U.S. patent number RE47,826 [Application Number 14/660,681] was granted by the patent office on 2020-01-28 for drug delivery device for providing local analgesia, local anesthesia or nerve blockage.
This patent grant is currently assigned to INNOCOLL PHARMACEUTICALS LIMITED. The grantee listed for this patent is INNOCOLL PHARMACEUTICALS LIMITED. Invention is credited to Michael Myers, Philip Wallace Reginald.
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United States Patent |
RE47,826 |
Myers , et al. |
January 28, 2020 |
Drug delivery device for providing local analgesia, local
anesthesia or nerve blockage
Abstract
The invention relates to a drug delivery device for providing
local analgesia, local anesthesia or nerve blockade at a site in a
human or animal in need thereof, the device comprising a fibrillar
collagen matrix; and at least one drug substance selected from the
group consisting of amino amide anesthetics, amino ester
anesthetics and mixtures thereof, the at least one drug substance
being substantially homogeneously dispersed in the collagen matrix,
and the at least one drug substance being present in an amount
sufficient to provide a duration of local analgesia, local
anesthesia or nerve blockade which lasts for at least about one day
after administration.
Inventors: |
Myers; Michael (Ashburn,
VA), Reginald; Philip Wallace (Buckinghamshire,
GB) |
Applicant: |
Name |
City |
State |
Country |
Type |
INNOCOLL PHARMACEUTICALS LIMITED |
Co. Roscommon |
N/A |
IE |
|
|
Assignee: |
INNOCOLL PHARMACEUTICALS
LIMITED (Co. Roscommon, IE)
|
Family
ID: |
69174157 |
Appl.
No.: |
14/660,681 |
Filed: |
March 17, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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11692337 |
Mar 28, 2007 |
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Reissue of: |
12058298 |
Mar 28, 2008 |
8034368 |
Oct 11, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
47/42 (20130101); A61K 31/13 (20130101); A61K
31/381 (20130101); A61K 31/445 (20130101); A61K
9/0024 (20130101); A61K 31/164 (20130101); A61K
31/381 (20130101); A61K 9/0021 (20130101); A61K
31/164 (20130101); A61K 9/0019 (20130101); A61K
31/21 (20130101); A61K 31/445 (20130101); A61K
31/13 (20130101); A61K 31/21 (20130101) |
Current International
Class: |
A61F
2/02 (20060101); A61K 31/445 (20060101); A61K
31/21 (20060101); A61K 9/00 (20060101); A61K
31/13 (20060101); A61K 31/381 (20060101); A61K
31/164 (20060101) |
Field of
Search: |
;424/426 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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53579 |
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Jun 1981 |
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IE |
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H08-143449 |
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Jun 1996 |
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JP |
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WO 2006/002365 |
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Jan 2006 |
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WO |
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WO 2006/034568 |
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Apr 2006 |
|
WO |
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WO 2006034568 |
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Apr 2006 |
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WO |
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WO 2008/117268 |
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Oct 2008 |
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WO |
|
Other References
Goldstein et al., Anesth. Analg., 91(2):403-7, 2000. cited by
examiner .
Bupivacaine, FDA prescribing information from Drugs.com. cited by
examiner .
Bupivacaine, PubChem. cited by examiner .
Godfrey et al., Comp. Meth. & Programs in Biomed., 104:62-69,
2011. cited by examiner .
Stemberger et al., Local treatment of bone and soft tissue
infections with the collagen-gentamicin sponge, Eur. J. Surg.,
163(S578):17-26, 1997, (Stemberger). cited by examiner .
International Preliminary Report on Patentability for International
Application No. PCT/IE2008/000035 dated Sep. 29, 2009, 6 pages.
cited by applicant .
Anonymous: "Innocoll Announces Filing of Investigational New Drug
Application for its CollaRx.RTM. Bupivacaine Implant for the
Management of Post-Operative Pain", Mar. 1, 2007, pp. 1-2,
Retrieved from the Internet:
URL:http://www.innocollinc.comjindex.php?mact=News.cntnt01.deta-
il.O&cntnt01articleid=13&cntnt01dateformat=%25d%20%25b%2C%20%25Y&cntnt01re-
turnid=63 [retrieved on Sep. 26, 2011]. cited by applicant .
Anonymous: "CollaRx.RTM. Bupivacaine Implant for the Management of
Post-operative Pain", Mar. 5, 2007, p. 1 Retrieved from the
Internet:
URL:http://www.biotech-Weblog.com/50226711/collarxa_bupivacaine_implant_f-
or_the_management_of_postoperative_pain.php [retrieved on Sep. 26,
2011]. cited by applicant .
Cusack, S.L., et al., "A randomized, multicenter, pilot study
comparing the efficacy and safety of a bupivacaine-collagen implant
(XaraColl.RTM.) with the ON-Q PainBuster.RTM. post-op pain relief
system following open gynecological surgery." Journal of Pain
Research (2012); 5: 453-461. cited by applicant .
Cusack, S.L., et al., "Clinical evaluation of XaraColl.RTM., a
bupivacaine-collagen implant, for postoperative analgesia in two
multicenter, randomized, double-blind, placebo-controlled pilot
studies." Journal of Pain Research (2012); 5: 217-225. cited by
applicant .
European Patent Application No. 16154811.0, Extended European
Search Report dated Jul. 22, 2016, 10 pages. cited by applicant
.
Hemsen, L., et al., "A feasibility study to investigate the use of
a bupivacaine-collagen implant (XaraColl) for postoperative
analgesia following laparoscopic surgery." Journal of Pain Research
(2013); 6: 79-85. cited by applicant .
Ruszczak and Friess, "Collagen as a carrier for on-site delivery of
antibacterial drugs." Advanced Drug Delivery Reviews (2003);
55(12): 1679-1698. cited by applicant .
"Innocoll Announces Filing of Investigational New Drug Application
for its CollaRx TM Bupivacaine Implant for the Management of
Post-Operative Pain", Mar. 1, 2007, pp. 1-2. cited by applicant
.
"CollaRx TM Bupivacaine Implant for the Management of
Post-operative Pain", Mar. 5, 2007, p. 1. cited by applicant .
Leung et al. "Effect of Pre-Incision Skin Infiltration on
Post-Hysterectomy Pain-A Double-Giind Randomized Controlled Trial",
Anaesth Intensive Care 2000 28:510-516. cited by applicant .
Internation Search Report for PCT/IE2008/000035. cited by applicant
.
Written Opinion for PCT/IE2008/000035. cited by applicant .
Gentamicin--DrugBank https://www.drugbank.ca/drugs/DB00798 accessed
May 13, 2019. 9 pgs. cited by applicant .
Bupivacaine--DrugBank--https://www.drugbank.ca/drugs/DB00297--accessed
May 13, 2019. 10 pgs. cited by applicant .
Scheinin et. al. "Effect of intraperitoneal bupivacaine on pain
after laparoscopic cholecystectomy" Acta Anaesthesiologica
Scandinavia, vol. 39: pp. 195-198. 4 pgs (1995). cited by applicant
.
Joris et. al. "Pain After Laparoscopic Cholecystectomy:
Characteristics and Effect of Intraperitoneal Bupivacaine"
Anesthesia & Analgesia, vol. 81, pp. 379-384. 6 pgs (1995).
cited by applicant .
Chundrigar et. al. "Intraperitoneal bupivacaine for effective pain
relief after laparoscopic cholecystectomy" Annals of The Royal
College of Surgeons of England, vol. 75, pp. 437-439, 3 pgs (1993).
cited by applicant .
Szem J.W. and Hydo, P.S. Barie "A double-blinded evaluation of
intraperitoneal bupivacaine vs saline for the reduction of
postoperative pain and nausea after laparoscopic cholecystectomy"
Surgical Endoscopy, 5 pgs (1996). cited by applicant .
Yanas, et al., "Cross-linking of Gelatine by Dehydration" Nature,
vol. 215, 2 pgs (Jul. 1967). cited by applicant .
Weadock et. al. "Effect of physical crosslinking methods on
collagen-fiber durability in proteolytic solutions" 6 pgs (1996).
cited by applicant .
Weadock et al., "Physical Crosslinking of Collagen Fibers:
Comparison of Ultraviolet Irradiation and Dehydrothermal
Treatment," Journ. Of Biomedical Materials Research, vol. 29, pp.
1373-1379 (1995). cited by applicant .
Weadock et. al. "Evaluation of collagen crosslinking techniques" 26
pgs (1984). cited by applicant .
Wang et. al. "Collagen fibres with improved strength for the repair
of soft tissue injuries" Biomaterials, vol. 15 No. 7. 6 pgs (1994).
cited by applicant .
Silver et. al. "In Vitro Blood Compatibility of
Glycosaminoglycan-Precipitated collagens" Journal of Biomedical
Research, vol. 13, pp. 701-716 16 pgs (1979). cited by applicant
.
Koide et. al. "A new type of biomaterial for artificial skin:
Dehydrothermally cross-linked composites of fibrillar and denatured
collagens" Journal of Biomedical Materials Research, vol. 27,
79-87, 9 pgs (1993). cited by applicant .
Khor, "Methods for the treatment of collagenous tissues for
bioprostheses" Biomaterials, vol. 18, No. 2. 11 pgs (1997). cited
by applicant .
Gorham et. al. "Effects of chemical modifications on the
susceptibility of collagen to proteolysis. II. Dehydrothermal
crosslinking." International Journal of Biological Macromolecules,
vol. 14, 10 pgs (Jun. 1992). cited by applicant .
Friess, "Collagen--Biomaterial for Drug Delivery", European Journal
of Pharmaceutics or Biopharmaceutics, vol. 45, Issue 2, Mar. 1998,
pp. 113-136. cited by examiner .
Bartholdy et al., "Preoperative infiltration of the surgical area
enhances postoperative analgesia of a combined low-dose epidural
bupivacaine and morphine regimen after upper abdominal surgery",
Acta Anaesthesiologica Scandinavica 1994 38:262-265. cited by
applicant .
