U.S. patent number RE41,571 [Application Number 11/799,610] was granted by the patent office on 2010-08-24 for method of providing sustained analgesia with buprenorphine.
This patent grant is currently assigned to Purdue Pharma L.P.. Invention is credited to Paul D. Goldenheim, Robert F. Kaiko, Robert F. Reder.
United States Patent |
RE41,571 |
Reder , et al. |
August 24, 2010 |
**Please see images for:
( Certificate of Correction ) ** |
Method of providing sustained analgesia with buprenorphine
Abstract
A method of effectively treating pain in humans is achieved by
administering buprenorphine in accordance with first order kinetics
over an initial three-day dosing interval, such that a maximum
plasma concentration from about 20 pg/ml to about 1052 pg/ml is
attained, and thereafter maintaining the administration of
buprenorphine for at least an additional two-day dosing interval in
accordance with substantially zero order kinetics, such that the
patients experience analgesia throughout the at least two-day
additional dosing interval.
Inventors: |
Reder; Robert F. (Greenwich,
CT), Kaiko; Robert F. (Weston, CT), Goldenheim; Paul
D. (Wilson, CT) |
Assignee: |
Purdue Pharma L.P. (Stamford,
CT)
|
Family
ID: |
26715643 |
Appl.
No.: |
11/799,610 |
Filed: |
May 1, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
11033106 |
Jan 11, 2005 |
|
|
|
|
60038919 |
Feb 24, 1997 |
|
|
|
Reissue of: |
08939068 |
Sep 29, 1997 |
05968547 |
Oct 19, 1999 |
|
|
Current U.S.
Class: |
424/449; 424/443;
424/447; 424/446 |
Current CPC
Class: |
A61P
29/00 (20180101); A61P 25/04 (20180101); A61P
25/36 (20180101); A61P 25/00 (20180101); A61K
9/7053 (20130101); A61K 9/7023 (20130101); A61K
9/0014 (20130101); A61K 31/4748 (20130101); A61K
9/7061 (20130101); A61K 31/485 (20130101); A61K
9/0019 (20130101) |
Current International
Class: |
A61F
13/00 (20060101); A61K 9/70 (20060101) |
Field of
Search: |
;424/449,443,446,447,489 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
3526339 |
|
Jan 1992 |
|
DE |
|
3546830 |
|
Jul 1995 |
|
DE |
|
19840758 |
|
Mar 2000 |
|
DE |
|
0368409 |
|
May 1990 |
|
EP |
|
430019 |
|
Jun 1991 |
|
EP |
|
432945 |
|
Jun 1991 |
|
EP |
|
819438 |
|
Jan 1998 |
|
EP |
|
821957 |
|
Feb 1998 |
|
EP |
|
1422230 |
|
May 2004 |
|
EP |
|
2165148 |
|
May 1989 |
|
GB |
|
166095 |
|
Mar 1995 |
|
PL |
|
9619975 |
|
Dec 1994 |
|
WO |
|
95/01167 |
|
Jan 1995 |
|
WO |
|
95/20393 |
|
Aug 1995 |
|
WO |
|
96/19975 |
|
Jul 1996 |
|
WO |
|
1997-004835 |
|
Feb 1997 |
|
WO |
|
97/48380 |
|
Dec 1997 |
|
WO |
|
1998-026780 |
|
Jun 1998 |
|
WO |
|
98/36728 |
|
Aug 1998 |
|
WO |
|
1999-012529 |
|
Mar 1999 |
|
WO |
|
1999-032120 |
|
Jul 1999 |
|
WO |
|
2000-035456 |
|
Jun 2000 |
|
WO |
|
2002-070524 |
|
Sep 2002 |
|
WO |
|
2002-085268 |
|
Oct 2002 |
|
WO |
|
2003-079945 |
|
Oct 2003 |
|
WO |
|
2004-103317 |
|
Dec 2004 |
|
WO |
|
2005-011579 |
|
Feb 2005 |
|
WO |
|
Other References
Buprenorphine: Differential Interaction with Opiate Receptor
Subtypes in Vivo, Wolfgang Sadee, et al., The Journal of
Pharmacology and Experimental Therapeutics, Copyright.RTM. 1982,
vol. 223, No. 1, pp.. 157-162. cited by other .
Human Pharmacolinetics of Intravenous, Sublingual and Buccal
Buprenorphine*, James J. Kuhlman, Jr., et al., Journal of
Analytical Toxicology, vol. 20, Oct. 1996. cited by other .
Transdermal Delivery of Buprenorphine through Cadaver Skin, Samir
D. Roy, et al., Journal of Pharmaceutical Sciences, vol. 83, No. 2,
Feb. 1994, pp. 126-130. cited by other .
Pharmacolinetic evaluation of transdermal burenorphine in man, I.R.
Wilding, et al., International Journal of Pharmaceutics 132 (1996)
81-87. cited by other .
Ling et al. A controlled trial comparing buprenorphine and
methadone maintenance in opiod dependence. Arch Gen Psychiatry.
1996 May;53(5):401-7. cited by other .
Catapres TTS.RTM. Product Information, Physicians' Desk Reference
1998, pp. 610-612. cited by other .
Climara.RTM. Product Information, Physicians' Desk Reference 1998,
pp. 672-676. cited by other .
Kuhlman, Jr., et al., Human pharmacokinetics of intravenous,
sublingual, and buccal buprenorphine. J Anal Toxicol. Oct. 1996:
20(6);369-78. cited by other .
McQuinn, R.L. et al., Sustained oral mucosal delivery in human
volunteers of buprenophine from a thin non-croding mucoadhesive
polymeric disk. Journal of Controlled Release 1995, 34:243-50.
cited by other .
Roy et al., Transdermal delivery of buprenorphine through cadaver
skin. J Pharma Sci 1994, 83(2):126-30. cited by other .
Sadee et al., Buprenorphine: Differential interaction with opiate
receptor subtypes in vivo. The Journal of Pharmacology and
Experimental Therapeutics, Copyright .COPYRGT. 1982, 223(1):157-62.
cited by other .
Van Buskirk et al., Scale-up of adhesive transdermal drug delivery
systems. Pharmaceutical Research 1997, 14(7). cited by other .
Wilding et al., Pharmacokinetic evaluation of transdermal
buprenorphine in man. International Journal of Pharmaceutics 1996,
132:81-7. cited by other .
Ashcroft et al., Buprenorphine TDS: Comparison with sublingual
buprenorphine in osteoarthritic pain. 10.sup.th World Congress on
Pain, Aug. 19, 2002 Abstract 510-P144. cited by other .
Becker et al., Transdermal buprenorphine: Abuse potential
assessment in non-opioid-dependent volunteers. CPDD Jun. 16-21,
2001 Abstract 40 (w/ PowerPoint presentation). cited by other .
Boas et al., Clinical actions of fentanyl and buprenorphine the
significance of receptor binding. Br. J. Anaesth. 1985, 57:192-6.
cited by other .
Buprenorphine Product Photo, Norspan.TM. 5, 10 & 20. cited by
other .
Capurso et al., Matrix transdermal technology: focus on a
buprenorphine transdermal system. ASHP Midyear Clinical Meeting,
Dec. 2001, p. 231D Abstract (w/ PowerPoint presentation). cited by
other .
Colucci, History of Buprenorphine. PowerPoint presentation
presented in Dec. 2002. cited by other .
El-Tahtawy et al., 7-Day bioavailability of buprenorphine from a
novel transdermal system in demographic subgroups. 13.sup.th Annual
ACCP Meeting Abstracts, Sep. 23-25, 2001, p. 1027, Abstract 56 (w/
PowerPoint presentation). cited by other .
Friend et al., Simple alkyl esters as skin permeation enhancers. J.
Controlled Release 1998 9:33-41. cited by other .
Friend et al., Transdermal delivery of levonorgestrel I: Alkanols
as permeation enhancers in vitro, J. Controlled Release 1988
7:243-50. cited by other .
Hale et al., Analgesic efficacy of buprenorphine transdermal system
vs. Oxy/APAP in patients with chronic low back pain. The
Gerontologist, vol. 41, Special Issue 1, Oct. 2001, Program
Abstracts from the Gerontological Society of America 54.sup.th
Annual Scientific Meeting, Nov. 15-18, 2001, p. 25 (w /PowerPoint
presentation first presented on May 7, 2002 and revised on Oct. 30,
2002). cited by other .
Hale et al., Dose proportionality and the dose response of
buprenorphine transdermal system in patients with chronic pain.
13.sup.th Annual ACCP Meeting Abstracts, Sep. 23-25, 2001, p. 1027,
Abstract 58(w/ PowerPoint presentation). cited by other .
Hale et al., Long-term use of buprenorphine transdermal system
(BTDS) in patients with chronic pain. PowerPoint presentation
presented May 2002. cited by other .
Hale et al., Treatment of patients with chronic low back pain with
buprenorphine transdermal system (BTDS) compared with
hydrocodone/acetaminophen. National Clinical Symposium of the
American College of Nurse Practitioners, Oct. 20, 2001 Abstract (w/
PowerPoint presentation). cited by other .
Jaffe et al., Opioid Analgesics and Antagonists. The
Pharmacological Basis of Therapeutic (8.sup.th ed. Pergamon Press)
1990, Chap. 21, pp. 485-521. cited by other .
Jeal et al., Transdermal fentanyl. A review of its pharmacological
properties and therapeutic efficacy in pain control. Drugs Jan.
1997, 53(1):109-38. Review. cited by other .
Kaiko et al., Transdermal buprenorphine. Memorial Sloan Kettering
Manuscript, Chapter 15 (w/ PowerPoint Final presentation presented
May 2, 2003). cited by other .
Lasseter et al., Systemic pharmacokinetic (PK) Study of
buprenorphine (B) in mild to moderate chronic hepatic impairment
(CHI). Amer. Society for Clinical Pharmacology and Therapeutics
69(2) 2(PI-4) Feb. 2001 Abstract (w/ PowerPoint presentation
presented Mar. 2001). cited by other .
Marquardt et al., Fentanyl remaining in a transdermal system
following three days of continuous use. Ann Pharmacother Oct. 1995,
29(10):969-71. cited by other .
Muller et al., Intra--and postoperative interactions between the 2
opioids fentanyl and buprenorphine. Anaesthesist. Apr. 1986,
35(4):219-25. (in German, w/ English abstract). cited by other
.
Noveck et al., Pharmacokinetics of buprenorphine transdermal system
(BTDS 10) employing the LPS pyrogen model. Clinical Pharmacology
& Therapeutics 69(2):3 200 2001 Abstract PI-7 (w/ PowerPoint
presentation). cited by other .
Payne et al., Guidelines for the clinical use of transdermal
fentanyl. Anticancer Drugs. Apr. 1995, 6 Suppl 3:50-3. cited by
other .
Peng et al., A review of the use of fentanyl analgesia in the
management of acute pain in adults. Anaesthesiology 1999,
90:576-99. cited by other .
Reidenberg et al., Absolute bioavailability of a novel
buprenorphine transdermal system (BTDS) applied for 7 days. J. Clin
Pharmacol. 2001 41(9):1014-1033, Abstract 55, p. 1026 (w/
PowerPoint presentation presented in the ACCP Meeting, Sep. 2001).
cited by other .
Reidenberg et al., Daily pharmacokinetic performance of a
buprenorphine transdermal system (BTDS) for up to 7 days. J. Clin
Pharmacol. 2001 41(9):1014-1033, Abstract 57, p. 1027 (w/
PowerPoint presentation). cited by other .
Reidenberg et al., Pharmacokinetics and safety of buprenorphine
transdermal system (BTDS) for 7-Day application comparing healthy
elderly and young adult subjects. Am Pain Soc, 19.sup.th Ann. Sci.
Meet., Nov. 2-5, 2000 Abstract 776 (w/ PowerPoint presentation).
cited by other .
Reidenberg et al., Physiologic effects of buprenorphine transdermal
system (BTDS) dose escalation in the young, healthy elderly and
elderly hypertensive subjects, FASEB J. 154), Mar. 2001 Abstract
457.3 (w/ PowerPoint presentation presented Apr. 2001). cited by
other .
Roy et al., "Controlled transdermal delivery of fentanyl:
characterizations of pressure-sensitive adhesives for matrix patch
design," J Pharm Sci. May 1996, 85(5):491-5. cited by other .
Sandler et al., A double-blind, placebo-controlled trial of
transdermal fentanyl after abdominal hysterectomy. Analgesic,
respiratory, and pharmacokinetic effects. Anesthesiology Nov. 1994,
81(5):1169-80; discussion 26A. cited by other .
Spyker et al., Effectiveness and safety of buprenorphine
transdermal system (BTDS) compared with hydrocodone/acetaminophen
in the treatment of patients with chronic low back pain. J. Pain
2002 3(Suppl.1):14 Abstract 653 (w/ PowerPoint presentation). cited
by other .
Spyker et al., Effectiveness of buprenorphine transdermal system
(BTDS) compared with oxycodone/acetaminophen and placebo in the
treatment of patients with chronic back pain. Morial Convention
Center, Oct. 15, 2001 Abstract (w/PowerPoint presentation). cited
by other .
Spyker et al., Transdermal buprenorphine system (BTDS) in
patient-controlled Analgesia (PCA). PowerPoint presentation
presented Mar. 2000. cited by other .
Spyker et al., Analgesic efficacy and safety of buprenorphine
transdermal system (BTDS) in patients with osteoarthritis. The
Journal of Pain 3(2, Supp. 1):12 Abstract 645 (w/ PowerPoint
presentation). cited by other .
Spyker et al., Effect Size (ES) Meta-analysis Approach to
Noinferiority Clinical Trials. Clinical Pharmacology &
Therapeutics 69(2):33 Abstract PII-3 (w/ PowerPoint presentation
presented Mar. 5, 2001). cited by other .
Transtec Summary of Product Characteristics, Oct. 2003. cited by
other .
Adriaensen et al. A long-term open, clinical and pharmacokinetic
assessment of sublingual buprenorphine in patients suffering from
chronic pain. Acta Anaesthesiol Belg. Mar. 1985; 36(1)33-40. cited
by other .
Amass et al. A preliminary investigation of outcome following
gradual or rapid buprenorphine detoxification. J Addict Dis. 1994;
13:33-45. cited by other .
Amass et al. Alternate-day dosing during buprenorphine treatment of
opioid dependence. Life Sci. 1994;54:1215-28. cited by other .
Amass et al. Detectability of buprenorphine dose alterations in
opioid-dependent humans. NIDA Res Monogr. 1993; 132:335. cited by
other .
Arditti et al. [Buprenorphine abuse in a series of 50 drug addicts
hospitalized at a drug dependence evaluation hospital center of
Marseille] Therapie. 1992; 47:561-2. [in French w/ English transl].
cited by other .
Banerjee et al. Haematological changes in buprenorphine-treated
mice. Folia Biol (Krakow). 1997;45(3-4):157-62. cited by other
.
Banks. Overdosage of buprenorphine: case report. N Z Med J. 1979;
89:255-6. cited by other .
Banys et al. An open trial of low dose buprenorphine in treating
methadone withdrawal. J Subst Abuse Treat. 1994;11:9-15. cited by
other .
Barrett et al. The pharmacokinetics and physiological effects of
buprenophine infusion in premature neonates. Br J Clin Pharmacol.
Sep. 1993;36(3):215-9. cited by other .
Barron et al. Prenatal buprenorphine exposure and sexually
dimorphic nonreproductive behaviors in rats. Pharmacol Biochem
Behav, Oct. 1997;58(2):337-43. cited by other .
Basu et al. Buprenorphine dependence: a new addiction in India.
Disabil Impair. 1990; 3:142-6. cited by other .
Baumevieille et al. Abuse of prescription medicines in southwestern
France. Ann Pharmacother 1997; 31:847-50. cited by other .
Bedi et al. Abuse Liability of Buprenorphine--A study Among
Experienced Drug Users. Indian J Physiol. Pharmacol. 1998;42(1),
95-100. cited by other .
Benos. [A case of secondary buprenorphine (Temgesic.RTM.)
dependence] Der Nervenarzt. 1983;54:259-61. [in German w/ English
trans]. cited by other .
Biagini et al. Evaluation of cutaneous responses and lung function
from exposure to opiate compounds among ethical
narcotics-manufacturing workers. J Allergy Clin Immunol. Jan. 1992;
89(1 Pt 1):108-18. cited by other .
Bickel et al. A clinical trial of buprenorphine: comparison with
methadone in the detoxification of heroin addicts. Clin Pharmacol
Ther. 1988;43:72-8. cited by other .
Bickel et al. A clinical trial of buprenorphine: I. Comparison with
methadone in the detoxification of heroin addicts. II. Examination
of its opioid blocking properties. NIDA Res Monogr. 1987;76:182-8.
cited by other .
Bickel et al. Buprenorphine: dose-related blockade of opioid
challenge effects in opioid dependent humans. J Pharmacol Exp Ther.
Oct. 1988;247(1):47-53. cited by other .
Bickel et al. Buprenorphine treatment of opioid dependence: a
review. Exp Clin Psychopharmacology 1995; 3:477-89. cited by other
.
Bickel et al. Effects of adding behavioral treatment to opioid
detoxification with buprenorphine. J Consult Clin Psychol. Oct.
1997;65(5):803-10. cited by other .
Bigelow (w/ Introduction by Blaine). Assessment of buprenorphine in
a drug discrimination procedure in humans. Buprenorphine: An
alternative Treatment for Opioid Dependence. NIDA Res Monogr.
1992;121:28-37. cited by other .
Bigelow et al. Abuse liability assessment of buprenorphine-naloxone
combinations. NIDA Res Monogr. 1987;76:145-9. cited by other .
Bigelow, Buprenorphine: Combatting drug abuse with a unique opioid.
1995;(Foreword):xi-Xiii. cited by other .
Bigelow, Human drug abuse liability assessment: opioids and
analgesics. Br J Addict. 1991; 86:1615-23. cited by other .
Blaine, Introduction, NIDA Res. Monogr. 1992;1-4. cited by other
.
Budd. High dose buprenorphine for postoperative analgesia.
Anaesthia. Sep. 1981;36(9):900-3. cited by other .
Bullingham et al. Buprenorphine kinetics. Clin Pharmacol Ther. Nov.
1980;28(5)667-72. cited by other .
Bullingham et al. Clinical pharmacokinetics of narcotics
agonist-antagonist drugs. Clin Pharmacokinet. Jul.-Aug.
1983;8(4):332-43. cited by other .
Bullingham et al. Sublingual buprenorphine used postoperatively:
ten hour plasma drug concentration analysis. Br J Clin Pharmacol.
May 1982;13(5):665-73. cited by other .
Buprenorphine is now a controlled drug. Drug Ther Bull. Oct. 16,
1989;27(21):84. cited by other .
Buprenorphine RTECS Info. In: RTCES Registry No. 52485-79-7. Jan
13, 2000. cited by other .
Buprenorphine RTECS Record. In: RTCES Registry No. 52485-79-7. Apr.
25, 2000. cited by other .
Carl et al. Pain relief after major abdominal surgery: a
double-blind controlled comparison of sublingual buprenorphine,
intramuscular buprenorphine, and intramuscular meperidine. Anesth
Analg. Feb. 1987; 66(2):142-6. cited by other .
Cervera et al. [Addiction to buprenorphine] Rev Clin Esp 1989;
184:159. Letter. [in Spanish w/ English transl]. cited by other
.
Cheskin et al. A controlled comparison of buprenorphine and
clonidine for acute detoxification from opiods. Drug Alchol Depend
1994;36:115-21. cited by other .
Clausen et al. Legal opioid consumption in Denmark 1981-1983, Eur J
Clin Pharmacol. 1995;48(5):321-5. cited by other .
Cowan et al. Agonist and antagonist properties of buprenorphine, a
new antinociceptive agent. Br J Pharmacol. Aug. 1977;60(4):537-45.
cited by other .
Cowan et al. The animal pharmacology of buprenorphine, an oripavine
analgesic agent. Br J Pharmacol. Aug. 1977;60(4):547-54. cited by
other .
Cowan. Update on the general pharmacology of buprenorphine.
Buprenorphine: Combatting Drug Abuse with a Unique Opioid,
1995;31-47. cited by other .
D'Arcy, [Drug reactions and interactions after drug reactions and
interactions] J Pharm Belg. Sep-Oct. 1988;43(5):401-4. [in French
w/ partial English transl]. cited by other .
Davies et al. Pharmacokinetics of opioids in renal dysfunction.
Clin Pharmacokinet. Dec. 1996;31(6):410-22. cited by other .
Dertwinkel et al. Clinical status of opioid tolerance in long-term
therapy of chronic noncancer pain. In: Progress in Pain Research
and Management. Opioid Sensitivity of Chronic Noncancer Pain, Kalso
et al., eds. 1999; 14:129-41. cited by other .
Diamant et al. Outpatient opiate detoxification treatment with
buprenorphine. Preliminary investigation. Eur Addict Res.
1998;4:198-202. cited by other .
Dini et al. [Controlled study of the analgesic effect and
tolerability of buprenorphine in cancer patients] Minerva Med. Jan.
28, 1986;77(3-4):93-104, [in Italian w/ English abstract]. cited by
other .
Dum et al. In vivo receptor binding of the opiate partial agonist,
buprenorphine, correlated with its agonistic and antagonistic
actions, Br J Pharmacol. Nov. 1981;74(3):627-33. cited by other
.
Eissenberg et al. Buprenorphine's physical dependence potential:
antagonist-precitated withdrawal in humans. J Pharmacol Exp Ther.
1996; 276:449-59. cited by other .
Eissenberg et al. Controlled opioid withdrawal evaluation during 72
h dose omission in buprenorphine-maintained patients. Drug Alchol
Depend. Apr. 14, 1997;45(1-2):81-91. cited by other .
Faroqui et al. Buprenophine, benzodiazepines and respiratory
depression. Anaesthesia. Oct. 1983;38(10):1002. cited by other
.
Fincham. Cardiopulmonary arrest and subsequent death administration
of buprenorphine in an elderly female: a case report. J. Geriatric
Drug Ther. 1989;3(3):103-5. cited by other .
Fischer et al. Buprenorphine maintenance in pregnant opiate
addicts. Eur Addict Res. 1998;4(Suppl 1):32-6. cited by other .
Forth. [another analgesic unmasked as an addictive substance: a
vicious circle] MMW Munch Med Wochenschr. Sep 30, 1983;
125(39):834. [in German w/ English transl]. cited by other .
Francaviglia et al. Subarachnoid buprenorphine administered by
implantable micropumps. Acta Neurochir (Wien), 1990;102(1-2):62-8.
cited by other .
Franklin et al. Risk assessment in dermatoxicology. In: Marzulli et
al. (Eds.) Dermatotoxicology (4.sup.th ed.) 1991. 1991;30:713-47.
cited by other .
Fraser. Clinical toxicology of drugs used in the treatment of
opiate dependency. Clinics in Laboratory Medicne, Jun. 1990;
10(2):375-86. cited by other .
Fudala et al. A multi-site efficacy evaluation of a
buprenorphine/naloxone product for opiate dependence treatment.
NIDA Res Monogr. Problems of Drug Dependent: Proceedings of the
60.sup.th annual Scientific Meeting; 1998:105. cited by other .
Fudala et al. Clinical efficacy studies of buprenorphine for the
treatment of opiate dependence. Buprenorphine: Combatting Drug
Abuse with a Unique Opioid. 1995:213-39. cited by other .
Fudala et al. Outpatient comparison of buprenorphine and methadone
maintenance. II. Effects on cocaine usage, retention time in study
and missed clinic visits. NIDA Res Monogr. 1991;105:587-8. cited by
other .
Fudala et al. Use of buprenorphine in the treatment of opioid
addiction. II. Physiologic and behavioral effects of daily and
alternate-day administration and abrupt withdrawl. Clin Pharmacol
Ther. 1990; 47:525-34. cited by other .
Fujimura et al. Influences of bathing and hot weather on the
pharmacokinetics of a new transdermal clonidine, M-5041T. J Clin
Pharmacol. Oct. 1996;36(10):892-6. cited by other .
Fullerton et al. Prolonged nausea and vomiting associated with
buprenorphine. Pharmacotherapy 1991;11:90-93. cited by other .
Gebhart et al, Opiod modulation of visceral pain. In: Progress in
Pain Research and Management. Opioid Sensitivity of Chronic
Noncancer Pain. Kalso et al., eds. 1999;225-35. cited by other
.
Gould. Buprenorphine causes pulmonary edema just like all othr
mu-opioid narcotics. Upper airway obstruction, negative alveolar
pressure. Chest. May 1995;107(5):1478. cited by other .
Gourlay. Different opioids--same actions? In: Progress in Pain
Research and Management. Opioid Sensitivity of Chronic Noncancer
Pain. Kalso et al., eds. 1999; 14:97-115. cited by other .
Grond et al. Clinical pharmacokinetics of transdermal opioids:
focus on transdermal fentanyl. Clin Pharmacokinet. Jan.
2000;38(1):59-89. cited by other .
Guilbaud et al. Antinociceptive effect of opioid susbstances in
different models of inflammatory pain. In: Progress in Pain
Research and Management. Opioid Sensitivity of Chronic Noncancer
Pain. Kalso et al., eds. 1999; 14:201-23. cited by other .
Hand et al. Buprenorphine disposition in patients with renal
impairment: single and continuous dosing, with special reference to
metabolites. Br J Anaesth. Mar. 1990;64(3):276-82. cited by other
.
Hand et al. Radioimmunoassay of buprenorphine in urine: studies in
patients and in a drug clinic. J Anal Toxicol. Mar-Apr.
1989;13(2):100-4. cited by other .
Heel et al. Buprenorphine: a review of its pharmacological
properties and therapeutic efficacy. Drugs. 1979;17:81-110. cited
by other .
Henrion. [Assessment of the effectiveness of measures taken in
France to reduce the risk of intravanenous heroin addiction] Bull
Acad Natl Med. Jun.-Jul. 1997;181(6):1177-85; discussion 1186-9,
[in French w/ English transl]. cited by other .
Hernandez-Mora et al. [Paroxysmal atrial fibrillation after
ingestion of buprenorphine.] Rev Clin Esp. Jun. 1988;183(2):99-100.
[in Spanish w/ English transl]. cited by other .
Hirschauer et al. [Is buprenorphine hepatotoxic?] Gastroenterol
Clin Biol. Jun. 1989;13(6-7):636. [in French w/ English transl].
cited by other .
Holdsworth et al. Transdermal fentanyl disposition in elderly
subjects. Gerontology. 1994;40(1):32-7. cited by other .
Holmes. Buprenorphine side effects. N Z Med J. Mar. 14,
1984;97(751):166. cited by other .
Hoskin et al. Opioid agonist-antagonist drug in acute and chronic
pain states. Drugs 1991;41:326-44. cited by other .
Huguet-Levet. [Buprenorphine: its ambiguity] Ann Pharm Fr.
1995;53(3):124-30. [in French w/ English transl]. cited by other
.
Jamison. Comprehensive pretreatment and outcome assessment for
chronic opioid therapy in nonmalignant pain. J Pain Symptom Manage.
Apr. 1996;11(4):231-41. cited by other .
Jasinski et al. Abuse liability assessment in human subjects.
Trends Pharmacol Sci. 1984;5:196-200. cited by other .
Jasinski et al. Human pharmacology and abuse potential of the
analgesic buprenorphine: a potential agent for treating narcotic
addiction. Arch Gen Psychiatry. 1978;35:501-16. cited by other
.
Jasinski et al. Laboratory studies of buprenorphine in opioid
abusers. In: Cowan A, Lewis JW, eds.. Buprenorphine: combatting
drug abuse with a unique opioid. New York: Wiley-Liss.
1995:189-211. cited by other .
Jasinski et al. Progress report from the NIDA Addiction Research
Center, Baltimore, Maryland, NIDA Res Monogr. Mar. 1984;49:69-76.
cited by other .
Jasinski et al. Progress report of the NIDA Addiction Research
Center, NIDA Res Monogr. 1982;41:45-52. cited by other .
Jasinski et al. Progress report of the NIDA Addiction Research
Center, Baltimore, Maryland, 1982. NIDA Res Monogr. Apr.
1983;43:92-8. cited by other .
Jasinski et al. Sublingual versus subcutaneous buprenorphine in
opiate abusers. Clinical Pharmacol Ther. 1989;45:513-9. cited by
other .
Johnson et al. A controlled trial of buprenorphine treatment for
opiod dependence. JAMA. 1992;267:2750-5. cited by other .
Kalso. Route of opioid administration--does it make a difference?
In: Progress in Pain Research and Management, Opioid Sensitivity of
Chronic Noncancer Pain. Kalso et al., eds. 1999; 14:117-28. cited
by other .
Kareti et al. Effects of buprenorphine, a new narcotic
agonist-antagonist analgesic on the EEG, power spectrum and
behavior of the rat. Neuropharmacology. Feb. 1980;19(2):195-201.
cited by other .
Keup et al. [Potential for buprenorphine abuse] MMW Munch Med
Wochenschr. Sep. 30, 1983;125(39):835-7. [in German w/ English
transl]. cited by other .
Keup. [Buprenorphine (Temgesic.RTM.) abuse and depenence]
Suchtgefahren. 1983;29:193-4. [in German w/ English transl]. cited
by other .
Lange et al. Safety and side-effects of buprenorphine in the
clinical management of heroin addiction. Drug Alchol Depend. Aug.
1990;26(1):19-28. cited by other .
Law et al. The feasibility of abrupt methadone-buprenorphine
transfer in British opiate addicts in an outpatient setting.
Addiction Bio. 1997;2:191-200. cited by other .
Leander. Buprenorphine has potent kappa opioid receptor antagonist
activity. Neuropharmacol. 1987; 26:1445-7. cited by other .
Leander. Buprenorphine is a potent kappa-opioid receptor antagonist
in pigeons and mice. Eur J Pharmacol. Jul. 14, 1988; 151(3):457-61.
cited by other .
Lewis et al. Buprenorphine--background to its development as a
treatment for opiate dependence. NIDA Res Monogr. 1992;121:5-11.
cited by other .
Lewis. Buprenorphine, Drug Alcohol Depend. 1985; 14:363-72. cited
by other .
Lewis. Clinical pharmacology of buprenorphine in relation to its
use as an analgesic, Buprenorphine: Combatting Drug Abuse with a
Unique Opioid. 1995;151-63. cited by other .
Lewis et al. The pharmacology and abuse potential of buprenorphine:
a new antagonist analgesic. Advances in substance abuse.
1983;3:103-54. cited by other .
Ling et al. Buprenorphine maintenance treatment of opiate
dependence: a multicenter, randomized clinical trial. Addiction.
1998;93:475-86. cited by other .
Ling et al. Methadyl acetate and methadone as maintenance
treatments for heroin addicts. A veterans administration
cooperative study. Arch Gen Psychiatry, Jun. 1976;33(6):709-20.
cited by other .
Ling et al. Substitution pharmacotherapies for opioid addiction:
from methadone to LAAM and buprenorphine, J Psychoactive Drugs,
Apr.-Jun. 1994;26(2):119-28. cited by other .
Litchfield, Buprenorphine in oral surgery. A comparison with
fentanyl. SAAD Dig. Oct. 1986;6(8):182-6. cited by other .
Liu et al. Rapid detoxification of heroin dependence by
buprenorphine. Acta Pharmacol. Sin. 1997;18:112-4. cited by other
.
Lizasoain et al. Buprenorphine: bell-shaped dose-response curve for
its antagonist effects. Gen Pharmacol. 1991;22(2):297-300. cited by
other .
Lloyd-Jones et al. Plasma concentration and disposition of
buprenorphine after intraveneous and intramuscular doses to
baboons. Eur J Drug Metab Pharmacokinet. 1980;5(4):233-9. cited by
other .
Macdonald et al. Psychomotor effects of ketorolac in comparison
with buprenorphine and diclofenac. Br J Clin Pharmacol. 1989;
27;453-9. cited by other .
Mackenzie et al. Influence of pretreatment with a monomine oxidese
inhibitor (Phenelzine) on the effects of buprenorphine and
pethidine in the conscious rabbit. Br J Anaesth. 1988;60:216-21.
cited by other .
Marquet et al. Buprenorphine withdrawal syndrome in a newborn. Clin
Pharmacol Ther. 1997;62:569-71. cited by other .
Marquet et al. [In utero exposure to Subutex induces no or mild
withdrawal syndromes in the newborn] Therapie. 1998;53-178. [in
German w/ English abstract]. cited by other .
Martin. History and development of mixed opioid agonists, partial
agonists and antagonist . Br J Clin Pharmacol. 1979;7:273S-9S.
cited by other .
Martin et al. The effects of morphine-and nalorphine-like drugs in
the nondependent and morphine-dependent chronic spinal dog. J
Pharmacol Exp Ther. 1976;197:517-32. cited by other .
Max et al. Single-dose analgesic comparisons. Advances in pain
research and therapy. 1991;18:55-95. cited by other .
McQuay et al. Buprenorphine kinetics. Advances in Pain Res and
Ther. 1986. 8:271-83. cited by other .
McQuay et al. Buprenorphine kinetics in humans. In: Buprenorphine:
Combatting Drug Abuse with a Unique Opioid. 1995;137-47. cited by
other .
McQuay et al. Clinical effects of buprenorphine during and after
operation. Br J Anaesth. Oct. 1980;52(10):1013-9. cited by other
.
