WO2005041968A2 - Formes posologiques orales d'oxycodone en dose quotidienne unique et a liberation controlee - Google Patents

Formes posologiques orales d'oxycodone en dose quotidienne unique et a liberation controlee Download PDF

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Publication number
WO2005041968A2
WO2005041968A2 PCT/US2004/036132 US2004036132W WO2005041968A2 WO 2005041968 A2 WO2005041968 A2 WO 2005041968A2 US 2004036132 W US2004036132 W US 2004036132W WO 2005041968 A2 WO2005041968 A2 WO 2005041968A2
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Prior art keywords
auc
oxycodone
formulation
hours
auco
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PCT/US2004/036132
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English (en)
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WO2005041968A3 (fr
Inventor
Stephen Hwang
Nishit B. Modi
Padmaja Shivanand
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Alza Corporation
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Priority to CA002546691A priority Critical patent/CA2546691A1/fr
Priority to JP2006538357A priority patent/JP2007509979A/ja
Priority to BRPI0415639-0A priority patent/BRPI0415639A/pt
Priority to EP04817492A priority patent/EP1677798A2/fr
Priority to AU2004285547A priority patent/AU2004285547A1/en
Publication of WO2005041968A2 publication Critical patent/WO2005041968A2/fr
Priority to IL175193A priority patent/IL175193A0/en
Priority to NO20062398A priority patent/NO20062398L/no
Publication of WO2005041968A3 publication Critical patent/WO2005041968A3/fr

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    • 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
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • This invention relates to in vitro and in vivo profiles, i.e., in vitro dissolution release profiles and in vivo single dose and in vivo steady state plasma profiles, for the opioid analgesic, oxycodone, when administered orally using a controUed-release dosage form.
  • the invention relates to in vitro and in vivo oxycodone profiles designed to produce effective pain management and a reduced probability of "liking" when oxycodone is orally administered to a patient on a once-a- day basis.
  • Oxycodone a Schedule II drug, is an opioid for the management of moderate to severe chronic pain, such as, pain due to surgery, cancer, trauma, biliary colic, renal colic, myocardial infarction and burns. Oxycodone has been marketed as an analgesic for more than 70 years. It is currently available in immediate release (IR) forms, as well as in a controlled release (CR) formulation indicated for b.i.d. dosing. [0006] The pharmacological and medical properties of analgesic opioids including oxycodone are known in Pharmaceutical Sciences. Remington, 17th Ed., pp. 1099-1107 (1985), and The Pharmacological Basis of Therapeutics.
  • Oxycodone has been administered in conventional forms, such as nonrate-controlling, dose-dumping immediate release tablets, or by dose-dumping capsules, and usually at multiple, repetitive dosing intervals throughout the day.
  • Oxycodone is also administered on a twice-a-day basis with a controlled release matrix system, OXYCONTLN ® (Purdue Pharma LP, Stamford, CT).
  • OXYCONTIN ® a controlled release matrix system
  • the OXYCONTIN ® mode of therapy continues to lead to an initial high dose of oxycodone in the blood after administration, followed by decreased levels of oxycodone in the blood.
  • this peak and trough pattern occurs twice during a 24-hour period due to the twice-a-day dosing regimen.
  • substantially zero order oxycodone release profiles produce low single dose C ma ⁇ values and thus are expected to have lower levels of "liking" than profiles that are not substantially zero order, such as biphasic profiles.
  • profiles that are not substantially zero order such as biphasic profiles.
  • Purdue Pharma's biphasic OXYCONTIN ® product has serious abuse problems, substantially beyond any issue of "liking.”
  • substantially zero order oxycodone release profiles achieve effective pain management.
  • oxycodone dosage forms which have substantially zero order in vitro release profiles can be used to achieve effective pain management without exaggerated tolerance problems and with a reduced probability of "liking" ⁇ a combination of benefits not previously known or expected from the existing state of the art. IV.
  • the invention provides a controlled-release oxycodone formulation for once-a-day oral administration to human patients comprising a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, said formulation providing (a) a mean, single dose, maximum plasma concentration C max and (b) a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC 0-48 which satisfy the relationships: 3.5 x 10 "4 liter -1 ⁇ C ma ⁇ / ⁇ 6.8 x 10 ⁇ 4 liter "1 , and 7.6 x 10 -3 hour/liter ⁇ AUC 0-48 /D ⁇ 16.7 x 10 "3 hour/liter, wherein said formulation provides pain relief for about 24 hours or more
  • the invention provides a controlled- release oxycodone formulation for once-a-day oral administration to human patients comprising a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, wherein: (a) the formulation provides a mean, single dose, plasma concentration profile that increases substantially monotonically over 24 hours or more; (b) the formulation provides a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC 0- 8 which satisfies the relationship: 7.6 x 10 ⁇ 3 hour/liter ⁇ AUC 0-48 /D ⁇ 16.7 x 10 "3 hour/liter; and (c) the formulation provides pain relief for about 24 hours or more after administration to the patient.
  • a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable
  • the invention provides a controlled-release oxycodone formulation for once-a-day oral administration to human patients comprising a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, said formulation providing (a) a mean, single dose, 12 hour plasma concentration C 12 and (b) a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC 0- 8 which satisfy the relationships: 2.7 x 10 -4 liter -1 ⁇ C ⁇ 2 /D ⁇ 5.7 x 10 -4 liter -1 , and 7.6 x 10 -3 hour/liter ⁇ AUC 0-48 /D ⁇ 16.7 x 10 -3 hour/liter, wherein said formulation provides pain relief for about 24 hours or more after administration to the patient.
  • a dose D of: (i) oxyco
  • the invention provides a controlled- release oxycodone formulation for once-a-day oral administration to human patients comprising a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, said formulation providing mean, steady state, areas under a plasma concentration-time curve for 0-6 hours AUC 0-6 , 6-12 hours AUC 6- ⁇ 2 , 12-18 hours AUC 12 .
  • AUC 0-6 /AUC 0-24 > 0.18 AUC 6- ⁇ 2 /AUC 0-24 > 0.18
  • AUCi2- ⁇ 8 /AUC 0-24 > 0.18 AUC 18-24 /AUC 0-24 > 0.18, wherein said formulation provides pain relief for about 24 hours or more after administration to the patient.
  • the invention provides a controlled-release oxycodone formulation for once-a-day oral administration to human patients comprising a dose of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, said formulation having an in vitro release profile in which: (a) 0-20% of the dose is released in 0-2 hours; (b) 30-65% of the dose is released in 0-12 hours; and (c) 80-100% of the dose is released in 0-24 hours; wherein the release profile is determined using a USP Type Nil bath indexer in a constant temperature water bath at 37°C and wherein said formulation provides pain relief for about 24 hours or more after administration to the patient.
  • the invention provides a controlled- release oxycodone formulation for once-a-day oral administration to human patients comprising a dose of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.
  • the invention provides a method of treating pain in humans comprising orally administering to a human patient on a once- a-day basis a controlled-release dosage form comprising a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, said dosage form providing (a) a mean, single dose, maximum plasma concentration C ma x and (b) a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC 0-48 which satisfy the relationships: 3.5 x 10 -4 liter -1 ⁇ C max /D ⁇ 6.8 x 10 -4 liter -1 , and 7.6 x 10 -3 hour/liter ⁇ AUC 0-48 /D ⁇ 16.7 x 10 -3 hour/liter, wherein the dosage form provides
  • the invention provides a method of treating pain in humans comprising orally administering to a human patient on a once- a-day basis a controlled-release dosage form comprising a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, wherein: (a) the dosage form provides a mean, single dose, plasma concentration profile that increases substantially monotonically over 24 hours or more; (b) the dosage form provides a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC 0-48 which satisfies the relationship: 7.6 x 10 -3 hour/liter ⁇ AUC 0-48 /D ⁇ 16.7 x 10 ⁇ 3 hour/liter; and (c) the dosage form provides pain relief for about 24 hours or more after administration to the patient.
  • a controlled-release dosage form comprising
  • the invention provides a method of treating pain in humans comprising orally administering to a human patient on a once-a-day basis a controlled-release dosage form comprising a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, said dosage form providing (a) a mean, single dose, 12 hour plasma concentration d and (b) a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUCo - 8 which satisfy the relationships: 2.7 x 10 -4 liter -1 ⁇ C ⁇ 2 /D ⁇ 5.7 x 10 -4 liter -1 , and 7.6 x 10 -3 hour/liter ⁇ AUC 0-48 /D ⁇ 16.7 x 10 "3 hour/liter, wherein said dosage form provides pain relief for about
  • the invention provides a method of treating pain in humans comprising orally administering to a human patient on a once- a-day basis a controlled-release dosage form comprising a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, said dosage form providing mean, steady state, areas under a plasma concentration-time curve for 0-6 hours AUC 0-6 , 6-12 hours AUC 6- ⁇ 2 , 12-18 hours AUC 12 -i 8 , 18-24 hours AUC ⁇ 8-24 , and 0-24 hours AUC 0-24 which satisfy the relationships: AUCo -6 /AUC 0-24 > 0.18, AUC 6- ⁇ 2 /AUC 0-24 > 0.18, AUCi2- ⁇ 8 /AUCo -24 > 0.18,
  • the invention provides a method of treating pain in humans comprising orally administering to a human patient on a once- a-day basis a controlled-release dosage form comprising a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, said dosage form providing pain relief for about 24 hours or more after administration to the patient and having an in vitro release profile in which: (a) 0-20% of the dose is released in 0-2 hours; (b) 30-65% of the dose is released in 0-12 hours; and (c) 80-100% of the dose is released in 0-24 hours; where the release profile is determined using a USP Type Nil bath indexer in a constant temperature water bath at 37°C.
  • the invention provides a method of treating pain in humans comprising orally administering to a human patient on a once- a-day basis a controlled-release dosage form comprising a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically- acceptable acid addition salts of oxycodone, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; (b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25; and (c) the dosage form provides pain relief for about 24 hours or more after adininistration to the patient.
  • a dose D of: (i) oxycodone, (ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically-
  • the various AUC and C values referred to above can be determined using plasma samples from individuals to whom one or more opioid antagonists (e.g., naltrexone) have been administered or by using samples from individuals to whom an antagonist has not been administered.
  • opioid antagonists e.g., naltrexone
  • antagonists are normally used, especially in studies involving healthy volunteers.
  • various of the numerical values set forth above are based on the pharmacokmetic data of Example 6, which used healthy volunteers and a dosage form which contained 80 mg of oxycodone HCl.
  • naltrexone was administered in this study.
  • naltrexone has a tendency to increase plasma oxycodone concentrations.
  • FIG. 1 illustrates one type of dosage form that can be used in the practice of the invention. The dosage form is shown in Figure 1 prior to administration to a subject.
  • Figure 2 illustrates a first embodiment of the. dosage form of Figure 1 in opened section. As shown, the dosage form comprises an internally-housed, pharmaceutically-acceptable therapeutic oxycodone composition.
