OXYMORPHONE CONTROLLED RELEASE FORMULATIONS
`
`EL618698014US
`
`BACKGROUND OF THE INVENTION
`
`Pain is the most frequently reported symptom and it is a common clinical problem which
`
`confronts the clinician. Almost 100 million people in the USA suffer from severe pain that,
`
`according to numerous recent reports, is chronically undertreated or inappropriately managed.
`
`The clinical usefulness of the analgesic properties of opioids has been recognized for centuries,
`
`and morphine and its derivatives have been widely employed for analgesia for decades in a
`
`variety of clinical pain states.
`
`Oxymorphone HC1 (14-hydroxydihydromorphinone hydrochloride) is a semi-synthetic
`
`phenanthrene-derivative opioid agonist, widely used in the treatment of acute and chronic pain,
`
`with analgesic efficacy comparable to other opioid analgesics. Oxymorphone is currently
`
`marketed as an injection (1 mg/mL in 1 mL ampules; 1 5 mg/mL in 1 mL ampules; 1.5 mg/mL in
`
`10 mL multiple dose vials) for intramuscular, subcutaneous, and intravenous administration, and
`
`as 5 mg rectal suppositories. At one time, a 10 mg oral immediate release (IR) tablet formation
`
`of oxymorphone HC1 was marketed. Oxymorphone HC1 is metabolized principally in the liver
`
`and undergoes conjugation with glucuronic acid and reduction to 6 alpha and beta hydroxy
`
`epimers.
`
`An important goal of analgesic therapy is to achieve continuous relief of chronic pain.
`
`Regular administration of an analgesic is generally required to ensure that the next dose is given
`
`before the effects of the previous dose have worn off Compliance with opioids increases as the
`
`required dosing frequency decreases. Non-compliance results in suboptimal pain control and
`
`poor quality of life outcomes. (Ferrell B et al. Effects of controlled-release morphine on quality
`
`of life for cancer pain. Oncol Nur Forum 1989;4:521-26). Scheduled, rather than as needed
`
`administration of opioids is currently recommended in guidelines for their use in chronic non-
`
`malignant pain. Unfortunately, evidence from prior clinical trials and clinical experience
`
`suggests that the short duration of action of IR oxymorphone would necessitate 4-hourly
`
`administration in order to maintain optimal levels of analgesia in chronic pain.
`
`935090_1
`
`ENDO - Ex. 2085
`Amneal v. Endo
`IPR2014-00360
`
`

`

`Oshlack et al US Patent 5,266,331 discloses oxycodone controlled release (CR)
`
`formulations. The oxycodone is incorporated into a CR matrix comprising (a) hydrophilic
`
`polymers, such as gum, cellulous ether, acrylic resins and protein-derived materials, (b)
`
`digestible hydrocarbons such as fatty acids, fatty alcohols, etc., and (c) polyalkylene glycols.
`
`The formulation can contain a hydrophobic polymer such as ethyl cellulose. Oxycodone can
`
`also be incorporated into an IR formulation then coated with a CR film. The Oshlack patent
`
`states that other analgesics may be used in place of oxycodone, including hydromorphone,
`
`dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, and the like.
`
`ChasM et al. US 5,958,459 discloses CR oral solid formulations of opioid analgesics.
`
`The Chasin patent states that the preferred opioids include mu-agonist opioid analgesics such as
`
`hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin,
`
`dihydrocodeine, codeine, dihydromorphine, buprenorphine, and the like. The formulation can be
`
`used in the form of granules, spheroids or pellets in a capsule or in any other suitable solid form.
`
`Other forms mentioned are tablets, microspheres, seeds, ion exchange resin beads, and other
`
`multiparticulate systems. Spheroids or other substrate containing the opioid (e.g. tablet core or
`
`inert pharmaceutical beads) are coated with a CR film of a hydrophobic cellulosic or acrylic
`
`polymer. Beads coated with opioid are prepared by dissolving the opioid in water then spraying
`
`the solution onto the substrate to coat it. The beads are then coated with hydrophobic polymer
`
`and curd to obtain a stabilized release rate.
`
`Sackler et al. US Patent 5,478,577 discloses 24 hour oral opioid formulations that provide
`
`a rapid rate of initial rise of plasma drug level. Oxymorphone is included in a long list of opioids
`
`which can be used. Where the extended release of opioid is due to a CR coating, an IR
`
`formulation can be overcoated on top of the CR coating. When the extended release is due to a
`
`CR matrix, the IR layer can be coated onto the surface of the substrate. Alternatively, a capsule
`
`can be provided that contains both CR particles, e.g., pellets, spheres, beads and the like, and IR
`
`powder or granulate, or a capsule containing CR particles can be coated with an IR formulation.
`
`Suitable materials mentioned in the Sackler patent for inclusion in a CR matrix are (a)
`
`hydrophilic polymers, such as gums, cellulose ethers and acrylic resins, (b) hydrocarbons such as
`
`fatty acids, fatty alcohols, mineral and vegetable oils and waxes, and (c) polyalkylene glycols.
`
`2
`
`935090_1
`
`

