IE20080229U1 - A drug delivery device for providing local analgesia, local anesthesia or nerve blockade - Google Patents
A drug delivery device for providing local analgesia, local anesthesia or nerve blockadeInfo
- Publication number
- IE20080229U1 IE20080229U1 IE2008/0229A IE20080229A IE20080229U1 IE 20080229 U1 IE20080229 U1 IE 20080229U1 IE 2008/0229 A IE2008/0229 A IE 2008/0229A IE 20080229 A IE20080229 A IE 20080229A IE 20080229 U1 IE20080229 U1 IE 20080229U1
- Authority
- IE
- Ireland
- Prior art keywords
- bupivacaine
- collagen
- local
- drug substance
- drug delivery
- Prior art date
Links
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
Abstract
ABSTRACT The invention relates to a drug deliver 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.
Description
A drug delivery device for providing local analgesia, local anesthesia or nerve
Field of the Invention
[0001] 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
[0002] 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.
[0003] 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.
[0004] 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.
[0005] 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
1
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
[0006] 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.
[0007] 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 hemiotomy, open
cholecystectomy, appendectomy, Caesarean 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.
[0008] 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, 500mg 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 45ml 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).
[0009] Studies in other models have shown short-term analgesic effects over 4 to 7 hours.
In three studies on Caesarean section, 0.25% or 0.5% bupivacaine 20ml 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) (l0mg) was noted and a reduction in visual
analogue scoring (VAS) only during mobilization was recorded (50mm) (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 hemiotomy 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.
[0010] 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.
[0011] 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.
[0012] 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 (12.5mg/hr) over 24 hours and showed a
significant reduction in incisional pain, deep pain and pain on coughing at 1-2 hours post
I--,5 ..... ,_ if
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.
[0013] The apparent efficacy of anesthetic infusions explains the widespread use of
ambulatory pain pumps, such as I-Flow’s ON-Q® Painbuster. However, such continuous
infusion devices use much higher total doses of bupivacaine (between 2.5mg/hr and
50mg/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.
[0014] 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 estcr
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.
[0015] 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
'5 - {B :0‘, ' "3
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
[0016] 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
[0017] Figure 1 shows, schematically, a flow diagram for the production of collagen.
[0018] Figure 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
[0019] 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.
[0020] 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
IE @ ti ,;
device compiising 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 iii 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.
[0021] 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 tibrillar 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.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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
. »~~ -»————-~--—---~ v
[E (" /“t .
’ * Fi. iv)’
- -; V‘
an ‘M
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.
[0027] 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, Prilocaine, 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, Prilocaine, Ropivacaine,
Articaine, Trimecaine and their salts and prodrugs.
[0028] Optionally, in the device or method of the invention, the fibrillar collagen matrix is
a Type I collagen matrix.
[0029] 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 8.0mg/cm3 type I collagen and about 2.0 to about 6.0mg/cm3
bupivacaine hydrochloride. Still further optionally, the drug delivery device comprises a
plurality of collagen sponges, each collagen sponge containing about 5.6mg/cm} type I
collagen and about 4.0mg/cm3 bupivacaine hydrochloride.
[0030] Optionally, in the method of the invention, the method is for providing local
analgesia, local anesthesia or nerve blockade in a human following laparotomy.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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 cm2(and a depth or thickness of 0.5 cm), for example
sponges having a total surface area of up to 125 cm2(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.
[0037] 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.
[0038] 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.
[0039] The suggested bupivacaine dosing regimens for the different abdominal surgeries
are as follows:
Hemiorrhaphy: sponges having a surface area of 50 cm: and a depth or thickness of
0.5 cm (100 mg bupivacaine hydrochloride)
0 Hysterectomy: sponges having a surface area of 75 cm2 and a depth or thickness of
0.5 cm (150 mg bupivacaine hydrochloride)
0 G1 surgery: sponges having a surface area of 75 or 100 cm2 and a depth or thickness
of 0.5 cm (150 or 200 mg bupivacaine hydrochloride)
[0040] The proposed maximum dose of 4 (each 5 x 5 cm with a thickness of0.5 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
[0041] 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,
t ,1», 7-Ti‘
ii ‘
Mepivacaine, Prilocaine, 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.
[0042] 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 HCI 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.
[0043] Toxicity related to bupivacaine is caused by high systemic levels and is
characterized by numbness of the tongue, light-headedness, dizziness and tremors,
followed by convulsions and cardiovascular disorders.
[0044] 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 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).
[0045] 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
[0046] 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 X1. 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-l chains, and one alpha-2 chain. These are coiled to fonn 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
[0047] 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.
