Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF INVENTION
Compositions and Methods For the Reduction of Post-Operative Pain
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of United States Provisional
Application 60/504,978,
filed Septeinber 23, 2003, Provisional Application Number 60/702,226 filed
July 25, 2005,
Provisional Application Number 60/758,300 filed January 12, 2006 and United
States Patent
Application Serial Number 10/941,890 filed September 16, 2004 all of which are
incorporated
herein by reference as though they were set forth verbatim herein
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
OR DEVELOPMENT
(Not Applicable)
REFERENCE TO A SEQUENCE LISTING, A TABLE, OR A COMPUTER
PROGRAM LISTING APPENDIX SUBMITTED ON COMPACT DISC
(SEE 37 CFR 1.52(e)(5))
(Not Applicable)
[0002] This Application is a Continuation-In-Part of United States Serial
Number
10/941,890 filed September 16, 2004 entitled "Absorbable Implants and Methods
For
Their Use In Hemostasis and In The Treatment of Osseous Defects"
BACKGROUND OF THE INVENTION
FIELD OF INVENTION
[0003] This invention relates to the surgical delivery of body implantable
compositions
comprising one or more anesthetics or analgesics having local pain-relieving
activity, for
the management of postoperative pain. The terms "analgesics" and "anesthetics"
are used
interchangeably herein.
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[0004] The relief of postoperative pain is an important aspect of surgical
pain
management. Systemic drugs such as NSAIDs, opioids and other analgesics or
anesthetics
are known to have significant clinical drawbacks. Other methods toward this
end, such as
external pumps that infuse aqueous solutions of local anesthetics through
percutaneous
transdermal catheters into the area of the surgical wounds, have been
employed, but have
not been considered totally acceptable.
[0005] During and following surgical procedures, soluble local anesthetics in
the form of
aqueous solutions, often are infused into or around the operative site to
reduce pain
associated with operative trauma. Unfortunately, they are relatively short-
lived in their
action.
[0006] Water solubility is made possible because most local anesthetics are
basic as a
result of the presence of an amino moiety and they readily form water-soluble
salts with
acids. Anesthetics in the free base form, however, usually are essentially
water-insoluble
and, in this form, are not deliverable using conventional aqueous systems. An
exception
involving the use of the free base involves topical anesthesia where the
anesthetic base is
dissolved in a non-aqueous ointment carrier, e.g., petroleum jelly, and, as
such, applied to
the surface of the skin.
[0007] The duration of action of a local anesthetic is proportional to the
time during which
it is in actual contact with neural tissue. Local anesthetics reversibly block
impulse
conduction in neural tissue thereby producing a transient loss of sensation in
a
circumscribed area of the body. Thus, local anesthetics may be used to prevent
pain during
surgical procedures. To prolong the action of local anesthetics,
vasoconstrictor drugs such
as norepinephrine, often are added to the anesthetic solution. Generally
speaking, duration
of pain relief much after the termination of the surgical procedure is not
usually obtained.
[0008] Local anesthetics may be divided into two groups, depending upon their
solubility
in water: the slightly soluble compounds and the soluble compounds. The
slightly soluble
compounds are used only for topical anesthesia and are of relatively longer
duration. On
the other hand, only the soluble anesthetics can be used for infiltration
anesthesia. Local
anesthetics may be further classified according to their chemical structures,
e.g., those
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having moieties joined through ester or amide linkages. In general, the esters
are more
toxic and short-lived while the amide type anesthetics have a longer duration
of action.
[0009] A difficulty with one prior art approach to post-operative pain relief
is that the
infused analgesic generally does not remain at the operative site for a
suitable period of
time. The present invention is directed to that aspect of the prior art
approach. That is, the
invention intends to provide an implantable, slowly absorbable composition
which
releases analgesic material into the operative site, post-operatively.
[0010] In the present inventor's United States Patent Application 10/941,890,
filed
September 16, 2004, now United States Patent Publication No. 2005-0065214-Al,
Published March 24, 2005 (incorporated herein by reference for all purposes),
absorbable
systems such as putty-like and non-putty like substances are described and
claimed for the
treatment of osseous defects and the control of bleeding from cut or
trauniatized bone and
soft tissue. An important characteristic of many of the described systems is
that they are
anhydrous and have an organic component in which free bases of local
anesthetics are
soluble.
[0011] The '890 application priority claimed herein; discloses the
incorporation of
analgesic drugs into the vehicle to mediate pain. Conventionally, the acid
addition salt, the
hydrochloride, for example, of a local anesthetic, would be admixed with an
appropriate
vehicle, a putty, for example. It was thought that the water-soluble
hydrochloride would be
eluted from the vehicle relatively rapidly (as compared to the slightly
soluble free base) in
the aqueous environment of the body and longer term effectiveness would be
reduced.
[0012] In Provisional Application, Serial number 60/758,300, filed January 12,
2006,
priority of which is claimed herein, the inventor herein disclosed that the
combination of
an organic-soluble free base and a water-soluble hydrochloride (or other acid
addition salt)
of the same or different anesthetic agent, would form a surgically
implantable, absorbable
combination providing extended pain management wherein the water-soluble
component
would elute relatively rapidly for early pain relief and the water-insoluble
free base
component would elute more slowly for extended pain relief. The basic concept
of the
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invention was to combine the water-soluble salt, e.g., hydrochloride, of an
anesthetic
together with its corresponding free base (or the free base form of another
analgesic) in a
substantially anhydrous, non-aqueous composition and then implant the
composition for
pain relief. The hydrochloride portion of the anesthetic e.g., lidocaine
hydrochloride, was
thought to be elutable from the system relatively rapidly while the free base,
e.g.,
lidocaine, dissolved in the non-aqueous carrier, would elute more slowly to
extend the
effectiveness of pain mediation. Because the carrier composition is absorbable
in the
body, any insoluble free base residue will be exhausted from the implant site
as the
implant is absorbed. Thus, extended anesthetic efficacy, not heretofore
possible using
aqueous media, was thought to be easily achieved.
BRIEF SUMMARY OF THE INVENTION
[0013] It has now been found, in accordance with the present invention, that
an analgesic
agent having the capability of providing intraoperative pain relief at an
internal surgical
site may be provided from an implant composition comprising a solid material
in finely
powdered form, intimately admixed with an organic liquid and an anesthetic
agent to be
described in more detail below. The composition is an absorbable, anhydrous or
essentially anhydrous implant which imparts post-surgical pain relief over
suitable period
of time when an appropriate non-aqueous liquid dispersing vehicle and an
anesthetic
having local pain-relieving activity is included therein.
[0014] Thus, the elements of the anhydrous or essentially anhydrous
composition of the
invention may be said to comprise the following three main categories in
intimate
admixture:
Component 1. a body-implantable, biocompatible, finely divided solid
material.
Component 2. an organic liquid, capable of dispersing or suspending
Component A.
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Component A. an anesthetic compound, or mixture of compounds, having
local pain-relieving activity.
Component B. an optional elution control agent which may be added to aid
in controlling the rate of release of the anesthetic from the
the implant.
[0015] If the end compound is desired to be anhydrous, then each of the
components
should be anhydrous. If the final composition is to be essentially anhydrous,
then each
component may itself be water-carrying. Anhydrous components may be used with
additional water optionally being added after or at any time during the
blending of the
components.
[0016] The components, when blended together, yield either the anhydrous
composition
or the essentially anhydrous composition of the invention, depending upon the
nature and
ratios of the components, resulting in a variety of physical forms such as
putties, lotions,
gels, creams and the like depending on the quantity of liquid Component 2. The
composition is preferably sterile.
[0017] The compositions of the invention provide an elutable source of
analgesic when
implanted at an internal surgical site. Active analgesic is generally elutable
over a period
of from about 0 to 8 days, post-surgery, during which time a pain-relieving
effective
amount is released.
[0018] An important characteristic of the composition which affects the
release rate of the
analgesic is the consistency or viscosity of the composition. In general,
lower viscosity
compositions tend to release the product more rapidly than higher viscosity
compositions.
The viscosities may range at the lower end from the freely flowable liquids,
such as
lotions and other liquids which quickly take the shape of the container
boundaries, if left
unimpeded, and which would flow out of the container by gravity if allowed to,
to the
higher viscosities of slowly flowable liquids such as those having the
viscosity of thick
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shampoos, honey, molasses and the like, to semi-solid materials such as gels,
pastes, and
creams, which are generally non-flowing under ambient conditions, to the
moldable
materials such as putties, waxes and other such materials which tend to remain
in place
when applied to a site, up to the hard, solid materials which are not moldable
under
ambient conditions, such as preformed, shaped materials such as rods, buttons
and the like.
[0019] Adjustment of the type and amount of Component 2 will also have an
effect on
elution of the analgesic from the final product. For example, hydrophobic
materials such
as the tocopherols, tocopheryl acetate, for example, tend to slow down the
elution rate.
[0020] Different anesthetics can be expected to yield different elution rates,
as well,
especially if they are present in particulate form. Thus, suspendable or
dispersible
anesthetics should be in finely divided form having relatively uniform
particle size
distribution, to lend a more reliable elution rate profile than would be
obtained with larger
or polydispersed particles.
[0021] The preferred manner of producing the composition is to dissolve,
disperse or
suspend the anesthetic compound in the liquid Component 2, optionally admixed
with an
elution control agent, to form a solution, dispersion or suspension, which is
then mixed
with the solid phase Component I to form a blend of all components. The
physical form
of the said product, i.e. putty, gel, lotion, or the like, depends upon the
physical
characteristics and relative quantity of the components. The most preferred
form for
surgical procedures is the so-called putty form. The invention in its
preferred form, thus
provides a body-implantable, biocompatible, essentially anhydrous, sterile,
body-
absorbable composition comprising Components 1, 2 and A, optional Component B
and
any other optional components, to be described below, which are left to the
discretion of
the user and the particular application sought.
[0022] Once implanted into the body of a surgical patient, the entrapped
anesthetic will
diffuse from the implant into surrounding tissue where pain signals to the
brain from
traumatized local nerve endings are interrupted. The compositions may contain
either the
slightly water-soluble anesthetics in acid addition salt form or in the free
base form, or
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both, to provide flexibility and variation in the availability of pain relief
depending on the
circumstances. In such cases, the salt is previously dispersed throughout
Component 1 or
alternatively dispersed in Component 2, and the dispersion thereafter
intimately admixed
with the solid phase Component 1 to form a dispersion. If a free base soluble
in the
organic medium is also used, it remains solubilized in the organic medium
which is
blended with the solid phase and is eluted along with the salt, albeit not at
the same rate.
[0023] It has further been found, in accordance with the invention, that the
ingredients of
the implantable composition may be varied in concentration to provide
differing drug
elution rates. For example, in a putty-like composition comprising lidocaine
free base,
calcium stearate and liquid triethyl citrate, the free base of lidocaine is
released over a
three day period. If the liquid component of the putty is changed from
triethyl citrate to
Pluronic L-35 (a liquid block copolymer of ethylene oxide and propylene
oxide) and
tocopheryl acetate, the free base of lidocaine is eluted over an eight day
period. Mixtures
of liquid Pluronics and solid Pluronics will extend the elution time over
that of liquid
Pluronic alone. Our studies indicate that tocopheryl acetate reduces the
elution rate while
tricalcium phosphate, and hydroxyapatite increase the elution rate. The free
base elutes
faster than the acid addition salt, and in a free base/salt mixture the free
base surprisingly
elutes more rapidly. Other non-toxic, non-aqueous liquid components, for
example, ethers
(such as polyalkylene glycols) in which the anesthetic free base is miscible,
may be
similarly employed.