`

`Oshlack et al. US Patent 5,958,452 discloses opioid CR formulations made by melt
`
`extrusion of a mixture of opioid, a hydrophobic material, and a retardant material. The Oshlack
`
`patent states that in certain preferred embodiments, the opioid is selected from a list that includes
`
`oxymorphone as well as morphine, codeine, hydromorphone, hydrocodone, oxycodone,
`
`dihydrocodeine, dihydromorphone and tramadol.
`
`A CR formulation of morphone has been demonstrated to provide patients fewer
`
`interruptions in sleep, reduced dependence on caregivers, improved compliance, enhanced
`
`quality of life outcomes, and increased control over the management of pain. In addition, the CR
`
`formulation of morphine provided more constant plasma concentration and clinical effects, less
`
`frequent peak to trough fluctuations, reduced dosing frequency, and possibly fewer side effects.
`
`(Thirlwell MP et al. Pharmacokinetics and clinical efficacy of oral morphine solution and
`
`controlled-release morphine tablets in cancer patients. Cancer 1989; 63:2275-83; Goughnour BR
`
`et al. Analgesic response to single and multiple doses of controlled-release morphine tablets and
`
`morphine oral solution in cancer patients. Cancer 1989; 63:2294-97; Ferrell B et al. Effects of
`
`controlled-release morphine on quality of life for cancer pain. Oncol Nur Forum 1989; 4:521-26.
`
`Oxymorphone IR exhibits low oral bioavailability, because oxymorphone is extensively
`
`metabolized in the liver. Prior to this invention, it was expected that an oxymorphone CR oral
`
`dosage form would also exhibit very low oral bioavailability, and thus would not be useful for
`
`treatment of pain, because it was known that metabolism of drugs that are extensively
`
`metabolized in the liver increases with decreasing release rate.
`
`SUMMARY OF THE INVENTION
`
`To overcome the difficulties associated with a 4-6 hourly dosing frequency of
`
`oxymorphone, this invention provides an oxymorphone CR oral solid dosage form comprising an
`
`analgesically effective amount of oxymorphone or a pharmaceutically acceptable salt of
`
`oxymorphone. Surprisingly, it has been found that the decreased rate of release of oxymorphone
`
`from the oral CR formulation of this invention does not substantially decrease the bioavailability
`
`of the drug as compared to a solution of oxymorphone administered orally. The bioavailability is
`
`sufficiently high that the CR dosage can be used to treat patients suffering moderate to severe
`
`3
`
`935090_1
`
`

`

`pain with once or twice daily dosing. The dosing form of the present invention can also be used
`
`with thrice daily dosing.
`
`The CR dosage form of this invention exhibits a dissolution rate in vitro, when measured
`
`by USP Procedure Drug Release USP 24, of about 25% to about 55% by weight oxymorphone
`
`released after 1 hour, about 55% to about 85% by weight oxymorphone released after 4 hours,
`
`and at least about 80% by weight oxymorphone released after 8 hours .
`
`When administered orally to humans the CR dosage form of this invention exhibits the
`
`following in vivo characteristics: (a) peak plasma level of oxymorphone occurs within about 2 to
`
`about 6 hours after administration; (b) duration of oxymorphone analgesic effect is about 8 to
`
`about 24 hours; and (c) relative oxymorphone bioavailability is in the range of about 0.5 to about
`
`1.5 compared to an orally-administered aqueous solution of oxymorphone.
`
`In one embodiment of the invention, the oxymorphone or salt of oxymorphone is
`
`dispersed in a controlled release delivery system that comprises a hydrophilic material which
`
`upon exposure to gastrointestinal fluid forms a gel matrix that releases oxymorphone at a
`
`controlled rate. The rate of release of oxymorphone from the matrix depends on the drug's
`
`partition coefficient between components of the matrix and the aqueous phase within the
`
`gastrointestinal tract. In a preferred form of this embodiment, the hydrophilic material of the
`
`controlled release delivery system comprises a mixture of a heteropolysaccharide gum and an
`
`agent capable of cross-linking the heteropolysaccharide in the presence of gastrointestinal fluid.
`
`The controlled release delivery system may also comprise a water-soluble pharmaceutical diluent
`
`mixed with the hydrophilic material. (cid:9)
`
`Preferably, the cross-linking agent is a
`
`homopolysaccharide gum and the inert pharmaceutical diluent is a mono-saccharide, a
`
`disaccharide, and polyhydric alcohol, or a mixture thereof.
`
`In a specific preferred embodiment, the oxymorphone is present as oxymorphone
`
`hydrochloride, the weight ratio of heteropolysaccharide to homopolysaccharide is in the range of
`
`about 1:3 to 3:1, the weight ratio of heteropolysaccharide to diluent is in the range of about 1:8 to
`
`8:1, and the weight ratio of heteropolysaccharide to oxymorphone hydrochloride is in the range
`
`of about 10:1 to 1:10. A preferred heteropolysaccharide is xanthan gum and a preferred
`
`homopolysaccharide is locust bean gum. The dosage form also comprises a cationic cross-
`
`4
`
`935090_1
`
`