McQuay et al. Delayed respiratory depression. A case report and a
new hypothesis. Acta Anaesthesiol Belg. 1979;30 Suppl:245-7. cited
by other .
Mello et al. Behavioral pharmacology of buprenorphine. Drug Alchol
Depend. Feb. 1985;14(3-4):283-303. cited by other .
Mello et al. Buprenorphine effects on human heroin
self-administration: an operant analysis. J Pharmacol Exp Ther.
1982;223:30-9. cited by other .
Mello et al. Buprenorphine self-administration by rhesus monkey.
Pharmacol Biochem Behav. 1981;15:215-25. cited by other .
Mello et al. Buprenorphine suppresses cocaine self-administration
by rhesus monkeys. Science. 1989;245:859-62. cited by other .
Mello et al. Buprenorphine suppresses heroin use by heroin addicts.
Science. 1980;207:657-9. cited by other .
Mello et al. Buprenorphine's effects on cocaine
self-administration: preclinical studies. In: Buprenorphine
Combatting Drug Abuse With A Unique Opioid. 1995;249-50. cited by
other .
Mendelson et al. Bioavailability of sublingual buprenorphine. J
Clin Pharmacol. 1997;37:31-7. cited by other .
Mendelson et al. Buprenorphine and naloxone interactions in
methadone maintenance patients. Biol Psychiatry. 1997;41:1095-101.
cited by other .
Mendelson et al. Buprenorphine attenuates the effects of cocaine on
adrenocorticotropin (ACTH) secretion and mood states in man.
Neuropsychopharmacology. 1992;7:157-62. cited by other .
Mendelson et al. Buprenorphine and naloxone interactions in
opiate-dependent volunteers. Clin Pharmacol Ther. Jul.
1996;60(1):105-14. cited by other .
Mendelson et al. Human laboratory studies of buprenorphine. NIDA
Res Monogr. 1992;121:38-60. cited by other .
Mitaka et al. Comparison of hemodynamic effects of morphine,
butorphanol, buprenorphine and pentzocine on ICU patients. Bull
Tokyo Med Dent Univ. Jun. 1985;32(2):31-9. cited by other .
Moa et al. Sublingual buprenorphine as postoperative analgesic: a
double-blind comparison with pethidine. Acta Anaesthesiol Scand.
1990;34:68-71. cited by other .
Mok et al. Multidose/observational, comparative clinical analgetic
evaluation of buprenorphine, J Clin Pharmacol. Jul.
1981;21(7):323-9. cited by other .
Moore et al. Reversal of postoperative hyperglycaemia by
buprenorphine. Lancet. Sep 13, 1980;2(8194):597-8. cited by other
.
Morrison, Psychoactive substance use an related behaviours of 135
regular illicit drug users in Scotland. Drug Alchol Depend.
1989;23:95-101. cited by other .
Mukhtar et al. Cutaneous cytochrome P-450. Drug. Metabolism Revs.
1989;20(204):657-73. cited by other .
Mukhtar et al. Cytochrome P-450 dependent metabolism of
testosterone in rat skin. Biochem Biophys Res Commun. Jun. 15,
1987;145(2):749-53. cited by other .
Nasar et al. An open study of sub-lingual buprenorphine in the
treatment of chronic pain in the elderly. Curr Med Res Opin.
1986;10(4):251-5. cited by other .
Nigam et al. Buprenorphine in opiate withdrawal: a comparison with
clonidine. J Subst Abuse Treat. Jul.-Aug. 1993;10(4):391-4. cited
by other .
Nizamie et al. Buprenorphine abuse: a case report. Indian J
Psychiatry. 1990;32:198-200. cited by other .
O'Brien. Drug adiction and abuse. In: Goodman & Gilman's The
Pharmacological Basis of Therapeutics. 9.sup.th ed. 1996;Chp.
24:557-577. cited by other .
O'Connor et al. Buprenorphine abuse among opiate addicts. Brit J
Addict. 1998; 83:1085-7. cited by other .
O'Connor et al. Rapid and ultrarapid detoxification techniques.
JAMA 1998;279:229-34. cited by other .
O'Connor et al. Three methods of opioid detoxification in a primary
care setting: a randomized trial. Ann Intern Med. 1997;127:526-30.
cited by other .
O'Neill. The cognitive and psychomotor effects of opioid drugs in
cancer management. Cancer Surv. 1994;21:67-84. cited by other .
Obel et al. Buprenorphine-supplemented anaesthia. Influence of dose
on duration of analgesia after cholecystectomy. Br J Anaesth. Mar.
1985;57(3):271-4. cited by other .
Ohtani et al. Kinetics of respiratory depression in rats induced by
buprenorphine and its metabolite, norbuprenorphine, J Pharmacol Exp
Ther. Apr. 1997;281(1):428-33. cited by other .
Olley et al. Plasma levels of opioid material in man following
sublingual and intravenous administration of buprenorphine:
exogenous/endogenous opioid interaction? J Pharm Pharmacol.
1988;40:667-7. cited by other .
Opioid agonist-antagonist analgesics. In: WHO Expert Committee on
Drug Dependence. 25.sup.th Report. Geneva: World Health
Organization Technical Report Series; 1989;775 16-24. cited by
other .
Orwin et al. A double blind comparison of buprenorphine and
morphine in conscious subjects following administration by the
intramuscular route. Acta Anaesthesiol Belg. 1976;27:171-81. cited
by other .
Orwin. Pharmacological aspects in man. Pain:vNew Perspect. Meas.
Manage. (Symp) 1977;141-59. cited by other .
Ouellette et al. Comparison of buprenorphine and morphine: a
multicenter, multidose study in patients with severe postoperative
pain. Contemp. Surg. 1986; 28:55,57-59,62-64. cited by other .
Ouellete. Bupreniorphine and morphine efficacy in postoperative
pain: a double-blind multiple-dose study. J Clin Pharmacol. Apr.
1982;22(4):165-72. cited by other .
Ouellete. Comparison of analgesic activity of buprenorphine
hydrochloride and morphine in patients with moderate to severe pain
postoperatively. Surg Gynecol Obstet. Sep. 1984;159(3):201-6. cited
by other .
Overweg-Van Kintz et al. [Failing pain suppression during
sublingual use of buprenorphine] Ned Tijdschr Geneeskd.
1987;131(44)1973-4. [in Dutch w/ English transl]. cited by other
.
Parran et al. A bupreniorphine stabilization and rapid-taper
protocol for the detoxification of opioid dependent patients. Am J
Addict. 1994;3:306-13. cited by other .
Pathre et al. Generalised seizure following sublingual
buprenorphine. J Assoc Physicans India. Apr. 1994;42(4):327-8.
cited by other .
Pausawasdi et al. comparison of buprenorphine and morphine for
immediate postoperative pain relief in Thai patients. J Med Assoc
Thai. May 1984;67(5):284-9. cited by other .
Pechnick et al. The effects of the acute administration of
buprenorphine hydrochloride on the release of anterior pituitary
hormones in the rat: evidence for the involvement of multiple
opiate receptors. Life Sci. Nov. 18, 1985;37(20): 1861-8. cited by
other .
Pedersen et al. Peroperative buprenorphine: do high dosages shorten
analgesia postoperatively? Acta Anaesthesiol Scand. Nov.
1986;30(8):660-3. cited by other .
Petti, Postoperative pain relief with pentazocine and
acetaminophen: comparison with other analgesic combinations and
placebo. Clin Ther. 1985;8(1):126-33. cited by other .
Ponsoda et al. The effects of buprenorphine on the metabolism of
human hepatocytes. Toxic. In vitro. 1991;5(3):219-24. cited by
other .
Pontani et al. Disposition in the rat of buprenorphine administered
parenterally and as a subcultaneous implant. Xenobiotica. Apr.
1985; 15(4):287-97. cited by other .
Preston et al. Abuse liability studies of opioid
agonist-antagonists in humans. Drug Alcohol Depend. 1991;28:49-82.
cited by other .
Preston et al. Abuse potential and pharmacological comparison of
tramadol and morphine. Drug Alcohol Depend. Jan. 1991;27(1):7-17.
cited by other .
Preston et al. Diazepam and methadone interactions in methadone
maintenance. Clin Pharmacol Ther. Oct. 1984;36(4):534-41. cited by
other .
Preston et al. Discrimination of agonist-antagonist opioids in
humans trained on two-choice saline-hydromorphone discrimination. J
Pharmacol Exp Ther. 1992;261:62-71. cited by other .
Preston et al. Drug discrimination assessment of agonist-antagonist
opioids in humans: a three-choice saline-hydromorphone-butorphanol
procedure. J Pharmacol Exp Ther. 1994;271:48-60. cited by other
.
Preston et al. Drug discrimination in human postaddicts:
agonist-antagonist opioids. J Pharmacol Exp Ther. 1989;250:184-96.
cited by other .
Preston et al. Effects of sublingually given naloxone in
opioid-dependent human volunteers. Drug Alchol Depend.
1990;25:27-34. cited by other .
Price et al. A psychophysical analysis of experimental factors that
selectively influence the affective dimension of pain. Pain. Apr.
1980;8(2):137-49. cited by other .
Quigley et al. A case of buprenorphine abuse. Med J Aust. 1984;
140:425-6. cited by other .
Rainey. Abuse of buprenorphine. N Z Med J. 1986;99-72. cited by
other .
Regini et al. [Buprenorphine withdrawal syndrome in a neonate.
Which treatment?] Ped Med Chir. 1998; 20:67-9. [in Italian with
English transl]. cited by other .
Reisine et al. Opioid analgesics and antagonists. In: Molinoff PB,
Ruddon RW, Gilman AG, editors. Goodman and Gilman's The
pharmacological basis of therapeutics. 9.sup.th ed. 1996; Chp.
23:521-55. cited by other .
Reisinger, [Value of comparing buprenorphine with methadone] Ann
Med Interne (Paris), Nov. 1994; 145 Suppl 3:23-5. [in French w/
English transl]. cited by other .
Reisinger. Buprenorphine as a new treatment for heroin dependence.
Drug Alcohol Depend. Dec. 1985;16(3):257-62. cited by other .
Reisinger. Results from experience with buprenorphine replacement
in outpatients in Belgium. Ann. Med. Interne.
1994;145(Supp.3):46-47. cited by other .
Reisinger. Treatment of four pregnant heroin addicts with
buprenorphine: history and outcome. NIDA Res Monogr 1995;162-261.
cited by other .
Report of the commission on the evaluation of pain. In: Soc.
Security Bull. 1986. cited by other .
Reynaud et al. Six deaths linked to concomitant use of
buprenorphine and benzodiazepines. Addiction 1998;93:1385-92. cited
by other .
Richard et al. [Vertiginous syndrome: side effect of
buprenorphine?] Cah Anesthesiol. 1988; 36:641-2. [in French with
English transl]. cited by other .
Richert et al. [Drug dependence on buprenorphine] MMW Munch
Wochenschr 1983; 125:1195-8 [. in German w/ English transl]. cited
by other .
Risbo et al. Sublingual buprenorphine for premedication and
postoperative pain relief in orthopaedic surgery. Acta Anaesthesiol
Scand. Feb. 1985;29(2):180-2. cited by other .
Robbie. A trial of sublingual bupreniorphine in cancer pain. Br J
Clin Pharmacol. 1979;7 Suppl 3:315S-317S. cited by other .
Robertson et al. Buprenorphine: dangerous drug or overlooked
therapy? Br Med J. 1986;292:1465. cited by other .
Robinson et al. The misuse of buprenorphine and a
buprenorphine-naloxone combination in Wellington, New Zealand. Drug
Alcohol Depend. 1993;33:81-6. cited by other .
Rolandi et al. Changes in pituitary secretion induced by an
agonist-antagonist opioid drug, buprenorphine. Acta Endocrinol
(Copenh). Nov. 1983;104(3):257-60. cited by other .
Rosen et al. Buprenorphine: duration of blockade of effects of
intramuscular hydromorphone. Drug Alcohol Depend. 1994;35:141-9.
cited by other .
Rosen et al. Effects of acute bupreniorphine on responses to
intranasal cocaine: a pilot study. Am J Drug Alcohol Abuse.
1993;19:451-64. cited by other .
Rosenfeldt et al. Haemodynamic effects of buprenorphine after heart
surgery. Br Med J. Dec. 9, 1978;2(6152):1602-3. cited by other
.
Rothman et al. Buprenorphine: a review of the binding literature.
In: Buprenorphine: Combatting Drug Abuse with a Unique Opioid.
1995;19-29. cited by other .
Saarialho-Kere et al. Psychomotor, respiratory, and
neuroendocrinological effects of buprenorphine and amitriptyline in
healthy volunteers. Eur J Clin Pharmacol. 1987;33:139-46. cited by
other .
Sakol et al. Buprenorphine and temazepam abuse by drug takers in
Glasgow--an increase. Brit J Addict. 1989;84:439-41. cited by other
.
San et al. [Prevalence of buprenorphine consumption in heroin
addicts undergoing treatment] Med Clin (Barc). 1989; 93:645-8. [In
Spanish w/ English transl]. cited by other .
San et al. Assessment and management of opioid withdrawal symptoms
in buprenorphine-dependent subjects. Br J Addict. Jan.
1992;871):55-62. cited by other .
San et al. Consumption of buprenorphine and other drugs among
heroin addicts under ambulatory treatment: results from
cross-sectional studies in 1988 and 1990. Addiction. 1993;
88:1341-9. cited by other .
San Molina et al. [Addiction to buprenorphine] Rev Clin Esp. 1987;
181:288-9. [in Spanish w/ English transl]. cited by other .
Schmidt et al. Postoperative pain relief with naloxone. Severe
respiratory depression and pain after high dose buprenorphine.
Anaesthesia. 1985;40:583-6. cited by other .
Schottenfeld et al. Buprenorphine vs. methadone maintenance
treatment for concurrent opioid dependence and cocaine abuse. Arch
Gen Psychiatry. 1997;54:713-20. cited by other .
Schuh et al. Buprenorphine, morphine, and naloxone effects during
ascending morphine maintenance in humans. J Pharmacol Exp Ther.
1996; 278:836-46. cited by other .
Sear et al. Buprenorphine for postoperative analgesia. Br J
Anaesth. Jan. 1979;51(1):71. cited by other .
Segal et al. Buprenorphine: what interests the national institute
on drug abuse? Buprenorphine: In: Combatting Drug Abuse with a
Unique Opioid. 1995;309-20. cited by other .
Segui et al. [Buprenorphine consumption, an indicator of poor
prognosis in the course of drug dependencies] Actas Luso Esp Neurol
Psiquiatr Ciene Afines. Jan.-Feb. 1992;20(1):17-22. [in Spanish w/
English transl]. cited by other .
Segui et al. [Data regarding buprenorphine consumption by
drug-addicted individuals] Rev Clin Esp. 1989; 185-271-2. [in
Spanish with English transl]. cited by other .
Segui et al. [Prevalence of buprenorphine consumption in a sample
of outpatient drug abusers] Rev Clin Esp. Jun. 1991;189(1):14-7.
[in Spanish w/ English transl]. cited by other .
Segui et al. [Subgroups of addicted buprenorphine-consuming
patients.] An Med Interna. Jan. 1991;8(1):18-22. [in Spanish w/
English transl]. cited by other .
Sekar et al. Buprenorphine benzodiazepines and prolonged
respiratory depression. Anaesthia. 1987;42:567-8. cited by other
.
Seow et al. Buprenorphine: a new maintenance opiate? Med J Aust.
Apr. 14. 1986;144(8):407-11. cited by other .
Sganzerla et al. Analgesic and hemodynamic effects of buprenorphine
in acute infarction of the heart. Jpn Heart J. Jan.
1987;28(1):63-71. cited by other .
Shannon et al. Morphine-like discriminative stimulus effects of
buprenorphine and demethoxybuprenorphine in rats: quantitive
antagonism by naloxone. J Pharmacol Exp Ther. 1984; 229:768-74.
cited by other .
Shuster. Fluoroquinolones and tendon rupture or tendinitis.
Buprenorphine-induced hypertension and tachycardia: rare but
serious. Hospital Pharmacy. 1996;31(1):41-2. cited by other .
Singh et al. Cases of buprenorphine abuse in India. Acta Psychiatr
Scand. 1992;86:46-8. cited by other .
Sjovall.Use of midazolam and buprenorphine in combination
anaesthia. Ann Clin Res. Aug. 1983;15(4):151-5. cited by other
.
Spitzer et al. Scientific approach to the assessment and management
of activity-related sphinal disorders. Spine. 1987;12(7):S9-S59.
cited by other .
Staritz. Pharmacology of the spincter of Oddi. Endoscopy. Aug.
1988;20 Suppl 1:171-4. cited by other .
Stellato et al. Human basophil/mast cell releasability. IX.
Heterogeneity of the effects of opioids on mediator release.
Anesthesiology. Nov. 1992;77(5):932-40. cited by other .
Stewart. Effect of scheduling of buprenorphine (Temgesic) on drug
abuse patterns in Glasgow. BMJ. Apr. 20, 1991;302(6782):969. cited
by other .
Stinchcomb et al. Permeation of buprenorphine and its 3-alkyl-ester
prodrugs through human skin. Pharm Res. Oct. 1996;13(10):1519-23.
cited by other .
Strain et al. Acute effects of buprenorphine, hydromorphone, and
naloxone in methadone-maintained volunteers. J Pharmacol Exp Ther.
1992;261:985-93. cited by other .
Strain et al. Buprenorphine effects in methadone-maintained
volunteers: effects at two hours after methadone. J Pharmacol Exp
Ther. 1995;272:628-38. cited by other .
Strain et al. Comparison of buprenorphine and methadone in the
treatment of opioid dependence. Am J Psychiatry. 1994;151:1025-30.
cited by other .
Strain et al. The effects of buprenorphine in
buprenorphine-maintained volunteers. Psychopharmacol.
1997;129:329-38. cited by other .
Strang. Abuse of buprenorphine (Temgesic) by snorting. BMJ. Apr.
20, 1991;302(6782):969. cited by other .
Strang. Abuse of buprenorphine. Lancet. Sep. 28, 1985;2(8457):725.
cited by other .
Streisand. Transdermal-mucosal sedative and analgesic delivery.
West. J Med. 1990;153:310. cited by other .
Su. Further demonstration of .kappa. opioid binding sites in the
brain: evidence of heterogeneity. J Pharmacol Exp Ther.
1985;232:144-8. cited by other .
Summerfield et al. Buprenorphine in end stage renal failure.
Anaesthesia. Sep. 1985;40(9):914. cited by other .
Swain et al. Primary addiction study. UM952. In: Minutes of the
Committee on Problems of Drug dependence, Washington (DC), National
Academy of Sciences, National Research Council. 1975;791. cited by
other .
Tallarida et al. Theory and statistics of detecting synergism
between two active drugs: cocaine and buprenorphine.
Psychoparmacology (Berl). Oct. 1997;133(4):378-82. cited by other
.
Tantucci et al. Acute respiratory effects of sublingual
buprenorphine: comparison with intramuscular morphine. Int J Clin
Pharmacol Ther Toxicol. Jun. 1992;30(6):202-7. cited by other .
Tebbett. Analysis of bupreniorphine by high-performance liquid
chromatography. J Chromatogr. Nov. 22, 1985;347(3):411-3. cited by
other .
Teoh et al. Acute interactions of buprenorphine with intravenous
cocaine and morphine: an investigational new drug phase I safety
evaluation. Clin Psychopharmacol. 1993;13:87-99. cited by other
.
Teoh et al. Buprenorphine effects on morphine--and cocaine-induced
subjective responses by drug-dependent men. J Clin Psychopharmacol.
Feb. 1994;14(1):15-27. cited by other .
Thammakumpee et al. Noncardiogenic pulmonary edema induced by
sublingual buprenorphine. Chest. Jul. 1994;106(1):306-8. cited by
other .
Tharp et al. Functional heterogeneity of human mast cells from
different anatomic sites: in vitro responses to morphine sulfate. J
Allergy Clin Immunol. Apr. 1987;79(4):646-53. cited by other .
Thorn et al. Prolonged respiratory depression caused by sublingual
buprenorphine. Lancet. Jan. 23, 1988;1(8578):179-80. cited by other
.
Tigerstedt et al. Double-blind, multiple-dose comparison of
buprenorphine and morphine in postoperative pain. Acta Anaesthesiol
Scand. Dec. 1980;24(6):462-8. cited by other .
Touzeau et al. Benzodiazepines and methadone: a dangerous
combination? Ann Med Interne (Paris). Nov. 1994;145 Suppl 3:19-22.
[in French w/ English transl]. cited by other .
Tracqui et al. [Prison, drugs and death: two deaths due to
overdoses in a prison environment] J Med Leg Droit Med.
1998a;41:185-92. [in French w/ English transl]. cited by other
.
Tracqui et al. Buprenorphine-related deaths among drug addicts in
France: a report on 20 fatalities. J Anal Toxicol. 1998c;22:430-4.
cited by other .
Uehlinger et al. Comparison of buprenorphine and methadone in the
treatment of opioid dependence. Swiss multicentre study. Eur Addict
Res. 1998;4 Suppl 1:13-8. cited by other .
Umbricht et al. Safety of buprenorphine: ceilling for
cardio-respiratory effects at high IV doses. NIDA Res Monogr.
1998;179:225. cited by other .
Van Loveren et al. Assessment of immunotoxicity of buprenorphine.
Lab Anim. Oct. 1994;28(4):355-63. cited by other .
Vanakoski et al. Exposure to high ambient temperature increases
absorption and plasma concentrations of transdermal nicotine. Clin
Pharmacol Ther. Sep. 1996;60(3):308-15. cited by other .
Varey. The safety of buprenorphine (Temgesic). N Z Med J. Jan. 24,
1990;103(882):24. cited by other .
Vargas et al. Buprenorphine: a case of abuse [letter] [in Spanish].
An Med Interna. 1987;4:366. cited by other .
Ventafridda et al. Chronic analgesic study on buprenorphine action
in cancer pain. Comnparison with pentazocine.
Arzneimittelforschung. 1983;33(4):587-90. cited by other .
Vignau. Preliminary assessment of a 10-day rapid detoxification
programme using high dosage buprenorphine. Eur Addict Res 1998;4
Suppl. 1:29-31. cited by other .
Villiger, Binding of buprenorphine to opiate receptors. Regulation
by guanyl nucleotides and metal ions. Neuropharmacology. Mar.
1984;23(3):373-5. cited by other .
Vocci. Basis for the reccommendation for rescheduling of
buprenorphine into Schedule IV of the Controlled Substances Act.
FDA Document 2726A; Jul. 31, 1980; 1-8. cited by other .
Waal. Buprenorphine (Temgesic)--new agent of abuse. Tidsskr Nor
Laegeforen 1989; 109:1326-7. [in Norwegian w/ English transl].
cited by other .
Walsh et al. Clinical pharmacology of buprenorphine: ceilling
effects at high doses. Clin Pharmacol Ther. 1994;55:569-80. cited
by other .
Walsh et al. The acute effects of high dose buprenorphine in
non-dependent humans. NIDA Res. Monogr. 1992;119:245. cited by
other .
Walter et al. Absorption, distribution, metabolism, and excretion
of buprenorphine in animals and humans. In: Burprenorphine:
Combatting Drug Abuse with a Unique Opiod. 1995;113-35. cited by
other .
Walter et al. Preclinical evaluation of buprenorphine. Research and
Clinical Forums. 1997;19(2):17-23. cited by other .
Wang et al. The study of analgesics following single and repeated
doses. J Clin Pharmacol. Feb.-Mar. 1981;21(2):121-5. cited by other
.
Watanabe et al. Rectal absorption and mucosal irritation of rectal
gels containing buprenorphine hydrochloride prepared with
water-soluble dietary fibers, xanthan gum and locust bean gum. J
Controlled Release. 1996;38:29-37, cited by other .
Weinberg et al. Sublingual absorption of selected opioid analgesics
Clin Pharmacol. Ther. 1988;44:335-42. cited by other .
Wiesenfeld-Hallin et al. Opioid sensitivity in antinociception:
Role of anti-opioid systems with emphasis on cholecystokinin and
NMDA receptors. In: Progress in Pain Research and Management.
Opioid Sensitivity of Chronic Noncancer Pain. Kalso et al., eds.
1999;14:237-52. cited by other .
Woods et al. Behavioral pharmacology of buprenorphine: issues
relevant to its treating drug abuse. NIDA Res Monogr.
1992;121:12-27. cited by other .
Wright et al. Acute physical dependence in humans: repeated
naloxone-precipitated withdrawal after a single dose of methadone.
Drug Alcohol Depend. 1991;27:139-48. cited by other .
Yanagita et al. Dependence potential of buprenorphine studied in
rhesus monkeys. NIDA Res Monogr. 1982;41:208-14. cited by other
.
Zacny et al. Comparing the subjective, psychomotor and
physiological effects of intravenous buprenorphine and morphine in
healthy volunteers. J Pharmacol Exp Ther. 1997;282:1187-97. cited
by other .
Zacny. A review of the effects of opioids on psychomotor and
cognitive functioning in humans. Experimental and Clin.
Psychopharmacol. 1995;3(4):432-66. cited by other .
Zola et al. Comparative effects and analgesic efficacy of the
agonist-antagonist opioids. Drug Intell Clin Pharm. Jun.
1983;17(6):411-7. cited by other .
7.2. Buprenorphine, MNH/PAD/87.11, pp. 29-63 (undated). cited by
other .
A review of data for the scientific community in preparation for
the WHO 2002 critical review of buprenorphine: Scientific, medical
and policy support for the continuing of Buprenorphine in Schedule
III of the 1971 Convention on Psychotropic Substance. Dec. 13, 2001
(30 pp.). cited by other .
Adams, Expert Report on Buprenorphine (undated). cited by other
.
Addendum to a review of data for the scientific community in
preparation for the WHO 2002 critical review of buprenorphine: Data
on reactions possibly related to abuse of Buprenorphine reported to
the WHO collaborating centre for international drug monitoring,
Uppsala Sweden and Data on seizures from the NFLIS. Feb. 26, 2002
(11 pp.). cited by other .
Agar et al., Buprenorphine: "field trials" of a new drug. Qual
Health Res. Jan. 2001;11(1):69-84. cited by other .
Annual report on the state of the drugs problem in the European
Union by EMCDDA. 1999 (33 pp.). cited by other .
Auriacombe et al., Buprenorphine prescribed by general
practitioners--A safe means of increasing patient access to
treatment?, in Maintenance Treatment in Heroin Addiction--Evidence
at the Crossroads (Wall and Haga, eds.), 2003 (5 pp.). cited by
other .
Bailey et al., Package inserts and other dosage guidelines are
especially useful with new analgesics and new analgesic delivery
systems. Anesth Analg. Dec. 1992;75(6):873-5. cited by other .
Begaud et al., of the Joint Ministerial Mission for Combating Drugs
and Drug Addiction Information Office, Evaluation of Subutex.RTM.
availability in the treatment of drug users. Summary review of the
literature and available data and proposals for a research program.
Jun. 1998 (83 pp.). cited by other .
Brown, Jr., of American Society of American Society of Addiction
Medicine, letter to DEA Administrator dated May 17, 2002 in
response to notice published in the Federal Register of Mar. 21,
2002. cited by other .
BTDS List of Studies (undated). cited by other .
BTDS Outstanding Issues--Awaiting FDA response from Oct. 2,
1999-Mar. 20, 2000. cited by other .
BTDS Planned FDA Submissions/Interactions for 2000. cited by other
.
Buprenorphine (Annex 3) (18 pp.) (undated). cited by other .
Buprenorphine DEA Review DocumentScheduling under the CSA. Feb.
2002 (26 pp.). cited by other .
Buprenorphine prescription withdrawn in Norway, available at
http://www.drugscope.org.uk. cited by other .
Bupreniorphine TDS Pre-NDA Meeting. Flux rate of Buprenorphine
transdermal delivery systems (BTDS) (undated). cited by other .
Buprenorphine transdermal system (IND 50,273) meeting minutes dated
Jan. 23, 1997. cited by other .
Buprenorphine transdermal system (IND 50,273) meeting minutes of
Jul. 14, 1999 ( 8 pp.). cited by other .
Buprenorphine transdermal system (IND 50,273) meeting minutes of
May 16, 1996. cited by other .
Buprenorphine transdermal system (IND 50,272) meeting minutes of
Nov. 18, 1998. cited by other .
Buprenorphine transdermal system (IND 50,273) nonclinical video
conference of Feb. 24, 1997 ( 4 pp.). cited by other .
Bushnell et al., Choosing the right analgesic. A guide to
selection. Drugs, Sep. 1993;46(3):394-408. cited by other .
Caplan et al., Transdermal fentanyl: An overview of clinical
progress in Opioids in Anesthesia II (Estafanous, ed.) ,
1991(21):267-73. cited by other .
Chapters 17 and 18 discussion in Opioids in Anesthesiia II
(Estafanous, ed.) 1991:223-38. cited by other .
Charuvastra et al., Buprenorphine versus placebo taste test. CPDD
1994 Annual Scientific Meeting Abstracts. cited by other .
Clarification of pharmtox requirements for NDA (IND 50,273) meeting
minutes with sponsor of Apr. 13, 1999. cited by other .
Clinical chronology for BTDS NDA from May 10, 1996-Feb. 4, 2000.
cited by other .
CMC chronology for BTDS NDA from Jun. 26, 1997-Mar. 2, 2000. cited
by other .
Clinical documentation (Part IV), vols. 6-37 Table of Contents from
Grunethal GmbH as of Dec. 13, 1999. cited by other .
Comparison of the analgesic efficacy and safety of buprenorphine in
the form of a sublingual tablet and a transdermal therapeutic
system (TTS 50) in chronic pain, Grunenthal; GmbH--Medical
Department, Germany, Report No. WIS-BUP 03, May 20, 1999. cited by
other .
Compton et al., What dose of buprenorphine reduces opiate use? A
double-blind dose-ranging study. CPDD 1994 Annual Scientific
Meeting Abstracts. cited by other .
Controlled Substance Staff--Background material for peripheral and
central nervous system advisory committee. Risk management plans
for recently approved drugs. Mar. 15, 2001. cited by other .
Coop et al. Ring constrained analogs of Buprenorphine. CPDD 1994
Annual Scientific Meeting Abstracts. cited by other .
Determination of the absolute bioavailability of buprenorphine from
a transdermal therapeutic system with 2 different loadings (20 and
40 mg) in comparison to an intravenous administration in an open
3-way crossovere trial with 24 healthy male volunteers. Gruenenthal
GmbH--Research Centre, Germany. Report No. FO-PK 391, May 6, 1996.
cited by other .
Determination of the analgesic efficacy of three buprenorphine
dosages versus placebo in a transdermal therapeutic system (TTS) in
patients with tumour pain and patients with chronic pain of
non-tumour-related origin. Grunenthal GmbH--Medical Department,
Germany. Report No. WIS-BUP 01, Jun. 17, 1999. cited by other .
Determination of the analgesic of three buprenorphine dosages
versus placebo in a transdermal therapeutic system (TTS) in
patients with tumour pain and patients with chronic non-tumour
related pain. Grunenthal GmbH--Medical Department, Germany. Report
No. WIS-BUP 02, Jun. 1, 1999. cited by other .
Determination of the pharmacokinetic paramenters of buprenorphine
from a transdermal therapeutic system with 3 different loadings
(20, 30, and 40 mg) in an open, balanced 3-parallel group study in
54 healthy volunteers. Chrysalis Clin. Pharmcol Services GmbH,
Germany. Final Report PK 402 Integrated PK, Jun. 30, 1997. cited by
other .
Determination of the plasma concentration of buprenorphine from a
transdermal therapeutic system with three different loadings in a
patient population. Gruenenthal GmbH--Research Centre, Germany.
Report No. WIS-BUP 02 PK, Jan. 20, 1999. cited by other .
Fentanyl Published Information (undated). cited by other .
Follow-up treatment with buprenorphine TTS 50 after completion of
the double-blind phase of studies. Grunenthal GmbH--Medical
Department, Germany. Report No. WIS-BUP FU, May 25, 1999. cited by
other .
Fukaze et al., Precipitation of morphine withdrawal by
buprenorphine and butorphanol in male cynomolgus monkeys. CPDD 1994
Annual Scientific Meeting Abstracts. cited by other .
Gasfriend et al., Long-term effects of buprenorphine for treatment
of combined opiate and cocaine dependence. CPDD 1994 Annual
Scientific Meeting Abstracts. cited by other .
Guo et al., Bioadhesive buccal polymer patches for buprenorphine
controlled delivery: Solubility consideration. Proceed Intern Symp
Control Rel Bioact Mater. 1995. cited by other .
Hawks et al., Buprenorphine-naloxone combination drug for the
treatment of drug addiction. CPDD 1994 Annual Scientific Meeting
Abstracts. cited by other .
Hayes, of FDA, Comments dated Mar. 31, 1997 regarding buprentrphine
patch (IND 50,273), Mar. 31, 1997 (2 pp.). cited by other .
Hogan & Hartson's supplemental filing dated Apr. 10, 2002 in
support of citizen petition filed on Dec. 11, 2001. cited by other
.
Hogan & Hartson's response dated May 9, 2002 to 67 FR 17074 of
Apr. 9, 2002. cited by other .
Hogan & Hartson's comments dated May 22, 2002 on 67 FR 13114 of
Mar. 21, 2002. cited by other .
Human immunodeficiency virus/acquired immunodeficiency syndrome in
the context of drug abuse. Report of the Executive Director, United
Nations Economic and Social Council. Jan. 30, 2003 (12 pp.). cited
by other .
