HK1186970A - Formulations and methods for attenuating respiratory depression induced by opioid overdose - Google Patents

Description

Formulations and methods for reducing respiratory depression caused by opioid overdose

Background

The Deactacore platform of King pharmaceutical companies (King Pharmaceuticals) has been developed to reduce the effects of excess opioids and drug addiction when products are misused or abused, which incorporates segregated (sequenced) naltrexone into the core of controlled release opioid dosage forms that are released only when the sequestering polymer matrix is destroyed. The Deactacore technique is described in detail in the following references: U.S. patents 7,682,633 and 7,682,634, U.S. patent publications US20080233156, US20090131466, US20040131552, US20100152221, US20100151014, and US20100143483, and PCT applications PCT/US08/087030, PCT/US08/087043, PCT/US08/87047, and PCT/US08/087055, which are incorporated herein by reference.

An example of a marketed pharmaceutical formulation embodying the deacact technology is an analgesic drug(also known as ALO-01). (prescription information:(morphine sulfate and naltrexone hydrochloride) sustained release capsules. Yalai pharmaceutical Co., Ltd, King pharmaceutical Co., Ltd, Bristol, Tennessee. 6 months 2009).Commercialized in 2009, were capsule formulations containing controlled release pellets that slowly release therapeutic doses of morphine sulfate over time. Naltrexone hydrochloride is sequestered in the inner core at a ratio of 1:20 to morphine, and is only released when the sequestering polymer matrix is broken. When taken as a whole, the inner core remained intact and naltrexone did not affect the analgesic potential of morphine. However, whenUpon chewing, crushing, or otherwise physically treating, naltrexone is released, is absorbed by the oral cavity, and competitively binds to the mu-opioid receptors, thereby alleviating or reducing the euphoric effect of morphine.

The amount of naltrexone in the Deactacore platform varies depending on the potency of the opioid analgesic. Embeda used 4% naltrexone (morphine to naltrexone ratio of 20: 1). Studies have shown that more than 12% naltrexone is optimal for oxycodone and hydrocodone. Although dose responses associated with euphoria and drug addiction have been explored in combination with opioid and opioid antagonists, the naltrexone dose response relationship associated with other pharmacological effects of opioids is almost unknown, including the major mechanism of lethal opioid overdose: respiratory depression (White JM and Irvine RJ. mechanisms of facial ocular overlay. Addition. 1999;94(7):961-72; Dahan A, Aarts L, and Smith TW. index, versal, and prediction of ocular-induced respiratory prediction. 2010;112: 226-38).

Naloxone is currently the drug of choice as a rescue medication for therapeutic use in the rapid reversal of opioid-induced activity and adverse reactions. (Longnecker DE, Grazis PA, and Eggers GWN. Naloxone for anti-inflammatory depression. Anesthesia and Analgesia Current research 1973;52(3): 447-53). Upon parenteral administration, the pharmacodynamic effects of naloxone, which are associated with the reversal of opioid-induced respiratory depression, are well characterized. (Yassen A, Olofsen E, van Dorp E, Sarton E, Teppem L, Danhof M, and Dahan A. mechanism-based pharmacological-pharmacological modifying of the reverse of decompression-induced decompression by naloxone. Clin pharmacological model.2007; 46(11):965-80; Kaufman RD, Gabthouler ML, and Beville W.Potention, duration of action and adenosine A₂in man of intravenous nanone measured by reverse of morphine-compressed regulation.J. of Pharmacol and Exp Ther.1981;219: 156-62. In known or suspected opioid overdoses, the usual IV dose of naloxone is 0.4-2mg to reverse opioid-induced respiratory depression. (America Hospital formulary Services (AHFS) information. Naloxone hydrochloride.2003: 2088-89). This initial infusion may be supplemented by multiple naloxone injections at frequent intervals or by continuous intravenous infusion. In a post-operative setting, a single dose of naloxone can be supplemented by a continuous IV infusion of naloxone at 3.7mcg/kg per hour to reverse exhalationAnd (4) inhibiting absorption.

Us patent 5,834,477 describes a homogeneous mixture composition containing both opioid agonist and antagonist which results in minimal respiratory depression. This patent describes the use of sufentanil oxalate and nalmefene in a 15:1 molar ratio.

The effect of Hydrocodone Bitartrate and Naltrexone Hydrochloride combinations on Respiratory depression in mice has been evaluated (k.hew, s.mason, and h.pentan, a Respiratory Safety pharmacological assessment of Hydrocodone Bitartrate and Naltrexone Hydrochloride). Comparisons of oxycodone and morphine have been made in patients with respiratory depression (Change et al, A composion of respiratory effects of oxycodone veras morphine: a random, double-blind, placebo controlled inhalation, Anaesthesia 2010). The study determined that the extent and rate of the onset of respiratory depression induced by oxycodone was dose-dependent and higher than an equivalent dose of morphine.

The use of naltrexone as a rescue medication in humans is completely new to this drug, as naltrexone is mainly administered orally and over a long period of time to treat opiate and alcohol dependence. Naltrexone is absorbed at least as rapidly as opioids when not isolated in the deacacore formulation, such as when ingested after crushing or chewing the formulation (figure 2), although opioids are longer in residence time than naltrexone. This suggests that naltrexone also has the same potential to prevent respiratory depression in the event of acute opioid overdose, as it can reverse or alleviate respiratory depression depending on the amount of each drug absorbed. Therefore, a better understanding of the dose-response relationship between naltrexone and opioid-induced respiratory depression is a clinically important issue.

Disclosure of Invention

The present invention relates to opioid compositions containing sequestering opioid antagonists that release the opioid antagonist when ingested after insult (e.g., crushing, chewing or dissolution) and that relieve respiratory depression when taken or ingested after insult. The compositions of the present invention comprise an opioid analgesic pharmaceutical formulation comprising a solid, controlled release oral dosage form comprising a plurality of multilayered pellets, each pellet comprising a water soluble core, an antagonist layer comprising naltrexone or a pharmaceutically acceptable salt thereof coating the core, a sequestering polymer layer coating the antagonist layer, an agonist layer comprising an opioid or a pharmaceutically acceptable salt thereof coating the sequestering polymer layer, and a controlled release layer coating the agonist layer. When the composition is administered intact to a human, this means that the composition is not damaged and substantially all of the naltrexone remains isolated. However, if the composition is damaged, which means that the composition is crushed, chewed, dissolved or otherwise altered, whereby naltrexone and the opioid in the composition are released from the initial dosage form, the composition has sufficient naltrexone to alleviate opioid-mediated respiratory depression in individuals who have taken the damaged form of the composition.

The present invention relates to an opioid analgesic pharmaceutical formulation comprising a solid controlled release oral dosage form comprising a plurality of multilayered pellets, each pellet comprising a water soluble core, an antagonist layer comprising naltrexone or a pharmaceutically acceptable salt thereof coating the core, a sequestering polymer layer coating the antagonist layer, an agonist layer comprising an opioid or a pharmaceutically acceptable salt thereof coating the sequestering polymer layer, and a controlled release layer coating the agonist layer, wherein upon intact administration to a human, naltrexone or a pharmaceutically acceptable salt thereof is not substantially released, and wherein when the dosage form is compromised prior to administration to the human, minimal respiratory depression is induced in the human.

The present invention also relates to a method of alleviating drug-induced respiratory depression in a human following administration of a drug that mediates respiratory depression to the human, wherein the method comprises administering to the human an opioid analgesic drug formulation comprising a solid, controlled release oral dosage form comprising a plurality of multilayered pellets, each pellet comprising a water soluble core, an antagonist layer comprising naltrexone or a pharmaceutically acceptable salt thereof coating the core, a sequestering polymer layer coating the antagonist layer, an agonist layer comprising an opioid or a pharmaceutically acceptable salt thereof coating the sequestering polymer layer, and a controlled release layer coating the agonist layer.

Drawings

FIG. 1 is a graph comparing naloxone and naltrexone plasma concentrations following treatment with naloxone (red) IV and following complete release of ALO-02 or ALO-04 containing 12% naltrexone (blue) from an 80mg oral dose.

