WO2010059504A1 - Forme posologique solide de sufentanil comprenant des désoxydants et leurs procédés d'utilisation - Google Patents

Forme posologique solide de sufentanil comprenant des désoxydants et leurs procédés d'utilisation Download PDF

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Publication number
WO2010059504A1
WO2010059504A1 PCT/US2009/064232 US2009064232W WO2010059504A1 WO 2010059504 A1 WO2010059504 A1 WO 2010059504A1 US 2009064232 W US2009064232 W US 2009064232W WO 2010059504 A1 WO2010059504 A1 WO 2010059504A1
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WO
WIPO (PCT)
Prior art keywords
sufentanil
dosage form
drug dosage
solid
meg
Prior art date
Application number
PCT/US2009/064232
Other languages
English (en)
Inventor
Shamim Pushpala
Larry Hamel
Stelios Tzannis
Evangeline Cruz
Original Assignee
Acelrx Pharmaceuticals, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to NZ593512A priority Critical patent/NZ593512A/xx
Priority to CA2743261A priority patent/CA2743261C/fr
Priority to BRPI0921519-0A priority patent/BRPI0921519B1/pt
Priority to DK09760659.4T priority patent/DK2367537T3/da
Priority to ES09760659T priority patent/ES2396150T3/es
Priority to EP09760659A priority patent/EP2367537B1/fr
Priority to SG2011036894A priority patent/SG171786A1/en
Priority to MX2011005370A priority patent/MX2011005370A/es
Application filed by Acelrx Pharmaceuticals, Inc. filed Critical Acelrx Pharmaceuticals, Inc.
Priority to AU2009316874A priority patent/AU2009316874B2/en
Priority to JP2011537511A priority patent/JP2012509325A/ja
Priority to CN200980146531.9A priority patent/CN102231980B/zh
Priority to RU2011125316/15A priority patent/RU2530579C2/ru
Publication of WO2010059504A1 publication Critical patent/WO2010059504A1/fr
Priority to IL212880A priority patent/IL212880A/en

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Classifications

    • 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
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to compositions, methods and systems effective to minimize or eliminate the presence of oxidative degradation products in solid dosage forms comprising sufentanil.
  • the solid dosage forms comprising sufentanil are packaged in a substantially oxygen impermeable container which includes at least one oxygen scavenging material.
  • Moisture resistant packaging has been shown to be a critical requirement for
  • Fentora a fentanyl buccal tablet (Cephalon application for Marketing Authorisation of
  • Solid sufentanil drug dosage forms are provided in a primary package containing an oxygen scavenger, wherein the percentage of sufentanil oxidative degradation products is minimized or eliminated in solid sufentanil drug dosage forms packaged with an oxygen scavenger relative to solid sufentanil drug dosage forms packaged in the absence of an oxygen scavenger.
  • the packaged solid sufentanil drug dosage forms may be stored for at least 6 months under conditions selected from the group consisting of 5 0 C and ambient humidity, 25 0 C, 60% relative humidity and 4O 0 C, 75% relative humidity, wherein following storage the percentage of sufentanil oxidative degradation products is minimized or eliminated in the solid sufentanil drug dosage forms packaged with an oxygen scavenger relative to the solid sufentanil drug dosage forms packaged in the absence of an oxygen scavenger.
  • the packaged solid sufentanil drug dosage forms have a mass of from about
  • the packaged solid sufentanil drug dosage forms have a thickness of from about 0.7mm to about 1.0mm or from about 0.75mm to about 0.95mm and may comprise 5 meg, 10 meg, 15 meg, 20 meg, 30 meg, 40 meg, 50 meg, 60 meg, 70 meg,
  • the packaged solid sufentanil drug dosage forms may be housed in a drug delivery dispenser such as a cartridge or a single dose applicator and the primary package may be a foil pouch.
  • Figure 1 provides a graphic depiction of % Total RS versus time (0, 0.5, 1, 2 and 3 months), for 5 meg sufentanil dosage forms made using a standard formulation following storage at 5 0 C and ambient humidity in HDPE bottles alone (5ug) or in HDPE bottles containing an oxygen scavenger (Stabilox®; Multisorb Technologies; 5ug-R).