  • Figure 3 illustrates a second embodiment of the dosage form of Figure 1 in opened section. As shown, the dosage form comprises an internally-housed, pharmaceutically-acceptable therapeutic oxycodone composition and a separate and contacting displacement composition comprising means for pushing the pharmaceutical oxycodone composition from the dosage form.
  • Figure 4 illustrates a dosage form which further includes an immediate- release overcoat of a pharmaceutically-acceptable therapeutic oxycodone composition.
  • Figure 5 is a plot of simulated single dose plasma concentrations for a substantially zero order (SZO) release rate (curve 100), a fast-followed-by-slow release rate (curve 102), and a slow-followed-by-fast release rate (curve 104).
  • Figure 6 is a plot of a preferred cumulative release range for the dosage forms of the invention. The vertical axis plots percent cumulative release of oxycodone and/or one or more of its pharmaceutically-acceptable acid addition salts (e.g., % of label claim for a dosage form that has received regulatory approval) and the horizontal axis plots time.
  • Figures 7A and 7B are plots of in vitro release profiles for the 17 mg oxycodone HCl dosage form identified as the "fast system" in Example 1.
  • Figure 7A (curve 106) plots the percent released per hour (e.g., % of label claim released per hour), while Figure 7B (curve 108) plots the cumulative release in percent (e.g., cumulative % of label claim).
  • Figures 8 A and 8B are plots of in vitro release profiles for the 17 mg oxycodone HCl dosage form identified as the "slow system" in Example 1.
  • Figure 8A (curve 110) plots the percent released per hour (e.g., % of label claim released per hour), while
  • Figure 8B (curve 112) plots the cumulative release in percent (e.g., cumulative % of label claim).
  • Figures 9A and 9B are plots of in vitro release profiles for the 20 mg oxycodone HCl dosage form of Example 2.
  • Figure 9A curve 114 plots the percent released per hour (e.g., % of label claim released per hour), while Figure 9B (curve 114)
  • Figures 10A and 10B are plots of in vitro release profiles for the 80 mg oxycodone HCl dosage form of Example 3.
  • Figure 10A (curve 118) plots the percent released per hour (e.g., % of label claim released per hour), while Figure 10B (curve 120) plots the cumulative release in percent (e.g., cumulative % of label claim).
  • Figure 11 is a plot of pupil diameter in millimeters (mm) versus time in hours for healthy male subjects who received placebo (curve 122), morphine (curve 122), morphine (curve 122), morphine (curve 122), morphine (curve 122), morphine (curve 122), morphine (curve 122), morphine (curve 122), morphine (curve 122), morphine (curve 122), morphine (curve 122),
  • Figure 12 is a plot of plasma concentrations in nanograms/milliliter (ng/mL) of oxycodone (curve 128), noroxycodone (curve 130), and oxymorphone (curve 132) versus time in hours for healthy male subjects who received the dosage form of
  • Figure 13 is a plot of simulated pharmacokinetics, specifically, single dose plasma concentrations, for immediate release (IR) dosing (q6h) (curve 134), as well as experimental data for the dosage form of Example 2 and a best-fit curve to that data
  • Figure 14 is a plot of simulated pharmacokinetics, specifically, steady-state plasma concentrations, for immediate release (IR) dosing (q6h) (curve 140), OXYCONTIN biphasic dosing (curve 138), and substantially zero order/once-a-day (SZO-24) dosing using a dosage form having the overcoat/sustained release drug distribution of Example 2, i.e., 5% of the drug in the overcoat (curve 142).
  • the y-axis in this figure shows oxycodone concentration.
  • Figure 15A shows the single dose profiles and Figure 15B shows the steady-state profiles.
  • the error bars associated with the data points show the standard deviation (SD) in one direction.
  • Figure 16A shows single dose and steady-state profiles
  • Figures 16B and 16C show single dose profiles
  • Figure 16D shows steady-state profiles.
  • the error bars associated with the data points show the standard deviation (SD) in one direction.
  • Figure 17A and 17B are plots of the data of Tables 12A and 12B, with Figure 17A plotting all of the data of these tables and Figure 17B plotting Day +3 data for tail flick testing doses of 0, 0.25, 0.5, 0.75, and 1.0 mg/kg.
  • drug form is meant a pharmaceutical composition or device comprising an active pharmaceutical agent, such as oxycodone and/or one or more of its pharmaceutically-acceptable acid addition salts, the composition or device also containing inactive ingredients, i.e., pharmaceutically acceptable excipients such as suspending agents, surfactants, disintegrants, binders, diluents, lubricants, stabilizers, antioxidants, osmotic agents, colorants, plasticizers, coatings and the like, that are used to manufacture and deliver active pharmaceutical agents.
  • active pharmaceutical agent such as oxycodone and/or one or more of its pharmaceutically-acceptable acid addition salts
  • inactive ingredients i.e., pharmaceutically acceptable excipients such as suspending agents, surfactants, disintegrants, binders, diluents, lubricants, stabilizers, antioxidants, osmotic agents, colorants, plasticizers, coatings and the like, that are used to manufacture and deliver active pharmaceutical agents.
  • active agent an agent, drug, or compound having the characteristics of oxycodone and/or one or more of its pharmaceutically-acceptable acid addition salts. If desired, other analgesics or, more generally, other medicaments, can be included in the dosage forms of the invention.
  • pharmaceutically-acceptable acid addition salts are meant those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and, as such, they are the pharmacological equivalents of the bases of the oxycodone compound.
  • Examples of pharmaceutically acceptable acids that are useful for the purposes of salt formation include but are not limited to hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, mandelic, phosphoric, nitric, mucic, isethionic, palmitic, and others.
  • sustained release is meant predetermined substantially continuous release of active agent to an environment over a prolonged period.
  • the expressions “exit,” “exit orifice,” “delivery orifice” or “drug delivery orifice,” and other similar expressions, as may be used herein include one or more members selected from the group consisting of a passageway; an aperture; an orifice; and a bore.
  • the expressions also include orifices that are formed or formable from a substance or polymer that erodes, dissolves or is leached from the dosage form to thereby form an exit orifice.
  • a drug "release rate” refers to the quantity of drug released from a dosage form per unit time, e.g., milligrams of drug released per hour (mg/hr).
  • Drug release rates for drug dosage forms are typically measured as an in vitro rate of release, i.e., a quantity of drug released from the dosage form per unit time measured under appropriate conditions and in a suitable fluid.
  • the release rate tests utilized in the examples described herein were performed on dosage forms placed in metal coil sample holders attached to a USP Type Nil bath indexer in a constant temperature water bath at 37°C. Aliquots of the release rate solutions were injected into a chromatographic system to quantify the amounts of drug released during the testing intervals.
  • release rate assay is meant a standardized assay for the determination of the release rate of a compound from a dosage form tested using a USP Type 7 interval release apparatus. It is understood that reagents of equivalent grade may be substituted in the assay in accordance with generally accepted procedures.
  • a drag release rate obtained at a specified time “following administration” refers to the in vitro drug release rate obtained at the specified time following implementation of an appropriate dissolution test.
  • the time at which a specified percentage of the drug within a dosage form has been released may be referenced as the "T x " value, where "x" is the percent of drug that has been released.
  • T x a commonly used reference measurement for evaluating drug release from dosage forms.
  • T 0 the time at which 70% of drag within the dosage form has been released. This measurement is referred to as the “T 0 " for the dosage form.
  • An "immediate-release dosage form” refers to a dosage form that releases drag substantially completely within a short time period following administration, i.e., generally within a few minutes to about 1 hour.
  • sustained release dosage form is meant a dosage form that releases drag substantially continuously for many hours (the “sustained release time period").
  • Sustained release dosage forms in accord with the present invention preferably exhibit T 0 values of at least about 10 to 20 hours and preferably 15 to 18 hours.
  • the dosage forms preferably continuously release drag for sustained periods of at least about 10 hours, more preferably 12 hours or more and, even more preferably, 16-20 hours or more.
  • Dosage forms in accord with the present invention preferably exhibit uniform release rates of oxycodone for a prolonged period of time within the sustained release time period.
  • uniform release rate is meant an average hourly release rate from the core that varies positively or negatively by no more than about 30% and preferably no more than about 25% and most preferably no more than 10% from either the preceding or the subsequent average hourly release rate as determined in a USP Type 7 Interval Release Apparatus where the cumulative release is between about 25% to about 75%.
  • prolonged period of time is meant a continuous period of time of at least about 4 hours, preferably 6-8 hours or more and, more preferably, 10 hours or more.
  • the exemplary osmotic dosage forms described herein generally begin releasing oxycodone at a uniform release rate within about 2 to about 6 hours following administration and the uniform rate of release, as defined above, continues for a prolonged period of time from about 25% to until at least about 75% and preferably at least about 85% of the drag is released from the dosage form. Release of oxycodone continues thereafter for several more hours although the rate of release is generally slowed somewhat from the uniform release rate.
  • a dosage form having a substantially zero order in vitro release profile and similar phrases is meant a dosage form which overall has substantially zero order in vitro release kinetics, i.e., the overall in vitro release rate is substantially constant over a 24 hour period.
  • a substantially zero order in vitro release profile means that the in vitro release rate resulting from the combined release of drug from the two components is substantially constant over a 24 hour period.
  • a dosage form that has a substantially zero order in vitro release profile produces an in vivo plasma profile that is substantially flat as opposed to being biphasic as with the OXYCONTIN product (see below).
  • C is meant the concentration of drug in the blood plasma of a subject, generally expressed as mass per unit volume, typically nanograms per milliliter. For convenience, this concentration may be referred to herein as “plasma drag concentration” or “plasma concentration” which is intended to be inclusive of drug concentration measured in any appropriate body fluid or tissue.
  • the plasma drag concentration at any time following drag administration is referenced as C t ime, as in C 9h or C 24 h, etc.
  • steady state is meant the condition in which the profile of drag present in the blood plasma of a subject does not vary significantly over a prolonged period of time.
  • a pattern of drug accumulation following continuous administration of a dosage form at constant dosing intervals eventually achieves a "steady-state" where the plasma concentration peaks and plasma concentration troughs are essentially unchanged for each dosing interval.
  • Plasma drug concentrations obtained in individual subjects will vary due to intrapatient variability in the many parameters affecting drug absorption, distribution, metabolism and excretion. For this reason, unless otherwise indicated, mean values obtained from groups of subjects are used herein for purposes of comparing plasma drag concentration data and for analyzing relationships between in vitro dosage form dissolution rates and in vivo plasma drug concentrations.
  • the present invention can be practiced using a variety of techniques known in the art for producing controlled-release oral dosage forms.