FIG. 2 is a graph comparing plasma concentrations of naltrexone and naloxone, following a theoretical crush dose of ALO-02 containing 80mg oxycodone and 12% (9.6mg) naltrexone.

Figure 3 is a graph of adjusted rebreathing ventilation.

FIG. 4 is end-tidal CO by therapy₂Mean (. + -. SD) E of_maxA graph of values.

FIG. 5 is a graph of mean (+/-SE) oxygen saturation over time (SpO) determined according to pulse oximetry after oral administration of oxycodone 60mg, oxycodone 60mg + naltrexone 7.2mg (12% -the naltrexone ratio in the current ALO-02) and placebo₂) A horizontal graph.

Detailed Description

Provided herein are compositions, and methods for administering a composition comprising a plurality of active agents to a mammal in a form or manner that minimizes the effect of any active agent on another active agent in vivo. The present invention particularly relates to opioid compositions that alleviate respiratory depression when administered to a human. In particular embodiments, the at least two active agents are formulated as part of a pharmaceutical composition. The first active opioid may provide a therapeutic effect in vivo. The second agent can be an antagonist of the first activity and can be used to alleviate respiratory depression if the composition is compromised. In normal use by the patient, the composition remains intact and does not release the antagonist. However, after the composition is damaged (e.g., crushed, chewed or dissolved), the antagonist may be released, thereby preventing, alleviating or alleviating the opioid-induced severe respiratory depression. In certain embodiments, both active agents are contained in a single unit, such as a pellet or bead, in the form of a layer. The active agent may be formulated, for example, as a controlled release composition from a substantially impermeable barrier, thereby minimizing release of the antagonist from the composition. In particular embodiments, the antagonist is released in an in vitro assay, but is not substantially released in vivo. In vitro and in vivo release of the active agent from the composition can be determined by any of several well-known techniques. For example, in vivo release can be determined by measuring plasma levels of the active agent or a metabolite thereof.

In one embodiment, the present invention provides a sequestering subunit comprising an opioid antagonist and a blocking agent, wherein the blocking agent substantially prevents release of the opioid antagonist from the sequestering subunit in the gastrointestinal tract for a period of time greater than 24 hours. The sequestering subunit is incorporated into a single pharmaceutical unit that also comprises an opioid agonist. The drug unit thus comprises a core portion to which the opioid antagonist is applied. Followed by the optional application of a blocking layer over the antagonist. The composition comprising the pharmaceutically active agent in a released form is applied after the blocking layer. An additional layer containing the same or a different blocking agent may optionally be applied, whereby the opioid agonist is released over time (i.e., controlled release) in the alimentary tract. Alternatively, the opioid agonist layer may be in an immediate release form. Thus, both the opioid antagonist and the opioid agonist are contained in a single pharmaceutical unit, which is typically in the form of beads.

As used herein, the term "sequestering subunit" refers to any pharmaceutical unit (e.g., bead or pellet) comprising means (means) for containing an antagonist and preventing or substantially preventing its release in the gastrointestinal tract when intact (i.e., when not damaged). As used herein, the term "blocking agent" refers to a means by which the sequestering subunit is capable of substantially preventing the release of the antagonist. The blocking agent may be a sequestering polymer, as described in detail below.

As used herein, the term "substantially prevent", "prevent", or any word derived therefrom, means that the antagonist is not substantially released from the sequestering subunit in the gastrointestinal tract. By "substantially not released" is meant that when the dosage form is orally administered to a host, such as a mammal (e.g., a human), as intended, the antagonist may be released in small amounts, but the amount released does not affect or does not significantly affect analgesic efficacy. As used herein, the terms "substantially prevent," "prevent," or any word derived therefrom, do not necessarily imply complete or 100% prevention. Rather, there are varying degrees of prevention that one skilled in the art would consider to be of potential benefit. In this regard, the blocking agent substantially prevents or prevents the release of the antagonist to such an extent that: preventing at least about 80% of the antagonist from being released from the sequestering subunit in the gastrointestinal tract over a period of more than 24 hours. Preferably, the blocking agent prevents at least about 90% of the antagonist from being released from the sequestering subunit in the gastrointestinal tract for a period of time greater than 24 hours. More preferably, the blocking agent prevents at least about 95% of the antagonist from being released from the sequestering subunit. Most preferably, the blocking agent prevents at least about 99% of the antagonist from being released from the sequestering subunit in the gastrointestinal tract for a period of more than 24 hours.

For the purposes of the present invention, the amount of antagonist released after oral administration may be determined in vitro by the dissolution test described in the United states pharmacopoeia (USP26) chapter <711> dissolution. For example, the release from the dosage unit at different times was determined at 37 ℃ using 0.1N HCl900mL, device 2 (paddle), 75 rpm. Other methods for determining the release of an antagonist from a sequestering subunit over a given period of time are known in the art (see, e.g., USP 26).

Without being bound by any particular theory, it is believed that the sequestering subunit of the invention overcomes the limitations of the sequestered forms of antagonists known in the art because the sequestering subunit of the invention reduces osmotically driven antagonist release from the sequestering subunit. Further, it is believed that the sequestering subunits of the present invention reduce the release of the antagonist over a longer period of time (e.g., over 24 hours) as compared to the sequestered forms of the antagonist known in the art. The fact that the sequestering subunit of the invention provides a longer period of time to prevent release of the antagonist is particularly important because the time after which the therapeutic agent is released and available for action, a prohibitive withdrawal can occur. It is well known that the gastrointestinal transit times of individuals vary greatly within a population. Thus, the residue of the dosage form may remain in the gastrointestinal tract for more than 24 hours, and in some cases, more than 48 hours. It is also well known that opioid analgesics cause reduced intestinal motility, further prolonging gastrointestinal transit time. Currently, the food and drug administration has approved sustained release dosage forms that are effective over a 24 hour period. In this regard, the sequestering subunits of the present invention, when undamaged, prevent antagonist release for a period of more than 24 hours.

The sequestering subunits of the present invention are designed to substantially prevent release of the antagonist when intact. By "intact" is meant that the dosage form has not experienced damage. In this manner, the antagonist and agonist are separated from each other within the complete dosage form. The term "spoiling" is meant to include any treatment, mechanical, thermal and/or chemical, which alters the physical properties of the dosage form. The damage may be, for example, crushing (e.g., by a mortar or pestle), shearing, grinding, chewing, dissolving in a solvent, heating (e.g., above 45 ℃), or any combination thereof. When the sequestering subunit of the invention has been damaged, the antagonist is immediately released from the sequestering subunit. A dosage form that has been compromised such that the antagonist has been released therefrom is considered "substantially compromised," wherein, upon administration of the dosage form to a subject (e.g., a human), the antagonist inhibits or otherwise interferes with the activity of the agonist in the subject, including interfering with the ability of the agonist to cause respiratory depression. Whether an antagonist inhibits or otherwise interferes with the activity of an agonist can be determined using any Pharmacodynamic (PD) or Pharmacokinetic (PK) assay available to those skilled in the art, including but not limited to those described herein. If an antagonist interferes with the action of an agonist, a statistically significant difference is typically observed between dosage forms in one or more PD or PK assays.

"subunit" is meant to include compositions, mixtures, particles, and the like, which when combined with another subunit, are capable of providing a dosage form (e.g., an oral dosage form). The subunits may be in the form of beads, pellets, granules, spheres, etc., and may be combined with additional subunits, which may be the same or different, in the form of capsules, tablets, etc., to provide a dosage form, e.g., an oral dosage form. A subunit may also be part of a larger single unit, forming part of the unit, such as a layer. For example, the subunit may be a core coated with an antagonist and a blocking layer; the subunit may then be coated with an additional composition comprising a pharmaceutically active agent, such as an opioid agonist.

By "antagonist of a therapeutic agent" is meant any drug or molecule, natural or synthetic, that binds to the same target molecule (e.g., receptor) of the therapeutic agent, but does not produce a therapeutic, intracellular, or in vivo response. In this regard, an antagonist of a therapeutic agent binds to a receptor of the therapeutic agent, thereby preventing the therapeutic agent from acting on the receptor. For opioids, antagonists may prevent respiratory depression.

