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`Docket No. 1207-R-01
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`OXYMORPHONE CONTROLLED RELEASE FORMULATIONS
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`BACKGROUND OF THE INVENTION
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`[0001] (cid:9)
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`This application relates to provisional patent application serial nos.
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`60/329,445 filed October 15, 2001, 60/329,432 filed October 15, 2001, 60/303,357 filed
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`July 6, 2001, and 60/329,444 filed October 15, 2001.
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`[0002] (cid:9)
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`Pain is the most frequently reported symptom and it is a common clinical
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`problem which confronts the clinician. Many millions of people in the USA suffer from
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`severe pain that, according to numerous recent reports, is chronically undertreated or
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`inappropriately managed. The clinical usefulness of the analgesic properties of opioids
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`has been recognized for centuries, and morphine and its derivatives have been widely
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`employed for analgesia for decades in a variety of clinical pain states.
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`[0003] (cid:9)
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`Oxymorphone HCl (14-hydroxydihydromorphinone hydrochloride) is a
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`semi-synthetic phenanthrene-derivative opioid agonist, widely used in the treatment of
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`acute and chronic pain, with analgesic efficacy comparable to other opioid analgesics.
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`Oxymorphone is currently marketed as an injection (1 mg/ml in 1 ml ampules; 1.5 mg/ml
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`in 1 ml ampules; 1.5 mg/ml in 10 ml multiple dose vials) for intramuscular,
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`subcutaneous, and intravenous administration, and as 5 mg rectal suppositories. At one
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`time, 2 mg, 5 mg and 10 mg oral immediate release (IR) tablet formulations of
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`oxymorphone HC1 were marketed. Oxymorphone HC1 is metabolized principally in the
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`PHDATA 949659_3
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`liver and undergoes conjugation with glucuronic acid and reduction to 6 a- and 13-
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`hydroxy epimers.
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`[0004] (cid:9)
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`An important goal of analgesic therapy is to achieve continuous relief of
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`chronic pain. Regular administration of an analgesic is generally required to ensure that
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`the next dose is given before the effects of the previous dose have worn off Compliance
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`with opioids increases as the required dosing frequency decreases. Non-compliance
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`results in suboptimal pain control and poor quality of life outcomes. (Ferrell B et al.
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`Effects of controlled-release morphine on quality of life for cancer pain. Oncol Nur
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`Forum 1989;4:521-26). Scheduled, rather than "as needed" administration of opioids is
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`currently recommended in guidelines for their use in chronic non-malignant pain.
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`Unfortunately, evidence from prior clinical trials and clinical experience suggests that the
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`short duration of action of immediate release oxymorphone would necessitate
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`administration every 4-6 hours in order to maintain optimal levels of analgesia in chronic
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`pain. A controlled release formulation which would allow less frequent dosing of
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`oxymorphone would be useful in pain management.
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`[0005] (cid:9)
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`For instance, a controlled release formulation of morphine has been
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`demonstrated to provide patients fewer interruptions in sleep, reduced dependence on
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`caregivers, improved compliance, enhanced quality of life outcomes, and increased
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`control over the management of pain. In addition, the controlled release formulation of
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`morphine was reported to provide more constant plasma concentration and clinical
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`effects, less frequent peak to trough fluctuations, reduced dosing frequency, and possibly
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`fewer side effects. (Thirlwell MP et al., Pharmacokineties and clinical efficacy of oral
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`morphine solution and controlled-release morphine tablets in cancer patients. Cancer
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`1989; 63:2275-83; Goughnour BR et al., Analgesic response to single and multiple doses
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`of controlled-release morphine tablets and morphine oral solution in cancer patients.
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`Cancer 1989; 63:2294-97; Ferrell B. et al., Effects of controlled-release morphine on
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`quality of life for cancer pain. Oncol. Nur. Forum 1989; 4:521-26.
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`[0006] (cid:9)
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`There are two factors associated with the metabolism of some drugs that
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`may present problems for their use in controlled release systems. One is the ability of the
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`drug to induce or inhibit enzyme synthesis, which may result in a fluctuating drug blood
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`plasma level with chronic dosing. The other is a fluctuating drug blood level due to
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`intestinal (or other tissue) metabolism or through a hepatic first-pass effect.
