OXYMORPHONE CONTROLLED RELEASE FORMULATIONS
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`RELATED APPLICATIONS
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`[0001]
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`This application is a continuation of U.S. Patent Application Serial No.
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`10/190,192 filed July 3, 2002 and claims priority to U.S. Provisional Patent Applications Serial
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`Nos. 60/329,445 filed October 15, 2001, 60/329,432 filed Oct. 15, 2001, 60/303,357 filed July 6,
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`2001, and 60/329,444 filed October 15, 2001, which are incorporated herein by reference to the
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`extent permitted by law.
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`BACKGROUND OF THE INVENTION
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`[0002]
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`Pain is the most frequently reported symptom and it is a common clinical problem
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`which confronts the clinician. Many millions of people in the USA suffer from severe pain that,
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`according to numerous recent reports, is chronically undertreated or inappropriately managed.
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`The clinical usefulness of the analgesic properties of opioids has been recognized for centuries,
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`and morphine and its derivatives have been widely employed for analgesia for decades in a
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`variety of clinical pain states.
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`[0003]
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`Oxymorphone HCl (14-hydroxydihydromorphinone hydrochloride) is a semi-
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`synthetic phenanthrene-derivative opioid agonist, widely used in the treatment of acute and
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`chronic pain, with analgesic efficacy comparable to other opioid analgesics. Oxymorphone is
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`currently marketed as an injection (1 mg/ml in 1 ml ampules; 1.5 mg/ml in 1 ml ampules; 1.5
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`mg/ml in 10 ml multiple dose vials) for intramuscular, subcutaneous, and intravenous
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`administration, and as 5 mg rectal suppositories. At one time, 2 mg, 5 mg and 10 mg oral
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`immediate release (IR) tablet formulations of oxymorphone HCl were marketed. Oxymorphone
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`HCl is metabolized principally in the liver and undergoes conjugation with glucuronic acid and
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`reduction to 6-alpha- and beta-hydroxy epimers.
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`[0004]
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`An important goal of analgesic therapy is to achieve continuous relief of chronic
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`pain. Regular administration of an analgesic is generally required to ensure that the next dose is
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`given before the effects of the previous dose have worn off. Compliance with opioids increases
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`as the required dosing frequency decreases. Non-compliance results in suboptimal pain control
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`and poor quality oflife outcomes. (Ferrell B et al. Effects of controlled-release morphine on
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`quality oflife for cancer pain. Oneal. Nur. Forum 1989;4:521-26). Scheduled, rather than "as
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`needed" administration of opioids is currently recommended in guidelines for their use in chronic
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`non-malignant pain. Unfortunately, evidence from prior clinical trials and clinical experience
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`suggests that the 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 pain. A
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`controlled release formulation which would allow less frequent dosing of oxymorphone would
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`be useful in pain management.
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`[0005]
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`For instance, a controlled release formulation of morphine has been demonstrated
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`to provide patients fewer interruptions in sleep, reduced dependence on caregivers, improved
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`compliance, enhanced quality of life outcomes, and increased control over the management of
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`pain. In addition, the controlled release formulation of morphine was reported to provide more
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`constant plasma concentration and clinical effects, less frequent peak to trough fluctuations,
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`reduced dosing frequency, and possibly fewer side effects. (Thirlwell M P et al.,
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`Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release
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`morphine tablets in cancer patients. Cancer 1989; 63:2275-83; Goughnour B Ret al., Analgesic
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`response to single and multiple doses of controlled-release morphine tablets and morphine oral
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`CHDB04 13321951.1 29-Jun-06 11:56
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`solution in cancer patients. Cancer 1989; 63:2294-97; Ferrell B. et al., Effects of controlled(cid:173)
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`release morphine on quality of life for cancer pain. Oneal. Nur. Forum 1989; 4:521-26.
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`[0006]
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`There are two factors associated with the metabolism of some drugs that may
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`present problems for their use in controlled release systems. One is the ability of the drug to
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`induce or inhibit enzyme synthesis, which may result in a fluctuating drug blood plasma level
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`with chronic dosing. The other is a fluctuating drug blood level due to intestinal (or other tissue)
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`metabolism or through a hepatic first-pass effect.