`

`linking agent and a hydrophobic polymer. In the most preferred embodiment, the dosage form is
`
`a tablet containing about 5 mg to about 80 mg of oxymorphone hydrochloride.
`
`The invention includes a method which comprises administering once or twice a day to a
`
`patient suffering moderate to severe, acute or chronic pain (e.g., pain associated with cancer,
`
`autoimmune diseases, infections, surgical and accidental traumas) and oxymorphone CR oral
`
`solid dosage form of the invention in an amount sufficient to alleviate the pain for a period of
`
`about 12 hours to about 24 hours.
`
`The invention also includes a method of making an oxymorphone controlled release oral
`
`solid dosage form of the invention which comprises mixing particles of oxymorphone or a
`
`pharmaceutically acceptable salt of oxymorphone with granules comprising the controlled
`
`release delivery system, preferably followed by directly compressing the mixture to form tablets.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Pharmaceutically accepted salts of oxymorphone which can be used in this invention
`
`include salts with all those inorganic and organic acids which are commonly used to produce
`
`nontoxic salts of medicinal agents containing amine functions. Illustrative examples would be
`
`those salts formed by mixing oxymorphone with hydrochloric, sulfuric, nitric, phosphoric,
`
`phosphorous, hydrobromic, maleric, malic, ascorbic, citric or tartaric, pamoic, lauric, stearic,
`
`palmitic, oleic, myristic, lauryl sulfuric, napthalinesulfonic, linoleic or linolenic acid, and the
`
`like. The hydrochloride salt is preferred.
`
`The oxymorphone CR oral solid dosage form of this invention can be made as described
`
`for CR oral solid dosage forms of other opioid analgesics in Oshlack et al. US Patent 5,226,331
`
`and Chaisin et al. US Patent 5,958,459, the entire disclosures of which are incorporated herein.
`
`In one embodiment, a core comprising oxymorphone or oxymorphone salt is coated with
`
`a CR film which comprises a water insoluble material and which upon exposure to
`
`gastrointestinal fluid releases oxymorphone from the core at a controlled rate. In a second
`
`embodiment, the oxymorphone or oxymorphone salt is dispersed in a controlled release delivery
`
`system that comprises a hydrophilic material which upon exposure to gastrointestinal fluid forms
`
`a gel matrix that releases oxymorphone at a controlled rate. A third embodiment is a
`
`5
`
`935090_1
`
`