  • % Total RS % total related substances
  • % SDP percent sufentanil degradation products
  • Figure 2 provides a graphic depiction of % Total RS versus time (0, 0.5, 1, 2 and 3 months), for 5mcg sufentanil dosage forms made using a standard formulation following storage at 25 0 C and 60% relative humidity in HDPE bottles alone (5ug) or in HDPE bottles containing an oxygen scavenger (5ug-R_Stabilox in HDPE).
  • Figure 3 provides a graphic depiction of % Total RS versus time (0, 0.5, 1, 2 and 3 months), for 5mcg sufentanil dosage forms made using a standard formulation following storage at 4O 0 C and 75% relative humidity in HDPE bottles alone (5ug) or in HDPE bottles containing an oxygen scavenger (5ug-R_Stabilox in HDPE).
  • Figure 4 provides a graphic depiction of % Total RS versus time (0, 0.5, 1, 2, 3 and 6 months) for 5mcg sufentanil dosage forms made using a standard formulation following storage at 5 0 C and ambient humidity in HDPE bottles containing desiccant (5ug - Desiccant in HDPE) or in HDPE bottles containing an oxygen scavenger (5ug- R_Stabilox in HDPE).
  • Figure 5 provides a graphic depiction of % Total RS versus time (0, 0.5, 1, 2, 3 and 6 months) for 5mcg sufentanil dosage forms made using a standard formulation following storage at 25 0 C and 60% relative humidity in HDPE bottles containing desiccant (5ug - Desiccant in HDPE) or in HDPE bottles containing an oxygen scavenger (5ug-R_Stabilox in HDPE).
  • Figure 6 provides a graphic depiction of % Total RS versus time (0, 0.5, 1, 2, 3 and 6 months) for 5mcg sufentanil dosage forms made using a standard formulation following storage at 4O 0 C and 75% relative humidity in HDPE bottles containing desiccant (5ug - Desiccant in HDPE) or in HDPE bottles containing an oxygen scavenger (5ug-R_Stabilox in HDPE).
  • compositions, methods and systems effective to minimize or eliminate the presence of oxidative degradation products in solid dosage forms comprising sufentanil.
  • compositions, methods and systems which constitute the invention.
  • the invention is not limited to the specific dosage forms, devices, methodology, systems, kits or medical conditions described herein, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.
  • analgesic is used with reference to any of a number of drugs used to relieve pain (achieve analgesia).
  • analgesic drug is used herein with reference to a drug which results in analgesia following administration to a subject, for example, sufentanil, or a sufentanil congener, such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil.
  • sufentanil or a sufentanil congener, such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil.
  • analgesic drug is not limited to sufentanil, a sufentanil congener, or formulations comprising sufentanil or a sufentanil congener.
  • antioxidant refers to a molecule or combination of molecules capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. Antioxidants typically terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves.
  • the term "cartridge” is used herein with reference to a replaceable, single use disposable cartridge configured to hold one or more drug dosage forms, typically a 1 to 5 day supply. In one exemplary embodiment, a cartridge holds sufficient drug dosage forms for 1-5 days of treatment, e.g., 40 tablets useful for 48 to 72 hours of treatment. [0030] .
  • the cartridge may comprise a smart cartridge recognition system with a physical keyed feature on the cartridge, a bar code on the cartridge, a magnetic tag on the cartridge, an RFID tag on the cartridge, an electronic microchip on the cartridge, or a combination thereof.
  • the cartridge may comprise one or more shipping tablets, wherein at least one shipping tablet is dispensed prior to dispensing of a drug dosage form.
  • replaceable cartridge or "disposable cartridge” is used with reference to a cartridge for housing drug dosage forms and is typically configured to hold a 1 to 5 day supply of drug dosage forms, wherein the cartridge is designed to be used in a dispensing device and discarded after use.
  • the term “degradation” refers to any change in a "drug”, “medication”, or “pharmacologically active agent” (such as the sufentanil in a sufentanil- containing solid dosage form) during storage, for example by hydrolysis and/or oxidation of the drug or other components/excipients contained in the formulation.
  • the term “degradation agent” refers to an agent, e.g., an oxidizing agent or moisture (water), which is exposed to a "drug", “medication”, or “pharmacologically active agent” (such as the sufentanil in a sufentanil-containing solid dosage form) and causes an undesirable by-product.
  • the term “degradation protectant” refers to any material which protects against degradation of a "drug", “medication”, or “pharmacologically active agent” (such as the sufentanil in a sufentanil-containing solid dosage form), e.g., an oxygen scavenger, a desiccant, an anti-oxidant or a combination thereof.