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`[0007]
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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 duration
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`of action of immediate release oxymorphone necessitates a four hour dosing schedule to
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`maintain optimal levels of analgesia. It would be useful to clinicians and patients alike to have
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`controlled release dosage forms of oxymorphone to use to treat pain and a method of treating
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`pain using the dosage forms.
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`SUMMARY OF THE INVENTION
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`[0008]
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`The present invention provides methods for relieving pain by administering a
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`controlled release pharmaceutical tablet containing oxymorphone which produces at least a
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`predetermined minimum blood plasma level for at least 12 hours after dosing, as well as tablets
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`that produce the sustained pain relief over this time period.
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`BRIEF DESCRIPTION OF THE FIGURES
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`[0009]
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`FIG. 1 is a pharmacokinetic profile for 6-hydroxy oxymorphone with PID scores.
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`[0010]
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`FIG. 2 is a pharmacokinetic profile for oxymorphone with PID scores.
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`[0011]
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`FIG. 3 is a pharmacokinetic profile for 6-hydroxy oxymorphone with categorical
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`pam scores.
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`[0012]
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`FIG. 4 is a pharmacokinetic profile for oxymorphone with categorical pain scores.
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`[0013]
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`FIG. 5 is a graph of the mean blood plasma concentration of oxymorphone versus
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`time for clinical study 1.
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`[0014]
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`FIG. 6 is a graph of the mean blood plasma concentration of oxymorphone versus
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`time for clinical study 2.
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`[0015]
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`FIG. 7 is a graph of the mean blood plasma concentration of oxymorphone versus
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`time for clinical study 3.
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`[0016]
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`FIG. 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]
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`FIG. 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]
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`FIG. 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]
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`The present invention provides methods for alleviating pain for 12 to 24 hours
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`using a single dose of a pharmaceutical composition by producing a blood plasma level of
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`oxymorphone and/or 6-0H oxymorphone of at least a minimum value for at least 12 hours or
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`more. As used herein, the terms "6-0H oxymorphone" and "6-hydroxy oxymorphone" are
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`interchangeable and refer to the analog of oxymorphone having an alcohol (hydroxy) moiety that
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`replaces the carboxy moiety found on oxymorphone at the 6-position.
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`[0020]
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`To overcome the difficulties associated with a 4-6 hourly dosing frequency of
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`oxymorphone, this invention provides an oxymorphone controlled release oral solid dosage
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`form, comprising a therapeutically effective amount of oxymorphone or a pharmaceutically
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`acceptable salt of oxymorphone. It has been found that the decreased rate of release of
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`oxymorphone from the oral controlled release formulation of this invention does not
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`substantially decrease the bioavailability ofthe drug as compared to the same dose of a solution
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`of oxymorphone administered orally. The bioavailability is sufficiently high and the release rate
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`is such that a sufficient plasma level of oxymorphone and/or 6-0H oxymorphone is maintained
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`to allow the controlled release dosage to be used to treat patients suffering moderate to severe
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`pain with once or twice daily dosing. The dosing form of the present invention can also be used
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`with thrice daily dosing.
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`[0021]
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`It is critical when considering the present invention that the difference between a
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`controlled release tablet and an immediate release formulation be fully understood. In classical
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`terms, an immediate release formulation releases at least 80% of its active pharmaceutical
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`ingredient within 30 minutes. With reference to the present invention, the definition of an
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`immediate release formulation will be broadened further to include a formulation which releases
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`more than about 80% of its active pharmaceutical ingredient within 60 minutes in a standard
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`USP Paddle Method dissolution test at 50 rpm in 500 ml media having a pH of between 1.2 and
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`6.8 at 37 °C. "Controlled release" formulations, as referred to herein, will then encompass any
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`formulations which release no more than about 80% of their active pharmaceutical ingredients
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`within 60 minutes under the same conditions.
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`[0022]
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`The controlled release dosage form of this invention exhibits a dissolution rate in
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`vitro, when measured by USP Paddle Method at 50 rpm in 500 ml media having a pH between
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`1.2 and 6.8 at 37 °C, of about 15% to about 50% by weight oxymorphone released after 1 hour,
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`about 45% to about 80% by weight oxymorphone released after 4 hours, and at least about 80%
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`by weight oxymorphone released after 10 hours.