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`[0007] (cid:9)
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`Oxymorphone is metabolized principally in the liver, resulting in an oral
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`bioavailability of about 10%. Evidence from clinical experience suggests that the short
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`duration of action of immediate release oxymorphone necessitates a four hour dosing
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`schedule to maintain optimal levels of analgesia. It would be useful to clinicians and
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`patients alike to have controlled release dosage forms of oxymorphone to use to treat pain
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`and a method of treating pain using the dosage forms.
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`SUMMARY OF THE INVENTION
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`[0008] (cid:9)
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`The present invention provides methods for relieving pain by administering
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`a controlled release pharmaceutical tablet containing oxymorphone which produces at
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`PHDATA 949659_3
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`least a predetermined minimum blood plasma level for at least 12 hours after dosing, as
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`well as tablets that produce the sustained pain relief over this time period.
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`BRIEF DESCRIPTION OF THE FIGURES
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`[0009] Figure 1 is a pharmacokinetic profile for 6-hydroxy oxymorphone with PID
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`scores.
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`[0010] Figure 2 is a pharmacokinetic profile for oxymorphone with PID scores.
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`[0011] Figure 3 is a pharmacokinetic profile for 6-hydroxy oxymorphone with categorical
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`pain scores.
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`[0012] Figure 4 is a pharmacokinetic profile for oxymorphone with categorical pain
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`scores.
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`[0013] Figure 5 is a graph of the mean blood plasma concentration of oxymorphone
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`versus time for clinical study 1.
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`[0014] Figure 6 is a graph of the mean blood plasma concentration of oxymorphone
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`versus time for clinical study 2.
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`[0015] Figure 7 is a graph of the mean blood plasma concentration of oxymorphone
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`versus time for clinical study 3.
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`[0016] Figure 8 is a graph of the mean blood plasma concentration of 6-hydroxy
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`oxymorphone versus time for clinical study 3.
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`[0017] Figure 9 is a graph of the mean blood plasma concentration of oxymorphone for
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`immediate and controlled release tablets from a single dose study.
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`[0018] Figure 10 is a graph of the mean blood plasma concentration of oxymorphone for
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`immediate and controlled release tablets from a steady state study.
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`DETAILED DESCRIPTION OF THE INVENTION
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`[0019] (cid:9)
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`The present invention provides methods for alleviating pain for 12 to 24
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`hours using a single dose of a pharmaceutical composition by producing a blood plasma
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`level of oxymorphone and/or 6-OH oxymorphone of at least a minimum value for at least
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`12 hours or more. As used herein, the terms "6-OH oxymorphone" and "6-hydroxy
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`oxymorphone" are interchangeable and refer to the analog of oxymorphone having an
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`alcohol (hydroxy) moiety that replaces the carboxy moiety found on oxymorphone at the
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`6-position.
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`100201 (cid:9)
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`To overcome the difficulties associated with a 4-6 hourly dosing frequency
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`of oxymorphone, this invention provides an oxymorphone controlled release oral solid
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`dosage form, comprising a therapeutically effective amount of oxymorphone or a
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`pharmaceutically acceptable salt of oxymorphone. It has been found that the decreased
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`rate of release of oxymorphone from the oral controlled release formulation of this
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`invention does not substantially decrease the bioavailability of the drug as compared to
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`the same dose of a solution of oxymorphone administered orally. The bioavailability is
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`sufficiently high and the release rate is such that a sufficient plasma level of
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`oxymorphone and/or 6-011 oxymorphone is maintained to allow the controlled release
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`dosage to be used to treat patients suffering moderate to severe pain with once or twice
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`daily dosing. The dosing form of the present invention can also be used with thrice daily
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`dosing.
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`[00211 (cid:9)
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`It is critical when considering the present invention that the difference
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`between a controlled release tablet and an immediate release formulation be fully
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`understood. In classical terms, an immediate release formulation releases at least 80% of
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`its active pharmaceutical ingredient within 30 minutes. With reference to the present
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`invention, the definition of an immediate release formulation will be broadened further to
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`include a formulation which releases more than about 80% of its active pharmaceutical
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`ingredient within 60 minutes in a standard USP Paddle Method dissolution test at 50 rpm
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`in 500 ml media having a pH of between 1.2 and 6.8 at 37°C. "Controlled release"
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`formulations, as referred to herein, will then encompass any formulations which release
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`no more than about 80% of their active pharmaceutical ingredients within 60 minutes
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`under the same conditions.