[0048] The following general method of manufacture refers to bupivacaine as the drug
substance. It will be appreciated that altemative 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
[0049] 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 (N aOH) to clean and purify the material and to deplete
the fat content followed by neutralization with 1N HCI. 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.
IE 0
[0050] 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 Figure 1.
Bupivacaine Collagen Sponge - Method of Manufacture
[0051] Figure 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
[0052] The fibrillar Type I collagen material prepared as in Figure 1 is added to pre-heated
water (below 42°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.
[0053] 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°C.
[0054] 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.
[0055] The dispersion is subsequently freeze-dried yielding a sponge containing, in one
embodiment, 5.6mg/cm3 of collagen and 4.0mg/cm3 of bupivacaine HCl in a final
lyophilized 5cm X 5cm product. Other product sizes can also be manufactured including a
12
cm x 10cm sponge also containing, in an embodiment, 5.6mg/cm3 of collagen and
4.0mg/cm} of bupivacaine HCI.
Filling/Lyophilization Process and Equipment
[0056] The collagen/drug dispersion is filled into appropriately sized lyophilization molds
or blister trays for freeze—drying and the filling process is perfomied using a positive
displacement pump. The pump is valve—less, has ceramic pistons and works on the
principle of positive displacement.
[0057] 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°C over 3.5 hours,
followed by drying to a temperature of 30°C over 14.5 hours.
Ethylene Oxide (Et0) Sterilization Process
[0058] 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.
[0059] Ethylene oxide (C2H4O) 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°C. These properties define the key
characteristics of the ethylene oxide sterilization process.
[0060] 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.
[0061] 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 fi.1I'lh€I‘ 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
[0062] Radiation sterilization including gamma and electron beam may be used instead of
the EtO sterilization process mentioned above.
[0063] 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
[0064] 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.
14
Pain Control after Surgery, such as Hysterectomies
[0065] 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 multifactorial. 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).
[0066] 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
62mg (Gupta, 2004) and the average postoperative morphine consumption using
bupivacaine infiltration in both and superficial layers of the wound after abdominal
hysterectomy was 54mg (Klein et al, 2000) and 44mg (Ng et al, 2002).
Collagen Products
[0067] 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.
[0068] Soluble collagen can be cross-linked to produce semi-permanent, non-absorbable
implants that can be delivered by intraderrnal injection such as those used in facial
aesthetics. These were first approved by the US Food and Drug Administration (FDA) in
the 19805.
[0069] 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.
[0070] 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.
[0071] 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
[0072] 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.
[0073] 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.
[0074] Patients received three 5cm x 5 cm (x 0.5cm 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 50mg of bupivacaine
hydrochloride, giving a total dose of 150mg per patient.
[0075] This was a single dose, open-label, prospective clinical study to investigate drug
delivery devices in the fonn 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 5cm x
5cm x 0.5cm bupivacaine-collagen sponges implanted at specified layers in the wound
prior to wound closure. Each bupivacaine-collagen sponge was impregnated with
mg/cm3 of bupivacaine.
PATIENT SELECTION CRITERIA
Inclusion
Aged between 18 to 60 years
- . ’- /5 2:“. “mil 5‘. it
.; _.. ,,y :_
,3 »._., . vi)‘
-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 lnvestigational Product in the previous 6 months
Haemodynamically 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.
0 To investigate the morphine sparing effect of using bupivacaine-collagen sponge as
part of the post-operative analgesia regimen.
0 To evaluate trends in numerical rating scales of pain intensity
The study outcomes comprise:
0 Visual analogue pain rating scale (VAS)
0 Morphine sparing effect
STUDY DURATION
[0076] Screening assessments (informed consent, medical history, vital signs, 12-lead
electrocardiogram, clinical biochemistry and haematology, 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
[0077] 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 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 differential Calcium Ferritin
PT Bicarbonate Transferritin
PTT Glucose GGT
Phosphorus Iron
Uric Acid C-reactive protein
Creatinine Total Cholesterol
Blood Urea Nitrogen Triglycerides
(BUN)
Efficacy Evaluations
[0078] Pain scoring using a visual analogue score (VAS) was used to assess the patients
experience of pain at 1, 1.5, 2, 3, 6, 9, 12, 18*, 24, 36, 48, 72 & 96 hour timepoints.
IE 0
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.