  • a desiccant is used herein with reference to a sorbant, in the form of a solid, liquid, or gel which has an affinity for water, and absorbs or adsorbs moisture from it's surrounding, thus controlling the moisture in the immediate environment.
  • drug means any substance that alters the physiology of an animal and can be effectively administered by the oral transmucosal route.
  • formulation refers to a physical composition containing at least one pharmaceutically active substance, which may be provided in any of a number of dosage forms for delivery to a subject.
  • the dosage form may be provided to the patient as a lozenge, pill, capsule, membrane, strip, liquid, patch, film, gum, gel, spray or other form.
  • hydrogel-forming preparation means a solid formulation largely devoid of water which upon contact with an aqueous solution, e.g., a bodily fluid, and in particular that of the oral mucosa, absorbs water in such a way that it forms a hydrated gel in situ. The formation of the gel follows unique disintegration (or erosion) kinetics while allowing for release of the therapeutic agent over time.
  • hydrogel-forming preparation describes a solid formulation largely devoid of water which upon contact with bodily fluids, and in particular those in the oral cavity, transforms into a film that releases the drug. Such films increase the surface area available for drug release and absorption thus enabling faster absorption of the drug.
  • oxygen scavenger refers to a chemical substance that is added to a drug formulation or reagent in order to reduce or eliminate the generation of unwanted oxidation products.
  • an “oxygen scavenger” is effective to absorb oxygen.
  • oxygen scavenger may be used interchangeably with the terms “oxygen scavenging element” and “oxygen absorber”.
  • drug delivery dispenser means the container which directly houses a drug, medication, or pharmacologically active agent. Examples include, a cartridge, a single dose applicator, a multiple dose applicator, a thermoplastic tray, a blister pack, a flexible container, and a rigid container.
  • drug dosage form refers to a physical entity containing at least one drug, medication, or pharmacologically active agent for delivery to a subject. It may be in the form of a lozenge, pill, tablet, capsule, membrane, strip, powder, patch, film, gel, spray, gum or other form.
  • the term "primary packaging” means the container which directly houses a drug, medication, or pharmacologically active agent. Examples include a foil pouch, a plastic container, a plastic film container, a blister pack, a glass container, and the like.
  • An exemplary foil pouch comprises one of more of aluminum, zinc, nickel, tin, iron, copper, chromium, cobalt, silver, gold, magnesium, manganese, lead, galvanized iron, and metal oxides.
  • small volume sufentanil-containing drug dosage form is used herein with reference to a small volume dosage form that contains an amount of sufentanil from about 2 micrograms (meg) to about 200 meg of sufentanil, e.g., 5 meg, 10 meg, 15 meg, 20 meg, 30 meg, 40 meg, 50 meg, 60 meg, 70 meg, 80 meg, 90 meg, or 100 meg or more of sufentanil.
  • solid dosage form or “solid drug dosage form” is used herein with reference to a dosage form that is a solid, e.g., a lozenge, a pill, a tablet, a membrane or a strip.
  • subject includes any subject, generally a mammal (e.g., human, canine, feline, equine, bovine, ungulate etc.), adult or child, in which treatment with a sufentanil-containing solid dosage form is desired.
  • subject and “patient” may be used interchangeably herein.
  • substantially oxygen impermeable material is used herein with reference to a material that allows the passage of little or no oxygen through the material.
  • Many drugs are susceptible to oxidative degradation. In particular, this can be a problem when the drug is present as a low percentage of the overall drug formulation.
  • a dosage form made from such a formulation e.g., a solid sufentanil dosage form
  • preservatives and antioxidants are often employed in the formulation to address this problem. In most cases, this is sufficient to minimize or eliminate the generation of oxidative degradation products.
  • Methods and compositions for protecting an oxidation-susceptible active drug, such as sufentanil, in a solid drug dosage form from oxidative degradation are disclosed.
  • the methods involve inclusion of an oxygen scavenger in the packaging for the drug dosage form.
  • drug dosage forms e.g., sufentanil tablets
  • sufentanil tablets are produced and stored under conditions wherein the active drug is protected from oxidative degradation, thus facilitating storage of the drug dosage form over extended periods of time.
  • packaging techniques designed to minimize exposure of the active drug to oxygen and/or moisture.
  • Exemplary packaging techniques include use of primary packaging wherein more than one oxygen scavenging material is employed alone or in combination with use of a desiccant.