`

`combination of the first two-a CR matrix coated with a CR film. In any of these embodiments,
`
`the dosage form can be a tablet, a plurality of granules in a capsule, or other suitable form, and
`
`can contain lubricants, colorants, diluents, and other conventional ingredients.
`
`CR coating embodiment
`
`In this embodiment, a core comprising oxymorphone or oxymorphone salt is coated with
`
`a CR film which comprises a water insoluble material. The film can be applied by spraying an
`
`aqueous dispersion of the water insoluble material onto the core. Suitable water insoluble
`
`materials include alkyl celluloses, acrylic polymers, waxes (alone or in admixture with fatty
`
`alcohols), shellac and zein. The aqueous dispersions of alkyl celluloses and acrylic polymers
`
`preferably contain a plasticizer such as triethyl citrate, dibutyl phthalate, propylene glycol, and
`
`polyethylene glycol. (cid:9)
`
`The film coat can contain a water soluble material such as
`
`polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC).
`
`The core can be a granule made, for example, by wet granulation of mixed powders of
`
`oxymorphone or oxymorphone salt and a binding agent such as HPMC, or by coating an inert
`
`bead with oxymorphone or oxymorphone salt and a binding agent such as HPMC, or by
`
`spheronizing mixed powders of oxymorphone or oxymorphone salt and a spheronizing agent
`
`such as microcrystalline cellulose. The core can be a tablet made by compressing such granules
`
`or by compressing a powder comprising oxymorphone or oxymorphone salt.
`
`The in vitro and in vivo release characteristics of this CR dosage form can be modified by
`
`using mixtures of different water insoluble and water soluble materials, using different
`
`plasticizers, varying the thickness of the CR film, including release-modifying agents in the
`
`coating, or by providing passageways through the coating.
`
`CR matrix embodiment
`
`In this embodiment, the oxymorphone or oxymorphone salt is dispersed in a controlled
`
`release delivery system that comprises a hydrophilic material (gelling agent) which upon
`
`exposure to gastrointestinal fluid forms a gel matrix that releases oxymorphone at a controlled
`
`rate. Such hydrophilic materials include gums, cellulose ethers, acrylic resins, and protein-
`
`derived materials. Suitable cellulose ethers include hydroxyalkyl celluloses and carboxyalkyl
`
`6
`
`935090_1
`
`

`

`celluloses, especially hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), HPMC,
`
`and carboxy methylcellulose (CMC). Suitable acrylic resins include polymers and copolymers
`
`of acrylic acid, methacrylic acid, methyl acrylate and methyl methacrylate. Suitable gums
`
`include heteropolysaccharide and homopolysaccharide gums, e.g., xanthan, tragacanth, acacia,
`
`karaya, alginates, agar, guar, hydroxypropyl guar, carrageenan, and locust bean gums.
`
`The preferred hydrophilic material comprises a heteropolysaccharide such as xanthan
`
`gum and a cross-linking agent capable of cross-linking the heteropolysaccharide, as disclosed in
`
`Baichwal et al. US Patents 4,994,276, 5,128,143 and 5,135,757, the entire disclosures of which
`
`are incorporated herein. The cross-linking agent can be a homopolysaccharide, preferably a
`
`galactomannan gum such as locust bean gum. Preferably, the ratio of heteropolysaccharide to
`
`homopolysaccharide is in the range of about 1:9 to about 9:1, preferably about 1:3 to about 3:1.
`
`In addition to the hydrophilic material, the controlled release delivery system can also
`
`contain an inert pharmaceutical diluent such as a monosaccharide, a disaccharide, a polyhydric
`
`alcohol and mixtures thereof. The ratio of diluent to hydrophilic matrix-forming material is
`
`generally in the range of about 1:3 to about 3:1.
`
`The controlled release delivery system may also contain a cationic cross-linking agent
`
`such as calcium sulfate in an amount sufficient to cross-link the gelling agent and increase the
`
`gel strength, and an inert hydrophobic material such as ethyl cellulose in an amount sufficient to
`
`slow the hydration of the hydrophilic material without disrupting it. Preferably, the controlled
`
`release delivery system is prepared as a pre-manufactured granulation. See Baichwal US Patents
`
`5,455,046, 5,554,387, and 5,512,297, the entire disclosures of which are incorporated herein.
`
`Examples 1-2
`
`EXAMPLES
`
`Two controlled release delivery systems are prepared by dry blending xanthan gum,
`
`locust bean gum, calcium sulfate dehydrate, and dextrose in a high speed mixed/granulator for 3
`
`minutes. A slurry is prepared by mixing ethyl cellulose with alcohol. While running
`
`choppers/impellers, the slurry is added to the dry blended mixture, and granulated for another 3
`
`minutes. The granulation is then dried to a LOD (loss on drying) of less than about 10% by
`
`7
`
`935090_1
`
`