[0024] The formulations of the present invention are compositions having
various
viscosities and cohesive strengths and include putty and non-putty formulation
consistencies. The term "putty" is used herein as it is used in the art and is
generally
known to the skilled artisan. Dough (such as pastry dough), modeling clay, and
glazier's
putty of varying viscosities, depending on the indications and ultimate use,
are examples
of the consistency of a suitable product. Putties of various viscosities
useable in the
invention include those that are capable of adhering to bone. In general,
putties which are
soft, moldable, preferably non-elastic, cohesive mixtures prepared from a
finely powdered
substance (Component 1) intimately admixed with the organic liquid (Component
2) and
having a shape which is capable of being deformed in any direction, are
suitable
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consistencies for the putty-like compositions of the invention. As described
herein,
however, compositions which have lower cohesive strengths than the putties
described
above, are within the scope of the invention, and may be used in specific
applications in
which the more viscous, higher cohesive strength putties are less suitable.
[0025] For purposes of this invention, a major difference between putties of
the invention
and materials not considered to be putties (herein non-putties), but which are
still within
the scope of the invention, is that the non-putties have lower cohesive
strengths than the
cohesive strengths of the putty formulations and in some cases, may have even
higher
cohesive strengths than the putties. Individual non-putties of the invention
at the lower
end of the cohesive strengths range, are characterized by having the cohesive
strength of
creams, pastes, ointments, lotions, foams, gels, and the like. Their use as
implants may be
facilitated by providing a lattice or structure to which the non-putties may
be applied and
the entire structure applied to the operative site. Preferably, the non-
putties have only a
fraction of the cohesive strength of putties,of the invention, tending to be
easily collapsible
or easily torn apart under small stresses that would not, generally speaking,
have the same
effect on putties. At the higher end, i.e. at viscosities higher than the
putties, the
composition can be in the more rigid, formed, non-deformable -stage as their
ultimate use
requires. The description which follows is given mainly in the context of the
putties of the
invention, it being understood, however, that if other less cohesive strength
materials are
desired, the skilled artisan will simply make the appropriate changes in the
proportions of
components or add other substances to achieve the same purpose.
[0026] The present invention involves formation of medically useful absorbable
putty-like
and non-putty-like compositions using virtually any solid phase which is bio-
compatible
and finely dividable to produce the requisite consistency when blended with
the
Component 2 liquid carrier.
[0027] Many compositions of the invention, in addition to their pain
management aspect,
are also sterile, absorbable, bone hemostatic agents. That is, they will
provide virtually
immediate surgical hemostasis, will absorb in the body after a relatively
short period of
time without compromising hemostasis efficacy and will allow the diffusing of
the
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analgesic to the surrounding operative sites. They would minimally inhibit
osteogenesis
and subsequent bone healing. They thus would have significant medical
advantages over
presently available materials. Moreover, bone-healing adjuvants such as growth
factors,
particularly, for example, platelet derived growth factor (PDGF) and/or bone
morphogenic
proteins (BMPs) and others, could be added to the formulations to stimulate
the bone
healing process. Furthermore, adding agents such as collagen, demineralized
bone matrix
(DBM), and/or hydroxyapatite could make the hemostatic/pain management
material
beneficially osteoconductive or osteoinductive. The addition of a suitable
anti-infective
agent such as antibiotics typified by tobramycin and gentamicin or
bacteriostatic and
bacteriocidal materials such as iodine, silver salts, triclosan, colloidal
silver, or the like
serve to reduce the potential for infection, particularly in contaminated open
wounds such
as compound fractures. The addition of colorants would aid in visibility
during the
operative procedure. The addition of radiopaque substances allows the
observation of
post-operative sequelae using radiography. The addition of chemotherapeutic
agents or
radionuclides is useful when the putty is used, for example, in bone cavities
arising from
tumor resection. While the analgesic compounds to reduce pain, constitute
Component A
of the composition, vasoconstrictors and/or blood clot-inducing agents to
reduce
hemorrhage, are useful additives.
DETAILED DESCRIPTION OF THE INVENTION
[0028] The compositions of the present invention include compositions
comprising at
least three, but also possibly four, or more components, at least one of which
is an
analgesic having local, pain-relieving activity, or combination of such
analgesics. They
are most preferably body absorbable and biocompatible. In many embodiments
they have
a putty-like consistency. In one embodiment, the compositions are mechanically
hemostatic tamponades useful in stopping the bleeding of bone by the
application of the
putty-like composition to the affected area while still possessing the ability
to release
analgesics. By "mechanically hemostatic tamponades" is meant that the
compositions
function by mechanically compressing the bleeding areas of the bone to arrest
hemorrhaging as opposed to functioning by chemically hemostatic means, i.e.
the arresting
of hemorrhaging, in whole or in part, using a chemical means or agent. Of the
at least
three components mentioned in the first sentence of this paragraph, Component
I is a
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finely powdered carrier vehicle or bulking material having an average particle
size
sufficiently small to form the desired consistency when intimately admixed
with the
second component, i.e. an organic liquid Component 2 of the invention in which
an
analgesic is dissolved, dispersed or suspended.
[0029] Illustrations of Component I are hydroxyapatite, (as used herein,
hydroxyapatite is
generic for all forms of calcium phosphate including tricalcium phosphate), a
carboxylic
acid salt, preferably a fatty acid salt such as calcium stearate or a homolog
thereof such as
calcium laurate, or other finely powdered agents such as synthetic absorbable
polymers,
e.g. polyglycolide, polylactide, co-polymers of lactide and glycolide,
polydioxanone,
polycaprolactone, as well as absorbable glasses, (such as those based upon
phosphorus
pentoxide and the like). The particular Component I solid phase is not
particularly
limited, and may be virtually any solid which is biocompatible and divisible
into fine
powder so that compositions of proper consistencies may be formed. Of course,
Component I is not soluble in Component 2.
[0030] The Component 2 dispersing vehicle is an organic liquid which, when
intimately
admixed with the analgesic Component A and then with Component 1, enables the
formation of the putty-like or non-putty-like implant.
[0031] While the three-component compositions of the invention provide the
basic
characteristics of suitable pain-relieving materials, some of which may be
hemostatic, as
described herein, they may also, if desired, but are not required to, contain
optional
ingredients illustrated by those shown below. For example, optional Component
3 is an
absorption accelerator, and optional Component 4 is a bone growth-inducing
material.
Other components may be added to provide additional attributes to the putty-
like and non-
putty like compositions of the present invention as will be explained in more
detail below.
[0032] Following is a detailed description of the various components.
Component I
Component 1 is comprised of a finely powdered, preferably micronized,
essentially water-
insoluble, preferably anhydrous (except for absorbed water), biocompatible,
body-
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absorbable substance which, when admixed with the organic liquid, analgesic-
containing
Component 2, forms compositions of the invention. Suitable compositions are
obtained
when the average particle sizes of Component 1 materials are about 100 microns
or less,
but the preferred average particle size range is between about 3 to about 50
microns and
most preferably about 6 to about 25 microns especially when putty-like
compositions are
desired. Particle sizes for non-putty compositions may range higher than those
of the
putty compositions, if desired.
[0033] Examples of one set of materials suitable for use herein are salts of
one or more
carboxylic acids having a carboxylate anion and a metal cation, some which are
known in
the art, having been described in U.S. Patent Nos. 4,439,420 and 4,568,536.
Suitably, the
salts may be the calcium, magnesium, zinc, aluminum, lithium or barium salts
of saturated
or unsaturated carboxylic acids containing about 6 to 22 carbon atoms in the
chain and
preferably 8 to 20 carbon atoms. The preferred saturated carboxylic acids
supplying the
carboxylate anion may be selected from aliphatic acids such as caprylic acid,
capric acid,
lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, and
intervening
homologs thereof, but the most preferred acids are the higher fatty acids such
as lauric,
myristic, palmitic, and stearic acids, with. stearic being most preferred.
Calcium and
aluminum palmitates and stearates are preferred salts with calcium stearate
being most
preferred because of its excellent safety profile, and putty-forming
characteristics.
However, aluminum stearate, aluminum palmitate, or aluminum laurate, are
suitable as
well.
[0034] Examples of suitable unsaturated aliphatic acids which may be used for
supplying
the carboxylate cation are oleic acid and linoleic acid for which the same
cations described
above are used.
[0035] It has been discovered that finely divided materials, for example,
average particle
size of microns about 100, but preferably below 50 microns or less, other than
carboxylate
salts, can be effective Component I substances. For exainple, it was
surprising to find that
finely powdered hydroxyapatite, especially when less than about 25 microns in
average
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particle size, formed an excellent putty, especially with tocopheryl acetate
or triethyl
citrate as the liquid dispersing agent (Component 2).
[0036] Furthermore, other materials, some of which are discussed in connection
with
Component 4, are useful as Component I when provided in finely powdered form.
Examples of these are demineralized bone matrix (DBM), mineralized bone matrix
(MBM), insoluble absorbable collagens, gelatin derived from collagens,
monosaccharides,
and polysaccharides. It is thought that any biocompatible material, when
converted to
very small particle sizes, will form medically useful compositions for use in
the present
invention. It would not be uncommon, when producing compositions of the
present
invention, to have, for example, hydroxyapatite (or any calcium phosphate or
tricalcium
phosphate) particles of around 20-30 microns as Component 1, a suitable
Component 2, as
described below, a suitable Component A, and bone chips such as a
demineralized bone
matrix or a mineralized bone matrix having a particle size of about 0.5 to
about 1 mm or
larger as Component 4.
[0037] Other examples of Component I substances are finely milled synthetic
absorbable
homo- and co-polymers, e.g., polyglycolide, polylactide, copolymers of lactide
and
glycolide, polydioxanones, polycaprolactones, copolymers of dioxanone and of
caprolactone and of trimethylene carbonate, gelatins, monosaccharides such as
glucose
and mannose, and polysaccharides such as carboxymethyl cellulose and oxidized
cellulose
typified by Surgicel , starches, sucrose, suitably in the form of
confectioner's sugar,
alginic acid, hyaluronic acid, chitosan and its acetyl derivatives, and the
like, as well as
absorbable glasses, and the like. In addition, certain biologically active
materials such as
bioglasses (discussed in more detail in connection with Component 4 below),
which may
not be considered as absorbable in the usual sense, can be used in finely
powdered form as
Component 1. For example, absorbable polymers having an average particle size
of about
25 microns will form a useful, stable absorbable hemostatic putty when mixed
with, for
example, tocopheryl acetate or the triglyceride oils, especially the castor
oil, of U.S. Patent
No. 4,439,420. Thus, any natural or synthetic absorbable polymer that can be
reduced to
sufficiently small particle size will form a stable, absorbable putty and non-
putty if
admixed with a suitable, compatible Component 2 vehicle in the proper ratio.
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[0038] It also has been discovered that absorbable glasses, based upon
phosphorus
pentoxide (instead of silicon dioxide), and containing alkali or alkaline
earth metal oxides
such as sodium, potassium, calcium and magnesium oxides as the network
polymer, are
slowly dissolvable in aqueous media and can be used as Component 1. In
addition, such
compounds may be used as absorption accelerants, in which case, they may, but
need not,
be used in as finely powdered a form as when they are used as Component 1.
U.S. Patent
No. 4,612,923 refers to the preparative prior art concerning these glasses as
well as their
application as additives for strength reinforcement and stiffness enhancement
for synthetic
absorbable surgical devices. When the 325 mesh glass described in Example 1 of
U.S.