  • an anti-oxidant such as BHT is included in the drug formulation
  • a drug delivery dispenser e.g., a cartridge
  • an oxygen scavenger is included in the primary packaging for the drug delivery dispenser, wherein gas exchange is possible between the drug delivery dispenser and the oxygen scavenger in the primary package.
  • an anti-oxidant such as BHT is included in the drug formulation
  • a desiccant is included in the drug delivery dispenser (e.g., a cartridge) which houses the drug dosage form(s)
  • an oxygen scavenger is included in the primary packaging wherein gas exchange is possible between the drug delivery dispenser and primary package.
  • the oxidative degradation of a drug such as sufentanil is reduced or eliminated by providing the drug in an oxygen impermeable primary package, such as a foil pouch, which comprises at least one oxygen scavenging material.
  • the antioxidant and/or the desiccant is incorporated into the material that is used to make the drug delivery dispenser or primary packaging.
  • the drug delivery dispenser or primary packaging material is comprised of an antioxidant packaging material.
  • the drug delivery dispenser is comprised of a material that does not generate degradation products upon exposure to a solid dosage form containing a pharmaceutically active agent, such as sufentanil.
  • Exemplary materials for use in packaging include, glass, polypropylene, polyethylene (e.g., high density polyethylene (HDPE) or low density polyethylene (LDPE), polyester, polystyrene, polyamide, fluoro polymers such as ACLAR®, ethylene covinyl alcohol (EVOH), , polycarbonate, polyurethane, polyvinylidene chloride (PVDC), polyvinyl alcohol (PVA) copolymers thereof, or blends thereof.
  • HDPE high density polyethylene
  • LDPE low density polyethylene
  • EVOH ethylene covinyl alcohol
  • PVDC polyvinylidene chloride
  • PVA polyvinyl alcohol
  • Exemplary materials for use in manufacture of single dose applicators include but are not limited to TecoFlex EG 8OA, Polyisoprene, Zylar 220; NAS 30 (NEOS NOVA), Versaflex, CL2242 (GLS Corp), KROl (Chevron Phillips), Housing Polymer, Delrin® acetal (DuPont), Polyester (Valox; Celanex), Polypropylene, Pro Fax PD702 (Basell) and the like.
  • Antioxidants commonly employed in pharmaceutical formulations include, but are not limited to, vitamin E, ascorbic acid, BHT (butylated hydroxytoluene), BHA (butylated hydroxyanisole), propyl gallate, ascorbyl palmitate, biflavonoids and the like.
  • An antioxidant may be included in the formulation of an oxidation-susceptible drug, such as sufentanil, in particular, when provided in low dose solid dosage forms.
  • Suitable oxygen scavengers include any organic or inorganic material that can absorb oxygen, for example, iron oxide powders, ferrous salts such as ferrous sulfate or ferrous chloride, sulfites, bisulfites, reducing sulfur compounds such as dithionite, ascorbic acid and/or their salts, erythorbic acid and/or their salts, reducing organic compounds such as catechol and hydroquinone, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA). See, e.g. U.S. Patent Publication Nos. 20060076536,
  • a number of oxygen scavengers and moisture absorbents are commercially available and may be purchased alone or in packages, e.g., StabilOx® (Multisorb
  • EMCM cyclohexene methyl acrylated
  • An oxygen scavenger may be included in the packaging in the form of pellets, canisters, packets, capsules, powders, solid materials, tablets, or as part of the packaging material itself.
  • Desiccants may be provided as pellets, canisters, packets, capsules, powders, solid materials, papers, boards, tablets, adhesive patches and films, and can be formed for specific applications, including injection moldable plastics.
  • Exemplary solid desiccants include, silica gel (sodium silicate), alumino-silicate, activated alumina, zeolite, molecular sieves, montmorillonite clay, calcium oxide and calcium sulfate.
  • one or more desiccants may be employed in a drug delivery dispenser, e.g., within a cartridge or single dose applicator containing drug dosage forms, or inside the primary packaging for the drug-containing drug delivery dispenser, as a means for protecting solid drug dosage forms from moisture.
  • exemplary locations include, in or adjacent the dosage form or delivery pathway, in or adjacent a tablet magazine or cartridge, in or adjacent other components of a dispensing device, formed as an injection molded component of a dispensing device, and any other location within or without the device wherein the desiccant is in sufficiently close proximity to the drug dosage form to pick up moisture.