Standard Pharmacodynamic (PD) and Pharmacokinetic (PK) assays can be used to compare the effect of different dosage forms (e.g., "intact" vs. "damaged" or "substantially damaged") on a subject or to determine whether a dosage form has been damaged or substantially damaged. Standard assays include, for example, known PD standards or scores including, but not limited to, one or more VAS-drug addictions (Balster), among others&Bigelow,2003; Griffiths et al 2003), VAS-total drug addiction, ARCI simple format (Martin et al, 1971), Cole/ARCI (Cole et al, 1982), Cole/ARCI-euphoria, subjective drug value (Girfiths, et al,1993; Griffiths, et al, 1996), Cole/ARCI abuse potential, ARCI-morphinanium group (MBG), VAS-well effects, VAS-sensory excitement, VAS-adverse effects, VAS-sensory discomfort, VAS-nausea, ARCI-LSD, Cole/ARCI-unpleasant-body, Cole/ARCI-dysphoria, VAS-any effects, VAS-dizziness, ARCI-amphetamine, ARCI-BG, Cole/ARCI-irritative-motor, VAS-sleepiness, ARCI-sedative-neuroleptic effects, VAS-ARCI-psychopsychoses, Sedation-locomotion and/or pupillometry (Knaggs, et al 2004). The assay may comprise an effect of 0-2h after administrationMean or median area under the curve (AUE)_(0-2h)) Area under the effect curve 0-8h after Administration (AUE)_(0-8h)) Area under the Effect Curve (AUE) 0-24h after administration_(0-24h)) Apparent post-dose pupil diameter (e.g., PC)_min、PAOC_(0-2h)、PAOC_(0-8h)、PAOC_(0-24h)) Initial fraction 1.5 hours after administration (HR1.5), maximal effect (E)_max) Time to maximum effect (TE)_max). Particularly informative are Emax assays for VAS-drug addiction, VAS-total drug addiction, Cole/ARCI-euphoria, subjective drug value, Cole/ARCI abuse potential, ARCI-MBG, VAS-good effect, VAS-sensory stimulation and pupillometry.

For the compositions described herein, PK assays related to morphine and naltrexone would be useful. Morphine, naltrexone, and/or 6-beta-naltrexone assays are useful in blood (e.g., plasma) and in patients who have taken various dosage forms. Specific PK parameters that can be determined include, for example, maximum plasma concentration (C)_max) Mean and/or median peak concentration, time to peak concentration (T)_max) Elimination rate constant (lambda)_z) Terminal half-life (T)_1/2) Area under the concentration-time curve from 0 hour after dosing to 8 hours after dosing (AUC)_0-8h) (pg x h/ml), area under the concentration-time curve from time zero to the last quantifiable concentration time (AUC)_last) (pg x h/ml), and area under the concentration time curve (AUC) extrapolated from zero time to infinity_inf) (pg x h/ml), elimination rate (ke) (1/h), clearance (L/h) and/or volume of distribution (L). Samples (e.g., blood) can be taken from those that have taken the dosage form at different time points (e.g., about any of 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours after taking). When the samples are blood, plasma can be prepared from these samples using standard techniques and assays can be performed therefrom. Mean and/or median plasma determinations can then be calculated and compared for various dosage forms.

In particular embodiments, one or more such criteria measurements observed after administration of a dosage form may be considered different, reduced or increased from those observed after administration of a different dosage form, wherein the difference between the dosage form effects differs according to about any of the following ranges: 5-10%, 10-15%, 15-20%, 10-20%, 20-25%, 25-30%, 20-30%, 30-35%, 35-40%, 30-40%, 40-45%, 45-50%, 40-50%, 50-55%, 55-60%, 50-60%, 60-65%, 65-70%, 60-70%, 70-75%, 75-80%, 70-80%, 80-85%, 85-90%, 80-90%, 90-95%, 95-100%, and 90-100%. In certain embodiments, assays may be considered "similar" to one another when there is any one of less than about a 0%, 5%, 10%, 15%, 20%, or 25% difference. The difference may also be expressed as a fraction or ratio. For example, the observed assay for a complete dosage form or a substantially damaged dosage form may be expressed as, for example, about 1/2 (one-half), 1/3 (one-third), 1/4 (one-fourth), 1/5 (one-fifth), 1/6 (one-sixth), 1/7 (one-seventh), 1/8 (one-eighth), 1/9 (one-ninth) of the substantially damaged dosage form or the complete dosage form, respectively, 1/10 (tenth), 1/20 (twentieth), 1/30 (thirtieth), 1/40 (forty), 1/50 (fiftieth), 1/100 (hundredth), 1/250 (two hundred and fifty), 1/500 (five hundredth), or 1/1000 (thousandths). Differences may also be expressed as ratios (e.g., any of about.001: 1,. 005:1,. 01:1, 0.1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1: 10).

To be considered "significant", "statistically significant", "significantly reduced" or "significantly higher", a statistical analysis may be performed, for example, on a numerical value or determination relating to the observed difference. Baseline measurements can be collected and significant baseline effects can be found. After baseline covariance adjustment in an analysis of covariance (ANCOVA) model, baseline treatment effects can be assessed. The model may include treatment, period, and order as fixed effects, and subjects are nested in order as random effects. For pharmacodynamic measurements with predose values, the model may include a predose baseline value as a covariance. The linear mixed effects model may be based on a population that conforms to the protocol. A 5% type I error rate with a value of less than 0.05p can be considered "statistically significant" for all individual hypothesis tests. All statistical tests can be performed using the two-tailed significance criteria. For each dominant effect, the null hypothesis may be "no dominant effect" and the alternative hypothesis may be "dominant effect". For each comparison, the null hypothesis may be "there is no difference in effect in the detection pair" and the alternative hypothesis may be "there is a difference in effect in the detection pair". The Benjamin and Hochberg programs can be used to control type I errors, which arise in multiple treatment comparisons for all primary endpoints.

Statistical significance can also be measured using analysis of variance (ANOVA) and the schiimann two-one-sided t-test procedure at a 5% significance level. For example, log-transformed PK exposure parameters Cmax, AUC may be compared_lastAnd AUC_infTo determine statistically significant differences between dosage forms. The 90% confidence interval for the geometric mean ratio (test/reference) can be calculated. In particular embodiments, a dosage form may be claimed, declared "bioequivalent" or "bioequivalent" if the lower and upper confidence intervals of the logarithmically converted parameters are any one of about 70-125%, 80% -125%, or 90-125% of each other. Bioequivalence or bioequivalence is preferably declared when the lower and upper confidence intervals of the logarithmically transformed parameter are about 80% -125%.

The in vitro release of morphine, naltrexone and 6-beta-naltrexone from different compositions may be determined using standard dissolution testing techniques such as those described in the united states pharmacopoeia (USP26), chapter <711> dissolution (e.g. 0.1N HCl900mL, apparatus 2 (paddle), 75rpm, 37 ℃; 37 ℃ and 100rpm) or in an appropriate buffer such as 500ml0.05m phosphate buffer, ph7.5, for 72 hours to determine release from the dosage form at different times. Other methods for determining the release of an antagonist from a sequestering subunit over a given period of time are known in the art (see, e.g., USP26), and may also be applied. These assays can also be applied in modified form, for example by using a buffer system containing a surfactant (e.g., in 0.2% Triton X-100/0.2% sodium acetate/0.002N HCl, pH5.5 for 72 hours). Blood levels (including, e.g., plasma levels) of morphine, naltrexone, and 6-beta-naltrexone can be determined using standard techniques.

An antagonist may be any chemical agent that counteracts the effects of a therapeutic agent or that attenuates the toxic effects of opioid-induced respiratory depression.

The therapeutic agent may be an opioid agonist. By "opioid" is meant to include natural or synthetic drugs, hormones, or other chemical or biological substances, or natural or synthetic derivatives thereof, that have sedative, anesthetic, or other effects similar to those of opiates. "opioid agonist" is sometimes used interchangeably herein with the terms "opioid" and "opioid analgesic" and is meant to include one or more opioid agonists alone or in combination, and is further meant to include bases of opioids, mixed or combined agonist-antagonists, partial agonists, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and combinations thereof.

