.
  • the morphinan-protected granules may be coated with a release-controlling polymer prior to incorporating the morphinan-protected granules into a solid tablet form in order to impart a modified release profile to the resulting tablet.
  • the solid tablet form may be coated with a release-controlling polymer to impart a modified release profile.
  • Other combinations of the embodiments described above may be used to produce additional embodiments having a desired release profile or other desired performance characteristic including but not limited to masked taste, acceptable tongue-feel and mouth-feel, and enhanced stability.
  • the pharmaceutical compositions in the form of a capsule may be produced using any suitable method known in the art including but not limited to direct loading into two-piece telescoping hard capsules.
  • suitable hard capsules include hard starch capsules, hard gelatin capsules, and hard cellulose capsules.
  • the capsule form of the pharmaceutical compositions may be produced by loading the morphinan-protected granules in to the hard capsule and sealing the capsule.
  • the morphinan-protected granules may be coated with a release-controlling polymer to impart a modified release profile to the hard capsule composition.
  • a fraction of the morphinan- protected granules may be coated with a release-controlling polymer and combined with the remaining uncoated morphinan-protected granules prior to loading the granules into the hard capsule.
  • An exemplary embodiment of a granule includes oxycodone
  • microcrystalline cellulose prege!atinized starch, Na 2 EDTA, and citric acid.
  • the overall composition of the exemplary oxycodon-protected granule embodiment is listed in Table 2 below.
  • the granules may be formed using the wet granulation method described in Example 1 below.
  • the oxycodone granules have a granule d 90 ranging from about 100 pm to about 400 ⁇ , and contain less than about 2% water by weight.
  • An exemplary embodiment of a solid dose pharmaceutical composition may be a bilayer tablet that includes the oxycodone-protected granules described above.
  • the exemplary bilayer tablet may be formed using the method described in Example 2 below.
  • the two layers of the bilayer tablet in this embodiment include an instant-release (IR) layer and a sustained release (SR) layer.
  • IR instant-release
  • SR sustained release
  • the overall compositions of the IR layer and the sustained release layer of the exemplary bilayer tablet embodiment are listed in Table 1 below.
  • the stability of the oxycodone in the exemplary bilayer tablet composition that incorporates oxycodone in a granular form is significantly better than a similar bi!ayer tablet composition that incorporates oxycodone in an unprotected powder form, as described in Example 2 below.
  • oxycodone-protected granules were divided into two groups to be incorporated into batches of instant release (IR) granules and into batches of sustained release (SR) granules used to form the IR and SR Layers of a bilayer tablet,
  • Both the IR granules and the SR granules were formed using separate fluid bed granulation processes. In each process, the previously-formed protected oxycodone granules, powdered acetaminophen (APAP), and various excipients including disintegrants, binders, and fillers were charged into the fluid bed granulation device and sprayed with a granulation fluid, resulting in the formation of IR granules in one batch and SR granules in a second batch.
  • the composition of the resulting IR and SR granules are summarized in Table 3:
  • the IR granules were blended with lubricant excipients in preparation for the tablet pressing process.
  • the SR particles were blended with various excipients including lubricants, and polyethylene oxide polymer, and a filler in preparation for the tablet pressing process.
  • the compositions of the IR blend and the SR blend are summarized in Table 4:
  • Unprotected bilayer tablets were formed using a process similar to that described in Example 1 , except that powdered oxycodone HCi, rather than protected oxycodone granules, were incorporated into the lR and SR granules formed using the fluid bed granulation device. Protected bilayer tablets formed using protected
  • oxycodone granules as described in Example 1 were also obtained.
  • the unprotected bilayer tablets were similar in composition to the protected bilayer tablets, except that the unprotected bilayer tablets lacked antioxidant excipients and oxycodone-protected granules, although the overall oxycodone contents of the two formulations of bilayer tablet were comparable.
  • a batch of protected bilayer tablets and a batch of unprotected tablets were placed into an environmental chamber and exposed to accelerated stability conditions.
  • all bilayer tablets were kept in the environmental chamber at a temperature of 55° C and a relative humidity of 80% for a period of six days.
  • the bilayer tablets were exposed to a temperature of 40° C and a relative humidity of 75%.
  • Example 4 Effect of Granulation Composition on Oxidative Stability of Solid Dose Qxycodone/APAP Formulations
  • Solid dose tablets were formed using the methods described in Example 2.
  • the solid dose tablets contained the oxycodone either in the protected granular form described in Example 3, or as the same ingredients in a powdered form rather than as granules.
  • the oxycodone and excipients were combined with APAP and polyethylene oxide (PEO) polymer.
  • Each tablet contained 10% of the oxycodone granule compositions described in Example 3, in either granulated or powdered form, 46.8% APAP, and 43.2% PEO polymer on a weight basis.