  • each dosage form contains from about 2mcg to about lOOmcg of sufentanil, from about 4mcg to about 50mcg of sufentanil, from about 6mcg to about 40mcg of sufentanil, from about 8mcg to about 30mcg of sufentanil, or from about lOmcg to about 20mcg of sufentanil.
  • the dosage form contains sufentanil, alone, or in combination with another drug, e.g., a benzodiazepine, such as triazolam.
  • the process for manufacture of solid dosage forms typically involves the use of an aqueous and/or organic solvent.
  • the sufentanil-containing solid dosage forms have a mass of from about lmg to about lOOmg or a volume of from about lmcL to about lOOmcL.
  • the dosage forms have a mass of from about lmg to about: lOOmg, 90mg, 80mg, 70mg, 60mg, 50mg, 40mg, 30mg, 29mg, 28mg, 27mg, 26mg, 25mg, 24mg, 23mg, 22mg, 21mg, 20mg, 19mg, 18mg, 17mg, 16mg, 15mg, 14mg, 13mg, 12mg, llmg, lOmg, 9mg, 8mg, 7mg, 6mg or 5mg; or a volume of from about lmcL to about: 100 mcL, 90 mcL, 80 mcL, 70 mcL, 60 mcL, 50 mcL, 40 mcL, 30 mcL, 29 mcL, 28 mcL, 27 mcL, 26 mcL, 25 mcL, 24 mcL
  • the sufentanil-containing solid dosage forms have a mass of from about 1 to about 8mg, from about 2 to about lOmg, from about 3 to about 15mg, from about 4 to about 20mg, from about 5 to about 25mg, or a volume of from about 1 to about 8mcl, from about 2 to about 10 mcl, from about 3 to about 15mcl; from about 4 to about 20mcl, or from about 5 to about 25 mcl.
  • the tablets have a mass of 5.85 mg.
  • the sufentanil-containing solid dosage forms, tablets or NanoTabsTM have a thickness of from about 0.25 to about 5.0mm; from about 0.5 to about 2.5mm, from about 0.6 to about 2.0mm, from about 0.7 to about 1.0mm, from about 0.75 to about 0.95mm, e.g., about 0.85mm; and a diameter of from about 1.0 to about 10.0mm, from about 2.0 to about 5.0mm, from about 2.5 to about 4.0mm, from about 3.0 to about 3.5mm, e.g., about 3.0mm.
  • Tablets for oral transmucosal delivery of the combination of an opioid, such as sufentanil typically have an erosion time of from about 2 minutes to about 40 minutes, from about 3 minutes to about 30 minutes, from about 4 minutes to about 25 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 30 seconds to about 15 minutes, from about 1 minute to about 15 minutes, or from about 6 minutes to about 12 minutes.
  • the solid dosage forms may have essentially any shape, examples of which include a round disc with a flat, concave, or convex face, an ellipsoid shape, a spherical shape, a polygon with three or more edges and flat, concave, or convex faces.
  • the solid dosage forms may be symmetrical or asymmetrical, and may have features or geometries that allow for controlled, convenient, and easy storage, handling, packaging or dosing.
  • the dosage forms typically have bioadhesive characteristics and may form a hydrogel upon contact with an aqueous solution.
  • An exemplary formulation is bioadhesive and comprises from about 0.04% to about 4% sufentanil, from about 0.08% to about 1.7% sufentanil or from abut 0.1% to about 2.0% sufentanil, e.g., about 0.04%, 0.08%, 0.1%, 0.2%, 2.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.2%, 2.2%, 2.4%, 2.5%, 2.6%, 2.8%, 3.0%, 3.2%, 3.5% or 4% sufentanil.
  • the formulation is provided as a substantially homogeneous composition which comprises sufentanil, one or more of bioadhesives, binders, hydrogel-forming excipients, bulking agents, lubricants, and other excipients and factors that affect dissolution time and/or drug stability.
  • the drug formulations and solid dosage forms are neither effervescent nor do they comprise an ordered mixture of microparticles of drug adhered to the surface of carrier particles, where the carrier particles are substantially larger than the microparticles of drug.
  • Dissolution of a dosage form comprising the formulation is generally independent of pH, e.g., over a pH range of about 4 to 8.
  • sufentanil-containing formulation is converted into sufentanil-containing solid dosage forms for delivery to a subject using procedures routinely employed by those of skill in the art, such as direct compression, wet granulation, etc.