Opioid agonists include, for example, alfentanil, allylmorphine, alfadine, anileridine, benzylmorphine, bezilimide, buprenorphine, butorphanol, lonicerazine, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, dinolamine, dihydrocodeine, dihydroetorphine, dihydromorphine, dextromethorphan, demeclovir, demezerol, dimethylclothianidin, morphobutyl, dipiperazone, etazocine, esomephenzine, ethidine, ethylmorphine, etoxazine, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxyperidine, isometholone, ketonine, levorphanol, fentanil, fentanyl, meperidine, meptazinol, metazocine, methadone, metominodone, morphine, milrinone, buprenorphine, normorphine, levorphanol, naloxone, morphine, methadone, meplate, naloxone, nalorphine, normorphine, norpiperazone, opium, oxycodone, oxymorphone, opiate alkaloids, pentazocine, phenomenone, phenazocine, fenorphan, phenperidine, pimonidine, pimonitride, pranoprazine, meperidine, propiveridine, propoxyphene, sufentanil, tramadol, tilidine, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof. Preferably, the opioid agonist is selected from the group consisting of: hydrocodone, hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof. Most preferably, the opioid agonist is morphine, hydromorphone, oxycodone, or hydrocodone. In a preferred embodiment, the opioid agonist comprises oxycodone and hydrocodone and is present in the dosage form in an amount of about 15 to about 45mg, and the opioid agonist comprises naltrexone and is present in the dosage form in an amount of about 0.5 to about 5 mg. The calculated equivalent analgesic doses (mg) of these opioids compared to the 15mg dose of hydrocodone were as follows: oxycodone (13.5mg), codeine (90.0mg), hydrocodone (15.0mg), hydromorphone (3.375mg), levorphanol (1.8mg), meperidine (15.0mg), methadone (9.0mg) and morphine (27.0).

Hydrocodone is a semi-synthetic narcotic analgesic and antitussive with multiple nervous system and gastrointestinal effects. Chemically, hydrocodone is 4, 5-epoxy-3-methoxy-17-methyl morphinan-6-one, also known as hydrocodone. Like other opioids, hydrocodone is addictive and capable of producing morphine-type drug dependence. Like other opioid derivatives, overdose of hydrocodone inhibits respiration.

Oral hydrocodone is also available as an antitussive in europe (e.g. belgium, germany, greece, italy, lucenburg, norway and switzerland). Parenteral formulations are also available in germany as antitussives. For use as an analgesic, hydrocodone bitartrate is generally only available in the united states as a fixed combination with non-opiate drugs (e.g., ibuprofen, acetaminophen, aspirin, etc.) for the relief of moderate to moderately severe pain.

In embodiments where the opioid agonist comprises hydrocodone, the sustained release oral dosage form may comprise an analgesic dose of about 8mg to 50mg hydrocodone per dosage unit. In a sustained release oral dosage form wherein the hydromorphone is a therapeutically active opioid, the hydromorphone hydrochloride is included in an amount from about 2mg to about 64 mg. In another embodiment, the opioid agonist comprises morphine and the sustained release oral dosage form of the present invention comprises from about 2.5mg to about 800mg by weight of morphine. In another embodiment, the opioid agonist comprises oxycodone and the sustained release oral dosage form comprises from about 2.5mg to about 800mg of oxycodone.

In a preferred embodiment, the opioid antagonist comprises naltrexone or a naltrexone salt. In the treatment of patients addicted before opioids, naltrexone has been used in large oral doses (greater than 100mg) to prevent the euphoric effect of opioid agonists. Naltrexone has been reported to exert a preferential blocking effect against the μ site over the δ site. Naltrexone is known to be a synthetic homologue of oxymorphone, lacking opioid agonist properties, and differs structurally from oxymorphone in that the methyl group at the nitrogen atom of oxymorphone is substituted with a cyclopropylmethyl group. The hydrochloride salt of naltrexone dissolves in water up to about 100 mg/cc. The pharmacological and pharmacokinetic properties of naltrexone have been evaluated in a number of animal and clinical studies. See, for example, Gonzalez et al, drugs35:192- & 213 (1988). Upon oral administration, naltrexone is rapidly absorbed (within 1 hour) and has a bioavailability in the range of 5-40% in the oral cavity. The protein binding of naltrexone was about 21% and the volume of distribution after a single dose administration was 16.1L/kg.

Naltrexone in the form of tablets (DuPont (Wilmington, Del.)) for the treatment of alcohol dependence and for the blockade of added opioids. See, e.g., Revia (naltrexone hydrochloride tablets), Physician's Desk Reference,51^sted., Montvale, N.J., and Medical Economics51: 957-. 50mg ofBlocks the pharmacological effect of 25mg intravenous heroin for up to 24 hours. It is known thatNaltrexone blocks the formation of physical dependence on opioids when co-administered with morphine, heroin or other opioids for a prolonged period of time. Naltrexone is believed to inhibit the heroin effect by competitively binding to opioid receptors. Naltrexone has been used to treat narcotic addiction by completely inhibiting the effects of opioids. The most successful use of naltrexone for narcotic addiction has been found to be in narcotic addicts with good prognosis, as part of comprehensive occupational or return projects involving behavioral control or other compliance-enhancing approaches. For narcotic-dependent therapy with naltrexone, it is desirable that the patient be exempted from opioids for at least 7-10 days. The initial dose of naltrexone is usually about 25mg for this purpose, and if there are no signs of withdrawal, the dose may be increased to 50mg per day. It is believed that a daily dose of 50mg may result in sufficient clinical suppression of the effects of parenterally administered opioids. Naltrexone is also used to treat alcoholism, as an adjunct to social and psychiatric treatment. Other preferred opioid antagonists include, for example, ciclovir and naltrexone, both having cyclopropanemethyl substitution on the nitrogen, retaining most of their efficacy by the oral route and for longer periods of time, with a duration of approximately 24 hours after oral administration.

Based on estimates of systemic clearance and half-life of naloxone, naloxone concentration curves generated by IV injections of 0.4mg with or without continuous naloxone infusion over 4 hours can be simulated as shown in fig. 1, with the solid red line representing plasma naloxone concentrations after a single dose and the dashed line representing the curves after a single dose and continuous infusion over 4 hours.

If all of the drug was released from ALO-02 (oxycodone 80mg) containing 12% naltrexone at a dose of 80mg, the naltrexone concentration profile was compared to the naloxone therapeutic concentration profile. Theoretically, if an isolated naltrexone preparation of oxycodone is chewed or crushed by misuse, the amount of naltrexone that reaches systemic circulation can act as an emergency drug when peak naltrexone concentrations reach as high as 2500 pg/mL. (Gonzalez JP and Brogden RN. naltrexone: A review of biochemical and pharmacological properties and pharmacological efficacy in Human management of optical decision. drugs.1988;35: 192. 213; Verebey K, Volavka J, Mute SJ, and Research RB. naltrexone: displacement, and tissue culture. clinn. and Ther.1976;20(3) network 315-28; Willeeth and nuclear localization. Drug. naxones: displacement and displacement of biological assay. NID. repair and modification of biological assay. repair. Drug and repair. 19828; N. D. NID. 1981. molecular repair and biological assay. NID. 2. D. biological assay, 2. D. N.S. 1. D.S. A. environmental test of biological assay and biological assay

The opioid agonist/naltrexone ratio that may alleviate opioid-induced respiratory depression may depend, in part, on the opioid agonist. Ideally, the ratio is such that if the formulation is damaged, when the damaged formulation is administered to a human, the amount of naltrexone released after the damage will prevent respiratory depression from being caused. The formulations of the present invention also include an opioid agonist/naltrexone ratio that reduces the severity of respiratory depression caused by opioid abuse. In certain embodiments, the ratio of oxycodone to naltrexone in the composition is from about 2% to about 30%. In another embodiment, the ratio of oxycodone to naltrexone in the composition is from about 2% to about 20%. In one embodiment, the ratio of oxycodone to naltrexone in the composition is from about 2:1(50%) to about 50:1 (2%). In a preferred embodiment, the ratio of oxycodone to naltrexone in the composition is from about 5:1(20%) to about 25:1 (4%). In a preferred embodiment, the ratio of oxycodone to naltrexone in the composition is from about 10:1(10%) to about 20:3 (15%).