  • Non-limiting examples of such techniques include osmotic systems, diffusion systems such as reservoir devices and matrix devices, dissolution systems such as encapsulated dissolution systems
  • Oxycodone dosage forms that operate in accord with any of these or other approaches are encompassed by the present invention to the extent that the drag release characteristics and/or the plasma oxycodone concentration characteristics of the appended claims are achieved by those dosage forms either literally or equivalently.
  • Osmotic dosage forms in general, utilize osmotic pressure to generate a driving force for imbibing fluid into a compartment formed, at least in part, by a semipermeable wall that permits free diffusion of fluid but not drag or osmotic agent(s), if present.
  • a significant advantage to osmotic systems is that operation is pH-independent and thus continues at the osmotically determined rate throughout an extended time period even as the dosage form transits the gastrointestinal tract and encounters differing microenvironments having significantly different pH values.
  • FIG 1 is a perspective view of one embodiment of a controlled release osmotic dosage form.
  • Dosage form 10 comprises wall 20 that surrounds and encloses an internal compartment (not seen in Figure 1).
  • the internal compartment contains a composition comprising oxycodone, and/or one or more of its pharmaceutically acceptable acid addition salts.
  • Wall 20 is provided with at least one drug delivery exit 60 for connecting the internal compartment with the exterior environment of use. Accordingly, following oral ingestion of dosage form 10, fluid is imbibed through wall 20 and oxycodone and/or one or more of its pharmaceutically acceptable acid addition salts is released through exit 60.
  • the preferred geometrical embodiment in Figure 1 illustrates a standard biconvex shaped tablet, the geometry may embrace a capsule shaped caplet and other oral dosage forms.
  • Figure 2 is a cutaway view of Figure 1 showing an embodiment of a controlled release osmotic dosage form with internal compartment 15 containing a single component layer referred to herein as drug layer 30, comprising drug 31, i.e., at least oxycodone and/or one or more of its pharmaceutically acceptable acid addition salts, in an admixture with selected excipients adapted to provide an osmotic activity gradient for driving fluid from an external environment through wall 20 and for forming a deliverable drag formulation upon imbibition of fluid.
  • the excipients may include a suitable suspending agent, also referred to herein as drag carrier 32, binder 33, lubricant 34 and an osmotically active agent, osmagent 35.
  • FIG. 3 is a cutaway view of Figure 1 with an alternate embodiment of internal compartment 15 having a bilayer configuration.
  • internal compartment 15 contains a bilayered-compressed core having a first component drug layer 30 and a second component push layer 40.
  • Drug layer 30, as described above with reference to Figure 1 comprises at least oxycodone and/or one or more of its pharmaceutically acceptable acid addition salts in an admixture with selected excipients.
  • second component push layer 40 comprises osmotically active component(s), but does not contain any active agent.
  • the components in push layer 40 typically comprise an osmagent 42 and one or more osmopolymers 41 having relatively large molecular weights which exhibit swelling as fluid is imbibed such that release of these osmopolymers through the drag delivery orifice 60 does not occur. Additional excipients such as binder 43, lubricant 44, antioxidant 45 and colorant 46 may also be included in push layer 40.
  • the second component layer is referred to herein as an expandable or a push layer since, as fluid is imbibed, the osmopolymer(s) swell and push against the deliverable drag formulation of the first component drag layer to thereby facilitate release of the drag formulation from the dosage form.
  • the osmotic activity gradient across wall 20 causes gastric fluid to be imbibed through wall 20 thereby forming drag layer 30 into a deliverable formulation and concurrently swelling the osmopolymer(s) in push layer 40.
  • the deliverable drag layer 30 is released through exit 60 as fluid continues to enter internal compartment 15 and push layer 40 continues to swell.
  • fluid continues to be imbibed and the push layer continues to swell thereby driving continued release. In this manner, drug is released in a sustained and continuous manner over an extended time period.
  • Drug layer 30, as described with reference to Figures 2 and 3 comprises oxycodone and/or one or more of its pharmaceutically acceptable acid addition salts in an admixture with selected excipients.
  • Push layer 40 as described with reference to Figure 3, comprises osmotically active component(s) but does not contain any active agent.
  • Drug layer 30 comprises a composition formed of a pharmaceutically effective amount of oxycodone drag 31, and/or one or more of its pharmaceutically acceptable salts, and a carrier 32.
  • the drug oxycodone is comprised of 4, 5-epoxy-14- hydroxy-3-methoxy-17-methylmorphinan-6-one possessing analgesic therapy.
  • Oxycodone is known in the art. The Merck Index, 11 th Ed., p. 1100 (1990).
  • the oxycodone salts are, for example, represented by one or more members selected from the group consisting of the following: oxycodone sulfate, oxycodone hydrochloride, oxycodone trifluoracetate, oxycodone thiosemicarbazone hydrochloride, oxycodone pentafluoropropionate, oxycodone p-nitrophenylhydrozone, oxycodone o- methyloxine, oxycodone thiosemicarbazone, oxycodone semicarbazone, oxycodone phenylhydroazone, oxycodone hydrazone, oxycodone hydrobromide, oxycodone mucate, oxycodone methylbromide, oxycodone oleate, oxycodone n-oxide, oxycodone acetate, oxycodone phosphate dibasic, oxycodone phosphate
  • the dosage form and the therapeutic composition in either manufacture can comprise 1 to 640 mg of oxycodone drag 31 and/or oxycodone drug 31 pharmaceutically acceptable salt. More typically, loading of compound in the dosage forms, whether using osmotic or other controlled-release technology, will provide doses of compound to the subject ranging from 10 mg to 160 mg and more usually 20 mg to 80 mg per day. Generally, if a total drag dose of more than 160 mg per day is required, multiple units of the dosage form may be administered at the same time to provide the required amount of drug.
  • the once-a-day dosage forms of the present invention comprise a dose D of oxycodone and/or one or more of its pharmaceutically acceptable acid addition salts that is greater than or equal to about 10 mg and less than or equal to about 80 mg.
  • immediate release oxycodone is typically administered at a starting dose of about 10 mg, administered in two or three doses per day.
  • the effective dose range has been determined to be generally 10 mg/day- 320 mg/day. Observations of the patient's tolerability to side effects and the need for additional clinical effect over the starting dose often results in the dose being increased in increments of 5 mg/day to 80 mg/day.
  • plasma concentrations in a subject may be determined by clinical assay to determine a correlation between side effect tolerability, clinical effect, and blood plasma concentrations of the drug.
  • Oxycodone plasma concentrations may range from 0.1 ng/ml to 100 ng/ml (nanograms per milliliter), more typically 4 ng/ml to 40 ng/ml.
  • Traditional systems utilizing salt in a drug formulation dealt with compounds exhibiting a strong common ion effect.
  • the amount of salt incorporated into the drag layer of the system is from about 25%o if using a high molecular weight polymer and low doses of drag to zero percent if using low molecular weight polymer and higher doses of drug.
  • Representatives of a salt to be incorporated into the drug composition include sodium chloride, potassium chloride and the like. Most preferable is sodium chloride.
  • the drag layer viscosity in operation is maintained between about 50cps and about lOOcps. In this way, products containing lower drag concentrations (5-15%) and higher drag concentrations (15-40%) can essentially be produced such that they have equivalent release functionality.
  • the drag layer viscosity can be attained by using any of many hydrophilic polymers. Examples include water-soluble cellulose polymers such as NaCMC, HPMC, etc. or polyethylene oxide polymers such as Polyox ® or water soluble sugars, such as maltodextrin, sucrose, mannitol. Any physical or chemical property of the polymer, which could be modified to achieve the desired viscosity, is also included in this description.
  • Carrier 32 may comprise a hydrophilic polymer represented by horizontal dashes in Figures 2 and 3. The hydrophilic polymer provides a hydrophilic polymer particle in the drag composition that contributes to the controlled delivery of active agent.
  • poly(alkylene oxide) of 100,000 to 750,000 number-average molecular weight including poly(ethylene oxide), poly(methylene oxide), poly(butylene oxide) and poly(hexylene oxide); and a poly(carboxymethylcellulose) of 40,000 to 400,000 number-average molecular weight, represented by poly(alkali carboxymethylcellulose), poly(sodium carboxymethylcellulose), poly(potassium carboxymethylcellulose) and poly(lithium carboxymethylcellulose).
  • the drag composition can comprise a hydroxypropylalkylcellulose of 9,200 to 125,000 number-average molecular weight for enhancing the delivery properties of the dosage form as represented by hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose and hydroxypropylpentylcellulose; and a poly(vinylpyrrolidone) of 7,000 to 75,000 number-average molecular weight for enhancing the flow properties of the dosage form.
  • Preferred among those polymers are the polyethylene oxide) of 100,000 - 300,000 number average molecular weight.
  • Carriers that erode in the gastric environment i.e., bioerodible carriers, are especially preferred.
  • Other carriers that may be incorporated into drag layer 30 include carbohydrates that exhibit sufficient osmotic activity to be used alone or with other osmagents.
  • Such carbohydrates comprise monosaccharide, disaccharides and polysaccharides.
  • Representative examples include maltodextrins (i.e., glucose polymers produced by the hydrolysis of corn starch) and the sugars comprising lactose, glucose, raffinose, sucrose, mannitol, sorbitol, and the like.
  • Preferred maltodextrins are those having a dextrose equivalence (DE) of 20 or less, preferably with a DE ranging from about 4 to about 20, and often 9-20.
  • DE dextrose equivalence
  • Maltodextrin having a DE of 9-12 has been found most useful.
  • Carbohydrates described above, preferably the maltodextrins may be used in the drag layer 30 without the addition of an osmagent, and obtain the desired release of oxycodone and/or one or more of its pharmaceutically acceptable acid addition salts from the dosage form, while providing a therapeutic effect over a prolonged period of time and up to 24 hours with once-a-day dosing.
  • the preferred molecular weight of the polymer carrier utilized in the drug layer range from 100,000 mw to 300,000 mw and more preferably about 200,000 mw.
  • Drug layer 30 may further comprise a therapeutically acceptable vinyl polymer binder 33 represented by vertical dashes in Figure 2 and Figure 3.
  • the vinyl polymer comprises a 5,000 to 350,000 average molecular weight, represented by a member selected from the group consisting of poly-n-vinylamide, poly-n- vinylacetamide, poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone, poly- n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, and poly-n-vinylpyrrolidone copolymers with a member selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laureate, and vinyl stearate.
  • Dosage form 10 and the therapeutic composition can comprise 0.01 to 25 mg of the binder or vinyl polymer that serves as a binder. Representative of other binders include acacia, starch and gelatin.
  • Dosage form 30 may further comprise lubricant 34 represented by a wavy line in Figures 2 and 3. The lubricant is used during manufacture to prevent sticking to die walls or punch faces. Typical lubricants include magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodium stearyl fumarate, and magnesium palmitate. The amount of lubricant present in the therapeutic composition can be 0.01 to 10 mg.
  • Drug layer 30 typically will be a dry composition formed by compression of the carrier and the drug as one layer and the push composition as the other layer in contacting relation.