Hyman, Phelps & McNamara P.C.'s comments and objections dated
Jul. 5, 2002 to the citizen petition. cited by other .
Hyman, Phelps & McNamara P.C.'s comments dated May 22, 2002 on
behalf of Purdue Pharma L.P. to 67 Fed. Reg. 13,114 of Mar. 21,
2002. cited by other .
Hyman, Phelps & McNamara P.C.'s response dated May 9, 2002 on
behalf of Purdue Pharma L.P. to 67 Fed. Reg. 17074 of Apr. 9, 2002.
cited by other .
Johnson et al., Daily versus alternate-day dosing of buprenorphine
in the outpatient treatment of opioid dependence. CPDD 1994 Annual
Scientific Meeting Abstracts. cited by other .
Jones et al., Buprenorphine and naloxone interactions in
heroin-dependent volunteers. CPDD 1994 Annual Scientific Meeting
Abstracts. cited by other .
Journal of Pain and Symptom Management. Apr. 1992 7(S3) (whole
journal). cited by other .
Kintz, Deaths involving buprenorphine: A compendium of French
cases. Forensic Sci Int. Sep. 15, 2001; 121(1-2):65-9. cited by
other .
Korte, Titration with TTS fentanyl systems for previously
uncontrolled cancer pain, and Lipman's response thereto. Anesth
Analg. Sep. 1994;79(3):612-4. cited by other .
Kumar, Chemists selling illegal drugs to be booked in The times of
India, Aug. 16, 2000. cited by other .
Lasseter et al., Systemic pharmacokinetic (PK) study of
buprenorphine (B) in mild to moderate chronic hepatic impairment
(CHI). Amer Soc for Clin Pharmacol and Therapeut. PI-4. cited by
other .
Liguori et al., Modification of respiratory effects of levorphanol
by nalbuphine, butorphanol, and buprenorphine in rhesus monkeys.
CPDD 1994 Annual Scientific Meeting Abstracts. cited by other .
Mann et al., Buprenorphine alone or in combination with naltrexone
for inpatient medically supervised opiate withdrawal. CPDD 1994
Annual Scientific Meeting Abstracts. cited by other .
McCance-Katz, of American Academy of Addiction Psychiatry, letter
to DEA Administration dated May 15, 2002 in response to proposed
rule: Rescheduling of Buprenorphine from Schedule V to Schedule
III, published in the Federal Register of Mar. 21, 2002. cited by
other .
McNeal, of FDA, Medical Review on IND 40,273, dated May 10, 1996.
cited by other .
McNeal, of FDA, Comments dated Aug. 30, 1996 on the protocols
submitted on Aug. 5, 1996 in Ser. No. #006 of IND 50,273. cited by
other .
McNicholas et al., Buprenorphine clinical practice guidelines.
Field review draft. Nov. 17, 2000. cited by other .
Mendelson et al., Buprenorphine treatment improves brain perfusiion
abnormalities in men with concurrent cocaine and heroin dependence:
A spect brain imaging analysis. CPDD 1994 Annual Scientific Meeting
Abstracts. cited by other .
Miller, Memorandum to Brogden, Napp Pharmaceuticals Ltd., re
Evaluation of clinical data received from Grunenthal buprenorphine
TTS, Nov. 11, 1999 ( 5 pp.). cited by other .
Non-Clinical Chronology for BTDS NDA from May 2, 1996-Apr. 2000.
cited by other .
O'Connor et al., A pilot study of primary care-based buprenorphine
maintenance. CPDD 1994 Annual Scientific Meeting Abstracts. cited
by other .
O'Keeffe, of Reckitt Benckiser Pharmaceuticals Inc. letter to DEA
Administrator dated Apr. 18, 2002 in response to proposed rule:
Rescheduling of buprenorphine from Schedule V to Schedule III,
published in the Federal Register on Mar. 21, 2002. cited by other
.
Payne et al., The role of transdermal fentanyl in the management of
cancer pain in Opioids in Anesthesia II (Estafanous. ed.),
1991(18):215-22. cited by other .
Pharmaceuticals: Restrictions in Use and Availability, Mar. 2001
(up to p. 5 re Buprenorphine). cited by other .
Pilot study on the dermal tolerability and adhesion of a
buprenorphine path and the absorption of the active substance over
an application period of 72 hours in 6 healthy volunteers, Final
Report, 1992. cited by other .
Portenoy et al. Acute and chronic pain in Substance Abuse. A
Comprehensive Textbook (Lowinson et al., eds.), 2.sup.nd ed. 2005.
52:691-721. cited by other .
Preston et al., Abuse liability evaluation of buprenorphine in
buprenorphine-treated patients. CPDD 1994 Annual Scientific Meeting
Abstracts. cited by other .
Report of the International Narcotics Control Board for 2001,
United Nations Publication. cited by other .
Response to the Critical Review (undated). cited by other .
Rigas et al., Transdermal fentanyl: Practical use in the hospital
and the home (undated). cited by other .
Schuh, A comparison of buprenorphine's and naltrexone'opioid
blockade abilities. CPDD 1994 Annual Scientific Meeting Abstracts.
cited by other .
Segal et al., A double blind, multicenter clinical trial comparing
four doses of buprenorphine. CPDD 1994 Annual Scientific Meeting
Abstracts. cited by other .
Singh et al., Cases of buprenorphine abuse in India. Acta Psychiatr
Scand. Jul. 1992;86(1):46-8. cited by other .
Slides on Buprenorphine (21 pp.) (undated). cited by other .
Smith, Grunenthal buprenorphine transdermal system. Review of
pharmacokinetic studies, 11/10/199 ( 7 pp.). cited by other .
Steinberg et al., Acute toxic delirium in a patient using
transdermal fentanyl. Anesth Analg. Dec. 1992;75(6):1014-6. cited
by other .
The Safety of High Doses of Buprenorphine. Table of Contents and
Introduction (undated). cited by other .
Using buprenorphine for office-based treatment of opiate
addiction.Reccommendations to the CSAT of the SAMHSA, from CSAT's
National Advisory Council, approved by the CSAT's National Advisory
Council on Sep. 15, 1999 (28 pp.). cited by other .
Wang et al., Negative opiates in urine of patients on buprenorphine
study. CPDD 1994 Annual Scientific Meeting Abstracts. cited by
other .
WHO Critical review of psychoactive substances, 33.sup.rd Expert
Committee on Drug Dependence, Sep. 17-20, 2002. cited by other
.
WHO Expert Committee on Drug Dependence 25.sup.th Report. WHO
technical Report Series. 1989. cited by other .
WHO Expert Committee on Drug Dependence 32.sup.nd Report. WHO
Technical Report Series. 2001. cited by other .
WHO Expert Committee on Drug Dependence 33.sup.rd Report. WHO
Technical Report Series. 2003. cited by other .
Wodak, Additional commentary on a proposed review of the
classification of buprenorphine in Schedule III of the 1971
Convention on Psychotropic substances (undated). cited by other
.
Ziedonis et al., Depression in cocaine abusing opioid addicts
treated with buprenorphine versus methadone. CPDD 1994 Annual
Scientific Meeting Abstracts. cited by other .
Bell et al., Evaluation of transdermal fentanyl for multi-day
analgesia in postoperative patients. Anesth Analg. 1989; Abstract
S22. cited by other .
Fiset et al., Biopharmaceutics of a new transdermal fentanyl
device. Anesthesiology. Sep. 1995;83(3):459-69. cited by other
.
Gibaldi, Prolonged-Release medication in Biopharmaceutics and
Clinical Pharmacokinetics. 1984;3.sup.rd ed.: 113-30. cited by
other .
Hadgraft, In vitro testing of dermal and transdermal products. Mar.
28, 2001 (6 pages). cited by other .
Harvey-Clark et al., Transdermal fentanyl compared with parenteral
buprenorphine in post-surgical pain in swine: a case study. Lab
Anim. Oct. 2000;34(4):386-98. cited by other .
Imoto et al., Transdermal prodrug concepts: permeation of
buprenorphine and its alkyl esters through hairless mouse skin and
influence of vehicles. Biol Pharm Bull. Feb. 1996;19(2):263-7.
cited by other .
Michaels et al., Drug permeation through human skin: Theory and in
vitro experimental measurement. AIChE J. 1975;221(5):985-96. cited
by other .
New Approaches to Pain Management. Progress in Palliative Care.
Meeting Report. Oct. 12-13, 2000; 100-101. cited by other .
Portenoy et al., Transdermal fentanyl for cancer pain. Repeated
dose pharmacokinetics. Anesthesiology. Jan. 1993;78(1):36-43. cited
by other .
Shah, Sr. Research Scientist, Center for Drug Evaluation and
Research, Food and Drug Administration, Rockville, MD, In vitro
release of special/novel dosage forms: What is its value?
(undated). cited by other .
Stinchcomb et al., Permeation of buprenorphine and its
3-alkyl-ester prodrugs through human skin. Pharm Res. Oct.
1996;13(10):1519-23. cited by other .
Hihuchi, William I., Ph.D. et al., "Particle Phenomena and Coarse
Dispersions" Chapter 21, p. 294. cited by other .
Colloidal Dispersions, p. 267. cited by other .
Catapres TTS.RTM. Product Information, Physicians' Desk Reference
(1998) pp. 610-612. cited by other .
Chien, pp. 31-44, col. 8 and 9. cited by other .
McQuinn, R.I., et al., "Sustained oral mucosal delivery in human
volunteers of buprenorphine from a thin non-eroding mucoadhesive
polymeric disk" J. Contr. Rel. (1995). cited by other .
Van Buskirk, G.A. et al., "Scale-up of adhesive transdermal drug
delivery systems" Pharmaceutical Research 14(7) (1997). cited by
other .
Sadee, W. et al., "Buprenorphine: Differential interaction with
opiate receptor subtypes in vivo" J. Pharm. Exp. Ther. 223(1) 1982.
cited by other .
Kuhlman, J.J., et al., "Human pharmacokinetics of Intravenous,
sublingual and buccal buprenorphine" J. Anal. Toxicol. v 20 (1996).
cited by other .
Roy, S.D. et al., Transdermal delivery of buprenorphine through
cadaver skin J. Pharm. Sci. 83(2): 126-30 (1994). cited by other
.
Wilding, I.R. et al., "Pharmacokinetic evaluation of transdermal
buprenorphine in man" Intl. J. Pharmaceutics 132:81-7 (1996). cited
by other .
Roy et al., "Controlled transdermal delivery of fentanyl:
characterizations of pressure-sensitive adhesives for matrix patch
design, " J Pharm Sci. May 1996, 85(5):491-5. cited by other .
Friend et al., Simple alkyl esters as skin permeation enhancers. J.
Controlled Release 1988 9:33-41. cited by other .
Friend et al., Transdermal delivery of levonorgestrel I: Alkanols
as permeation enhancers in vitro, J. Controlled Release 1988
7:243-50. cited by other .
Agin M, Kazierad DJ, Abel R, et al., Assessing QT variability in
healthy volunteers. J. Clin. Pharmacol. 2003; 43:1028. cited by
other .
Ahmadi, J. et al., Treatment of heroin dependence. German Journal
of Psychiatry 2004;7(2): 1-5. cited by other .
Baker JR. Effect of buprenorphine and antiretroviral agents on the
QT interval in opioid-dependent patients. Annals of Pharmacotherapy
2006: 40:392-6. cited by other .
Bauer, K.H. et al. Pharmazuetische Technologie, (1986) pp. 362-365.
cited by other .
Bigelow GE. Forward. In: Cowan A, Lewis JW, eds. Buprenorphine:
Combating Drug Abuse With a Unique Opioid. New York, NY:
Wiley-Liss: 1995:xi-xiii. cited by other .
Bliesener N, et al., Plasma Testosterone and Sexual Function in Men
Receiving Buprenorphine Maintenance for Opioid Dependence. The
Journal of Clinical Endocrinology & Metabolism 90(1):203-6,
2005. cited by other .
Boger RH. Renal impairment: a challenge for opioid treatment? The
role of buprenorphine. Palliative medicine 2006; 20:S17-S23. cited
by other .
Briefing document, cardiovascular and renal drug products advisory
committee. May 29, 2003. Division of reproductive and urologic drug
products. Apr. 29, 2003. Available at:
http://www.fda.gov/ohrms/dockets/ac/03/briefing/3956B1_01_FDA-alfuzosin.p-
df. cited by other .
Bruce RD. Pharmacokinetic interactions between buprenorphine and
antiretroviral medications. Clinical Infectious Diseases 2006; 43
(Suppl 4):S216-S223. cited by other .
Cherny NJ, Chang V, Frager G, Ingham JM, Tiseo PJ, Popp B, Portenoy
RK, Foley KM. Opioid Pharmacotherapy in the Management of Cancer
Pain: A Survey of Strategies Used by Pain Physicians for the
Selection of Analgesic Drugs and Routes of Administration. Cancer
1995; 76:1288-1293. cited by other .
Ciraulo DA. Pharmacokinetics and pharmacodynamics of multiple
sublingual buprenorphine tablets in dose-escalation trials. Journal
of Clinical Pharmacology 2006;46(2):179-92. cited by other .
Cranmer, K.W. et al., Transdermal buprenorphine (BTDS) on
associated health outcomes in the elderly. Presented at the 11th
World Congress on Pain, Sydney, Australia, Aug. 21-26, 2005: Abstr
691-P297. (Study sponsored by Purdue Pharma L.P.). cited by other
.
Cymbalta.RTM. (duloxetine hydrochloride) Delayed-release Capsules)
Package Insert. cited by other .
Dahan A. Opioid effects on respiratory function and analgesia: New
data on buprenorphine and fentanyl in a new human model [abstract].
3.sup.rd Research Forum of the European Association for Palliative
Care, Stesa, Italy, 2004. cited by other .
Duragesic.RTM. [package insert]. Titusville, NJL Janssen
Pharmaceutica; 2001. cited by other .
Eissenberg T et al., Buprenorphine's physical dependence potential:
Antagonist-precipitated withdrawal in humans. J. Pharmacol. Exp.
Ther. 276: 449-459, 1996. cited by other .
Escher, M. et al., Pharmacokinetics and analgesic effects of
intravenous buprenorphine (abstract). Clinical Pharmacology and
Therapeutics 2005; 77(2 Suppl): 51. cited by other .
Fleiss JL. Statistical Methods for Rates and Proportions. 2nd ed.
New York, NY: John Wiley & Sons; 1981:33-45, 272-273 (Table
A.3). cited by other .
Flitz J. Effects of intermittent hemodialysis on buprenorphine and
norbuprenorphine plasma concentrations in chronic pain patients
treated with transdermal buprenorphine. European Journal of Pain
2006;10(8):743-8. cited by other .
Gaulier J-M, et al., Ingestion of High-Dose Buprenorphine by a 4
Year-Old Child. Journal ofToxicology-Clinical Toxicology
42(7):993-5, 2004. cited by other .
Gerra G. Naltrexone and buprenorphine combination in the treatment
of opioid dependence. Journal of psychopharmacology
2006;20(6):806-14. cited by other .
Hale ME, Ahdieh H, Ma T, Rauck R, for the Oxymorphone ER Study
Group. Efficacy and Safety of OPANA ER (Oxymorphone Extended
Release) for Relief of Moderate to Servere Chronic Low Back Pain in
Opioid-Experienced Patients: A 12-Week, Randomized, Doubleblind,
Placebo-controlled Study. J Pain 2007; 8(2):175-184. cited by other
.
Halpern SD, Karlawish JHT, Berlin JA. The Continuing Unethical
Conduct of Underpowered Clinical Trials. JAMA 2002; 288:358-362.
cited by other .
Heel RC, Brogden RN, Speight TM, A very GS. Buprenorphine: a review
of its pharmacological properties and therapeutic efficacy. Drugs.
1979; 17:81-110. cited by other .
Heilman, K. Therapeutische Systeme (1984) pp. 26-27 and pp. 48-53.
cited by other .
Herve S, et al., Acute hepatitis due to buprenorphine
administration. European Journal of Gastroenterology &
Hepatology 16(10):1033-7, 2004. cited by other .
Hoskin PJ, Hanks GW. Opioid agonist-antogonist drugs in acute and
chronic pain states. Drugs. 1991; 41(3):326-344. cited by other
.
ICH harmonized tripartite guideline: the clinical evaluation of
QT/QTc interval prolongation and proarrhythmic potential for
non-antiarrhythmic drugs, E14, Final Draft May 12, 2005. Available
at [http://www.ich.org/cache/compo/475-272-1.httml #E14]. cited by
other .
Jagadheesan K and Muihead D., Possible manic potential of
buprenorphine [letter]. Australian and New Zealand Journal of
Psychiatry 37*8):560-1, 2004. cited by other .
Katchman AN, McGroary KA, Kilborn MJ, et al., Influence of opioid
agonists on cardiac human ether-a-go-go-related gene K(+) currents,
2002. J Pharmacol Exp Ther 303:688-94. cited by other .
Kolloch RE, Mehlburger L, Schumacher H, Gobel Bo. Efficacy and
safety of two different galenic formulations of a transdermal
clonidine system in the treatment of hypertension. Clin Auton Res.
1993;3:373-378. cited by other .
Kosten T, et al., Depression Predicts Higher Rates of Heroin Use on
Desipramine with Buprenorphine than with Methadone. The American
Journal of Addictions 13:191-201, 2004. cited by other .
Krantz, M.J. et al., Effects of buprenorphine on cardiac
repolarization in a patient with methadone-related torsade de
pointes. Pharmacotherapy 2005; 25(4): 611-614. cited by other .
Landau, C.J. et al., The safety and tolerability of buprenorphine
7-day transdermal system in patients with nonmalignant pain
syndromes responsive to opioids. Presented at the 11th World
Congress on Pain, Sydney Australia, Aug. 21-26, 2005: Abstr.
690-P296 (Study sponsored by Purdue Pharma L.P.). cited by other
.
McCance-Katz EF. Interactions between buprenorphine and
antiretrovirals. II. The protease inhibitors nelfinavir,
lopinavir/ritonavir, and ritonavir. Clinical infectious Diseases
2006; 43 (Supp 4):S235-S246. cited by other .
McCance-Katz EF, Interactions between buprenorphine and
antiretrovirals. I. The nonnucleoside reverse-transcriptase
inhibitors efavirenz and delaviridine. Clinical infectious Diseases
2006; 43(Suppl 4):S224-S234. cited by other .
McMahon FG, Jain AK, Vargas R, Fillingim J. A double-blind
comparison of transdermal clonidine and oral captopril is essential
hypertension. Clin.Ther. 1990; 12:88-100. cited by other .
Muriel, C. et al., Effectiveness and tolerability of the
buprenorphine transdermal system in patients with moderate to
severe chronic pain: a multicenter, open-label, uncontrolled,
prospective, observational clinical study. Clinical Therapeutics
2005; 27(4): 451-462. (Study sponsored by Grunenthal GmbH). cited
by other .
Neri, S. et al., Randomized clinical trial to compare the effects
of methadone and buprenorphine on the immune system in drug
abusers. Psychopharmacology 2005; 179(3): 700-704. cited by other
.
Nielsen, S.; Taylor, D.A. The effect of buprenorphine and
benzodiazepines on respiration in the rat. Drug and Alchol
Dependence 2005;79:95-101. cited by other .
Noveck, R. et al., Lack of effect of inhibitor ketoconazole on
transdermally administered buprenorphine. Presented at the 106th
Annual Meeting of the American Society for Clinical Pharmacology
and Therapeutics, Orlando, FL., Mar. 2-5, 2005. (Study sponsored by
Purdue Pharma L.P.). cited by other .
Opana.RTM. ER( (Oxymorphone Hydrochloride) Extended Release
Tablets)) Package Insert. cited by other .
Patterson S, Agin M, Anziano R, et al., Investigating drug-induced
QT and QTc prolongation in the clinic: a review of statistical
design and analysis considerations. Report from the pharmaceutical
research and manufacturers of America QT statistics expert team.
Drug Information Journal 2003:39:243-265. cited by other .
Philipz, J. et al., Pharmacokinetics of transdermal buprenorphine
(Transtec.RTM.) in patients with renal insufficiency. Presented at
the 9th Congress of the European Association for Palliative Care,
Aachen, Germany, Apr. 8-10, 2005. (Study sponsored by Grunenthal
GmbH). cited by other .
Pirnay S, et al., A critical review of the causes of death among
post-mortem toxicological investigations: analysis of 34
buprenorphine-associated and 35 methadone-associated deaths.
Addiction 99:978-88, 2004. cited by other .
Quang-Cantagrel N.D., Wallace M.S., Magnuson S.K. Opioid
Substitution to Improve the Effectiveness of Chronic Noncancer Pain
Control: A Chart Review: Anest Anag 2000; 90:933-937. cited by
other .
Raja SN, Haythornthwaite, JA, Pappagallo M, Clark MR, Travison TG,
Sabeen S, Royall RM, and Max MB. Opioids versus antidepressants in
postherpetic neuralgia: A randomized, placebo-controlled trial.
Neurology 59: 1015-1021, 2002. cited by other .
Rozenbaum H, Birkhauser M, DeNooyer C, et al., Comparison of two
estradiol transdermal systems (Oesclim.RTM. 50 and Estraderm
TTS.RTM. 50). II. Local skin tolerability. Maturitas. 1996;
25:175-185. cited by other .
Schmid-Grendelmeier P. A comparison of the skin irritation
potential of transdermal fentanyl versus transdermal buprenorphnie
in middle-aged to elderly healthy volunteers. Current Medical
Research and Opinion 2006;22(3)501-9. cited by other .
Sittl, R. et al., Equipotent doses of transdermal fentanyl and
transdermal buprenorphine in patients with cancer and noncancer
pain: Results of a retrospective cohort study. Clinical
Therapeutics 2005; 27(2):225-237. (Study sponsored by Grunenthal
GmbH). cited by other .
Soyka, M. et al., Less impairment on one portion of a
driving-relevant psychomotor battery in buprenorphine-maintained
that in methadone-maintained patients: results of a randomized
clinical trial. Journal of Clinical Psychopharmacology 2005;
25(5):490-493. cited by other .
Sporer KA, Buprenorphine: A Primer for Emergency Physicians. Annals
of Emergency Medicine 43(5):580-4, 2004. cited by other .
Turk DC, Melzack R. The measurement of pain and the assessment of
people experiencing pain. In: Turk DC, Melzack R, eds. Handbook of
Pain Assessment. New York, NY: The Guilford Press; 1992:3-12. cited
by other .
World Medical Association Declaration of Helsinki, Ethical
Principals for Medical Research Involving Human Subjects. 2004.
cited by other .
Yassen A. Mechanisms-based PK/PD modeling of the respiratory
depressant effect of buprenorphine and fentanyl in healthy
volunteers. Clinical Pharmacology & Therapeutics
2007;8(1):50-8. cited by other .
Wallenstein, "Crossover Trials in Clinical Analgesic Assays:
Studies of Buprenorphine and Morphine" Pharmacotherapy 6(5):228-235
(1986). cited by other .
Johnson RE, Fudala PJ, Payne R. Buprenorphine: considerations for
pain management. JPain Symptom Manage 2005;29:297-326. cited by
other .
Lemens HJM, Wada DR, Munera C, El-Tahtawy A, Stanski DR. Enriched
analgesic efficacy studies: an assessment by clinical trial
simulation. Contemp Clin Trials, 2006;27; 165-1 73. cited by other
.
Cranmer K, Landau CJ, Friedman My Turner NG, Ripa SR. The safety
and tolerability 0 of 7-day buprenorphine TDS in the analgesic
management of pain in the elderly--a 6-month evaluation.
www.ASCP/com.education/postersandpapersam05.com. Poster 34. (Study
BUP3002S). cited by other .
D'Ambrosio P, McCarberg By Landau CJ, Hsu Y, Colucci R, Ripa S.
Conversion from Vicodin.RTM. to buprenorphine transdermal system in
subjects with osteoarthritis pain. J Pain 2006; 7(4) (Suppl 2):S5
1. Abstract 801. (Study BUP3018). cited by other .
Harris S, Hoelscher D, Kristensen A, O'Keefe S, Schemera A. Effects
of bupreorphine transdermal system 10 mg and 2 .times.20 mg on QT
intervals in healthy subjects. Clin Pharmacol ner 2006; 79(2):P35.
(Study BUP1011). cited by other .
Razzetti AJ, Carr W, Landau CJ, Munera C, Ripa SR, Sessler N.
Effectiveness of 7-day buprenorphine transdermal system in the
management of chronic nonmalignant pain syndromes. J Pain 2005;
6(3) Suppl I:542. (Study BUP3201). cited by other .
Schnoll SH, Smith MY, Colucci RD, Munoz A. Development of a
denominator for calculating rates of opioid abuse. CPDD Annual
Meeting Abstracts. 2004. (Study BUP3018 and non-BTDS studies).
cited by other .
Shannon MJ, Kivitz A, Landau CJ, Sessler NE, Xia Y, Ripa SR.
Buprenorphine transdermal system in chronic pain due to
osteoarthritis. Arch Phys Med Rehabil2005; 86(9):e32. (Study
BUP3012). cited by other .
Spyker DA, Hale ME, Lederman My Creanga DL, Coles C, Reder RF,
Long-term use of buprenorphine transdermal system (BTDS) in
patients with chronic pain. JAm Geriatr Soc 2002; 50(4 Suppl):S66.
Abstract P162. (Study BP96-0103). cited by other .
Spyker DA, Hale ME, Munera CL, Wright C. Treatment of patients with
chronic low back pain with buprenorphine transdermal system (BTDS)
compared with hydrocodone/acetaminophen. Pain Mgmt 2001: PF2001-85.
(Study BP98-1201). cited by other .
Wright C, Zalman M-A, Haddox JD, Kramer ED, Colucci RD, D'Ambrosio
P., Systematic assessment of abuse or diversion in a clinical trial
of analgesics. CPDD Annual Meeting Abstracts. 2006. (Study
BUP3018). cited by other .
Barry, "Reflections on Transdermal Drug Delivery", Pharmaceutical
Science & Technology Today 2(2):41-43 (1999). cited by other
.
Abse et al., "The poppy: therapeutic potential in cases of
demential with depression" Ann. NY Acad. Sci.398: 79-83 (1982).
cited by other .
Ahmedzai, S, "New approached to pain control in patients with
cancer" Eur. J. Cancer 33(Suppl. 6): S8-S14 (1997). cited by other
.
Akatsuka et al., "The relief of postoperative pain by suppositories
of buprenorphine or NSAID" Masui 45(3):298-303 (1996). (Abstract).
cited by other .
Al-Gommer O. Sexual dysfunctions in male opiate users: A
comparative study of heroin, methadone, and buprenorphine.
Addictive Disorders and their Treatment 2007;6(3): 137-43. cited by
other .
Ang-Lee K. Single dose of 24 milligrams of buprenorphine for heroin
detoxification: An open-label study of five inpatients. Journal of
psychoactive drugs 2007; 38(4):505-12. cited by other .
Bates' Guide to Physical Examination and History Taking, 6th ed.,
Bickley t al., eds., Lippincott Williams & Wilkins Publishers,
1995, pp. 276-280. cited by other .
Bellamy N, Buchanan WW, Goldsmith CH, Campbell J. Stitt LW.
Validation study of WOMAC: a health status instrument for measuring
clinically important subject relevant outcomes to antirheumatic
drug therapy in subjects with osteoarthritis of the hip or knee. J.
Rheumatol 1988; 15:1833-1840. cited by other .
Bellamy N, Campbell J, Hill J, Band P. A comparative study of
telephone versus onsite completion of the WOMAC 3.0 Osteoarthritis
Index. J Rheumatol 2002; 29:783-786. cited by other .
Bellamy N. WOMAC Osteoarthritis Index, a user's guide. London,
Ontario, Canada: Victoria Hospital Corporation, 1995. cited by
other .
Bentley et al., "Age and fentanyl pharmacokinetics" Anesth. Analg.
61: 968-971 (1982). cited by other .
Berrocoso et al., "Differential role of 5-HT1A and 5-HT1B receptors
on the antiociceptive and antidepressant effect of tramdol in mice"
Psychopharmacology 188(1): 111-118 (2006). cited by other .
Bodkin et al., "Buprenorphine treatment of refractory depression"
J. Clin. Psychoparmacology 15(1): 49-57 (1995). cited by other
.
Bonica, JJ, "Past and current status of pain research and therapy"
Semin. Anesth. 5:82-99 (1986). cited by other .
Brema et al., "Oral tramadol and buprenorphine in tumor pain. An
Italian multicentre trial" Int. J. Clin. Pharm. Rex. 16(4/5) :
109-116 (1996). cited by other .
Brenn et al., "Epidural analgesia in children with cerebral palsy"
45(12): 1156-1161 (1998). cited by other .
Buchwald et al., "Quantitative structure-metabolism relationships:
Steric and non-steric effects in the enzymatic hydrolysis of
noncongener carboxylic esters" J. Med. Chem. 42:5160-5168 (1999).
cited by other .
Bundgaard, H (ed.) Design of Prodrugs Elsevier: Amsterdam, New York
1985. cited by other .
Callaway, E., "Buprenorphine for depression: The un-adoptable
orphan" Biol. Psychiatry 39: 989-990 (1996). cited by other .
Callesen et al., "Prospective study of chronic pain after groin
hernia repair" Br. J. Surg. 86: 1528-1531 (1999). cited by other
.
Capogna et al., "Intrathecal buprenorphine for postoperative
analgesia in the elderly patient" Anaesthesia 43: 128-130 (1988).
cited by other .
Cathelin et al, "Comparison between the side-effects of
buprenorphine and morphine in conscious man" Anesth. Analg. (Paris)
37(5-6): 283-293 (1980). English abstract. (Original in French).
cited by other .
Cherny, J., "New strategies in opioid therapy for cancer pain" J.
Oncol. Management 9: 8-15 (2000). cited by other .
Cirado et al., "Reduction of isoflurane MAC with buprenorphine and
morphine in rats" Laboratory Animals 34(3): 252-9 (2000). cited by
other .
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain
Inventory. Ann Acad Med. 1994;23(2):129-138. cited by other .
Coli et al., "Evaluation of the effectiveness of NSAIDs in the
prevention of postoperative pain. Comparison between pre-and
postoperative administration of sodium naproxen in orthopedic
surgery" Minerva Anestesiol. 59(10): 531-535 (1993). (Abstract).
cited by other .
Crook et al., "The prevalance of pain complaints in a general
population" Pain 18: 299-314 (1984). cited by other .
Daut RL, Cleeland,CS, Flanery RC. Development of the Wisconsin
Brief Pain Questionaire to assess pain in cancer and other
diseases. Pain 1983; 17:197-210. cited by other .
Davids et al., "Buprenorphine in the treatment of opioid
dependence" European Neuropsycharmacology 14: 209-216 (2004). cited
by other .
Dayer et al., "Pharmacology of tramadol" Drugs 53(Suppl. 2): 18-24
(1997). English abstract. (Original in French). cited by other
.
Dean et al., "Depressive symptoms during buprenorphine vs.
methadone maintenance: Findings from a randomized, controlled trial
in opioid dependence" European Psychiatry 19:510-513 (2004). cited
by other .
Desjardins et al., "The injectable cyclooxegenase-2 specific
inhibitor parecoxib sodium has analgesic efficacy when administered
preoperatively" Anesth. Analg. 93: 721-727 (2001). cited by other
.
Dionne et al., "Evaluation of preoperative ibuprofen for
postoperative pain after removal of third molars" Oral Surgery 45:
851-856 (1978). cited by other .
Dionne et al., "Suppression of postoperative pain by preoperative
administration of ibuprofen in comparison to placebo,
acetaminophen, and acetaminophen plus codeine" J. Clin. Pharmacol.
23: 37-43 (1983). cited by other .
Dum et al., "Opioids and Motivation" Interdisciplinary Science
Reviews 12(2): 180-190 (1987). cited by other .
Eder at al., "Buprenorphin in der Schwangerschaft" Psychiat. Prax.
28: 267-269 (2001). (XP009068360). (Abstract). cited by other .
Eke et al., "An open comparative study of dispersible piroxicam
versus soluble acetylsalicylic acid for the treatment of
osteoarticular painful attack during sickle cell crisis" Tropical
Medicine and International Health 5(2): 81-84 (2000). cited by
other .
Emrich et al. "Antidepressant effects of buprenorphine" Lancet 2:
709 (1982). cited by other .
Emrich et al., "Current perspectives in the pharmacopsychiatry of
depression and mania" Neuropharmacology 22(3 Special No.): 385-388
(1983). cited by other .
Emrich et al., "Possible antidepressive effects of opioids: action
of buprenorphine" Ann. NY Acad. Sci. 398: 108-112 (1982). cited by
other .
Emrich, HM, in: "Typical and Atypical Antidepressants: Clinical
Practice" Costa et al., (Eds.), Raven Press: New York, 1982 pp. 77
et seq. cited by other .
Holloway, M. (Erickson, D.), "Rx for addiction" Sci. Am. 264(3):
94-103 (1991). cited by other .
Etchepare F, Coutaux, A, Edel Y, Bourgeois P. Enterobacter cloacae
spondylodiscitis through misuse of high-dose intravenous
buprenorphine, La Presse Medicale 2005; 34(10):729-731. cited by
other .
Everhart et al., "Subnanogram-concentration measurement of
buprenorphine in human plasma by electron-capture capillary gas
chromatography: application to pharmacokinetics of sublingual
buprenorphine" Clin. Chem. 43(12): 2292-2302 (1997). cited by other
.