Patent No. 4,612,923 is further pulverized to average particle sizes below 50
microns, the
resulting fine powder forms a medically useful absorbable putty when admixed
with the
vehicles described in United States Patent No. 4,439,420 (incorporated herein
by
reference) and in this specification. The rate of aqueous dissolution
(absorption) of such
glasses can be increased by increasing the proportion of alkali metal oxides
and decreased
by increasing the proportion of alkaline earth metal oxides.
[0039] This novel approach, discussed above, i.e., forming useful absorbable
putties and
non-putties by drastically reducing the particle size of the bulking vehicle
Component 1,
overcomes many of the difficulties of the prior art, especially, e.g., those
of synthetic
absorbable polymers as bone hemostatic agents.
Com onp ent 2
[0040] As the second component, i.e., the organic liquid, there may be
mentioned, as
illustrative, several classes of materials that have not been heretofore
employed as
dispersing vehicles for preparing medical compositions such as putties or non-
putties,
although it should be emphasized that even materials already known as
dispersing vehicles
may be employed. Component 2 acts as the vehicle for dispersing or suspending
Component A, the analgesic, and in this aspect of the invention, Component 2
is a
biocompatible, essentially anhydrous organic liquid which facilitates the
admixture with
Component 1 to form the putty or non-putty mass. Though not preferred,
Component 2
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may be solid if it comprises a separately supplied organic liquid vehicle (a
liquefying
agent, as more fully discussed below). The term "Component 2" is meant to
apply to
such a case as well.
[0041] While Component 2 is usually water immiscible it may also be water
miscible.
The important consideration is that it be either anhydrous or essentially
anhydrous so as to
produce an anhydrous or essentially anhydrous final pain relief composition.
In this
regard, it is appropriate at this point to illustrate what is meant by
"essentially anhydrous".
The preferred compositions of the invention are devoid of water except perhaps
water that
is present by absorption from the atmosphere. Thus, it is preferred that each
of the
Components used to make up the final composition be themselves devoid of
water.
[0042] Under some circumstances however, minor amounts of water can be
tolerated, and
even desirable, in the Components or the final composition for various
reasons. Thus,
amounts of water ranging up to about 10 % by weight of the entire composition,
would be
acceptable. Compositions with zero percent of water, except for absorbed
water, would be
considered anhydrous while compositions containing up to about 10% water would
be
considered essentially anhydrous herein. Components should not contain so much
water
as to yield a final composition having more than about 10% water. Preferably,
the
compositions of the present invention have less than 5% water and most
preferably zero
percent added water (except absorbed water). In the latter case, they would be
considered
"anhydrous" as that term is normally used in the art.
[0043] To aid in understanding the terms used herein and to help differentiate
this aspect
of the invention from that of the prior art, it would, perhaps, at this point,
be useful to
emphasize the nature of the chemical entities referred to in this
Specification by briefly
reviewing relevant classical chemistry terminology to ensure the appropriate
chemical
distinctions are understood.
[0044] Carboxylic acids are substances defined by the attachment of an OH
group to a
carbonyl function through a covalent bond. As a result, carboxylic acids
possess physical
and chemical properties totally distinct from substances containing either the
carbonyl
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functionality (e.g., aldehydes, ketones) or the hydroxyl functionality
(alcohols). The same
distinction holds true for substances containing both the carbonyl and
hydroxyl groups not
directly attached through a covalent bond, such as hydroxyacetone, which
displays both
ketone and alcohol properties, but not carboxylic acid characteristics.
Carboxylic acids
always combine a carbonyl and an OH group and have acidic characteristics, but
the OH
group does not have the characteristics of the hydroxyl group of an alcohol. A
monocarboxylic acid would, therefore, not be described as a monohydroxy
compound. To
illustrate this, consider acetic acid and ethanol which are both two-carbon
compounds
containing an OH group. In acetic acid, the hydrogen atom of the OH group is
liberated as
an ion in water, whereas in ethanol, the hydrogen atom of the hydroxyl group
is not so
liberated, Thus, carboxylic acids dissociate and form carboxylate salts with
bases, e.g.,
calcium stearate, a distinctive property that clearly differentiates the OH
group of
carboxylic acids from the hydroxyl group of alcohols that do not dissociate to
form salts
with bases. Thus, it would be entirely incorrect to characterize a carboxylic
acid as an
alcohol, a monohydric alcohol, or some such term since it is, in no chemical
sense, an
alcohol. Nor could a polycarboxylic acid be,referred to as a polyalcohol, or a
polyhydroxy
compound or a polyol simply because it contains carboxylic OH groups. Such
groups are
not characterized as alcohols. An example of these distinctions is illustrated
by
considering the well-known molecule, citric acid. This substance has three
carboxylic
groups and one hydroxyl group in the same molecule. Citric acid is a
monohydroxy
(monohydric) alcohol as well as a polycarboxylic acid. The fact that citric
acid contains
three carboxylic OH groups does not classify this monohydroxy compound as a
polyhydroxy compound. Because of the major differences in reactivity,
synthesis and
reactions, in every textbook of organic chemistry, the chemistry of alcohols
always is
considered in a separate chapter from the chemistry of carboxylic acids.
[0045] Alcohols may be regarded either as hydroxyl derivatives of hydrocarbons
or as
alkyl derivatives of water. They are typified by the R-OH structure where R is
an alkyl
group. In contradistinction to the readily ionizable hydrogen atom of the
carboxylic acid
hydroxyl group, the R-OH hydrogen atom is virtually unionized in water. On
this basis,
aliphatic alcohols are considered neutral rather than acidic. One or more
hydroxyl groups
may be appended to a hydrocarbon moiety so that, for example, propane may have
one
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hydroxyl group (propyl alcohol), two hydroxyl groups (propanediol or propylene
glycol)
or three hydroxyl groups (propanetriol or glycerol). Propylene glycol and
glycerol are
simple examples of polyols. Polysaccharides, such as hyaluronic acid, contain
many
hydroxyl groups on each monomer unit and are correctly termed polyols.
Alcohols may
have short alkyl chains such as methyl alcohol, ethyl alcohol, propyl alcohol,
etc., or they
may have longer alkyl chains such as lauryl alcohol, myristyl alcohol, etc. It
is of critical
importance to note that lauric acid (C11H23COOH, a fatty acid) and lauryl
alcohol
(C12H250H, a fatty alcohol) are completely different molecules in oxidation
state and
functionality, even though they both contain twelve carbon atoms.
[0046] Esters are commonly derived from the reaction of a carboxylic acid with
an alcohol
and can be converted back to the original carboxylic acid and alcohol by
hydrolysis. Thus,
acetic acid and ethyl alcohol are combined in the esterification process to
form ethyl
acetate and water. The term fat (or vegetable or animal oil) is confined to
esters of a
variety of long chain saturated or unsaturated fatty acids with glycerine
(glycerides). Oils,
cited in the prior art as vehicles for preparing putty-li(ce materials, are
exclusively
glycerides, e.g., castor oil, sesame oil, olive oil, etc., as well as simple
fatty acid esters
such as ethyl laurate. What never have been proposed in the prior art as
vehicles for
preparing putty-like substances, are free liquid fatty carboxylic acids such
as the saturated
caprylic acid and the unsaturated oleic acid. Most important, the use of
esters of fatty
alcohols with low molecular weight mono- or polycarboxylic acids, e.g., lauryl
acetate
(the ester of lauryl alcohol and acetic acid) are completely novel for the
preparation of
putty-like materials and are chemically distinct from the prior art cited
ethyl laurate (the
ester of lauric acid with ethyl alcohol).
[0047] Returning now to the description of the Components of the present
invention, more
particularly Component 2, the elements are more specifically described as
follows:
[0048] Among the many classes of organic liquids that may be used as Component
2,
there may be mentioned the following:
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[0049] As a first class of Component 2, there are one or more absorbable
esters of a C8-
Cig inonohydric alcohol with a C2-C6 aliphatic monocarboxylic acid. The
monohydric
alcohols may be selected from C8-Cl8 alcohols such as octyl alcohol, decyl
alcohol, lauryl
alcohol, myristyl alcohol, stearyl alcohol, and intervening homologs thereof.
The
preferred alcoliols are the higher aliphatics such as lauryl alcohol, myristyl
alcohol, and
stearyl alcohol. Illustrative of the useful esters formed with the C2 - C6
monocarboxylic
acids are lauryl acetate and myristyl propionate.
[0050] As a second class of Component 2, there are one or more absorbable
esters of a C2
- C,$ monohydric alcohol with a polycarboxylic acid. The C2 - C18 monohydric
alcohols
include, in addition to the C8 - C1$ alcohols described in the first class of
esters there are
the lower aliphatic, C2 - C8, alcohols such as ethanol, propanol, butanol,
pentanol,
heptanol, hexanol, and octanol which yield the corresponding ethyl, propyl,
butyl, pentyl,
heptyl, hexyl, and octyl moieties. The polycarboxylic acids may be selected
from
malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic,
maleic, fumaric,
glutaconic, citric, malic acids, and esters of the hydroxy function, if any,
of the esterified
polycarboxylic acid, especially acetyl citric acid and acetyl malic,acids. It
will be obvious
to those skilled in the art that many combinations of alcohol/acid esters may
be selected
from the above, but the preferred ones for use in the invention from the
monohydric
alcohol/polyacid esters are diethyl succinate, dioctyl succinate, triethyl
citrate, tributyl
citrate, and higher and lower homologs thereof, acetyl triethyl citrate,
acetyl tributyl citrate
and higher and lower homologs thereof, butyryl triethyl citrate, diethyl
malate, di-pentyl
malate, and acetyl diethyl malate, and higher and lower homologs thereof.
[0051] Another class of materials, suitable as Component 2, are the higher C8-
C12 up to
about C30 and preferably liquid or liquefiable monohydric alcohols such as
octanol and
decanol. An especially surprisingly suitable embodiment of this class is the
aromatic
alcohol tocopherol (Vitamin E) in its optically active or racemic forms and in
any of the
alpha, beta, gamma or delta forms, as well as liquid tocopherol esters
(sometimes referred
to herein as tocopheryl esters) with a C2 - CIo aliphatic monocarboxylic acid,
a
polycarboxylic acid or mixtures thereof. Useful are the tocopherol esters such
as acetates,
butyrates, caproates, caprylates, caprates, and intervening homologs thereof,
and
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polycarboxylic acid ester such as those mentioned in the previous paragraph,
especially
esters of succinic, citric, and malic acids, with succinate being preferred.
Tocopherol
acetate is also useful as an elution control agent (Component B).
[0052] Another class of materials, useful as Component 2, are hydrocarbons
having from
about 10-14 carbons atoms. For example, decane and dodecane are suitable.
[0053] Another class of materials, useful as Component 2, are the liquid or
liquefiable
saturated or unsaturated, free carboxylic acids such as the non-esterfied
fatty acids, oleic,
linoleic, caprylic, capric, and lauric. In this class, the normally liquid,
saturated fatty acids
would be suitable but may not be desirable because of their unpleasant odor.
Some low
melting saturated free-fatty acid mixtures that form a lower-melting eutectic
mixture
which is liquid-at-room-temperature may also be suitable. One advantage of
saturated
free-fatty acids lies in their improved stability to radiation sterilization
whereas the
unsaturated acids, e.g., oleic, may require radiation sterilization in an
oxygen-free
container. Higher homologs of solid acids can also be used in admixture with
Component
I in the presence of a liquefying medium or other suitable component. Any
compatible
liquid may be used as long as it ensures the liquefaction of Component 2 and
is
biocompatible as well.