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`[00221 (cid:9)
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`The controlled release dosage form of this invention exhibits a dissolution
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`rate in vitro, when measured by USP Paddle Method at 50 rpm in 500 ml media having a
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`pH between 1.2 and 6.8 at 37°C, of about 15% to about 50% by weight oxymorphone
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`released after 1 hour, about 45% to about 80% by weight oxymorphone released after 4
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`hours, and at least about 80% by weight oxymorphone released after 10 hours.
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`6
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`[00231 (cid:9)
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`When administered orally to humans, an effective controlled release dosage
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`form of oxymorphone should exhibit the following in vivo characteristics: (a) peak
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`plasma level of oxymorphone occurs within about 1 to about 8 hours after administration;
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`(b) peak plasma level of 6-OH oxymorphone occurs within about 1 to about 8 hours after
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`administration; (c) duration of analgesic effect is through about 8 to about 24 hours after
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`administration; (d) relative oxymorphone bioavailability is in the range of about 0.5 to
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`about 1.5 compared to an orally-administered aqueous solution of oxymorphone; and (e)
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`the ratio of the area under the curve of blood plasma level vs. time for 6-OH
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`oxymorphone compared to oxymorphone is in the range of about 0.5 to about 1.5. Of
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`course, there is variation of these parameters among subjects, depending on the size and
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`weight of the individual subject, the subject's age, individual metabolism differences, and
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`other factors. Indeed, the parameters may vary in an individual from day to day.
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`Accordingly, the parameters set forth above are intended to be mean values from a
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`sufficiently large study so as to minimize the effect of individual variation in arriving at
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`the values. A convenient method for arriving at such values is by conducting a study in
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`accordance with standard FDA procedures such as those employed in producing results
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`for use in a new drug application (or abbreviated new drug application) before the FDA.
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`Any reference to mean values herein, in conjunction with desired results, refer to results
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`from such a study, or some comparable study. Reference to mean values reported herein
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`for studies actually conducted are arrived at using standard statistical methods as would
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`be employed by one skilled in the art of pharmaceutical formulation and testing for
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`regulatory approval.
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`[0024] (cid:9)
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`In one specific embodiment of the controlled release matrix form of the
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`invention, the oxymorphone or salt of oxymorphone is dispersed in a controlled release
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`delivery system that comprises a hydrophilic material which, upon exposure to
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`gastrointestinal fluid, forms a gel matrix that releases oxymorphone at a controlled rate.
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`The rate of release of oxymorphone from the matrix depends on the drug's partition
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`coefficient between components of the matrix and the aqueous phase within the
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`gastrointestinal tract. In a preferred form of this embodiment, the hydrophilic material of
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`the controlled release delivery system comprises a mixture of a heteropolysaccharide
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`gum and an agent capable of cross-linking the heteropolysaccharide in the presence of
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`gastrointestinal fluid. The controlled release delivery system may also comprise a water-
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`soluble pharmaceutical diluent mixed with the hydrophilic material. Preferably, the
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`cross-linking agent is a homopolysaccharide gum and the inert pharmaceutical diluent is
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`a monosaccharide, a disaccharide, or a polyhydric alcohol, or a mixture thereof.
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`[0025] (cid:9)
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`In a specific preferred embodiment, the appropriate blood plasma levels of
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`oxymorphone and 6-hydroxy oxymorphone are achieved using oxymorphone in the form
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`of oxymorphone hydrochloride, wherein the weight ratio of heteropolysaccharide to
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`homopolysaccharide is in the range of about 1:3 to about 3:1, the weight ratio of
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`heteropolysaccharide to diluent is in the range of about 1:8 to about 8:1, and the weight
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`ratio of heteropolysaccharide to oxymorphone hydrochloride is in the range of about 10:1
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`to about 1:10. A preferred heteropolysaccharide is xanthan gum and a preferred
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`homopolysaccharide is locust bean gum. The dosage form also comprises a cationic
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`cross-linking agent and a hydrophobic polymer. In the preferred embodiment, the dosage
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`form is a tablet containing about 5 mg to about 80 mg of oxymorphone hydrochloride. In
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`a most preferred embodiment, the tablet contains about 20 mg oxymorphone
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`hydrochloride .
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`[0026] (cid:9)
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`The invention includes a method which comprises achieving appropriate
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`blood plasma levels of drug while providing extended pain relief by administering one to
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`three times per day to a patient suffering moderate to severe, acute or chronic pain, an
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`oxymorphone controlled release oral solid dosage form of the invention in an amount
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`sufficient to alleviate the pain for a period of about 8 hours to about 24 hours. This type
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`and intensity of pain is often associated with cancer, autoimmune diseases, infections,
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`surgical and accidental traumas and osteoarthritis.