Extein et al., "Deficient prolactin response to morphine in
depressed patients" Am. J. Psychiatry 137:845-846 (1980). cited by
other .
Extein et al., "Methadone and morphine in depression"
Psychopharmacol. Bull. 17(1): 29-33 (1981). cited by other .
Faponle, AF, "Management of pain after surgery--A short review"
Nigerian Journal of Medicine 10(3): 112-115 (Jul./Sep. 2001). cited
by other .
Feinberg et al., "The effect of morphine on symptoms of endogenous
depression" in: Harris, (ed.)Problems of Drug Dependence, 1992
National Institute on Drug Abuse Research Monograph 43 pp. 245-250
(1982). cited by other .
Ferrell et al., "Principles of pain management in older people"
Compr. Ther. 17: 53-58 (1991). cited by other .
Ferrell, BA, "Pain evaluation and management in the nursing home"
Ann. Int. Med. 123(9): 681-687 91995). cited by other .
Fischer et al., "Treatment of opioid-dependent pregnant women with
buprenorphine" Addiction 95(2): 239-244 (2000). cited by other
.
Fletcher D, "Prevention of postoperative pain" Ann. Fr. Anesth.
Reanim. 17(6): 622-632 (1998). (Abstract). cited by other .
Gautschi OP, Zellweger R. Images in emergency medicine. Extensive
groin abscess and myositis after intravenous cubital buprenorphine
injection. Annals of Emergency Medicine 2006; 48(6):656-859. cited
by other .
Gerra et al., "Buprenorphine treatment outcome in dually diagnosed
heroin dependent patients: A retrospective study" Progress in
Neuro-Psychopharmacology & Biological Psychiatry 30:265-272
(2006). cited by other .
Gerra et al., "Buprenorphine versus methadone for opioid
dependence: predictor variables for treatment outcome" Drug and
Alcohol Dependence 75: 37-45 (2004). cited by other .
Glasper et al., "Induction of patients with moderately severe
methadone dependence onto buprenorphine" Addiction Biology 10:
149-155 (Jun. 2005). cited by other .
Gold et al., "Antimanic, antidepressant, and antipanic effects of
opiates: clinical, neuroanatomical, and biochemical evidence" Ann.
NY Acad. Sci. 398: 140-150 (1982). cited by other .
Gold et al., "Clinical evidence of antidepressant and antipanic
effects of opiates" Am. J. Psychiatry 136: 982-983 (1979). cited by
other .
Goldstein, "Methadone for depression" Biol. Psychiatry 19 1272-1273
(1984). cited by other .
Golianu, B., "Pediatric acute pain management" Pediatr. Clin. North
Am. 47(3): 559-587 (2000). cited by other .
Goodman & Gilman's The Pharmacological Basis of Therapeutics
Hardman, JG(ed.) McGraw-Hill Professional Publishing 2001, p. 586.
cited by other .
Goodman & Gilman's The Pharmacological Basis of
therapeuticHardman, JG (ed.) McGraw-Hill Professional Publishing
2001, pp. 31-32. cited by other .
Goodman & Gillman's The Pharmacological Basis of Therapeutics
Hardman, JG (ed.), McGraw-Hill Professional Publishing, 2001, pp.
530-532. cited by other .
Griffin et al., "High-dose intravenous methylprednisolone therapy
for pain in children and adolescents with sickle cell disease" N.
Engl. J. Med. 330(11): 733-737 (1994). cited by other .
Guidline for Industry--Clinical Safety Data management: Definitions
and Standards for Expedited Reporting ICH-E2A, Mar. 1995, pp. 5-7.
cited by other .
Hambrook JM, Rance MJ. The interaction of buprenorphine with opiate
receptor: lipophilicity as a determining factor in drug-receptor
kinetics. In: Kosterlitz HW, editor. Opiates and endogenous opioid
peptide. Amsterdam: Elsevier/North Holland, Biomedical Press; 1976.
p. 295-301. cited by other .
Hannibal et al., "Preoperative wound infiltration with bulpivacaine
reduces early and late opioid requirement after hysterectomy"
Anesth. Analg. 83: 376-381 (1996). cited by other .
Heel et al., Curr.Ther. 5: 29-33 (1979). cited by other .
Hoffman D, Freidman M, Colucci S, Richards, P, Zhang P. Validation
of the Brief Pain Inventory for subjects with osteoarthritis. J
Pain 2002; 3(2):(suppl)3. cited by other .
Huang et al., "Atmospheric pressure ionization mass spectrometry"
Anal. Chem. 62(13): 713A-725A (1990). cited by other .
Inagaki et al., "Mode and site of analgesic action of epidural
buprenorphine in humans" Anesth. Analg. 830: 530-536 (1996). cited
by other .
International Search Report, PCT/US2003/039793, dated Mar. 31,
2004, 2 ppgs. cited by other .
Jacobsen et al., "Age-related changes in sebaceous wax ester
secretion rates in men and women" J. Invest. Dermatol. 85: 483-485
(1985). cited by other .
Jakobovits SL, Mcdonough M, Chen RY. Buprenorphine-associated
gastroparesis during in-patient heroin detoxification. Addiction
2007; 101: 490-491. cited by other .
Jernite et al., "Burprenorphine and pregnancy. Analysis of 24
cases" Arch. Pediatr. 6:1179-1185 (1999). cited by other .
Juhlin-Dannefelt et al., "Premedication with sublingual
buprenorphine for out-patient arthroscopy: Reduced need for
postoperative pethidine but higher incidence of nausea" Acta
Anaesthesio. Scand. 39: 633-636 (1995). cited by other .
Kahila H. A prospective study on buprenorphine use during
pregnancy: Effects on maternal and neonatal outcome. Acta
Obstetricia et Gynecologica Scandinavica 2007; 86(2): 185-90. cited
by other .
Kahila H. Brain magnetic resonance imaging of infants exposed
prenatally to buprenorphine. Acta Radiologica 2007; 48(2):228-31.
cited by other .
Kakinohana et al., "Pre-emptive analgesia with intravenous ketamine
reduces postoperative pain in young patients after appendectomy: A
randomized control study" Masui 49(10): 1092-1096 (2000). (
Abstract). cited by other .
Kalbfleisch JD, Prentice RL. The statistical analysis of failure
time data. New York: John Wiley and Sons (2nd edition). 2002, pp.
22-23. cited by other .
Kenny et al., Clin. Geriatr. 8: 1-4 (2000). cited by other .
Kinney et al., AACN's Clinical Reference Clinical Reference for
Critical Care Nursing, Mosby, 4th ed., 1998, pp. 285-287. cited by
other .
Kokki et al., "Comparison of pre-and postoperative administration
of ketoprofen for analgesia after tonsillectomy in children"
Pediatric Anesthesia 12(2): 162-167 (2002). cited by other .
Kosten et al., "Depressive symptoms during buprenorphine treatment
of opioid abusers" Journal of Substance Abuse Treatment 7: 51-54
(1990). cited by other .
Lehmann et al., "Treatment of depression with dexedrine and
demerol" Curr. Therapeutic Res. Clin. Exp. 13(1): 42-49 (1971).
cited by other .
Lichtenstein et al., "Disaggregating pain and its effect on
physical functional limitations" J. Gerontol. 53(5): M361-M371
(1998). cited by other .
Lintzeris N. Interactions on mixing diazepam with methadone or
buprenorphine in maintenance patients. Journal of clinical
psychopharmacology 2006; 26(3):274-283. cited by other .
Lovell et al., "Type I and III collagen content and fibre
distribution in normal human skin during ageing" Br. J. Dermatol.
117: 419-328 (1987). cited by other .
Luukinen et al., "Prognosis of diastolic and systolic orthostatic
hypotension in older persons" Arch. Int. Med. 159: 273-280 (1999).
cited by other .
Marek, GJ "Behavioral evidence for .mu.-opioid and 5-HT2A receptor
interactions" European Journal of Pharmacology 474: 77-83 (2003).
cited by other .
Markowitz et al., "Venlafaxine-tramadol similarities" Med.
Hypotheses 51(2): 167-168 (1998). cited by other .
Mauryama S, Nomura Y, Fukushige T, Eguchi T, Nishi J, Yoshinaga M,
Kawano Y. Suspected Takotsubo cardiomyopathy caused by withdrawal
of buprenorphine in a child. Circulation Journal 2006; 70:509-511.
cited by other .
Matussek et al., "Investigations with the specific .mu.-opiate
receptor antagonist fentanyl in depressive patients: Growth
hormone, prolactin, cortisol, noradrenaline and euphoric responses"
Neuropsychobiology 21: 1-8 (1989). cited by other .
McCance-Katz EF. Interaction between buprenorphine and atazanavir
or atazanavir/ritonavir. Drug and Alcohol Dependence 2007;
91(2-3):269-78. cited by other .
Mello et al., "Buprenorphine treatment of opiate and cocaine abuse:
Clinical and preclinical studies" Harvard Rev. Psychiatry 1:
168-183 (1993). cited by other .
Melon et al., "Buprenorphine. Haemodynamic study" Anesth. Analg.
(Paris) 37(3-4): 121-125 (1980). English abstract. (Original in
French). cited by other .
Mendelson et al., "Dose proportionality of 4, 8, 16 and 32 mg
sublingual buprenorphine solutions" American Society for Clinical
Pharmacology and Therapeutics 65(2): 154 Abstract PII-28 (1999).
cited by other .
Mercadante et al., "Alternatives to oral opioids for cancer pain"
Oncology 13(2):215-220 (1999). cited by other .
Mercadante, "Opioid rotation in cancer pain: rationale and clinical
aspects" Cancer 86:1 1856-66 (1999). cited by other .
Mobily et al., "An epidemiologic analysis of pain in the elderly"
J. Aging Health 6: 139-154 (1994). cited by other .
Mongan et al., "Buprenorphine responders" Biol. Psychiatry 28:
1078-1080 (1990). cited by other .
Moragas et al., "Image analysis of dermal collagen changes during
skin aging" Analyt. Quant. Cytol. Histol. 20: 493-499 (1998). cited
by other .
Nanovskaya et al., "Transplacental transfer and methabolism of
buprenorphine" J. Pharmacol. Exp. Ther. 300(1): 26-33 (2002). cited
by other .
Noble et al., "Protection of endogenous enkephalin catabolism as
natural approach to novel analgesic and antidepressant drugs"
Expert Opinion on Therapeutic Targets 11(2): 145-159 (Nov. 2007).
cited by other .
Nolan et al., "Anaesthesia and pain management in cerebral palsy"
Anaesthesia 55(1): 32-41 (2000). cited by other .
Nyhuis et al., "Opiate receptors in ECT-resistant depression"
European Neuropsychopharmacology 15(3): S420 (2005). cited by other
.
Oda et al., "Fentanyl inhibits metabolism of midazolam: competitive
inhibition of CYP3A4 in vivtro " Br. J. Anaesthesia 82(6): 900-903
(1999). cited by other .
Oliveto et al., "Desipramine, amantadine, or fluoxetine in
buprenorphine-maintained cocaine users" Journal of Substance Abuse
Treatment 12(6): 423-428 (1995). cited by other .
Paetzold et al., "Buprenorphine: therapeutical use in
opioid-dependence, depression and schizophrenia" Nervenheilkunde
19(3): 143-150 (2000). (w/ English abstract. cited by other .
Pani et al., "Buprenorphine: A controlled clinical trial in the
treatment of opioid dependence" Drug and Alcohol Dependence
60:39-50 (2000). cited by other .
Parmelee, P.A., "Assessment of pain in the elderly" Annual Review
of Gerontology and Geriatrics 14: 281-301 (1994). cited by other
.
Pereira et al., "Analgesic effects of diclofenac suppository and
injection after postoperative administration" Int. J. Clin. Pharm.
Res. 19(2): 47-51 (1999). cited by other .
Perttunen et al., "Chronic pain after thoracic surgery: a follow-up
study" Acta Anaesthesiol. Scand. 43: 563-567 (1999). cited by other
.
Pickar et al., "Behavioral and biological effects of acute
beta-endorphin injection in schizophrenic and depressed patients"
Am. J. Psychiatry 138: 160-166 (1981). cited by other .
Potter, Fundamentals of Nursing, Mosby, 4th ed., 1997 p. 633. cited
by other .
Reddy L, Kranjnik M, Zylicz Z. Transdermal buprenorphine may be
effective in the treatment of pruritus in primary biliary
cirrhosis. Journal of Pain and Symptom Management 2007;
34(5):455-456. cited by other .
Romero et al., "Opioid peptide receptor studies. 12. Buprenorphine
is a potent and selective .mu./.kappa. antagonist in the
[.sup.35S]-GTP-.gamma.-S functional binding assay" Synapse 34:
83-94 (1999). cited by other .
Rooke et al., "Maximal skin blood flow is decreased in elderly men"
J. Appl. Physiol. 77: 11-14 (1994). cited by other .
Rothman et al., "An open-label study of a functional opioid .kappa.
antagonist in the treatment of opioid dependence" Journal of
Substance Abuse Treatment 18: 277-281 (2000). cited by other .
Russo and Brose, Ann. Rev. Med. 49: 123-133 (1998). cited by other
.
Schriek P. Treatment of cancer-related pain with transdermal
buprenorphine: a report of three cases. European Support Care
Cancer 2004; 12:882-884. cited by other .
Seet RCS, Lim ECH. Intravenous use of buprenorphine tablets
associated with rhabdomyolysis and compressive sciatic neuropathy.
Annals of Emergency Medicine 2006; 47(4):396-397. cited by other
.
Seet RCS, Rathakrishnan R, Chan BP, Lim ECH. Diffuse-cystic
leucoencephalopathy after buprenorphine injection. Journal of
Neurology, Neurosurgery and Psychiatry 2005; 76(6):890-891. cited
by other .
Seidenari et al., "Echographic evaluation with image analysis of
normal skin: variation according to age and sex" Skin Pharmacol.
7:201-209 (1994). cited by other .
Seifert et al., "Detoxification of opiate addicts with multiple
drug abuse: a comparison of buprenorphine vs. methadone"
Pharmacopsychiatry 35: 159-164 (2000). cited by other .
Seifert et al., "Mood and affect during detoxification of opiate
addicts: A comparison of buprenorphine versus methadone" Addiction
Biology, 10: 157-164 (Jun. 2005). cited by other .
Shapira et al., "Treatment of refractory major depression with
tramadol monotherapy" Am. J. Psychiatry 62(3):205-206 (2001). cited
by other .
Sheikh et al., "Geriatric Depression Scale: Recent evidence and
development of a shorter version" Clin. Gerontol. 5: 165-173
(1986). cited by other .
Singh J, Grover S, Basu D. Very high-dose intravenous buprenorphine
dependence: A case report. German J Psychiatry 2004; 7:58-59. cited
by other .
Soyka M, Penning R, Wittchen U. Fatal poisoning in methadone and
buprenorphine treated patients--are there differences?
Pharmacopsychiatry 2006; 39:85-87. cited by other .
Spyker et al., Clin. Pharmacol. Ther. 67(2): 145, Abstract PII-12.
cited by other .
Stanway, GW, "A preliminary investigation comparing pre-operative
morphine and buprenorphine for postoperative analgesia and sedation
in cats" Veterinary Anaesthesia and Analgesia 29:29-35 (2002).
cited by other .
Stewart et al., eds., "Medical Outcomes Study Pain Evaluation" in:
Measuring Functioning and Well-Being--The Medical Outcomes Study
Approach, Durham and London: Duke University Press, 1992. cited by
other .
Stinchcomb et al., "A solubility and related physicochemical
property of buprenorphine and its 3-alkyl esters" Pharmaceutical
Research 12(10): 1526-1529 (1995). cited by other .
Supplementary partial European Search Report for EP Application No.
03721427, dated Mar. 31, 2006. cited by other .
Tanaka et al., "Preoperative fluribiprofen provides pain relief
after laparascopic cholecystectomy" Masui 46(5): 679-683 (1997).
Abstract). cited by other .
Tauzin-Fin et al., "Effect of balanced analgesia with buprenorphine
on pain response and general anesthesia requirement during
lithotripsy procedures" European Journal of Anaesthesiology 15:
147-152 (1998). cited by other .
Thompson et al., "Perioperative pharmacokinetics of transdermal
fentanyl in elderly and young adult patients" Br. J. Anaesth. 81:
152-154 (1998). cited by other .
Torrens et al., "Buprenorphine versus heroin dependence: Comparison
of toxicologic and psychopathologic characteristics" Am. J.
Psychiatry 150(5): 822-824 (1993). cited by other .
Varga et al., "The effect of codeine on involutional and senile
depression" Ann. NY Acad. Sci. 398: 103-105 (1982). cited by other
.
Verhaeverbeke et al., "Drug-induced orthostatic hypotension in the
elderly: avoiding its onser" Drug Safety 17: 108-118 (1997). cited
by other .
Vibbert et al., eds., "Modified Brief Pain Inventory," in: The 1995
Medical Outcomes and Guidelines Sourcebook, New York: Faulkner
& Gray, Inc., 1994, pp. 269-270. cited by other .
Walsh et al., "Acute administration of buprenorphine in humans:
Partial agonist and blockade effects" The Journal of Pharmacology
and Experimental Therapeutics 274(1): 361-372 (1995). cited by
other .
Weber et al., "Current and historic concepts of opiate treatment in
psychiatric disorders" Int. Clin. Psychopharmacology 3: 255-266
(1988). cited by other .
Weiss et al., "Analysis of the diminished skin perfusion in elderly
people by laser doppler flowmetry" Age Ageing 21:237-241 (1992).
cited by other .
Williams et al., "Case-finding for depression in primary care: a
randomized trial" Am. J. Med. 106(1):36-43 (1999). cited by other
.
Woods et al., "Efficacy of nalbuphine as a parenteral analgesic for
the treatment of painful episodes in children with sickle cell
disease" J. Assoc. Acad. Minor Phys. 1(3): 90-92 (1990). cited by
other .
Yashiki et al., "Dual mass spectrometry of trifluoracetyl
derivatives of opioid bases" GC-MS News 13(4): 101-106 (1985).
cited by other .
Yassen A. Mechanism-based pharmacokinetic-pharmacodynamic modeling
of the reversal of buprenorphine-induced respiratory depression by
naloxone: a study in healthy volunteers. Clinical Pharmacokinetics
2007; 46(11):965-80. cited by other .
Yaster et al., "Epidural analgesia in the management of severe
vaso-occlusive sickle cell crisis" Pediatrics 93(2): 310-315
(1994). cited by other .
Yaster et al., "The management of pain in sickle cell disease"
Pediatr. Clin. North Am. 47(3):699-710 (2000). cited by other .
Office Actions issued in the prosecution of U.S. Appl. No.
09/08/939,068 to Reder et al., filed Sep. 29, 1997. cited by other
.
Office Actions issued in the prosecution of U.S. Appl. No.
09/311,997 to Reder et al., filed Jun. 14, 1999. cited by other
.
Office Actions issued in the prosecution of U.S. Appl. No.
09/756,419 to Reder et al., filed Jan. 18, 2001. cited by other
.
Office Actions issued in the prosecution of U.S. Appl. No.
10/033,056 to Reder et al., filed Dec. 27, 2001. cited by other
.
Office Actions issued in the prosecution of U.S. Appl. No.
10/394,425 to Kaiko et al., filed Mar. 27, 2003. cited by other
.
Office Actions issued in the prosecution of U.S. Appl. No.
10/402,288 to Reder et al., filed Mar. 28, 2003. cited by other
.
Office Actions issued in the prosecution of U.S. Appl. No.
10/476,601 to Tavares et al., filed Nov. 20, 2003. cited by other
.
Office Actions issued in the prosecution of U.S. Appl. No.
10/736,043 to Reidenberg et al., filed Dec. 15, 2003. cited by
other .
Office Actions issued in the prosecution of U.S. Appl. No.
10/736,049 toReder et al., filed Dec. 15. 2003. cited by other
.
Office Actions issued in the prosecution of U.S. Appl. No.
11/033,106 to Reder et al., filed Jan. 11, 2005. cited by other
.
Office Actions issued in the prosecution of U.S. Appl. No.
11/033,107 to Reder et al., filed Jan. 11, 2005. cited by other
.
Office Actins issued in the prosecution of U.S. Appl. No.
11/033,108 to Reder et al., filed Jan. 11, 2005. cited by other
.
Buprenorphine TDS Pre-NDA Meeting. Flux rate analysis of
Buprenorphine transdermal delivery systems (BTDS) Jun. 9, 1999.
cited by other .
Rigas et al., "Transdermal fentanyl: Practical use in the hospital
and the home" ASHP Midyear Clinical Meeting v.27 (1992). cited by
other .
The Safety of High Doses of Burprenorphine. Tables of Contents and
Introduction. Feb. 22, 2002. cited by other .
Schott, H., Colloidal Dispersions, Remington's Pharmaceutical
Sciences, 16.sup.th ed., ppg. 266-293 (1980). cited by other .
Chien YW "Developmental Concepts and Practice in Transdermat
Therapeutic Systems" in : Chien, YW (ed.), Transdermal Controlled
SystemicMedications New York: Marcel Dekker, Inc. pp. 25-44.
(1987). cited by other .
Definition of "Aldehyde," printed on Sep. 1, 2009 from Answers.com.
cited by other .
Definition of "Photoinitiator," printed Sep. 1, 2009 from
Answers.com. cited by other .
Definition of "Polymerize," printed on Sep. 1, 2009 from
Answers.com. cited by other .
Definition of "Tannin," printed on Sep. 1, 2009 from
Wikipedia.org., the free encyclopedia. cited by other .
Bauer, KH (ed.) Pharmaceutische Technologie pp. 362-365 (1993).
cited by other .
Budd, K., "Experience with partial agonists in the treatment of
cancer pain" in: Doyle, D (ed.), Opioids in the Treatment of Cancer
Pain, Royal Society of Medicine Services International Congress and
Symposium Series No. 146 (1990). cited by other .
Burke et al., "Increased rates of drug abuse and dependence after
onset of mood or anxiety disorders in adolescence" Hospital&
Community Psychiatry 45(5): 455 (1994) (Abstract only). cited by
other .
Curran et al., "Recognition and management of depression in a
substance use disorder treatment population" American Journal of
Drug& Alchol Abuse 33(4): 563-569 (Abstract only). cited by
other .
Currie et al., "Comorbidity of major depression with substance use
disorders" Canadian Journal of Psychiatry 50(10): 660-666 (2005).
cited by other .
Davis et al., "Major depression and comorbid substance use
disorders" Current Opinions in Psychiatry 21(1):14-18 (2008). cited
by other .
Declaration of Prof. Jonathan Hadgraft dated Apr. 22, 2009. cited
by other .
Declaration of Prof. Jonathan Hadgraft dated Jul. 9, 2004. cited by
other .
Declaration of Prof. Jonathan Hadgraft dated Oct. 8, 2004. cited by
other .
Declaration of Prof. Jonathan Hadgraft dated Oct. 11, 2007. cited
by other .
Driscoll, CE Primary Care 14(2): 337-352 (1987). cited by other
.
Excerpt of Review for Approval issued Aug. 7, 1990 by the FDA for
Duragesic.RTM.. cited by other .
Grond, S et al., Pain 69: 191-198 (1997). cited by other .
Heilman, N Therapeutische System , 4.sup.th ed., Stuttgart: Enke
pp. 67-77 and 83-86 (1984). cited by other .
Heilman, N Therapeutische Systems , 4.sup.th ed., Stuttgart: Enke
pp. 104-106 (1984). cited by other .
Introduction to the Pharmacology of Opioids. (Apr. 23, 2009). cited
by other .
Jin-Jie, G. "Synthesis of biodegradable polyurethane foams
condensed tannin and bark of Acacia mearnsii" Bull. Kyushu Univ.
For. 79: 21-85 (1998). cited by other .
Landau, CJ et al., "Buprenorphine transdermal delivery system in
adults with persistent noncancer-related pain syndromes who require
opioid therapy: a multicenter, 5 week run-in and randomized,
double-blind maintenance-of-analgesia study" Clinical Therapeutics
29(10): 2179-2193 (2007). cited by other .
Markou et al., "Neurobiological similarities in depression and drug
dependence: a self-medication hypothesis" Neuropsychopharmagology
18(3): 135-174 (1998). cited by other .
Mongan, Mary Louise Hack The Effects of Low Dose Buprenorphine on
Selected Psychiatric Patients San Francisco State University, San
Francisco, CA. 1992. 105 ppg. cited by other .
Nagle, CJ et al., Current Anaesthesia and Care 1: 247-252 (1990).
cited by other .
Office Actions dated Sep. 19, 2008 and Feb. 9, 2009, issued in the
prosecution of U.S. Appl. No. 10/394,425 to Kaiko et al. filed Mar.
20, 2003. cited by other .
Office Actions dated Dec. 15, 2008, and Feb. 18, 2009 and Apr. 6,
2009, issued in the prosecution of U.S. Appl. No. 10/476,601 to
Tavares et al. filed Nov. 20, 2003. cited by other .
Physician's Desk Reference 49.sup.th ed., 1995, entry on
Duragesic.RTM.. cited by other .
Physician's Desk Reference 50.sup.th ed., 1996, entry on
Duragesic.RTM.. cited by other .
Product Monograph for Duragesic.RTM. (2008). cited by other .
Regier et al., "Comorbidity of mental disorders with alcohol and
other drug abuse. Results from Epidemiological Catchment Area (ECA)
Study" JAMA 264(19):2549-2550 (990) (Abstract only). cited by other
.
Roy, SD et al., J. Pharmaceutical Sciences 83: 1723-1728 (1994).
cited by other .
Sorrell, DC Nursing 24:30 (1994). cited by other .
Southam, MA Anti-Cancer Drugs 6(suppl. 3): 29-34 (1995). cited by
other .
Steiner, D et al., "The efficacy and safety of buprenorphine
transdermal system (BTDS) in subjects with moderate to severe low
back pain" Presentation #305, PowerPoint Presentation at American
Pain Society Annual Meeting, May 6-9, 2009, San Diego, CA. cited by
other .
Subramaniam et al., "Baseline depressive symptoms predict poor
substance use outcome following adolescent residential treatment"
Journal of the American Academy of Child& Adolescent Psychiatry
46(8): 1062-1069 (2007) (Abstract only). cited by other .
Swendsen et al., "The comorbidity of depression and substance use
disorders" Clin. Psychol. Rev. 20(2): 173-189 (2000) (Abstract
only). cited by other .
Wall, PD, et al., Textbook of Pain 2.sup.nd ed., New York:
Churchill Livingstone, pp. 686-701 (1989). cited by other .
Woodroffe, MA et al., Canadian Family Physician 43: 268-272 (1997).
cited by other .
Hexal AG Opposition against EP-B-964677, dated May 15, 2007. (in
German, w/ Engl. translation). cited by other .
Novosis AG Opposition against EP-B-964677, dated May 15, 2007. (in
German, w/ Engl. translation). cited by other .
Letter from counsel for Purdue Pharma LP, dated Dec. 20, 2007, to
EPO re EP-B-964677 opposition proceedings (English). cited by other
.
Summons to attend oral proceedings pursuant to Rule 115(1) EPC re
EP-B-964677 opposition proceedings dated Dec. 29, 2008. cited by
other .
Letter from counsel for Acino AG (previously Novosis AG), dated
Apr. 17, 2009, to EPO re EP-B-964677 opposition proceedings. (in
German, w/Engl. translation). cited by other .
Letter from counsel for Purdue Pharma LP, dated Apr. 23, 2009, to
EPO re EP-B-964677 opposition proceedings (English). cited by other
.
Letter from counsel for Purdue Pharma LP, dated Jun. 4, 2009, to
EPO re EP-B-964677 opposition proceedings (English). cited by other
.
Minutes of the oral proceedings before the Opposition Division held
Jun. 23, 2009 re: EP-B-964677. cited by other .
Decision revoking the European Patent EP-B-964677, dated Jul. 24,
2009. cited by other .
Japanese Supreme Court, Third Petty Branch decision dated Jan. 16,
2007. (English translation). cited by other.
|
Primary Examiner: Fubara; Blessing M
Attorney, Agent or Firm: Duane Morris LLP
Parent Case Text
.[.This application claims the benefit of U.S. provisional
application No. 60/038,919, filed Feb. 24, 1997, by Robert F.
Reder, Paul D. Goldenheim and Robert F. Kaiko, now
abandoned..].
.Iadd.More than one reissue application has been filed for reissue
on U.S. Pat. No. 5,968,547. This application is a continuation of
reissue application Ser. No. 11/033,106, filed on Jan. 11, 2005,
now abandoned, which is a reissue of application Ser. No.
08/939,068, filed on Sep. 29, 1997, now U.S. Pat. No. 5,968,547,
which claims priority to U.S. Provisional Application No.
60/038,919, filed Feb. 24, 1997..Iaddend.
Claims
We claim:
1. A method of treating pain in a human patient, comprising
administering buprenorphine transdermally to said human patient by
applying a transdermal delivery system to the skin of a patient,
and maintaining said transdermal delivery system in contact with
the patient's skin for .[.at least 5 days.]. .Iadd.a seven day
dosing interval.Iaddend., said transdermal delivery system
maintaining a mean relative release rate of from about 3 ug/hr to
about 86 ug/hr and providing a substantially first order plasma
level increase of buprenorphine from the initiation of the dosing
interval until about 72 hours after the initiation of the dosing
interval; and a mean relative release rate of about 0.3 ug/hr to
about 9 ug/hr and providing a substantially zero order plasma level
fluctuation of buprenorphine from about 72 hours after the
initiation of the dosing interval until the end of .[.at least.].
the .[.five.]. .Iadd.seven.Iaddend.-day dosing interval, such that
the following mean plasma concentrations are achieved: a mean
plasma concentration from about 0.3 to about 113 pg/ml at about 6
hours after initiation of the dosing interval; a mean plasma
concentration from about 3 to about 296 pg/ml at about 12 hours
after initiation of the dosing interval; a mean plasma
concentration from about 7 to about 644 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 753 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 16 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 20 to about 984 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 21 to about 1052 pg/ml at about 72 hours
after initiation of the dosing interval; .[.and a mean plasma
concentration from about 19 to about 1052 pg/ml over at least the
next 48 hours.]. .Iadd.a mean plasma concentration from about 23 to
about 1052 pg/ml at about 96 hours after initiation of the dosing
interval; a mean plasma concentration from about 23 to about 1052
pg/ml at about 120 hours after initiation of the dosing interval; a
mean plasma concentration from about 22 to about 970 pg/ml at about
144 hours after initiation of the dosing interval; and a mean
plasma concentration from about 19 to about 841 pg/ml at about 168
hours after initiation of the dosing interval.Iaddend..
.[.2. The method of claim 1, further comprising maintaining the
buprenorphine transdermal delivery system in contact with the
patient's skin such that the mean plasma concentrations are
maintained as follows: a mean plasma concentration from about 23 to
about 1052 pg/ml at about 96 hours after initiation of the dosing
interval; a mean plasma concentration from about 23 to about 1052
pg/ml at about 120 hours after initiation of the dosing interval; a
mean plasma concentration from about 22 to about 970 pg/ml at about
144 hours after initiation of the dosing interval; and a mean
plasma concentration from about 19 to about 841 pg/ml at about 168
hours after initiation of the dosing interval..].
3. A method of treating pain in a human patient, comprising
administering buprenorphine transdermally to said human patient by
applying a transdermal delivery system to the skin of a patient,
and maintaining said transdermal delivery system in contact with
the patient's skin for .[.at least 5 days.]. .Iadd.a seven day
dosing interval.Iaddend., said transdermal delivery system
maintaining a mean relative release rate of from about 13 ug/hr to
about 21 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 1 ug/hr to about 2 ug/hr from
about 72 hours after the initiation of the dosing interval until
the end of .[.at least.]. the .[.five.]. .Iadd.seven.Iaddend.-day
dosing interval, such that the following mean plasma concentrations
are achieved: a mean plasma concentration from about 1 to about 28
pg/ml at about 6 hours after initiation of the dosing interval; a
mean plasma concentration from about 14 to about 74 pg/ml at about
12 hours after initiation of the dosing interval; a mean plasma
concentration from about 30 to about 161 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 51 to about 188 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 62 to about 246 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 79 to about 246 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 85 to about 263 pg/ml at about 72 hours
after initiation of the dosing interval; .[.and a mean plasma
concentration from about 77 to about 263 pg/ml over at least the
next 48 hours.]. .Iadd.a mean plasma concentration from about 92 to
about 263 pg/ml at about 96 hours after initiation of the dosing
interval; a mean plasma concentration from about 94 to about 263
pg/ml at about 120 hours after initiation of the dosing interval; a
mean plasma concentration from about 86 to about 243 pg/ml at about
144 hours after initiation of the dosing interval; and a mean
plasma concentration from about 77 to about 210 pg/ml at about 168
hours after initiation of the dosing interval.Iaddend..
.[.4. The method of claim 3, further comprising maintaining the
buprenorphine transdermal delivery system in contact with the
patient's skin such that the mean plasma concentrations are
maintained as follows: a mean plasma concentration from about 92 to
about 263 pg/ml at about 96 hours after initiation of the dosing
interval; a mean plasma concentration from about 94 to about 263
pg/ml at about 120 hours after initiation of the dosing interval; a
mean plasma concentration from about 86 to about 243 pg/ml at about
144 hours after initiation of the dosing interval; and a mean
plasma concentration from about 77 to about 210 pg/ml at about 168
hours after initiation of the dosing interval..].