  • the process for preparation of sufentanil-containing solid dosage forms typically involves use of aqueous and/or organic solvents and is optimized for each formulation in order to achieve high dose content uniformity.
  • the cartridge for housing drug dosage forms may be cylindrical, disk-shaped, helical, rectilinear, non-ordered, or may take the form of any assemblage of drug dosage forms that allows a drug dispensing device to dispense them in a controlled manner.
  • a cartridge may hold sufficient drug dosage forms for 1-5 days of treatment, e.g., 40 tablets useful for 48 to 72 hours of treatment.
  • a cartridge or other drug dispensing device may provide a means of sealing the drug dosage forms from exposure to moisture. This may accomplished by use of a cartridge that contains a desiccant or other absorbent or adsorbent material to absorb or adsorb moisture that penetrates the cartridge either prior to use or during normal use.
  • the desiccant is a sorbant, in the form of a solid, liquid, or gel that has an affinity for water, and absorbs or adsorbs moisture from the surrounding, thus controlling the moisture in the immediate environment.
  • Any commercial desiccant may be used.
  • Such commercial desiccants typically take the form of pellets, canisters, packets, capsules, powders, solid materials, papers, boards, tablets, adhesive patches, and films, and can be formed for specific applications, including injection moldable plastics.
  • silica gel sodium silicate, which is a solid, not a gel
  • alumino-silicate activated alumina
  • zeolite molecular sieves
  • montmorillonite clay calcium oxide and calcium sulfate, or others, any of which may be used in practicing the present invention.
  • a single dose applicator is used as the drug delivery dispenser for a solid sufentanil drug dosage form.
  • the SDA is contained in a primary package which is not oxygen permeable.
  • the SDA is contained in a primary package which is oxygen permeable.
  • the primary package is contained in a secondary package which is not oxygen permeable.
  • the SDA may contain the dosage form within, may have the drug dosage form attached or affixed to it, and/or may afford a seal against moisture, humidity, and light.
  • the single dose applicator may be manually manipulated by a patient, healthcare provider, or other user to place the dosage form in the proper location for drug delivery.
  • the SDA may be provided as a pair of forceps, a syringe, a stick or rod, a straw, a pad, a capsule, a cup, a spoon, a strip, a tube, an applicator, a dropper, a patch, an adhesive pad, an adhesive film, a sprayer, an atomizer, or any other form suitable for the application of a single drug dosage form to the oral mucosa of a subject, e.g., the oral mucosa in the sublingual space.
  • the SDA design may vary, so long as it is effective to place a drug dosage form, such as a tablet, in the desired location, e.g., in the sublingual space, in a manner that preserves integrity of the drug dosage form in the dispensing process. After use, the SDA is disposed of.
  • a drug dosage form such as a tablet
  • the dosage form may be provided in a drug delivery dispenser that consists of molded plastic or laminate that has indentations ("blisters") into which a dosage form is placed, referred to herein as a "blister pack".
  • a blister pack may or may not have preformed or molded parts and may be used to package an SDA of any type.
  • SDAs may be provided in a child resistant multiple drug dispenser (MDD), which may serve to dispense the dosage forms housed therein or may be used for storage of a plurality of SDAs.
  • MDD child resistant multiple drug dispenser
  • an SDA serves as the drug delivery dispenser and an MDD serves as the primary package.
  • a desiccant may or may not be included in the drug delivery dispenser and an oxygen scavenger is typically included in the primary package.
  • Example 1 Stability Studies with Solid Sufentanil Dosage Forms in the Presence and Absence of Oxygen Scavengers.
  • the 5mcg sufentanil formulation included 0.128% sufentanil citrate in a matrix of mannitol, hydroxypropylmethyl cellulose, stearic acid, magnesium stearate, dicalcium phosphate and butylated hydroxyl toluene (BHT), as follows.
  • Samples analyzed for sufentanil degradation products were a composite of NanoTabsTM that provided about 50ug/mL (of sufentanil) in solution.
  • the number of NanoTabsTM and the volume needed to achieve a nominal concentration of about 50 ⁇ g/mL was calculated, then an amount of extraction solution equivalent to approximately 30% of the sample volume was pipetted into the container, the mixture was sonicated for 15 minutes, followed by dilution to volume with 2OmM ammonium phosphate buffer and thorough mixing.