LIST OF ABBREVIATIONS
AE Adverse Events
AUCMS1 Area under the plasma concentration-time curve from time zero to time t
(time of last quantifiable plasma concentration)
AUCinf Area under the plasma concentration-time curve from time zero to infinity
Cmax Maximum plasma concentration
LOQ Limit of quantification
PCA Patient Controlled Analgesia
PRN per re nata (as needed)
nag Lag-time
tmax Time of maximum plasma concentration
to, Terminal half life
Terminal phase rate constant
VAS Visual Analogue Scale
Pain Control Medication (Supplemental to the Bupivaeaine-Collagen Sponge)
[0079] At induction, patients received 50-75ug fentanyl. Following catheterization and
prior to the commencement of surgery, they also received 100 mg diclofenac rectally.
lntra-operatively, 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
[0080] 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
[0081] 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 2: Prohibited Concomitant Therapies
Strong or Moderate Inhibitors of the lnducers of the CYP3A4 Pathway
CYP3A4 Pathway
Grapefruit juice troglitazone
Methadone phenytoin
ltraconazole rifampicin
Ketoconazole carbamazepine
Fluconazolc phenobarbal
Clarithromycin St. John’s Wort (hypericin)
Erythromycin
Nefazodone
Fluoxetine
Ritonavir
lndinavir
Nelfinavir
Amprenavir
Saquinavir
RESULTS
Safety Analysis
Current Safety Data from Clinical Study
lfreatment Outcome '
Urine infection Unlikely Moderate Antilfiiootics R6832;/Cg by
Nausea on 27 -01 Unlikely Moderate Odénsgtion & resowed by
ciclizine Day 8
Visual Disturbances Possibly Moderate None resggflg by
Raised white cell count Unlikely Mild None Resolved
Raised neutrophil count Unlikely Mild None Resolved
l Nausea on 27 -01 Unlikely Mild None Resolved
predose event: blood in
urine, high ALT
O02 Anemia Unlikely Mild None Resolved
002 High ALT Possible Mild None Resolved
Increased BP lst few
hours considered normal . Resolved by
003 for patient & not Unlikely Moderate None Day 2
significant
003 Raised C-reactive Protein Unlikely Moderate None Resolved J
004 Anaemia HB 11 to 3 Unlikely Moderate 2 Uni“ bl°°d Hb 10
transfusion
Augmentin
004 Urine infection Unlikely Moderate 625 TDS 5 Resolved
Days
004 Blood in urine Unlikely Moderate none Unresolved
004 Raised C-reactive Protein Unlikely Moderate None Resolved
005 Bruising Around Possible Moderate None Umesolved
Abdomen
005 Wheezing Unlikely Mild None resolved
005 Raised C-reactive Protein Unlikely Mild None Unresolved
. Concomitant
O06 Itch) chest and. bagk with unknown Moderate medication Resolved
rash - urticaria .
Required
006 Anaemia unknown Mild None Resolved
007 Raised Phosphate Possible Mild None Resolved
. Concomitant
007 Itchy skm on face’ ne.ck’ Unlikely Moderate medication Resolved
right arm, feet — pruritus .
,,¢- 77 ~A \ , xx ‘ - , Requlred
Concomitant
O07 wound infection Unlikely Moderate medication Resolved
- .. . . . , .,, y~ lReC1ul“°~d
007 wound dehiscence Unlikely Mild none Resolved
007 Urine infection Unlikely Moderate None Resolved
O07 Raised Phosphorus Possible Mild None Resolved
007 Diarrhoea Unlikely Moderate None Resolved
Resuture
007 wound dehiscence Unlikely Moderate under local Resolved
anesthetic
Concomitant
008 Lower back pain Not related Moderate medication Resolved
Required
Heat rash Not related Mild None Resolved
008 Rise of C-reactive protein Unlikely Mild None Resolving
008 Rise of White cell count Unlikely Mild None Resolved
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 J
Concomitant
010 Low back pain Unlikely Mild medication Resolved
Required
Concomitant
Nausea, vomiting Unlikely +++ melllcatlon Resolved
given.
Cyclizine
PT out of range Unlikely UN None Resolved
Concomitant
Nausea Unlikely Moderate meclléallon Resolved
giv en.
Cyclizine
Abdominal "wind" pain Unlikely Mild None Resolved
Low serum phosphate Possible Mild None Resolved
Efficacy Analysis
[0082] 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 Sage)
[0083] 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
[0084] 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.
[0085] 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 100mm 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.
[0086] 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
postoperative morphine consumption using bupivacaine infiltration in both deep and
superficial layers of the wound after abdominal hysterectomy was 54mg (Klein et al, 2000)
and 44mg (Ng et al, 2002) and narcotic consumption during the first 24 hours varied from
to 62 mg (Gupta, 2004).