Cobby et al., "Wound infiltration with local anaesthetic after
abdominal hysterectomy", British Journal of Anaesthesia 1997
78:431-432. cited by applicant .
Gupta et al., "Postoperative Pain After Abdominal Hysterectomy:A
Double-Blind Comparison Between Placebo and Local Anesthetic
Infused Intraperitoneally", Anesth Analg 2004 99:1173-1179. cited
by applicant .
Hannibal et al., "Preoperative Wound Infiltration with Bupivacaine
Reduces Early and Late Opioid Requirement After Hysterectomy",
Anesth Analg 1996 83:376-381. cited by applicant .
Klein et al., "Infiltration of the abdonimal wall with local
anaesthetic after total abdominal hysterectomy has no
opioid-sparing effect", British Journal fo Anaesthesia 2000
84(2):248-249. cited by applicant .
Leung et al. "Effect of Pre-Incision Skin Infiltration on
Post-Hysterectomy Pain-A Double-Glind Randomized Controlled Trial",
Anaesth Intensive Care 2000 28:510-516. cited by applicant .
Moiniche et al., "A qualitative systematic review of incisional
local anaesthesia for postoperative pain relief after abdonimal
operations", British Journal of Anaesthesia 1998 81:377-383. cited
by applicant .
Ng et al., "The Analgesic Effects of Intraperitoneal and Incisional
Bupivacaine with Epinephrine After Total Abdonimal Hysterectomy",
Anesth Analg 2002 95:158-162. cited by applicant .
Sinclair et al., "Postoperative pain relief by topical lidocaine in
the surigcal wound of hysterectomized patients", Acta
Anaesthesiologica Scandinavica 1996 40:589-954. cited by applicant
.
Victory et al., "Effect of Preincision versus Postincision
Infiltration with Bupivacaine on Postoperative Pain", Journal of
Clinical Anesthesia 1995 7:192-196. cited by applicant.
|
Primary Examiner: Turner; Sharon
Attorney, Agent or Firm: Foley & Lardner LLP
Parent Case Text
INTRODUCTION
This application is a continuation-in-part of U.S. Ser. No.
11/692,337 filed Mar. 28, 2007 now abandoned, which is herein
incorporated by reference in its entirety.
Claims
What is claimed is:
.[.1. A drug delivery device for providing local analgesia, local
anesthesia or nerve blockade at a site in a human or animal in need
thereof, the device comprising a fibrillar collagen matrix; and at
least one drug substance selected from the group consisting of
amino amide anesthetics, amino ester anesthetics and mixtures
thereof, the at least one drug substance being substantially
homogeneously dispersed in the collagen matrix, and the at least
one drug substance being present in an amount sufficient to provide
a duration of local analgesia, local anesthesia or nerve blockade
which lasts for at least about one day after administration..].
.[.2. The drug delivery device of claim 1, wherein the at least one
drug substance is present in an amount sufficient to provide a
duration of local analgesia, local anesthesia or nerve blockade
which lasts for at least about two days after
administration..].
.[.3. The drug delivery device of claim 1, wherein the at least one
drug substance is present in an amount sufficient to provide a
duration of local analgesia, local anesthesia or nerve blockade
which lasts for at least about three days after
administration..].
.[.4. The drug delivery device of claim 1, wherein the at least one
drug substance is an amino amide anesthetic selected from the group
comprising Bupivacaine, Levobupiyacaine, Lidocaine, Mepivacaine,
Prilocaine, Ropivacaine, Articaine, Trimecaine and their salts and
prodrugs..].
.[.5. The drug delivery device of claim 1, wherein the at least one
drug substance is an amino amide anesthetic selected from
bupivacaine and salts and pro drugs thereof..].
.[.6. The drug delivery device of claim 1, wherein the fibrillar
collagen matrix is a Type I collagen matrix..].
.[.7. The drug delivery device of claim 1, wherein the fibrillar
collagen matrix is a Type I collagen matrix and the at least one
drug substance is an amino amide anesthetic selected from
bupivacaine and salts and prodrugs thereof..].
.[.8. The drug delivery device of claim 7, wherein the drug
delivery device comprises a plurality of collagen sponges, each
collagen sponge containing about 3.6 to about 8.0 mg/cm.sup.3 type
I collagen and about 2.0 to about 6.0 mg/cm.sup.3 bupivacaine
hydrochloride..].
.[.9. The drug delivery device of claim 7, wherein the drug
delivery device comprises a plurality of collagen sponges, each
collagen sponge containing about 5.6 mg/cm.sup.3 type I collagen
and about 4.0 mg/cm.sup.3 bupivacaine hydrochloride..].
.[.10. A method for providing local analgesia, local anesthesia or
nerve blockade in a human or animal in need thereof, the method
comprising administering at a site in a human or animal in need
thereof a drug delivery device comprising a fibrillar collagen
matrix; and at least one drug substance selected from the group
consisting of amino amide anesthetics, amino ester anesthetics and
mixtures thereof, the at least one drug substance being
substantially homogeneously dispersed in the collagen matrix, and
the at least one drug substance being present in an amount
sufficient to provide a duration of local analgesia, local
anesthesia or nerve blockade which lasts for at least about one day
after administration..].
.[.11. The method of claim 10, wherein the at least one drug
substance is present in an amount sufficient to provide a duration
of local analgesia, local anesthesia or nerve blockade which lasts
for at least about two days after administration..].
.[.12. The method of claim 10, wherein the at least one drug
substance is present in an amount sufficient to provide a duration
of local analgesia, local anesthesia or nerve blockade which lasts
for at least about three days after administration..].
.[.13. The method of claim 10, wherein the at least one drug
substance is an amino amide anesthetic selected from the group
comprising Bupivacaine, Levobupivacaine, Lidocaine, Mepivacaine,
Prilocaine, Ropivacaine, Articaine, Trimecaine and their salts and
prodrugs..].
.[.14. The method of claim 10, wherein the at least one drug
substance is an amino amide anesthetic selected from bupivacaine
and salts and prodrugs thereof..].
.[.15. The method of claim 10, wherein the fibrillar collagen
matrix is a Type I collagen matrix..].
.[.16. The method of claim 10, wherein the fibrillar collagen
matrix is a Type 1 collagen matrix and the at least one drug
substance is an amino anode anesthetic selected from bupivacaine
and salts and prodrugs thereof..].
.[.17. The method of claim 16, wherein the drug delivery device
comprises a plurality of collagen sponges, each collagen sponge
containing about 3.6 to about 8.0 mg/cm.sup.3 type I collagen and
about 2.0 to about 6.0 mg/cm.sup.3 bupivacaine
hydrochloride..].
.[.18. The method of claim 16, wherein the drug delivery device
comprises a plurality of collagen sponges, each collagen sponge
containing about 5.6 mg/cm.sup.3 type I collagen and about 4.0
mg/cm.sup.3 bupivacaine hydrochloride..].
.[.19. The method of claim 10, wherein the method is for providing
local analgesia, local anesthesia or nerve blockade in a human
following laparotomy..].
.[.20. The method of claim 10, wherein the method is for providing
local analgesia, local anesthesia or nerve blockade in a human
following orthopedic, abdominal, gynecological or thoracic surgical
procedures..].
.[.21. The method of claim 17, wherein the method is for providing
local analgesia, local anesthesia or nerve blockade in a human
following orthopedic, abdominal, gynecological or thoracic surgical
procedures..].
.[.22. The method of claim 18, wherein the method is for providing
local analgesia, local anesthesia or nerve blockade in a human
following orthopedic, abdominal, gynecological or thoracic surgical
procedures..].
.[.23. The method of claim 10, wherein the drug delivery device
comprises a plurality of collagen sponges and wherein at least one
sponge is placed adjacent the surgical site, at least one sponge is
placed across the incision in the wall of the body cavity and at
least one sponge is placed between the sheath and skin around the
incision..].
.Iadd.24. A method for inducing a post-surgical analgesia-sparing
effect in a subject in need thereof with a surgical site, the
method comprising: implanting at the surgical site a collagen
sponge consisting of (a) a porous matrix of about 3.6 to about 8.0
mg/cm.sup.3 fibrillar Type I collagen, and (b) bupivacaine, or a
pharmaceutically acceptable salt thereof, wherein the bupivacaine
or pharmaceutically acceptable salt thereof is substantially
homogeneously dispersed in the collagen sponge; wherein the
collagen sponge provides a duration of local anesthesia of at least
about one day following implantation; and the method induces the
post-surgical analgesia-sparing effect in the subject.
.Iaddend.
.Iadd.25. The method of claim 24, wherein the collagen sponge
consists of (a) a porous matrix of about 3.6 to about 8.0
mg/cm.sup.3 fibrillar Type I collagen, and (b) about 2.0 to about
6.0 mg/cm.sup.3 bupivacaine, or a pharmaceutically acceptable salt
thereof, wherein the bupivacaine hydrochloride is substantially
homogeneously dispersed in the collagen sponge. .Iaddend.
.Iadd.26. The method of claim 24, wherein the collagen sponge
consists of (a) a porous matrix of about 3.6 to about 8.0
mg/cm.sup.3 fibrillar Type I collagen, and (b) about 2.0 to about
6.0 mg/cm.sup.3 bupivacaine hydrochloride, wherein the bupivacaine
hydrochloride is substantially homogeneously dispersed in the
collagen sponge. .Iaddend.
.Iadd.27. The method of claim 24, wherein the collagen sponge
consists of (a) a porous matrix of about 5.6 mg/cm.sup.3 fibrillar
Type I collagen, and (b) about 4.0 mg/cm.sup.3 bupivacaine
hydrochloride, wherein the bupivacaine hydrochloride is
substantially homogeneously dispersed in the collagen sponge.
.Iaddend.
