WO2018013771A1 - Traitement de la douleur au moyen de formulations d'hydrocodone - Google Patents

Traitement de la douleur au moyen de formulations d'hydrocodone Download PDF

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Publication number
WO2018013771A1
WO2018013771A1 PCT/US2017/041869 US2017041869W WO2018013771A1 WO 2018013771 A1 WO2018013771 A1 WO 2018013771A1 US 2017041869 W US2017041869 W US 2017041869W WO 2018013771 A1 WO2018013771 A1 WO 2018013771A1
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WIPO (PCT)
Prior art keywords
dosage form
hydrocodone
dose
hydrocodone bitartrate
fed
Prior art date
Application number
PCT/US2017/041869
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English (en)
Inventor
Walid A. HABIB
Ehab Hamed
Manuel A. Vega Zepeda
Randal A. SEBURG
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Cima Labs Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cima Labs Inc. filed Critical Cima Labs Inc.
Publication of WO2018013771A1 publication Critical patent/WO2018013771A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present disclosure relates to treatment of pain using opioid analgesics.
  • Hydrocodone is the most commonly prescribed opioid in the United States (IMS Institute for Healthcare Informatics, 2011), where, until recently, it was available only as an immediate-release (IR) formulation in combination with other nonopioid analgesics such as acetaminophen and ibuprofen (The American Society of Health- System Pharmacists, 2011).
  • IR immediate-release
  • acetaminophen and ibuprofen The American Society of Health- System Pharmacists, 2011.
  • Key limitations associated with the use of hydrocodone combination products include the toxicity profile of the nonopiod analgesic (acetaminophen-induced liver toxicity and gastrointestinal, renal, and cardiovascular complications associated with ibuprofen) (Barkin, 2001) and restrictions to dose titration due to the dosage ceiling of the nonopiod analgesic (American Pain Society, 2012).
  • Extended-release (ER) opioid formulations which can be administered once or twice daily, offer several advantages over IR formulations that require administration every 4 to 6 hours, including smaller fluctuations in peak-to-trough plasma concentrations, which may lead to more consistent control of pain (Beaulieu, 2007), and decreased dosing frequency, which potentially can improve adherence (Argoff, 2009; Beaulieu, 2007; McCarberg, 2001).
  • opioids have the potential to be abused when the tablets are ingested or when they are manipulated to increase the rate of opioid release (Argoff, 2009; Larochelle, 2015).
  • newer ER opioid formulations are being developed with properties that potentially make them less attractive to abusers (Larochelle, 2015).
  • a single-agent i.e., acetaminophen- and ibuprofen-free ER hydrocodone bitartrate formulation (Teva Branded Pharmaceutical Products R & D, Inc., Frazer, PA) was developed to provide sustained pain relief with doses of up to 90 mg twice daily (Darwish, 2015).
  • This hydrocodone ER formulation employs CIMA® Abuse-Deterrence Technology (ADT; CIMA LABS, Inc., Brooklyn Park, MN), a platform that is intended to hinder rapid release of hydrocodone when tablets are comminuted (i.e., broken into small pieces by crushing, milling, grating, or grinding) and to prevent dose dumping if the tablets are taken with alcohol (CIMA LABS Inc., 2012).
  • CIMA LABS Inc. CIMA LABS Inc., 2012
  • an analgesic dose (30, 45, 60, or 90 mg every 12 hours) in an open-label titration period and were treated with the identified dose in a 12-week double-blind treatment period.
  • patients receiving hydrocodone ER experienced significantly greater reductions in pain intensity than patients receiving placebo (Hale, 2015).
  • Food intake can alter the pharmacokinetics of certain medications and lead to variability in drug bioavailability by altering gastric pH, modifying absorption, delaying gastric emptying, and/or physically or chemically interacting with the formulation/drug substance (Charman, 1997; Singh, 1999).