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`[0023]
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`When administered orally to humans, an effective controlled release dosage form
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`of oxymorphone should exhibit the following in vivo characteristics: (a) peak plasma level of
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`oxymorphone occurs within about 1 to about 8 hours after administration; (b) peak plasma level
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`of 6-0H oxymorphone occurs within about 1 to about 8 hours after administration; (c) duration
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`of analgesic effect is through about 8 to about 24 hours after administration; (d) relative
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`oxymorphone bioavailability is in the range of about 0.5 to about 1.5 compared to an orally(cid:173)
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`administered aqueous solution of oxymorphone; and (e) the ratio of the area under the curve of
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`blood plasma level vs. time for 6-0H oxymorphone compared to oxymorphone is in the range of
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`about 0.5 to about 1.5. Of course, there is variation of these parameters among subjects,
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`depending on the size and weight of the individual subject, the subject's age, individual
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`metabolism differences, and other factors. Indeed, the parameters may vary in an individual from
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`day to day. 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 the
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`values. A convenient method for arriving at such values is by conducting a study in accordance
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`with standard FDA procedures such as those employed in producing results for use in a new drug
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`application (or abbreviated new drug application) before the FDA. Any reference to mean values
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`herein, in conjunction with desired results, refer to results from such a study, or some
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`comparable study. Reference to mean values reported herein for studies actually conducted are
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`arrived at using standard statistical methods as would be employed by one skilled in the art of
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`pharmaceutical formulation and testing for regulatory approval.
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`[0024]
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`In one specific embodiment ofthe controlled release matrix form of the invention,
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`the oxymorphone or salt of oxymorphone is dispersed in a controlled release delivery system that
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`comprises a hydrophilic material which, upon exposure to gastrointestinal fluid, forms a gel
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`matrix that releases oxymorphone at a controlled rate. The rate of release of oxymorphone from
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`the matrix depends on the drug's partition coefficient between components of the matrix and the
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`aqueous phase within the gastrointestinal tract. In a preferred form of this embodiment, the
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`hydrophilic material of the controlled release delivery system comprises a mixture of a
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`heteropolysaccharide gum and an agent capable of cross-linking the heteropolysaccharide in
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`presence of gastrointestinal fluid. The controlled release delivery system may also comprise a
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`water-soluble pharmaceutical diluent mixed with the hydrophilic material. Preferably, the cross(cid:173)
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`linking agent is a homopolysaccharide gum and the inert pharmaceutical diluent is a
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`monosaccharide, a disaccharide, or a polyhydric alcohol, or a mixture thereof.
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`[0025]
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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 of
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`oxymorphone hydrochloride, wherein the weight ratio ofheteropolysaccharide 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 ratio of
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`heteropolysaccharide to oxymorphone hydrochloride is in the range of about 10:1 to about 1:10.
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`A preferred heteropolysaccharide is xanthan gum and a preferred homopolysaccharide is locust
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`bean gum. The dosage form also comprises a cationic cross-linking agent and a hydrophobic
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`polymer. In the preferred embodiment, the dosage form is a tablet containing about 5 mg to
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`about 80 mg of oxymorphone hydrochloride. In a most preferred embodiment, the tablet contains
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`about 20 mg oxymorphone hydrochloride.
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`[0026]
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`The invention includes a method which comprises achieving appropriate blood
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`plasma levels of drug while providing extended pain relief by administering one to three times
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`per day to a patient suffering moderate to severe, acute or chronic pain, an oxymorphone
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`controlled release oral solid dosage form of the invention in an amount sufficient to alleviate the
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`pain for a period of about 8 hours to about 24 hours. This type and intensity of pain is often
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`associated with cancer, autoimmune diseases, infections, surgical and accidental traumas and
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`osteoarthritis.
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`[0027]
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`The invention also includes a method of making an oxymorphone controlled
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`release oral solid dosage form of the invention which comprises mixing particles of
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`oxymorphone or a pharmaceutically acceptable salt of oxymorphone with granules comprising
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`the controlled release delivery system, preferably followed by directly compressing the mixture
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`to form tablets.