Morphine Sparing ]PCA[
[0087] PCA morphine usage was collated over 24 hours and the average consumption was
l6.8mg (all 12 patients) (see Table 3 below). This mean value includes two outliers. One
patient consumed 58mg of morphine due to an underlying back condition and a second
patient consumed 74mg, who received non-standard anesthesia/analgesia during surgery.
Without these two outliers, the mean morphine consumption was 7.1mg. Literature data
indicates morphine use ranging between 32 to 65mg over the first 24 hours and the study
data showing consumption of 31 to 99mg morphine over 24 hours. Table 3 provides data
on PCA morphine consumption for each patient.
Visual Analogue Scores (Pain)
[0088] The onset of pain relief occurred around 6 hours (mean VAS of 10.3mm) 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 6.8mm (25% of patients scored 0); at 48 hours it was 2.8mm (7 of
12 patients scored 0) and at 72 hours the mean VAS was 2.7mm 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 4: Summary of VAS Pain Scores: Efficacy Population
4——] VAS Pain Score (mm) j
Implantation (hours) Mean SD Range
Pharmacokinetics:
[0089] The mean Cm,‘ was 0.221.Lg/ml and the highest individual Cum was 0.44ug/ml,
which is well below the known systemic toxicity level of 2-411g/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 5: Summary of Bupivacaine Hydrochloride Pharrnacokinetic Results: Efficacy
Population
Parameter 11 Mean SD
mg (11)* 12 0.000 0.00 — 0.00
(ng/mL) 12 224.911 83.100
{max (h) ‘ 12 12.000 0.53 — 24.00
)\«z (11") 11 0.07084 0.01307
I1/31 11 1.836
Aricm, (ng~h/mL) 12 6531.2 2243.9
AUCmr (ng~h/mL) 11 6359.8 2230.1
Safetv:
There were a total of 45 adverse events (AE5) 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:
[0090] 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-Iaparoscopic benign gynecological procedures such as myomectomy and
adnexal surgery
[0091] 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.
[0092] Each bupivacaine-containing drug delivery sponge has a surface area of 25 cm2 (5
x 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/cmz. 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.
[0093] 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 G1
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 cm2 and a thickness
of 0.5 cm will be sufficient to adequately cover the areas of disrupted tissue.
[0094] The present inventors are studying efficacy in both moderate (hemiorrhaphy) and
major surgeries (total abdominal hysterectomy and open gastrointestinal surgery). The
proposed dosing regimens for these different surgeries are as follows:
Hemiorrhaphy: sponges having a total surface area of 50 em2 and a thickness of 0.5
cm (100 mg bupivacaine hydrochloride)
0 Hysterectomy: sponges having a total surface area of 75 cm2 and a thickness of 0.5
cm (150 mg bupivacaine hydrochloride)
0 GI surgery: sponges having a total surface area of 75 or 100 cm: and a thickness of
0.5 cm (150 or 200 mg bupivacaine hydrochloride)
[0095] The proposed maximum dose of 4 (5 x 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.
[0096] In summary, it is believed that the variable dosing regimens as provided by a fixed
dose of 2 mg/cm: bupivacaine hydrochloride (50 mg/ sponge; 5 x 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/cmz 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
cm2 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 crnz 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.
lE€l l
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/cmz) 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.
[0097] 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 SE, Crafoord K, and Rawal N (2004).
Postoperative pain after abdominal hysterectomy: a double-blind comparison between
placebo and local anesthetic infused intrapcritoneally. Anesth Analg 9911173-1 179.
Leung CC, Chan YM, Ngai SW, 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 J oumal of Anaethesiology :78: 43 1-432
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
Mesiniche 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
Claims (5)
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, optionally at least about two days, further optionally at least about three days, after administration.
2. The drug delivery device of Claim 1, wherein the fibrillar collagen matrix is a Type I collagen matrix.
3. Use of 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 for the manufacture of a medicament for providing local analgesia, local anesthesia or nerve blockade in the human or animal in need thereof, the use comprising administering the medicament at the site in a human or animal in need thereof.
4. The drug delivery device of Claim 1 or 2 or the use of Claim 3, 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, wherein the at least one drug substance is, optionally, an amino amide anesthetic selected from bupivacaine and salts and prodrugs thereof.
5. The drug delivery device of Claim 1 or 2 or the use of Claim 3 or 4, 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. Flow Diagram for Production of Collagen
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IEIRELAND28/03/20072007/0220 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE20080229U1 true IE20080229U1 (en) | 2008-12-24 |
IES85185Y1 IES85185Y1 (en) | 2009-04-01 |
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