  • Pharmacokinetic parameters included maximum hydrocodone plasma concentration (C max ) and area under the concentration-vs.-time curve from 0 to infinity (AUC 0 . ⁇ ) in Study 1 (day 1) and for one dosing interval at steady state (AUC YSS ) in Study 2 (day 11). Results indicated that the single-dose Cma X was 40% higher under fed vs. fasted conditions (least squares mean ratio [90% CI]: 1.40 [1.31, 1.51]; Study 1), while overall exposure was relatively similar (AUCo- ⁇ : 1.11 [1.06-1.16]).
  • extended release, abuse deterrent dosage forms in which the active ingredient consists essentially of hydrocodone, wherein administration of the dosage form to a subject in at least one dose per day over multiple days does not produce a therapeutically significant effect on one or more pharmacokinetic parameters following a first dose or at steady state.
  • Also provided are methods of treating pain in a subject comprising
  • administering to the subject at least one dose per day over multiple days of an extended release, abuse deterrent dosage form in which the active ingredient consists essentially of hydrocodone, wherein the administration does not produce a therapeutically significant effect on one or more pharmacokinetic parameters following a first dose or at steady state.
  • FIG. 1 Subject disposition.
  • ER extended release.
  • FIG. 2 Mean (+SD) plasma hydrocodone concentration through 72 hours and 12 hours (inset) after administration of a single dose of hydrocodone ER 90 mg in fed or fasted healthy subjects in Study 1 : pharmacokinetic analysis set.
  • FIG. 3 Mean (+SD) plasma hydrocodone concentration (single dose [day 1]; steady state [day 11]) after administration of hydrocodone ER 90 mg bid in fed or fasted healthy subjects in Study 2: pharmacokinetic analysis set.
  • FIG. 4 Fitted hydrocodone concentrations at single dose (a) and predicted hydrocodone concentrations at steady state (b) under fed and fasted conditions.
  • Key exclusion criteria included any clinically significant uncontrolled medical condition; any disorder that would interfere with absorption, distribution, metabolism, or excretion; a history of drug or alcohol abuse or habitual consumption of >21 units of alcohol per week; or clinically significant abnormalities in laboratory, electrocardiogram (ECG), or physical examination findings. Subjects were also excluded if they had used nicotine products within 12 months or topical or oral nicotine cessation products within 3 months of the first dose of hydrocodone ER or were poor metabolizers via CYP2D6.
  • subjects were administered hydrocodone ER on an empty stomach on the mornings of days 2-7 and evenings of days 2-6 and after a minimum 4-hour fast on the mornings of days 8-10 and evenings of days 7-10, whereas subjects in the fed state were administered hydrocodone ER approximately 30 minutes after ingesting a meal in the mornings and evenings of days 2-10.
  • the fed and fasted sequences were separated by a washout of >14 days.
  • Venous blood samples (3 mL) were collected for pharmacokinetic analyses within approximately 5 minutes before dosing and at various time points after dosing for 72 hours (single-dose study) or for the intended 12-hour dosing interval on days 1 and 1 1 (multiple- dose study).
  • Concentrations of hydrocodone and the active metabolite, hydromorphone, were determined using a validated high-performance liquid chromatography method with tandem mass spectrometric detection.
  • the validated quantifiable range of the assay was 0.100 to 100 ng/mL for hydrocodone and 0.0500 to 50 ng/mL for hydromorphone.
  • the pharmacokinetic parameters assessed included the Cniax, the time to Cmax (tmax), the apparent terminal half-life (tv 2 ), and the area under the plasma concentration -time curve (AUC) from time 0 to infinity (AUC 0 . ⁇ ).
  • the percentage extrapolation was also calculated as (AUC 0 . ⁇ - AUC 0 -t)/AUC 0 . ⁇ x 100, where AUC 0 . t represents AUC from time 0 to the time of the last quantifiabl e concentration.