[0054] Another class of materials, useful as Component 2, are ethers of the
simple dialkyl
ether class and alkyl aryl ether class as well as cyclic polymers of alkylene
glycol e.g.,
ethylene glycol, known as crown ethers, all having boiling points greater than
about 80 C
such as di-n-butyl ether, di-n-hexyl ether, di-n-octyl ether, and
unsymmetrical ethers such
as ethyl hexyl ether, ethyl phenyl ether, and the like, or random copolymers
of ethylene
oxide and propylene oxide, but preferably block (non-random) copolymers of
ethylene
oxide and propylene oxide in various ratios of ethylene oxide to propylene
oxide and
various molecular weights, preferably from 1000 to 10,000, (Pluronic ). They
are
available in liquid or solid form. The preferred form for use in the present
invention are
the liquid Pluronic which are characterized by their manufacturer (see below)
with the
prefix "L". Solid forms of Pluronic characterized as "F" for flake or "P" for
powder
may be dissolved, dispersed or suspended in the liquid Pluronic or if
desired, used with
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another liquefying agent. Illustrative of suitable materials are those shown
below in the
Examples. In addition to their suitability for use as a Component 2, they may
also be used
as an absorption accelerants. They are available under the trade name Pluronic
from
BASF Corp. Mt. Olive, New Jersey 07828.
[0055] Another class of materials, useful as Component 2, are symmetrical and
unsymmetrical dialkyl ketones and alkyl aryl ketones having boiling points
greater than
about 80 C such as methyl propyl ketone, diethyl ketone, methyl butyl ketone,
ethyl
propyl ketone, methyl pentyl ketone, and 2-octanone, 2-nonanone, 2-decanone,
and methyl
phenyl ketone.
[0056] Another class of materials useful as Component 2 are selected from a
member of
the group consisting of polyhydroxy compounds, polyhydroxy compound esters,
solutions
of polyhydroxy compound, and mixtures thereof, and fatty acid esters.
Preferred among
these are the liquid polyhydroxy compounds selected from the group consisting
of acyclic
polyhydric alcohols, polyalkylene glycols, and mixtures thereof. Specific
examples of the
foregoing are ethylene glycol, diethylene glycol, triethylene glycol, 1,2-
propanediol,
trimethylolethane, trimethylopropane, erythritol, pentaerythritol,
polyethylene glycols, a
liquid solution of a fatty acid monoester of glycerol such as glycerol
monolaurate. Solids
among the foregoing may be dissolved or dispersed in a suitable solvent medium
such as
propylene glycol, glycerol, monoacetin, diacetin, liquid polyethylene glycol,
and mixtures
thereof. As glycerides, there may be mentioned monoglycerides, e.g., glyceryl
acetate,
glyceryl stearate, homologs thereof, and the like, diglycerides such as
glyceryl diacetate,
glyceryl dicaprate, dibutyrate, dilaurate, and the like, and triglycerides
such as olive oil,
castor oil, almond oil, sesame oil, cottonseed oil, corn oil, cod liver oil,
safflower oil and
soya oil. It should be noted that the foregoing polyhydroxy compounds may also
be used,
if desired, as absorption accelerants.
[0057] As a statement of general applicability, it should be noted that
Component 2
materials which are liquid at room temperature are the preferred substances
for
Component 2, and since they are liquids, a liquefying agent is not necessary.
Also useful
as Component 2 substances, however, are compounds which are solid at room
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temperature. In such cases, especially when putties are desired, a solid
Component 2 is
converted to a liquid form preferably before, but also during, or after
admixture with
Component A and then Component 1, through the use of an absorbable
biocompatible
liquefying agent capable of liquefying, solubilizing, dispersing or suspending
Component
A therein. By "liquefying agent" as used herein, is meant an agent, such as a
suitable
organic solvent, which can solubilize disperse or suspend Component A and then
be
blended with the solid Component 2. Other agents may be used, even though the
agent
may not be considered an organic "solvent" in the usual sense of that term, or
an agent
which can liquefy the solid, such as heat, or which can disperse the solid in
a liquid as a
dispersion so as to aid in the formation of a homogenous putty, cream or paste-
like
mixture. The particular agent used will, of course, depend upon the nature of
Component
2 and Component A used in the particular formulation. Suitable agents are
materials
similar to Component 2 though not precisely described herein as Component 2.
[0058] The foregoing novel concepts and compositions especially those
utilizing the esters
of monoalcohols with the mono- or polycarboxylic acids described above,
provide an
absorbable bone hemostatic implant with the releasable analgesic. The novel
utilization of
relatively low molecular weight, non-toxic and rapidly degradable simple
esters such as
diethyl succinate and triethyl citrate have been found to provide superior
alternatives to the
much higher molecular weight fatty acid triglycerides, e.g., castor oil, for
Component 2.
This aspect of the invention thus permits one to avoid, if desired, both the
art-known
version of Component 2, i.e. hydrophobic, slowly absorbed esters such as the
triglycerides
typified by the ricinoleic acid triglyceride, castor oil, as well as by fatty
acid esters such as
isopropyl myristate.
[0059] These art-known putty compositions containing the art-known Component 2
materials, such as those of U.S. Patent 4,439,420 can, however, be used to
obtain useful
pain relief compositions of the inventions in any case but especially in
osteogenic bone
hemostatic materials in accordance with the following aspect of the invention.
It has been
discovered that, when it is desired to have a bone hemostatic composition
having
osteogenic properties albeit with slower absorption characteristics, the art-
known
composition may be improved by the addition of osteogenic materials, e.g.,
demineralized
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bone matrix (DBM), mineralized bone matrix (MBM), hydroxyapatite, tri-calcium
phosphate, or growth factors such as bone morphogenic protein (BMP) and
platelet
derived growth factor (PDGF), as will described below.
[0060] Preferred for use as Component 2, in specific embodiments are the
following:
tocopheryl acetate, triethyl citrate, liquid block copolymers of ethylene
oxide and
propylene oxide having a molecular weight of about 1900 to about 8000
(Pluronic L-35,
molecular weight 1900, is especially preferred), and a blend of Pluronice L-35
and F-68
(a flake form of Pluronic ).
Component A
[0061] Component A is a critical ingredient of the invention, namely an
analgesic having
local pain-relieving activity suitable for internal relief of pain as
described above. It does
not matter whether or not the anesthetic is normally an injectable or
systemically used
analgesic, provided it has local (topical) pain-relieving activity when
implanted at the
surgical site. These are sometimes referred to herein and the Examples which
follow as
"the analgesic component". The analgesics useful in the invention are
preferably those
that exist in free base form (which includes analgesics with moieties
connected through
ester or amide linkages) and in the acid addition salt form thereof.
Illustrative of these are
analgesics having the "-caine" suffix included among which are, benzocaine,
bupivacaine,
dibucaine, lidocaine, mepivacaine, prilocaine, procaine, chloroprocaine,
etidocaine,
tetracaine, xylocaine, and propivacaine. As acid addition salts there may be
employed the
hydrohalides such as the hydrochloride, the hydrobromide, and the like.
Preferred are
lidocaine and lidocaine hydrochloride.
[0062] There also may be employed numerous other analgesics which have local
pain-
relieving activity such as the non-steroidal anti-inflammatory compounds such
as
ibuprofen, aspirin, acetaminophen, naprosyn and the like, non-opioids such as
fentanyl and
pain-relieving prostaglandins. The actual drugs used are not especially
limited provided
they have local pain-relieving effect at the site and are biocompatible, i.e.,
not intolerably
toxic, at the dosages used.
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Component B
[0063] There may be added materials which alter the elution rate of the
analgesic from the
putty. For example, it has been found that the addition of hydrophilic,
biocompatible,
absorbable materials, e.g., esters of fatty acids or fatty alcohols such as
ethyl laurate or
lauryl acetate and tocopherols, such as tocopheryl acetate, retard the elution
of anesthetic
compounds from the putty. On the other hand, the addition of more hydrophobic
additives
such as tricalcium phosphate, hydroxyapatite DBM or lecithin cause an increase
in the
elution rate of anesthetics from the putty. Hydrophobic compounds may be added
up to
concentrations of about 20% while up to 40% of hydrophilic additives are
effective in
increasing the rate of elution.
Component 3- Optional
[0064] Component 3, is optionally included as an absorption accelerant and may
even be
used to control the kinetics of absorption by physically assisting in the
disintegration of
the implanted mass. Accelerants used in the prior art may be used if they are
not toxic or
otherwise bioincompatible. One or a combination of such prior art compounds as
Carbowax , Pluronic , (See discussion under Component 2 supra and discussion
below)
and glycerine, propylene glycol, lecithin, betaine, and polyhydroxy compounds
such as
hyaluronic acid, carboxymethylcellulose and chitosan and its acetyl
derivatives may be
used as absorption enhancers in the compositions of the invention, with the
above caveat.
[0065] It is preferred, however, to use for this purpose, other materials
which are
swellable or soluble and absorbable, such as either soluble or insoluble
natural or synthetic
polypeptides, exemplified by purified, powdered insoluble fibrillar, but
swellable
collagens, the more rapidly absorbable soluble tropocollagens such as Vitrogen
and the
more rapidly absorbable cold and hot water soluble polypeptides, e.g. the
gelatins.
Lecithin and octylphenyl ethoxylates, such as Triton X-100, may be used as
biocompatible surfactants to aid in swellability. Polyvinylpyrrolidone and
other soluble,
absorbable polymers such as the block copolymers of ethylene oxide and
propylene oxide
discussed supra in connection with Component 2, and relatively hydrophilic
polypeptides,
e.g., polyaspartic acid, polyglutamic acid, and their salts are also
functional in this context.
The compositions of the present invention may contain, as the Component 3,
insoluble,
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fibrillar collagen, soluble collagen, gelatin, octylphenyl ethoxylates (e.g.
Triton X-100),
the block or random copolymers of ethylene oxide and propylene oxide,
polyvinylpyrrolidone or absorbable phosphorus pentoxide-based glasses or
stable mixtures
of the foregoing.
[0066] Particle sizes in the range of about 200-500 microns produce suitable
results
although larger or smaller particle sizes may be employed depending on the
desires of the
end user. Gelatin, PVP and other polymers have been used in the demineralized
bone art
as thickening additives but not as absorption accelerants. The thickening
properties of
gelatin vary directly with the Bloom number of the gelatin. Gelatin having
Bloom
numbers ranging from 100-300 are suitable in the compositions of the
invention, although
values above or below those numbers may be employed if the resulting product
is
acceptable to the end user.
[0067] Illustrative of some suitable proportions of the foregoing Components
which
produce compositions having the properties described above, are the following
(based on
the weight of final composition):
Component 1. From about 5 to 80%, preferably about 20 to 60%.
Component 2. From about 5 to about 70%, preferably about 20 to 60%.
Component A. A pharmaceutically effective amount, suitably from about
to 25 %, preferably about 10 to 20% by weight.
Component B 0 to about 40 %.
Water 0 to about 10 %.
[0068] While the foregoing discussion has been presented largely in the
context of
materials having the consistency of a putty, in some applications it may be
desired to have
a relatively less viscous or less cohesive composition or even a more viscous,
more
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cohesive composition. For example, it may be desired to place the composition
of the
invention into a void in the bone (drilled or otherwise formed, e.g., hairline
fractures) into
which a putty of high viscosity can be applied only with difficulty. A less
viscous form of
the putty compositions of the invention would be a desirable alternative. All
one needs to
do is modify the proportions presented herein to allow for a higher or lower
liquid
concentration or add a compatible liquid diluent to achieve this purpose.
Using this
approach, an injectable form of the material can be obtained as well. Other
less cohesive
strength, non-putty compositions, such as creams, ointments, gels, lotions,
and the like
previously referred to, may be prepared in the same manner.