  • Drug layer 30 is formed as a mixture containing oxycodone and/or one or more of its pharmaceutically acceptable acid addition salts and the carrier that when contacted with biological fluids in the environment of use provides a slurry, solution or suspension of the compound that may be dispensed by the action of the push layer.
  • the drug layer may be formed from particles by comminution that produces the size of the drag and the size of the accompanying polymer used in the fabrication of the drag layer.
  • the means for producing particles include granulation, spray drying, sieving, lyophihzation, crashing, grinding, jet milling, micronizing and chopping to produce the intended micron particle size.
  • the process can be performed by size reduction equipment, such as a micropulverizer mill, a fluid energy grinding mill, a grinding mill, a roller mill, a hammer mill, an attrition mill, a chaser mill, a ball mill, a vibrating ball mill, an impact pulverizer mill, a centrifugal pulverizer, a coarse crasher and a fine crusher.
  • size reduction equipment such as a micropulverizer mill, a fluid energy grinding mill, a grinding mill, a roller mill, a hammer mill, an attrition mill, a chaser mill, a ball mill, a vibrating ball mill, an impact pulverizer mill, a centrifugal pulverizer, a coarse crasher and a fine crusher.
  • the size of the particle can be ascertained by screening, including a grizzly screen, a flat screen, a vibrating screen, a revolving screen, a shaking screen, an oscillating screen and a reciprocating screen.
  • Drag layer 30 may further comprise surfactants and disintegrants.
  • Exemplary of the surfactants are those having an HLB value of between about 10 - 25, such as polyethylene glycol 400 monostearate, polyoxyethylene-4-sorbitan monolaurate, polyoxyethylene-20-sorbitan monooleate, polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene-20-monolaurate, polyoxyethylene-40 -stearate, sodium oleate and the like.
  • Disintegrants may be selected from starches, clays, celluloses, algins and gums and crosslinked starches, celluloses and polymers.
  • Push layer 40 comprises a displacement composition in contacting layered arrangement with the first component drag layer 30 as illustrated in Figure 3.
  • Push layer 40 comprises osmopolymer 41 that imbibes an aqueous or biological fluid and swells to push the drag composition through the exit means of the device.
  • a polymer having suitable imbibition properties may be referred to herein as an osmopolymer.
  • the osmopolymers are swellable, hydrophilic polymers that interact with water and aqueous biological fluids and swell or expand to a high degree, typically exhibiting a 2- 50 fold volume increase.
  • the osmopolymer can be non-crosslinked or crosslinked, but in a preferred embodiment are at least lightly crosslinked to create a polymer network that is too large and entangled to exit the dosage form.
  • the expandable composition is retained within the dosage form during its operative lifetime.
  • Push layer 40 comprises 20 to 375 mg of osmopolymer 41, represented by "N" in Figure 3.
  • Osmopolymer 41 in layer 40 possesses a higher molecular weight than osmopolymer 32 in drag layer 20.
  • Representatives of fluid-imbibing displacement polymers comprise members selected from poly(alkylene oxide) of 1 million to 15 million number-average molecular weight, as represented by poly(ethylene oxide), and poly(alkali carboxymethylcellulose) of 500,000 to 3,500,000 number-average molecular weight, wherein the alkali is sodium, potassium or lithium.
  • Examples of additional polymers for the formulation of the push-displacement composition comprise osmopolymers comprising polymers that form hydrogels, such as Carbopol ® acidic carboxypolymer, a polymer of acrylic cross-linked with a polyallyl sucrose, also known as carboxypolymethylene, and carboxyvinyl polymer having a molecular weight of 250,000 to 4,000,000; Cyanamer ® polyacrylamides; cross-linked water swellable indenemaleic anhydride polymers; Good-rite ® polyacrylic acid having a molecular weight of 80,000 to 200,000; Aqua-Keeps ® acrylate polymer polysaccharides composed of condensed glucose units, such as diester cross-linked polygluran; and the like.
  • osmopolymers comprising polymers that form hydrogels, such as Carbopol ® acidic carboxypolymer, a polymer of acrylic cross-linked with a polyallyl sucrose, also known as carboxypolym
  • Push layer 40 can comprise 0 to 75 mg, and presently 5 to 75 mg of an osmotically effective compound, osmagent 42, represented by circles in Figure 3.
  • the osmotically effective compounds are known also as osmagents and as osmotically effective solutes.
  • Osmagent 42 that may be found in the drug layer and the push layer in the dosage form are those which exhibit an osmotic activity gradient across the wall 20.
  • Suitable osmagents comprise a member selected from the group consisting of sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium acid phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, raffinose, sucrose, glucose, lactose, sorbitol, inorganic salts, organic salts and carbohydrates.
  • Push layer 40 may further comprise a therapeutically acceptable vinyl polymer 43 represented by triangles in Figure 3.
  • the vinyl polymer comprises a 5,000 to 350,000 viscosity-average molecular weight, represented by a member selected from the group consisting of poly-n-vinylamide, poly-n-vinylacetamide, poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone, poly-n-vinylcaprolactone, poly-n- vinyl-5-methyl-2-pyrrolidone, and poly-n-vinylpyrrolidone copolymers with a member selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laureate, and vinyl stearate.
  • Push layer can contain 0.01 to 25 mg of vinyl polymer.
  • Push layer 40 may further comprise 0 to 5 mg of a nontoxic colorant or dye 46, identified by vertical wavy lines in Figure 3.
  • Colorant 35 includes Food and Drag Administration Colorant (FD&C), such as FD&C No. 1 blue dye, FD&C No. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide, carbon black, and indigo.
  • FD&C Food and Drag Administration Colorant
  • Push layer 40 may further comprise lubricant 44, identified by half circles in Figure 3.
  • Typical lubricants comprise a member selected from the group consisting of sodium stearate, potassium stearate, magnesium stearate, stearic acid, calcium stearate, sodium oleate, calcium palmitate, sodium laurate, sodium ricinoleate and potassium linoleate.
  • the concentration of lubricant can be 0.01 to 10 mg.
  • Push layer 40 may further comprise an antioxidant 45, represented by slanted dashes in Figure 3 to inhibit the oxidation of ingredients comprising expandable formulation 40.
  • Push layer 40 can comprise up to 5 mg of an antioxidant.
  • antioxidants comprise a member selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2,6-ditertiary butylphenol, alpha- tocopherol, and propylgallate.
  • FIG. 4 depicts a preferred embodiment of the present invention comprising an overcoat 50 of drug 31 on the dosage form of Figure 3.
  • Overcoat 50 can be a therapeutic composition comprising 0.5 to 75 mg of oxycodone 31 and/or one or more of its pharmaceutically acceptable acid addition salts and 0.5 to 275 mg of a pharmaceutically acceptable carrier selected from the group consisting of alkylcellulose, hydroxyalkylcellulose and hydroxypropylalkylcellulose.
  • the overcoat can contain methylcellulose, hydroxyethylcellulose, hydroxybutylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose and hydroxypropylbutylcellulose.
  • Overcoat 50 provides therapy immediately as overcoat 50 dissolves or undergoes dissolution in the presence of gastrointestinal fluid and concurrently therewith delivers oxycodone drug 31 and/or one or more of its pharmaceutically acceptable acid addition salts into the gastrointestinal tract for immediate oxycodone therapy.
  • Exemplary solvents suitable for manufacturing the dosage form components comprise aqueous or inert organic solvents that do not adversely harm the materials used in the system.
  • the solvents broadly include members selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatics, aromatics, heterocyclic solvents and mixtures thereof.
  • Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n- butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetfachlori.de nitroethane, nitropropane tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water,
  • Wall 20 is formed to be permeable to the passage of an external fluid, such as water and biological fluids, and it is substantially impermeable to the passage of oxycodone and/or one or more of its pharmaceutically acceptable acid addition salts, osmagent, osmopolymer, and the like. As such, it is semipermeable.
  • the selectively semipermeable compositions used for forming the wall are essentially nonerodible and they are substantially insoluble in biological fluids during the life of the dosage form.
  • Representative polymers for forming wall 20 comprise semipermeable homopolymers, semipermeable copolymers, and the like. Such materials comprise cellulose esters, cellulose ethers and cellulose ester-ethers.
  • the cellulosic polymers have a degree of substitution (DS) of their anhydroglucose unit of from greater than 0 up to 3, inclusive.
  • Degree of substitution (DS) means the average number of hydroxyl groups originally present on the anhydroglucose unit that are replaced by a substituting group or converted into another group.
  • the anhydroglucose unit can be partially or completely substituted with groups such as acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkylcarbamate, alkylcarbonate, alkylsulfonate, alkysulfamate, semipermeable polymer forming groups, and the like, wherein the organic moieties contain from one to twelve carbon atoms, and preferably from one to eight carbon atoms.
  • groups such as acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkylcarbamate, alkylcarbonate, alkylsulfonate, alkysulfamate, semipermeable polymer forming groups, and the like, wherein the organic moieties contain from one to twelve carbon atoms, and preferably from one to eight carbon atoms.
  • the semipermeable compositions typically include a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tri-cellulose alkanylates, mono-, di-, and tri-alkenylates, mono-, di-, and tri-aroylates, and the like.
  • Exemplary polymers include cellulose acetate having a DS of 1.8 to 2.3 and an acetyl content of 32 to 39.9%; cellulose diacetate having a DS of 1 to 2 and an acetyl content of 21 to 35%>; cellulose triacetate having a DS of 2 to 3 and an acetyl content of 34 to 44.8%; and the like.
  • More specific cellulosic polymers include cellulose propionate having a DS of 1.8 and a propionyl content of 38.5%; cellulose acetate propionate having an acetyl content of 1.5 to 7% and an acetyl content of 39 to 42%; cellulose acetate propionate having an acetyl content of 2.5 to 3%, an average propionyl content of 39.2 to 45%), and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having a DS of 1.8, an acetyl content of 13 to 15%, and a butyryl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%; cellulose triacylates having a DS of 2.6 to 3, such as cellulose trivalerate, cellulose trilamate, cellulose tripalmitate, cellulose trio
  • Additional semipermeable polymers for forming the outer wall 20 comprise cellulose acetaldehyde dimethyl acetate; cellulose acetate ethylcarbamate; cellulose acetate methyl carbamate; cellulose dimethylammoacetate; semipermeable polyamide; semipermeable polyurethanes; semipermeable sulfonated polystyrenes; cross-linked selectively semipermeable polymers formed by the coprecipitation of an anion and a cation, as disclosed in U.S. Patents Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142; semipermeable polymers, as disclosed by Loeb, et al.
  • Wall 20 may also comprise a flux-regulating agent.
  • the flux regulating agent is a compound added to assist in regulating the fluid permeability or flux through wall 20.
  • the flux-regulating agent can be a flux-enhancing agent or a flux-decreasing agent.