5. A method of treating pain in a human patient, comprising
administering buprenorphine transdermally to said human patient by
applying a transdermal delivery system to the skin of a patient,
and maintaining said transdermal delivery system in contact with
the patient's skin for .[.at least 5 days.]. .Iadd.a seven day
dosing interval.Iaddend., said transdermal delivery system
maintaining a mean relative release rate of from about 3 ug/hr to
about 5 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 0.3 ug/hr to about 0.6 ug/hr
from about 72 hours after the initiation of the dosing interval
until the end of .[.at least.]. the .[.five.].
.Iadd.seven.Iaddend.-day dosing interval, such that the following
mean plasma concentrations are achieved: a mean plasma
concentration from about 0.3 to about 7 pg/ml at about 6 hours
after initiation of the dosing interval; a mean plasma
concentration from about 4 to about 19 pg/ml at about 12 hours
after initiation of the dosing interval; a mean plasma
concentration from about 7 to about 40 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 47 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 16 to about 62 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about .[.20.]. .Iadd.21 .Iaddend.to about 62
pg/ml at about 60 hours after initiation of the dosing interval; a
mean plasma concentration from about .[.21.]. .Iadd.20 .Iaddend.to
about 66 pg/ml at about 72 hours after initiation of the dosing
interval; .[.and a mean plasma concentration from about 19 to about
66 pg/ml over at least the next 48 hours.]. .Iadd.a mean plasma
concentration from about 23 to about 66 pg/ml at about 96 hours
after initiation of the dosing interval; a mean plasma
concentration from about 23 to about 66 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 22 to about 61 pg/ml at about 144 hours
after initiation of the dosing interval; a mean plasma
concentration from about 19 to about 53 pg/ml at about 168 hours
after initiation of the dosing interval.Iaddend..
.[.6. The method of claim 5, further comprising maintaining the
buprenorphine transdermal delivery system in contact with the
patient's skin such that the mean plasma concentrations are
maintained as follows: a mean plasma concentration from about 23 to
about 66 pg/ml at about 96 hours after initiation of the dosing
interval; a mean plasma concentration from about 23 to about 66
pg/ml at about 120 hours after initiation of the dosing interval; a
mean plasma concentration from about 22 to about 61 pg/ml at about
144 hours after initiation of the dosing interval; and a mean
plasma concentration from about 19 to about 53 pg/ml at about 168
hours after initiation of the dosing interval..].
7. A method of treating pain in a human patient, comprising
administering buprenorphine transdermally to said human patient by
applying a transdermal delivery system to the skin of a patient,
and maintaining said transdermal delivery system in contact with
the patient's skin for .[.at least 5 days.]. .Iadd.a seven day
dosing interval.Iaddend., said transdermal delivery system
maintaining a mean relative release rate of from about 6 ug/hr to
about 11 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 0.7 ug/hr to about 1 ug/hr from
about 72 hours after the initiation of the dosing interval until
the end of .[.at least.]. the .[.five.]. .Iadd.seven.Iaddend.-day
dosing interval, such that the following mean plasma concentrations
are achieved: a mean plasma concentration from about 0.7 to about
14 pg/ml at about 6 hours after initiation of the dosing interval;
a mean plasma concentration from about 7 to about 37 pg/ml at about
12 hours after initiation of the dosing interval; a mean plasma
concentration from about 15 to about 80 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 25 to about 94 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 31 to about 123 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 40 to about 123 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 42 to about 132 pg/ml at about 72 hours
after initiation of the dosing interval; .[.and a mean plasma
concentration from about 38 to about 132 pg/ml over at least the
next 48 hours.]. .Iadd.a mean plasma concentration from about 46 to
about 132 pg/ml at about 96 hours after initiation of the dosing
interval; a mean plasma concentration from about 47 to about 132
pg/ml at about 120 hours after initiation of the dosing interval; a
mean plasma concentration from about 43 to about 121 pg/ml at about
144 hours after initiation of the dosing interval; and a mean
plasma concentration from about 38 to about 105 pg/ml at about 168
hours after initiation of the dosing interval.Iaddend..
.[.8. The method of claim 7, further comprising maintaining the
buprenorphine transdermal delivery system in contact with the
patient's skin such that the mean plasma concentrations are
maintained as follows: a mean plasma concentration from about 46 to
about 132 pg/ml at about 96 hours after initiation of the dosing
interval; a mean plasma concentration from about 47 to about 132
pg/ml at about 120 hours after initiation of the dosing interval; a
mean plasma concentration from about 43 to about 121 pg/ml at about
144 hours after initiation of the dosing interval; and a mean
plasma concentration from about 38 to about 105 pg/ml at about 168
hours after initiation of the dosing interval..].
9. A method of treating pain in a human patient, comprising
administering buprenorphine transdermally to said human patient by
applying a transdermal delivery system to the skin of a patient,
and maintaining said transdermal delivery system in contact with
the patient's skin for .[.at least 5 days.]. .Iadd.a seven day
dosing interval.Iaddend., said transdermal delivery system
maintaining a mean relative release rate of from about 26 ug/hr to
about 43 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 2 ug/hr to about 4 ug/hr from
about 72 hours after the initiation of the dosing interval until
the end of .[.at least.]. the .[.five.]. .Iadd.seven.Iaddend.-day
dosing interval, such that the following mean plasma concentrations
are achieved: a mean plasma concentration from about 3 to about 57
pg/ml at about 6 hours after initiation of the dosing interval; a
mean plasma concentration from about 28 to about 148 pg/ml at about
12 hours after initiation of the dosing interval; a mean plasma
concentration from about 59 to about 322 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 102 to about 377 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 124 to about 492 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 159 to about 492 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 169 to about 526 pg/ml at about .[.60.].
.Iadd.72 .Iaddend.hours after initiation of the dosing interval;
.[.a mean plasma concentration from about 153 to about 526 pg/ml
over at least the next 48 hours.]. .Iadd.a mean plasma
concentration from about 184 to about 526 pg/ml at about 96 hours
after initiation of the dosing interval; a mean plasma
concentration from about 187 to about 526 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 173 to about 485 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 153 to about 420 pg/ml at about 168 hours
after initiation of the dosing interval.Iaddend..
.[.10. The method of claim 9, further comprising maintaining the
buprenorphine transdermal delivery system in contact with the
patient's skin such that the mean plasma concentrations are
maintained as follows: a mean plasma concentration from about 184
to about 526 pg/ml at about 96 hours after initiation of the dosing
interval; a mean plasma concentration from about 187 to about 526
pg/ml at about 120 hours after initiation of the dosing interval; a
mean plasma concentration from about 173 to about 485 pg/ml at
about 144 hours after initiation of the dosing interval; a mean
plasma concentration from about 153 to about 420 pg/ml at about 168
hours after initiation of the dosing interval..].
11. A method of treating pain in a human patient, comprising
administering buprenorphine transdermally to said human patient by
applying a transdermal delivery system to the skin of a patient,
and maintaining said transdermal delivery system in contact with
the patient's skin for .[.at least 5 days.]. .Iadd.a seven day
dosing interval.Iaddend., said transdermal delivery system
maintaining a mean relative release rate of from about 38 ug/hr to
about 64 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 4 ug/hr to about 7 ug/hr from
about 72 hours after the initiation of the dosing interval until
the end of .[.at least.]. the .[.five.]. .Iadd.seven.Iaddend.-day
dosing interval, such that the following mean plasma concentrations
are achieved: a mean plasma concentration from about 4 to about 85
pg/ml at about 6 hours after initiation of the dosing interval; a
mean plasma concentration from about 42 to about 222 pg/ml at about
12 hours after initiation of the dosing interval; a mean plasma
concentration from about 89 to about 483 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 152 to about 565 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 186 to about 738 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 238 to about 738 pg/ml at about .[.48.].
.Iadd.60 .Iaddend.hours after initiation of the dosing interval; a
mean plasma concentration from about 254 to about 789 pg/ml at
about .[.60.]. .Iadd.72 .Iaddend.hours after initiation of the
dosing interval; .[.a mean plasma concentration from about 230 to
about 789 pg/ml over at least the next 48 hours.]. .Iadd.a mean
plasma concentration from about 276 to about 789 pg/ml at about 96
hours after initiation of the dosing interval; a mean plasma
concentration from about 281 to about 789 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 259 to about 727 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 230 to about, 630 pg/ml at about 168 hours
after initiation of the dosing interval.Iaddend..
.[.12. The method of claim 11, further comprising maintaining the
buprenorphine transdermal delivery system in contact with the
patient's skin such that the mean plasma concentrations are
maintained as follows: a mean plasma concentration from about 276
to about 789 pg/ml at about 96 hours after initiation of the dosing
interval; a mean plasma concentration from about 281 to about 789
pg/ml at about 120 hours after initiation of the dosing interval; a
mean plasma concentration from about 259 to about 727 pg/ml at
about 144 hours after initiation of the dosing interval; and a mean
plasma concentration from about 230 to about, 630 pg/ml at about
168 hours after initiation of the dosing interval..].
13. A method of treating pain in a human patient, comprising
administering buprenorphine transdermally to said human patient by
applying a transdermal delivery system to the skin of a patient,
and maintaining said transdermal delivery system in contact with
the patient's skin for .[.at least 5 days.]. .Iadd.a seven day
dosing interval.Iaddend., said transdermal delivery system
maintaining a mean relative release rate of from about 51 ug/hr to
about 86 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 5 ug/hr to about 9 ug/hr from
about 72 hours after the initiation of the dosing interval until
the end of .[.at least.]. the .[.five.]. .Iadd.seven.Iaddend.-day
dosing interval, such that the following mean plasma concentrations
are achieved: a mean plasma concentration from about 5 to about 113
pg/ml at about 6 hours after initiation of the dosing interval; a
mean plasma concentration from about 55 to about 296 pg/ml at about
12 hours after initiation of the dosing interval; a mean plasma
concentration from about 118 to about 644 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 203 to about 753 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 247 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 317 to about 984 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 339 to about 1052 pg/ml at about 72 hours
after initiation of the dosing interval; .[.and a mean plasma
concentration from about 306 to about 1052 pg/ml over at least the
next 48 hours.]. .Iadd.a mean plasma concentration from about 369
to about 1052 pg/ml at about 95 hours after initiation of the
dosing interval; a mean plasma concentration from about 374 to
about 1052 pg/ml at about 120 hours after initiation of the dosing
interval; a mean plasma concentration from about 346 to about 970
pg/ml at about 144 hours after initiation of the dosing interval;
and a mean plasma concentration from about 306 to about 841 pg/ml
at about 168 hours after initiation of the dosing
interval.Iaddend..
.[.14. The method of claim 13, further comprising maintaining the
buprenorphine transdermal delivery system in contact with the
patient's skin such that the mean plasma concentrations are
maintained as follows: a mean plasma concentration from about 369
to about 1052 pg/ml at about 96 hours after initiation of the
dosing interval; a mean plasma concentration from about 374 to
about 1052 pg/ml at about 120 hours after initiation of the dosing
interval; a mean plasma concentration from about 346 to about 970
pg/ml at about 144 hours after initiation of the dosing interval; a
mean plasma concentration from about 306 to about 841 pg/ml at
about 168 hours after initiation of the dosing interval..].
15. A method of treating pain in a human patient, comprising
administering buprenorphine transdermally to said human patient
.Iadd.for a seven day dosing interval .Iaddend.such that mean
relative release rates are achieved over .[.a.]. .Iadd.the
.Iaddend.dosing interval as follows: a mean relative release rate
of from about 3 ug/hr to about 86 ug/hr from the initiation of the
dosing interval until about 72 hours after the initiation of the
dosing interval; and a mean relative release rate of about 0.3
ug/hr to about 9 ug/hr from about 72 hours after the initiation of
the dosing interval until the end of the .Iadd.seven day
.Iaddend.dosing interval.
16. The method of claim 15, wherein the mean relative release rates
achieved over the .Iadd.seven day .Iaddend.dosing interval are as
follows: a mean relative release rate of from about 3 ug/hr to
about 5 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 0.3 ug/hr to about 0.6 ug/hr
from about 72 hours after the initiation of the dosing interval
until the end of the .Iadd.seven day .Iaddend.dosing interval.
17. The method of claim 15, wherein the mean relative release rates
achieved over the .Iadd.seven day .Iaddend.dosing interval are as
follows: a mean relative release rate of from about 6 ug/hr to
about 11 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 0.7 ug/hr to about 1 ug/hr from
about 72 hours after the initiation of the dosing interval until
the end of the .Iadd.seven day .Iaddend.dosing interval.
18. The method of claim 15, wherein the mean relative release rates
achieved over the .Iadd.seven day .Iaddend.dosing interval are as
follows: a mean relative release rate of from about 13 ug/hr to
about 21 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 1 ug/hr to about 2 ug/hr from
about 72 hours after the initiation of the dosing interval until
the end of the .Iadd.seven day .Iaddend.dosing interval.
19. The method of claim 15, wherein the mean relative release rates
achieved over the .Iadd.seven day .Iaddend.dosing interval are as
follows: a mean relative release rate of from about 26 ug/hr to
about 43 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 3 ug/hr to about 4 ug/hr from
about 72 hours after the initiation of the dosing interval until
the end of the .Iadd.seven day .Iaddend.dosing interval.
20. The method of claim 15, wherein the mean relative release rates
achieved over the .Iadd.seven day .Iaddend.dosing interval are as
follows: a mean relative release rate of from about 39 ug/hr to
about 64 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 4 ug/hr to about 7 ug/hr from
about 72 hours after the initiation of the dosing interval until
the end of the .Iadd.seven day .Iaddend.dosing interval.
21. The method of claim 15, wherein the mean relative release rates
achieved over the .Iadd.seven day .Iaddend.dosing interval are as
follows: a mean relative release rate of from about 51 ug/hr to
about 86 ug/hr from the initiation of the dosing interval until
about 72 hours after the initiation of the dosing interval; and a
mean relative release rate of about 5 ug/hr to about 9 ug/hr from
about 72 hours after the initiation of the dosing interval until
the end of the .Iadd.seven day .Iaddend.dosing interval.
22. A method of treating pain in a human patient, comprising
applying a transdermal delivery system containing buprenorphine as
the active ingredient onto the skin of said human patient to
provide a substantially first order plasma level increase of
buprenorphine over a first three-day dosing interval, such that a
mean plasma concentration from about 21 to about 1052 pg/ml is
attained about 72 hours after application of said transdermal
delivery system; and maintaining said transdermal delivery system
on the skin of said human patient for .[.at least.]. an additional
.[.two.]. .Iadd.four.Iaddend.-day dosing interval, such that a mean
relative release rate from about 0.3 .mu.g/hr to about 9 .mu.g/hr
is maintained over said .[.at least two.]. .Iadd.four.Iaddend.-day
additional dosing interval and said transdermal delivery system
provides a therapeutic effect to said human patient throughout the
.[.at least two.]. .Iadd.four.Iaddend.-day additional dosing
interval.
.[.23. The method of claim 22, wherein from about 68% to about 95%
of the buprenorphine is contained in the transdermal delivery
system at the end of the dosing interval..].
24. The method of .[.claim 23.]. .Iadd.claims 1, 3, 5, 7, 9, 11,
13, 15 or 22.Iaddend., wherein the Tmax occurs from about 3 to
about 5 days after application of said transdermal delivery
system.
.[.25. The method of claim 22, wherein the mean plasma
concentration attained about 72 hours after application of said
transdermal delivery system is from about 85 to about 263 pg/ml;
and the mean relative release rate maintained over said at least
two-day additional dosing interval is from about 13 .mu.g/hr to
about 21 .mu.g/hr and said transdermal delivery system provides a
therapeutic effect to said human patient throughout the at least
two-day additional dosing interval..].
.[.26. The method of claim 25, wherein from about 68% to about 95%
of the buprenorphine is contained in the transdermal delivery
system at the end of the dosing interval..].
.[.27. The method of claim 25, wherein the Tmax occurs from about 3
to about 5 days after application of said transdermal delivery
system..].
28. The method of claim 22, wherein the mean plasma concentration
attained about 72 hours after application of said transdermal
delivery system is from about .[.21.]. .Iadd.20 .Iaddend.to about
66 pg/ml; and the mean relative release rate maintained over said
.[.at least two.]. .Iadd.four.Iaddend.-day additional dosing
interval is from about 0.3 .mu.g/hr to about 0.6 .mu.g/hr and said
transdermal delivery system provides a therapeutic effect to said
human patient throughout the .[.at least two.].
.Iadd.four.Iaddend.-day additional dosing interval.
.[.29. The method of claim 28, wherein from about 68% to about 95%
of the buprenorphine is contained in the transdermal delivery
system at the end of the dosing interval..].
.[.30. The method of claim 28, wherein the Tmax occurs from about 3
to about 5 days after application of said transdermal delivery
system..].
31. The method of claim 22, wherein the mean plasma concentration
attained about 72 hours after application of said transdermal
delivery system is from about 42 to about 132 pg/ml; and the mean
relative release rate maintained over said .[.at least two.].
.Iadd.four.Iaddend.-day additional dosing interval is from about
0.7 .mu.g/hr to about 1 .mu.g/hr and said transdermal delivery
system provides a therapeutic effect to said human patient
throughout the .[.at least two.]. .Iadd.four.Iaddend.-day
additional dosing interval.
.[.32. The method of claim 31, wherein from about 68% to about 95%
of the buprenorphine is contained in the transdermal delivery
system at the end of the dosing interval..].
.[.33. The method of claim 31, wherein the Tmax occurs from about 3
to about 5 days after application of said transdermal delivery
system..].
34. The method of claim 22, wherein the mean plasma concentration
attained about 72 hours after application of said transdermal
delivery system is from about 169 to about 526 pg/ml; and the mean
relative release rate maintained over said .[.at least two.].
.Iadd.four.Iaddend.-day additional dosing interval is from about
.[.3.]. .Iadd.2 .Iaddend..mu.g/hr to about 4 .mu.g/hr and said
transdermal delivery system provides a therapeutic effect to said
human patient throughout the .[.at least two.].
.Iadd.four.Iaddend.-day additional dosing interval.
.[.35. The method of claim 34, wherein from about 68% to about 95%
of the buprenorphine is contained in the transdermal delivery
system at the end of the dosing interval..].
.[.36. The method of claim 34, wherein the Tmax occurs from about 3
to about 5 days after applications of said transdermal delivery
system..].
37. The method of claim 22, wherein the mean plasma concentration
attained about 72 hours after application of said transdermal
delivery system is from about 254 to about 789 pg/ml; and the mean
relative release rate maintained over said .[.at least two.].
.Iadd.four.Iaddend.-day additional dosing interval is from about 4
.mu.g/hr to about 7 .mu.g/hr and said transdermal delivery system
provides a therapeutic effect to said human patient throughout the
.[.at least two.]. .Iadd.four.Iaddend.-day additional dosing
interval.
.[.38. The method of claim 37, wherein from about 68% to about 95%
of the buprenorphine is contained in the transdermal delivery
system at the end of the dosing interval..].
.[.39. The method of claim 37, wherein the Tmax occurs from about 3
to about 5 days after application of said transdermal delivery
system..].
40. The method of claim 22, wherein the mean plasma concentration
attained about 72 hours after application of said transdermal
delivery system is from about 339 to about 1052 pg/ml; and the mean
relative release rate maintained over said .[.at least two.].
.Iadd.four.Iaddend.-day additional dosing interval is from about 5
.mu.g/hr to about 9 .mu.g/hr and said transdermal delivery system
provides a therapeutic effect to said human patient throughout the
.[.at least two.]. .Iadd.four.Iaddend.-day additional dosing
interval.
.[.41. The method of claim 40, wherein from about 68% to about 95%
of the buprenorphine is contained in the transdermal delivery
system at the end of the dosing interval..].
.[.42. The method of claim 40, wherein the Tmax occurs from about 3
to about 5 days after application of said transdermal delivery
system..].
43. A method of treating pain in a human patient, comprising
applying a transdermal delivery system containing buprenorphine as
the active ingredient onto the skin of said human patient to
provide a first order release rate of buprenorphine over a
three-day dosing interval, such that a maximum plasma concentration
from about 20 pg/ml to about 1052 pg/ml is attained, and
maintaining said transdermal delivery .[.systems.]. .Iadd.system
.Iaddend.on the skin of said human patient for .[.at least.]. an
additional .[.two.]. .Iadd.four.Iaddend.-day dosing interval during
which said transdermal delivery system provides substantially zero
order kinetics, such that said transdermal delivery system provides
a therapeutic effect to said human patient throughout the .[.at
least two.]. .Iadd.four.Iaddend.-day additional dosing
interval.
44. A method of treating a human patient suffering from moderate to
severe pain by applying a transdermal delivery system containing
buprenorphine onto the skin of the human patient and maintaining
the transdermal delivery system in contact with the skin for a 3
day dosing interval, the transdermal delivery system containing an
amount of buprenorphine sufficient to maintain an adequate relative
release rate to provide a therapeutic effect in the patient for
approximately only 3 days, comprising maintaining the transdermal
delivery system in contact with the human patient's skin for .[.at
least 2 to about 5.]. .Iadd.4 .Iaddend.additional days beyond said
3 day dosing interval, such that the human patient continues to
receive a therapeutic effect from said transdermal buprenorphine
delivery system.
45. In a method of treating a human patient suffering from moderate
to severe pain by applying a transdermal delivery system containing
buprenorphine onto the skin of the human patient and maintaining
the transdermal delivery system in contact with the skin for a 3
day dosing interval, the transdermal delivery system containing an
amount of buprenorphine sufficient to maintain an adequate relative
release rate to provide a therapeutic effect in the patient for
about 3 days, .[.the.]. .Iadd.an .Iaddend.improvement comprising
maintaining the transdermal delivery system in contact with the
human patient's skin for .[.at least 2 to about 5.]. .Iadd.4
.Iaddend.additional days beyond said 3 day dosing interval.
.[.46. The method of claim 2 wherein the plasma level of
buprenorphine at 72 hours does not decrease by more than 30% over
the next 48 hours..].
.[.47. The method of claim 2 wherein the plasma level of
buprenorphine at 120 hours does not decrease by more than 30% over
the next 48 hours..].
.Iadd.48. The method of claim 1, wherein the transdermal delivery
system comprises from about 0.1% to about 30% weight
buprenorphine..Iaddend.
.Iadd.49. The method of claim 48, wherein the transdermal delivery
system comprises 10% buprenorphine base, 10-15% acid, 10% softener,
55-70% polyacrylate, and 0-10% polyvinylpyrrollidone..Iaddend.
.Iadd.50. The method of claim 43, wherein the active ingredient
consists essentially of buprenorphine..Iaddend.
.Iadd.51. The method of claim 43, wherein the active ingredient
consists of buprenorphine..Iaddend.
.Iadd.52. A method of treating pain in a human patient, comprising
transdermally administering an active ingredient, wherein the
active ingredient consists essentially of buprenorphine, to said
human patient by applying a transdermal delivery system to the skin
of a patient, and maintaining said transdermal delivery system in
contact with the patient's skin for a seven day dosing interval,
said transdermal delivery system maintaining a mean relative
release rate of from about 3 ug/hr to about 86 ug/hr and providing
a substantially first order plasma level increase of buprenorphine
from the initiation of the dosing interval until about 72 hours
after the initiation of the dosing interval; and a mean relative
release rate of about 0.3 ug/hr to about 9 ug/hr and providing a
substantially zero order plasma level fluctuation of buprenorphine
from about 72 hours after the initiation of the dosing interval
until the end of the seven-day dosing interval, such that the
following mean plasma concentrations are achieved: a mean plasma
concentration from about 0.3 to about 113 pg/ml at about 6 hours
after initiation of the dosing interval; a mean plasma
concentration from about 3 to about 296 pg/ml at about 12 hours
after initiation of the dosing interval; a mean plasma
concentration from about 7 to about 644 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 753 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 16 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 20 to about 984 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 21 to about 1052 pg/ml at about 72 hours
after initiation of the dosing interval; a mean plasma
concentration from about 23 to about 1052 pg/ml at about 96 hours
after initiation of the dosing interval; a mean plasma
concentration from about 23 to about 1052 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 22 to about 970 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 19 to about 841 pg/ml at about 168 hours
after initiation of the dosing interval..Iaddend.
.Iadd.53. The method of claim 52, wherein the transdermal delivery
system comprises from about 0.1% to about 30% weight
buprenorphine..Iaddend.
.Iadd.54. The method of claim 53, wherein the transdermal delivery
system comprises 10% buprenorphine base, 10-15% acid, 10% softener,
55-70% polyacrylate, and 0-10% polyvinylpyrrollidone..Iaddend.
.Iadd.55. A method of treating pain in a human patient, comprising
transdermally administering an active ingredient, wherein the
active ingredient consists of buprenorphine, to said human patient
by applying a transdermal delivery system to the skin of a patient,
and maintaining said transdermal delivery system in contact with
the patient's skin for a seven day dosing interval, said
transdermal delivery system maintaining a mean relative release
rate of from about 3 ug/hr to about 86 ug/hr and providing a
substantially first order plasma level increase of buprenorphine
from the initiation of the dosing interval until about 72 hours
after the initiation of the dosing interval; and a mean relative
release rate of about 0.3 ug/hr to about 9 ug/hr and providing a
substantially zero order plasma level fluctuation of buprenorphine
from about 72 hours after the initiation of the dosing interval
until the end of the seven-day dosing interval, such that the
following mean plasma concentrations are achieved: a mean plasma
concentration from about 0.3 to about 113 pg/ml at about 6 hours
after initiation of the dosing interval; a mean plasma
concentration from about 3 to about 296 pg/ml at about 12 hours
after initiation of the dosing interval; a mean plasma
concentration from about 7 to about 644 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 753 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 16 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 20 to about 984 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 21 to about 1052 pg/ml at about 72 hours
after initiation of the dosing interval; a mean plasma
concentration from about 23 to about 1052 pg/ml at about 96 hours
after initiation of the dosing interval; a mean plasma
concentration from about 23 to about 1052 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 22 to about 970 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 19 to about 841 pg/ml at about 168 hours
after initiation of the dosing interval..Iaddend.
.Iadd.56. The method of claim 55, wherein the transdermal delivery
system comprises from about 0.1% to about 30% weight
buprenorphine..Iaddend.
.Iadd.57. The method of claim 56, wherein the transdermal delivery
system comprises 10% buprenorphine base.about.10-15% acid, 10%
softener, 55-70% polyacrylate, and 0-10%
polyvinylpyrrollidone..Iaddend.
.Iadd.58. A method of treating a human patient suffering from
moderate to severe pain by applying a transdermal delivery system
containing an active ingredient wherein the active ingredient
consists essentially of buprenorphine, onto the skin of the human
patient and maintaining the transdermal delivery system in contact
with the skin for a 3 day dosing interval, the transdermal delivery
system containing an amount of buprenorphine sufficient to maintain
an adequate relative release rate to provide a therapeutic effect
in the patient for approximately only 3 days, comprising
maintaining the transdermal delivery system in contact with the
human patient's skin for 4 additional days beyond said 3 day dosing
interval, such that the human patient continues to receive a
therapeutic effect from said transdermal buprenorphine delivery
system..Iaddend.
.Iadd.59. The method of claim 58, wherein the active ingredient
consists of buprenorphine..Iaddend.
.Iadd.60. In a method of treating a human patient suffering from
moderate to severe pain by applying a transdermal delivery system
containing an active ingredient, wherein the active ingredient
consists of buprenorphine, onto the skin of the human patient and
maintaining the transdermal delivery system in contact with the
skin for a 3 day dosing interval, the transdermal delivery system
containing an amount of buprenorphine sufficient to maintain an
adequate relative release rate to provide a therapeutic effect in
the patient for about 3 days, the improvement comprising
maintaining the transdermal delivery system in contact with the
human patient's skin for 4 additional days beyond said 3 day dosing
interval..Iaddend.
Description
BACKGROUND OF THE INVENTION
It is the intent of all sustained-release pharmaceutical
preparations to provide a longer period of pharmacologic effect
after the administration of a drug than is ordinarily experienced
after the administration of immediate release preparations of the
same drug. Such longer periods of efficacy can provide many
inherent therapeutic benefits that are not achieved with
corresponding immediate release preparations. The benefits of
prolonged analgesia afforded by sustained release oral analgesic
preparations have become universally recognized and oral opioid
analgesic sustained-release preparations are commercially
available.
Prolonged analgesia is particularly desirable in patients suffering
from moderate to severe pain, such as cancer patients. Available
oral preparations provide a duration of effect lasting e.g., about
twelve hours (and sometimes 24 hours) such that a drug may only
have to be administered to a patient one to three times a day. For
example, morphine, which has been considered to be the prototypic
opioid analgesic, has been formulated into twice-daily, oral
controlled release formulations (e.g., MS Contin.RTM. tablets,
commercially available from The Purdue Frederick Company).
Another approach to sustained delivery of a therapeutically active
agent are transdermal delivery systems, such as transdermal
patches. Generally, transdermal patches contain a therapeutically
active agent (e.g., an opioid analgesic), a reservoir or matrix
containing the opioid or other active ingredient(s) and an adhesive
which allows the transdermal device to adhere to the skin, allowing
for the passage of the active agent from the device through the
skin of the patient. Once the active agent has penetrated the skin
layer, the drug is absorbed into the blood stream where it can
exert a desired pharmacotherapeutic effect, such as analgesia.
Transdermal delivery systems in which an opioid analgesic is the
active ingredient have been contemplated. For example, a
commercially available opioid analgesic transdermal formulation is
Duragesic.RTM. (commercially available from Janssen Pharmaceutical;
active ingredient is fentanyl). The Duragesic.RTM. patch is said to
provide adequate analgesia for up to 48 to 72 hours (2 to 3
days).
Buprenorphine, a partially synthetic opiate, has also been
contemplated for prolonged analgesia. Although other types of
opioid analgesic transdermal formulations have been reported in the
literature (such as fentanyl, discussed above), buprenorphine
transdermal delivery systems are of particular interest because
buprenorphine is a potent, partial agonist opioid analgesic with
desirable therapeutic properties. For example, buprenorphine is 50
to 100 times more potent than morphine, but has a much safer
therapeutic index than morphine (see Wallenstein S L, et al.,
Crossover Trials in Clinical Analgesic Assays: Studies of
Buprenorphine and Morphine, Pharmacotherapy, G(5): 225-235, 1986
hereby incorporated by reference). Further, the partial agonist
properties of buprenorphine are useful in the treatment of opioid
addiction.
There are several types of transdermal formulations of
buprenorphine reported in the literature. See, for example, U.S.
Pat. No. 5,240,711 (Hille et al.), U.S. Pat. No. 5,225,199 (Hidaka
et al.), U.S. Pat. No. 5,069,909 (Sharma et al.), U.S. Pat. No.
4,806,341 (Chien et al.), and U.S. Pat. No. 5,026,556 (Drust et
al.), all of which are hereby incorporated by reference.
Buprenorphine has a low oral bioavailability and has been
considered by certain of those skilled in the art to be like other
narcotics which are habit-forming (see, e.g., U.S. Pat. No.
5,240,711 to Hille, et. al.) and induce tolerance (see, e.g., U.S.
Pat. No. 5,613,958 to Kochinke, et. al.). As reported in Hille,
et.al., experts are of the opinion that the form of administration
of a medicinal drug contributes to the risk of addiction, and
higher than necessary blood levels created immediately after
administration of a drug such as buprenorphine, followed by a
drastic decrease (causing in succession euphoria and then
ineffective pain treatment), cause the patient to start to long for
the next dosage (referred to as an "iatrogenic" addiction). In the
case of buprenorphine, Hille, et al. reported that continuous
infusion would be considered the most suitable mode to avoid such
an iatrogenic addition by providing constant blood levels; however,
continuous infusion requires physician control and insertion of a
cannula (which may cause inflammation at the site). This problem is
considered to be overcome by Hille, et al. by virtue of their use
of a transdermal delivery system which includes buprenorphine or
one of its pharmaceutically compatible salts and which releases the
drug over a period of at least 24 hours in a controlled manner, and
ensures that the buprenorphine does not notably decompose when the
transdermal delivery system is stored, and which further ensures
that the buprenorphine in-vivo penetrates through the skin at the
required amount.
Kochinke et al. describe a transdermal system for the modulated
administration of tolerance-inducing drugs. Buprenorphine is
identified therein as such a drug. The system is designed to
deliver the drug through the patient's skin via a three-phase drug
delivery profile. In the first phase, which begins with patch
application and ends at 2-10 hours after patch application, plasma
levels of the drug are obtained. This phase is followed by a second
phase in which therapeutic plasma levels of the drug are
maintained. The second phase begins at about two to ten hours after
patch application and ends at about 8-18 hours after patch
application. In a third phase, sub-therapeutic levels of the drug
are maintained, via inherent patch design and/or patch removal. The
rationale behind the drug delivery profile of Kochinke et al. is
that initial high blood levels may be more effective when followed
by a period of decreasing dosage (down to sub-therapeutic levels),
than if the blood levels are maintained either at the higher or
lower level (i.e., sub-therapeutic levels) throughout the entire
administration period. By virtue of this modulated profile, it is
said that the onset of tolerance to the drug being administered can
be prevented or greatly reduced.
Despite these advances in the art, there remains a need for methods
of treating patients with buprenorphine that provide effective
analgesic levels of buprenorphine for prolonged periods of time
while eliminating or minimizing dependence, tolerance, and side
effects, thus providing a safe and effective method of pain
management.