Component 4- Optional
[0069] Included in the products described above are suitable pain-relieving
products
which also may allow the growth of bone at the bone wound site. Thus, they are
osteoconductive. A desirable aspect of the invention is to make the product
osteoinductive
as well, that is, to provide the product with Component 4, a bone growth-
inducing material
in an amount effective to induce bone growth. Thus, the inclusion of
osteogenic materials
such as growth factors, e.g., Platelet Derived Growth Factor (PDGF),
Transforming
Growth Factor beta (TGF-beta), Insulin-Related Growth Factor-I (IGF-I),
Insulin-Related
Growth Factor-II (IGF-II), Fibroblast Growth Factor (FGF), Beta-2-
Microglobulin (BDGF
II), bone morphogenic protein (BMP), and combinations thereof stimulate
osteogenesis to
varying degrees. Other bone growth-inducing materials such as demineralized
bone
matrix (DBM), osteonectin, osteocalcin, osteogenin, and combinations thereof,
mineralized bone matrix (MBM) tri-calcium phosphate, as well as bioactive
glasses,
render the hemostatic product suitably osteogenic.
[0070] When used, a suitable amount of osteogenic material to be added to the
compositions of the present invention ranges from about 0.001 to about 60%
depending
upon the material and preferably about 0.001 to about 40% by weight. When used
as
Component 4, i.e., as an osteogenic material, it is preferred to use certain
agents such as
DBM or mineralized bone in the form of larger average particle sizes. Suitable
larger
average particle sizes are in the range of about 0.05 to 10 mm preferably
about 0.1 to 5
mm and most preferably about 0.5 to 1 mm. However, the use of Component 4 in
smaller
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or larger particle sizes or in higher or lower amounts will also be suitable
if the
requirements of the ultimate user are satisfied.
[0071] With regard to the relative amounts of osteogenic material to be used
in a
composition of the invention, one would use a bone growth-inducing effective
amount, by
which is meant material adequate in amount and form to be osteoinductive in
the
composition. The amount used may vary depending upon the efficacy of the
osteogenic
agent and the average particle size of the solid material. For example, growth
factors such
as BMP, Platelet Derived Growth Factor (PDGF) and the like are effective in
fractional
weight percent concentrations, whereas effective amounts of DBM, and
mineralized bone
matrix, are usually in higher weight percent concentrations, e.g., about 10%
to about 50%
or higher, and preferably in somewhat larger average particle sizes than those
used in
Component 1.
[0072] The addition of the bone growth-inducing material improves not only the
compositions of the invention, but also irpproves the prior art hemostatic
formulations to
yield novel compositions therewith. Such additions will render these
hemostatic
formulations osteogenic as well. It is believed that the presence of the
osteogenic material
will also improve osteoconductive properties because the relatively large
particles tend to
"open up" the putty structure, thus providing spaces into which induced bone
may
proliferate.
[0073] The type of prior art hemostatic formulations which will especially be
improved by
such addition are the ones disclosed in U.S. Patents, 4,439,420 and 4,568,536
each of
which is incorporated herein by reference for all purposes. Thus, the present
specification
and claims are to be read as though the complete specification and claims of
the
aforementioned patents were reproduced herein verbatim. For purposes of
convenience,
the formulations of those patents may be generally characterized as comprising
an
absorbable hemostatic composition for use in the control of osseous
hemorrhage,
comprising: a component comprising a biocompatible fatty acid salt, the cation
of said
fatty acid salt being selected from the group consisting of calcium,
magnesium, zinc,
aluminum, lithium and barium and a component comprising a body absorbable
biocompatible base selected from the group consisting of ethylene
oxide/propylene oxide
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block copolymers, polyhydroxy compounds, polyethylene glycols and
methoxypolyethylene glycols, triglycerides and fatty acid esters, and an
optional
absorption enhancing agent. Thus, in this aspect of the invention, the bone
growth-
inducing materials are added to the above prior art formulations to produce an
osteogenic
hemostatic material as well as an osteoinductive bone defect filling material.
Other Optional Ingredients
[0074] To any of the compositions described infra, may be added a
pharmaceutically
effective amount of an anti-infective agent, either alone or bound to a
substrate to slow its
release. Illustrative of such anti-infective materials are antibiotics such as
tetracycline,
vancomycin, cephalosporins, and aminoglycosides such as tobramycin and
gentamicin,
alone or bound to collagen, for example, as well as Tricolsan, iodine, alone,
or as a PVP
complex, colloidal silver, silver salts, alone or bound to a carrier such as
gelatin, collagen,
and the like.
[0075] Other materials, such as vasoconstrictors and blood clot-inducing
agents, e.g.,
epinephrine, tannic acid, ferrous sulfate, and the double-sulfates of a
trivalent metal and a
univalent metal such as potassium aluminum sulfate and ammonium aluminum
sulfate;
anti-neoplastic agents such as methotrexate, cis-platinum, doxorubicin, and
combinations
thereof, radionuclides such as Strontium 89, and the like; analgesics as
referred to infra,
such as benzocaine, lidocaine, tetracaine, fentanyl (a potent non-opioid), and
the like; anti-
inflammatory substances such as the non-specific ibuprofen and aspirin, or the
COX-2
specific inhibitors such as celeboxib; radiopaque substances such as iodo
compounds, e.g.,
ethylmonoiodo stearate available as Ethiodol (Savage Laboratories), and
barium salts
such as barium stearate, may be added to the formulations in amounts which are
effective
to achieve their therapeutic or diagnostic purposes. Depending upon the
characteristics of
the colorant selected, colorants such as gentian violet, D&C Violet #2, and
D&C Green #6
are suitable.
[0076] In some embodiments of the invention, it may be desirable to intimately
admix
water with the compositions of the invention. The presence of a small amount
of water, of
the order of up to ten percent or more, aids in a variety of ways among which
is changing
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the tactile quality of the composition. In this regard, the resulting
compositions often
impart a sensation of reduced coarseness over what may have existed in the
compositions
without the water addition. In some instances, it is desirable to provide a
putty-like
formulation or a less dense non-putty formulation having a cohesive strength
less than that
of a putty, such as a cream, a paste, or other such materials as previously
set forth herein,
based upon water or other aqueous liquids rather than on more hydrophobic
vehicles.
Bulking agents such as the metal fatty acid salts, e.g., calcium stearate and
other non-
wettable bulking agents described herein, are not wetted by water and do not
provide
putty-like (or less dense) compositions with water. We have found, however,
that the
treatrnent of the bulking agent with a small amount of surface-active
material, e.g.,
lecithin, a Pluronic such as Pluronic L-35 , renders the unwettable bulking
agent
sufficiently wettable to enable the preparation of a suitable fatty acid salt-
water
formulation when Component 2 is an aqueous vehicle. Suitable aqueous vehicles
are
water, saline, various biocompatible buffer solutions, various body fluids,
such as blood,
serum, blood component concentrates, and the like.
6
[0077] If water soluble anesthetic salts are used in the formulatiorr, they
may be dissolved
in a minimal quantity of water prior to adding-to the other Components of the
formulation.
While the above putties have less resistance to irrigation compared with the
putties
prepared using more hydrophobic materials, they have applications in bone
defect repair
where more rapid disintegration of the implant is desired. Non-ionic,
cationic, and anionic
surfactants are suitable, although virtually any biocompatible surfactant may
be used as
exemplified by dodecyl trimethyl ammonium chloride, sodium lauryl sulfate,
nonoxynol-
9, the Tweens, e.g., polyoxyethylenesorbitan monolaurate, Tergitol-7, i.e.,
sodium
heptadecyl sulfate, and the antimicrobial surfactant, 1-lauryl-3-ethylbenzo-
triazolium
bromide, and the like. Non-putty-like compositions, such as creams, pastes,
and the like,
may be prepared by using additional quantities of water or Component A. This
is
especially useful during surgical procedures when it is desired to form a
putty- or cream-
like composition using, for example, blood instead of water.
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[0078] The foregoing discussion relating to the use of blood clot-inducing
agents in the
present invention illustrates the embodiment wherein the compositions are
capable of
chemical hemostasis in use. That is, the addition of a styptic material to the
compositions
of the present invention, whether those compositions are mechanically
hemostatic or not,
yields compositions having the ability to act as chemical hemostatic
materials. Thus, an
already mechanically hemostatic putty can be made more efficiently hemostatic
by adding
a blood clot-inducing material. Similarly, a lower cohesive strength cream or
paste, which
may lack significant mechanical hemostatic properties, can be made hemostatic
by the
addition of a blood clotting material. An example of the latter is the
application of a thin
layer of a vasoconstrictor-modified paste of the invention to a bleeding
acetabulum in hip
surgery.
[0079] The components described above, when added together in suitable
proportions,
yield useful, putty-like and non-putty like agents having, to varying degrees,
many
favorable characteristics. Various combinations of the components may require
different
times and temperatures in the preparation process in order for the putty-like
characteristics
to develop. For example, some materials such as finely divided hydroxyapatite
may take
longer than other components to achieve the putty-like state. In general, the
putty-like
compositions of the prdsent invention are absorbable within a reasonable time,
usually
within 30 - 60 days although absorption times may be extended to several
months or
longer for some applications. They are moldable and shapeable by hand at
ambient
temperatures, handle well in presence of blood, and are washable with saline.
They
sometimes are tacky to the touch, but do not stick to any great degree to
surgical gloves,
wet or dry. They can be radiation sterilized when radiation-sensitive material
such as
DBM or certain antimicrobials are not present.
[0080] The actual proportions of the materials selected will vary depending
upon the
materials themselves, the number of components used, and the end use desired
for the
final putty composition. The user will be guided initially by the requirement
for the
desired viscosity, cohesive strength, and consistency to be obtained, i.e.
compositions
ranging from flowable liquid consistencies to consistencies of creams, pastes,
ointments,
gels, and the like to the more cohesive putty-like consistencies, while
maintaining other
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characteristics desired in the ultimate use of the component. For example, for
a number of
procedures, it is important to be able to secure the analgesic composition to
the site from
which the pain originates. In orthopaedic surgery, compositions are provided
to adhere to
the surface of the bone as it releases the analgesic to the local environment.
In general
surgery, however, there usually is no hard surface to which putty-like, or
even higher
viscosity, compositions can adhere. Such difficulties are addressed by this
embodiment.
Specifically, it has been found that a sieve-like or fabric-like or felt-like
or non-woven
structure can be uniformly impregnated with such materials containing
analgesic drugs to
yield a fabric-putty laminate containing analgesics. Of course, other drug
substances such
as for example, antimicrobial, anti-inflammatory and anti-cancer agents as
well as growth
stimulating agents such as PDGF, etc., described herein, can be incorporated
in the devices
of this embodiment of the invention.
[0081] While the solid component of this invention is universally absorbable
to avoid
long-term residence of solid foreign bodies, the fabric component may be
absorbable or
non-absorbable, depending on the surgical need. For example, a fabric-putty
laminate
serves to provide a standardized amount of drug per unit area as well as a
means for
securing the device to the area of need (if simple placement of the laminate
of this
invention on or in the tissue is not adequate) by using tack sutures or
staples to attach the
fabric component to the adjacent tissue.