  • the agent can be preselected to increase or decrease the liquid flux.
  • Agents that produce a marked increase in permeability to fluid such as water are often essentially hydrophilic, while those that produce a marked decrease to fluids such as water are essentially hydrophobic.
  • the amount of regulator in the wall when incorporated therein generally is from about 0.01% to 20% by weight or more.
  • the flux regulator agents may include polyhydric alcohols, polyalkylene glycols, polyalkylenediols, polyesters of alkylene glycols, and the like.
  • Typical flux enhancers include polyethylene glycol 300, 400, 600, 1500, 4000, 6000 and the like; low molecular weight glycols such as polypropylene glycol, polybutylene glycol and polyamylene glycol: the polyalkylenediols such as poly(l,3-propanediol), poly(l,4-butanediol), poly(l,6-hexanediol), and the like; aliphatic diols such as 1,3-butylene glycol, 1,4- pentamethylene glycol, 1,4-hexamethylene glycol, and the like; alkylene triols such as glycerine, 1,2,3-butanetriol, 1,2,4-hexanetriol, 1,3,6-hexanetriol and the like; est
  • Presently preferred flux enhancers include the group of difunctional block-copolymer polyoxyalkylene derivatives of propylene glycol known as pluronics (BASF).
  • Representative flux-decreasing agents include phthalates substituted with an alkyl or alkoxy or with both an alkyl and alkoxy group such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate, and [di(2-ethylhexyl) phthalate], aryl phthalates such as triphenyl phthalate, and butyl benzyl phthalate; polyvinyl acetates, triethyl citrate, eudragit; insoluble salts such as calcium sulfate, barium sulfate, calcium phosphate, and the like; insoluble oxides such as titanium oxide; polymers in powder, granule and like form such as polystyrene, polymethylmethacrylate, polycarbonate, and polysulf
  • Suitable materials include phthalate plasticizers such as dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, straight chain phthalates of six to eleven carbons, di-isononyl phthalte, di-isodecyl phthalate, and the like.
  • the plasticizers include nonphthalates such as triacetin, dioctyl azelate, epoxidized tallate, tri-isoctyl trimellitate, tri-isononyl trimellitate, sucrose acetate isobutyrate, epoxidized soybean oil, and the like.
  • the amount of plasticizer in a wall when incorporated therein is about 0.01% to 20% weight, or higher.
  • Pan coating may be conveniently used to provide the completed dosage form, except for the exit orifice.
  • the wall-forming composition for wall 20 is deposited by successive spraying of the appropriate wall composition onto the compressed single or bilayered core comprising the drag layer for the single layer core or the drag layer and the push layer for the bilayered core, accompanied by tumbling in a rotating pan.
  • a pan coater is used because of its availability at commercial scale. Other techniques can be used for coating the compressed core.
  • the wall can be dried in a forced-air oven or in a temperature and humidity controlled oven to free the dosage form of solvent(s) used in the manufacturing. Drying conditions will be conventionally chosen on the basis of available equipment, ambient conditions, solvents, coatings, coating thickness, and the like.
  • the wall or walls of the dosage form may be formed in one technique using the air-suspension procedure.
  • This procedure consists of suspending and tumbling the compressed single or bilayer core in a current of air and the semipermeable wall forming composition, until the wall is applied to the core.
  • the air-suspension procedure is well suited for independently forming the wall of the dosage form.
  • the air-suspension procedure is described in U.S. Patent No. 2,799,241; in J. Am. Pharm. Assoc. Vol. 48, pp. 451-459 (1959); and, ibid., Vol. 49, pp. 82-84 (1960).
  • the dosage form also can be coated with a Wurster ® air-suspension coater using, for example, methylene dichloride methanol as a cosolvent for the wall forming material.
  • An Aeromatic air-suspension coater can be used employing a cosolvent.
  • Dosage forms in accord with the present invention are manufactured by standard techniques.
  • the dosage form may be manufactured by the wet granulation technique. In the wet granulation technique, the drag and carrier are blended using an organic solvent, such as denatured anhydrous ethanol, as the granulation fluid.
  • the remaining ingredients can be dissolved in a portion of the granulation fluid, such as the solvent described above, and this latter prepared solution is slowly added to the drag blend with continual mixing in the blender.
  • the granulating fluid is added until a wet blend is produced, which wet mass blend is then forced through a predetermined screen onto oven trays.
  • the blend is dried for 18 to 24 hours at 24°C to 35°C in a forced-air oven.
  • the dried granules are then sized.
  • magnesium stearate, or another suitable lubricant is added to the drag granulation, and the granulation is put into milling jars and mixed on a jar mill for 10 minutes.
  • the composition is pressed into a layer, for example, in a Manesty ® press or a Korsch LCT press.
  • a bilayered core the drag-containing layer is pressed and a similarly prepared wet blend of the push layer composition, if included, is pressed against the drag-containing layer.
  • the intermediate compression typically takes place under a force of about 50-100 newtons.
  • Final stage compression typically takes place at a force of 3500 newtons or greater, often 3500-5000 newtons.
  • the single or bilayer compressed cores are fed to a dry coater press, e.g., Kilian ® Dry Coater press, and subsequently coated with the wall materials as described above.
  • One or more exit orifices are drilled in the drag layer end of the dosage form, and optional water soluble overcoats, which maybe colored (e.g., Opadry colored coatings) or clear (e.g., Opadry Clear), may be coated on the dosage form to provide the finished dosage form.
  • optional water soluble overcoats which maybe colored (e.g., Opadry colored coatings) or clear (e.g., Opadry Clear)
  • the drag and other ingredients comprising the drug layer are blended and pressed into a solid layer.
  • the layer possesses dimensions that correspond to the internal dimensions of the area the layer is to occupy in the dosage form, and it also possesses dimensions corresponding to the second push layer, if included, for forming a contacting arrangement therewith.
  • the drug and other ingredients can also be blended with a solvent and mixed into a solid or semisolid form by conventional methods, such as ballmilling, calendering, stirring or rollmilling, and then pressed into a preselected shape.
  • a layer of osmopolymer composition is placed in contact with the layer of drug in a like manner.
  • the layering of the drug formulation and the osmopolymer layer can be fabricated by conventional two-layer press techniques.
  • the compressed cores then may be coated with the semipermeable wall material as described above.
  • Another manufacturing process that can be used comprises blending the powdered ingredients for each layer in a fluid bed granulator. After the powdered ingredients are dry blended in the granulator, a granulating fluid, for example, poly(vinylpyrrolidone) in water, is sprayed onto the powders. The coated powders are then dried in the granulator. This process granulates all the ingredients present therein while adding the granulating fluid. After the granules are dried, a lubricant, such as stearic acid or magnesium stearate, is mixed into the granulation using a blender e.g., V-blender or tote blender. The granules are then pressed in the manner described above.
  • a granulating fluid for example, poly(vinylpyrrolidone) in water
  • Exit 60 is provided in each dosage form. Exit 60 cooperates with the compressed core for the uniform release of drag from the dosage form.
  • the exit can be provided during the manufacture of the dosage form or during drag delivery by the dosage form in a fluid environment of use.
  • Exit 60 may include an orifice that is formed or formable from a substance or polymer that erodes, dissolves or is leached from the outer wall to thereby form an exit orifice.
  • the substance or polymer may include, for example, an erodible poly(glycolic) acid or poly(lactic) acid in the semipermeable wall; a gelatinous filament; a water-removable poly(vinyl alcohol); a leachable compound, such as a fluid removable pore-former selected from the group consisting of inorganic and organic salt, oxide and carbohydrate.
  • the exit can be formed by leaching a member selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, sodium citrate and mannitol to provide a uniform-release dimensioned pore-exit orifice.
  • the exit can have any shape, such as round, triangular, square, elliptical and the like for the uniform metered dose release of a drug from the dosage form.
  • the dosage form can be constructed with one or more exits in spaced-apart relation or one or more surfaces of the dosage form.
  • Drilling, including mechanical and laser drilling, through the semipermeable wall can be used to form the exit orifice.
  • Such exits and equipment for forming such exits are disclosed in U.S. Patents Nos. 3,916,899, by Theeuwes and Higuchi and in U.S. Patent No. 4,088,864, by Theeuwes, et al., each of which is incorporated in its entirety by reference herein. It is presently preferred to utilize a single exit orifice.
  • Techniques corresponding to those described above for osmotic systems are used for dosage forms employing other controlled-release technologies. For example, matrix systems are described in various of the patents relating to Purdue Pharma's OXYCONTIN products.
  • One of the advantages of the preferred embodiments of the invention is the production of single dose plasma profiles that have small C max values.
  • C max values that are large are known to be undesirable for a variety of reasons.
  • high oxycodone concentrations are known to be associated with respiratory depression and resulting high CO 2 levels in the blood. See Leino et al, "Time course of changes in breathing pattern in morphine- and oxycodone-induced respiratory depression," Anaesthesia. 1999, 54:835-840.
  • the present invention provides substantially zero order (SZO) release profiles.
  • SZO substantially zero order release profiles.
  • the plasma oxycodone concentration profile for an oral controlled-release dosage form with a constant release rate of R can be modeled using the following equation: where k a is an absorption rate constant, k e is an elimination rate constant, and N d /F is the mean apparent volume of distribution.
  • k e can be derived as the ratio of CL/F to N d F, where CL/F is the mean apparent clearance.
  • each of these curves have higher C ma ⁇ values than curve 100.
  • the C max values for curves 102 and 104 are set forth in Table 2.
  • the C max value for curve 100 is 46.5, i.e., 18% lower than the curve 102 value and 24% lower than the curve 104 value.
  • C max for a single dose is specified to be: 3.5 x 10 ⁇ 4 liter -1 ⁇ C max /D ⁇ 6.8 x 10 -4 liter -1 Eq. 2 where D is the dose.
  • the specified upper and lower limits on the C m ⁇ -to-dose ratio (C ma ⁇ fD) in Equation (2) are based on the mean C max value reported in Table 8 for SZO-24 oxycodone, plus and minus the reported standard deviation for C max .
  • AUC 0-48 /D the upper and lower limits on the AUC 0- 8 -to-dose ratio (AUC 0-48 /D) of these aspects of the invention, as well as of the second, third, eighth, and ninth aspects, are based on the mean AUC 0- 8 value for SZO-24 oxycodone reported in Table 8, plus and minus its reported standard deviation.
  • the AUCo -48 /D ratio specified in the first, seventh, and other aspects of the invention is characteristic of how the body absorbs and eliminates oxycodone.
  • OXYCONTIN administers its incorporated dose during such time as the dosage form is in the body, its AUC 0-48 /D ratio is within the range for AUC 0-48 /D ratios specified in the first and seventh aspects of the invention.
  • the first and seventh aspects of the invention specify a single dose AUC value which brackets OXYCONTIN, but a lower C max .