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`[0027] (cid:9)
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`The invention also includes a method of making an oxymorphone
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`controlled release oral solid dosage form of the invention which comprises mixing
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`particles of oxymorphone or a pharmaceutically acceptable salt of oxymorphone with
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`granules comprising the controlled release delivery system, preferably followed by
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`directly compressing the mixture to form tablets.
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`[0028] (cid:9)
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`Pharmaceutically acceptable salts of oxymorphone which can be used in
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`this invention include salts with the inorganic and organic acids which are commonly
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`used to produce nontoxic salts of medicinal agents. Illustrative examples would be those
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`salts formed by mixing oxymorphone with hydrochloric, sulfuric, nitric, phosphoric,
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`phosphorous, hydrobromic, maleric, malic, ascorbic, citric or tartaric, pamoic, lauric,
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`stearic, palmitic, oleic, myristic, lauryl sulfuric, naphthylenesulfonic, linoleic or linolenic
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`acid, and the like. The hydrochloride salt is preferred.
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`[0029] (cid:9)
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`It has now been found that 6-0I1 oxymorphonc, which is one of the
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`metabolites of oxymorphone may play a role in alleviating pain. When oxymorphone is
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`ingested, part of the dosage gets into the bloodstream to provide pain relief, while another
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`part is metabolized to 6-OH oxymorphonc. This metabolite then enters the bloodstream
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`to provide further pain relief. Thus it is believed that both the oxymorphone and 6-
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`hydroxyoxymorphone levels are important to pain relief.
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`[0030] (cid:9)
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`The effectiveness of oxymorphone and 6-hydroxyoxymorphone at relieving
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`pain and the pharmacokinetics of a single dose of oxymorphone were studied. The blood
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`plasma levels of both oxymorphone and 6-hydroxyoxymorphone were measured in
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`patients after a single dose of oxymorphone was administered. Similarly, the pain levels
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`in patients were measured after a single administration of oxymorphone to determine the
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`effective duration of pain relief from a single dose. Figures 1-2 show the results of these
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`tests, comparing pain levels to oxymorphone and 6-hydroxy oxymorphone levels.
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`[0031] (cid:9)
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`For these tests, pain was measured using a Visual Analog Scale (VAS) or a
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`Categorical Scale. The VAS scales consisted of a horizontal line, 100 mm in length. The
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`left-hand end of the scale (0 mm) was marked with the descriptor "No Pain" and the
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`right-hand end of the scale (100 mm) was marked with the descriptor "Extreme Pain".
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`Patients indicated their level of pain by making a vertical mark on the line. The VAS
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`score was equal to the distance (in mm) from the left-hand end of the scale to the
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`patient's mark. For the categorical scale, patients completed the following statement,
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`"My pain at this time is" using the scale None = 0, Mild = 1, Moderate = 2, or Severe = 3.
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`[0032] (cid:9)
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`As can be seen from these figures, there is a correlation between pain relief
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`and both oxymorphone and 6-hydroxyoxymorphone levels. As the blood plasma levels
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`of oxymorphone and 6-hydroxyoxymorphone increase, pain decreases (and pain intensity
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`difference and pain relief increases). Thus, to the patient, it is the level of oxymorphone
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`and 6-hydroxyoxymorphone in the blood plasma which is most important. Further it is
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`these levels which dictate the efficacy of the dosage form. A dosage form which
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`maintains a sufficiently high level of oxymorphone or 6-hydroxyoxymorphone for a
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`longer period need not be administered frequently. Such a result is accomplished by
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`embodiments of the present invention.
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`[0033] (cid:9)
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`The oxymorphone controlled release oral solid dosage form of this
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`invention can be made using any of several different techniques for producing controlled
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`release oral solid dosage forms of opioid analgesics.