`

`weight. The granulation is then milled using 20 mesh screen. The relative quantities of the
`
`ingredients are listed in the table below.
`
`Table la
`
`Controlled Release Delivery System
`
`Example 1
`
`Excipient
`
`Locust Bean Gum, FCC
`
`Xanthan Gum, NF
`
`Dextrose, USP
`
`Calcium Sulfate Dihydrate, NF
`
`Ethylcellulose, NF
`
`Alcohol, SD3A (Anhydrous)1
`
`Total
`
`25.0
`
`25.0
`
`35.0
`
`10.0
`
`5.0
`
`(10)1
`
`100.0
`
`Example 2
`
`
`30.0
`
`30.0
`
`40.0
`
`0.0
`
`0.0
`
`(20.0)-1
`
`100.0
`
`1. Volatile, removed during processing
`
`Examples 3 to 7
`
`A series of tablets containing different amounts of oxymorphone hydrochloride were
`
`prepared using the controlled release delivery system of Example 1. The quantities of
`
`ingredients per tablet are as listed in the following table.
`
`Table 4
`
`Component
`
`Oxymorphone HCI, USP
`
`Controlled release delivery system
`
`Silicified mmicrocrystalline
`cellulose, N.F.
`Sodium stearyl fumarate, NF
`Total weight
`Opadry (colored)
`Opadry (clear)
`
`Examples 8 and 9
`
`Ex. 3 (cid:9)
`
`Ex. 4 (cid:9)
`
`Ex. 5 Ex. 6 Ex. 7
`
`mg
`
`5
`
`160
`
`20
`
`2
`187
`7.48
`0.94
`
`mg
`
`10
`
`160
`
`20
`
`2
`192
`7.68
`0.96
`
`mg
`
`20
`
`160
`
`20
`
`2
`202
`8.08
`1.01
`
`mg
`
`40
`
`mg
`
`80
`
`160
`
`160
`
`20
`
`20
`
`2
`2
`222
`262
`8.88 10.48
`1.11
`1.31
`
`8
`
`935090_1
`
`

`

`Two batches of tablets were prepared as described above for Examples 1-7, using the
`
`controlled release delivery system of Example 1. One batch was formulated to provide relatively
`
`fast controlled release, the other batch was formulated to provide relatively slow controlled
`
`release. Compositions of the tablets are shown in the following table.
`
`Table 6a
`
`Ingredients
`
`Oxymorphone HCI, USP
`
`Controlled Release Delivery
`
`System
`
`Silicified Microcrystalline
`
`Cellulose, NF
`
`Sodium stearyl fumarate, NF
`
`Coating (color)
`
`Total weight
`
`Example
`
`slow release
`
`mg/tab
`
`Example
`
`fast release
`
`mg/tab
`
`20
`
`360
`
`20
`
`4
`
`12.12
`
`416.12
`
`20
`
`160
`
`20
`
`2
`
`12.12
`
`214.12
`
`The tables of Examples 8 and 9 were tested for in vitro release rate according to USP
`
`Procedure Drug Release USP 24. Results are shown in the following table.
`
`Table 7a
`
`Time (hr)
`
`0.5
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`8
`
`Example 8
`
`Example 9
`
`slow release
`
`fast release
`
`18.8
`
`27.8
`
`40.5
`
`50.2
`
`58.1
`
`64.7
`
`70.2
`
`79.0
`
`21.3
`
`32.3
`
`47.4
`
`58.5
`
`66.9
`
`73.5
`
`78.6
`
`86.0
`
`9
`
`935090_1
`
`

`

`10
`
`12
`
`85.3
`
`89.8
`
`90.6
`
`93.4
`
`Example 10: Clinical Study
`
`A clinical study was conducted to (1) assess the relative bioavailability (rate and extent of
`
`absorption) of oxymorphone CR (20 mg) (fast release formulation of Example 9) compared to
`
`oral solution oxymorphone (10 mg) under fasted conditions, (2) to assess the relative
`
`bioavailability of oxymorphone CR (20 mg) compared to oral solution oxymorphone (10 mg)
`
`under fed conditions, (3) to assess the relative bioavailability of oxymorphone CR (20 mg) fed
`
`compared to oxymorphone CR (20 mg) fasted, (4) to assess the relative bioavailability of oral
`
`solution oxymorphone fed compared to oral solution oxymorphone fasted, and (5) to assess the
`
`relative safety and tolerability of controlled-release oxymorphone (20 mg) under fed and fasted
`
`conditions.
`
`Study Design and Conduct
`
`This study had a single-center, open-label, analytically blinded, randomized, four-way
`
`crossover design. Subjects randomized to Treatment A and Treatment C, as described below,
`
`were in a fasted state following a 10-hour overnight fast. Subjects randomized to Treatment B
`
`and Treatment D, as described below, were in the fed state, having had a high fat meal,
`
`completed ten minutes prior to dosing. There was a 14-day washout interval between the four
`
`dose administrations. The subjects were confined to the clinic during each study period. Subject
`
`assigned to receive Treatment A and Treatment B were discharged from the clinic on Day 3
`
`following the 48-hour procedures, and subjects assigned to receive Treatment C and Treatment D
`
`were discharged from the clinic on Day 2 following the 36-hour procedures. On Day 1 of each
`
`study period the subjects received one of four treatments:
`
`Treatments A and B: oxymorphone CR 20 mg tablets. Subjects randomized to
`
`Treatment A received a single oral dose of one 20 mg oxymorphone CR tablet taken with 240
`
`mL of water after a 10-hour fasting period. Subjects randomized to Treatment B received a
`
`single oral dose of one 20 mg oxymorphone CR tablet taken with 240 mL of water 10 minutes
`
`after a standardized high fat meal.
`
`10
`
`935090_1
`
`(cid:9)
`