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`[0028]
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`Pharmaceutically acceptable salts of oxymorphone which can be used in this
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`invention include salts with the inorganic and organic acids which are commonly used to
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`produce nontoxic salts of medicinal agents. Illustrative examples would be those salts formed by
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`mixing oxymorphone with hydrochloric, sulfuric, nitric, phosphoric, phosphorous, hydrobromic,
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`maleric, malic, ascorbic, citric or tartaric, pamoic, lauric, stearic, palmitic, oleic, myristic, lauryl
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`sulfuric, naphthylenesulfonic, linoleic or linolenic acid, and the like. The hydrochloride salt is
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`preferred.
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`[0029]
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`It has now been found that 6-0H oxymorphone, which is one ofthe metabolites
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`of oxymorphone, may play a role in alleviating pain. When oxymorphone is ingested, part of the
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`dosage gets into the bloodstream to provide pain relief, while another part is metabolized to 6-
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`0H oxymorphone. This metabolite then enters the bloodstream to provide further pain relief.
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`Thus it is believed that both the oxymorphone and 6-hydroxyoxymorphone levels are important
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`to pain relief.
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`[0030]
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`The effectiveness of oxymorphone and 6-hydroxyoxymorphone at relieving pain
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`and the pharmacokinetics of a single dose of oxymorphone were studied. The blood plasma
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`levels of both oxymorphone and 6-hydroxyoxymorphone were measured in patients after a single
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`dose of oxymorphone was administered. Similarly, the pain levels in patients were measured
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`after a single administration of oxymorphone to determine the effective duration of pain relief
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`from a single dose. FIGS. 1-2 show the results of these tests, comparing pain levels to
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`oxymorphone and 6-hydroxy oxymorphone levels.
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`[0031]
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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 left(cid:173)
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`hand end of the scale (0 mm) was marked with the descriptor "No Pain" and the right-hand end
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`of the scale (100 mm) was marked with the descriptor "Extreme Pain". Patients indicated their
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`level of pain by making a vertical mark on the line. The VAS score was equal to the distance (in
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`mm) from the left-hand end of the scale to the patient's mark. For the categorical scale, patients
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`completed the following statement, "My pain at this time is" using the scale None =0, Mild =1,
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`Moderate =2, or Severe =3.
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`[0032]
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`As can be seen from these figures, there is a correlation between pain relief and
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`both oxymorphone and 6-hydroxyoxymorphone levels. As the blood plasma levels of
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`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 and 6-
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`hydroxyoxymorphone in the blood plasma which is most important. Further it is these levels
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`which dictate the efficacy ofthe dosage form. A dosage form which maintains a sufficiently high
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`level of oxymorphone or 6-hydroxyoxymorphone for a longer period need not be administered
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`frequently. Such a result is accomplished by embodiments of the present invention.
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`[0033]
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`The oxymorphone controlled release oral solid dosage form of this invention can
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`be made using any of several different techniques for producing controlled release oral solid
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`dosage forms of opioid analgesics.
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`[0034]
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`In one embodiment, a core comprising oxymorphone or oxymorphone salt is
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`coated with a controlled release film which comprises a water insoluble material and which upon
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`exposure to gastrointestinal fluid releases oxymorphone from the core at a controlled rate. In a
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`second embodiment, the oxymorphone or oxymorphone salt is dispersed in a controlled release
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`delivery system that comprises a hydrophilic material which upon exposure to gastrointestinal
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`fluid forms a gel matrix that releases oxymorphone at a controlled rate. A third embodiment is a
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`combination of the first two: a controlled release matrix coated with a controlled release film. In
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`a fourth embodiment the oxymorphone is incorporated into an osmotic pump. In any of these
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`embodiments, the dosage form can be a tablet, a plurality of granules in a capsule, or other
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`suitable form, and can contain lubricants, colorants, diluents, and other conventional ingredients.
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`[0035]
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`Osmotic Pump
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`[0036]
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`An osmotic pump comprises a shell defining an interior compartment and having
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`an outlet passing through the shell. The interior compartment contains the active pharmaceutical
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`ingredient. Generally the active pharmaceutical ingredient is mixed with excipients or other
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`compositions such as a polyalkylene. The shell is generally made, at least in part, from a material
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`(such as cellulose acetate) permeable to the liquid of the environment where the pump will be
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`used, usually stomach acid. Once ingested, the pump operates when liquid diffuses through the
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`shell of the pump. The liquid dissolves the composition to produce a saturated situation. As more
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`liquid diffuses into the pump, the saturated solution containing the pharmaceutical is expelled
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`from the pump through the outlet. This produces a nearly constant release of active ingredient, in
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`the present case, oxymorphone.