.Iadd.28. The method of claim 24, wherein the collagen sponge has a
surface area of about 25 cm.sup.2. .Iaddend.
.Iadd.29. The method of claim 24, wherein the collagen sponge has
dimensions of about 5 cm.times.5 cm. .Iaddend.
.Iadd.30. The method of claim 24, wherein the collagen sponge has a
depth or thickness of about 0.5 cm. .Iaddend.
.Iadd.31. The method of claim 24, wherein the collagen sponge has
dimensions of about 5 cm.times.5 cm.times.0.5 cm. .Iaddend.
.Iadd.32. The method of claim 24, wherein the subject has undergone
a laparotomy, orthopedic surgery, abdominal surgery, gynecological
surgery, or thoracic surgery. .Iaddend.
.Iadd.33. The method of claim 25, wherein the collagen sponge has a
surface area of about 25 cm.sup.2. .Iaddend.
.Iadd.34. The method of claim 25, wherein the collagen sponge has
dimensions of about 5 cm.times.5 cm. .Iaddend.
.Iadd.35. The method of claim 25, wherein the collagen sponge has a
depth or thickness of about 0.5 cm. .Iaddend.
.Iadd.36. The method of claim 25, wherein the collagen sponge has
dimensions of about 5 cm.times.5 cm.times.0.5 cm. .Iaddend.
.Iadd.37. The method of claim 25, wherein the subject has undergone
a laparotomy, orthopedic surgery, abdominal surgery, gynecological
surgery, or thoracic surgery. .Iaddend.
.Iadd.38. The method of claim 26, wherein the collagen sponge has a
surface area of about 25 cm.sup.2. .Iaddend.
.Iadd.39. The method of claim 26, wherein the collagen sponge has
dimensions of about 5 cm.times.5 cm. .Iaddend.
.Iadd.40. The method of claim 26, wherein the collagen sponge has a
depth or thickness of about 0.5 cm. .Iaddend.
.Iadd.41. The method of claim 26, wherein the collagen sponge has
dimensions of about 5 cm.times.5 cm.times.0.5 cm. .Iaddend.
.Iadd.42. The method of claim 26, wherein the subject has undergone
a laparotomy, orthopedic surgery, abdominal surgery, gynecological
surgery, or thoracic surgery. .Iaddend.
Description
FIELD OF THE INVENTION
The present invention relates to a drug delivery device for
providing local analgesia, local anesthesia or nerve blockade and a
method for providing local analgesia, local anesthesia or nerve
blockade in a human or animal in need thereof.
RELATED BACKGROUND ART
Post-surgical pain is a complex response to tissue trauma during
surgery that stimulates hypersensitivity of the central nervous
system. Post-operative pain increases the possibility of
post-surgical complications, raises the cost of medical care and,
most importantly, interferes with recovery and return to normal
activities of daily living. Management of post-surgical pain is a
basic patient right. When pain is controlled or removed, a patient
is better able to participate in activities such as walking or
eating, which will encourage his or her recovery. Patients will
also sleep better, which aids the healing process.
Collagen sponges have been used globally as hemostatic agents. The
present inventors have developed a drug delivery device in the
optional form of a collagen sponge impregnated with at least one
anesthetic such as bupivacaine hydrochloride, intended for use in
the management of post-operative pain following surgery including,
but not limited to, moderate/major orthopedic, abdominal,
gynecological or thoracic surgery. The at least one anesthetic is
contained, in one embodiment, within a collagen matrix comprised of
fibrillar collagen, such as Type I collagen purified from bovine
Achilles tendons.
Bupivacaine, introduced in 1963, is a widely used amide local
anesthetic with a prolonged duration of action. It affects sensory
nerves more than motor nerves and can also be used to provide
several days' effective analgesia without motor blockade.
Bupivacaine is characterized by its longer duration and slow onset
compared with other local anesthetics. Bupivacaine is markedly
cardiotoxic. Systemic exposure to excessive quantities of
bupivacaine mainly result in central nervous system (CNS) and
cardiovascular effects--CNS effects usually occur at lower blood
plasma concentrations and additional cardiovascular effects present
at higher concentrations, though cardiovascular collapse may also
occur with low concentrations. CNS effects may include CNS
excitation (nervousness, tingling around the mouth, tinnitus,
tremor, dizziness, blurred vision, seizures) followed by depression
(drowsiness, loss of consciousness, respiratory depression and
apnea). Cardiovascular effects include hypotension, bradycardia,
arrhythmias, and/or cardiac arrest--some of which may be due to
hypoxemia secondary to respiratory depression.
Incisional Local Anesthesia
Wound infiltration with local anesthesia is used widely for
postoperative pain: it is simple, safe and low cost. However, it is
unclear whether differences in surgical procedure or whether
visceral components influence efficacy. Incisional anesthesia
includes infiltration, topical administration or instillation of
local anesthetic at the following sites: skin, subcutaneous tissue,
fascia, muscle and/or the parietal peritoneum. However, in spite of
widespread use, wound infiltration is still inconsistently and
randomly used by many surgeons and anesthetists.
Although there is a great number of papers and reviews on this
topic, there is little consensus available on when and after which
surgical procedures, incisional local anesthesia may provide
clinically relevant post-operative pain alleviation. Of special
interest may be to what extent differences in surgical procedure or
involvement of visceral components influence efficacy. Incisional
local anesthesia has been studied in a broad range of surgical
models, including abdominal hysterectomy, inguinal herniotomy, open
cholecystectomy, appendectomy, Caesarian section and other
laparotomy procedures. A laparotomy is a surgical maneuver
involving an incision through the abdominal wall to gain access
into the abdominal cavity.
The anesthetics assessed for post-operative pain relief include
lidocaine, bupivacaine, ropivacaine and mepivacaine, which all
belong to the amino amide anesthetic group. On review of the data
on the use of incisional anesthesia in hysterectomy surgery,
conflicting results have been obtained. In a study by Sinclair et
al, 1996, 500 mg of lidocaine administered as an aerosol
subcutaneously caused a significant reduction of approximately 50%
in pain scores and supplementary analgesic consumption during the
first 24 hours of the study, but not later. In a study by Hannibal
and co-workers, 0.25% bupivacaine solution 45 ml infiltrated
subfascially and subcutaneously caused a 50% reduction in analgesic
consumption but not in pain scores or time to first analgesic
request. In contrast, two studies evaluating subcutaneous
infiltration of bupivacaine solution compared with no treatment
showed no improvement in analgesia (Cobby et al, 1997, Victory et
al, 1995).
Studies in other models have shown short-term analgesic effects
over 4 to 7 hours. In three studies on Caesarian section, 0.25% or
0.5% bupivacaine 20 ml caused a 20-50% reduction in analgesic
consumption but this effect only lasted for 4 hours. In another
study in upper abdominal surgery, only a slight reduction in daily
morphine administration (supplemental intramuscular morphine) (10
mg) was noted and a reduction in visual analogue scoring (VAS) only
during mobilization was recorded (50 mm) (Bartholdy et al, 1994).
In a review of incisional anesthesia for the control of
post-operative pain, Moiniche et al (1998) assessed 26 studies
involving over 1200 patients in surgeries using abdominal incision.
The results showed a consistent statistical and clinical effect of
incisional anesthesia in herniotomy surgery, although the analgesia
was short-lived (2-7 hours). However, in the other surgical models
evaluated including hysterectomy the results were variable between
studies.
Of the 26 studies evaluated (Moiniche et al, 1998), eight were
unequivocally negative. Although the majority of studies showed
significant differences in at least one pain measure, several were
of questionable clinical importance and the authors were surprised
that local anesthesia was not associated with more consistent
positive results. The authors also noted the importance in the
technique used and site to administer the anesthetics.
Since the 1998 review, surgical wound infiltration trials have
continued to be performed and published as the practice remains
relatively common despite the lack of strong evidence. For example,
a group in Leicester, UK, has published two hysterectomy trials
(Klein et al, 2000 and Ng et al, 2002), which at best have
concluded a duration of effect only up to 4 hours
post-operatively.
In contrast, trials where bupivacaine has been instilled
post-operatively on a continuous or intermittent basis via an
indwelling catheter have tended to prove much more successful and
effective. Gupta et al (2004) compared an infusion of normal saline
against an infusion of 0.25% levobupivacaine (12.5 mg/hr) over 24
hours and showed a significant reduction in incisional pain, deep
pain and pain on coughing at 1-2 hours post hysterectomy surgery.
Total ketobemidone (PCA narcotic) was significantly reduced over
the 4-24 hour period and the authors conclude that the
intraperitoneal infusion of levobupivacaine has significant opioid
sparing effects after elective abdominal hysterectomy.
The apparent efficacy of anesthetic infusions explains the
widespread use of ambulatory pain pumps, such as I-Flow's ON-Q.RTM.
Painbuster. However, such continuous infusion devices use much
higher total doses of bupivacaine (between 2.5 mg/hr and 50 mg/hr
with a maximum dosing duration of 5 and 2 days, respectively) and
of course are less convenient than a biodegradable implant. The
in-dwelling catheter used in the pain pump system can lead to
infection and must be removed by a physician or nurse. In contrast,
a drug delivery device such as the bupivacaine-collagen sponge
provides, as will be demonstrated hereunder, effective, long
lasting analgesia but at a dose only equivalent to a once-off bolus
infiltration of the wound.