`

`Treatments C and D: oxymorphone HC1 solution, USP, 1.5 mg/mL injection 10 mL
`
`vials. Subjects randomized to Treatment C received a single oral dose of 10 mg (6.7 mL)
`
`oxymorphone solution taken with 240 mL of water after a 10-hour fasting period. Subjects
`
`randomized to Treatment D received a single oral dose of 10 mg (6.7mL) oxymorphone solution
`
`taken with 240 mL of water 10 minutes after a standardized high-fat meal.
`
`A total of 28 male subjects were enrolled in the study, and 24 subjects completed the
`
`study. The mean age of the subjects was 27 years (range of 19 through 38 years), the mean
`
`height of the subjects was 69.6 inches (range of 64.0 through 75.0 inches), and the mean weight
`
`of the subjects was 169.0 pounds (range 117.0 through 202.0 pounds). The subjects were not to
`
`consume any alcohol-, caffeine-, or xanthine-containing foods or beverages for 24 hours prior to
`
`receiving study medication for each study period. Subjects were to be nicotine and tobacco free
`
`for at least 6 months prior to enrolling in the study. In addition, over-the-counter medications
`
`were prohibited 7 days prior to dosing and during the study. Prescription medications were not
`
`allowed 14 days prior to dosing and during the study.
`
`The subjects were screened within 14 days prior to study enrollment. The screening
`
`procedure included medical history, physical examination (height, weight, frame size, vital signs,
`
`and ECG), and clinical laboratory tests (hematology, serum chemistry, urinalysis, HIV antibody
`
`screen, Hepatitis B surface antigen screen, Hepatitis C antibody screen, and a screen for
`
`cannabinoids).
`
`During the study, the subjects were to remain in an upright position (sitting or standing)
`
`for 4 hours after the study drug was administered. Water was restricted 2 hours predose to 2
`
`hours postdose. During the study, the subjects were not allowed to engage in any strenuous
`
`activity.
`
`Subjects reported to the clinic on the evening prior to each dosing. The subjects then
`
`observed a 10-hour overnight fast. On Day 1, subjects randomized to Treatment B and
`
`Treatment D received a high-fat breakfast within 30 minutes prior to dosing. A standardized
`
`meal schedule was then initiated with lunch 4 hours postdose, dinner 10 hours postdose, and a
`
`snack 13 hours postdose. On Day 2, a standardized meal was initiated with breakfast at 0815,
`
`11
`
`935090_1
`
`

`

`lunch at 1200, and dinner at 1800. Subjects randomized to Treatment A and Treatment B
`
`received a snack at 2100 on Day 2.
`
`Vital signs (sitting for 5 minutes and consisting of blood pressure, pulse, respiration, and
`
`temperature), and 12-lead ECG were assessed at the —13 hour of each check-in period and at the
`
`completion of each period. A clinical laboratory evaluation (hematology, serum chemistry,
`
`urinalysis) and a brief physical examination were performed at the —13 hour of each check-in
`
`period and at the completion of the each period. Subjects were instructed to inform the study
`
`physician and/or nurses of any adverse events that occurred during the study.
`
`Blood samples (7 mL) were collected during each study period at the 0 hour (predose),
`
`and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, and 48 hours post-dose (19
`
`samples) for subjects randomized to Treatment A and Treatment B. Blood samples (7 mL) were
`
`collected during each study period at the 0 hour (predose), and at 0.25, 0.5, 0.75, 1, 1.25, 1.5,
`
`1.75, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, and 36 hours post-dose (21 samples) for subjects
`
`randomized to Treatment C and Treatment D. A total of 80 blood samples (560 mL) per subject
`
`were drawn during the study for drug analysis. Plasma samples were separated by
`
`centrifugation, and then frozen at —70°C, and kept frozen until assayed.
`
`Analytical Method
`
`An LC/MS/MS method was developed and validated for the determination of
`
`oxymorphone in human EDTA plasma. Samples were spiked with internal standard, d3_
`oxymorphone, and placed on the RapidTrace® for automatic solid phase extraction. Extracts
`
`were dried under nitrogen and reconstituted with acetonitrile before injection onto an
`
`LC/MS/MS. The Perkin Elmer Sciex API III+, or equivalent using a turbo ion spray interface,
`
`was employed in this study. Positive ions were monitored in the MRM mode.
`
`Pharmacokinetic and Statistical Methods
`
`The following pharmacokinetic parameters were computed from the plasma
`
`oxymorphone concentration-time data:
`
`12
`
`935090_1
`
`