OBJECTS AND SUMMARY OF THE INVENTION
It is an object of the present invention to provide a method which
allows for reduced plasma concentrations of buprenorphine over a
prolonged time period than possible according to prior art methods,
while still providing effective pain management.
It is a further object of the present invention to provide a method
for treating patients in pain with buprenorphine which achieves
prolonged and effective pain management, while at the same time
provides the opportunity to reduce side effects, dependence and
tolerance which the patients may experience when subjected to
prolonged treatment with a narcotic such as buprenorphine.
It is yet a further object to provide a method for the treatment of
pain in patients by utilizing a transdermal delivery system which
contains buprenorphine in a manner which maximizes the dosage
interval, i.e., the interval during which the transdermal delivery
system is maintained in contact with the skin, and minimizes the
plasma concentrations in the patients during the dosage interval,
while .[.surprisingly.]. maintaining effective pain management.
A further object of the invention is to provide a method for
treating opioid-addicted patients in a manner which gradually
reduces the plasma concentration of opioid in the patients' plasma
while at the same time providing effective plasma concentrations
for those patients to be detoxified.
The invention is directed in part to the .[.surprising.]. result
that effective pain management is provided by providing a
substantially first order rate of increase of blood plasma
concentrations of buprenorphine over about a three day (e.g., 72
hours) time interval, followed by a prolonged time period of at
least about two days (e.g., 48 hours) during which the plasma
concentrations of buprenorphine are maintained according to
substantially zero order pharmacokinetics.
In accordance with the above objects and others, the invention
relates in part to a method of effectively treating pain in humans,
comprising administering buprenorphine to human patients in a
manner such that the following mean plasma concentrations are
achieved over a 72 hour dosing interval: a mean plasma
concentration from about 0.3 to about 113 pg/ml at about 6 hours
after initiation of the dosing interval; a mean plasma
concentration from about 3 to about 296 pg/ml at about 12 hours
after initiation of the dosing interval; a mean plasma
concentration from about 11 to about 644 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 630 pg/ml at about 30 hours
after initiation of the dosing interval; a mean plasma
concentration from about 15 to about 715 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 20 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 21 to about 914 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 24 to about 850 pg/ml at about 72 hours
after initiation of the dosing interval; and thereafter
administering the buprenorphine in a manner such that the mean
plasma concentrations are maintained from about 19 to about 850
pg/ml over at least the next 48 hours. In certain preferred
embodiments, the dosing interval is maintained over a seven day
period.
Any mode of administration may be utilized to attain the above
plasma concentrations over time. For example, the buprenorphine may
be administered transdermally, parenterally, sublingually, orally,
buccally, rectally, etc. Oral bioavailability of buprenorphine is
very low (estimated as 15%). In order to better control plasma
concentrations of buprenorphine within the concentrations desired
in the herein-described inventive methods, it is preferred that the
buprenorphine is administered via a transdermal delivery system or
via continuous infusion.
In a further preferred embodiment of the invention, the method
comprises applying a transdermal delivery system containing
buprenorphine as the active ingredient onto the skin of patients
which provide a release rate of buprenorphine over about a 72 hour
dosing interval such that a maximum plasma concentration from about
20 pg/ml to about 850 pg/ml is attained (depending upon the dosage
levels needed to maintain analgesia in the particular patients),
and then maintaining the transdermal delivery systems on the skin
of the patients for at least an additional 24 hour interval during
which the plasma concentrations of buprenorphine in the patients
are maintained above minimum effective concentrations of the drug
and the patients continue to experience effective pain management
during this additional dosing interval.
The invention is further directed to a method of effectively
treating pain in humans, comprising administering buprenorphine
transdermally to human patients such that mean relative release
rates are achieved as follows: a mean relative release rate of from
about 3 ug/hr to about 86 ug/hr from initiation of the dosing
interval until about 72 hours thereafter; and a mean relative
release rate of about 0.3 ug/hr to about 9 ug/hr from about 72
hours after the initiation of the dosing interval until at least
about 120 hour hours after the initiation of the dosing interval.
In certain preferred embodiments, the mean relative release rate of
about 0.3 ug/hr to about 9 ug/hr is maintained from about 72 hours
after the initiation of the dosing interval until at least about
168 hours after the initiation of the dosing interval.
The present invention is further related to a method of effectively
treating pain in humans, comprising administering buprenorphine
transdermally to human patients such that a mean relative release
rate from about 3 ug/hr to about 86 ug/hr of buprenorphine is
achieved until about 72 hours after the application of a
transdermal delivery system, and thereafter providing (either with
the same transdermal delivery system or upon removal of the system
and replacement with a different transdermal delivery system) a
mean relative release rate of about 0.3 ug/hr to about 9 ug/hr from
about 72 hours after the intimation of the dosing interval until at
least about 120 hours after the initiation of the dosing interval,
and preferably until at least about 168 hours after the initiation
of the dosing interval.
In preferred embodiments, the method comprises the application of a
transdermal delivery system which is designed to .[.be.]. provide
analgesia for about 72 hours, and which provides a release rate of
the drug when applied to the skin which generally follows first
order pharmacokinetics over that 72 hour period, and further
comprises taking advantage of the fact that such transdermal
delivery systems typically provide a dramatic drop-off in the
release rate of buprenorphine after the first 72 hours, but
nevertheless provide a relatively small but sufficient release of
buprenorphine to maintain analgesia and desirable plasma
concentrations in the patients over a further period of time of at
least, e.g., preferably at least 48 hours, by leaving the
transdermal delivery system in contact with the skin of the patient
for such additional desired dosing interval, which may be as long
as, e.g., an additional 96 hours or more. .[.Surprisingly, it.].
.Iadd.It .Iaddend.has been found that such transdermal dosage
systems exhibit substantially zero order release after about the
initial 72 hour dosage interval, and therefore are capable of
maintaining effective plasma concentrations of buprenorphine for a
much longer period than previously reported in the prior art.
.[.However, the inventive method also contemplates the possibility
of utilizing a first transdermal delivery system which provides the
desired substantially first order kinetics, and thereafter the
removal of the first transdermal delivery system and its
replacement with a second system which provides the desired
substantially zero order pharmacokinetics for a prolonged period of
time (e.g., at least about 24 hours, preferably at least about 48
hours, and most preferably about 96 hours). This second system may
be a second transdermal delivery system which provides the
afore-mentioned mean relative release rate of about 0.3 ug/hr to
about 9 ug/hr. On the other hand, the second system may even
utilize a different mode of administration, for example, continuous
infusion..].
The present invention is also related, in part, to a method of
effectively treating pain in patients, comprising applying onto the
skin of the patients a transdermal delivery system containing
buprenorphine which transdermal delivery system delivers the
buprenorphine substantially according to first order kinetics to
provide a mean plasma concentration from about 24 to about 850
pg/ml about 3 days after application, and then maintaining the
transdermal buprenorphine formulation in contact with the skin of
the human patient for about 2 to about 6 additional days without
removing the transdermal formulation, such that the patient
continues to receive effective analgesia from the transdermal
buprenorphine formulation.
The invention also provides, in certain preferred embodiments, an
improvement in a method of treating pain in human patients by
applying a 3 day transdermal delivery system containing
buprenorphine onto the skin of the patient and maintaining the
transdermal delivery system in contact with the skin for a 3 day
dosing interval, the transdermal delivery system containing an
amount of buprenorphine sufficient to provide effective analgesia
in the patient for about 3 days, the improvement comprising
maintaining the transdermal dosage form in contact with the
patient's skin for at least 2 to about 6 additional days beyond the
3 day dosing interval.
The present invention also relates to a method of treating opioid
addiction by administering buprenorphine transdermally to human
patients which provides a release rate of the drug when applied to
the skin which generally follows first order pharmacokinetics over
a 72 hour period, such that the addict attains a buprenorphine
plasma concentration from about 1000 to about 10,000 .mu.g/ml, and
preferably from about 5000 to about 8000 .mu.g/ml, about 72 hours
after application of a buprenorphine transdermal delivery system,
and thereafter maintaining the transdermal delivery system in
contact with the skin of the addict such that a mean relative
release rate of buprenorphine approximating zero order kinetics
over an additional dosing interval of at least about 48 hours, to
provide the desired therapeutic effect (detoxification). In
preferred embodiments the transdermal delivery system is maintained
in contact with the addict's skin for about 7 days.
The methods of the present invention are described in further
detail in the following sections. However, it should be understood
that for purposes of the present invention, the following terms
have the following meanings:
The term "effective analgesia" is defined for purposes of the
present invention as a satisfactory reduction in or elimination of
pain, along with the process of a tolerable level of side effects,
as determined by the human patient.
The term "effective pain management" means for purposes of the
present invention as the objective evaluation of a human patient's
response (pain experienced versus side effects) to analgesic
treatment by a physician as well as subjective evaluation of
therapeutic treatment by the patient undergoing such treatment. The
skilled artisan will understand that effective analgesia will vary
according to many factors, including individual patient
variations.
The term "breakthrough pain" means pain which the patient
experiences despite the fact that the patient is being administered
generally effective amounts of, e.g., an opioid analgetic such as
buprenorphine.
The term "rescue" refers to a dose of an analgesic which is
administered to a patient experiencing breakthrough pain.
The term "first order" pharmacokinetics is defined as plasma
concentrations which increase over a specified time period. Drug
release from suspension matrices according to first order kinetics
may be defined as follows: .times. .times..times. .times..times.
.times..times. .times..times. .times. .function. .times..times.
.times..times. .times. ##EQU00001## D.sub.eff=apparent diffusion
coefficient M/.sup. t=2C.sub.O {square root over (D.sub.eff/.pi.)}
C.sub.O=initial drug concentration in the transdermal delivery
system C.sub.S=saturation concentration t=time Assumptions: perfect
sink; diffusion of dissolved drug is rate controlling; therefore
Q=const..sup. t
Drug release from solution matrices according to first order
kinetics may be defined as follows: .times. .times..times.
.times..times. .times..times. .times..times. .times. .function..pi.
.times..times. .times..times. .times. ##EQU00002## Assumptions:
perfect sink; diffusion of dissolved drug is rate controlling;
M.sub.t.ltoreq.0.4M.sub.0 therefore Q=cost..sup. t
The term "zero order" pharmacokinetics contemplates an amount of
drug released from a buprenorphine formulation which substantially
maintains plasma concentrations at a relatively constant level. For
purposes of the present invention, a relatively constant plasma
concentration is defined as a concentration which does not decrease
more than about 30% over a 48 hour time period.
Drug release from membrane-controlled systems may be defined as
follows: Amount released per area unit Q=const (zero order
kinetics)
The term "mean relative release rate" is determined from the amount
of drug released per unit time from the transdermal delivery system
through the skin and into the bloodstream of a human patient. Mean
relative release rate may be expressed, e.g, as .mu.g
drug/cm.sup.2/hr. For example, a transdermal delivery system that
releases 1.2 mg of buprenorphine over a time period of 72 hours is
considered to have a relative release rate of 16.67 .mu.g/hr. For
purposes of the invention, it is understood that relative release
rates may change between any particular time points within a
particular dosing interval, and the term therefore only reflects
the overall release rate during the particular dosing interval. For
purposes of the present invention, relative release rate should be
considered synonomous with the term "flux rate".
The term "sustained release" is defined for purposes of the present
invention as the release of the drug (opioid analgesic) from the
transdermal formulation at such a rate that blood (e.g., plasma)
concentrations (levels) are maintained within the therapeutic range
(above the minimum effective analgesic concentration or "MEAC") but
below toxic levels over a period of time of about 3 days or
longer.
The term "steady state" means that the blood plasma concentration
curve for a given drug has been substantially repeated from dose to
dose.
The term "minimum effective analgesic concentration" is defined for
purposes of this invention as the minimum effective therapeutic
blood plasma level of the drug at which at least some pain relief
is achieved in a given patient. It will be well understood by those
skilled in the medical art that pain measurement is highly
subjective and great individual variations may occur among
patients.
For purposes of the present invention, the term "buprenorphine"
shall include buprenorphine base, pharmaceutically acceptable salts
thereof, stereoisomers thereof, ethers and esters thereof, and
mixtures thereof.
The term "overage" means for the purposes of the present invention
the amount of buprenorphine contained in a transdermal delivery
system which is not delivered to the patient. The overage is
necessary for creating a concentration gradient by means of which
the active agent (e.g., buprenorphine) migrates through the layers
of the transdermal dosage form to the desired site on a patient's
skin.
BRIEF DESCRIPTION OF THE DRAWINGS
The following drawings are illustrative of embodiments of the
invention and are not meant to limit the scope of the invention as
encompassed by the claims.
FIG. 1 is a graphical representation of the mean plasma
concentration (pg/ml) versus time (days) for Example 1;
FIG. 2 is a graphical representation of pharmacodynamic variables
versus time (days) for Example 1;
FIG. 3 is a graphical representation of the plasma concentration
(pg/ml) over time (hours) for Comparative Example A;
FIG. 4 is a graphical representation of the plasma concentration
(pg/ml) over time (hours) for Comparative Example B (intravenous
concentrations divided by 100);
FIG. 5 is a graphical representation of the plasma concentration
(pg/ml) over time (hours) for Comparative Example C;
FIG. 6 is a graphical representation pharmacodynamic variables
versus time (hours) for Comparative Example A;
FIG. 7 is a graphical representation pharmacodynamic variables
versus time (hours) for Comparative Example B;
FIG. 8 is a graphical representation pharmacodynamic variables
versus time (hours) for Comparative Example C;
FIG. 9 is a graphical representation of the plasma concentration
(pg/ml) over time (hours) for Comparative Example D;
FIG. 10 is a graphical representation of the plasma concentration
(pg/ml) over time (hours) for Comparative Example E;
FIG. 11 is a graphical representation of the plasma concentration
(pg/ml) over time (hours) for Comparative Example F;
FIG. 12 is a graphical representation pharmacodynamic variables
versus time (hours) for Comparative Example D;
FIG. 13 is a graphical representation pharmacodynamic variables
versus time (hours) for Comparative Example E; and
FIG. 14 is a graphical representation pharmacodynamic variables
versus time (hours) for Comparative Example F.
DETAILED DESCRIPTION
While chronic pain is often manageable with the use of the
combination of "mild" analgesics, and nonpharmacologic
interventions, selected patients continue to experience
unacceptably intense pain. Some patients with chronic pain cannot
tolerate therapeutic doses of "mild" analgesics, while others
develop pain of such severity that "strong" analgesics should be
considered for subacute or chronic use.
The phrase "strong analgesics" encompasses, inter alia, several
classes of opioid analgesics, including the partial agonists.
Parenteral buprenorphine (a Schedule V drug under the Controlled
Substances Act) is the only example of a partial agonist opioid
analgesic currently marketed in the United States.
Partial agonists provide several therapeutic advantages in many
patients when compared to morphine-like agonists and mixed
agonists-antagonists. For example, unlike the mixed
agonists-antagonists (e.g., pentazocine, butorphanol, nalbuphine),
buprenorphine is devoid of psychotomimetic adverse reactions; in
comparison with agonists (e.g., morphine and fentanyl), the
dose-responsive relationship for respiratory depression with
buprenorphine is relatively low and the abuse liability of
buprenorphine is less.
The chemical of name of buprenorphine is
21-cyclopropyl-7-[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6,14-endo-ethano-6-
,7,8,14-tetrahydrooripavine. The molecular weight of buprenorphine
base is 467.7; the empirical formula is
C.sub.29H.sub.41NO.sub.4.
The structural formula of buprenorphine is shown below:
##STR00001##
Buprenorphine is an opioid partial agonist and shares many of the
actions, such as analgesia, of opioid agonists. A "ceiling effect"
to analgesia (i.e., no additional analgesia with increasing dose)
is well documented with respect to buprenorphine in many animal
models. It is highly lipophilic and dissociates slowly from opioid
receptors. Buprenorphine is considered in the art to be a partial
agonist at .mu. opioid receptors in the central nervous system
("CNS") and peripheral tissues. It is further thought that
buprenorphine binds with high affinity to .mu. and .kappa..sub.1
receptors, and, with lower affinity, to .delta. receptors. The
intrinsic agonist activity at the .kappa. receptor seems to be
limited and most evidence suggests that buprenorphine has
antagonist activity at .kappa. receptors. The lack of .kappa.
agonism accounts for buprenorphine's freedom from the dysphoric and
psychotomimetic effects often seen with agonist/antagonist drugs.
Other studies suggest that the opioid antagonist effects of
buprenorphine may be mediated via an interaction with .delta.
opioid receptors.
It is known in the art that buprenorphine binds slowly with, and
dissociates slowly from, the .mu. receptor. The high affinity of
buprenorphine for the .mu. receptor and its slow binding to, and
dissociation from, the receptor is thought to possibly account for
the prolonged duration of analgesia, and in part, for the limited
physical dependence potential observed with the drug. The high
affinity binding may also account for the fact that buprenorphine
can block the .mu. agonist effects of other administered
opioids.
Like other opioid agonists, buprenorphine produces dose-related
analgesia. The exact mechanism has not been fully explained, but
analgesia appears to result from a high affinity of buprenorphine
for .mu. and possibly .kappa. opioid receptors in the CNS. The drug
may also alter the pain threshold (threshold of afferent nerve
endings to noxious stimuli). On a weight basis, the analgesic
potency of parenteral buprenorphine appears to be about 25 to about
50 times that of parenteral morphine, about 200 times that of
pentazocine, and about 600 times that of meperidine. Buprenorphine
may produce sex-related differences in analgesia, with females
requiring substantially less drug than males to produce adequate
analgesia.
For a study of transdermal delivery of buprenorphine through
cadaver skin, see Roy, Samir D. et al., "Transdermal Delivery of
Buprenorphine Through Cadaver Skin", Journal of Pharmaceutical
Sciences, Vol. 83, No. 2, pp. 126-130, (1994), hereby incorporated
by reference. For a discussion of buprenorphine pharmacokinetics
resulting from application of a fillable transdermal therapeutic
system, see Wilding, I. R. et al., "Pharmacokinetic evaluation of
transdermal buprenorphine in man," International Journal of
Pharmaceutics, 132 (1996) pp. 81-87, hereby incorporated by
reference. For a discussion of the permeation of buprenorphine and
alkyl esters thereof, see Imoto, et al., "Transdermal Prodrug
Concepts: Permeation of Buprenorphine and its Alkyl Esters Through
Hairless Mouse Skin and Influence of Vehicles," Biol. Pharm. Bull.,
19(2)263-267 (1996), hereby incorporated by reference.
Buprenorphine has a low abuse liability compared to full agonist
opioids. Although infrequent, however, buprenorphine may also
produce limited physical dependence, and signs and symptoms of mild
withdrawal may appear following discontinuance of prolonged therapy
with the drug alone. Due to buprenorphine's slow binding with and
slow dissociation from the .mu. receptor, elimination of the drug
from the CNS is prolonged following abrupt discontinuance;
consequently, signs and symptoms of acute withdrawal are less
intense than those produced by morphine and are delayed in
appearance.
In patients physically dependent on opioids, buprenorphine produces
many of the subjective and objective effects of opioids; however,
the drug may not be a satisfactory substitute for opioid agonists
in all patients physically dependent on opioids. Tolerance to the
opioid agonist activity of the drug reportedly develops rarely, if
at all.
Buprenorphine may produce psychological dependence. Buprenorphine
is a partial opioid agonist with behavioral and psychic effects
similar to morphine. Unlike pentazocine, however, buprenorphine
rarely causes psychotomimetic effects. Like other opioid agonists,
buprenorphine may produce increases in cerebrospinal fluid
pressure.
The pharmacokinetics of buprenorphine administered parenterally and
sublingually are known. Intravenous administration of a single dose
of about 0.3 mg of buprenorphine has been shown to provide mean
peak plasma drug concentrations of about 18 ng/ml which occur
within about 2 minutes; plasma concentrations declined to about 9
and about 0.4 ng/ml after about 5 minutes and about 3 hours,
respectively. Following intramuscular administration of a second
0.3-mg dose 3 hours after the initial intravenous dose, mean peak
plasma buprenorphine concentrations of about 3.6 ng/ml occur within
about 2 to about 5 minutes and decline to about 0.4 ng/ml after
about 3 hours. Approximately 10 minutes after administration,
plasma concentrations of buprenorphine are similar following
intravenous or intramuscular injection.
A parenteral solution of buprenorphine hydrochloride (0.3 mg
buprenorphine/ml) is commercially available as Buprenex.RTM.
(Reckitt & Colman) for intramuscular and intravenous
administration. The usual adult dose (over age 13) is 0.3 mg IM or
IV every 6 to 8 hours as needed for moderate to severe pain. The
pediatric dose in patients age 2 to 12 is 2-6 mcg/kg of body weight
every 4-6 hours. The increased frequency of administration in the
pediatric population is believed to be caused by increased
clearance of buprenorphine compared to the adult population. The
mean duration of analgesia generally is six hours following single
intramuscular or intravenous doses of 0.2 to 0.3 mg or 2 to 4
.mu.g/kg; however, in some studies, the mean duration of analgesia
reportedly ranged from 4 to 10 hours following single intramuscular
doses of 0.2 to 0.6 mg and 2 to 24 hours following single
intravenous doses of 0.3 mg or 2 to 15 .mu.g/kg.
For reference, the mean peak plasma buprenorphine concentration,
time to peak concentration, and systemic availability for a 0.4 mg
and 0.8 mg single-dose sublingual dose of buprenorphine has been
reported by Cowan, Alan and Lewis John, W., Buprenorphine:
Combating Drug Abuse With a Unique Opioids, Wiley-Liss, Inc., New
York, pp. 137-147 (1995), hereby incorporated by reference in its
entirety. For a 0.4 mg sublingual dose, the Cmax was reported as
0.50.+-.0.06 ng/ml; the Tmax was reported 210.+-.40 minutes; and a
systemic availability of 57.7%.+-.6. For a 0.8 mg sublingual dose,
the Cmax was reported at 1.04.+-.0.27 ng/ml; the Tmax was reported
192.+-.49 minutes; and a systemic availability of
54.1%.+-.12.7.
It has previously been reported that a usual sublingual analgesic
dose of buprenorphine is 0.2 to 0.4 mg every 8 hours (e.g.,
Kuhlman, J J et al. J Analyt Toxicol 1996; 20(10)). For a
transdermal patch which might provide a nominal delivery rate of
about 12.5 .mu.g/hr, the total buprenorphine administered over a 24
hour period would be about 0.3 mg, and the sublingual equivalent
dose over the same period would be about 0.6 mg. For a transdermal
delievery system (e.g., a transdermal patch) which might provide a
nominal delivery rate of about 25 ug/hr, the total buprenorphine
administered over a 24 hour period would be about 0.6 mg, and the
sublingual equivalent dose over the same period would be about 1.2
mg. For a transdermal patch which might provide a nominal delivery
rate of about 50 ug/hr, the total buprenorphine administered over a
24 hour period would be about 1.2 mg, and the sublingual equivalent
dose over the same period would be about 2.4 mg. It is contemplated
that one of ordinary skill in the art will appreciate that by
simple pharmaceutical calculations, the equivalent doses for
achieving the inventive buprenorphine plasma concentration set
forth herein can be determined regardless of the mode of
administration. In the present discussion, the comparison is made
between transdermal dose and sublingual dose.
Distribution of buprenorphine into human body tissues and fluids
has not been well characterized. Following oral or intramuscular
administration in rats, buprenorphine distributes into the liver,
brain, placenta, and GI tract; highest concentrations were attained
in the liver within 10 or 40 minutes following oral or
intramuscular administration, respectively. The hepatic extraction
ratio of buprenorphine is approximately 1. The drug and its
metabolites are distributed into bile. Following intravenous
administration in humans, the drug rapidly distributes into cerebro
spinal fluid ("CSF") (within several minutes). CSF buprenorphine
concentrations appear to be approximately 15% to 25% of concurrent
plasma concentrations. Buprenorphine is approximately 96% bound to
plasma proteins, mainly to and .beta. globulins; the drug does not
appear to bind substantially to albumin.
Buprenorphine is almost completely metabolized in the liver,
principally by N-dealkylation, to form norbuprenorphine
(N-dialkylbuprenorphine); buprenorphine and norbuprenorphine also
undergo conjugation with glucuronic acid. Like the metabolites of
other opioid agonists, norbuprenorphine may have weak analgesic
activity; however, studies to determine the analgesic activity of
the metabolites of buprenorphine have not been performed.
Buprenorphine and its metabolites are excreted principally in feces
via biliary elimination and also in urine. Buprenorphine is
excreted in feces mainly as unchanged drug; small amounts of
norbuprenorphine are also excreted in feces. The drug and its
metabolites are believed to undergo enterohepatic circulation.
Norbuprenorphine appears to be excreted principally in urine at a
slower rate than the parent drug. Total plasma clearance of
buprenorphine reportedly is approximately 1.28 l/minute in
conscious postoperative patients. Limited data indicate that there
is considerable interindividual variability in buprenorphine
pharmacokinetics in children; however, clearance of the drug
appears to be increased in children (e.g., those 5 to 7 years of
age) compared with that in adults. Optimal dosing interval of
buprenorphine may have to be decreased in pediatric patients.
Achieving effective analgesic plasma opioid concentrations in
patients is very complicated and involves a host of considerations,
including the inherent chemical and physical properties of the
opioid itself. Further considerations include in-vivo metabolism,
individual patient response and tolerance. Generally, however,
there is a "minimally effective analgesic concentration" (MEAC) in
plasma for a particular opioid below which no analgesia is
provided. There is relationship between plasma opioid levels and
analgesia. Higher plasma levels are generally associated with
greater pain relief, and (possibly) greater incidence and severity
of side effects.
In preferred embodiments of the present invention where the
patient(s) is being treated for moderate to severe pain, the
buprenorphine is administered in a manner such that the following
mean plasma concentrations are achieved over a 72 hour dosing
interval: a mean plasma concentration from about 0.3 to about 113
pg/ml at about 6 hours after initiation of the dosing interval; a
mean plasma concentration from about 3 to about 296 pg/ml at about
12 hours after initiation of the dosing interval; a mean plasma
concentration from about 7 to about 644 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 753 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 16 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 20 to about 984 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 21 to about 1052 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, the
buprenorphine is administered in a manner such that the mean plasma
concentrations are maintained from about 19 to about 1052 pg/ml
over at least the next 48 hours. In further preferred embodiments,
this method further comprises maintaining the dosing of
buprenorphine during the at least next 48 hours in accordance with
zero under kinetics. Preferably, the mean plasma concentrations are
maintained after the 72 hour dosing interval as follows: a mean
plasma concentration from about 23 to about 1052 pg/ml at about 96
hours after initiation of the dosing interval; a mean plasma
concentration from about 23 to about 1052 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 22 to about 970 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 19 to about 841 pg/ml at about 168 hours
after initiation of the dosing interval (for a seven day dosing
interval). In this embodiment where a transdermal delivery system
is used, a mean relative release rate from about 3 ug/hr to about
86 ug/hr is preferably maintained from the initiation of the dosing
interval until about 72 hours after the initiation of the dosing
interval; and a mean relative release rate is preferably maintained
from about 0.3 ug/hr to about 9 ug/hr from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval.
Preferably, the administration of buprenorphine is accomplished via
a mode selected from the group consisting of transdermally,
continuous infusion, and a mixture of transdermally and continuous
infusion. Most preferably, the administration is accomplished by
applying a transdermal delivery system to the skin of a patient,
and maintaining said transdermal delivery system in contact with
the patient's skin for at least 5 days.
In a further preferred embodiment of the invention, buprenorphine
is administered to human patients in a manner such that the
following mean plasma concentrations are achieved over a 72 hour
dosing interval: a mean plasma concentration from about 1 to about
28 pg/ml at about 6 hours after initiation of the dosing interval;
a mean plasma concentration from about 14 to about 74 pg/ml at
about 12 hours after initiation of the dosing interval; a mean
plasma concentration from about 30 to about 161 pg/ml at about 24
hours after initiation of the dosing interval; a mean plasma
concentration from about 51 to about 188 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 62 to about 246 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 79 to about 246 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 85 to about 263 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, buprenorphine
is administered in a manner such that the mean plasma
concentrations are maintained from about 77 to about 263 pg/ml over
at least the next 48 hours. Preferably, the plasma concentrations
are maintained after the 72 hour dosing interval as follows: a mean
plasma concentration from about 92 to about 263 pg/ml at about 96
hours after initiation of the dosing interval; a mean plasma
concentration from about 94 to about 263 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 86 to about 243 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 77 to about 210 pg/ml at about 168 hours
after initiation of the dosing interval (for a seven day dosing
interval). In this embodiment wherein a transdermal delivery system
is used, it is preferred that a mean relative release rate of from
about 13 ug/hr to about 21 ug/hr is maintained from the initiation
of the dosing interval until about 72 hours after the initiation of
the dosing interval; and that a mean relative release rate of about
1 ug/hr to about 2 ug/hr from about 72 hours after the initiation
of the dosing interval until the end of the dosing interval is
maintained (e.g., about 168 hours after initiation for a seven-day
dosing interval).
In a further preferred embodiment of the invention, buprenorphine
is administered to human patients in a manner such that the
following mean plasma concentrations are achieved over a 72 hour
dosing interval: a mean plasma concentration from about 0.3 to
about 7 pg/ml at about 6 hours after initiation of the dosing
interval; a mean plasma concentration from about 4 to about 19
pg/ml at about 12 hours after initiation of the dosing interval; a
mean plasma concentration from about 7 to about 40 pg/ml at about
24 hours after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 47 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 16 to about 62 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 21 to about 62 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 20 to about 66 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, the
buprenorphine is administered in a manner such that the mean plasma
concentrations are maintained from about 19 to about 66 pg/ml over
at least the next 48 hours. Preferably, the buprenorphine is
administered in a manner such that the mean plasma concentrations
are maintained as follows: a mean plasma concentration from about
23 to about 66 pg/ml at about 96 hours after initiation of the
dosing interval; a mean plasma concentration from about 23 to about
66 pg/ml at about 120 hours after initiation of the dosing
interval; a mean plasma concentration from about 22 to about 61
pg/ml at about 144 hours after initiation of the dosing interval;
and a mean plasma concentration from about 19 to about 53 pg/ml at
about 168 hours after initiation of the dosing interval (for a
seven day dosing interval). In embodiments where a transdermal
delivery system is used, a mean relative release rate is maintained
from about 3 ug/hr to about 5 ug/hr from the initiation of the
dosing interval until about 72 hours after the initiation of the
dosing interval; and a mean relative release rate of about 0.3
ug/hr to about 0.6 ug/hr from about 72 hours after the initiation
of the dosing interval until the end of the dosing interval (e.g.,
about 168 hours after initiation of a seven-day dosing
interval).
In a further preferred embodiment of the invention, buprenorphine
is administered to human patients in a manner such that the
following mean plasma concentrations are achieved over a 72 hour
dosing interval: a mean plasma concentration from about 0.7 to
about 14 pg/ml at about 6 hours after initiation of the dosing
interval; a mean plasma concentration from about 7 to about 37 pg/m
at about 12 hours after initiation of the dosing interval; a mean
plasma concentration from about 15 to about 80 pg/ml at about 24
hours after initiation of the dosing interval; a mean plasma
concentration from about 25 to about 94 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 31 to about 123 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 40 to about 123 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 42 to about 132 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, the
buprenorphine is administered in a manner such that the mean plasma
concentrations are maintained from about 38 to about 132 pg/ml over
at least the next 48 hours. Preferably, the buprenorphine is
further administered in a manner such that the mean plasma
concentrations are maintained as follows: a mean plasma
concentration from about 46 to about 132 pg/ml at about 96 hours
after initiation of the dosing interval; a mean plasma
concentration from about 47 to about 132 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 43 to about 121 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 38 to about 105 pg/ml at about 168 hours
after initiation of the dosing interval (for a seven day dosing
interval). In embodiments where a transdermal delivery system is
used, a mean relative release rate from about 6 ug/hr to about 11
ug/hr is maintained from the initiation of the dosing interval
until about 72 hours after the initiation of the dosing interval;
and a mean relative release rate of about 0.7 ug/hr to about 1
ug/hr is maintained from about 72 hours after the initiation of the
dosing interval until the end of the dosing interval (e.g., about
168 hours after initiation of a seven day dosing interval).
In a further preferred embodiment of the invention, buprenorphine
is administered to human patients in a manner such that the
following mean plasma concentrations are achieved over a 72 hour
dosing interval: a mean plasma concentration from about 3 to about
57 pg/ml at about 6 hours after initiation of the dosing interval;
a mean plasma concentration from about 28 to about 148 pg/ml at
about 12 hours after initiation of the dosing interval; a mean
plasma concentration from about 59 to about 322 pg/ml at about 24
hours after initiation of the dosing interval; a mean plasma
concentration from about 102 to about 377 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 124 to about 492 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 159 to about 492 ml at about 60 hours;
after initiation of the dosing interval; a mean plasma
concentration from about 169 to about 526 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, the
buprenorphine is administered in a manner such that the mean plasma
concentrations are maintained from about 153 to about 526 pg/ml
over at least the next 48 hours. Preferably, the buprenorphine is
administered in a manner such that the mean plasma concentrations
are maintained as follows: a mean plasma concentration from about
184 to about 526 pg/ml at about 96 hours after initiation of the
dosing interval; a mean plasma concentration from about 187 to
about 526 pg/ml at about 120 hours after initiation of the dosing
interval; a mean plasma concentration from about 173 to about 485
pg/ml at about 144 hours after initiation of the dosing interval; a
mean plasma concentration from about 153 to about 420 pg/ml at
about 168 hours after initiation of the dosing interval (for a
seven day dosing interval). In embodiments where a transdermal
delivery system is used, a mean relative release rate from about 26
ug/hr to about 43 ug/hr is maintained from the initiation of the
dosing interval until about 72 hours after the initiation of the
dosing interval; and a mean relative release rate of about 2 ug/hr
to about 4 ug/hr is maintained from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval (e.g., about 168 hours after initiation of a seven-day
dosing interval).