[0082] For procedures involving the need for permanent support or
reinforcement such as
hernia repair, a non-absorbable fabric may be indicated. Thus, in the post-
operative stage,
as the analgesic becomes exhausted and the putty absorbs, the remaining non-
absorbable
fabric serves to permanently reinforce the repaired defect. Fabrics such as
those prepared,
for example, by knitting polyester, polypropylene or polyethylene fibers, or
non-woven or
felt-like fabric are examples of useful materials since they are presently and
successfully
used in other body-compatible procedures. Thus, the present invention is
useful with any
type of fabric, absorbable or non-absorbable, provided the fabric is
compatible with the
exigencies of the particular surgery being performed. In fact, the substrate
need not be a
"fabric" in the usual sense that the word "fabric" is normally used. For
example, the
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substrate may be a non-woven or felt-like fabric upon which the compositions
are applied
to or impregnated into.
[0083] For procedures not requiring permanent reinforcement, absorbable
fabrics such as
those made from synthetic absorbable polymers such as polyglycolic acid and
natural
absorbable polymers such as collagen, alginates, and the like, are applicable.
In this case,
the entire device is absorbed after its drug delivery function has been
fulfilled.
[0084] This aspect of the invention utilizes not only creams and putties as
the analgesic
carrier vehicle, but also other compositions which can be applied to a
substrate and be
supported thereon. The analgesics employable herein can be any which are
internally
tolerated such as those previously described herein. Illustrative of others
that may be used
are non-steroidal anti-inflammatory compounds such as Torodol , ibuprofen,
aspirin,
acetaminophen and the like.
[0085] For many uses, a substrate in the form of a netting, gauze, fabric,
felt or non-woven
structure is suitable. The form may be rigid, flexible, flat or contour-shaped
as desired or
required by the procedure. One may visualize a shape in the form of, for
example, a
gauze-like substrate, fashioned out of the appropriate material to which a
layer of the
composition described herein may be applied, much as in the manner that a
layer of
Vaseline (t is applied to a cotton gauze. There is no particular limitation on
the substrate
as long as it can support the analgesic composition and is body-compatible.
[0087] The composite or laminate of this aspect of the invention is thus
amenable to use in
a variety of procedures, of which the following are typical, but only
illustrative:
a) collagen substrate covered with a putty comprising ibuprofen as the
analgesic,
applied in orthopaedic surgeries such as knee, hip and shoulder replacements.
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b) absorbable polymer mesh bearing a putty composition as the analgesic-
delivering composition containing any of the "-caine" analgesic compounds in
free base or acid addition salt for or combinations thereof, applied to cut
bone
to staunch bleeding and provide post operative pain relief in a hernia
operation, for example:
c) a knitted fabric of an absorbable material such as Vicryl carrying an
impregnated coating of a thick paste or cream composition of the invention
comprising an analgesic wherein the fabric may be attached or applied to, or
draped over surgically exposed tissue.
[0088] The compositions described in this Specification, when used surgically,
must be
sterile. All, except those noted below, are radiation sterilizable using, for
example, a
standard cobalt-60 radiation source and a nominal dose of 25 kGy. Exceptions
are
formulations containing radiation-sensitive additives such as demineralized
bone matrix,
bone morphogenic protein, certain antibiotics, unsaturated molecules such as
oleic acid
and the like. When such materials are used, sterility may be achieved by
radiation-
sterilizing the bulk putty-like or non-putty like material and aseptically
adding the sterile
radiation-sensitive additive followed by aseptic packaging.
[0089] The compositions described in this Specification may be sterile or
sterilizable and
may be packaged in several formats. The packages themselves may be sterile or
sterilizable. The compositions may be packaged as an amorphous (i.e.,
shapeless or
having no definite shape) material such as a paste, cream, or putty, or in the
shape of its
container. They may be shaped generally as a parallelepiped or as a generally
rounded
form, examples of the former being small brick-shapes or slabs (in the shape
of a stick of
chewing gum), and examples of the latter being cylindrically shaped, egg-
shaped, or
spherically shaped products. Alternatively, when the application permits and
the viscosity
is suitable, the product can be packaged in a syringe-like or plunger-assisted
dispenser
expressible or extrudable through an orifice of appropriate cross section and
shape. A
mechanical assist device similar to that used for caulking may be included.
Another
package contains the product in a squeezable, deformable tube such as a
toothpaste-type
tube or a collapsible tube such as those used in caulking applications, with
an orifice
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shaped and sized to dispense any suitable shape onto the surface to be
treated. The
package may comprise an outer barrier as an overwrap, for example, a peelable
blister
pouch, to allow aseptic delivery of the package to the sterile field.
[0090] The present invention also contemplates methods of use of the
compositions of the
invention. For example, one embodiment is the method of mechanically
controlling the
bleeding of bone by the application of an effective amount of any of the
compositions of
the invention to bleeding bone; wherein the composition has a sufficiently
dense
consistency, such as in the putty compositions of the invention. In such a
case, the
composition is a mechanical hemostatic tamponade.
[0091] Another embodiment of the method of use of the invention is the method
of
chemically controlling the bleeding of bone by the application of an effective
amount of
any of the compositions of the invention, wherein the composition contains a
blood clot-
inducing agent as heretofore set forth. In the case of putties, the
composition is a chemical
hemostatic tamponade. Mechanical hemostatic tamponades of the invention which
also
comprise a clot-inducing agent will act as both a mechanical hemostat and a
chemical
hemostat.
[0092] Another method of the invention is the method for inducing the growth
of bone in
a bone defect by applying an effective amount of any composition of the
invention
containing a bone growth-inducing agent, to the affected area of bone,
especially when the
composition includes a bone growth-inducing material such as DBM, mineralized
bone
matrix, bone morphogenic protein, hydroxyapatite, or the like. Another method
is the
method for treating an infection in or around a bone by applying an effective
amount of
any composition of the invention containing an anti-infective agent, to the
affected area of
bone to be treated.
[0093] Another method is the method for destroying cancer cells in or around a
bone by
applying an effective amount of any composition of the invention containing an
anti-
neoplastic agent, to the affected area of bone which contains such cells.
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[0094] Another method is the method for reducing pain from an area in or
around a bone
by applying an effective amount of any composition of the invention containing
an
analgesic agent, to the affected area.
[0095] Another method is the method for controlling inflammation in or around
a bone by
applying an effective amount of any composition of the invention containing an
anti-
inflammatory agent, to the affected area.
[0096] Another method is the method for assessing the status of an area in
bone to which
an implant has been applied by applying an effective amount of any composition
of the
invention containing a radiopaque agent, to the affected area and thereafter
radiographically visualizing the area and making a determination of the status
of the area.
[0097] Another method is the method for rendering wettable any of the bulking
agents
used in the invention which may be hydrophobic by treating the bulking agent
with a
cationic, anionic, or non-ionic surfactant and then making a water-based putty
from the
treated bulking agent using any source of liquid such as water itself, saline,
or body fluids
such as blood, serum, or the like.
[0098] Other methods are each of the foregoing methods for treating or
managing post-
operative pain wherein the composition comprises an analgesic.
[0099] Those skilled in the art will be aware of the manner in which the
compositions are
applied and the amount thereof. In some applications, large amounts of the
tamponade
may be used while in others only small amounts may be required or desired.
[0100] The methods and examples provided below are intended to more fully
describe
preferred embodiments of the invention and to demonstrate its advantages and
applicability.
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[0101] The following examples illustrate specific embodiments of the present
invention.
EXAMPLE 1
[0102] In this example and in all subsequent examples, unless otherwise
indicated, the
composition was prepared by mechanical blending of all dry reagents first and
thereafter
adding gradually any liquid reagents. The composition was "worked" with a
spatula at
room temperature until the desired consistency was obtained. In some cases, if
the
material needed additional ingredients to improve the consistency, that
material was added
and the mixture continually kneaded or "worked" until the desired putty-like
consistency
was obtained. The components are presented in parts by weight.
Component 1 Calcium stearate 4 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3 g.
[0103] The sample yielded a putty-like mass with excellent water resistance,
physical and
hemostatic characteristics and water resistance properties, i.e., it resisted
strongly attempts
at washing it away under the force of flowing tap water.
EXAMPLE 1 a)
[0104] By varying the proportion of the liquid components, the compositions of
the
present invention can be rendered into states of lower (i.e. more liquid) or
higher (i.e.
more rigid) viscosities. Illustrative of a lowered viscosity formulation is
the following: to
the putty formulation of Example 1 is added 3 g. of acetyl triethyl citrate.
The resulting
product has a cream-like consistency and may be applied, in appropriate
circumstances, to
bone as a hemostatic agent or as a delivery agent for a variety of additives
such as drugs.
EXAMPLE 2
[0105] Partial replacement of calcium stearate with bone growth-inducing
materials
a) Component 1 Calcium stearate 3 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3 g.
Component 4 Hydroxyapatite (6-12 micron particle size) 1 g.
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[0106] The resulting product is a putty-like mass with properties comparable
to the
product in Example 1. When a small amount of gentian violet sufficient to
impart a
discriminating light violet color is added to the above formulation, a colored
product with
the characteristics of the product of Example 1 is obtained.
b) Complete replacement of calcium stearate with hydroxyapatite.
Component 1 Hydroxyapatite (6-12 micron particle size) 2 g.
Component 2 Tocopheryl acetate 2.5 g.
Component 3 Gelatin 2 g.
[0107] The composition was allowed to stand at room temperature for 72 hours
yielding a
product that had the characteristics of the product of Example 1.
EXAMPLE 3
[0108] Component 1 Aluminum Palmitate 5 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3 g.
[0109] The resulting product is a putty-like mass with properties similar to
those described
for the product in Example 1.
EXAMPLE 3 a), 3 b), 3 c)
[0110] The putty-like formulation of Example 3 is rendered into less viscous
compositions by modifying the Example 3 formulation as follows:
Ex. 3 Ex. 3a Ex. 3b Ex. 3c
Component 1 Aluminum Palmitate 5 5 5 5
Component 2 Tocopheryl acetate 3 4 6 8
Component 3 Gelatin 3 0 0 0
Formulation 3a has the consistency of a soft putty.
Formulation 3b has the consistency of a thick cream much like cake icing.
Formulation 3c has the consistency of a slowly flowable composition much like
cold
honey.
Each of them can be applied to bone as a hemostatic agent.
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EXAMPLE 4
[0111] Component 1 Calcium stearate 5 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3 g.
Component 4 DBM 3 g.
[0112] The resulting product has, in addition to hemostatic properties of the
product of
Example 1, the additional property of osteoconductivity.
EXAMPLE 5 5 a. S b.
[0113] Component 1 Calcium stearate 2 g. 1.3
Component 2 Triethyl citrate 1.6 g. 0.98
Component 3 Triton X-100 0 0.02
[0114] The resulting product 5a, was putty-like and had physical
characteristics similar to
those of Example 1. Product 5b was also putty-like and is more rapidly
absorbable than
5a. Triton X-100 is available from Dow Chemical Co., Midland, Michigan.
EXAMPLE 6
[0115] Component I Calcium stearate 4 g.
Component 2 Triethyl citrate 3 g.
Component 3 Gelatin 3 g.
[0116] The resulting product was putty-like and had physical characteristics
useful as a
hemostat, but not preferred when compared to the product of Example 5.
EXAMPLE 7
[0117] Component I Calcium stearate 2 g.
Component 2 Acetyl triethyl citrate 2 g.
[0118] The resulting product has excellent putty-like characteristics and
physical
characteristics comparable to those of Example 1.
EXAMPLE 8
[0119] Component 1 Calcium stearate 0.5 g.
Component 2 Triethyl citrate 1 g.
Component 4 Hydroxyapatite 2 g.
[0120] There resulted a low viscosity injectable composition having hemostatic
properties.
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EXAMPLE 9
[0121] Component I Calcium stearate .5 g.
Compoiient 2 Tocopheryl acetate 2 g.