  • Figure 16D confirms that this is precisely what is observed.
  • the SZO-24 steady state profile curve 150
  • the OXYCONTIN profile curve 152
  • a steady state plasma profile is sufficiently flat to achieve the pain management benefits of the invention if the ratio of the AUC (area under the curve) for each quartile for the profile to the AUC for the full profile, i.e., the full dosing period of 24-hours, is greater than 0.18 (such a profile is hereinafter referred to as a ">18%>/quartile steady state profile").
  • the first quartile begins at 0 hours (i.e., the time of administration of the dosage form) and ends at 6 hours
  • the second quartile begins at 6 hours and ends at 12 hours
  • the third quartile begins at 12 hours and ends at 18 hours
  • the fourth quartile begins at 18 hours and ends at 24 hours.
  • the plasma profiles are mean profiles obtained from a study population and the AUC values for the quartiles and for the entire profile are obtained using the trapezoidal method. More particularly, the AUC ratios are determined for each individual and then those values are averaged. Samples are taken from subjects in accordance with a sampling scheme selected to reflect the time course of the plasma profile, e.g., there may be more sampling points where the profile is changing rapidly in time.
  • the ratio of the AUC for each quartile of the profile to the AUC for the full profile is greater than or equal to about 0.20. Even more preferably, the difference in ratios between any two adjacent quartiles is less than about 0.03 and/or the difference in ratios between any two quartiles is less than about 0.05. Most preferably, both these criteria are satisfied, i.e., the difference in ratios between any two adjacent quartiles is less than about 0.03 and the difference in ratios between any two quartiles is less than about 0.05. [000131] As the data present below demonstrates, it has been found that
  • such substantially monotonically increasing mean profile comprises a first rising phase and a second phase, where the slope of the first phase is greater than the magnitude of the slope of the second phase, where the slope of a phase is defined as the slope of a best fit straight line to the portion of the mean profile making up the phase.
  • the slope of the first phase can be at least approximately 10 times the magnitude of the slope of the second phase
  • the first rising phase can include a first rising subphase followed by a second rising subphase, where the slope of the first rising subphase is greater than the slope of the second rising subphase, where slopes are defined in the same manner as for the first and second phases.
  • the transition from the first phase to the second phase occurs at about 14 hours, e.g., between about 12 hours and about 16 hours, while the transition from the first subphase to the second subphase occurs at about 2 hours, e.g., between about 1 hour and about 3 hours.
  • the single dose plasma profiles also preferably have their maximum , concentration values (C ma ⁇ ) at a time (T max ) which is greater than about 17 hours, more preferably greater than about 18 hours, and most preferably greater than about 19 hours.
  • the single dose plasma profiles also preferably have a 12-24 hour AUC which is greater than their 0-12 hour AUC.
  • the ratio of the 12-24 hour AUC to the 0-12 hour AUC is preferably greater than about 1.5, more preferably greater than about 1.7, and most preferably about 2.0.
  • the single dose plasma profile preferably has a Cm ax /(Tm ax x dose) ratio which is less than about 3xl0 "4 hour _1 liter "1 , more preferably less than about 4xl0 "5 hour -1 liter "1 , and most preferably less than about 3x10 "5 hour _1 liter "1 .
  • the user of the dosage form does not achieve an early, strong bolus of oxycodone and thus is less likely to experience the euphoria and other effects which can lead to a liking response.
  • the commercial OXYCONTIN product which is known to suffer from a liking, indeed, an abuse, problem, has a C max /(T max x dose) ratio of about 4xl0 "4 hour -1 liter "1 for its 40 mg dosage strength.
  • the single dose profiles are mean profiles obtained from a study population and the sampling scheme is selected to reflect the time course of the single dose plasma profile. As discussed above, the slopes are determined from the mean profiles. However, T max , C max , and C max /(T max x dose) ratios are obtained for individual subjects and then averaged. 3. IN VITRO RELEASE PROFILES
  • the desired >18% ⁇ /quartile steady state profiles are related to the in vitro dissolution/release profile of the dosage form.
  • the in vitro dissolution/release profile preferably comprises an initial loading dose component and a controlled release component.
  • the ratio of the amount of oxycodone in the initial loading dose to the total amount of oxycodone in the dosage form is less than 0.25, more preferably less than 0.10, and most preferably less than or equal to 0.05.
  • the 0.25 upper limit on initial loading dose ensures that the dosage form does not generate plasma concentrations above those produced by an immediate release dosage form administered at an equivalent daily dose, and thus the probability of the dosage form having "liking" problems or other adverse side effects will be no worse than for an immediate release product.
  • the 0.10 and 0.05 levels should make such "liking" and other problems even less.
  • the controlled release component preferably has a substantially constant in vitro dissolution release rate so that when combined with the initial loading dose, the overall dosage form has substantially zero order in vitro release kinetics, i.e., the overall in vitro release rate is substantially constant over a 24 hour period.
  • Figures 9 and 10 are non-limiting examples of release profiles for dosage forms which employ a controlled-release component and an initial loading dose and exhibit substantially zero order in vitro release kinetics, while Figure 8 is an example of a release profile for a dosage form which achieves those kinetics with only a controlled-release component.
  • the dosage form releases 70% of the dosage form's label dose within a period (the T 0 period) of between about 15 hours to about 18 hours. More particularly, the dosage form preferably has a delivery dose pattern of from 0%> to 20% in 0-2 hours, 30 to 65% (preferably 33 to 63%) in 0 to 12 hours, and 80 to 100% in 0 to 24 hours, as shown schematically in Figure 6.
  • EXAMPLE 1 Oxycodone Hydrochloride 17 mg Osmotic Push Pull Systems (Fast and Slow) [000145]
  • a dosage form adapted, designed and shaped as an osmotic drug delivery device was manufactured as follows: Two granulations were made by the following procedure: 1479 g of oxycodone hydrochloride, USP and 7351 g of polyethylene oxide N80 with average molecular weight of 200,000 were added to a fluid bed granulator bowl. Next a binder solution was prepared by dissolving 500 g of polyvinylpyrrolidone identified as K29-32 in 4500 g of water. The dry materials were fluid bed granulated by spraying with 1800 g of binder solution.
  • the wet granulation was dried in the granulator to an acceptable moisture content.
  • the two granulations were then sized by passing through a 7-mesh screen into the same container.
  • the granulation was transferred to a blender and mixed with 3.53 g of butylated hydroxytoluene as an antioxidant and lubricated with 88 g of magnesium stearate.
  • a push composition was prepared as follows: first, a binder solution was prepared. 27.3 kg of polyvinylpyrrolidone identified as K29-32 having an average molecular weight of 40,000 was dissolved in 182.7 kg of water. Then, 22.4 kg of sodium chloride and 1.12 kg of ferric oxide were sized using a Quadro Comil with a 21-mesh screen. Then, the screened materials and 82.52 kg of polyethylene oxide (approximately 2,000,000 molecular weight) were added to a fluid bed granulator bowl. The dry materials were fluidized and mixed while 43 kg of binder solution was sprayed from 3 nozzles onto the powder. The granulation was dried in the fluid-bed chamber to an acceptable moisture level.
  • the granulation process was repeated four times and the granulations were blended together during sizing.
  • the coated granules were sized using a Fluid Air mill with a 7-mesh screen.
  • the granulations were transferred to a tote tumbler, mixed with 224 g of butylated hydroxytoluene and lubricated with 1.12 kg stearic acid.
  • the oxycodone hydrochloride drag composition and the push composition were compressed into bilayer tablets.
  • 113 mg of the oxycodone hydrochloride composition was added to the die cavity and pre-compressed; then, 103 mg of the push composition was added and the layers were pressed into a 5/16" diameter round, standard concave, bilayer arrangement.
  • the bilayered arrangements were coated with a semi-permeable wall.
  • the wall forming composition comprised 99% cellulose acetate having a 39.8%) acetyl content and 1%> polyethylene glycol comprising a 3.350 viscosity-average molecular weight.
  • the wall-forming composition was dissolved in an acetone:water (95:5 wt:wt) co solvent to make a 5% solids solution.
  • the wall-forming composition was sprayed onto and around the bilayered arrangements in a pan coater until approximately 20 mg of membrane was applied to each tablet to create "fast” systems.
  • the coating process was repeated and approximately 30 mg of membrane was applied to each tablet to create "slow” systems.
  • one 25 mil (0.64 mm) exit passageway was laser drilled through the semi-permeable wall to connect the drug layer with the exterior of the dosage system.
  • the residual solvent was removed by drying for 48 hours as 45°C and 45% humidity followed by 4 hours at 45°C to remove excess moisture.
  • the dosage forms produced by this manufacture were designed to deliver 17mg of oxycodone HCl, USP from the core containing 15.8% oxycodone hydrochloride USP, 81.68% polyethylene oxide N80 possessing a 200,000 molecular weight, 2% polyvinylpyrrolidone possessing a 40,000 molecular weight, 0.02% butylated hydroxytoluene, and 0.5% magnesium stearate.
  • the push composition comprised 73.7% polyethylene oxide comprising a 7,000,000 molecular weight, 20% sodium chloride, 5% polyvinylpyrrolidone possessing an average molecular weight of 40,000, 1% ferric oxide, 0.05% butylated hydroxytoluene, and 0.25% magnesium stearate.
  • the semi-permeable wall comprised 99% cellulose acetate of 39.8% acetyl content and 1% polyethylene glycol.
  • the dosage forms comprised one passageway, 25 mils (0.64 mm) on the center of the drug side.
  • the final dosage forms had a mean release rate of 1.35 mg oxycodone hydrochloride, USP per hour (7.95 %/hr) and 0.97 mg oxycodone hydrochloride USP per hour (5.70 %/hr) for the "fast” and “slow” systems, respectively.
  • EXAMPLE 2 Oxycodone Hydrochloride 20 mg Osmotic Push Pull System
  • a dosage form adapted, designed and shaped as an osmotic drag delivery device was manufactured as follows: 1933 g of oxycodone hydrochloride, USP , 7803 g of polyethylene oxide N80 with average molecular weight of 200,000, and 200 g of polyvinylpyrrolidone identified as K29-32 having an average molecular weight of 40,000 were added to a fluid bed granulator bowl. Next a binder solution was prepared by dissolving 500 g of the same polyvinylpyrrolidone in 4500 g of water.
  • the dry materials were fluid bed granulated by spraying with 2000 g of binder solution.
  • the wet granulation was dried in the granulator to an acceptable moisture content, and sized by passing through a 7-mesh screen.
  • the granulation was transferred to a blender and mixed with 2 g of butylated hydroxytoluene as an antioxidant and lubricated with 25 g of magnesium stearate.