  • Safety and tolerability were assessed by evaluating AEs, clinical laboratory data, 12-lead ECG data, physical examination findings, vital signs (i.e., pulse, blood pressure, and respiratory rate), oxyhemoglobin saturation monitoring (Sp0 2 ), and concomitant
  • the safety analysis sets in both studies included all subjects who received >1 dose of hydrocodone ER.
  • the pharmacokinetic analysis set included all subjects in the safety analysis set who had sufficient data to calculate pharmacokinetic parameters
  • the pharmacokinetic analysis set included all subjects in the safety analysis set who had sufficient data to calculate Cmaxss and AUC XSS (day 11) for both administration sequences.
  • Ratio is the geometric means ratio of the fed to fasted states.
  • hydrocodone ER Under fed conditions, 10%, 20%, and 70% of the bioavailable doses were absorbed via the fast, medium and slow absorption processes, respectively, while under fasted conditions, 10%, 0%, and 90% of the bioavailable doses were absorbed through them.
  • the slower absorption peak obviously did not influence the Cmax after the single dose but would influence the Cma X seen after multiple doses.
  • the influence of the slower absorption rate constant on any subsequent Cmax becomes more significant because of accumulation (i.e., the slower absorption rate under fasted conditions causes a proportion of the dose to be absorbed at a later time than under fed conditions, thereby contributing to overall concentrations that increase with subsequent doses until steady-state is attained).
  • ER formulations which are designed to provide controlled dmg release over time and thus have a higher drug content than JR formulations.
  • Dose dumping which can produce high systemic drug concentrations and possible toxicity, is a potential concern for any ER formulation (Fleisher, 1999) and is particularly critical for opioids.
  • the FDA generally requires that the food effect assessment be performed after single-dose administration only, it may be meaningful clinically to determine the effects of food on steady-state pharmacokinetics with ER opioid formulations as they are administered chronically.
  • the high-fat, high-calorie meal used in typical food-effect studies is also an extreme-case scenario relative to the fasted condition and it is understood that it does not necessarily represent a typical meal consumed by actual patients; so the results observed in these food-effect studies may exaggerate those that would be observed during real-world patient use.
  • the multiple-dose study also confirmed the simulations and hypotheses that food would have a non-clinically relevant, much less pronounced effect on hydrocodone maximum exposure (Cma x ) at steady state, with the 90% CIs for the LSM ratios for both hydrocodone Cma x ss and AUC y ss being completely within the pre-established range of 0.80 to 1.25 and enabling the conclusion of an absence of a food effect on the pharmacokinetics of hydrocodone ER at steady state.
  • BBaarrkkiinn R RLL. AAcceettaammiinnoopphheenn,, aassppiiririnn,, oorr iibbuupprrooffeenn iinn ccoommbbiinnaattiioonn aannaallggeessiicc pprroodduuccttss.. AAmm JJ TThheerr.. 22000011;;88((66))::443333--4422..
  • Hysingla ER [package insert]. Stamford, CT: Purdue Pharma; 2015.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formes pharmaceutiques inviolables à libération prolongée dans lesquelles la substance active est essentiellement constituée d'hydrocodone, l'administration de la forme pharmaceutique à un sujet à au moins une dose par jour sur plusieurs jours ne produisant pas un effet thérapeutiquement significatif sur un ou plusieurs paramètres pharmacocinétiques après une première dose ou à l'état stationnaire. L'invention concerne en outre des procédés de traitement de la douleur au moyen de telles formes pharmaceutiques.
PCT/US2017/041869 2016-07-13 2017-07-13 Traitement de la douleur au moyen de formulations d'hydrocodone WO2018013771A1 (fr)