In a further preferred embodiment of the invention, buprenorphine
is administered to human patients in a manner such that the
following mean plasma concentrations are achieved over a 72 hour
dosing interval: a mean plasma concentration from about 4 to about
85 pg/ml at about 6 hours after initiation of the dosing interval;
a mean plasma concentration from about 42 to about 222 pg/ml at
about 12 hours after initiation of the dosing interval; a mean
plasma concentration from about 89 to about 483 pg/ml at about 24
hours after initiation of the dosing interval; a mean plasma
concentration from about 152 to about 565 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 186 to about 738 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 238 to about 738 pg/ml at 60 hours after
initiation of the dosing interval; a mean plasma concentration from
about 254 to about 789 pg/ml at about 72 hours after initiation of
the dosing interval. Thereafter; the buprenorphine is administered
in a manner such that the mean plasma concentrations are maintained
from about 230 to about 789 pg/ml over at least the next 48 hours.
Preferably, the buprenorphine is administered in a manner such that
the mean plasma concentrations are maintained as follows: a mean
plasma concentration from about 276 to about 789 pg/ml at about 96
hours after initiation of the dosing interval; a mean plasma
concentration from about 281 to about 789 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 259 to about 727 pg/ml at about 144 hours
after initiation of the dosing interval; a mean plasma
concentration from about 230 to about 630 pg/ml at about 168 hours
after initiation of the dosing interval (for a seven day dosing
interval). In embodiments where a transdermal delivery system is
used, a mean relative release rate of from about 38 ug/hr to about
64 ug/hr is maintained from the initiation of the dosing interval
until about 72 hours after the initiation of the dosing interval;
and a mean relative release rate of about 4 ug/hr to about 7 ug/hr
is maintained from about 72 hours after the initiation of the
dosing interval until the end of the dosing interval (e.g., about
168 hours after the initiation of a seven-day dosing interval).
In a further preferred embodiment of the invention, buprenorphine
is administered to human patients in a manner such that the
following mean plasma concentrations are achieved over a 72 hour
dosing interval: a mean plasma concentration from about 5 to about
113 pg/ml at about 6 hours after initiation of the dosing interval;
a mean plasma concentration from about 55 to about 296 pg/ml at
about 12 hours after initiation of the dosing interval; a mean
plasma concentration from about 118 to about 644 pg/ml at about 24
hours after initiation of the dosing interval; a mean plasma
concentration from about 203 to about 753 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 247 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 317 to about 984 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 339 to about 1052 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, the
buprenorphine is administered in a manner such that the mean plasma
concentrations are maintained from about 306 to about 1052 pg/ml
over at least the next 48 hours. Preferably, the buprenorphine is
administered in a manner such that the mean plasma concentrations
are maintained as follows: a mean plasma concentration from about
369 to about 1052 pg/ml at about 96 hours after initiation of the
dosing interval; a mean plasma concentration from about 374 to
about 1052 pg/ml at about 120 hours after initiation of the dosing
interval; a mean plasma concentration from about 346 to about 970
pg/ml at about 144 hours after initiation of the dosing interval; a
mean plasma concentration from about 306 to about 841 pg/ml at
about 168 hours after initiation of the dosing interval (for a
seven day dosing interval). In embodiments where a transdermal
delivery system is used, a mean relative release rate of from about
51 ug/hr to about 86 ug/hr is maintained from the initiation of the
dosing interval until about 72 hours after the initiation of the,
e.g., dosing interval; and a mean relative release rate of about 5
ug/hr to about 9 ug/hr is maintained from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval, e.g., about 168 hours after the initiation of a seven-day
dosing interval (e.g., about 168 hours after the initiation of a
seven-day dosing interval).
In further embodiments of the invention, the method comprises the
administration of buprenorphine transdermally to human patients
according to very different relative release rates for the first 3
day portion of the dosing interval (indicative of substantially
first order release), and the additional at least 2 day long
portion of the dosing interval (substantially zero order release)
such that mean relative release rates are achieved over the dosing
interval as follows: a mean relative release rate of from about 3
ug/hr to about 86 ug/hr from the initiation of the dosing interval
until about 72 hours after the initiation of the dosing interval;
and a mean relative release rate of about 0.3 ug/hr to about 9
ug/hr from about 72 hours after the initiation of the dosing
interval until the end of the dosing interval (e.g., about 168
hours after the initiation of a seven-day dosing interval).
In one preferred embodiment, the mean relative release rates
achieved over the dosing interval are as follows: a mean relative
release rate of from about 3 ug/hr to about 5 ug/hr from the
initiation of the dosing interval until about 72 hours after the
initiation of the dosing interval; and a mean relative release rate
of about 0.3 ug/hr to about 0.6 ug/hr from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval (e.g., about 168 hours after initiation of a seven-day
dosing interval).
In another preferred embodiment, the mean relative release rates
achieved over the dosing interval are as follows: a mean relative
release rate of from about 6 ug/hr to about 11 ug/hr from the
initiation of the dosing interval until about 72 hours after the
initiation of dosing interval; and a mean relative release rate of
about 0.7 ug/hr to about 1 ug/hr from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval (e.g., about 168 hours after initiation of a seven-day
dosing interval).
In another preferred embodiment, the mean relative release rates
achieved over the dosing interval are as follows: a mean relative
release rate of from about 13 ug/hr to about 21 ug/hr from the
initiation of the dosing interval until about 72 hours after the
initiation of the dosing interval; and a mean relative release rate
of about 1 ug/hr to about 2 ug/hr from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval (e.g., about 168 hours after initiation of a seven-day
dosing interval).
In yet another preferred embodiment, the mean relative release
rates achieved over the dosing interval are as follows: a mean
relative release rate of from about 26 ug/hr to about 43 ug/hr from
the initiation of the dosing interval until about 72 hours after
the initiation of the dosing interval; and a mean relative release
rate of about 3 ug/hr to about 4 ug/hr from about 72 hours after
the initiation of the dosing interval until the end of the dosing
interval (e.g., about 168 hours after the initiation of a seven-day
dosing interval).
In yet a further preferred embodiment, the mean relative release
rates achieved over the dosing interval are as follows: a mean
relative release rate of from about 39 ug/hr to about 64 ug/hr from
the initiation of the dosing interval until about 72 hours after
the initiation of the dosing interval; and a mean relative release
rate of about 4 ug/hr to about 7 ug/hr from about 72 hours after
the initiation of the dosing interval until the end of the dosing
interval (e.g., about 168 hours after the initiation of a seven-day
dosing interval).
In yet a further preferred embodiment, the mean relative release
rates achieved over the dosing interval are as follows: a mean
relative release rate of from about 51 ug/hr to about 86 ug/hr from
the initiation of the dosing interval until about 72 hours after
the initiation of the dosing interval; and a mean relative release
rate of about 5 ug/hr to about 9 ug/hr from about 72 hours after
the initiation of the dosing interval until the end of the dosing
interval, e.g., about 168 hours after the initiation of the dosing
interval.
The method of the present invention may be accomplished by any mode
of administration useful for buprenorphine known to those skilled
in the art. However, certain modes of administration are more
practical than others. Preferably, the mode of administration is
via continuous infusion, through the oral mucosa, or most
preferably, transdermally.
In embodiments of the invention where the plasma concentrations
described herein are accomplished intravenous infusion, the pattern
of plasma concentrations seen through time in this invention can be
achieved by using the injectable, parenteral form of, e.g.,
buprenorphine hydrochloride suitably diluted in an intravenous
infusion solution. The infusion rate would be controlled by a
programmable infusion pump, to provide the desired plasma
profile.
In preferred embodiments of the invention, the mode of
administration of the buprenorphine is transdermal. Transdermal
delivery of active agents is measured in terms of "relative release
rate" or "flux", i.e., the rate of penetration of the active agent
through the skin of an individual. Skin flux may be generally
determined from the following equation: dM/dt=J=P*C where J is the
skin flux, P is the permeability coefficient and C is the
concentration gradient across the membrane, assumed to be the same
as the donor concentration. M represents the cumulative amount of
drug entering the blood stream. The variables dM and dt represent
the change in cumulative amount of drug entering the blood stream
and change in time, respectively.
It is well understood in the art of transdermal delivery systems
that in order to maintain a desired flux rate for a desired dosing
period, it is necessary to include an overage of active agent in
the transdermal delivery system in an amount that is substantially
greater than the amount to be delivered to the patient over the
desired time period. For example, to maintain the desired flux rate
for a three day time period, it is considered necessary to include
much greater than 100% of a three day dose of an active agent in a
transdermal delivery system. This overage is necessary for creating
a concentration gradient by means of which the active agent
migrates through the layers of the transdermal delivery system to
the desired site on a patient's skin. The remainder of the active
agent remains in the transdermal delivery system. It is only the
portion of active agent that exits the transdermal delivery system
that becomes available for absorption into the skin. The total
amount of active agent absorbed into the patient's blood stream is
less than the total amount available. The amount of overage to be
included in a transdermal delivery system is dependent on these and
other factors known to the skilled artisan.
.[.Surprisingly, it.]. .Iadd.It .Iaddend.has been found that it is
possible to treat pain according to the present invention by
providing a transdermal delivery system containing a sufficient
amount of opioid, e.g..Iadd., .Iaddend.buprenorphine, to provide a
desired relative release rate for up to 3 days, and after single
administration (application) of the transdermal dosage form,
leaving the dosage form on the skin for approximately a 5 to 8 day
time period, thereby resulting in the flux being maintained over
the prolonged period and effective blood plasma levels and pain
management being maintained over the prolonged period. Preferably,
the desired flux is maintained at least about 5, preferably at
least 8 days after application of the transdermal delivery system.
If the transdermal delivery system is removed 3 days after its
administration, no analgesia is present a short time after removal.
.[.Surprisingly however.]. .Iadd.However.Iaddend., if the same
transdermal delivery system is maintained in contact with the skin
for an about 5 to about 8 day period, analgesia is maintained over
the prolonged period of contact, but the patient continues to
experience analgesia. In other words, inclusion of the
aforementioned overage of buprenorphine provides analgesia for at
least about twice the expected 3 day dosing interval.
Any type of transdermal delivery system may be used in accordance
with the methods of the present invention so long as the desired
pharmacokinetic and pharmacodynamic response(s) are attained over
at least 3 days, e.g., from about 5 to about 8 days. Preferable
transdermal delivery systems include e.g., transdermal patches,
transdermal plasters, transdermal discs, iontophoretic transdermal
devices and the like.
Transdermal dosage forms used in accordance with the invention
preferably include a backing layer made of pharmaceutically
acceptable material which is impermeable to the buprenorphine. The
backing layer preferably serves as a protective cover for the
active agent, e.g. buprenorphine and may also provide a support
function. Examples of materials suitable for making the backing
layer are films of high and low density polyethylene,
polypropylene, polyvinylchloride, polyurethane, polyesters such as
poly(ethylene phthalate), metal foils, metal foil laminates of such
suitable polymer films, textile fabrics, if the components of the
reservoir cannot penetrate the fabric due to their physical
properties and the like. Preferably, the materials used for the
backing layer are laminates of such polymer films with a metal foil
such as aluminum foil. The backing layer can be any appropriate
thickness which will provide the desired protective and support
functions. A suitable thickness will be from about 10 to about 200
microns. Desirable materials and thickness will be apparent to the
skilled artisan.
In certain preferred embodiments, the transdermal dosage forms used
in accordance with the invention contain a polymer matrix layer.
Generally, the polymers used to form the biologically acceptable
polymer matrix are those capable of forming thin walls or coatings
through which pharmaceuticals can pass at a controlled rate. A
non-limiting list of exemplary materials for inclusion in the
polymer matrix includes polyethylene, polypropylene,
ethylene/propylene copolymers, ethylene/ethylacrylate copolymers,
ethylenevinyl acetate copolymers, silicones, rubber, rubber-like
synthetic homo-, co- or block polymers, polyacrylic esters and the
copolymers thereof, polyurethanes, polyisobutylene, chlorinated
polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate
copolymer, polymethacrylate polymer (hydrogel), polyvinylidene
chloride, poly(ethylene terephthalate), ethylene-vinyl alcohol
copolymer, ethylene-vinyloxyethanol copolymer, silicones including
silicone copolymers such as polysiloxane-polymethacrylate
copolymers, cellulose polymers (e.g., ethyl cellulose, and
cellulose esters), polycarbonates, polytetrafluoroethylene and
mixtures thereof
Preferred materials for inclusion in the polymer matrix layer are
silicone elastomers of the general polydimethylsiloxane structures,
(e.g., silicone polymers). Preferred silicone polymers cross-link
and are pharmaceutically acceptable. Other preferred materials for
inclusion in the polymer matrix layer include: silicone polymers
that are cross-linkable copolymers having dimethyl and/or
dimethylvinyl siloxane units which can be crosslinked using a
suitable peroxide catalyst. Also preferred are those polymers
consisting of block copolymers based on styrene and 1,3-dienes
(particularly linear styrene-isoprene-block copolymers of
styrene-butadiene-block copolymers), polyisobutylenes, polymers
based on acrylate and/or methacrylate.
The polymer matrix layer may optionally include a pharmaceutically
acceptable crosslinking agent. Suitable crosslinking agents
include, e.g., tetrapropoxy silane.
Preferred transdermal delivery systems used in accordance with the
methods of the present invention include an adhesive layer to affix
the dosage form to the skin of the patient for a desired period of
administration, e.g., about 5 to about 8 days. If the adhesive
layer of the dosage form fails to provide adhesion for the desired
period of time, it is possible to maintain contact between the
dosage form with the skin by, for instance, affixing the dosage
form to the skin of the patient with an adhesive tape, e.g.,
surgical tape. It is not critical for purposes of the present
invention whether adhesion of the dosage form to the skin of the
patient is achieved solely by the adhesive layer of the dosage form
or in connection with a peripheral adhesive source, such as
surgical tape, provided that the dosage form is adhered to the
patient's skin for the requisite administration period.
The adhesive layer preferably includes using any adhesive known in
the art that is pharmaceutically compatible with the dosage form
and preferably hypoallergenic, such as polyacrylic adhesive
polymers, acrylate copolymers (e.g., polyacrylate) and
polyisobutylene adhesive polymers. In other preferred embodiments
of the invention, the adhesive is a pressure-sensitive contact
adhesive, which is preferably hypoallergenic.
The transdermal dosage forms which can be used in accordance with
the present invention may optionally include permeation enhancing
agent. Permeation enhancing agents are compounds which promote
penetration and/or absorption of the buprenorphine into the blood
stream of the patient. A non-limiting list of permeation enhancing
agents includes polyethylene glycols, surfactants, and the
like.
Alternatively, permeation of buprenorphine may be enhanced by
occlusion of the dosage form after application to the desired site
on the patient with, e.g. an occlusive bandage. Permeation may also
be enhanced by removing hair from the application site by, e.g.
clipping, shaving or use of a depilatory agent. Another permeation
enhancer is heat. It is thought that heat enhancement can be
induced by, among other things, using a radiating heat form, such
as an infrared lamp, onto the application site after application of
the transdermal dosage form. Other means of enhancing permeation of
buprenorphine such as the use of iontophoretic means are also
contemplated to be within the scope of the present invention.
A preferred transdermal dosage form which may be used in accordance
with the present invention includes a non-permeable backing layer
made, for example, of polyester; an adhesive layer made, for
example of a polyacrylate; and a matrix containing the
buprenorphine and other desirable pharmaceutical aids such as
softeners, permeability enhancers, viscosity agents and the
like.
The active agent may be included in the device in a drug reservoir,
drug matrix or drug/adhesive layer. Preferably, the active agent is
buprenorphine or a pharmaceutically acceptable salt thereof.
Certain preferred transdermal delivery systems also include a
softening agent. Suitable softening agents include higher alcohols
such as dodecanol, undecanol, octanol, esters of carboxylic acids,
wherein the alcohol component may also be a polyethoxylated
alcohol, diesters of dicarboxylic acids, such as
di-n-butyladiapate, and triglycerides particularly medium-chain
triglycerides of the caprylic/capric acids or coconut oil, have
proved to be particularly suitable. Further examples of suitable
softeners are multivalent alcohols, for example, levulinic acid,
cocprylic acids glycerol and 1,2-propanediol which can also be
etherified by polyethylene glycols.
A buprenorphine solvent may also be included in the transdermal
delivery systems of the present invention. Preferably, the solvents
dissolve the buprenorphine to a sufficient extent thereby avoiding
complete salt formation. A non-limiting list of suitable solvents
include those with at least one acidic group. Particularly suitable
are monoesters of dicarboxylic acids such as monomethylglutarate
and monomethyladipate.
Other pharmaceutically acceptable compounds which may be included
in the reservoir or matrix include: solvents, for example alcohols
such as isopropanol; permeation enhancing agents such as those
described above; and viscosity agents, such as cellulose
derivatives, natural or synthetic gums, such as guar gum, and the
like.
In preferred embodiments, the transdermal dosage form includes a
removable protective layer. The removable protective layer is
removed prior to application, and consists of the materials used
for the production of the backing layer described above provided
that they are rendered removable, for example, by a silicone
treatment. Other removable protective layers, for example, are
polyletra-fluoroethylene, treated paper, allophane, polyvinyl
chloride, and the like. Generally, the removable protective layer
is in contact with the adhesive layer and provides a convenient
means of maintaining the integrity of the adhesive layer until the
desired time of application.
The composition of the transdermal dosage forms used in accordance
with the invention and the type of device used are not considered
critical to the method of the invention, provided that the device
delivers the active agent, e.g. buprenorphine, for the desired time
period and at the desired flux rate and/or the desired delivery
rate of the transdermal dosage form.
Certain preferred transdermal dosage forms for use in accordance
with the present invention are described in U.S. Pat. No. 5,240,711
(Hille, et. al.; assigned to LTS Lohmann Therapie-Systeme GmbH
& Co.), hereby incorporated by reference. Such buprenorphine
transdermal delivery systems may be a laminated composite having an
impermeable backing layer containing buprenorphine, and optionally,
a permeation enhancer combined with a pressure-sensitive adhesive.
A preferred transdermal dosage form in accordance with the '711
patent includes: (i) a polyester backing layer which is impermeable
to buprenorphine; (ii) a polyacrylate adhesive layer; (iii) a
separating polyester layer; and (iv) a matrix containing
buprenorphine, a solvent for the buprenorphine, a softener and a
polyacrylate adhesive. The buprenorphine solvent may or may not be
present in the final formulation. The transdermal delivery device
described therein includes a backing layer which is impermeable to
the active substance, a pressure-sensitive adhesive reservoir layer
and optionally, a removable protective layer. Preferably, the
reservoir layer includes about 10 to about 98%-wt polymeric
material, about 0.1 to about 40%-wt softener, about 0.1 to about
30%-wt buprenorphine. A solvent for the buprenorphine base or
pharmaceutically acceptable salt thereof may be included as about
0.1 to about 30%-wt.
In a preferred embodiment, the transdermal delivery system is
prepared in accordance with Example 1 appended hereto. In this
example, the transdermal delivery system was prepared in accordance
with the disclosure of International Patent Application No. WO
96/19975 (Hille, et. al.; assigned to LTS Lohmann Therapie-Systeme
GMBH), hereby incorporated by reference. In this device, the
buprenorphine transdermal delivery device contains
resorption-promoting auxiliary substances. The resorption-promoting
auxiliary substance forms an undercooled mass. The delivery system
contains 10% buprenorphine base, 10-15% acid (such as levulinic
acid), about 10% softener (such as oleyoleate); 55-70%
polyacrylate; and 0-10% polyvinylpyrollidone (PVP).
In embodiments of the present invention wherein the buprenorphine
plasma concentrations described herein are achieved via the use of
a transdermal delivery device prepared in accordance with WO
96/19975, it is contemplated for example that the nominal delivery
rate of buprenorphine from such patches will be, e.g., from about
12.5 to about 100 ug/hr. In certain preferred embodiments, in order
to achieve a nominal delivery rate of 12.5 ug/hr, the total of
buprenorphine included in the transdermal patch is about 5 mg, the
active surface area is about 6.25 cm.sup.2 and the patch size may
be, e.g., about 19.4 cm.sup.2. In certain preferred embodiments, in
order to achieve a nominal delivery rate of 25 ug/hr, the total of
buprenorphine included in the transdermal patch is about 10 mg, the
active surface area is about 12.5 cm.sup.2 and the patch size may
be, e.g., about 30.6 cm.sup.2. In certain preferred embodiments, in
order to achieve a nominal delivery rate of 50 ug/hr, the total of
buprenorphine included in the transdermal patch is about 20 mg, the
active surface area is about 25 cm.sup.2 and the patch size may be,
e.g., about 51.8 cm.sup.2. In certain preferred embodiments, in
order to achieve a nominal delivery rate of 75 ug/hr, the total of
buprenorphine included in the transdermal patch is about 30 mg, the
active surface area is about 37.5 cm.sup.2 and the patch size may
be, e.g., about 69.8 cm.sup.2. In certain preferred embodiments, in
order to achieve a nominal delivery rate of 100 ug/hr, the total of
buprenorphine included in the transdermal patch is about 40 mg, the
active surface area is about 50 cm.sup.2 and the patch size may be,
e.g., about 87.8 cm.sup.2.
.[.In accordance with a method of the invention, the.]. .Iadd.The
.Iaddend.above-described transdermal delivery system has been
designed to be adhered to the patient for only three days and is
expected to release analgetically effective doses of buprenorphine
for only about 3 days. Instead, in accordance with the present
invention, the transdermal delivery device is maintained in contact
with the skin of the patient for a much longer time period, e.g.,
from about 5 to about 8 days, without any change in the formulation
of the transdermal device itself. It has .[.surprisingly.]. been
found that analgesia is maintained for this extended period of time
(the time beyond the useful life designed for the transdermal
formulation).
In other embodiments, the buprenorphine transdermal delivery system
may be a plaster such as that described in U.S. Pat. No. 5,225,199
to Hidaka et al., hereby incorporated by reference. Such plasters
include a film layer including a polyester film of about 0.5 to
about 4.9 .mu.m thickness, about 8 to about 85 g/mm strength,
respectively in the two directions intersecting substantially at
right angles, about 30 to about 150% elongation, in the two
directions intersecting substantially at right angles and an
elongation ratio of A to B of about 1.0 to about 5.0, wherein A and
B represent data in two directions intersecting at right angles,
and A is greater than B and wherein said polyester film includes
about 0.01 to about 1.0% by weight, based on the total weight of
the polyester film, of solid fine particles in which the average
particle size is about 0.001 to about 3.0 .mu.m and an adhesive
layer which is composed of an adhesive containing transdermally
absorbable drugs; wherein the adhesive layer is laminated on said
film layer over the surface in about 2 to about 60 .mu.m thickness.
The average particle size is substantially not more than 1.5 times
the thickness of the polyester film.
The transdermal delivery system used in the present invention may
also be prepared in accordance with U.S. Pat. No. 5,069,909 (Sharma
et al.), hereby incorporated by reference. This patent describes a
laminated composite for administering buprenorphine transdermally
to treat pain. The composite includes an impermeable backing layer
providing a protective covering for the composite which may be made
from an elastomeric polymer such as polyurethane, polyether amide,
or copolyester and may be about 15-250 microns in thickness. The
composite further includes a reservoir lamina composed of
buprenorphine (base or HCl) in n amount of 1-12% by weight and a
pressure-sensitive adhesive, e.g., polyisobutylene, or a silicone
adhesive such as silastic, or an acrylate adhesive, and 2-35%
permeation enhancer (comprising propylene glycol monolaurate in
combination with capric acid or oleic acid). The amounts of
buprenorphine and permeation enhancer are sufficient to cause the
buprenorphine to pass through the skin at a rate of about 1 to 100
.mu.g/cm.sup.2/hr.
The transdermal delivery system used in the present invention may
also be prepared in accordance with U.S. Pat. No. 4,806,341 (Chien
et al.), hereby incorporated by reference. This patent describes a
transdermal morphinan narcotic analgesic or antagonist (including
buprenorphine) pharmaceutical polymer matrix dosage unit having a
backing layer which is substantially impervious to the
buprenorphine, and a polymer matrix disc layer which is adhered to
the backing layer and which has microdispersed therein effective
dosage amounts of the buprenorphine. The polymer matrix may be a
silicon polymer or copolymer, such as methyl silicone polymer or
copolymer, or methylvinyl silicone polymer or copolymer. The
polymer matrix layer preferably has dispersed therein a skin
permeation enhancing agent such as isopropyl myristate, azone, or a
combination of ethyl caprylate and capryl alcohol.
The transdermal delivery system used in the present invention may
also be that described in U.S. Pat. No. 5,026,556 (Drust et al.),
hereby incorporated by reference. Therein, compositions for the
transdermal delivery of buprenorphine comprise buprenorphine in a
carrier of a polar solvent material selected from the group
consisting of C.sub.3-C.sub.4 diols, C.sub.3-C.sub.6 triols, and
mixtures thereof, and a polar lipid material selected from the
group consisting of fatty alcohol esters, fatty acid esters, and
mixtures thereof; wherein the polar solvent material and the lipid
material are present in a weight ratio of solvent material:lipid
material of from 60:40 to about 99:1.
The transdermal delivery system used in the present invention may
also be that described in U.S. Pat. No. 4,588,580 (Gale, et. al.),
hereby incorporated by reference. That system comprises a reservoir
for the drug having a skin proximal, material releasing surface
area in the range of about 5-100 cm.sup.2 and containing between
0.1 and 50% by weight of a skin permeable form of the
buprenorphine. The reservoir contains an aqueous gel comprising up
to about 47-95% ethanol, 1-10% gelling agent, 0.1-10%
buprenorphine, and release rate controlling means disposed in the
flow path of the drug to the skin which limits the flux of the
buprenorphine from the system through the skin. The release rate
controlling means is more permeable to the buprenorphine than to
the ethanol, and may be for example low density polyethylene
(LDPE), ehtylene-vinyl acetate (EVA) copolymers, heat sealable
polyesters, and elastomeric polyester block copolymers, such as
HYTREL.RTM. from DuPont. This system is said to be capable of
providing an administration rate of about 10-300 .mu.g/hr. It is
contemplated that each of the transdermal delivery systems
described herein (other than the system exemplified in Example 1
appended hereto) would require minor manipulation in order to
achieve the methods of the invention. Such modifications are within
the abilities of one skilled in the art of formulating such
transdermal delivery systems.
The present invention may also be accomplished via the use of a
sustained oral mucosal delivery system. Such a system is described
by McQuinn, R. L. et al., "Sustained Oral Mucosal Delivery in Human
Volunteers J. Controlled Release; (34) 1995 (243-250). Therein,
oral mucosal patches were prepared by homogeneously mixing
buprenorphine free base (8%), Carbopol 934 (52%), polyisobutylene
(35%) and polyisoprene (5%, w/w) via a two-roll mill and then
compressing the mixture to the appropriate thickness. A membrane
backing (ethylcellulose) was applied to one side of the compressed
material and then circular disks (0.5 cm.sup.2) were punched from
the material. The backing was included in order to retard drug
release from one side of the disk and to prohibit adhesion to
opposing side tissues. Each soft, flexible disk was approximately
0.6 mm thick and contained 2.9 mg buprenorphine. These patches were
worn by the subjects for 12 hours. Gum and lip application was
tested, although adhesion at the gum site was considered superior.
After the initial appearance of serum buprenorphine (.gtoreq.25
pg/ml), levels generally increased relatively rapidly and persisted
until the patch was removed. After the patch was removed,
buprenorphine levels fell promptly and were at a relatively low
(but measureable) level by 24 hours post-dose. It was estimated
that 0.42.+-.0.18 mg were delivered via the gum treatment. From
this discussion, it is apparent that an oral mucosal patch can be
prepared which will provide plasma concentrations considered
desirable according to the present invention.
A significantly higher incidence in side effects such as nausea,
vomiting or drowsiness would normally be expected when high blood
levels of opioid analgesics are administered. The present
invention, by maintaining a lower blood level of drug over the 7
day dosing period while maintaining effective pain management, has
a lower incidence of side effects. In comparison, a much higher
plasma concentration is seen in patients over the same period of
time when a new transdermal delivery device of the same strength is
put on every three days, and therefore increased side effects are
expected with each new 3 day transdermal application.
.[.In general, upon administration of an opioid analgesic, there is
a lag time or "hysteresis", between the pharmacodynamic effects and
the time course of opioid plasma concentration levels. Generally,
peak plasma level concentrations are often attained prior to
exhibition of the maximum pharmacotherapeutic or side effect
response. It has been surprisingly discovered that the method
according to the present invention provides a "reverse hysteresis",
i.e. the rise in plasma concentrations follow the appearance and
rise of certain of the pharmacodynamic events and side
effects..].
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The following examples illustrate various aspects of the present
invention. They are not to be construed to limit the claims in any
manner whatsoever.
EXAMPLE 1
A seven day pharmacokinetic/pharmacodynamic study was conducted on
24 healthy human patients. The subjects were comprised of
approximately an equal number of male and female subjects. In this
study, the buprenorphine was administered via a transdermal patch
which is described in WO 96/19975.
The transdermal patch is prepared in accordance with the disclosure
of WO 96/19975 for Example 1 therein as follows: 1.139 g of a 47.83
w/% polyacrylate solution with a selfnetting acrylate copolymers
containing 2-ethylhexylacrylates, vinyl acetates, acrylic acid
(dissolving
agent:ethylacetate:heptan:isopropanol:toluol:acetylacetonate in the
ratio of 37:26:26:4:1), 100 g laevulinic acid, 150 g oleyloleate,
100 g polyvinylpyrollidone, 150 g ethanol, 200 g ethyl acetate and
100 g buprenorphine base are homogenized. The mixture is stirred
for about 2 hours and then examined visually to determine if all
solid substances have been dissolved. One has to control the
evaporation loss by method of weighing back and makes up for the
solvent with the help of ethylacetate, if necessary. Thereafter,
the mixture is put onto a 420 mm wide, transparent polyester foil,
since the surface weight of the dried layer of paste is 80 g per
m.sup.2. The polyester foil which can be dissolved again with
treatment of silicone serves as a protective layer. The solvent is
removed by drying with heated air which is led over a moist lane.
With this treatment of warmth not only do solvents evaporate but
the the laevulinic acid melts as well. Thereafter, the sealing film
is covered with a polyester foil 15 .mu.ab. A surface of about 16
cm.sup.2 is cut with the help of the appropriate cutting tool, and
the rims that have been left between the individual systems are
removed.
The formulation utilized for Example 1 is substantially the same as
that described in Example 3 of WO 96/19975, which is prepared in
accordance with Example 1 and is stated therein to include 10%
buprenorphine, 10% levulinic acid, 10% polyvinylpyrollidone, 10%
oleyloeate, and 60% polyacrylate.
In order to achieve the nominal delivery rate of 25 ug/hr expected
for the formulation of Example 1, the total of buprenorphine
included in the transdermal patch is about 10 mg, the active
surface area is about 12.5 cm.sup.2 and the patch size may be,
e.g., about 30.6 cm.sup.2.
The dosing regimen was one (1) patch containing 10 mg buprenorphine
base/patch reservoir applied to the subject's skin and maintained
in contact with the skin for a time period of seven (7) days.
The adhesive patch with the medication being tested was placed on
the right midaxillary line at the level of the 5th intercostal
space at approximately 0800 hr on day 1. For patch application, the
skin was washed with lukewarm soapy water, then rinsed with clear
water and left to air dry. The skin was not rubbed while it was
being washed. The application site was relatively hairless. Hair
was not clipped or shaven. The patches were removed at
approximately 0800 hr on day 8. Following patch removal, the patch
site was not washed or rubbed until the last blood collection for
that treatment period was over. Each patch was placed unfolded onto
its release liner and the patch/release liner unit was placed back
in the correct pouch, which was then sent to a bioanalytical
laboratory for residual buprenorphine assay.
Blood sampling (10 ml at each time point) started on day 1, and
continued thereafter at the following times: 1 hr (pre-dose) and at
regular intervals thereafter during the 7 day dosing interval.
Patch site skin observations of the patch sites were performed by
the investigator/staff rating the quality of the skin at the site
of the actual medication reservoir of the patch at 0 hr (prior to
patch placement) and 30 minutes after patch removal. The rating
scale was as follows: Erythema: 0=No visible redness; 1=Very slight
redness (just perceptible); 2=Slight but well-defined redness;
3=Moderately intense redness; 4=Severe erythema (dark red
discoloration of the skin). Edema: 0=No visible reactions; 1=Very
mild edema (just perceptible); 2=Mild edema (corners of the area
are well defined due to noticeable swelling); 3=Moderate edema (up
to 1 mm swelling in diameter); 4=Severe edema (more than 1 mm
swelling in diameter, protruding over the edges of the patch).