In one embodiment, the ratio of hydrocodone to naltrexone in the composition is from about 1:1(100%) to about 100:1 (1%). In a preferred embodiment, the ratio of hydrocodone to naltrexone in the composition is from about 5:1(20%) to about 25:1 (4%). In a preferred embodiment, the ratio of hydrocodone to naltrexone in the composition is from about 10:1(10%) to about 20:3 (15%).

In one embodiment, the ratio of morphine to naltrexone in the composition is from about 1:1(100%) to about 100:1 (1%). In a preferred embodiment, the ratio of morphine to naltrexone in the composition is from about 5:1(20%) to about 25:1 (4%). In a preferred embodiment, the ratio of morphine to naltrexone in the composition is from about 50:1(2%) to about 20:3 (15%).

Respiration is the exchange of oxygen and carbon dioxide. Adequate respiration can be measured as maintaining arterial blood carbon dioxide and oxygen tension within normal ranges. Usually enough to sustain arterial blood CO₂And O₂Alveolar ventilation of (c) to describe ventilation. Unfortunately, arterial blood gas tension cannot be measured continuously and non-invasively. At best, intermittent blood gas sampling is possible, but this requires placement of invasive arterial lines and may be clinically inapplicable in certain research populations. Thus, arterial blood CO has been sought₂And O₂Alternative thereto, e.g. respectively end-tidal CO₂(carbon dioxide levels in human breath, which are 4% to 6% normal; this corresponds to 35 to 45mm Hg) and SpO₂(pulse oximetry provides arterial oxyhemoglobin saturation by non-invasively determining oxyhemoglobin saturation using light wavelengths (SaO)₂) An estimate of (d).

Ventilation requires an intact respiratory system (lung unit, open bowel airways) and an intact neural drive (brain stem respiratory center, spinal cord). The physical components of the measured (e.g., respiratory rate, tidal volume) and reported ventilation (minute ventilation = respiratory rate x tidal volume) may be measured alone or in combination. Neural drive can be determined by measuring the ventilatory response to induced hypoxia and/or hypercapnia. It is difficult for observers to determine the respiration rate, especially at low or irregular respiration rates. Indirect determination of respiration rate using changes in ECG resistance can produce respiration rates, but these are prone to error. End-tidal CO₂The trace measurement relies on the unobstructed airway, as is the tidal volume measurement from a respiratory airflow tachometer.

A characteristic type of opioid-induced respiratory depression is reduced respiration rate (hypopnea), with profound, sighing ventilation. Patients are usually conscious, but lack respiratory drive. The patient will follow when the verbal command is given to breathe, and will breathe when the instruction is given. Loss of central respiratory drive is characteristic of opioids, but it is difficult to quantify this characteristic.

Mean arterial blood carbon dioxide tension was 38mmHg and did not change with age. In contrast, arterial blood oxygen tension does vary with age (typically 94mmHg within the age range 20-29 and 81mmHg within the age range 60-69). Furthermore, whenever arterial blood oxygen tension is reported, it is important to indicate the fraction of inspired oxygen. For purposes of breath studies, it is preferred that the study be conducted by subjects breathing room air rather than supplemental oxygen.

If respiration is sufficient arterial blood CO₂And O₂Maintenance of tension, then respiratory depression may be defined as the inability to maintain those arterial blood CO₂And O₂Tension. Some papers have highlighted the difficulty in defining specific thresholds for respiratory depression, since arterial blood gas data is generally not known and therefore other respiratory parameters are chosen. There is currently no consensus as to which individual parameters or combinations of parameters adequately constitute respiratory depression.

Thus, for the purposes of this application, the primary threshold for respiratory depression may be the formation of hypercapnia, a condition in which abnormally high levels of carbon dioxide are present in the circulating blood (PaCO)₂>45 mmHg). In clinically significant respiratory depression, hypercapnia often occurs in combination with a decrease in ventilatory performance, often manifested as a decrease in respiratory rate, a decrease in end-tidal volume, a decrease in minute ventilation, a decrease in arterial blood pH, O₂Saturation reduction and end-tidal CO₂(ET CO₂) Elevated or transcutaneous CO₂Any combination of elevated levels. The reduction in respiratory depression induced by opioids using naltrexone can be demonstrated by: p_ETCO₂Significant decrease in aeration performance, increase in pH, O₂Elevated, hypercapnic ventilation (HCVR) -based ventilation-P_ETCO₂The increase in the slope of the relationship. Opioid-induced respiratory depression relief may be defined as at least 5% P_ETCO₂Reduced or 5% elevated ventilation or at least 5% hypercapnic ventilation-P_ETCO₂The increase in the slope of the relationship. In preferred embodiments, the reduction in opioid-induced respiratory depression will provide at least 10% P_ETCO₂Reduced or at least 10% elevated ventilation or at least 10% hypercapnic ventilation-P_ETCO₂The increase in the slope of the relationship. In a more preferred embodiment, the reduction in respiratory depression caused by opioids will provide at least 20% of P_ETCO₂Reduced or at least 20% elevated ventilation or at least 20% hypercapnic ventilation-P_ETCO₂The increase in the slope of the relationship.

Accordingly, the present invention relates to opioid analgesic pharmaceutical formulations and methods of administering those formulations wherein respiratory depression in a human is alleviated when the formulation has been compromised prior to administration to the human.

Further embodiments and features of the present invention are provided in the following non-limiting examples.

Examples

Example 1

Effect of intravenous naltrexone on morphine induced respiratory depression in healthy subjects

The respiratory depression study was a double-blind, randomized, 4-way crossover study in healthy subjects, male or female subjects between ages 21 and 35 (including 21 and 35 years of age), and in overall good health as determined by the investigator.

At part a dosing period 1, after a 15 day screening period, groups of 4 subjects meeting study inclusion/exclusion requirements were selected to receive randomized morphine sulfate injections of 10mg (N =3) or placebo (N =1) at a 3:1 ratio.

Each subject was admitted to the clinical unit on the evening of day-1 during each treatment period. On day 1, subjects received study drug and received pharmacodynamic, pharmacokinetic and safety assessment procedures. Subjects remained in the clinical unit until the morning of day 2, at which time they left the clinical unit at the investigator's discretion.

At the end of part a dosing period 1, investigators and sponsors evaluated non-blind safety and PD endpoint data to determine the suitability for increasing morphine sulfate doses to 20 mg.

A second group of 4 subjects, if deemed medically safe and appropriate, received injections of 20mg (N =3) or placebo (N =1) of morphine sulfate at a ratio of 3:1 at random. At the end of dosing period 2, investigators and sponsors evaluated non-blind safety and PD-focus data to determine the suitability of increasing morphine sulfate dose to 30 mg.

A second group of 4 subjects received 30mg (N =3) morphine sulfate or placebo (N =1) at a ratio of 3:1 at random if deemed medically safe and appropriate. At the end of dosing period 3, investigators and sponsors evaluated non-blind safety and PD-focus data, and made decisions regarding the appropriate dose of morphine sulfate injection, and entered phase B.

Subjects were confined to a clinical unit of about 40 hours (2 nights and 3 days) at each dosing period (IA-IIIA) of part a, and each dosing period was separated by a washout period of at least 7 days.

And part B: stage of treatment

Part B is a randomized, double-blind, placebo-controlled 4-way crossover study among 12 healthy subjects. After the screening period of part B15 days, subjects meeting study inclusion/exclusion requirements were selected and randomized into 4 treatment time series (1-4) as shown below. Each subject received all 4 treatments (A, B, C and D), each treatment being separated by a washout period of at least 1 week. The injectable dose of morphine sulfate used in part B was determined to be medically safe and suitable in part a.

TABLE 1 treatment regimen

Treatment A: morphine sulfate i.v. + placebo (saline) i.v.

Treatment B: morphine sulfate i.v. + naltrexone 4% i.v.

Treatment C: morphine sulfate i.v. + naloxone 4% i.v.