`

`AUC(0-t)
`
`AUC(0-inf)
`
`AUC(0-24)
`
`Cmax
`Tmax
`Kel
`
`T1/2e1
`
`Area under the drug concentration-time curve from time zero to the time of
`the last quantifiable concentration (Ct), calculated using linear trapezoidal
`summnation.
`Area under the drug concentration-time curve from time zero to infinity.
`AUC(0-inf) = AUC(0-t) + Ct/Kel, where Kel is the terminal elimination
`rate constant.
`Partial area under the drug concentration-time curve from time zero to 24
`hours.
`Maximum observed drug concentration.
`Time of the observed maximum drug concentration.
`Elimination rate constant based on the linear regression of the terminal
`linear portion of the LN(concentration) time curve.
`Half life, the time required for the concentration to decline by 50%,
`calculated as LN(2)/Kel
`
`Terminal elimination rate constants were computed using linear regression of a minimum
`
`of three time points, at least two of which were consecutive. Kel values for which correlation
`
`coefficients were less than or equal to 0.8 were not reported in the pharmacokinetic parameter
`
`tables or included in the statistical analysis. Thus, T1/2e1, AUC(0-inf), Cl/F, MRT, and LN-
`
`transformed T1/2e1, AUC(0-inf), and Cl/F were also not reported in these cases.
`
`A parametric (normal-theory) general linear model was applied to each of the above
`
`parameters (excluding Tmax and Frel), and the LN-transformed parameters Cmax, AUC(0-24),
`
`AUC(0-t), AUC(0-inf), Cl/F, and Tl/2el. Initially, the analysis of variance (ANOVA) model
`
`included the following factors: treatment, sequence, subject within sequence, period, and
`
`carryover effect. If carryover effect was not significant, it was dropped from the model. The
`
`sequence effect was tested using the subject within sequence mean square, and all other main
`
`effects were tested using the residual error (error mean square). The following treatment
`
`comparisons of relative rate and extent of absorption were made: Treatment B versus Treatment
`
`A, Treatment A versus Treatment C (dose normalized to 20 mg). Treatment B versus Treatment
`
`D (dose normalized to 20 mg), and Treatment D versus Treatment C (dose normalized to 20 mg
`
`for both treatments). The 90% confidence intervals of the ratios of the treatment least squares
`
`parameter means were calculated. Tmax was analyzed using the Wilcoxon Signed Ranks test.
`
`Summary statistics were presented for Frel.
`
`13
`
`935090_1
`
`