  • a push composition was prepared as follows: first, a binder solution was prepared. 15.6 kg of polyvinylpyrrolidone identified as K29-32 having an average molecular weight of 40,000 was dissolved in 104.4 kg of water. Then, 24 kg of sodium chloride and 1.2 kg of ferric oxide were sized using a Quadro Comil with a 21 -mesh screen. Then, the screened materials and 88.44 kg of polyethylene oxide
  • 113 mg of the oxycodone hydrochloride composition was added to the die cavity and pre-compressed; then, 103 mg of the push composition was added and the layers were pressed into a 5/16" diameter round, standard concave, bilayer arrangement.
  • the bilayered arrangements were coated with a semi-permeable wall.
  • the wall forming composition comprised 99% > cellulose acetate having a 39.8% acetyl content and 1% polyethylene glycol comprising a 3.350 viscosity-average molecular weight.
  • the wall-forming composition was dissolved in an acetone:water (95:5 wt:wt) co solvent to make a 5% solids solution.
  • the wall-forming composition was sprayed onto and around the bilayered arrangements in a pan coater until approximately 37 mg of membrane was applied to each tablet.
  • one 40 mil (1 mm) exit passageway was laser drilled through the semi-permeable wall to connect the drag layer with the exterior of the dosage system.
  • the residual solvent was removed by drying for 48 hours as 45°C. and 45% humidity. After drilling, the osmotic systems were dried for 4 hours at 45°C. to remove excess moisture.
  • the drag overcoat was an 8%> solids aqueous solution containing 157.5 g of oxycodone HCl, USP and 850 g of hydroxypropyl methylcellulose possessing an average molecular weight of 11,200.
  • the drag overcoat solution was sprayed onto the dried coated cores until an average wet coated weight of approximately 8 mg per system was achieved.
  • the drag-overcoated systems were color overcoated.
  • the color overcoat was a 12% solids suspension of Opadry in water.
  • the color overcoat suspension was sprayed onto the drag overcoated systems until an average wet coated weight of approximately 8 mg per system was achieved.
  • the color-overcoated systems were clear coated.
  • the clear coat was a 5% solids solution of Opadry in water.
  • the clear coat solution was sprayed onto the color coated cores until an average wet coated weight of approximately 3 mg per system was achieved.
  • clear-coated systems were coated with approximately 1 g of Camuaba wax by dispersing the wax over the systems as they tumbled in the pan coater.
  • the dosage form produced by this manufacture was designed to deliver 1 mg of oxycodone hydrochloride USP as an immediate release from an overcoat comprised of 15% oxycodone HCl, USP and 85% hydroxypropyl methylcellulose followed by the controlled delivery of 19 mg of oxycodone HCl, USP from the core containing 17.7% oxycodone hydrochloride USP, 78.03% polyethylene oxide possessing a 200,000 molecular weight, 4% polyvinylpyrrolidone possessing a 40,000 molecular weight, 0.02% butylated hydroxytoluene, and 0.25% magnesium stearate.
  • the push composition comprised 73.7% polyethylene oxide comprising a 7,000,000 molecular weight, 20% sodium chloride, 5% polyvinylpyrrolidone possessing an average molecular weight of 40,000, 1% ferric oxide, 0.05% butylated hydroxytoluene, and 0.25% magnesium stearate.
  • the semi permeable wall comprised 99% cellulose acetate of 39.8% acetyl content and 1% polyethylene glycol.
  • the dosage form comprised one passageway, 40 mils (1 mm) on the center of the drag side.
  • the final dosage form contained a color overcoat, a clear overcoat and a wax coat and had a mean release rate of 0.93 mg oxycodone hydrochloride, USP per hour (4.66 %/hr).
  • the formulation of this example is summarized in Table 4 and is referred to hereinafter as the "Example 2 SZO-24 dosage form.”
  • EXAMPLE 3 Oxycodone Hydrochloride 80 mg Osmotic Push Pull System
  • a dosage form adapted, designed and shaped as an osmotic drag delivery device was manufactured as follows: 34.36 kg of oxycodone hydrochloride, USP , 63.7 kg of polyethylene oxide N150 with average molecular weight of 200,000, and 0.02 kg of ferric oxide red, were added to a fluid bed granulator bowl.
  • a binder solution was prepared by dissolving 5.40 kg of polyvinylpyrrolidone identified as K29-32 having an average molecular weight of 40,000 in 49.6 kg of water.
  • the dry materials were fluid bed granulated by spraying with 33.3 kg of binder solution.
  • the wet granulation was dried in the granulator to an acceptable moisture content, and sized by passing through a 7-mesh screen. The granulation was then transferred to a blender and mixed with 0.02 kg of butylated hydroxytoluene as an antioxidant and lubricated with 0.25 kg of magnesium stearate.
  • a push composition was prepared as follows: First, a binder solution was prepared by dissolving 7.8 kg of polyvinylpyrrolidone identified as K29-32 having an average molecular weight of 40,000 in 52.2 kg of water. Then, 24 kg of sodium chloride and 1.2 kg of ferric oxide were sized using a Quadro Comil with a 21 -mesh screen. The sized materials and 88.5 kg of polyethylene oxide (approximately 2,000,000 molecular weight) were added to a fluid bed granulator bowl. The dry materials were fluidized and mixed while 46.2 kg of binder solution was sprayed from 3 nozzles onto the powder. The granulation was dried in the fluid-bed chamber to an acceptable moisture level.
  • the coated granules were sized using a Fluid Air mill with a 7-mesh screen. The granulation was transferred to a tote tumbler, mixed with 24 g of butylated hydroxytoluene and lubricated with 300 g magnesium stearate. [000164] Next, the oxycodone hydrochloride drag composition and the push composition were compressed into bilayer tablets. First, 250 mg of the oxycodone hydrochloride composition was added to the die cavity and pre-compressed, then 192 mg of the push composition was added and the layers were pressed into a 13/32" (1.03 cm) diameter round, standard concave, bilayer arrangement.
  • the bilayered arrangements were coated with a semi-permeable wall.
  • the wall forming composition comprised 99% cellulose acetate having a 39.8% acetyl content and 1% polyethylene glycol comprising a 3.350 viscosity-average molecular weight.
  • the wall-forming composition was dissolved in an acetone:water (95:5 wt:wt) solvent mixture to make a 5 % solids solution.
  • the wall-forming composition was sprayed onto and around the bilayered arrangements in a pan coater until approximately 44 mg of membrane was applied to each tablet.
  • two 40 mil (1 mm) exit passageways were laser drilled through the semi-permeable wall to connect the drag layer with the exterior of the dosage system. The residual solvent was removed by drying for 72 hours as 45°C and 45% humidity followed by 4 hours at 45 °C to remove excess moisture.
  • the drug overcoat was a 12% solids aqueous solution containing 1.33 kg of oxycodone HCl, USP and 7.14 kg of OpadryTM Clear.
  • the drag overcoat solution was sprayed onto the coated systems until an average wet coated weight of approximately 27 mg per system was achieved.
  • the drag-overcoated systems were color overcoated.
  • the color overcoat was a 12% solids suspension of Opadry in water.
  • the color overcoat suspension was sprayed onto the drag overcoated systems until an average wet coated weight of approximately 8 mg per system was achieved.
  • the color-overcoated systems were coated with approximately 100 ppm of Camuaba wax by dispersing the wax over the systems as they tumbled in the pan coater.
  • the dosage form produced by this manufacture was designed to deliver 4 mg of oxycodone hydrochloride USP as an immediate release from an overcoat comprised of 15% oxycodone HCl, USP and 85% OpadryTM Clear followed by the controlled delivery of 76 mg of oxycodone HCl, USP from the core containing 32% oxycodone hydrochloride USP, 63.73% polyethylene oxide N150 possessing a 200,000 molecular weight, 4% polyvinylpyrrolidone possessing a 40,000 molecular weight, 0.02%o butylated hydroxytoluene, and 0.25% magnesium stearate.
  • the push composition comprised 73.7% polyethylene oxide comprising a 7,000,000 molecular weight, 20%) sodium chloride, 5% polyvinylpyrrolidone possessing an average molecular weight of 40,000, 1% ferric oxide, 0.05%> butylated hydroxytoluene, and 0.25%) magnesium stearate.
  • the semi permeable wall comprised of 99%> cellulose acetate of 39.8% acetyl content and 1% polyethylene glycol.
  • the dosage form comprised two passageways, 40 mils (1 mm) equidistant on the center of the drag side.
  • the final dosage form contained a color overcoat and a wax coat and had a mean release rate of 3.94 mg oxycodone hydrochloride, USP per hour (4.93 %/hr).
  • the formulation of this example is summarized in Table 5 and is referred to hereinafter as the "Example 3 SZO-24 dosage form.”
  • Example 4 Pharmacokinetics and Pharmacodynamics of Osmotic Oxycodone Hydrochloride (Fast and Slow) and Immediate Release Oxycodone Hydrochloride in Healthy Volunteers
  • This study investigated the pharmacokinetics and pharmacodynamics of the "fast” and “slow” osmotic oxycodone HCl systems of Example 1 and immediate release (IR) oxycodone HCl in healthy male volunteers.
  • the fast-release formulation produced a larger reduction in the pain score than either the slow-release formulation or IR oxycodone HCl.
  • the reduction in pain scores with the slow-release formulation were generally comparable to those seen with IR oxycodone HCl.
  • Example 5 Pilot Study to Evaluate SZO-24 Oxycodone Hydrochloride Pharmacodynamics [000178] A single-center, randomized, three-treatment, double-blind, crossover study was performed to compare the Example 2 SZO-24 dosage form (2x20mg), IN morphine (10 mg), and placebo in healthy male subjects. This study was designed to determine the dose of oxycodone HCl when administered by the Example 2 SZO-24 dosage form that provides a statistically significant pharmacodynamic response as measured by the cold pain test.
  • a pharmacokinetic model consisting of the in-vitro release rate for the Example 2 SZO-24 dosage form and a first-order abso ⁇ tion, first-order elimination disposition model was fitted to the plasma oxycodone concentration data using ⁇ O ⁇ MEM. As the data were not sensitive to the abso ⁇ tion rate constant, the abso ⁇ tion rate constant was set to 6.48 h "1 . The population mean apparent clearance (Cl/F) was 67.7 L/h and the population mean apparent volume (N/F) was 556 L. The mean best-fit curve underestimated the mean data during the first few hours after dosing as shown in Figure 13.
  • Treatment B two doses of OXYCONTIN ® , 40 mg each dose, administered 12- hours apart followed 72 hours later by a ql2h regimen of OXYCONTIN, 40 mg for 5 days.
  • All subjects took 50 mg naltrexone orally starting 14 hours before dosing and every 12 hours during the treatment periods and 24 hours after the last dosing day of oxycodone.
  • the objectives of the study were:
  • the single dose plasma profile for the dosage forms of the invention satisfies the relationship: 2.7 x 10 -4 liter -1 ⁇ C i2 /D ⁇ 5.7 x 10 -4 liter -1 .