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`[0034J (cid:9)
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`In one embodiment, a core comprising oxymorphone or oxymorphone salt
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`is coated with a controlled release film which comprises a water insoluble material and
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`which upon exposure to gastrointestinal fluid releases oxymorphone from the core at a
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`controlled rate. In a second embodiment, the oxymorphone or oxymorphone salt is
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`dispersed in a controlled release delivery system that comprises a hydrophilic material
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`which upon exposure to gastrointestinal fluid forms a gel matrix that releases
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`oxymorphone at a controlled rate. A third embodiment is a combination of the first two:
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`a controlled release matrix coated with a controlled release film. In a fourth embodiment
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`the oxymorphone is incorporated into an osmotic pump. In any of these embodiments,
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`the dosage form can be a tablet, a plurality of granules in a capsule, or other suitable
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`form, and can contain lubricants, colorants, diluents, and other conventional ingredients.
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`Osmotic Pump
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`[0035] (cid:9)
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`An osmotic pump comprises a shell defining an interior compai (cid:9) tment and
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`having an outlet passing through the shell. The interior compartment contains the active
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`pharmaceutical ingredient. Generally the active pharmaceutical ingredient is mixed with
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`excipients or other compositions such as a polyalkylene. The shell is generally made, at
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`least in part, from a material (such as cellulose acetate) permeable to the liquid of the
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`environment where the pump will be used, usually stomach acid. Once ingested, the
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`pump operates when liquid diffuses through the shell of the pump. The liquid dissolves
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`the composition to produce a saturated situation. As more liquid diffuses into the pump,
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`the saturated solution containing the pharmaceutical is expelled from the pump through
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`the outlet. This produces a nearly constant release of active ingredient, in the present
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`case, oxymorphone.
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`Controlled Release Coating
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`11!
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`[0036] (cid:9)
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`In this embodiment, a core comprising oxymorphone or oxymorphone salt
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`is coated with a controlled release film which comprises a water insoluble material. The
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`film can be applied by spraying an aqueous dispersion of the water insoluble material
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`onto the core. Suitable water insoluble materials include alkyl celluloses, acrylic
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`polymers, waxes (alone or in admixture with fatty alcohols), shellac and zein. The
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`aqueous dispersions of alkyl celluloses and acrylic polymers preferably contain a
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`plasticizer such as triethyl citrate, dibutyl phthalate, propylene glycol, and polyethylene
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`glycol. The film coat can contain a water-soluble material such as polyvinylpyrrolidone
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`(PVP) or hydroxypropylmethylcellulose (HPMC).
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`[0037] (cid:9)
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`The core can be a granule made, for example, by wet granulation of mixed
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`powders of oxymorphone or oxymorphone salt and a binding agent such as IIPMC, or by
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`coating an inert bead with oxymorphone or oxymorphone salt and a binding agent such as
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`HPMC, or by spheronising mixed powders of oxymorphone or oxymorphone salt and a
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`spheronising agent such as microcrystalline cellulose. The core can be a tablet made by
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`compressing such granules or by compressing a powder comprising oxymorphone or
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`oxymorphone salt.
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`10038] (cid:9)
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`The in vitro and in vivo release characteristics of this controlled release
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`dosage form can be modified by using mixtures of different water insoluble and water
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`soluble materials, using different plasticizers, varying the thickness of the controlled
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`release film, including release-modifying agents in the coating, or by providing
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`passageways through the coating.
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`Controlled Release Matrix
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`[0039] (cid:9)
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`It is important in the present invention that appropriate blood plasma levels
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`of oxymorphonc and 6 hydroxy oxymorphone be achieved and maintained for sufficient
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`time to provide pain relief to a patient for a period of 12 to 24 hours. The preferred
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`composition for achieving and maintaining the proper blood plasma levels is a controlled-
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`release matrix. In this embodiment, the oxymorphone or oxymorphone salt is dispersed
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`in a controlled release delivery system that comprises a hydrophilic material (gelling
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`agent) which upon exposure to gastrointestinal fluid forms a gel matrix that releases
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`oxymorphone at a controlled rate. Such hydrophilic materials include gums, cellulose
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`ethers, acrylic resins, and protein-derived materials. Suitable cellulose ethers include
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`hydroxyalkyl celluloses and carboxyalkyl celluloses, especially hydroxyethyl cellulose
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`(HEC), hydroxypropyl cellulose (HPC), HPMC, and carboxy methylcellulose (CMC).
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`Suitable acrylic resins include polymers and copolymers of acrylic acid, methacrylic acid,
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`methyl acrylate and methyl methacrylate. Suitable gums include heteropolysaccharide
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`and homopolysaccharide gums, e.g., xanthan, tragacanth, acacia, karaya, alginates, agar,
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`guar, hydroxypropyl guar, carrageenan, and locust bean gums.