`

`Plasma oxymorphone concentrations were listed by subject at each collection time and
`
`summarized using descriptive statistics. Pharmacokinetic parameters were also listed by subject
`
`and summarized using descriptive statistics.
`
`Results
`
`A total of 26 analytical runs were required to process the clinical samples from this study.
`
`Of these 26 analytical runs, 26 were acceptable for oxymorphone. Standard curves for the 26
`
`analkytical runs in EDTA plasma used in this study covered a range of 0.0500 to 20.000 mg/mL
`
`with a limit of quantitation of 0.0500 ng/mL for both compounds. Quality control samples
`
`analyzed with each analytical run had coefficients of variation less than or equal to 14.23% for
`
`oxymorphone.
`
`A total of 28 subjects received at least one treatment. Only subjects who completed all 4
`
`treatments were included in the summary statistics and statistical analysis.
`
`The mean oxymorphone plasma concentration versus time curves for Treatments A, B, C,
`
`and D are presented in Figure 1 (linear scale, with S.D.). Figure 2 (linear scale, without S.D.)
`
`and Figure 3 (semi-log scale).
`
`Individual concentration versus time curves were characterized by multiple peaks which
`
`occurred in the initial 12-hour period following the dose. In addition, a small "bump" in plasma
`
`oxymorphone concentration was generally observed in the 24 to 48 hour post-dose period.
`
`The arithmetic means of the plasma oxymorphone pharmacokinetic parameters and the
`
`statistical for Treatment B versus Treatment A are summarized in table 1.
`
`TABLE 1
`
`Summary of the Pharmacokinetic Parameters of Plasma Oxymorphone for Treatments B and A
`Plasma Oxymorphone (cid:9)
`
`Treatment A (cid:9)
`Treatment B
`
`Pharmacokinetic (cid:9)
`Parameters (cid:9)
`Cmax(ng/mL) (cid:9)
`
`Tmax(hr) (cid:9)
`
`Arithmetic (cid:9)
`Arithmetic (cid:9)
`Mean
`Mean (cid:9)
`Mean (cid:9)
`90% CI (cid:9)
`SD (cid:9)
`SD (cid:9)
`Ratio
`1.7895 0.6531 1.1410 0.4537 125.4-191.0 158.2
`
`5.65 (cid:9)
`
`9.39 (cid:9)
`
`5.57 (cid:9)
`
`7.14
`
`14
`
`935090_1
`
`(cid:9)
`

`

`Auc(0-24)(ng*hr/mL)
`
`AUC(0-0(ng*hr/mL)
`
`AUC(0-inf)(ng*hr/mL)
`
`T 1/2e1(hr)
`
`14.27
`
`19.89
`
`21.29
`
`12.0
`
`4.976
`
`6.408
`
`6.559
`
`3.64
`
`11.64
`
`17.71
`
`19.29
`
`12.3
`
`3.869
`
`8.471
`
`5.028
`
`3.99
`
`110.7-134.0
`
`122.3
`
`100.2-123.6
`
`111.9
`
`105.3-133.9
`
`119.6
`
`57.4-155.2
`
`106.3
`
`Treatment B - 1 x 20 mg oxymorphone CR Tablet, Fed: test
`
`Treatment A = 1 x 20 mC oxymorphone CR Tablet, Fasted: reference
`
`The arithmetic means of the plasma oxymorphone pharmacokinetic parameters and the
`
`statistical comparisons for Treatment A versus Treatment C are summarized in table 2.
`
`TABLE 2
`
`Summary of the Pharmacokinetic Parameters of Plasma Oxymorphone for Treatments A and C
`
`Plasma Oxymorphone (cid:9)
`
`
`
`Treatment A
`
`Treatment C
`
`SD
`
`Arithmetic
`Mean
`2.2635
`0.978
`12.39
`14.53
`18.70
`16.2
`
`SD
`1.0008
`1.14
`4.116
`4.909
`6.618
`11.4
`
`90% CI
`33.4-66.0
`
`82.8-104.6
`107.7-136.3
`80.2-108.4
`32.9-102.1
`
`Mean
`Ratio
`49.7
`
`93.7
`122.0
`94.3
`67.5
`
`Arithmetic
`Pharmacokinetic
`Parameters
`Mean
`0.4537
`1.1410
`Cmax(ng/mL)
`7.14
`5.57
`Tmax(hr)
`11.64
`Auc(0-24)(ng*hr/mL)
`3.869
`8.471
`17.71
`AUC(0-I)(ng*hr/mL
`19.29
`AUC(0-inf)(ng*hr/mL)
`5.028
`3.99
`12.3
`T 1/2e1(hr)
`Treatment A = 1 x 20 mg oxymorphone CR Tablet, Fasted: test
`Treatment C = 10 mg/6.7 mL oxymorphone HCI Oral Solution, Fasted: Dose Normalized to 20 ng: reference.
`
`The arithmetic means of the plasma oxymorphone pharmacokinetic parameters and the
`
`statistical comparisons for Treatment D versus Treatment C are summarized in table 3.
`
`TABLE 3
`
`Summary of the Pharmacokinetic Parameters of Plasma Oxymorphone for Treatments A and C
`Plasma Oxymorphone (cid:9)
`
`Treatment B
`Treatment D
`Arithmetic
`Arithmetic
`Mean
`SD
`Mean
`1.7895
`3.2733 1.3169
`
`Pharmacokinetic
`P