Treatment D: placebo (saline) i.v. + naltrexone 4% i.v

Doses of morphine sulphate (10, 20 or 30mg) will be determined from study part a. Naltrexone HCl and naloxone HCl (antagonists) of part B would be 4% of the morphine sulfate used in part B (e.g., 10mg morphine with 0.4mg antagonist, 20mg morphine with 0.8mg antagonist, and 30mg morphine with 1.2mg antagonist)

Each subject was admitted to the clinical unit on the evening of day-1 during each treatment period. On day 1, the subject received study drug and received pharmacodynamic, pharmacokinetic and safety assessment procedures. The subjects remained in the clinical unit until the 2 nd morning when they left the clinical unit at the investigator's discretion. Subjects remained in the clinical unit until the morning of day 2, at which time they left the clinical unit at the discretion of the investigator.

In each of the 4 treatment sessions (I-IV) of part B, subjects were confined to a clinical unit of about 40 hours (2 evenings and 3 daytime) with each treatment separated by a washout period of at least 7 days. Final safety assessments were performed at the study endpoint.

Intravenous solutions of morphine sulfate and naloxone HCl and naltrexone were obtained from commercial suppliers. The intravenous dose solution was drawn into a syringe and diluted with normal saline (0.9% sodium chloride for injection) so that the final volume of the dose solution for each drug was the same: morphine sulfate =10mg in 10mL saline; naltrexone =0.4mg in 10mL of saline; naloxone =0.4mg in 10mL saline and placebo =10mL saline. All study drugs (i.e., morphine + placebo; morphine + naltrexone; morphine + naloxone; and placebo + naltrexone) were administered intravenously, while using a dual-junction (bi-fuse) device connected to a submicrovolumetric catheter, which was delivered by a syringe infusion pump. This method of delivery allows for simultaneous injection of the two drugs with minimal mixing, thereby reducing the risk of intravenous compatibility problems. Each drug was infused over a2 minute period. The time and schedule of events for conducting the study are shown in table 2.

TABLE 2 Overall arrangement of time and events

¹Treatment periods will be separated between doses by a 7 day washout period.

²Defined as about 24 hours after IV administration of part B administration period.

³The physical examination will include height, weight and BMI.

⁴Clinical laboratory tests will be conducted.

⁵Screening for HIV-1, HIV-2, hepatitis B and hepatitis C.

⁶Vital signs (blood pressure, heart rate, respiration rate) will be determined. Vital signs will be continuously monitored during the period of part a and part B administration for the first 6 hours post administration. Oral temperature will be collected during screening and at registration prior to each dosing session (part a and part B).

⁷BIS will be monitored continuously until 6 hours after the dosing period of part B.

⁸Will complete breath flow tracing and breath induction plethysmography (RIP).

⁹The hypercapnic ventilation challenge will be developed at baseline (within 1 hour prior to dosing) and at 1 and 4 hours post-dosing. HCVR will be assessed at baseline (within 1 hour prior to dosing), at the lowest point of respiratory depression and after recovery of respiratory depression.

¹⁰Arterial blood gas will be determined.

¹¹PK sampling will be complete.

¹²Pupillometry will be completed.

As outlined in the time and event schedule (table 2), for dosing periods IA to IIIA and I to IV (part B), subjects will follow the procedure outlined below during every 40 hours left in the duke clinical study center. Each treatment will be separated between doses of study drug by a washout period of at least 1 week.

Study day-1 (evening before dosing)

Based on screening assessments, subjects meeting entry criteria will be reported to the DCRU at least 10 hours prior to dosing. Depending on the time of check-in, the subject may be provided with a suitable meal and/or snack. The following recorded procedure will be completed:

subjects will be assigned to treatment schedules according to a randomized schedule (part B only).

Urinary pregnancy test (female only).

Urine drug screening. For subjects to continue, the test must be negative.

Urine alcohol test. For subjects to continue, the test must be negative.

Determine the use of the combination and record on the eCRF.

Vital signs including oral cavity temperature.

All subjects will experience a minimum of 6 hours of supervised fasting prior to treatment. Except before and 2 hours after administration, water was allowed to drink as needed. During the hospitalization period, the subject was monitored throughout. The physician is informed by face or telephone at the time of the study.

Treatment period

After an overnight fast of at least 6 hours under supervision, the study procedure will be started. The subject will be confined to a bed at an angle of about 35 ° for at least 6 hours, during which time the subject will be rested in full cooperation with the investigator and personnel responsible for administering study medication, testing safety, and acquiring experimental data. One hour prior to study drug administration in parts a and B, 0.4mg of ondansetron was provided. All study drugs were administered intravenously and simultaneously over a2 minute period using a dual-linked mini-pump set capable of infusing both drugs simultaneously.

Breath emanation was performed every two hours for 15 minutes in a six hour period (portions a and B) following administration, at which time the subject was provided with a full fluid diet.

After the 6 hour time point, study participants could be ambulatory as allowed by the DCRU staff, at the discretion of the investigator. At that time, the subject will be given a standard lunch. Thereafter, there will be no restriction on water or walking, and a standard dinner may be served at night. Subjects will remain in the DCRU until 24 hours post-dose (day 2), and then the subjects will leave after meeting the study requirements.

Each treatment will be separated between doses by a washout period of at least 1 week.

Pharmacodynamic assay

The following procedure was completed for each treatment described in part a and part B.Will be referred to All sampling times were determined by the time at which drug infusion began.

Completing breath emanation tracing to determine division of timeClock ventilation, respiration rate, end-of-breath volume and CO₂: pre-dose (pre-dose baseline value) -30 min, -10 min and-5 min and 5, 15, 30 and 45 min and 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-study drug administration.

Intermittent sampling of arterial blood was done at the following times: 15 minutes (pre-dose) and 5, 15 and 30 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4,5 and 6 hours post-dose to determine arterial blood carbon dioxide levels (PaCO)₂) Arterial blood pH and oxygen saturation (SaO)₂)。

Pulse oximetry to detect oxygen saturation (SpO) was performed continuously from-30 minutes before dosing until 6 hours after dosing₂). Likewise, heart rate and blood pressure were detected using electrocardiographic telemetry, and transcutaneous carbon dioxide (PtcCO) was continuously monitored using a SenTec instrument₂) And brain electrical dual-frequency index (BIS) monitoring is used to monitor the level of consciousness over the same period. Measurements were recorded at-15 minutes (pre-dose) and 5, 15 and 30 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4,5, 6, 8, 12 and 24 hours post-dose.

Continuous monitoring of transcutaneous carbon dioxide (PtcCO) using a SenTec instrument₂) And brain electrical dual frequency index (BIS) monitoring will be used to monitor the level of consciousness over the same period.

Pupillometry was done-20 minutes before and 10, 20 and 40 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4,5, 6, 8, 12 and 24 hours after dosing.

Respiratory rate and minute ventilation from-30 minutes prior to dosing up to 6 hours post-dose were monitored using Respiratory Induced Plethysmography (RIP) as a secondary assay.

At the discretion of the investigator, hypercapnic ventilatory response (HCVR) challenges were completed at baseline (within 1 hour prior to dosing) and 1 hour and 4 hours post-dosing. Hypercapnic ventilation response was assessed at baseline, at the lowest point of respiratory depression and after recovery of respiratory depression.

Cardiac telemetry will be used continuously to monitor heart rate, blood pressure, respiration rate from-30 minutes up to 6 hours post-dose. Thereafter, vital signs will be taken for time points of 8, 12 and 24 hours after dosing, with the subject in a sitting position, with both feet flat on the floor. The subject should sit still for about 2 minutes before blood pressure and heart rate measurements are obtained.

Serial sampling of venous blood was accomplished as follows.

Pharmacokinetic determination

Blood sample collection and storage

Part A: in the study part a period, a total of up to 195mL of blood (13 samples per treatment x 5mL per sample x 3 treatments) was drawn for quantification of morphine, M3G and M6G concentrations in plasma. Blood samples were taken at time 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours post-dose at appropriately labeled K₂-EDTA(collection) tube. Naloxone or naltrexone was not analyzed during this part of the study.