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`[0040] (cid:9)
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`Preferably, the controlled release tablet of the present invention is formed
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`from (I) a hydrophilic material comprising (a) a heteropolysaccharide; or (b) a
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`heteropolysaccharide and a cross-linking agent capable of cross-linking said
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`heteropolysaccharide; or (c) a mixture of (a), (b) and a polysaccharide gum; and (II) an
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`inert pharmaceutical filler comprising up to about 80% by weight of the tablet; and (III)
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`oxymorphone.
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`[0041] (cid:9)
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`The term "heteropolysaccharide" as used herein is defined as a water-
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`soluble polysaccharide containing two or more kinds of sugar units, the
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`heteropolysaccharide having a branched or helical configuration, and having excellent
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`water-wicking properties and immense thickening properties.
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`[0042] (cid:9)
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`A preferred heteropolysaccharide is xanthan gum, which is a high
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`molecular weight (>106) heteropolysaccharide. Other preferred heteropolysaccharides
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`include derivatives of xanthan gum, such as deacylated xanthan gum, the carboxymethyl
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`ether, and the propylene glycol ester.
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`[0043] (cid:9)
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`The cross linking agents used in the controlled release embodiment of the
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`present invention which are capable of cross-linking with the heteropolysaccharide
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`include homopolysaccharide gums such as the galactomannans, i.e., polysaccharides
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`which are composed solely of mannose and galactose. Galactomannans which have
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`higher proportions of unsubstituted mannose regions have been found to achieve more
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`interaction with the heteropolysaccharide. Locust bean gum, which has a higher ratio of
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`mannose to the galactose, is especially preferred as compared to other galactomannans
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`such as guar and hydroxypropyl guar.
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`[0044] (cid:9)
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`Preferably, the ratio of heteropolysaccharide to homopolysaccharide is in
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`the range of about 1:9 to about 9:1, preferably about 1:3 to about 3:1. Most preferably,
`
`15
`
`PI-IDATA 949659_3
`
`(cid:9)
`
`
`the ratio of xanthan gum to polysaccharide material (i.e., locust bean gum, etc.) is
`
`preferably about 1:1.
`
`[0045] (cid:9)
`
`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.
`
`[0046] (cid:9)
`
`The controlled release properties of the controlled release embodiment of
`
`the present invention may be optimized when the ratio of heteropolysaccharidc gum to
`
`homopolysaccharide material is about 1:1, although heteropolysaccharide gum in an
`
`amount of from about 20 to about 80% or more by weight of the heterodisperse
`
`polysaccharide material provides an acceptable slow release product. The combination of
`
`any homopolysaccharide gums known to produce a synergistic effect when exposed to
`
`aqueous solutions may be used in accordance with the present invention. It is also
`
`possible that the type of synergism which is present with regard to the gum combination
`
`of the present invention could also occur between two homogeneous or two
`
`heteropolysaccharides. Other acceptable gelling agents which may be used in the present
`
`invention include those gelling agents well-known in the art. Examples include vegetable
`
`gums such as alginates, carrageenan, pectin, guar gum, xanthan gum, modified starch,
`
`hydroxypropylmethylcellulose, methylcellulose, and other cellulosic materials such as
`
`sodium carboxymethylcellulose and hydroxypropyl cellulose. This list is not meant to be
`
`exclusive.
`
`16
`
`PHDATA 949659_3
`
`(cid:9)
`
`
`100471 (cid:9)
`
`The combination of xanthan gum with locust bean gum with or without the
`
`other homopolysaccharide gums is an especially preferred gelling agent. The chemistry
`
`of certain of the ingredients comprising the excipients of the present invention such as
`
`xanthan gum is such that the excipients are considered to be self-buffering agents which
`
`are substantially insensitive to the solubility of the medicament and likewise insensitive
`
`to the pH changes along the length of the gastrointestinal tract.
`
`100481 (cid:9)
`
`The inert filler of the sustained release excipient preferably comprises a
`
`pharmaceutically acceptable saccharide, including a monosaccharide, a disaccharide, or a
`
`polyhydric alcohol, and/or mixtures of any of the foregoing. Examples of suitable inert
`
`pharmaceutical fillers include sucrose, dextrose, lactose, microcrystalline cellulose,
`
`fructose, xylitol, sorbitol, mixtures thereof and the like. However, it is preferred that a
`
`soluble pharmaceutical filler such as lactose, dextrose, sucrose, or mixtures thereof be
`
`used.