In the present invention, this long lasting analgesia is achieved
through the use of a drug delivery device for providing local
analgesia, local anesthesia or nerve blockade at a site in a human
or animal in need thereof, the device comprising a fibrillar
collagen matrix; and at least one drug substance selected from the
group consisting of amino amide anesthetics, amino ester
anesthetics and mixtures thereof, the at least one drug substance
being substantially homogeneously dispersed in the collagen matrix,
and the at least one drug substance being present in an amount
sufficient to provide a duration of local analgesia, local
anesthesia or nerve blockade which lasts for at least about one day
after administration. Accordingly, the invention provides, in a
first aspect, a drug delivery device for providing local analgesia,
local anesthesia or nerve blockade at a site in a human or animal
in need thereof, the device comprising a fibrillar collagen matrix;
and at least one drug substance selected from the group consisting
of amino amide anesthetics, amino ester anesthetics and mixtures
thereof, the at least one drug substance being substantially
homogeneously dispersed in the collagen matrix, and the at least
one drug substance being present in an amount sufficient to provide
a duration of local analgesia, local anesthesia or nerve blockade
which lasts for at least about one day after administration.
It is hypothesized that such drug delivery devices as the
bupivacaine-collagen sponge will afford post-operative pain
management to patients without adverse effects associated with
toxicity from the collagen sponge or elevated systemic anesthetic
(such as bupivacaine) levels. It is hypothesized that such drug
delivery devices as the bupivacaine-collagen sponge will provide
local pain relief to patients for up to 48 or 72 hours at the
surgical site and reduce the patient's demand for systemic
analgesia and the associated adverse effects.
SUMMARY OF THE INVENTION
The present invention is directed to a drug delivery device for
providing local analgesia, local anesthesia or nerve blockade at a
site in a human or animal in need thereof, the device comprising a
fibrillar collagen matrix; and at least one drug substance selected
from the group consisting of amino amide anesthetics, amino ester
anesthetics and mixtures thereof, the at least one drug substance
being substantially homogeneously dispersed in the collagen matrix,
and the at least one drug substance being present in an amount
sufficient to provide a duration of local analgesia, local
anesthesia or nerve blockade which lasts for at least about one day
after administration. The present invention is directed, in an
optional embodiment, to a biodegradable, leave-behind device.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows, schematically, a flow diagram for the production of
collagen.
FIG. 2 shows, schematically, a flow diagram for the production of a
drug delivery device in the optional form of a bupivacaine-collagen
sponge.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a drug delivery device for providing
local analgesia, local anesthesia or nerve blockade at a site in a
human or animal in need thereof, the device comprising a fibrillar
collagen matrix; and at least one drug substance selected from the
group consisting of amino amide anesthetics, amino ester
anesthetics and mixtures thereof the at least one drug substance
being substantially homogeneously dispersed in the collagen matrix,
and the at least one drug substance being present in an amount
sufficient to provide a duration of local analgesia, local
anesthesia or nerve blockade which lasts for at least about one day
after administration.
In a second aspect, the invention relates to a method for providing
local analgesia, local anesthesia or nerve blockade in a human or
animal in need thereof, the method comprising administering at a
site in a human or animal in need thereof a drug delivery device
comprising a fibrillar collagen matrix; and at least one drug
substance selected from the group consisting of amino amide
anesthetics, amino ester anesthetics and mixtures thereof, the at
least one drug substance being substantially homogeneously
dispersed in the collagen matrix, and the at least one drug
substance being present in an amount sufficient to provide a
duration of local analgesia, local anesthesia or nerve blockade
which lasts for at least about one day after administration.
Incorporation of the at least one drug substance selected from the
group consisting of amino amide anesthetics, amino ester
anesthetics and mixtures thereof in the fibrillar collagen matrix
to provide the drug delivery device of the present invention delays
the release of the at least one drug substance from the fibrillar
collagen matrix and, thereby, prolongs the duration of local
analgesia, local anesthesia or nerve blockade to at least about one
day after administration of the drug delivery device.
By "site" or "surgical site" is meant the tissue(s) or organ(s)
that is/are the intended aim of the surgical procedure, for
example, around the now-removed uterus for hysterectomy as the
surgical procedure.
Without being bound by theory, it is thought that the duration of
local analgesia, local anesthesia or nerve blockade is prolonged by
at least three times (optionally at least four times, further
optionally at least five times) the duration of local analgesia,
local anesthesia or nerve blockade that is achieved without being
incorporated in the drug delivery device of the present
invention.
Optionally, in the device or method of the invention, the at least
one drug substance is present in an amount sufficient to provide a
duration of local analgesia, local anesthesia or nerve blockade
which lasts for at least about two days after administration.
Optionally, in the device or method of the invention, the at least
one drug substance is present in an amount sufficient to provide a
duration of local analgesia, local anesthesia or nerve blockade
which lasts for at least about three days, further optionally at
least four days, after administration.
The at least one drug substance is selected from the group
consisting of amino amide anesthetics, amino ester anesthetics and
mixtures thereof. Mixtures of amino amide anesthetics; mixtures of
amino ester anesthetics; and mixtures of amino amide anesthetics
and of amino ester anesthetics are specifically contemplated as
forming part of the devices and methods of the present invention.
In addition, optional devices and methods of the present invention
may, in addition, contain one or more further drug substances, said
one or more further drug substances not being amino amide
anesthetics, amino ester anesthetics and mixtures thereof. Such
further drug substances may comprise drugs efficacious in providing
local analgesia, local anesthesia or nerve blockade.
Optionally, in the device or method of the invention, the at least
one drug substance is an amino amide anesthetic selected from the
group comprising Bupivacaine, Levobupivacaine, Lidocaine,
Mepivacaine, Prilocalne, Ropivacaine, Articaine, Trimecaine and
their salts and prodrugs. Further optionally, in the device or
method of the invention, the at least one drug substance is an
amino amide anesthetic selected from bupivacaine and salts and
prodrugs thereof. Still further optionally, in the device or method
of the invention, the at least one drug substance is an amino amide
anesthetic selected from the group comprising Levobupivacaine,
Lidocaine, Mepivacaine, Prilocalne, Ropivacaine, Articaine,
Trimecaine and their salts and prodrugs.
Optionally, in the device or method of the invention, the fibrillar
collagen matrix is a Type I collagen matrix.
Optionally, in the device or method of the invention, the fibrillar
collagen matrix is a Type I collagen matrix and the at least one
drug substance is an amino amide anesthetic selected from
bupivacaine and salts and prodrugs thereof. Further optionally, the
drug delivery device comprises a plurality of collagen sponges,
each collagen sponge containing about 3.6 to about 8.0 mg/cm.sup.3
type I collagen and about 2.0 to about 6.0 mg/cm.sup.3 bupivacaine
hydrochloride. Still further optionally, the drug delivery device
comprises a plurality of collagen sponges, each collagen sponge
containing about 5.6 mg/cm.sup.3 type I collagen and about 4.0
mg/cm.sup.3 bupivacaine hydrochloride.
Optionally, in the method of the invention, the method is for
providing local analgesia, local anesthesia or nerve blockade in a
human following laparotomy.
Optionally, in the method of the invention, the method is for
providing local analgesia, local anesthesia or nerve blockade in a
human following orthopedic, abdominal, gynecological or thoracic
surgical procedures, such as benign abdominal or thoracic surgical
procedures. Optionally, the benign abdominal or thoracic surgical
procedures include benign gynecological procedures such as
abdominal hysterectomies, myomectomy and adnexal surgery.
Optionally, in the method of the invention, the site in the human
or animal in need thereof comprises a surgical site, such as a
surgical site within a body cavity, for example, an abdominal or
thoracic cavity. Further optionally, in the method of the present
invention, a number of drug delivery devices of the present
invention are placed at one or more sites of tissue disruption
adjacent the surgical site, the number being such as to provide
effective local analgesia, local anesthesia or nerve blockade in
the human or animal in need thereof.
Optionally, in the method of the invention, the drug delivery
device comprises a plurality of collagen sponges and wherein one
sponge is divided between areas adjacent the surgical site, one
sponge is divided and placed across the incision in the wall of the
body cavity, for example the peritoneum, and one sponge is divided
and placed between the sheath and skin around the incision.
Further optionally, in the method of the invention, the drug
delivery device comprises a plurality of collagen sponges and
wherein at least one sponge is placed adjacent the surgical site,
optionally adjacent the site or sites of tissue disruption; at
least one sponge is placed across the incision in the wall of the
body cavity, for example the peritoneum (abdominal cavity wall);
and at least one sponge is placed between the sheath and skin
around the incision.
Still further optionally, in the method of the invention, the drug
delivery device comprises a plurality of collagen sponges and
wherein at least one sponge is placed adjacent the site or sites of
tissue disruption such as one or more of the surgical site itself,
skin, subcutaneous tissue, fascia, muscle and/or the parietal
peritoneum.
Optionally, the total implanted dose is controlled according to the
number and size of sponges administered and the location of the
implanted sponges. Dosing is based on the principle that a surgeon
implants one or more sponges on and around the various areas of
tissue disruption. For example, in the case of abdominal or
gastrointestinal (GI) surgery, sponges will be positioned below the
skin incision and across the peritoneal incision. The number and
size of sponges required (and hence the total dose of drug) will
depend upon the type of surgical procedure and variables such as
the size of the incision. For the overwhelming majority of routine
surgical procedures, it is considered that sponges having a total
surface area of up to 500 cm.sup.2 (and a depth or thickness of 0.5
cm), for example sponges having a total surface area of up to 125
cm.sup.2 (and a depth or thickness of 0.5 cm), will be sufficient
to provide effective local analgesia, local anesthesia or nerve
blockade to the areas of disrupted tissue.
Optionally, the dose employed in the method of the present
invention can be tailored to a particular surgical procedure
according to the extent of tissue disruption by varying the number
and size of sponges implanted.
Optionally, the dose employed in the method of the present
invention can be tailored to a particular surgical procedure
according to the sites of tissue disruption by varying the location
of the sponges to be implanted. Further optionally, the dose
employed in the method of the present invention can be tailored to
a particular surgical procedure according to the sites of tissue
disruption, by placing the sponges to cover the tissue disruption,
such as adjacent the sites of tissue disruption adjacent the
surgical site, adjacent the incision in the wall of the body
cavity, for example the peritoneum, and/or between the sheath and
skin around the incision.