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`[0037]
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`Controlled Release Coating
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`[0038]
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`In this embodiment, a core comprising oxymorphone or oxymorphone salt is
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`coated with a controlled release film which comprises a water insoluble material. The film can be
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`applied by spraying an aqueous dispersion of the water insoluble material onto the core. Suitable
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`water insoluble materials include alkyl celluloses, acrylic polymers, waxes (alone or in
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`admixture with fatty alcohols), shellac and zein. The aqueous dispersions of alkyl celluloses and
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`acrylic polymers preferably contain a plasticizer such as triethyl citrate, dibutyl phthalate,
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`propylene glycol, and polyethylene glycol. The film coat can contain a water-soluble material
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`such as polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC).
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`[0039]
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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 HPMC, or by coating
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`an inert bead with oxymorphone or oxymorphone salt and a binding agent such as HPMC, or by
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`spheronising mixed powders of oxymorphone or oxymorphone salt and a spheronising agent
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`such as microcrystalline cellulose. The core can be a tablet made by compressing such granules
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`or by compressing a powder comprising oxymorphone or oxymorphone salt.
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`[0040]
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`The in vitro and in vivo release characteristics of this controlled release dosage
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`form can be modified by using mixtures of different water insoluble and water soluble materials,
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`using different plasticizers, varying the thickness of the controlled release film, including
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`release-modifying agents in the coating, or by providing passageways through the coating.
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`[0041]
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`Controlled Release Matrix
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`- 12-
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`[0042]
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`It is important in the present invention that appropriate blood plasma levels of
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`oxymorphone and 6-hydroxy oxymorphone be achieved and maintained for sufficient time to
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`provide pain relief to a patient for a period of 12 to 24 hours. The preferred composition for
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`achieving and maintaining the proper blood plasma levels is a controlled-release matrix. In this
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`embodiment, the oxymorphone or oxymorphone salt is dispersed in a controlled release delivery
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`system that comprises a hydrophilic material (gelling agent) which upon exposure to
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`gastrointestinal fluid forms a gel matrix that releases oxymorphone at a controlled rate. Such
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`hydrophilic materials include gums, cellulose ethers, acrylic resins, and protein-derived
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`materials. Suitable cellulose ethers include hydroxyalkyl celluloses and carboxyalkyl celluloses,
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`especially hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), HPMC, and carboxy
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`methylcellulose (CMC). Suitable acrylic resins include polymers and copolymers of acrylic acid,
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`methacrylic acid, methyl acrylate and methyl methacrylate. Suitable gums include
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`heteropolysaccharide and homopolysaccharide gums, e.g., xanthan, tragacanth, acacia, karaya,
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`alginates, agar, guar, hydroxypropyl guar, carrageenan, and locust bean gums.
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`[0043]
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`Preferably, the controlled release tablet of the present invention is formed from (I)
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`a hydrophilic material comprising (a) a heteropolysaccharide; or (b) a heteropolysaccharide and a
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`cross-linking agent capable of cross-linking said heteropo1ysaccharide; or (c) a mixture of (a), (b)
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`and a polysaccharide gum; and (II) an inert pharmaceutical filler comprising up to about 80% by
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`weight of the tablet; and (liD oxymorphone.
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`[0044]
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`The term "heteropolysaccharide" as used herein is defined as a water-soluble
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`polysaccharide containing two or more kinds of sugar units, the heteropolysaccharide having a
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`branched or helical configuration, and having excellent water-wicking properties and immense
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`thickening properties.
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`[0045]
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`A preferred heteropolysaccharide is xanthan gum, which is a high molecular
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`weight (> 1 06
`) heteropolysaccharide. Other preferred heteropolysaccharides include derivatives
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`ofxanthan gum, such as deacylated xanthan gum, the carboxymethyl ether, and the propylene
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`glycol ester.