Component 4 Hydroxyapatite 2 g.
[0122] There resulted a composition having excellent putty-like
characteristics and water
resistance.
EXAMPLE 10
[0123] Component 1 Hydroxyapatite 2 g.
Component 2 Triethyl citrate 2.5 g.
[0124] There resulted a composition which is easily applied to rough bone
surfaces with
good adhesion and filling characteristics.
EXAMPLE 11
[0125] Component I Calcium stearate 3 g.
Component 2 Tocopheryl acetate 1.0 g.
Component 2 Triethyl citrate 1.5 g.
Component 3 Gelatin 2 g.
[0126] The resulting product was a good material with putty-like physical
characteristics
similar to those of Example 1 and somewhat more sticky than that of Example 1.
EXAMPLE 12
[0127] Component 1 Calcium stearate 4 g.
Component 2 Lauric acid 4 g.
Component 2 Tocopheryl acetate .5 g.
[0128] The calcium stearate was blended with melted lauric acid and formed a
good putty
which, upon cooling, solidified. The solid was then crushed and blended with
the
tocopherol to yield a good putty.
[0129] The resulting product has a putty-like consistency at body temperatures
and a
somewhat harder consistency at room temperature.
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EXAMPLE 13
[0130] Component 1 Calcium stearate 4 g.
Component 2 Triethyl citrate 4 g.
Component 2 Lauric acid 4 g.
[0131] The resulting product was putty-like and had physical characteristics
similar to
those of Example I and with somewhat less cohesiveness.
EXAMPLE 14
[0132] Component 1 Calcium stearate 2 g.
Component 2 Dodecane 1 g.
[0133] The resulting product had good water resistance, was of lower viscosity
and
compared well with the other physical characteristics of Example 1.
EXAMPLE 15
[0134] Component 1 Calcium stearate 2 g.
Component 2 Octanol-1 1 g.
[0135] The resulting product was of lower viscosity and had physical
characteristics
similar to those of Example 14 but somewhat less cohesive.
EXAMPLE 16
[0136] Component 1 Calcium stearate 2 g.
Component 2 Diethyl succinate 2 g.
Component 3 Gelatin 2 g.
[0137] The resulting product was a good putty similar to Example 1.
EXAMPLE 17
[0138] Component 1 Calcium stearate 4 g.
Component 2 Diethyl succinate 3 g.
[0139] The resulting product was a good putty which had improved consistency
over that
of Example 16.
EXAMPLE 18
[0140] Component 1 Calcium stearate 4 g.
Component 2 Acetyl triethyl citrate 3 g.
Component 3 Gelatin 3 g.
[0141] The resulting product was comparable to that obtained in Example 1.
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EXAMPLE 19
[0142] Component 1 Aluminum palmitate 4 g.
Component 2 Tocopheryl acetate .3 g.
Component 2 Triethyl citrate 3 g.
[0143] The resulting product was a soft, somewhat translucent putty with good
water
resistance and good hemostatic characteristics.
EXAMPLE 20
[0144] Component 1 Calcium stearate 3 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3 g.
Component 4 Demineralized bone matrix 1 g.
[0145] The resulting product is a putty-like mass with properties comparable
to the
product in Example I and has osteogenic properties as well.
EXAMPLE 21
[0146] Component 1 Hydroxyapatite 3 g.
Component 2 Tocopheryl acetate 3.5 g.
Component 3 Gelatin 3 g.
[0147] In this example, the material initially was soft and oily and lacked
coherence.
However, upon standing at room temperature for 72 hours, an excellent putty
with good
water resistance formed. Increasing the amount of tocopheryl acetate by an
additional 3 g.
yields a paste having a coarseness attributable to the gelatin.
EXAMPLE 22
[0149] Component 1 Calcium stearate 3 g.
Component 2 Di-n-hexylether 2.5 g.
Component 3 Gelatin 2 g.
[0150] The resulting product is putty-like and has good water resistance and
physical
characteristics similar to those of Example 1.
EXAMPLE 23
Component 1 Calcium stearate 3 g.
Component 2 Di-n-pentylketone 2.5 g.
Component 3 Gelatin 2 g.
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[0151] The resulting product is putty-like and has good water resistance and
physical
characteristics similar to those of Example 22.
EXAMPLE 24
[0152] Component I Calcium stearate 3 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Bovine collagen (powdered) 3 g,
[0153] The resulting product is putty-like, has good water resistance and
physical
characteristics similar to those of Example 23. In addition, the putty has a
fibrous texture
as a result of the fibrous powdered collagen sponge additive present as the
absorption
accelerant (Component 3).
EXAMPLE 25
[0154] Component 1 Calcium stearate 3 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 *Bovine collagen (powdered) 3 g.
containing gentamicin sulfate.
*CollatampG, available in Europe
[0155] There results a hemostatic putty with anti-infective properties.
EXAMPLE 26
[0156] Component 1 Calcium stearate 4 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3g.
Anti-Infective Gentamicin sulfate 120 mg.
[0157] Example 1 is repeated except that 120 mg. of gentamicin sulfate is
combined with
the dry components before the tocopheryl acetate is added to make a putty.
This example
demonstrates the preparation of a putty with anti-infective properties.
EXAMPLE 27
[0158] Component 1 Calcium stearate 4 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3 g.
[0159] Example 1 is repeated except that the gelatin is soaked in 2% aqueous
silver nitrate
for 2 hours at room temperature, washed with two changes of distilled water
and one of
acetone and then dried overnight. This preparation has anti-infective
properties as a result
of the presence of silver/gelatin complexes.
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EXAMPLE 28
[0160] Component 1 Calcium stearate 4 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3 g.
[0161] Example I is repeated except that 10 mg of the gelatin is incubated
overnight in
one ml. of an aqueous solution containing 10 micrograms of lyophilized human
bone
morphogenetic protein (BMP-2, Sigma-Aldrich) followed by air-drying overnight.
The
damp gelatin is washed with acetone to remove residual moisture and combined
with the
remainder of the gelatin to prepare the putty having osteogenic and hemostatic
properties.
EXAMPLE 29
[0162] Component I Calcium stearate 4 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3 g.
[0163] Example 1 is repeated except that 0.5m1 of Betadine (povidone-iodine,
10%;
equivalent to 1% available iodine) was mixed into 10g. of the formed putty of
Example 1.
The mass turned to a brown color and has anti-infective properties.
EXAMPLE 30
[0164] Component 1 Micronized polylactic acid 3 g.
Component 2 Tocopheryl acetate 1.5g.
[0165] The mixture formed an excellent putty with good water resistance and
properties
comparable to the product in Example 1.
EXAMPLE 31
[0166] The following composition is described in U.S. Patent No. 4,439,420 as
a preferred
composition of about 40% calcium stearate, 30% dextran and 30% castor oil. If
water is
added, the preferred composition is 38% calcium stearate, 28% dextran, 27%
castor oil
and 7% water (all weights are weight percent). The composition was prepared by
mechanical mixing at ambient temperatures to avoid possible degradation of
heat-sensitive
components.
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Calcium stearate 4 g.
Castor oil 3 g.
Dextran 3 g.
[0167] The calcium stearate and dextran were dry blended in a 50ml glass
beaker and the
castor oil was added with stirring using a spatula. After several minutes of
"working" the
mixture with the spatula at room temperature, the consistency gradually
changed. The
mixture became crumbly and, after further working, became putty-like. The
addition of a
small amount of water (about 1 g.) reduces the gritty nature of the dextran.
EXAMPLE 32
[0168] The formulation in Example 31 was modified as indicated below to make a
novel,
putty-like composition of the present invention. The mass is an effective
hemostat and is
an effective osteogenic bone defect filler.
Calcium stearate 2 g.
Castor oil 1.5 g.
Dextran 1.5 g.
DBM (demineralized bone matrix) 1.5 g.
[0169] The purpose of this example is to show that DBM can be added to the
compositions described in U.S. Patent No. 4,439,420 to obtain a putty-like
mass with
osteogenic properties.
EXAMPLE 33
[0170] Component 1 Aluminum Pahnitate 5 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3 g.
Additive Methotrexate .2 g.
[0171] The now chemotherapeutic putty is packed into a bone defect following
surgical
excision of a bone tumor.
EXAMPLE 34
[0172] Component 1 Aluminum Palmitate 5 g.
Component 2 Tocopheryl acetate 3 g.
Component 3 Gelatin 3 g.
Additive Strontium 89 (as a salt)
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[0173] The above formulation, when provided with radioactively effective
amounts of
Strontium 89, yields a radiotherapeutic putty as described in Example 33.
EXAMPLE 35
[0174] Component I Pulverized Absorbable Phosphate Glass 3 g.
Component 2 Tocopheryl Acetate 1 g.
[0175] A crucible containing sodium dihydrogen phosphate hydrate was heated
for 4
hours at about 800 degrees C. and then rapidly cooled. The resulting
absorbable
phosphorus glass mass then was broken up with a hammer and the fragments
pulverized to
a fine powder in a rotating ball mill for about 72 hours. The finely
pulverized glass (3 g.)
was stirred with tocopheryl acetate (1.0 g.) until a putty-like mass formed
having good
physical properties and water resistance.
EXAMPLE 36
[0176] Component 1 Calcium stearate 3 g.
Component 2 Ethyl laurate 3 g.
Component 4 Demineralized bone matrix I g.
[0177] The purpose of this example is to show that DBM can be added to the
compositions described in U.S. Patent No. 4,439,420 to obtain a putty-like
mass with
osteogenic properties.
EXAMPLE 37
[0178] Component 1 Hydroxyapatite 3 g.
Component 2 Isopropyl palmitate 3.5 g.
Component 3 Gelatin 3 g.
[0179] Upon standing at room temperature for 72 hours, an excellent putty with
good
water resistance comparable to that of Example 2 is obtained.
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EXAMPLE 38
[0180] Component 1 Calcium Stearate 5 g.
Component 2 Glycerol (USP) 15 g.
[0181] Three grams of calcium stearate were mixed with 3 gram incremental
quantities of
glycerol until the mixture displayed a cream-like consistency (total of 15 g.
glycerol). At
that stage, an additional two grams of calcium stearate were blended into the
mixture to
obtain a composition having the consistency and appearance of well-beaten egg
whites.
EXAMPLE 39
[0182] Component 1 Calcium Stearate 1 g.
Component 2 Tocopheryl acetate 1 g.
Component 3 Glycerol .25 g.
[0183] There resulted a relatively soft putty with excellent water resistance.
EXAMPLE 40
[0184] Component I Sucrose (Confectioner's Sugar) 3 g.
Component 2 Olive Oil 2 g.
[0185] This results in a relatively rigid putty which washes away very easily
and is useful
where low water resistance is desired.
EXAMPLE 41
[0186] Three grams of the product from Example 38 above was mixed with 0.75
ml. of
deionized water containing 30 ppm of colloidal silver (Source Naturals, Inc.,
Scotts
Valley, CA 98006). The resulting hemostatic cream became off-white in color,
due to the
presence of the anti-microbial silver, and was somewhat less viscous than the
original
cream.
EXAMPLE 42
[0187] Component 1 Calcium Stearate 4 g;
Component 2 Pluronic L-35* 0.2 g
(Molecular Wt. 1900)
Component 12 Water 2 g
* Pluronic 588310, Lot WPAW-502B, BASF, Corp. Mt. Olive, NJ 07828-1234
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[0188] The ingredients are combined with stirring until a putty-like mass
results. The
material is easily dispersed in excess water.
EXAMPLE 43
[0189] Component 1 Calcium Stearate 12.0 g.