The suggested bupivacaine dosing regimens for the different
abdominal surgeries are as follows: Herniorrhaphy: sponges having a
surface area of 50 cm.sup.2 and a depth or thickness of 0.5 cm (100
mg bupivacaine hydrochloride) Hysterectomy: sponges having a
surface area of 75 cm.sup.2 and a depth or thickness of 0.5 cm (150
mg bupivacaine hydrochloride) GI surgery: sponges having a surface
area of 75 or 100 cm.sup.2 and a depth or thickness of 0.5 cm (150
or 200 mg bupivacaine hydrochloride)
The proposed maximum dose of 4 (each 5.times.5 cm with a thickness
of 0.5 cm) sponges corresponds to a total bupivacaine hydrochloride
dose of 200 mg. According to the package insert for USP Bupivacaine
Injection, this marginally exceeds the standard bolus dose of 175
mg but is well within the recommended daily dose limit of 400 mg.
It will, of course, be appreciated that the maximum number and size
of implanted sponges (and, therefore, the drug dose) may vary
according to the recommended daily dose limit for the drug or drugs
in question.
Drug Substance
Suitable drug substances comprise amino amide anesthetics and amino
ester anesthetics and their salts, hydrates and prodrugs. Such drug
substances include, but are not limited to, amino amides such as
Bupivacaine, Levobupivacaine, Lidocaine, Mepivacaine, Prilocalne,
Ropivacaine, Articaine, Trimecaine and their salts and prodrugs;
and amino esters such as Benzocaine, Chloroprocaine, Cocaine,
Procaine, Tetracaine and their salts and prodrugs. Bupivacaine, and
its salts and prodrugs is an optional drug substance. Mixtures of
amino amides are contemplated, as are mixtures of amino esters.
Mixtures of amino amides and amino esters are also
contemplated.
Bupivacaine Hydrochloride (HCl) is a potent anesthetic and can
produce moderate to prolonged anesthesia. When compared to other
available amino amide anesthetics, the relatively longer duration
of action coupled with its action on sensory block, rather than
motor-block, permits prolonged anesthesia for post-operative pain.
Bupivacaine HCl can provide effective sensory block and analgesia
for several days. Bupivacaine HCl is indicated for moderate to
prolonged local anesthesia and, therefore, treatment of moderate to
acute pain.
Toxicity related to bupivacaine is caused by high systemic levels
and is characterized by numbness of the tongue, lightheadedness,
dizziness and tremors, followed by convulsions and cardiovascular
disorders.
The pharmacokinetics and pharmacodynamics of bupivacaine are well
understood. Bupivacaine is about 95% bound to plasma proteins.
Reported half-lives are from 1.5 to 5.5 hours in adults and about 8
hours in neonates. It is metabolized in the liver and is excreted
in the urine, principally as metabolites with only 5 to 6% as
unchanged drug. Bupivacaine is distributed into breast milk in
small quantities. It crosses the placenta but the ratio of fetal to
maternal concentrations is relatively low. Bupivacaine also
diffuses into the cerebrospinal fluid (CSF).
The toxic threshold for bupivacaine plasma concentrations is
considered to lie in the range of 2 to 4 micrograms/mL and, in the
US, the maximum single recommended dose for anhydrous bupivacaine
hydrochloride is 175 mg. Measurement of bupivacaine levels in the
clinical setting needs to demonstrate dosing and systemic levels
within these safety parameters. Thus, when it is suggested to
administer bupivacaine, whether in one or several collagen sponges,
it is suggested that the total dose should be no more than about
250 mg, optionally no more than about 200 mg, for anhydrous
bupivacaine hydrochloride.
Collagen
Fibrillar collagen from different sources may be used including
commercially available fibrillar collagen, for example, biomedical
collagen from Devro Biomedical Collagen, Australia. Currently there
are five known types of fibrillar collagen; Type I, II, III, V and
XI. Alternatively, collagen can be extracted from tendons or hides
of different animals, including horses, cattle, sheep and pigs. The
attention of the skilled reader is drawn to Gelse et al (Advanced
Drug Delivery Reviews 55 (2003), 1531-1546), the whole contents of
which are incorporated herein by reference for further details on
the various types of collagen. The present inventors have used a
bovine-derived collagen Type I for the manufacture of
bupivacaine-collagen sponges. Equine-derived collagen Type I is
also suitable for use in the present invention, as are fibrillar
collagen such as type I collagen from pigs and sheep. Type I
collagen is a connective tissue extracted from animal tendons and
other sources; in this case, the collagen is derived from bovine
tendons. The Type I collagen consists of three approximately 1,050
amino-acid-long polypeptide chains, two alpha-I chains, and one
alpha-2 chain. These are coiled to form a right-hand helix (known
as a triple helix) around a common axis. The rod-shaped molecule
has a length of 2900 Angstrom, a diameter of 14 Angstrom and a
molecular weight of approx. 300,000 Daltons.
Method of Manufacture
The following general method of manufacture refers to type I
collagen being produced from bovine tendons. However, alternative
sources of fibrillar collagen such as alternative sources of type I
or III collagen may be used in place of this methodology, without
departing from the scope of the teaching of this invention.
The following general method of manufacture refers to bupivacaine
as the drug substance. It will be appreciated that alternative drug
substance(s), or additional drug substance(s) (i.e. additional to
bupivacaine), may be used in place of bupivacaine alone, without
departing from the scope of the teaching of this invention.
Collagen
Production of Type I Collagen from Bovine Tendons: The collagen is
extracted from bovine Achilles tendon. During the manufacturing
process, bovine tendons are first treated with 1N sodium hydroxide
(NaOH) to clean and purify the material and to deplete the fat
content followed by neutralization with 1N HCl. This step is
followed by treatment with 0.9% sodium chloride (NaCl) solution to
remove low molecular weight soluble components of the collagen. A
treatment with hydrogen peroxide solution ensures bleaching of the
tendons.
Reduction of the particle size of the collagen material is followed
by fermentative breakdown using pepsin. Treatment with pepsin is
used to degrade contaminating serum protein components, primarily
bovine serum albumin and causes the detachment of non-helical
portions of the collagen molecule (telopeptides). After filtration,
precipitation of the collagen is accomplished by means of
manipulation of the pH (from acidic pH to neutral pH). The
fibrillar Type I collagen material is finally precipitated out of
solution, washed again with distilled water to remove residual
pepsin and then concentrated by means of centrifugation. The
production process is outlined in FIG. 1.
Bupivacaine Collagen Sponge--Method of Manufacture
FIG. 2 is a flow diagram representing the production of the
bupivacaine-collagen sponge. The skilled reader will appreciate
that other drug substance(s) may be used in place of, or in
addition to, the bupivacaine.
Compounding Process and Equipment
The fibrillar Type I collagen material prepared as in FIG. 1 is
added to pre-heated water (below 42.degree. C.) in a stainless
steel (SS) vessel. Collagen swelling and subsequent dispersion
formation is afforded by the use of a high-shear homogenizer. The
homogenizer employed possesses a rotor-stator head that is designed
to create high shear forces by pulling the collagen material
through the rotating homogenizer head and forcing it against the
proximal stationary stator head. It is this design that facilitates
the high shear forces required to separate the fibrous collagen
mass at the beginning of dispersion preparation.
Following completion of collagen dispersion formation, the
dispersion is transferred to a closed heated jacketed vessel for
final compounding. The jacket temperature is maintained at
36-38.degree. C.
The or each drug substance (such as bupivacaine HCl) raw material
is first dissolved in a portion of water at room temperature and is
then introduced into the heat-jacketed SS vessel under low shear
mixing to achieve homogeneity in the drug-loaded collagen
dispersion. The collagen/bupivacaine dispersion is a free flowing
opaque white to off-white liquid.
The dispersion is subsequently freeze-dried yielding a sponge
containing, in one embodiment, 5.6 mg/cm.sup.3 of collagen and 4.0
mg/cm.sup.3 of bupivacaine HCl in a final lyophilized 5 cm.times.5
cm product. Other product sizes can also be manufactured including
a 10 cm.times.10 cm sponge also containing, in an embodiment, 5.6
mg/cm.sup.3 of collagen and 4.0 mg/cm.sup.3 of bupivacaine HCl.
Filling/Lyophilization Process and Equipment
The collagen/drug dispersion is filled into appropriately sized
lyophilization molds or blister trays for freeze-drying and the
filling process is performed using a positive displacement pump.
The pump is valve-less, has ceramic pistons and works on the
principle of positive displacement.
Upon completion of tray filling, the filled moulds or blister trays
are placed into the lyophilizer. Thermocouples are placed both in
product and on shelves and a conductivity probe is also employed to
provide in-process feedback on process temperatures and
conductivity. The lyophilization process cycle used for the
bupivacaine-collagen sponge involves freezing down to a temperature
of -38.degree. C. over 3.5 hours, followed by drying to a
temperature of 30.degree. C. over 14.5 hours.
Ethylene Oxide (EtO) Sterilization Process
The lyophilized sponge is packed into suitable packaging material,
which may comprise of a sealed polyethylene blister or low density
polyethylene (LDPE) sachet in an outer pouch consisting of
polyethylene/LDPE laminate or aluminum foil. The product is then
subjected to terminal sterilization, which can be gas-mediated
ethylene oxide sterilization or radiation (gamma or electron beam).
In the preferred embodiment, sterilization by ethylene oxide gas
has been selected.
Ethylene oxide (C.sub.2H.sub.4O) is a gas at operating temperature
and sterilizes via its action as a powerful alkylating agent. Under
the correct conditions, cellular constituents of organisms such as
nucleic acid complexes, functional proteins and enzymes will react
with ethylene oxide, causing the addition of alkyl groups. As a
result of the alkylation, cell reproduction is prevented and cell
death ensues. Specific processing conditions and parameters must be
met to achieve this effect within the target product; including but
not limited to, acceptable concentration of ethylene oxide in the
chamber and a minimum water activity level within the organism. The
process is essentially a chemical reaction and is therefore
temperature dependent; the rate of reaction increases with
temperature. The optimum temperature is within the range of 30 and
40.degree. C. These properties define the key characteristics of
the ethylene oxide sterilization process.