`
`10049] (cid:9)
`
`The cationic cross-linking agent which is optionally used in conjunction
`
`with the controlled release embodiment of the present invention may be monovalent or
`
`multivalent metal cations. The preferred salts are the inorganic salts, including various
`
`alkali metal and/or alkaline earth metal sulfates, chlorides, borates, bromides, citrates,
`
`acetates, lactates, etc. Specific examples of suitable cationic cross-linking agents include
`
`calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride,
`
`tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium
`
`bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate,
`
`17
`
`PHDATA 9496593
`
`(cid:9)
`
`
`calcium lactate, magnesium sulfate and sodium fluoride. Multivalent metal cations may
`
`also be utilized. However, the preferred cationic cross-linking agents are bivalent.
`
`Particularly preferred salts are calcium sulfate and sodium chloride. The cationic cross-
`
`linking agents of the present invention are added in an amount effective to obtain a
`
`desirable increased gel strength due to the cross-linking of the gelling agent (e.g., the
`
`heteropolysaccharide and homopolysaccharide gums). In preferred embodiments, the
`
`cationic cross-linking agent is included in the sustained release excipicnt of the present
`
`invention in an amount from about 1 to about 20% by weight of the sustained release
`
`excipient, and in an amount about 0.5% to about 16% by weight of the final dosage form.
`
`10050] (cid:9)
`
`In the controlled release embodiments of the present invention, the
`
`sustained release excipient comprises from about 10 to about 99% by weight of a gelling
`
`agent comprising a heteropolysaccharide gum and a homopolysaccharide gum, from
`
`about 1 to about 20% by weight of a cationic crosslinking agent, and from about 0 to
`
`about 89% by weight of an inert pharmaceutical diluent. In other embodiments, the
`
`sustained release excipient comprises from about 10 to about 75% gelling agent, from
`
`about 2 to about 15% cationic crosslinking agent, and from about 30 to about 75% inert
`
`diluent. In yet other embodiments, the sustained release excipient comprises from about
`
`30 to about 75% gelling agent, from about 5 to about 10% cationic cross-linking agent,
`
`and from about 15 to about 65% inert diluent.
`
`[0051] (cid:9)
`
`The sustained release excipient used in this embodiment of the present
`
`invention (with or without the optional cationic cross-linking agent) may be further
`
`18
`
`PHDATA 949659_3
`
`(cid:9)
`
`
`11:!! .;11, '1;1111.,11 (cid:9)
`
`iril (cid:9)
`
`iT.!!
`
`modified by incorporation of a hydrophobic material which slows the hydration of the
`
`gums without disrupting the hydrophilic matrix. This is accomplished in preferred
`
`embodiments of the present invention by granulating the sustained release excipient with
`
`the solution or dispersion of a hydrophobic material prior to the incorporation of the
`
`medicament. The hydrophobic polymer may be selected from an alkylcellulose such as
`
`ethylcellulose, other hydrophobic cellulosic materials, polymers or copolymers derived
`
`from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters,
`
`zein, waxes, shellac, hydrogenated vegetable oils, and any other pharmaceutically
`
`acceptable hydrophobic material known to those skilled in the art. The amount of
`
`hydrophobic material incorporated into the sustained release excipient is that which is
`
`effective to slow the hydration of the gums without disrupting the hydrophilic matrix
`
`formed upon exposure to an environmental fluid. In certain preferred embodiments of the
`
`present invention, the hydrophobic material is included in the sustained release excipient
`
`in an amount from about 1 to about 20% by weight. The solvent for the hydrophobic
`
`material may be an aqueous or organic solvent, or mixtures thereof.
`
`[00521 (cid:9)
`
`Examples of commercially available alkylcelluloses are Aquacoat coating
`
`(aqueous dispersion of ethylcellulose available from FMC of Philadelphia, PA) and
`
`Surelease coating (aqueous dispersion of ethylcellulose available from Colorcon of West
`
`Point, PA). Examples of commercially available acrylic polymers suitable for use as the
`
`hydrophobic material include Eudragit RS and RL polymers (copolymers of acrylic and
`
`19
`
`PH DATA 949659_3
`
`(cid:9)
`
`
`Itn
`tr—b —11„
`
`methacrylic acid esters having a low content (e.g., 1:20 or 1:40) of quaternary ammonium
`
`compounds av