Component 2 d,l-alpha Tocopheryl Acetate 7.5 g.
Component 3 Soya Lecithin Granules 1.3 g.
[0190] The calcium stearate and lecithin (Archer-Daniels-Midland Ultralec P)
were mixed
dry and the tocopheryl acetate was then added with vigorous stirring. A putty
formed
which had good water resistance and handling properties, but which was
slightly more
tacky than corresponding formulations containing gelatin instead of lecithin.
EXAMPLE 44
[0191 ] Component I calcium stearate 0.6 g.
Component 1 potato starch* 3.8 g.
Component 2 d, I-alpha tocopheryl acetate 1.6 g.
* - Razin International, Inc.
6527 Route 9
Howell, New Jersey 07731
[0192] The tocopheryl acetate and calcium stearate were mixed together and the
starch
was then added. The mixture formed a soft, white putty with good water
resistance. To
prevent the formation of post-operative adhesions, it may be desirable to
sterilize the putty
using 25 kGy of ionizing gamma radiation from a cobalt 60 source in order to
degrade the
starch. Alternatively, the starch may be subjected to radiation degradation
prior to
formulating it into the putty.
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[0193] The following Examples 45-52 show putty compositions, prepared as in
Example
1, having good water resistance and incrementally increasing absorbabilities
from slowly
absorbable to more rapidly absorbable as the amount of gelatin is increased
relative to the
amount of calcium salt.
[0194] Parts Ca salt Parts component 2 Parts - gelatin-%
EXAMPLE 45 12 Ca stearate 7.5 tocopheryl acetate 0 0
EXAMPLE 46 12 Ca stearate 7.5 tocopheryl acetate 2.0 10
EXAMPLE 47 12 Ca stearate 7.5 tocopheryl acetate 3.5 15
EXAMPLE 48 12 Ca stearate 7.5 tocopheryl acetate 5.0 20
EXAMPLE 49 12 Ca laurate 7.5 tocopheryl acetate 4.5 20
EXAMPLE 50 12 Ca stearate 7.5 triethyl citrate 4.5 20
EXAMPLE 51 0.6 Ca stearate 1.6 tocopheryl acetate 5.0 70
a)parts- % b arts- %
EXAMPLE 52
[0195] Component 1 Ca stearate 3.4 31 2.35 21
Component 2 tocopheryl acetate 3.2 29 2.21 20
Component 3 Gelatin (150 Bloom) 4.4 40 3.04 ' 28
Component 4 DBM 0 3.40 31
TOTAL 11.0 11.0
The resulting product has characteristics similar to the putty of Example 53.
[0196] The gelatin in formulation a) is present at 40% by weight and the
composition has
good putty consistency with good water resistance and absorbability.
[0197] When it is desired to obtain a denser formulation that may be used as a
vehicle in
anchoring pins or screws, such as pedicle screws, to bone in orthopedic
procedures, the
foregoing formulation a) may be modified by including therein large particle
size bone
chips and applied to the appropriate bone site. Thus, when 31 parts of DBM,
particle size
1-5 mm, are added to 69 parts of formulation a), formulation b) results,
comprising 31%
DBM and 28% gelatin. The consistency is that of a thick, dense putty into
which pins or
screws may be placed and anchored into adjoining bone. In time, the osteogenic
character
of the formulation will allow bone growth around the pins or screws thus
permanently
anchoring them to adjoining bone structures.
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EXAMPLE 53
[0198] Component 1 Ca stearate 3.0 g
Component 2 tocopheryl acetate 0.4 g
Component 2 tributyl citrate 2.3 g
Component 3 gelatin 2.0 g
There resulted a putty having very good hemostatic and absorbability
characteristics.
EXAMPLE 54
[0199] Component 1 Ca stearate 3.0
Component 2 tocopheryl acetate 0.4
Component 2 acetyl tributyl citrate 2.3
Component 3 gelatin 2.0
The resulting product has characteristics similar to the putty of Example 53.
EXAMPLE 55
[0200] Component I Calcium Stearate 2.0 g.
Component 2 Tocopheryl acetate 1.5 g.
Component 3 Pluronic qD F-38* 2.0 g.
(Molecular Wt. 4700)
*Product 583095, Lot WP1W-515B, BASF Corp., Mt. Olive, NJ 07828-1234
[0201] The Pluronic was provided as a "Pastille" and ground to a powder before
mixing.
The mixture formed an excellent putty.
EXAMPLE 56
[0202] Component 1 Calcium Stearate 4.0 g.
Component 2 Pluronic L-35 3.0 g.
(Molecular Wt. 1900)
[0203] The Pluronic in this example was a viscous liquid and formed an
excellent putty.
Because this Pluronic is water soluble, it was not necessary to add an
absorption
accelerant.
[0204] All of the Compositions in the following Examples 57-63 have a putty-
like consistency
and are easily applied to cut bone or soft tissue. Unless otherwise indicated,
they are prepared
by dissolving, suspending or dispersing the analgesic Component A in liquid
Component 2 and
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Component B, if any, to form a uniform blend and then mixing that blend with
solid Component
1. Percent indications are all percent by weight of the entire composition.
[0205] An evaluation of elution rates was obtained by submitting the
compositions under
consideration to the following: A quantity of the composition in the form of a
0.5 gm "button"
having a diameter of 1 cm. is placed in 500 cc of phosphate buffer, pH 7.4, at
37 C. and slowly
stirred. The surface area exposed to the buffer is about 0.785 sq. cm. One cc
aliquots of the
buffer solution are taken over a three day period, every 2 hours during
business hours of day
one, then several times on each of days two and three. Each sample is analyzed
for lidocaine by
HPLC-UV spectrophotoinentry versus a standard of lidocaine. The presence of
lidocaine in the
supematant over the three day period is evidence of the release of pain-
relieving amounts of the
analgesic. The same procedure was followed for measurement of the elution of
bupivacaine
free base and hydrochloride.
[0206] In some cases, a similar amount of components was applied topically to
the arm of a
patient and the site of application tested with needle sticks periodically
over a three day period
for numbness is indication of efficasion elution of pain relieving amounts of
analgesic.
EXAMPLE 57.
[0207] The following compositions are prepared:
Composition I. Component 1. Calcium Stearate 55 %
Component 2. a. Triethyl Citrate 24 %
Component A. Lidocaine Free Base 16 %
Component B. Tocopheryl Acetate 5%
II. Component 1. Calcium Stearate 50 %
Component 2. a. Pluronic L-35 29 %
Component A. a. Lidocaine Free Base 8%
b. Lidocaine HCI 8 %
Component B. Tocopheryl Acetate 5 %
III. Component 1. Calcium Stearate 47 %
Component 2. Triethyl Citrate 37 %
Component A. Lidocaine HCl 16 %
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IV. Component 1. Calcium Stearate 55%
Component 2. a) Pluronic L-35 12%
b) Pluronic F-68 12%
Component A. 1. Lidocaine Free Base 8%
2. Lidocaine HCI 8%
Component B. Tocopheryl Acetate 5%
[0208] Pluronic L-35 is a liquid ethylene oxide/propylene oxide block
copolymer, molecular
weight about 1900, available from BASF, Mt. Olive, New Jersey 07828.
[0209] Pluronic F-68 is a solid (flake) ethylene oxide/propylene oxide block
copolymer which
is easily soluble in warm L-35. Pluronic (F-68), has a molecular weight of
8,400 so that the
average molecular weight of the Pluronic Component 2 is 4,500 compared with
1,900 for L-
35alone.
[0210] To produce the Component 2 mixture with Component A, the L-35 (liquid),
F-68
(solid) and the tocopheryl acetate were blended and warmed on a hot plate with
swirling
whereupon the solid quickly dissolved. To avoid solidification of the mixture,
the liquid
was not allowed to cool. While the Pluronic mixture was still warm (not hot)
and liquid,
the calcium stearate was added and the mixture was stirred with a spatula in
the usual way
until a putty formed. This putty appeared stable in consistency at room
temperature over
several days and qualitatively resisted irrigation.
V. The following Composition is prepared
Component 1. Calcium Stearate 2.0 g
Component 2 a. Tocopheryl Acetate 1.5 g
Component 2 b. Pluronic F-38 2.0 g
Component A 1. Lidocaine Free Base .65 g
2. Lidocaine HCI .65 g
EXAMPLE 5 8
[0211] Component 1 Calcium Stearate 47 %
Component 2 Pluronic L-35 28%
Component A. Lidocaine HCI 20 %
Component B. Tocopheryl Acetate 5 %
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EXAMPLE 59.
[0212] Osteoconductive materials such as hydroxyapatite (HAP), tricalcium
phosphate
(TCP), A blend of HAP/TCP (40:60), a blend of HAP/TCP (20:80), having particle
sizes
between 0.5 and 1.5 mm. (to allow osteoconduction), are available commercially
from
Berkeley Advanced Biomaterial and may be added to produce any of the
compositions of
the invention to yield osteoconductive compositions. For example, the
following:
1. Component 1. Calcium Stearate 37 %
Component 2. Triethyl Citrate 32 %
Component A. Lidocaine 16 %
Component 4. TCP 15 %
II. Component 1. Calcium Stearate 32.04%
Component 2. Triethyl Citrate 24.665
Component A 1. Lidocaine Free Base 6.65%
2. Lidocaine Hydrochloride 6.65%
Component 4. Hydroxyapatite 30.00%
III. Component 1. Calcium Stearate 24.66%
Component 2. Pluronic L-35 32.04%
Component A 1. Lidocaine Free Base 6.65%
2. Lidocaine hydrochloride 6.65%
Component 4. DBM 30.00%
EXAMPLE 60
[0213] Component 1. Calcium Stearate 60%
Component 2. Triethyl Citrate 27%
Component A 1. Lidocaine Free Base 6.5%
2. Lidocaine HCl 6.5%
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EXAMPLE 61.
[0214] Component 1. Calcium Stearate 49.00 %
Coinponent 2. Triethyl Citrate 37.70 %
Componeiit A. 1. Lidocaine Free Base 6.65 %
2. Lidocaine Hydrochloride 6.65 %
EXAMPLE 62.
[0215] Component 1. Calcium Stearate 49.0
Component 2. Pluronic L-35 37.7
Component A. 1. Lidocaine Free Base 6.65
2. Lidocaine HCI 6.65
[0216] Examples 58-62 yield products suitable as implantable pain-relieving
compositions.
EXAMPLE 63.
[0217] The products of the invention may be separately applied to an
absorbable or non-
absorbable knitted or non-woven structure or felt to provide a wound
reinforcement device
that will release local anesthetic to manage post-operative pain in soft
tissue. The fabric
component, based upon a synthetic absorbable mesh, is rapidly degraded and
absorbed in
situ.
[0218] For example, the product of Example 62 may be spread over a fabric mesh
prior to
implantation in a hernia repair operation:
Component 1. Calcium Stearate 49.05
Component 2. Pluronic L-35 37.7%
Component A. 1. Lidocaine Free Base 6.65%
2. Lidocaine HC1 6.65%
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[0219] While the foregoing examples are given in connection with lidocaine
free base and
lidocaine hydrochloride, it will be appreciated that any analgesic/anesthetic
free base/acid
addition salt combination may be employed as well as any combination of the
same or
different analgesic/anesthetic in free base or acid addition salt, as
appropriate. In
addition, any such analgesic or combinations thereof may be included in any
composition
of the foregoing Examples whether or not the Example contains an analgesic.
[0220] The foregoing Examples contain illustrative specific embodiments of the
present
invention. Other embodiments, within the scope of the present invention, may
be prepared
by those skilled in the art as described in the foregoing Specification.
52