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`[0046]
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`The cross linking agents used in the controlled release embodiment of the present
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`invention which are capable of cross-linking with the heteropolysaccharide include
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`homopolysaccharide gums such as the galactomannans, i.e., polysaccharides which are
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`composed solely of mannose and galactose. Galactomannans which have higher proportions of
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`unsubstituted mannose regions have been found to achieve more interaction with the
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`heteropolysaccharide. Locust bean gum, which has a higher ratio of mannose to the galactose, is
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`especially preferred as compared to other galactomannans such as guar and hydroxypropyl guar.
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`[0047]
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`Preferably, the ratio ofheteropolysaccharide to homopolysaccharide is in the
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`range of about 1 :9 to about 9: 1, preferably about 1 :3 to about 3:1. Most preferably, the ratio of
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`xanthan gum to polysaccharide material (i.e., locust bean gum, etc.) is preferably about 1:1.
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`[0048]
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`In addition to the hydrophilic material, the controlled release delivery system can
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`also contain an inert pharmaceutical diluent such as a monosaccharide, a disaccharide, a
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`polyhydric alcohol and mixtures thereof. The ratio of diluent to hydrophilic matrix-forming
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`material is generally in the range of about 1:3 to about 3:1.
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`[0049]
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`The controlled release properties of the controlled release embodiment of the
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`present invention may be optimized when the ratio ofheteropolysaccharide gum to
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`homopolysaccharide material is about 1:1, although heteropolysaccharide gum in an amount of
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`from about 20 to about 80% or more by weight of the heterodisperse polysaccharide material
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`provides an acceptable slow release product. The combination of any homopolysaccharide gums
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`known to produce a synergistic effect when exposed to aqueous solutions may be used in
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`accordance with the present invention. It is also possible that the type of synergism which is
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`present with regard to the gum combination of the present invention could also occur between
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`two homogeneous or two heteropolysaccharides. Other acceptable gelling agents which may be
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`used in the present invention include those gelling agents well-known in the art. Examples
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`include vegetable gums such as alginates, carrageenan, pectin, guar gum, xanthan gum, modified
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`starch, hydroxypropylmethylcellulose, methylcellulose, and other cellulosic materials such as
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`sodium carboxymethylcellulose and hydroxypropyl cellulose. This list is not meant to be
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`exclusive.
`
`[0050]
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`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.
`
`[0051]
`
`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
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`pharmaceutical fillers include sucrose, dextrose, lactose, microcrystalline cellulose, fructose,
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`CHDB04 13321951.1 29-Jun-06 11:56
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`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.
`
`[0052]
`
`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, calcium lactate, magnesium sulfate and sodium
`
`fluoride. Multivalent metal cations may also be utilized. However, the preferred cationic cross(cid:173)
`
`linking agents are bivalent. Particularly preferred salts are calcium sulfate and sodium chloride.
`
`The cationic cross-linking agents ofthe present invention are added in an amount effective to
`
`obtain a desirable increased gel strength due to the cross-linking ofthe gelling agent (e.g., the
`
`heteropolysaccharide and homopolysaccharide gums). In preferred embodiments, the cationic
`
`cross-linking agent is included in the sustained release excipient 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.
`
`[0053]
`
`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
`
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`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.
`
`[0054]
`
`The sustained release excipient used in this embodiment of the present invention
`
`(with or without the optional cationic cross-linking agent) may be further 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 ofhydrophobic 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.
`
`[00_55]
`
`Examples of commercially available alkylcelluloses are Aquacoat coating
`
`(aqueous dispersion of ethylcellulose available from FMC of Philadelphia, Pa.) and Surelease
`
`coating (aqueous dispersion ofethylcellulose available from Colorcon ofWest Point, Pa.).
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`Examples of commercially available acrylic polymers suitable for use as the hydrophobic
`
`material include Eudragit RS and RL polymers (copolymers of acrylic and methacrylic acid
`
`esters having a low content (e.g., 1 :20 or 1 :40) of quaternary ammonium compounds available
`
`from Rohm America of Piscataway, N.J.).
`
`[0056]
`
`The controlled release matrix useful in the present invention 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.
`
`EXAMPLES
`
`Example 1
`
`[0057]
`
`