Applications Claiming Priority (2)

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US201662362017P 2016-07-13 2016-07-13
US62/362,017 2016-07-13

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010149169A2 (fr) * 2009-06-24 2010-12-29 Egalet A/S Formulations à libération contrôlée
WO2011106416A2 (fr) * 2010-02-24 2011-09-01 Cima Labs Inc. Formulations à l'épreuve d'un usage abusif
US9216176B2 (en) 2006-09-15 2015-12-22 Cima Labs Inc. Abuse resistant drug formulation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9216176B2 (en) 2006-09-15 2015-12-22 Cima Labs Inc. Abuse resistant drug formulation
WO2010149169A2 (fr) * 2009-06-24 2010-12-29 Egalet A/S Formulations à libération contrôlée
WO2011106416A2 (fr) * 2010-02-24 2011-09-01 Cima Labs Inc. Formulations à l'épreuve d'un usage abusif

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
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"OraGuardTM: tamper-deterrent, alcohol-resistant extended release technology", 15 March 2016, CIMA LABS INC.
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BEAULIEU AD; PELOSO P; BENSEN W ET AL.: "A randomized, double-blind, 8-week crossover study of once-daily controlled-release tramadol versus immediate-release tramadol taken as needed for chronic noncancer pain", CLIN THER., vol. 29, no. 1, 2007, pages 49 - 60, XP022041510, DOI: doi:10.1016/j.clinthera.2007.01.001
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DARWISH M; BOND M; ROBERTSON P, JR. ET AL.: "Effect of food intake on the pharmacokinetics of a novel extended-release hydrocodone tablet formulated with OraGuardTM technology [abstract", PAINWEEK, 5 September 2012 (2012-09-05), Retrieved from the Internet <URL:http://conference.painweek.org/media/mediafile attachements/02/572-painweek2012abstracts.pdf.>
DARWISH M; BOND M; SHU C ET AL.: "Effect of food on the pharmacokinetics of the hydrocodone extended-release tablet in healthy volunteers [abstract 404", J PAIN, vol. 13, no. 4, 2012, pages S77
DARWISH M; BOND M; TRACEWELL W ET AL.: "Pharmacokinetics of hydrocodone extended-release tablets formulated with different levels of coating to achieve abuse deterrence compared with a hydrocodone immediate-release/acetaminophen tablet in healthy subjects", CLIN DRUG INVESTIG., vol. 35, no. 1, 2015, pages 13 - 22
DARWISH M; YANG R; TRACEWELL W ET AL.: "Effects of renal impairment and hepatic impairment on the pharmacokinetics of hydrocodone after administration of a hydrocodone extended-release tablet formulated with abuse-deterrence technology", CLIN PHARMACOL DRUG DEV., vol. 5, no. 2, 2016, pages 141 - 9
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DARWISH MONA ET AL: "Single- and Multiple-dose Pharmacokinetics of a Hydrocodone Bitartrate Extended-release Tablet Formulated With Abuse-deterrence Technology in Healthy, Naltrexone-blocked Volunteers", CLINICAL THERAPEUTICS, vol. 37, no. 2, February 2015 (2015-02-01), pages 390 - 401, XP002774603 *
FARR SJ; ROBINSON CY; RUBINO CM.: "Effects of food and alcohol on the pharmacokinetics of an oral, extended-release formulation of hydrocodone in healthy volunteers", CLIN PHARMACOL., vol. 7, 2015, pages 1 - 9
FLEISHER D; LI C; ZHOU Y ET AL.: "Drug, meal and formulation interactions influencing drug absorption after oral administration", CLINICAL IMPLICATIONS. CLIN PHARMACOKINET, vol. 36, no. 3, 1999, pages 233 - 54
HALE ME; ZIMMERMAN TR; EYAL E ET AL.: "Efficacy and safety of a hydrocodone extended-release tablet formulated with abuse-deterrence technology in patients with moderate-to-severe chronic low back pain", J CLIN PHARMACOL., 2016
HYSINGLA ER; STAMFORD, CT, PURDUE PHARMA, 2015
IMS INSTITUTE FOR HEALTHCARE INFORMATICS: "The use of medicines in the United States: review of 2010", 2011, IMS INSTITUTE FOR HEALTHCARE INFORMATICS
INTERNATIONAL CONFERENCE ON HARMONISATION WORKING GROUP: "International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use", ICH HARMONISED TRIPARTITE GUIDELINE: GUIDELINE FOR GOOD CLINICAL PRACTICE E6 (R1, 10 June 1996 (1996-06-10), Retrieved from the Internet <URL:http://www.ich.org/fileadmin/Public Web Site/ICH Products/Guidelines/Efficacy/E6/E6 Rl G uideline.pdf>
KAPIL RAM P ET AL: "Pharmacokinetic Profile and Sustained 24-hour Analgesia of a Once-daily Hydrocodone Bitartrate Extended-release Tablet with Abuse-deterrent Properties", CLINICAL THERAPEUTICS, EXCERPTA MEDICA, PRINCETON, NJ, US, vol. 38, no. 2, 31 December 2015 (2015-12-31), pages 302 - 314, XP029421955, ISSN: 0149-2918, DOI: 10.1016/J.CLINTHERA.2015.12.003 *
LAROCHELLE MR; ZHANG F; ROSS-DEGNAN D ET AL.: "Rates of opioid dispensing and overdose after introduction of abuse-deterrent extended-release oxycodone and withdrawal of propoxyphene", JAMA INTERN MED., vol. 175, no. 6, 2015, pages 978 - 87
MCCARBERG BH; BARKIN RL.: "Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia", AM J THER., vol. 8, no. 3, 2001, pages 181 - 6
SINGH BN.: "Effects of food on clinical pharmacokinetics", CLIN PHARMACOKINET, vol. 37, no. 3, 1999, pages 213 - 55, XP009176403, DOI: doi:10.2165/00003088-199937030-00003
STEPHEN FARR ET AL: "Effects of food and alcohol on the pharmacokinetics of an oral, extended-release formulation of hydrocodone in healthy volunteers", CLINICAL PHARMACOLOGY: ADVANCES AND APPLICATIONS, 1 January 2015 (2015-01-01), pages 1, XP055414992, DOI: 10.2147/CPAA.S70831 *
THE AMERICAN SOCIETY OF HEALTH-SYSTEM PHARMACISTS: "The American Society of Health-System Pharmacists", HYDROCODONE, 2011, Retrieved from the Internet <URL:http://www.nlm.nih.gov/medlineplus/druginfo/meds/a60 1006.html>
US FOOD AND DRUG ADMINISTRATION: "Guidance for Industry", 2002, U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES, article "Food-effect bioavailability and fed bioequivalence studies"

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