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Abstract

La présente invention concerne des procédés de production de compositions pharmaceutiques galéniques solides stabilisées. En particulier, l'invention concerne des procédés de préparation de granules enrobés contenant des morphinanes, et des compositions pharmaceutiques galéniques solides produites en utilisant les granules enrobés à base de morphinanes.
PCT/US2010/061400 2009-12-22 2010-12-21 Procédés de production de compositions pharmaceutiques galéniques solides stabilisées contenant des morphinanes Ceased WO2011087765A2 (fr)

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US13/995,810 US9198861B2 (en) 2009-12-22 2011-06-22 Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
BR112013015622A BR112013015622A2 (pt) 2010-12-21 2011-06-22 métodos de produção de composições farmacêuticas de dosagem sólida estabilizadas contendo morfinanos
JP2013546107A JP5897036B2 (ja) 2010-12-21 2011-06-22 モルフィナンを含む安定した固体剤形の薬学的組成物を生成する方法
AU2011345329A AU2011345329B2 (en) 2010-12-21 2011-06-22 Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
US13/166,770 US8597681B2 (en) 2009-12-22 2011-06-22 Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
EP11731589.5A EP2654727A1 (fr) 2010-12-21 2011-06-22 Procédés de production de compositions pharmaceutiques dosifiées solides stabilisées contenant des morphinanes
MX2013007057A MX2013007057A (es) 2010-12-21 2011-06-22 Metodos para producir composiciones farmaceuticas estabilizadas de dosis solida que contienen morfinanos.
CN201180068100.2A CN103402499B (zh) 2010-12-21 2011-06-22 制备包含吗啡喃的稳定的固体剂型药物组合物的方法
CA2822553A CA2822553A1 (fr) 2010-12-21 2011-06-22 Procedes de production de compositions pharmaceutiques dosifiees solides stabilisees contenant des morphinanes
RU2013132138/15A RU2013132138A (ru) 2010-12-21 2011-06-22 Способы получения стабилизированной твёрдой дозированной формы фармацевтических композиций, содержащих морфинаны
KR1020137019037A KR101748906B1 (ko) 2010-12-21 2011-06-22 모르피난을 함유한 안정화된 고체 투여 제약 조성물의 제조 방법
PCT/US2011/041533 WO2012087377A1 (fr) 2010-12-21 2011-06-22 Procédés de production de compositions pharmaceutiques dosifiées solides stabilisées contenant des morphinanes
ZA2013/03988A ZA201303988B (en) 2010-12-21 2013-05-31 Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
US14/092,375 US8980319B2 (en) 2009-12-22 2013-11-27 Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
JP2015154715A JP2015193668A (ja) 2010-12-21 2015-08-05 モルフィナンを含む安定した固体剤形の薬学的組成物を生成する方法
US14/921,188 US20160184232A1 (en) 2009-12-22 2015-10-23 Methods of Producing Stabilized Solid Dosage Pharmaceutical Compositions Containing Morphinans

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