The process is dependent on the water content existing in the
sponges and a consistent range of moisture content is achieved by
equilibration of the product with atmospheric humidity prior to
sterilization. An optimum water content is not less than 9%. The
product is loaded into stainless steel wire mesh baskets and placed
into the stainless steel sterilizer chamber using a defined loading
pattern. The sterilization chamber is then evacuated to remove air
and ethylene oxide is introduced until the required concentration
is achieved.
Product is held under these conditions for a defined period and, on
completion of the pre-determined dwell period, ethylene oxide from
the chamber is exhausted to the atmosphere via catalytic
converters. These units ensure catalytic conversion of ethylene
oxide to carbon dioxide and water with high efficiency. The
sterilization chamber and its contents are then repeatedly flushed
with air to remove the remaining ethylene oxide from the chamber.
After completion of post sterilization flushing, the product is
transferred to a holding area for longer term aeration. This phase
of the process serves to further scavenge low level residual
ethylene oxide from the product and packaging. The product is held
at room temperature until the limits for ethylene oxide derivative
residues have been reached.
Alternative Sterilization Process and Equipment
Radiation sterilization including gamma and electron beam may be
used instead of the EtO sterilization process mentioned above.
The bupivacaine-collagen sponge manufactured under this general
method of manufacture is a drug-delivery system composed of a Type
I collagen matrix containing the amide local anesthetic bupivacaine
HCl. The release of bupivacaine is primarily by dissolution and
diffusion from the porous matrix with the collagen sponge acting as
an inert delivery system.
Hysterectomies
Hysterectomy is the second most common surgery among women in the
United States (US). According to the National Center For Health
Statistics, there were 617,000 hysterectomies performed in the US
in 2004. Indications for hysterectomy include benign tumors, such
as fibroids, heavy periods, painful periods and chronic pelvic
pain. The most common route for performing hysterectomy is through
an incision in the abdominal wall; however, about 20% are performed
vaginally. Laparoscopic-assisted vaginal hysterectomy is performed
when warranted.
Pain Control after Surgery, Such as Hysterectomies
Effective postoperative pain management is important in ensuring
that surgical subjects have a smooth and successful recovery after
their operation. Pain after abdominal hysterectomy can be
multifactoral. Incision pain, pain from deeper (visceral)
structures, and particularly, dynamic pain, such as during
straining, coughing, or mobilizing, can be quite severe. In one
study, the authors found that visceral pain dominated during the
first 48-hours after hysterectomy (Leung, 2000).
Morphine is often used via patient-controlled analgesic (PCA) pumps
to control post-operative pain, but the large quantities required
can lead to fatigue, nausea and vomiting, as well as the inability
to mobilize because of drowsiness. Subjects usually require PCA for
at least 24-hours, after which they receive oral analgesic drugs.
The average postoperative narcotic consumption during the first
24-hours varies from 35 to 62 mg (Gupta, 2004) and the average
postoperative morphine consumption using bupivacaine infiltration
in both and superficial layers of the wound after abdominal
hysterectomy was 54 mg (Klein et al, 2000) and 44 mg (Ng et al,
2002).
Collagen Products
The properties of insoluble and soluble collagen have led to its
use in a variety of medical applications ranging from heart valves
to dermal implants. Soluble collagen can be used to produce
biodegradable or non-biodegradable materials that give useful
mechanical properties and biocompatibility.
Soluble collagen can be cross-linked to produce semi-permanent,
non-absorbable implants that can be delivered by intradermal
injection such as those used in facial aesthetics. These were first
approved by the US Food and Drug Administration (FDA) in the
1980s.
The present collagen matrix can be a localized drug delivery system
based on a fibrillar (Type I or Type III) collagen matrix,
optionally derived from bovine Achilles tendons. The products are
manufactured as a lyophilized sponge.
Embodiments of the invention will now be demonstrated by reference
to the above-mentioned General Method of Manufacture, which is then
exemplified by reference to the Clinical Study described
hereunder.
Specific embodiments of the invention will now be demonstrated by
reference to the following general methods of manufacture and
examples. It should be understood that these examples are disclosed
solely by way of illustrating the invention and should not be taken
in any way to limit the scope of the present invention.
EXAMPLES
Clinical Study
The effective relief of pain is of paramount importance to those
treating patients undergoing surgery. This should be achieved for
humanitarian reasons, but there is now evidence that pain relief
has significant physiological benefit. Not only does effective pain
relief mean a smoother postoperative course with earlier discharge
from hospital, but it may also reduce the onset of chronic pain
syndromes. Topical or local administration of anesthetics directly
at the surgical site has the advantage of producing high local
anesthetic concentrations, while minimizing potentially toxic
systemic concentrations.
The bupivacaine-collagen sponge is highly malleable and can be
applied directly, rolled or folded, giving the surgeon great
flexibility in terms of application in wounds scheduled for
closure.
Patients received three 5 cm.times.5 cm (.times.0.5 cm thick)
sponges; one sponge divided between areas adjacent the surgical
site (in this case, adjacent the location of the now-removed
uterus), one sponge divided and placed across the incision in the
wall of the body cavity (in this case, the peritoneum) and the
final sponge divided and placed between the sheath and skin around
the incision. Each sponge contained 50 mg of bupivacaine
hydrochloride, giving a total dose of 150 mg per patient.
This was a single dose, open-label, prospective clinical study to
investigate drug delivery devices in the form of a
bupivacaine-collagen sponge in patients following hysterectomy, for
pain control in hysterectomy. The patients were scheduled to
receive a hysterectomy in the absence of uterine adenocarcinoma,
cervical cancer, leiomyosarcoma or the suspicion of these cancers.
Enrolled patients were to receive a total of three 5 cm.times.5
cm.times.0.5 cm bupivacaine-collagen sponges implanted at specified
layers in the wound prior to wound closure. Each
bupivacaine-collagen sponge was impregnated with 4 mg/cm.sup.3 of
bupivacaine.
Patient Selection Criteria
Inclusion Aged between 18 to 60 years 60-95 Kg in weight Able and
willing to comply with pain relief regime outlined in the protocol
Exclusion Known hypersensitivity to amide local anesthetics,
NSAIDS, opioids and bovine collagen Cardiac arrhythmias or AV
conduction disorders Concomitant use of other amide local
anesthetics Concomitant use of anti-arrhythmics e.g. Amiodarone
Concomitant use of propanolol Spinal blockade Concomitant use of
strong/moderate CYP3A4 inhibitors or inducers e.g. macrolide
antibiotics, grapefruit juice etc. Previous major surgery in last 6
months Hepatic impairment Any clinically significant unstable
cardiac, neurological, immunological, renal or haematological
disease or any other condition that in the opinion of the
Investigator would interfere with the course of the study
Participation in a clinical trial using an Investigational Product
in the previous 6 months Hemodynamically unstable at any point in
the previous 4 weeks Requirement for blood transfusion in the
previous 3 months Haemoglobin below 10 g/dL Objectives Objectives
To investigate the potential analgesic effect of the
bupivacaine-collagen sponge in the hysterectomy wound. To
investigate the morphine sparing effect of using
bupivacaine-collagen sponge as part of the post-operative analgesia
regimen. To evaluate trends in numerical rating scales of pain
intensity The study outcomes comprise: Visual analogue pain rating
scale (VAS) Morphine sparing effect Study Duration
Screening assessments (informed consent, medical history, vital
signs, 12-lead electrocardiogram, clinical biochemistry and
hematology, urinalysis and demographics) took place between 1 and
14 days prior to administration of the bupivacaine-collagen sponge.
Baseline (0 hours) procedures included allocation of study number,
baseline pain scoring and implantation of the sponge. Follow-up
procedures took place over 96 hours post implantation. A follow-up
call was performed 8 days after implantation.
Methodology
Safety Analysis
Vital signs and clinical assessment for signs of systemic
bupivacaine toxicity were repeated at 30 mins, 1, 1.5, 2, 3, 4, 5,
6, 9, 12 & 96 hours. A follow-up call was to be performed 8
days after surgery to check if the patient was suffering from any
adverse event or is experiencing any problem with the wound.
Concomitant medication (including doses of morphine and other pain
medications) was collected from the screening until assessment
18.
TABLE-US-00001 TABLE 1 Safety Blood and Urinalysis Tests
Haematology Blood Chemistry Urinalysis Haematocrit Sodium Total
bilirubin pH Haemoglobin Chloride Direct bilirubin Protein RBC
Magnesium ALT (SGPT) Glucose Platelet Potassium AST (SGOT) Occult
blood WBC with Calcium Ferritin differential Bicarbonate
Transferritin PT Glucose GGT PTT Phosphorus Iron Uric Acid
C-reactive protein Creatinine Total Cholesterol Blood Urea Nitrogen
Triglycerides (BUN)
Efficacy Evaluations
Pain scoring using a visual analogue score (VAS) was used to assess
the patient's experience of pain at 1, 1.5, 2, 3, 6, 9, 12, 18*,
24, 36, 48, 72 & 96 hour timepoints. Following surgery,
patients were provided with PRN (per re nata, as needed) morphine
via a PCA pump. Patient demand for morphine was recorded. *The pain
assessment at 18 hours was optional so that sleep is not
disturbed.