  • a glass syringe was used to filter the supernatant solution through a 0.45 ⁇ m Millipore Millex Nylon syringe filter. The first mL of filtrate was discarded, then the remainder was used to fill HPLC 9 mm TFE/SIL/TFE blue cap containers, followed by HPLC analysis.
  • Table IA shows the results of HPLC analysis of solid sufentanil dosage forms for the presence of degradation products following storage at 5°C and ambient humidity, as evidenced by peaks at relative retention times (RRT) of 0.37, 0.50 and 0.56 following storage in HDPE bottles for 2 weeks, 1 month, 2 months, 3 months and 6 months.
  • RRT relative retention times
  • Total Deg. Total degradation is reported as a percentage (%) of total sufentanil peak area.
  • RRT relative retention times
  • Figure 1 shows the % Total RS versus time (0, 0.5, 1, 2 and 3 months), for 5 meg sufentanil dosage forms made using a standard formulation following storage at 5 0 C and ambient humidity in HDPE bottles alone (5ug) or containing an oxygen scavenger (Stabilox®; Multisorb Technologies; 5ug-R).
  • % Total RS % total related substances
  • % SDP percent sufentanil degradation products
  • Table 2A Stability Evaluation of 5 mc ⁇ Sufentanil Tablets at 25 0 C and 60%RH in HDPE Bottles.
  • RRT relative retention times
  • Table 2B Stability Evaluation of 5 mc ⁇ Sufentanil Tablets Stored at 25 0 C and 60% RH in HDPE Bottles Containin Ox en Scaven ers.
  • Figure 2 shows the % Total RS versus time (0, 0.5, 1, 2 and 3 months) for 5mcg sufentanil dosage forms made using a standard formulation following storage at 25 0 C and 60% humidity in HDPE bottles alone (5ug) or containing an oxygen scavenger (5ug-R).
  • RRT relative retention times
  • RRT relative retention times
  • Figure 3 shows the % Total RS versus time (0, 0.5, 1, 2 and 3 months) for 5mcg sufentanil dosage forms made using a standard formulation following storage at 4O 0 C and 75% humidity in HDPE bottles alone (5ug) or containing an oxygen scavenger (5ug-R).
  • Table 4 shows the results of HPLC analysis of solid sufentanil dosage forms for the presence of degradation products, following storage at 5°C and ambient humidity in HDPE bottles with or without an oxygen scavenger, reported as % Total RS versus time.
  • Table 5 shows the results of HPLC analysis of solid sufentanil dosage forms for the presence of degradation products following storage at 25 0 C and 60% RH in HDPE bottles for 0, 0.5, 1, 2, 3 and 6 months in HDPE bottles with or without an oxygen scavenger, reported as % Total RS versus time.
  • Table 6 shows the results of HPLC analysis of solid sufentanil dosage forms for the presence of degradation products following storage at 40 0 C and 70%RH, in HDPE bottles +Stabilox® or without Stabilox®, reported as % Total RS versus time.
  • Example 1 The results presented in Example 1 show that the generation of sufentanil degradation products following storage of solid sufentanil dosage forms is reduced or eliminated by storing the solid sufentanil drug dosage forms (e.g., tablets) in the presence of an oxygen scavenger.
  • solid sufentanil drug dosage forms e.g., tablets
  • Example 2 Stability Studies with Solid Sufentanil Dosage Forms in the Presence of Desiccant or Oxy ⁇ en Scavengers.
  • HPLC profile of solid sufentanil dosage forms stored with StabilOx® or desiccant was evaluated following storage in HDPE bottles for 0.5 months, 1 month, 2 months, 3 months and 6 months.
  • an oxygen scavenger 5ug- R_Stabilox®
  • desiccant 5ug - Desiccant
  • an oxygen scavenger 5ug-R
  • desiccant 5ug - Desiccant
  • Table 8 Stability Evaluation of 5 mc ⁇ Sufentanil Tablets Stored at Stored at 25 0 C and 60% RH in HDPE Bottles With Oxy ⁇ en Scavengers or Desiccant.
  • an oxygen scavenger 5ug-R_Stabilox®
  • desiccant 5ug - Desiccant
  • Example 3 Stability Studies with Solid Sufentanil Dosage Forms in Cartridges in the Presence of Oxygen Scavengers.
  • the sufentanil formulation was the following: 0.256% sufentanil citrate in matrix of mannitol, hydroxypropylmethyl cellulose, stearic acid, magnesium stearate, dicalcium phosphate and butylated hydroxyl toluene (BHT).