Immediately after sampling, each blood collection tube was gently inverted several times to ensure complete mixing of the anticoagulant with the blood, before freezing in a freezer (or ice bath). Within 45 minutes after collection, the blood samples were centrifuged at 3,000RPM for 10 minutes at 4 ℃. Using appropriate pipetting techniques, plasma from each sample was transferred to 2 polypropylene screw cap transfer tubes (one primary and one spare) for labeling studies and subject information. Plasma samples were stored in a vertical position at-20 ± 10 ℃ or colder temperatures until analysis.

And part B: in part B of the study, up to 520mL total blood was drawn (13 samples per treatment x 10mL per sample x 3 treatments) for quantification of morphine, naloxone or naltrexone, and related metabolites (M3G, M6G, 6- β -naltrexone) concentrations in plasma. At time 0 (pre-administration) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,Blood samples were collected at appropriately labeled K at 12 and 24 hours₂-EDTA(collection) tube.

Immediately after sampling, each blood collection tube was gently inverted several times to ensure complete mixing of the anticoagulant with the blood, before freezing in a freezer (or ice bath). Within 45 minutes after collection, the blood samples were centrifuged at 3,000RPM for 10 minutes at 4 ℃. Using appropriate pipetting techniques, plasma from each sample was transferred to 2 polypropylene screw cap transfer tubes (one for morphine and one for naloxone/naltrexone) labeled study and subject information (i.e., donor name, study number, subject ID, date, nominal time, analyte). Plasma samples were stored in a vertical position at-20 ± 10 ℃ or colder temperatures until analysis.

The primary Pharmacodynamic (PD) parameter of interest will include the maximum effect that occurs within 4 hours of taking the study drug (e.g., PaCO)₂And ET CO₂E of (A)_max) Or minimal effect (e.g. MV, RR, ETCO)₂Slope and arterial blood pH E_min). For PaCO₂Other supportive parameters for MV would include from baseline (time 0) to 1 hour post-dose (AUE)_0-1h) 2 hours after Administration (AUE)_0-2h) 3 hours after Administration (AUE)_0-3h) 4 hours after Administration (AUE)_0-4h) And 6 hours after dosing (AUE)_0-6h) Area under the effect curve in time and time to maximum effect (T)_max)。

Primary endpoint

Peak arterial blood carbon dioxide (PaCO)₂)

Secondary endpoint

Minute Ventilation (MV)

Respiration rate

End of breath CO₂(ET CO₂)

MV to PaCO₂Slope of the curve (hypercapnia ventilation response)

Arterial blood pH

Arterial blood O₂Degree of saturation

Transcutaneous carbon dioxide levels (PtcCO)₂)

Pupil diameter

Brain electrical double frequency index (BIS)

Pharmacokinetic endpoint

Where applicable, the following pharmacokinetic parameters will be calculated for morphine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), naltrexone, 6- β -naltrexone, and naloxone:

peak concentration (C)_max) And peak concentration time (T)_max)

Area under plasma concentration time curve (AUC)

Distribution and elimination half-lives (t 1/2. alpha. and t 1/2. beta.) and Mean Residence Times (MRT)

System Clearance (CL)

Example 2

Effect of intravenous naltrexone on morphine-induced respiratory depression in male subjects with independent opioid preference

A single dose, three-way crossover study in 28 opioid-experienced, independent male subjects showed that naltrexone hydrochloride 1.2mg administered intravenously in combination with morphine sulfate 30mg (treatment a) significantly reduced morphine-induced respiratory depression compared to either morphine sulfate 30mg alone (treatment B) or normal saline (placebo, treatment C) (figure 4). With the crossover design, all subjects were randomized to three consecutive treatment doses. Subjects received one on each dosing day in a double-blind, crossover fashionDose (6 days between outpatient visits). EtCO₂Exploratory analysis of (D) detected a mean value for E in LS between all treatment groups_maxSignificant difference from partial AUEs (p)<0.0001). No EtCO was detected between the morphine + naltrexone and placebo groups₂The difference in level (p =0.3064) emphasizes the PD effect of morphine substitution by naltrexone on the μ -opioid receptor.

Example 3

Naltrexone dose range study to block oxycodone induced respiratory depression

Design and study plan:

this study is a randomized, double-blind, 5-way crossover study that assesses the effect of oral naltrexone on oxycodone-induced respiratory depression in healthy male and female adult subjects. The oxycodone threshold dose that caused respiratory depression was examined as a two-part study. In part A (Oxycodone dose response) An increasing single dose of an oxycodone Immediate Release (IR) tablet would be orally administered to healthy subjects to determine an appropriate dose of oxycodone that would safely cause a discernible reduction in respiratory function in healthy subjects, measured as reduced minute ventilation. The oxycodone dose selected from part a was used in part B (naltrexone dose response) in healthy subjects to evaluate the naltrexone dose response relationship associated with alleviation of oxycodone induced respiratory depression.

Screening

All subjects were asked to meet the study inclusion/exclusion criteria and the overall screening requirements to participate in part a and part B of the study. Screening was completed no more than 30 days prior to receiving study drug.

Part A: oxycodone dose response and naltrexone "test" doses

Part a of the study was completed in 6 healthy male and female subjects in a dose escalating fashion. This study evaluated safety and pharmacodynamic endpoints associated with a single dose of 40mg of IR oxycodone administered orally under non-mixed dose conditions according to the study procedure described below. If a single dose of 40mg of IR oxycodone is well tolerated, a second treatment consisting of a single dose of 80mg of IR oxycodone is administered. However, if an IR oxycodone dose of 40mg is not well tolerated, the oxycodone dose is reduced to 20 mg. All treatments will be separated by a washout period of at least 1 week.

Safety and PD were assessed prior to each dose increase, however, the objective was to select the maximum oxycodone dose for part B that could be safely tolerated and resulted in minute ventilation defined as inhibition, resulting in PaCO above 45mmHg₂Significant respiratory depression of the values (fig. 3). After the appropriate oxycodone dose was confirmed, 25mg of the "test dose" of naltrexone was administered along with the appropriate dose of oxycodone to confirm that administration of naltrexone in combination with oxycodone ameliorated the inhibition of respiration by oxycodone. Per minute ventilation, along with PaCO₂The concomitant decline and the regression baseline value, which is considered to be the "clinical recovery" of respiratory depression, to determine efficacy.

And part B: naltrexone dose response

The study of part B was completed in 12 healthy male and female adult subjects using a randomized, five-way crossover design in which a standard dose of oxycodone (e.g., 80mg) was co-administered with a varying (blind) dose of naltrexone, which was determined as a percentage of the oxycodone dose as described in table 1 and in the study drug and protocol below. The naltrexone dose used for treatments a-E ultimately depends on the oxycodone dose (20mg, 40mg or 80mg) selected from the part a study.

TABLE 1 naltrexone dosage depending on treatment

Amount of naltrexone in ALO-02(12% NTX)

Study procedure

Subjects admitted to a Clinical Research Unit (CRU) at the evening of day-1 for each dosing period. On day 1, after an overnight fast of at least 10 hours, the study procedure was started. Baseline measurements of HCVR were performed under hyperoxic and hypoxic challenge conditions. Similarly, arterial blood carbon dioxide (PaCO) was established using Respiratory Induced Plethysmography (RIP)₂) Systemic pH, transdermal carbon dioxide (PtcCO)₂) Tidal volume, and respiratory rate. Subjects received the study for 6 hours in a sitting position at an angle of 35 ° during which they were resting, in cooperation with the investigator (personnel) responsible for controlling study conditions, administering study medication, monitoring safety and obtaining primary and secondary endpoints.

An oral study drug consisting of a fixed dose of IR oxycodone in aqueous solution ± varying amounts of naltrexone (treatments A-E). Where applicable, certain PD evaluations (PtcCO) were subsequently performed continuously and recorded₂Respiratory rate, tidal volume). Yet others ((PaCO)₂And systemic pH) at specific time points (0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours) were determined according to the protocol. Similarly, serial sampling of venous blood was done before dosing (time 0) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dosing for determination of oxycodone, naltrexone and related metabolite concentrations in plasma.