The following pharmacokinetic parameters were estimated:
AUC.sub.(O-last) (pg.hr/ml)--the area under the curve from time
zero to the time of last non-zero plasma buprenorphine
concentration, calculated by the linear trapezoidal method;
C.sub.max (pg/ml)--maximum observed plasma buprenorphine
concentration over the dosing interval; if C.sub.max occurs at more
than one time point, T.sub.max is defined as the time point for the
first C.sub.max; residual=buprenorphine remaining in used patches
(mg/patch).
A summary of the plasma buprenorphine concentrations (provided in
picograms per milliliter, or pg/ml), is set forth in Table 1
below:
TABLE-US-00001 TABLE 1 HOURS.sup.1 MEAN.sup.2 STD. DEV..sup.3 CV
%.sup.4 6 1.76 6.20 352.77 12 18.47 26.00 140.78 18 39.45 36.16
91.67 24 58.94 44.66 75.76 30 67.69 48.78 72.06 36 82.44 53.02
64.32 42 107.61 65.43 60.81 48 104.69 60.69 57.97 54 105.81 66.68
63.02 60 112.93 63.02 55.81 66 129.25 64.37 49.80 72 130.55 64.16
49.14 78 122.83 54.97 44.75 84 129.03 51.50 39.92 90 139.50 68.26
48.93 96 146.70 62.76 42.78 102 130.19 57.68 44.31 108 135.49 67.72
49.98 114 150.24 71.69 47.72 120 136.22 63.62 46.70 126 130.25
57.77 44.35 132 124.78 52.82 42.34 138 138.55 58.34 42.11 144
115.23 48.30 41.92 150 116.30 49.04 42.16 156 120.07 50.88 42.38
162 117.66 52.71 44.80 168 102.00 49.92 48.94 .sup.1hours after
administration of dose (e.g., application of patch) .sup.2mean
blood plasma concentration for the 24 test subjects (pg/ml)
.sup.3standard deviation of mean blood plasma concentrations
.sup.4coefficient of variation (%)
The mean plasma concentrations are further depicted in FIG. 1
(concentration pg/ml vs. time (days)). It is apparent from the
pharmacokinetic results obtained with respect to Example 1 that the
mean blood plasma concentrations rose steadily and peaked at about
the 3-day time point during the dosing interval (e.g., about 72
hours after application of the patch), and thereafter
.[.surprisingly.]. remained relatively steady throughout the
remaining portion of the dosing interval (e.g., to about the 7-day
time point, 168 hours after initiation of the dosing interval).
Further, it is apparent from the buprenorphine plasma
concentrations that first order kinetics were present during the
first 72 hours of the dosing interval, and substantially zero order
kinetics were present thereafter.
A summary of the pharmacokinetic parameters obtained for Example 1
are set forth in Table 2 below:
TABLE-US-00002 TABLE 2 GEOMETRIC MEAN STD. DEV. MEAN CV % AUC
(0-168 hrs) 17740.68 7503.50 16263.88 42.30 Cmax (pg/ml) 184.80
68.84 171.78 37.25 Tmax (hrs) 110.50 26.48 23.96
The following pharmacodynamic parameters were assessed 5 minutes
prior to each blood collection by having each patient respond to
several questions by placing a vertical mark at the appropriate
spot on a 100 mm visual analog scale ("VAS") anchored on one end by
"not at all" and on the other end by "an awful lot". The first
question asked to the subjects was "Do you feel any effect of the
drug?" After the patient marked his/her response on the VAS to this
question, responses were obtained via the VAS as to whether the
subjects had experienced (i) nausea, (ii) dizziness, and (iii)
sleepiness. The results are set forth in Table 3. All
pharmacodynamic parameters were summarized and tabulated. Then a
mixed (linear or non-linear) effect was used to model the
pharmacokinetic and pharmacodynamic relationships. The results
concerning pharmacodynamic parameters (VAS) are set forth in FIG.
2.
TABLE-US-00003 TABLE 3 SUMMARY OF SEVERITY FOR THE MOST COMMONLY
REPORTED (>=10% OF SUBJECTS) ADVERSE EVENTS (RELATED TO
TREATMENT) (N = 24) MILD MODERATE SEVERE TOTAL N (%) N (%) N (%) N
(%) CONSTIPATION 3 12.5 0 0.0 0 0.0 3 12.5 DIZZINESS 8 33.3 0 0.0 0
0.0 8 33.3 HEADACHE 7 29.2 0 0.0 0 0.0 7 29.2 NAUSEA 6 25.0 0 0.0 0
0.0 6 25.0 RASH 20 83.3 0 0.0 0 0.0 20 83.3 SOMNOLENCE 11 45.8 0
0.0 0 0.0 11 45.8 VOMITING 2 8.3 1 4.2 0 0.0 3 12.5
As can be seen from the results set forth in Table 3, there was
only one incident of a moderate adverse event, and no incidents of
severe adverse events reported by the test subjects during the
application interval. Further, turning to FIG. 2, it can be seen
that the level of dizziness, nausea and sleepiness significantly
decreased after day 3 of the dosage interval. Other side effects
such as headache, vomiting and constipation were also low in
occurrence.
Table 4 provides a summary of the amount of drug which was measured
as remaining in the patches which were removed from the subjects
after 7 days.
TABLE-US-00004 TABLE 4 (mg) AMOUNT LEFT IN PATCH MEAN 8.59 SE 0.11
% RELEASED (ASSAY) MEAN 14.02 SE 1.08
COMPARATIVE EXAMPLES A-C
A three (3) treatment, randomized, crossover study was conducted in
normal volunteers. The treatments consisted of Comparative Example
A (a single application buprenorphine transdermal delivery system);
Comparative Example B (a single dose of buprenorphine administered
intravenously) and Comparative Example C (3 sequential
applications, every three days, of the buprenorphine transdermal
delivery system used in Comparative Example A). A 10-14 day washout
period intervened between the first dosing (application) day of
each treatment. For the buprenorphine transdermal delivery system,
the wash-out started when the third sequential patch was removed.
This study was not analytically blinded due to analytical chemistry
considerations and different sampling times.
The buprenorphine transdermal delivery system (patch) used in the
Comparative Examples A and C contained 20 mg buprenorphine base,
and is prepared in accordance with Example 1. It was contemplated
that the buprenorphine patch of Comparative Examples A and C would
provide approximately double the dose and approximately double the
relative release rate as compared to the buprenorphine patch of
Example 1. For Comparative Examples A and C, it was contemplated
that approximately 1.2 mg buprenorphine would be released from the
patch per day, which is equivalent to an intravenous dose of 0.3 mg
every 6 hours. The reference buprenorphine intravenous injection
(Comparative Example B) was 0.3 mg (Temgesic.RTM.) Injectable 0.3
mg/ml, [1 ml/vial]).
In Comparative Example A, the buprenorphine transdermal delivery
system (single dose) was adhered to a relatively hairless area of a
subject's right thorax at the level of the fifth intercostal space
in the midaxillary line at approximately 8 am on day 1 and removed
at approximately 8 am on day 4. For Comparative Example A
(buprenorphine transdermal delivery system single dose), blood
sampling was conducted as follows: Day 1: 0, (buprenorphine
transdermal delivery system adhered) 2, 3, 4, 6, 8, 10, 12, and 16
hr; Day 2: 0, 6, 12 hr; Day 3: 0, 12 hr; Day 4: 0 (prior to
removal), 0.25, 0.5, 0.75, 1, 2, 3, 6, 12 hr post-removal; Day 5:
0, 12 hr; Day 6: 0, 12 hr; Day 7: 0 hr.
With respect to Comparative Example B, buprenorphine intravenous
(IV) injection, 0.3 mg was infused over 2 minutes at approximately
8 am on day 1 through an in-dwelling cannula in the right
anticubital vein. The buprenorphine intravenous 0.3 mg blood
sampling was conducted as follows: Day 1: 0, 1, 2, 3, 5, 10, 15,
20, 25, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 10, 12, 24 hr;
arterial blood sampling (left radial artery) for the first 4 hours;
venous blood sampling from 2 hours post-dose to 24 hours post-dose.
Therefore arterial and venous blood sampling occurred
simultaneously 2, 3 and 4 hours post-dose.
With respect to Comparative Example C, the buprenorphine
transdermal delivery system (3 sequential applications), was
adhered to a relatively hairless area of a subject's right thorax
at the level of the fifth intercostal space in the midaxillary line
at approximately 8 am on day 1 and removed at approximately 8 am on
day 4. The second buprenorphine transdermal delivery system 50
.mu.g/hr was placed just adjacent to the first patch after the
first was removed on day 4 at approximately 8 am and removed on day
7 at approximately 8 am. The third buprenorphine transdermal
delivery system 50 .mu.g/hr was placed just adjacent to the second
patch but not in the same place as the first patch after the second
patch is removed on day 7 at approximately 8 am and removed on day
10 at approximately 8 am. Blood samples for Comparative Example C,
buprenorphine transdermal delivery system 3 sequential
applications, were obtained as follows: Day 1: 0, (buprenorphine
transdermal delivery system adhered), 2, 3, 4, 6, 8, 10, 12, and 16
hr; Day 2: 0, 6, 12 hr; Day 3: 0, 12 hr; Day 4: 0 (prior to
removal), and 2, 3, 4, 6, 8, 10, 12, 16 hrs (after second
buprenorphine transdermal delivery system adhered); Day 5: 0, 6, 12
hr; Day 6: 0, 12 hr; Day 7: 0 (prior to removal), and 2, 3, 4, 6,
8, 10, 12, 16 hrs (after third buprenorphine transdermal delivery
system adhered); Day 8: 0, 6, 12 hr; Day 9: 0, 12 hr; Day 10: 0
(prior to buprenorphine transdermal delivery system removal), and
0.25, 0.5, 0.75, 1, 2, 3, 6, 12 hr (post-removal); the wash-out
period started after patch removal on Day 10; Day 11: 0, 12 hr; Day
12: 0, 12 hr; and Day 13: 0.
The pharmacokinetic variables determined for Comparative Examples
A-C were as follows: AUC.sub.(O-last): pg-hr/ml--The area under the
curve, as calculated by the linear trapezoidal method, up to the
last observed value; AUC.sub.inf: pg-hr/ml--The area under the
curve, calculated using the linear trapezoidal method; C.sub.max:
pg/ml--Maximum measured plasma buprenorphine over the time span
specified; T.sub.max: hrs--Time of the maximum measured plasma
buprenorphine; when the maximum value occurs in more than one time
point, T.sub.max is defined as the first time point with this
value; T.sub.(1/2)elm: The plasma half life of buprenorphine
elimination, defined as ln2/K.sub.elm, where K.sub.elm is the
apparent first order elimination constant. The elimination rate
constant was obtained from the slope of the terminal portion of the
plasma-concentration time curve determined by regression analysis
techniques; T.sub.(1/2)abs: The absorption half life of transdermal
buprenorphine elimination, defined as ln2/K.sub.abs, where
K.sub.abs is the apparent first order absorption constant.
Absorption rate was calculated only for the transdermal
buprenorphine; Cl: ml/min or 1/hr--Total clearance characterizes
the clearing of the hypothetical plasma volume of drug per unit
time; V.sub.d: 1 or 1/kg--Hypothetical volumes in which the drug is
distributed in the body; and Absorption Rate: .mu.g/hr--The rate at
which buprenorphine enters the systemic circulation.
Plasma concentration data was analyzed using standard
noncompartmental and compartmental techniques to derive
pharmacokinetic parameters. In addition, various exploratory
methods including fitting the intravenous data to pharmacokinetic
models to determine which model best describes the data, and
deconvolution analysis to determine the absorption rate was
employed. Other parameters such as clearance, volumes of
distribution, absorption rate, amount absorbed and bioavailability
were determined by either standard noncompartmental or
compartmental analysis or exploratory methods.
The intravenous data was also analyzed utilizing compartmental
modeling techniques.
A summary of plasma buprenorphine concentrations for Comparative
Example A is provided in Table 5 below:
TABLE-US-00005 TABLE 5 Comparative Example A MEAN PLASMA HOUR CONC.
(pg/ml) STD. DEV CV % 2 2.04 5.87 287.10 3 7.96 16.28 204.47 4
14.84 18.63 125.51 6 23.49 25.81 109.85 8 42.34 37.91 89.52 10
72.03 71.36 99.07 12 85.96 68.69 79.90 16 133.89 103.43 77.25 24
175.58 120.17 68.44 30 169.15 108.65 64.23 36 200.16 134.45 67.17
48 251.10 156.66 62.39 60 250.11 125.01 49.98 72 286.50 131.58
45.92 78 168.73 61.26 36.30 84 114.68 52.72 45.97 96 90.75 39.12
43.11 108 56.82 25.66 45.17 120 44.85 23.80 53.06 132 30.40 21.87
71.95 144 29.14 20.27 69.58
A summary of plasma buprenorphine concentrations (pg/ml) for
Comparative Example C at each sampling time is set forth in Table 6
below:
TABLE-US-00006 TABLE 6 Comparative Example C MEAN PLASMA HOUR CONC.
(pg/ml) STD. DEV CV % 2 0.54 2.63 489.90 3 5.70 13.18 231.23 4
10.33 14.64 141.71 6 28.84 31.19 108.13 8 54.62 65.83 120.52 10
78.92 81.23 102.93 12 95.14 75.70 79.57 16 162.26 114.80 70.75 24
218.57 153.58 70.27 30 206.10 141.70 68.75 36 205.08 110.76 54.01
48 265.04 123.66 46.66 60 256.18 133.48 52.11 72 306.02 152.77
49.92 74 278.22 135.14 48.57 75 245.91 112.66 45.82 76 237.01 83.41
35.19 78 213.54 94.42 44.22 80 215.45 103.75 48.15 82 216.00 107.68
49.85 84 210.52 107.67 51.14 88 219.77 110.46 50.26 96 269.91
134.61 49.87 102 205.54 102.03 49.64 108 225.11 87.97 39.08 120
310.27 153.57 49.50 132 300.34 157.05 52.29 144 305.99 159.75 52.21
146 301.39 141.37 46.91 147 289.96 132.91 45.84 148 287.68 151.93
52.81 150 260.04 130.19 50.07 152 236.61 119.77 50.62 154 284.15
158.84 55.90 156 271.83 145.11 53.38 160 303.46 182.37 60.10 168
340.71 209.87 61.60 174 302.22 179.74 59.47 180 322.67 183.63 56.91
192 395.95 220.27 55.63 204 344.83 201.90 58.55 216 415.33 229.92
55.36 216.25 388.64 186.67 48.03 216.50 390.97 208.34 53.29 216.75
392.63 188.89 48.11 217 399.51 197.86 49.53 218 312.65 173.12 55.37
219 295.17 148.13 50.18 222 201.37 85.54 42.48 228 173.89 75.96
43.68 240 119.13 48.99 41.13 252 84.21 49.61 58.91 264 72.33 37.86
52.42 276 50.18 25.83 51.47 288 43.06 26.61 61.79
A summary of mean plasma buprenorphine concentrations (pg/ml) at
each sampling time for Comparative Example B (buprenorphine
intravenous 0.3 mg single dose) is provided in Table 7 below:
TABLE-US-00007 TABLE 7 Comparative Example B MEAN PLASMA HOUR CONC.
(pg/ml) STD. DEV CV % 0.02 14812.04 11319.10 76.42 0.03 31052.04
16156.81 52.03 0.05 24547.00 16461.86 67.06 0.08 6418.80 1976.26
30.79 0.17 3360.76 2457.58 73.13 0.25 1747.96 465.81 26.65 0.33
1210.08 219.28 18.12 0.42 1050.00 242.10 23.06 0.50 931.52 207.25
22.25 0.75 692.92 175.29 25.30 1.00 584.40 148.93 25.48 1.50 457.44
131.44 28.73 2.00 335.12 79.36 23.68 3.00 238.80 63.03 26.39 4.00
170.87 49.84 29.17
A summary of the mean maximum concentration (Cmax) for Comparative
Examples A-C measured in pg/ml is set forth in Table 8 below:
TABLE-US-00008 TABLE 8 C.sub.max Values for Comparative Examples
A-C Comparative Comparative Cmax (pg/ml) - Comparative Example A
Example C Example B Mean 318.20 477.33 38635.56 Std. Dev. 151.24
216.92 14499.55 Geometric 291.13 435.50 35251.92 Mean CV % 47.53
45.44 37.53
A summary of mean Tmax values obtained for Comparative Examples A-C
is set forth in Table 9 below:
TABLE-US-00009 TABLE 9 Tmax Prior to Patch Removal (hrs) Tmax (hrs)
Comparative Comparative Comparative Example A Example C Example B
Mean 61.92 168.39 0.04 (out of 72 hrs total) (out of 260 hrs total)
Std. Dev. 13.27 42.68 0.01 CV % 21.43 25.35 26.26
Table 10 provides a summary of the area under the curve (AUC) (0-t)
for Comparative Examples A-C:
TABLE-US-00010 TABLE 10 Comparative Comparative Comparative Example
A Example C Example B Mean 18,829.13 65,217.25 3,699.91 Std. Dev.
9,136.12 31,124.37 526.64 Geometric 16,760.39 57,794.90 3,666.65
Mean CV % 48.52 47.72 14.23
The pharmacodynamics were determined via VAS "drug effect"
observations. The subject was asked "do you feel any effect of the
drug?". The subject then rated the item by placing a vertical mark
along a 100 mm visual analog scale (VAS) anchored on one end by
"not at all" and on the other end by "an awful lot". The "drug
effect" question was assessed just prior to each blood sample
during the study. The following adverse effects were elicited just
prior to blood sampling using the VAS: nausea; dizziness; and
sleepiness. Asymmetric blood sampling was used in this study due to
the number of sampling times.
The pharmacokinetic results (concentration in pg/ml vs. hours) for
Comparative Examples A-C are depicted in FIGS. 3-5, respectively.
FIG. 4 depicts the plasma concentration obtained divided by 100.
The pharmacodynamic results (PD variables (VAS)) for Comparative
Examples .[.A-C.]. .Iadd.C, B, A .Iaddend.are depicted in FIGS.
.[.6-8.]. .Iadd.6, 7, 8.Iaddend., respectively.
COMPARATIVE EXAMPLES D-F
The bioequivalence between a buprenorphine transdermal delivery
system in accordance with Example 1 is compared to identically
prepared patches having different sizes and therefore different
amounts of buprenorphine contained therein.
Comparative Example D utilized a patch identical in size and
containing the same amount of buprenorphine as Example 1. The total
of buprenorphine included in the transdermal patch is 10 mg, the
active surface area is 12.5 cm.sup.2 and the patch size is 30.6
cm.sup.2. In Comparative Example E, two patches are utilized, each
patch including total of buprenorphine of about 5 mg, and having an
active surface area of 6.25 cm.sup.2 and a patch size of 19.4
cm.sup.2. Comparative Example F allows for the determination of the
dose proportionality of a buprenorphine transdermal delivery system
(patch) having twice the dose as compared to Example 1. In
Comparative Example F, the total of buprenorphine included in the
transdermal patch is 20 mg, the active surface area is 25 cm.sup.2
and the patch size is 51.8 cm.sup.2. The study was conducted via a
3-way cross-over design. The patches were left in place for 72
hours and then removed.
Table 11 provides a summary of mean plasma buprenorphine
concentrations (pg/ml) at each sampling time for Comparative
Example D:
TABLE-US-00011 TABLE 11 MEAN PLASMA HOUR CONC. (pg/ml) STD. DEV CV
% 3 1.92 8.82 458.26 6 22.69 30.98 136.54 9 38.54 48.79 126.62 12
59.22 62.92 106.24 16 89.85 78.93 87.84 24 128.70 72.79 56.55 30
125.99 84.68 67.21 36 143.07 78.40 54.80 48 196.72 101.50 51.59 60
182.72 82.61 45.21 72 169.95 65.04 38.27 84 122.19 41.69 34.12 96
83.30 35.56 42.69 108 55.09 30.82 55.94 120 41.63 20.74 49.82 132
27.14 25.47 93.84 144 17.54 20.09 114.51
Table 12 provides a summary of the pharmacokinetic parameters for
Comparative Example D:
TABLE-US-00012 TABLE 12 ARITHMETIC GEOMETRIC PARAMETER MEAN (SE)
MEAN (SE) AUC (0-Infinity) 16278.05 (1246.6) 15255.84 (1272.5) AUC
(0-Last) 14446.10 (1292.0) 13162.96 (1340.6) Cmax (pg/ml) 229.87
(19.29) 214.47 (17.92) T 1/2 Elim. (hrs) 30.53 (2.80) Tmax (hrs)
67.02 (3.14)
Table 13 provides a summary of mean plasma buprenorphine
concentrations for Comparative Example E:
TABLE-US-00013 TABLE 13 MEAN PLASMA HOUR CONC. (pg/ml) STD. DEV CV
% 3 1.63 7.29 447.21 6 19.61 33.28 169.70 9 29.09 44.04 151.40 12
44.43 56.91 128.09 16 59.77 66.25 110.86 24 110.49 98.86 89.48 30
107.58 86.83 80.71 36 116.36 83.01 71.34 48 154.35 83.40 54.03 60
151.22 90.70 59.98 72 145.20 62.84 43.28 84 106.91 38.86 36.35 96
82.61 34.87 42.21 108 44.83 26.74 59.65 120 29.68 24.26 81.73 132
22.52 24.42 108.44 144 9.24 17.28 186.93
Table 14 provides a summary of the pharmacokinetic parameters for
Comparative Example E:
TABLE-US-00014 TABLE 14 ARITHMETIC GEOMETRIC PARAMETER MEAN (SE)
MEAN (SE) AUC (0-Infinity) 13450.96 (1326.8) 12315.56 (1142.0) AUC
(0-Last) 12026.65 (1318.7) 10796.23 (1110.3) Cmax (pg/ml) 199.10
(17.50) 186.49 (14.69) T 1/2 Elim. (hrs) 25.82 (1.51) Tmax (hrs)
68.26 (3.18)
Table 15 provides a summary of mean plasma buprenorphine
concentrations for Comparative Example F:
TABLE-US-00015 TABLE 15 MEAN PLASMA HOURS CONC. (pg/ml) STD. DEV.
CV % 3 5.23 13.21 252.44 6 34.49 55.11 159.80 9 58.67 91.17 155.40
12 94.52 111.07 117.51 16 137.07 118.65 86.56 24 195.58 148.53
75.94 30 201.51 142.24 70.59 36 229.52 154.25 67.20 48 283.35
124.06 43.78 60 314.17 173.81 55.32 72 306.60 124.57 40.63 84
209.66 62.84 29.97 96 143.30 43.88 30.62 108 113.53 70.33 61.95 120
78.71 37.46 47.59 132 75.29 47.92 63.64 144 44.45 32.26 72.57
Table 16 provides a summary of the dose-corrected pharmacokinetic
parameters for Comparative Example F. The values are calculated
based on a Cmax value which is one-half the actual reported
value:
TABLE-US-00016 TABLE 16 ARITHMETIC GEOMETRIC PARAMETER MEAN (SE)
MEAN (SE) AUC (0-Infinity) 14761.59 (1469.7) 13540.78 (1228.3) AUC
(0-Last) 12558.04 (1313.9) 11456.76 (1067.0) Cmax (pg/ml) 191.84
(16.93) 179.60 (14.23) T 1/2 Elim. (hrs) 26.59 (1.52) Tmax (hrs)
72.37 (1.89)
Table 17 provides a summary of the buprenorphine patch residuals
for each of Comparative Examples D-F:
TABLE-US-00017 TABLE 17 SUMMARY OF BUPRENORPHINE PATCH RESIDUALS
Ex. D Ex. F Ex. E AMOUNT LEFT IN PATCH (mg) N 27 27 52 MEAN 8.76
18.31 4.75 SE 0.07 0.15 0.03 % RELEASED (ASSAY) N 27 27 52 MEAN
12.31 10.84 8.43 SE 0.67 0.73 0.53
The pharmacokinetic results (concentration in pg/ml vs. hours) for
Comparative Examples D-F are depicted in FIGS. 9-11, respectively.
The pharmacodynamic results (PD variables (VAS)) for Comparative
Examples .[.A-C.]. .Iadd.D-F .Iaddend.are depicted in FIGS. 12-14,
respectively.
CONCLUSIONS
In order to readily consider the results obtained comparing the
method of the present invention to the Comparative Examples, the
following tables are provided.
Table 18 provides a direct comparison of the plasma concentrations
obtained from Example 1 (a 10 mg buprenorphine patch maintained in
contact with the subjects' skin for 7 days) to Comparative Example
A (20 mg buprenorphine patch left on the subjects' skin for only 3
days, then removed) to Comparative Example C (three sequential
applications of a 20 mg buprenorphine patch left on the subjects'
skin for only 3 days, then removed). In order to compare the plasma
concentrations, the plasma concentrations of Comparative Examples A
and C are also presented at 50% concentrations for each time
interval:
TABLE-US-00018 TABLE 18 COMPARISON OF PLASMA CONCENTRATIONS
COMPARATIVE COMPARATIVE EXAMPLE C EXAMPLE A HOUR/ Ex. 1 MEAN MEAN
(DAY) MEAN MEAN (1/2 DOSE) MEAN (1/2 DOSE) 24 (1) 58.94 218.57
109.29 175.58 87.79 48 (2) 104.69 265.04 132.52 251.10 125.55 72
(3) 130.55 306.02 153.01 286.50 143.25 96 (4) 146.70 269.91 134.96
90.75 45.38 120 (5) 136.22 310.27 155.14 44.85 22.43 144 (6) 115.23
305.99 153.00 29.14 14.57 168 (7) 102.00 340.71 170.36 192 (8)
395.95 197.98
The data presented in Table 18 shows that.[., surprisingly,.].
plasma levels effective to provide analgesia were present in
Example 1 (patch remained on skin for 7 days) even 7 days after
application of the patch; whereas in Comparative Example A (patch
removed after 3 days), blood levels fell dramatically once the
patch was removed, such that plasma levels which would be
indicative of ineffective treatment for the dosage of buprenorphine
occurred not long after patch removal. On the other hand, turning
to Comparative Example C, it is apparent that the plasma levels
obtained from 3-day sequential administration of the buprenorphine
patch resulted in significant increases in Cmax levels during each
day dosing interval. This fact is confirmed by the graph of plasma
concentration over time for Comparative Example C provided in FIG.
3. In contrast, the plasma level for Example 1 remained
substantially level over the time-frame of 72 hours-168 hours after
patch application. .[.The results indicate that the method of the
present invention has the surprising benefit of reducing total
plasma concentrations of buprenorphine required to allow patients
to experience effective analgesia..]. Furthermore, comparing the
VAS results graphically depicted for Example 1 to Comparative
Example C, it is apparent that side effects were significantly
reduced according to the method of Example 1, during the 7-day
dosage interval. Further benefits are obtained from the invention
with respect to modes of administration other than transdermally
where the large plasma concentration peaks obtained in the prior
art, e.g., through intravenous dosing, can be avoided. For example,
in Comparative Example B, a Cmax in excess of about 30,000 pg/ml
was obtained.
Table 19 provides a direct comparison of the plasma concentrations
of Example 1 (a 10 mg buprenorphine patch maintained in contact
with the subjects' skin for 7 days) to Comparative Example D (same
10 mg buprenorphine patch left on the subjects' skin for only 3
days, then removed) to Comparative Example E (two 5 mg
buprenorphine patches left on the subject' skin for only 3 days,
then removed):
TABLE-US-00019 TABLE 19 COMPARISON OF PLASMA CONCENTRATIONS (PG/ML)
Hours Ex. 1 Ex. D Ex. E (Post-Application) MEAN CONC. MEAN CONC.
MEAN CONC. 3 1.92 1.63 6 1.76 22.69 19.61 9 38.54 29.09 12 18.47
59.22 44.43 16 89.85 59.77 24 58.94 128.70 110.49 30 67.69 125.99
107.58 36 82.44 143.07 116.36 48 104.69 196.72 154.35 60 112.93
182.72 151.22 72 130.55 169.95 145.20 84 129.03 122.19 106.91 96
146.70 83.30 82.61 108 135.49 55.09 44.83 120 136.22 41.63 29.68
132 124.78 27.14 22.52 144 115.23 17.54 9.24
The results depicted in Table 19 confirm that the method according
to the present invention provides effective plasma levels over the
7-day period; whereas if the patch (or patches) containing the same
dose is removed after 3 days, the buprenorphine plasma levels fall
precipitously over the next 24 hour interval to levels which would
be indicative of ineffective treatment for the dosage of
buprenorphine. This result is surprising in view of the fact that
the patches are designed to provide effective analgetic levels of
buprenorphine only for a three day period--these patches are not
designed to provide effective plasma levels of buprenorphine over a
substantially longer period of time. (It must be noted that the
absolute mean plasma levels of Example 1 and the Comparative
Examples are not directly comparable because these results are
taken from different studies involving different subjects,
etc.).
.[.Further surprising results are apparent from the data provided
in.]. Table 20 below.[., which.]. compares the amount of
buprenorphine retained in the transdermal delivery systems in
Example 1 to certain Comparative Examples, as well as their
relative release rates:
TABLE-US-00020 TABLE 20 BUPRENORPHINE PATCH RELEASE RATES cum. amt.
RR [mg/ RR [mg/ RR.sub.norm Patch released patch/day] patch/day]
[mg/cm.sup.2/ strength Example [mg] 3 days appl. 7 days appl. day]
5 MG E 0.44 mg 0.146 -- 0.0234 10 MG D 1.23 mg 0.410 -- 0.0328 20
MG F 2.52 mg 0.742 -- 0.0297 20 MG A, C 3.21 mg 1.090 -- 0.0437 10
MG 1 1.40 mg -- 0.200 0.160
The total amount of buprenorphine released for Example 1 (1.40 mg)
may be expressed as 0.2 mg buprenorphine administered per day, when
averaged over the seven day dosing interval. In contrast,
Comparative Example .[.E.]. .Iadd.D .Iaddend.(same patch over 3
days) released a total of 1.23 mg, which may be expressed as 0.41
mg buprenorphine administered per day. .[.Comparing the cumulative
amount released for Example 1 as compared to Comparative Example D,
it can be seen that the present invention results in one-half the
dose (mg/patch/day) which would be administered based on prior art
methodology. Further, it is apparent that almost all of the
buprenorphine dose for Example 1 is released over the first 72
hours (3 days)--1.23 mg released from the 10 mg patch over 3 days
is 87.86% of the 1.4 mg released from the same patch over 7 days.
It is surprising that analgesia can be maintained given the very
low amount of buprenorphine released from the 10 mg patch over the
72-168 hour dosing interval..].
Further, the results indicate that over the first 72 hours the
buprenorphine is released substantially according to first order
kinetics, whereas during the 72-168 hour time period after
administration, the buprenorphine is released substantially
according to zero order kinetics. This is confirmed from the plasma
concentration curve provided for Example 1 in FIG. 1. .[.Thus,
during the first 72 hours after administration according to the
invention, a relative release rate of 17.1 ug/hr is obtained (1.23
mg divided by 72 hours); whereas from 72-168 hours after
administration according to the invention, the relative release
rate may be lowered to only 1.77 ug/hr (1.40 mg minus 1.23 mg=0.17
mg divided by 96 hours) while maintaining effective analgetic
levels of buprenorphine in human patients..].
EXAMPLE 2
In Example 2, the method of the present invention is accomplished
via a different mode of administration, i.e., intravenous infusion.
The pattern of plasma concentrations seen through time in this
invention can be achieved by using an intravenous infusion using
the injectable, parenteral form of, e.g., buprenorphine
hydrochloride suitably diluted in an intravenous infusion solution.
The infusion rate would be controlled by a programable infusion
pump, to provide the desired plasma concentration profile. The rate
of infusion through time can be determined and adjusted based upon
pharmacodynamic parameters such as pupil size (pupilometry) or pain
relief (analgesia) or by the results of a suitable bioassay to
determine the plasma buprenorphine concentrations at any particular
point in time. In addition, it is possible to model the desired
curve using pharmacokinetic modeling techniques; in this way the
desired curve can be approximated without need for pharmacokinetic
or pharmacodynamic monitoring. However, periodic plasma
concentration determinations would make the model more accurate and
allow further adjustment of the infusion rate.
Following the method set forth above, mean plasma concentrations
are obtained as follows: a mean plasma concentration from about 1
to about 28 pg/ml at about 6 hours after initiation of the dosing
interval; a mean plasma concentration from about 14 to about 74
pg/ml at about 12 hours after initiation of the dosing interval; a
mean plasma concentration from about 30 to about 161 pg/ml at about
24 hours after initiation of the dosing interval; a mean plasma
concentration from about 51 to about 188 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 62 to about 246 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 79 to about 246 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 85 to about 263 pg/ml at about 72 hours
after initiation of the dosing interval; a mean plasma
concentration from about 92 to about 263 pg/ml at about 96 hours
after initiation of the dosing interval; a mean plasma
concentration from about 94 to about 263 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 86 to about 243 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 77 to about 210 pg/ml at about 168 hours
after initiation of the dosing interval (for a seven day dosing
interval).
It will be readily apparent that various modifications to the
invention may be made by those skilled in the art without departing
from the scope of this invention. For example, many different
transdermal delivery systems may be utilized in order to obtain the
relative release rates and plasma levels described herein. Further,
it is possible that mean values for plasma concentrations over a
particular patient population for a particular described time point
along the dosing interval may vary from the plasma concentration
ranges described herein for that time point. Such obvious
modifications are considered to be within the scope of the appended
claims.
* * * * *
References