  • BHT butylated hydroxyl toluene
  • RRT relative retention times
  • ⁇ QL means less than quantitation limit.
  • RRT relative retention times
  • Table 11A Stability Evaluation of 10 mc ⁇ Sufentanil Tablets Stored at 4O 0 C and 75% RH in Cartridges With Oxygen Scavengers.
  • sufentanil formulation is provided in Example 3, above.
  • HPLC profile of solid sufentanil dosage forms stored in the presence of oxygen scavengers was evaluated following storage in SDAs for 1 month, 2 months, 3 months and 6 months, using the conditions provided in Example 1, above.
  • RRT relative retention times
  • Table 12A Stability Evaluation of 20 mc ⁇ Sufentanil Tablets Stored at 2-8 0 C and Ambient Humidity in SDAs Packaged With Oxygen Scavengers.
  • Table 12B Stability Evaluation of 20 meg Sufentanil Tablets Stored at 25°C and 60% RH in SDAs Packa ed With Ox en Scaven ers.
  • Table 12C Stability Evaluation of 20 meg Sufentanil Tablets Stored at 4O 0 C and 75% RH in SDAs Packaged With Oxygen Scavengers.

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

L'invention porte sur des compositions et des procédés efficaces pour minimiser ou éliminer la présence de produits de dégradation oxydante dans des formes posologiques solides comprenant du sufentanil.
PCT/US2009/064232 2008-11-21 2009-11-12 Forme posologique solide de sufentanil comprenant des désoxydants et leurs procédés d'utilisation WO2010059504A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
SG2011036894A SG171786A1 (en) 2008-11-21 2009-11-12 Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same
BRPI0921519-0A BRPI0921519B1 (pt) 2008-11-21 2009-11-12 Forma de dosagem de fármaco sufentanil sólida embalada e método para prevenir a degradação oxidativa da referida forma de dosagem
DK09760659.4T DK2367537T3 (da) 2008-11-21 2009-11-12 Fast sufentanil-lægemiddeldoseringsform omfattende oxygenopfangende midler og fremgangsmåder til anvendelse heraf
ES09760659T ES2396150T3 (es) 2008-11-21 2009-11-12 Formas de dosificación sólidas de sufentanilo que comprenden eliminadores de oxígeno y procedimiento de uso de las mismas
EP09760659A EP2367537B1 (fr) 2008-11-21 2009-11-12 Forme posologique solide de sufentanil comprenant des desoxydants et leurs procedes d'utilisation
NZ593512A NZ593512A (en) 2008-11-21 2009-11-12 Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same
MX2011005370A MX2011005370A (es) 2008-11-21 2009-11-12 Formas de dosis orales de sufentanilo que comprenden agentes barredores de oxígeno y métodos de uso de los mismos.
CA2743261A CA2743261C (fr) 2008-11-21 2009-11-12 Forme posologique solide de sufentanil comprenant des desoxydants et leurs procedes d'utilisation
AU2009316874A AU2009316874B2 (en) 2008-11-21 2009-11-12 Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same
JP2011537511A JP2012509325A (ja) 2008-11-21 2009-11-12 酸素捕捉剤を含むスフェンタニル固形剤形及びその使用方法
CN200980146531.9A CN102231980B (zh) 2008-11-21 2009-11-12 包含氧清除剂的苏芬太尼(sufentanil)固体剂型和其使用方法
RU2011125316/15A RU2530579C2 (ru) 2008-11-21 2009-11-12 Твердые лекарственные формы суфентанила, содержащие поглотители кислорода, и способы их применения
IL212880A IL212880A (en) 2008-11-21 2011-05-12 Solid forms of supentanil containing oxygen traps and their methods of use

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US12/275,485 US8945592B2 (en) 2008-11-21 2008-11-21 Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same

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ES2396150T3 (es) 2013-02-19
CN102231980A (zh) 2011-11-02
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CA2743261A1 (fr) 2010-05-27
US8945592B2 (en) 2015-02-03
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MX2011005370A (es) 2011-09-15
EP2367537B1 (fr) 2012-10-17
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NZ593512A (en) 2012-12-21
BRPI0921519A2 (pt) 2017-05-30
US20100130551A1 (en) 2010-05-27
IL212880A0 (en) 2011-07-31
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RU2530579C2 (ru) 2014-10-10
DK2367537T3 (da) 2013-01-07

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