TABLE-US-00002 LIST OF ABBREVIATIONS AE Adverse Events AUC.sub.last
Area under the plasma concentration-time curve from time zero to
time t (time of last quantifiable plasma concentration) AUC.sub.inf
Area under the plasma concentration-time curve from time zero to
infinity C.sub.max Maximum plasma concentration LOQ Limit of
quantification PCA Patient Controlled Analgesia PRN per re nata (as
needed) t.sub.lag Lag-time t.sub.max Time of maximum plasma
concentration t.sub.1/2 Terminal half life .lamda..sub.z Terminal
phase rate constant VAS Visual Analogue Scale
Pain Control Medication (Supplemental to the Bupivacaine-Collagen
Sponge)
At induction, patients received 50-75 .mu.g fentanyl. Following
catheterization and prior to the commencement of surgery, they also
received 100 mg diclofenac rectally. Intraoperatively, morphine was
administered intravenously as required to maintain adequate levels
of analgesia. Post-operatively, patients received 1 g paracetamol
six hourly, 50 mg diclofenac every 8 hours, with a maximum of 3
doses in any 24 hours, and morphine PRN (per re nata, as needed)
using a patient controlled analgesia pump.
Concomitant Therapy
Permitted Concomitant Therapies
In order to ensure conformity in the amount of analgesia received
post-operatively, all patients received 1000 mg paracetamol at 6
hourly intervals and 50 mg diclofenac at 8 hourly intervals and
morphine PRN using a PCA pump.
Prohibited Concomitant Therapies
All analgesics were stopped for 24 hours prior to the study
commencing. In addition, the following therapies (Table 2) were not
administrated concomitantly with the implantation of the
bupivacaine-collagen sponge.
TABLE-US-00003 TABLE 2 Prohibited Concomitant Therapies Strong or
Moderate Inhibitors of the CYP3A4 Pathway Inducers of the CYP3A4
Pathway Grapefruit juice troglitazone Methadone phenytoin
Itraconazole rifampicin Ketoconazole carbamazepine Fluconazole
phenobarbal Clarithromycin St. John's Wort (hypericin) Erythromycin
Nefazodone Fluoxetine Ritonavir Indinavir Nelfinavir Amprenavir
Saquinavir
Results Safety Analysis Current Safety Data from Clinical Study
TABLE-US-00004 Pt No AE Description Causality Severity Treatment
Outcome 001 Urine infection Unlikely Moderate No Antibiotics
Resolved by Day 8 001 Nausea on 27 -01 Unlikely Moderate Odensatron
& resolved by ciclizine Day 8 001 Visual Disturbances Possibly
Moderate None resolved by Day 8 001 Raised white cell Unlikely Mild
None Resolved count 001 Raised neutrophil Unlikely Mild None
Resolved count 002 Nausea on 27 -01 Unlikely Mild None Resolved 002
2 predose event: -- -- -- -- blood in urine, high ALT 002 Anemia
Unlikely Mild None Resolved 002 High ALT Possible Mild None
Resolved 003 Increased BP 1st Unlikely Moderate None Resolved by
few hours Day 2 considered normal for patient & not significant
003 Raised C-reactive Unlikely Moderate None Resolved Protein 004
Anaemia HB 11 to Unlikely Moderate 2 Units blood Hb 10 8
transfusion 004 Urine infection Unlikely Moderate Augmentin 625
Resolved TDS 5 Days 004 Blood in urine Unlikely Moderate none
Unresolved 004 Raised C-reactive Unlikely Moderate None Resolved
Protein 005 Bruising Around Possible Moderate None Unresolved
Abdomen 005 Wheezing Unlikely Mild None resolved 005 Raised
C-reactive Unlikely Mild None Unresolved Protein 006 Itchy chest
and back unknown Moderate Concomitant Resolved with rash -
urticaria medication Required 006 Anaemia unknown Mild None
Resolved 007 Raised Phosphate Possible Mild None Resolved 007 Itchy
skin on face, Unlikely Moderate Concomitant Resolved neck, right
arm, feet - medication pruritus Required 007 wound infection
Unlikely Moderate Concomitant Resolved medication Required 007
wound dehiscence Unlikely Mild none Resolved 007 Urine infection
Unlikely Moderate None Resolved 007 Raised Phosphorus Possible Mild
None Resolved 007 Diarrhoea Unlikely Moderate None Resolved 007
wound dehiscence Unlikely Moderate Resuture under Resolved local
anesthetic 008 Lower back pain Not related Moderate Concomitant
Resolved medication Required 008 Heat rash Not related Mild None
Resolved 008 Rise of C-reactive Unlikely Mild None Resolving
protein 008 Rise of White cell Unlikely Mild None Resolved count
009 Low platelet count Unlikely Moderate None Resolved 009 Raise of
Phosphate Unlikely Mild None Resolved 009 Raise of ALT Possible
Mild None Resolved 009 Raise of AST Possible Mild None Resolved 010
Low back pain Unlikely Mild Concomitant Resolved medication
Required 011 Nausea, vomiting Unlikely +++ Concomitant Resolved
medication given: Cyclizine 011 PT out of range Unlikely UN None
Resolved 012 Nausea Unlikely Moderate Concomitant Resolved
medication given: Cyclizine 012 Abdominal "wind" Unlikely Mild None
Resolved pain 012 Low serum Possible Mild None Resolved
phosphate
Efficacy Analysis
Efficacy of the bupivacaine-collagen sponge was determined by use
of visual analogue scales and by the morphine sparing effect.
Pain Scoring (Visual Analogue Pain Rating Scale)
Pain scoring using a visual analogue scale ranging from 0 (no pain)
to 100 (worst imaginable pain). These were assessed from 1 hour
onwards according to the assessment schedule. Individual pain
scores were listed for each assessment time.
Morphine Sparing
Patients were given 6 hourly doses of 1000 mg paracetamol, 8 hourly
doses of 50 mg diclofenac and morphine PRN via patient controlled
analgesia (PCA) pump. The doses of morphine demanded by each
patient over the first 24 hours of the treatment period were
recorded and compared to historical data in the literature. Total
doses of morphine required over the treatment period were listed
for each patient.
12 subjects have, to date, been dosed and completed in this study.
The total morphine usage and pain scores (Visual Analog Scale of 0
to 100 mm where 0 is no pain and 100 is the worst imaginable pain)
that have been reported by these 12 subjects are presented in
Tables 3 and 4.
Table 3 below shows that the average postoperative morphine
consumption for the first 4 enrolled patients was 9 mg over the
first 24 hours post-op. In contrast, the average post-operative
morphine consumption using bupivacaine infiltration in both deep
and superficial layers of the wound after abdominal hysterectomy
was 54 mg (Klein et al, 2000) and 44 mg (Ng et al, 2002) and
narcotic consumption during the first 24 hours varied from 35 to 62
mg (Gupta, 2004).
Morphine Sparing (PCA)
PCA morphine usage was collated over 24 hours and the average
consumption was 16.8 mg (all 12 patients) (see Table 3 below). This
mean value includes two outliers. One patient consumed 58 mg of
morphine due to an underlying back condition and a second patient
consumed 74 mg, who received non-standard anesthesia/analgesia
during surgery. Without these two outliers, the mean morphine
consumption was 7.1 mg. Literature data indicates morphine use
ranging between 32 to 65 mg over the first 24 hours and the study
data showing consumption of 31 to 99 mg morphine over 24 hours.
Table 3 provides data on PCA morphine consumption for each
patient.
Visual Analogue Scores (Pain)
The onset of pain relief occurred around 6 hours (mean VAS of 10.3
mm) and was maintained up to day of discharge (day 4-6) according
to the VAS data. At 24 hours post-op, the mean score was 6.8 mm
(25% of patients scored 0); at 48 hours it was 2.8 mm (7 of 12
patients scored 0) and at 72 hours the mean VAS was 2.7 mm and 50%
of the patients scored 0 at this time-point. Several patients
reported no pain even on application of pressure to the wound.
Table 4 provides a summary of the VAS pain scores and Table 3
presents a table of individual pain scores and morphine consumption
for all patients at key time-points.
TABLE-US-00005 TABLE 3 Summary of PCA Morphine Usage and Pain
Scores of First 12 Subjects Enrolled in Ongoing Clinical Study
Patient no 001 002 003 004 005 006 007 Age 35 45 45 48 44 45 44
Date of enrollment 26 Jan. 2007 2 Feb. 2007 8 Feb. 2007 8 Feb. 2007
16 Feb. 2007 23 Mar. 2007 23 Mar. 2007 (date of surgery) Total
Amount of 28 7 0 1 10 62 2 Morphine consumed (mgs) VAS Pain 1 h 68
45 2 19 36 34 22 scores 1.5 h 49 34 7 19 31 32 24 (mm) 2 h 43 56 13
30 27 25 41 3 h 43 65 13 24 0 14 41 6 h 16 5 0 10 0 17 5 9 h 4 2 0
12 4 9 3 12 h 4 0 6 6 1 13 20 18 h ND 0 4 6 8 65 24 24 h 14 3 2 4 0
25 1 36 h 24 2 3 0 21 11 0 48 h 2 0 0 0 7 3 0 72 h 1 9 0 0 2 11 6
96 h 0 6 0 0 1 7 11 Day of discharge 5 4 5 5 6 UNK 4 Patient no 008
009 010 011 012 Age 41 42.00 34 40 40 Date of enrollment 13 Apr.