Using ear clip as an estimate of arterial blood PaCO₂To determine percutaneous carbon dioxide (PtcCO)₂). Basal vital signs were determined using a cardiac monitor. In addition, subjects wear VivoMetrics life shirts containing elastic bands to determine the relative expansion of the chest and abdomen to determine tidal volume and respiration rate based on Respiratory Induction Plethysmography (RIP).

HCVR under high oxygen and hypoxia challenge conditions is the most laborious procedure, taking up to 20 minutes to complete each test. It was completed at time 0 (baseline) and 1, 2, 4 and 6 hours after study drug administration. The procedure involves passing throughThe plastic respirract mask was fixed to the face of the subject, after which the CO was controlled₂/O₂The mixed gas is delivered to the subject. This "rebreathing" technique is typically performed in two different O' s₂Performed under conditions of hypoxia (PO)₂50mmHg) and hyperoxia (PO)₂150 mmHg). Hypoxic conditions enhance peripheral chemoreceptor activity, whereby the ventilatory response remains a result of both central and peripheral chemoreceptor activity. In contrast, hyperoxic conditions inhibit peripheral chemoreceptor activity, reflecting (or isolating) central chemoreceptor activity, which is considered to be a key component associated with respiratory depression by lethal opioids.

At 6 hours post-dose, the arterial line will be removed after the 6 hour HCVR test is satisfactorily completed. Approximately 8 hours after dosing, subjects consumed a standard diet at the discretion of the investigator. Subjects remained in the CRU until the morning of day 2, when they left the CRU at the investigator's discretion. After a washout period of at least 7 days, subjects returned to CRU and the study procedure described above was repeated for treatment periods II-V. Final safety assessments were performed at the end of the study. Subjects were restricted to CRU for about 40 hours (2 evenings and 3 daytime) during each treatment period.

Time course of subject participation:

screening was included for about 10 weeks.

The study population is as follows:

24 subjects may participate in the study in an attempt to complete 6 subjects in part A and 12 subjects in part B.

Study drug and protocol

Oxycodone was provided as 5mg immediate release tablets.

Naltrexone was provided as 50mg tablets used to prepare a "stock" of naltrexone (0.5mg/mL) from which the naltrexone dose was made. An example of naltrexone treatment in relation to an 80mg oxycodone dose is shown below.

Treatment A0mL stock solution was added to 150mL apple juice

Treatment B2.0mL stock solution was added to 148mL apple juice

Treatment C9.6mL of stock solution added to 140.4mL of apple juice

Treatment D19.2mL stock solution was added to 130.8mL apple juice

Treatment E50mL stock solution was added to 100mL apple juice

Treatments A-E were followed by 90mL of water for administration of a total volume of 240mL of liquid per treatment.

Statistical method

Sample size

24 subjects will participate in the study in an attempt to complete 6 subjects in part a and 12 subjects in part B.

Analysis of population

The safe population consists of all patients receiving at least one dose of oxycodone. The PK/PD population consists of all patients undergoing intensive PK sampling and PD assessment for at least 6 hours.

Efficacy and/or PK/PD assays

Clock ventilation, arterial blood PaCO at primary endpoint₂And ventilation response to CO₂The slope of the curve. However, depending on the treatment, using descriptive statistics, the graphs summarize and classify data for all PDs and PD endpoints, including mean, standard deviation, median, minimum, maximum, and 95% Confidence Interval (CI) for the evaluable population. Dose response of naltrexone was examined graphically. The graph represents the time course for all PD determinations according to treatment.

All PD endpoints were analyzed using a mixed effects model for cross-over studies, with treatment, period and sequence as fixed effects and subjects within the sequence as random effects. Statistical significance of all treatment differences was reported using two-tailed significance criteria.

Security analysis

All AEs were coded into system organ classifications and preferred terms using the supervised active medical dictionary (MedDRA), and summarized according to age group and treatment group. Treatment-induced AEs were defined as AEs occurring at or after oxycodone administration. Adverse events triggered by treatment are summarized below:

the number of patients with AEs classified by systemic organs and preferred terminology;

the number of patients with AEs classified by maximum intensity, systemic organ classification, and preferred term;

by the number of patients with AEs in relation to study drug, systemic organ classification and preferred terminology;

the number of patients with SAEs classified by systemic organs and preferred terminology.

Clinical trial test data (chemical, hematological and urinalysis) were summarized at the screening follow-up period, post-operative period and treatment period, and subsequent assessment of safety after treatment, where applicable. Vital signs were summarized at each time point.

Example 4

Effect of intravenous naltrexone on oxycodone-induced respiratory depression in healthy subjects

A randomized, placebo-controlled, six-way, crossover study was performed to evaluate the effect of naltrexone (12% w/w) on the euphoric effect induced by oxycodone in adult subjects experiencing opioids. As part of the safety of this study, pulse oximetry was monitored periodically to monitor signs and symptoms of oxycodone-induced respiratory depression. FIG. 5 illustrates mean (+/-SE) oxygen saturation (SpO) over time₂) Level, which is 60mg of oxycodone orally; oxycodone 60mg + naltrexone 7.2mg (12%) and placebo followed by pulse oximetry.

The results show that naltrexone alleviates the respiratory depression effect of oxycodone, in addition to reducing the euphoric effect of 60mg of oxycodone. This relief is most pronounced at the approximate peak time of oxycodone and naltrexone absorption, about 1 hour after administration.

Claims (12)

1. An opioid analgesic formulation comprising a solid, controlled release oral dosage form comprising a plurality of multilayered pellets, each pellet comprising:

a) a water-soluble core;

b) an antagonist layer comprising naltrexone or a pharmaceutically acceptable salt of naltrexone coating the core;

c) a sequestering polymer layer coating the antagonist layer;

d) an agonist layer comprising an opioid or a pharmaceutically acceptable salt of the opioid coating the sequestering polymer layer; and

e) a controlled release layer coating the agonist layer,

wherein substantially no naltrexone or pharmaceutically acceptable salt of naltrexone is released when the formulation is administered intact to a human, and wherein respiratory depression induced in the human is alleviated by the release of naltrexone or pharmaceutically acceptable salt of naltrexone when the formulation is compromised prior to administration to the human.

2. The formulation of claim 1, wherein said alleviation of respiratory depression is by P_ETCO₂Is measured by the decrease in.

3. The formulation of claim 2, wherein said P is_ETCO₂The reduction of (b) is at least 5%.

4. The formulation of claim 1, wherein said alleviation of respiratory depression is by oxygen saturation (SpO)₂) The increase in level.

5. The formulation of claim 1, wherein the opioid is morphine or a pharmaceutically acceptable salt of morphine.

6. The formulation of claim 1 wherein the opioid is oxycodone or a pharmaceutically acceptable salt of oxycodone.

7. Use of an opioid analgesic formulation in the manufacture of a medicament for relieving respiratory depression induced by a human being following administration of a respiratory depression-mediating opioid drug, wherein the formulation comprises a plurality of multilayered pellets, each of the pellets comprising:

a) a water-soluble core;

b) an antagonist layer comprising naltrexone or a pharmaceutically acceptable salt of naltrexone coating the core;

c) a sequestering polymer layer coating the antagonist layer;

d) an agonist layer comprising an opioid or a pharmaceutically acceptable salt of the opioid coating the sequestering polymer layer; and

e) a controlled release layer coating the agonist layer,

wherein substantially no naltrexone or pharmaceutically acceptable salt of naltrexone is released when the formulation is administered intact to a human, and wherein respiratory depression induced in the human is alleviated by the release of naltrexone or pharmaceutically acceptable salt of naltrexone when the formulation is compromised prior to administration to the human.

8. The formulation of claim 7, wherein said alleviation of respiratory depression is by P_ETCO₂Is measured by the decrease in.

9. The formulation of claim 8, wherein said P is_ETCO₂The reduction of (b) is at least 5%.

10. The formulation of claim 7, wherein said alleviation of respiratory depression is by oxygen saturation (SpO)₂) The increase in level.

11. The formulation of claim 7, wherein the opioid is morphine or a pharmaceutically acceptable salt of morphine.

12. The formulation of claim 7 wherein the opioid is oxycodone or a pharmaceutically acceptable salt of oxycodone.