  • the amount of oxycodone provided by the Example 3 SZO-24 oxycodone dosage form given once-daily is bioequivalent to that of OXYCONTIN given twice- daily in the same total daily dose.
  • the C m j hand value for the Example 3 SZO-24 dosage form was 121% that for OXYCONTIN, while the Cmax value for the Example 3 SZO- 24 dosage form was 78% that for OXYCONTIN.
  • the C max values were significantly different (i.e., the ratio was significantly different from 1 (p ⁇ 0.001)).
  • Example 3 SZO-24 dosage form produces a steady state profile that is clearly flatter than that produced by OXYCONTIN, which clearly continues to be biphasic.
  • Example 7 Phase II Clinical Study of SZO-24 Oxycodone Hydrochloride [000195]
  • a Phase II, two-week, placebo-controlled study using the Example 2 SZO- 24 dosage form (20 mg and 2x20 mg 40 mg) in patients with osteoarthritis pain of the hips and/or knees was performed.
  • 40 mg showed statistically significant differences from placebo in pain assessments over the two-week treatment period, while 20 mg was superior to placebo over the first week of treatment but less consistently so during the second week, despite the fact that the study was not powered to show a statistically significant difference between the 20 mg and placebo in either week.
  • the results showed the general trend that 40 mg was more effective than 20 mg, as expected, although the two dosage strengths did not show statistically different results in most cases.
  • the specific objective of the study was to compare the degree of antinociceptive tolerance developed in rats administered oxycodone hydrochloride (HCl) for a period of three days, either by a biphasic dosing regimen (bolus/twice-a-day) or an SZO dosing regimen (substantially zero order/continuous).
  • the biphasic dosing regimen used subcutaneous (SC) infusion, and the SZO regimen used subcutaneously-implanted ALZET ® osmotic pumps.
  • the vehicle control for the study was 0.9% saline.
  • the test solutions were oxycodone HCl dissolved in saline.
  • the rodent tail-flick assay was used to assess analgesia (antinociception). This assay is a well-characterized and standard method to assess antinociception and tolerance to opioid drags (Cleary 1994, D'Armour & Smith 1941). In the assay, rodents are briefly restrained and radiant heat is applied to the tip of the tail. The time it takes for the animal to flick its tail is recorded; a delay in this response compared to pre-dose readings is indicative of antinociception.
  • tail flick latency methods used in the present study were similar to those described previously in the literature to assess antinociception (Duttaroy & Yoburn 1995, Nielsen et al 2000) with slight modifications from the original method described by D'Armour and Smith (1941).
  • An IITC Model 33 Tail Flick Analgesia Meter was used to apply heat to the animal's tail (IITC Life Science, Woodland Hills, CA).
  • the meter was programmed with the following conditions: (1) Active Intensity: 75% (intensity of the stimulation light during the test); (2) Trigger Temperature: 30°C (this temperature allows pre-warming of the animal's tail to allow for more uniform measurements from day-to-day and test-to-test); (3) Cutoff Time: 10 seconds (i.e., the length of time from the start of the test until the unit automatically ends the test to prevent tissue damage). [000200] The animals were briefly restrained in plexiglass restrainers and radiant heat was applied to the tip of the animal's tail (approximately 1-2 cm from the tip). After the temperature reached 30°C, the meter increased the light intensity providing a noxious stimulus to the animal's tail.
  • the infusion regimen produced a biphasic profile, with two peaks (Cmax) between 2 to 4 hours and 14 and 16 hours, and two troughs (Cmin) at approximately 12 hours and 24 hours.
  • the ratio of Cmax to Cmin was between three and four.
  • Extra animals were employed in the biphasic dosing regimen to take account of damaged catheters, but only enough animals were dosed on Day +3 to replace the animals with damaged catheters.
  • the study was performed in compliance with the animal welfare regulations of 9 CFR 1-3 and the Guide for the Care and Use of Laboratory Animals (National Research Council 1996).
  • the animals were divided into four groups and on Day -1, each group was further divided into six subgroups and administered 0, 0.25, 0.5, 0.75, 1 or 1.5 mg/kg oxycodone by subcutaneous (SC) injection, respectively. Animals were tested for antinociception (tail-flick latency) approximately 15 minutes after injection. On Day 0, animals in each group were treated in accordance with Table 11.
  • each subgroup of Groups 1-4 was administered 0, 0.25, 0.5, 0.75, 1 or 3 mg/kg oxycodone by subcutaneous (SC) injection, respectively. Animals were tested for antinociception (tail-flick latency) approximately 15 minutes after injection.
  • the dose of oxycodone over the 72 hour (3 day) test period was on average approximately 10 mg/kg-d, i.e., a total of approximately 30 mg/kg was administered over the testing period.
  • Tables 12A and 12B The results of these experiments are shown in Tables 12A and 12B, and in Figures 17A and 17B, where Figure 17A plots all of the data of Tables 12A and 12B, while Figure 17B plots the Day +3 data for tail flick testing doses of 0, 0.25, 0.5, 0.75, and 1.0 mg/kg.
  • curve numbers in Figures 17A and 17B correspond to the following: curve 154a: SZO ⁇ Day -1/Saline Group; curve 154b SZO ⁇ Day +3/Saline Group; curve 156a: SZO ⁇ Day -1/Oxycodone Group; curve 156b: SZO — Day +3/Oxycodone Group; curve 158a: biphasic ⁇ Day -1 /Saline Group; curve 158b biphasic ⁇ Day +3/S aline Group; curve 160a: biphasic — Day -1/Oxycodone Group; curve 160b: biphasic ⁇ Day +3 /Oxycodone Group.
  • the full variance model consisted of the three primary factors, their first-order interaction terms and their second order interaction term, namely: dosing regimen, 3 -day treatment, tail flick testing dose, dosing regimen x 3 -day treatment, dosing regimen x tail flick testing dose, 3-day treatment x tail flick testing dose, and dosing regiment x 3-day treatment x tail flick testing dose.
  • the estimated mean tolerance difference was -10.7 %MPE between the oxycodone and saline treated rats and -3.2 %MPE between with the SZO dosing regimen and the biphasic dosing regimen.
  • the -10.7 %MPE difference was statistically different at an ⁇ -value of 0.05, but the -3.2 %oMPE value was not.
  • the lack of a statistically significantly difference between rats treated with a SZO dosing regimen versus a biphasic dosing regimen is in direct contrast with the concerns expressed in the literature that substantially zero order dosing will be more likely to lead to tolerance than biphasic dosing (see Benziger et al. 1997 and Kaiko 1997 discussed above). Based on this literature, one would have expected that the rats treated with the SZO dosing regimen would have exhibited more tolerance at a statistically significant level than those treated with the biphasic dosing regimen, but no such statistically significant difference was found.
  • the invention provides dosage forms suitable for providing once-daily dosing of oxycodone and/or one or more its pharmaceutically-acceptable salts for relief of moderate to severe pain in patients requiring an opioid for more than a few days.
  • Potential advantages for once-a-day dosing over current IR and CR oxycodone formulations include improved convenience, better compliance, a simpler dosing regimen, and more consistent pain relief with fewer adverse events over a 24-hour period.

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Abstract

L'invention porte sur des préparations d'oxycodone produisant in vivo des profils plasmatiques sensiblement constants. Les niveaux de tolérance associés à ces profils et ceux associés aux profils biphasés se sont avérés statistiquement identiques. Ces profils plasmatiques sensiblement constants in vivo sont produits par des formes posologiques présentant des profils in vitro d'ordre sensiblement nul. De tels profils de libération produisent in vivo pour une faible dose unique des niveaux de Cmax pouvant réduire la probabilité d'effets secondaires adverses.
PCT/US2004/036132 2003-10-29 2004-10-28 Formes posologiques orales d'oxycodone en dose quotidienne unique et a liberation controlee WO2005041968A2 (fr)

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CA002546691A CA2546691A1 (fr) 2003-10-29 2004-10-28 Formes posologiques orales d'oxycodone en dose quotidienne unique et a liberation controlee
JP2006538357A JP2007509979A (ja) 2003-10-29 2004-10-28 １日１回の、経口用、制御放出、オキシコドン投与形態物
BRPI0415639-0A BRPI0415639A (pt) 2003-10-29 2004-10-28 formas de dosagem de oxicodona de liberação controlada, oral, uma vez por dia
EP04817492A EP1677798A2 (fr) 2003-10-29 2004-10-28 Formes posologiques orales d'oxycodone en dose quotidienne unique et a liberation controlee
AU2004285547A AU2004285547A1 (en) 2003-10-29 2004-10-28 Once-a-day, oral, controlled-release, oxycodone dosage forms
IL175193A IL175193A0 (en) 2003-10-29 2006-04-25 Once-a-day, oral, controlled-release, oxycodone dosage forms
NO20062398A NO20062398L (no) 2003-10-29 2006-05-26 Daglig, oral, kontrollert frigivnings oksycodon-doserings form

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US51588003P 2003-10-29 2003-10-29
US60/515,880 2003-10-29

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AU (1) AU2004285547A1 (fr)
BR (1) BRPI0415639A (fr)
CA (1) CA2546691A1 (fr)
EC (1) ECSP066534A (fr)
IL (1) IL175193A0 (fr)
MA (1) MA28215A1 (fr)
NO (1) NO20062398L (fr)
RU (1) RU2006118323A (fr)
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EP1416921A2 (fr) * 2001-05-02 2004-05-12 Euro-Celtique S.A. Formulations d'oxycodone a administration quotidienne unique
US8323889B2 (en) 2004-07-01 2012-12-04 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US8815289B2 (en) 2006-08-25 2014-08-26 Purdue Pharma L.P. Tamper resistant dosage forms
US9056052B1 (en) 2000-10-30 2015-06-16 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9226907B2 (en) 2008-02-01 2016-01-05 Abbvie Inc. Extended release hydrocodone acetaminophen and related methods and uses thereof
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9655894B2 (en) 2001-05-02 2017-05-23 Purdue Pharma L.P. Once-A day oxycodone formulations
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9669024B2 (en) 1999-10-29 2017-06-06 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
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US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
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US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
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US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11337977B2 (en) 2016-08-10 2022-05-24 Genentech, Inc. Pharmaceutical compositions comprising Akt protein kinase inhibitors
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
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BRPI0415639A (pt) 2006-12-12
NO20062398L (no) 2006-07-27
KR20060108690A (ko) 2006-10-18
RU2006118323A (ru) 2007-12-10
CA2546691A1 (fr) 2005-05-12
ZA200604310B (en) 2007-11-28
MA28215A1 (fr) 2006-10-02
ECSP066534A (es) 2006-11-24
CN1933837A (zh) 2007-03-21
IL175193A0 (en) 2008-04-13
AU2004285547A1 (en) 2005-05-12
WO2005041968A3 (fr) 2006-06-22
JP2007509979A (ja) 2007-04-19
EP1677798A2 (fr) 2006-07-12

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