2007 39206.00 11 May 2007 25 May 2007 13 Jul. 2007 (date of
surgery) Total Amount of 57* 15.00 2 74** 0 Morphine consumed (mgs)
VAS Pain 1 h 48 5.32 0.00 100.00 17.02 scores 1.5 h 55 0.00 47.87
72.34 18.09 (mm) 2 h 34 29.79 28.72 80.85 17.02 3 h 21 50.00 29.79
84.04 9.57 6 h 12 14.89 10.64 34.04 2.13 9 h 2 10.64 12.77 34.04
1.06 12 h 2 3.19 13.83 23.40 5.32 18 h 8 1.06 7.45 21.28 14.89 24 h
0 0.00 3.19 26.60 3.19 36 h 0 0.00 3.19 4.26 2.13 48 h 0 0.00 0.00
22.34 1.06 72 h 0 0.00 0.00 2.13 0.00 96 h 0 0.00 0.00 0.00 0.00
Day of discharge 6 6 5 5.sup. 4 *Patient suffered from an
underlying lower back pain problem **Patient received non-standard
anesthesia/analgesia
TABLE-US-00006 TABLE 4 Summary of VAS Pain Scores: Efficacy
Population Time Post Implantation VAS Pain Score (mm) (hours) Mean
SD Range 1 33.5 29.3 0-100 1.5 31.6 20.1 0-72 2 34.7 17.5 13-81 3
32.0 23.7 0-84 6 10.3 9.3 0-34 9 7.9 9.2 0-34 12 7.9 7.4 0-23 18
14.4 18.4 0-65 24 6.8 9.5 0-27 36 5.8 8.4 0-25 48 2.8 6.1 0-22 72
2.7 3.9 0-11 96 2.2 3.7 0-11
Pharmacokinetics:
The mean C.sub.max was 0.22 .mu.g/ml and the highest individual
C.sub.max was 0.44 .mu.g/ml, which is well below the known systemic
toxicity level of 2-4 .mu.g/ml for bupivacaine. The PK profile was
similar for all patients and showed a decline in systemic levels
after 24 hours. Table 5 provides a summary of the PK
parameters.
TABLE-US-00007 TABLE 5 Summary of Bupivacaine Hydrochloride
Pharmacokinetic Results: Efficacy Population Parameter n Mean SD
t.sub.lag (h)* 12 0.000 0.00-0.00 C.sub.max (ng/mL) 12 224.911
83.100 t.sub.max (h)* 12 12.000 0.53-24.00 .lamda..sub.z (h.sup.-1)
11 0.07084 0.01307 t.sub.1/2z (h) 11 10.092 1.836 AUC.sub.last (ng
h/mL) 12 6531.2 2248.9 AUC.sub.inf (ng h/mL) 11 6359.8 2230.1
Safety:
There were a total of 45 adverse events (AEs) reported by all
patients, of which 44 were treatment-emergent. The majority of AEs
reported in the study were not classified as being
treatment-related, with only eight out of the 44 being deemed to be
related. Of these, the majority were mild in severity and were all
resolved. There was one serious adverse event reported during the
study, which was moderate in severity and not related to the use of
the Bupivacaine-containing drug delivery device of the present
invention.
Conclusion:
The results of this trial are very encouraging and demonstrate pain
relief coverage over the first 72 hours (and beyond) post-op
according to VAS data. The low morphine use observed is a key
feature for the drug delivery device of the present invention to
facilitate recovery of the patient and to avoid debilitating
narcotic side-effects.
EXAMPLE
Clinical Study-Dose Determination for Abdominal Hysterectomies and
Other Non-Laparoscopic Benign Gynecological Procedures Such as
Myomectomy and Adnexal Surgery
The drug delivery device of the present invention is designed to
provide prolonged, local analgesia by direct application of the
drug delivery device to the site of tissue disruption. However, it
should be emphasized that the drug delivery device of the present
invention is not expected to provide complete relief from all
postoperative pain or entirely eliminate the need for rescue
analgesia medication but, instead, is intended as part of
multimodal therapy for safe and effective pain management.
Each bupivacaine-containing drug delivery sponge has a surface area
of 25 cm.sup.2 (5.times.5 cm) and a thickness of approximately 0.5
cm. The active ingredient (bupivacaine hydrochloride) is
homogenously dispersed throughout the collagen drug delivery matrix
and, on a surface area basis, has a concentration of 2 mg/cm.sup.2.
This concentration targets the maximum achievable bupivacaine drug
loading that still maintains the optimum physicochemical properties
and performance attributes of the drug delivery device of the
present invention; it corresponds to a weight ratio of 5 parts
bupivacaine hydrochloride to 7 parts collagen.
Although the bupivacaine dose is fixed on a surface area basis, the
total implanted dose is controlled according to the number of
sponges administered and the location of administration of the
sponges. Dosing is based on the principle that a surgeon implants
the sponge on and around the areas of tissue disruption. For
example, in the case of GI surgery, the sponge will be positioned
below the skin incision and across the peritoneal incision. The
number of sponges required (and hence the total dose of bupivacaine
hydrochloride) will depend upon the type of surgical procedure and
variables such as the size of the incision. For the overwhelming
majority of routine surgical procedures, it is considered that
sponges having a total surface area of up to 100 or 125 cm.sup.2
and a thickness of 0.5 cm will be sufficient to adequately cover
the areas of disrupted tissue.
The present inventors are studying efficacy in both moderate
(herniorrhaphy) and major surgeries (total abdominal hysterectomy
and open gastrointestinal surgery). The proposed dosing regimens
for these different surgeries are as follows: Herniorrhaphy:
sponges having a total surface area of 50 cm.sup.2 and a thickness
of 0.5 cm (100 mg bupivacaine hydrochloride) Hysterectomy: sponges
having a total surface area of 75 cm.sup.2 and a thickness of 0.5
cm (150 mg bupivacaine hydrochloride) GI surgery: sponges having a
total surface area of 75 or 100 cm.sup.2 and a thickness of 0.5 cm
(150 or 200 mg bupivacaine hydrochloride)
The proposed maximum dose of 4 (5.times.5 cm, with a thickness of
0.5 cm) sponges corresponds to a total bupivacaine hydrochloride
dose of 200 mg. According to the package insert for USP Bupivacaine
Injection, this marginally exceeds the standard bolus dose of 175
mg but is well within the recommended daily dose limit of 400
mg.
In summary, it is believed that the variable dosing regimens as
provided by a fixed dose of 2 mg/cm.sup.2 bupivacaine hydrochloride
(50 mg/sponge; 5.times.5 cm, with a thickness of 0.5 cm) is
justified for the following reasons when taking established safety,
efficacy and product technology factors and principles into
account: i) The upper dose limit (on an mg/cm.sup.2 basis) is
primarily controlled by the drug delivery technology of the present
invention. The potential for local analgesia at the site of tissue
disruption using this technology is therefore maximized by having
an optimally high drug loading in the drug delivery sponge of the
present invention. ii) The dose of the drug substance (such as
bupivacaine) can be tailored to a particular surgical procedure
according to the extent of tissue disruption by varying the number
and size of sponges implanted. iii) The dose of the drug substance
(such as bupivacaine) can be tailored to a particular surgical
procedure according to the sites of tissue disruption by varying
the location of the sponges to be implanted. iv) A maximum drug
substance dose in sponges having a surface area of up to 500
cm.sup.2 and a thickness of 0.5 cm provides sufficient coverage for
the majority of moderate and major surgeries. A maximum bupivacaine
dose in sponges having a surface area of up to 125 cm.sup.2 and a
thickness of 0.5 cm provides sufficient coverage for the
overwhelming majority of moderate and major surgeries. The
corresponding maximum dose of bupivacaine hydrochloride is 200 mg
which, although it marginally exceeds the standard bolus dose, is
well within the recommended daily dose (400 mg) for USP Bupivacaine
Injection. v) The bupivacaine-containing drug delivery sponge of
the present invention is intended as part of multimodal therapy for
the management of postoperative pain and is not expected to provide
complete relief from postoperative pain or entirely eliminate the
need for rescue medications. Clinical trials investigating lower
drug loadings (i.e. less than 2 mg/cm.sup.2) are therefore
considered to be of limited value since the expected result is one
of reduced patient benefit and a greater dependence on rescue
medications.
The invention is not limited to the embodiments described and
exemplified herein, which may be modified and amended without
departing from the scope of the present invention. While the
invention has been described above with reference to specific
embodiments thereof, it is apparent that many changes,
modifications, and variations can be made without departing from
the inventive concept disclosed herein. Accordingly, it is intended
to embrace all such changes, modifications, and variations that
fall within the spirit and broad scope of the appended claims.
REFERENCES
Gupta A, Perniola A, Axelsson K, Thorn S E, Crafoord K, and Rawal N
(2004). Postoperative pain after abdominal hysterectomy: a
double-blind comparison between placebo and local anesthetic
infused intraperitoneally. Anesth Analg 99:1173-1179. Leung C C,
Chan Y M, Ngai S W, et al (2000). Effect of pre-incision skin
infiltration on post-hysterectomy pain--a double-blind randomized
controlled trial. Anaesth Intensive Care 2000; 28:510-516. Ng A,
Swami A, Smith G, et al (2002). The analgesic effects of
intraperitoneal and incisional bupivacaine with epinephrine after
total abdominal hysterectomy. Anesth Analg 2002; 95:158-162.
Sinclair et al, 1996 Postoperative pain relief by topical lidocaine
in the surgical wound of hysterectomized patients; Acta
Anaesthesiologica Scandinavica 40: 589-594 Hannibal et al, 1996
Preoperative wound infiltration with bupivacaine reduces early and
late opioid requirements after hysterectomy. British Journal of
Anaethesiology 83: 376-381 Cobby et al, 1997 Wound infiltration
with local anaesthetic after abdominal hysterectomy British Journal
of Anaethesiology: 78: 431-432 Victory et al, 1995 Effect of
preincision versus postincision infiltration with bupivacaine on
postoperative pain Journal of Clinical Anesthesia 7:192-196
Bartholdy et al, 1994 Preoperative infiltration of the surgical
area enhances postoperative analgesia of a combined low-dose
epidural bipivacaine and morphine regimen after upper abdominal
surgery. Acta Anaesthesiologica Scandinavica 38: 262-265 Moiniche
et al, 1998 A qualitative systemic review of incisional local
anaesthesia for postoperative pain relief after abdominal
operations; British Journal of Anaesthesia; 81: 377-383 Klein et
al, 2000 Infiltration of the abdominal wall with local anaesthetic
after total abdominal hysterectomy with no opioid-sparing effect;
British Journal of Anaesthesia 84 (2): 248-9.
* * * * *
References