U.S. patent application number 12/205510 was filed with the patent office on 2008-12-25 for sterile polymerizable systems and kits and methods of their manufacture and use.
This patent application is currently assigned to Vita Special Purpose Corporation. Invention is credited to Erik M. Erbe, Vasanth Prabhu, Jeffrey J. Wicklund, Anthony M. Wilkes.
Application Number | 20080319380 12/205510 |
Document ID | / |
Family ID | 24906297 |
Filed Date | 2008-12-25 |
United States Patent
Application |
20080319380 |
Kind Code |
A1 |
Prabhu; Vasanth ; et
al. |
December 25, 2008 |
Sterile Polymerizable Systems And Kits And Methods Of Their
Manufacture And Use
Abstract
The present invention overcomes the difficulties in the
sterilization and delivery of viscous, multi-component compositions
that require pre-mixing prior to usage by disclosing a sterile,
multi-component, ready-to-use product wherein each component is
sterilized independently and then assembled into a sterilized
delivery kit. In certain preferred embodiments of the present
invention, a sterile, polymerizable system is provided that
comprises a plurality of sterile polymerizable monomers, said
monomers having been sterilized by passing them through a filter;
at least one sterile filler which has been exposed to conditions
effective to render said filler sterile, and the sterile monomers
and the sterile filler being blended together to form at least one
substantially homogeneous blend contained within a sterile delivery
vessel. Still other embodiments include a single-use kit that
comprises a delivery gun, mix tips, and cartridges that comprise
one or more pastes of the present invention that are housed within
one or more pouches to ensure sterility of the internal
contents.
Inventors: |
Prabhu; Vasanth;
(Charlestown, PA) ; Wicklund; Jeffrey J.;
(Downingtown, PA) ; Erbe; Erik M.; (Berwyn,
PA) ; Wilkes; Anthony M.; (Limerick, PA) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
CIRA CENTRE, 12TH FLOOR, 2929 ARCH STREET
PHILADELPHIA
PA
19104-2891
US
|
Assignee: |
Vita Special Purpose
Corporation
Wilmington
DE
|
Family ID: |
24906297 |
Appl. No.: |
12/205510 |
Filed: |
September 5, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10914254 |
Aug 9, 2004 |
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12205510 |
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09723445 |
Nov 28, 2000 |
6800245 |
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10914254 |
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Current U.S.
Class: |
604/60 ; 422/1;
422/22 |
Current CPC
Class: |
A61L 2/0017 20130101;
A61L 2/206 20130101; A61L 2/04 20130101; A61L 2/081 20130101; A61L
2/0023 20130101; A61L 2/022 20130101; A61L 2202/24 20130101 |
Class at
Publication: |
604/60 ; 422/1;
422/22 |
International
Class: |
A61M 5/178 20060101
A61M005/178; A61L 2/08 20060101 A61L002/08; A61L 2/04 20060101
A61L002/04 |
Claims
1. A method of preparing a sterile, polymerizable blend, the method
comprising: exposing at least one filler, said filler having been
at least partially coated with a coupling agent, to dry heat for a
time and at a temperature sufficient to render the at least one
filler sterile and maintain the integrity of the coating; and
combining the filler with at least one monomer.
2. The method of claim 1, wherein the filler is bioactive glass,
bioactive glass-ceramic, barium glass, barium-boroaluminosilicate
glass, silica, or combinations thereof.
3. The method of claim 1, wherein the coupling agent is silane.
4. The method of claim 1 wherein the filler is sterilized at a
temperature of about 121.degree. C. for at least 8 hours.
5. The method of claim 1 wherein the filler is sterilized at a
temperature of about 140.degree. C. for at least 6 hours.
6. A method of preparing a sterile, biologically compatible
restorative composition, the method comprising: exposing at least
one filler, said filler having been at least partially coated with
a coupling agent, to dry heat for a time and at a temperature
sufficient to render the at least one filler sterile and maintain
the integrity of the coating.
7. The method of claim 6, wherein the filler is bioactive glass,
bioactive glass-ceramic, barium glass, barium-boroaluminosilicate
glass, silica, or combinations thereof.
8. The method of claim 6, wherein the coupling agent is silane.
9. A method of restoring osseous tissue in an animal, the method
comprising: exposing at least one filler, said filler having been
at least partially coated with a coupling agent, to dry heat for a
time and at a temperature sufficient to render the at least one
filler sterile and maintain the integrity of the coating; combining
the filler with at least one sterile monomer to form at least one
sterile polymerizable restorative composition; containing the
sterile polymerizable restorative composition into a sterile
delivery vessel; and delivering the sterile polymerizable
restorative composition from the sterile delivery vessel to an
osseous defect in the animal.
10. The method of claim 9, wherein the filler is bioactive glass,
bioactive glass-ceramic, barium glass, barium-boroaluminosilicate
glass, silica, or combinations thereof.
11. The method of claim 9, wherein the coupling agent is
silane.
12. A method of preparing a sterile, polymerizable blend, the
method comprising: exposing at least one filler, said filler having
been at least partially coated with a coupling agent, to gamma
radiation, E beam radiation, light, or ethylene oxide under
conditions sufficient to render the at least one filler sterile and
maintain the integrity of the coating; and combining the filler
with at least one monomer.
13. The method of claim 12, wherein the filler is bioactive glass,
bioactive glass-ceramic, barium glass, barium-boroaluminosilicate
glass, silica, or combinations thereof.
14. The method of claim 12, wherein the coupling agent is silane.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/914,254, filed Aug. 9, 2004, which is a continuation of U.S.
Ser. No. 09/723,445, now U.S. Pat. No. 6,800,245, filed Nov. 28,
2000, the entire contents of which are incorporated herein by
reference.
TECHNICAL FIELD
[0002] The present invention relates generally to sterile,
polymerizable compositions together with systems, kits, and methods
for the sterile manufacture, packaging, and delivery of same. More
particularly, the present invention relates to sterile,
polymerizable systems and kits that are comprised of pre-mixed,
viscous, sterile compositions, especially restorative, and methods
of making same.
BACKGROUND
[0003] Sterilization is generally defined as rendering a substance
incapable of reproduction. In terms of food, medical products or
pharmaceuticals, sterilization relates to rending an article free
from living microorganisms. The rate of destruction of
microorganisms is logarithmic and can be described by the following
expression:
N.sub.o/N.sub.t=e.sup.-kt
wherein N.sub.t represents the number of organisms alive at time
`t`, N.sub.o represents the initial number of organisms, and k
equals the kinetic rate constant.
[0004] A common manner of expressing sterilization is the sterility
assurance level ("SAL"). Because microbiological destruction is
logarithmic and expressed in terms of the probability of a
survivor, the term "sterile device" does not actually refer to a
device that is totally free of viable organisms, but rather to one
whose probability of containing a viable organism is so small that
it is considered acceptable for a given purpose. Hence, the
sterility assurance level (SAL) defines the probability of a viable
microorganism being present on an article after sterilization is
complete. According to the present FDA regulations, topical medical
devices should have a minimum SAL of 10.sup.-3 whereas devices or
articles that will directly contact blood or compromised tissues
should have a minimum SAL of 10.sup.-6. The integrity of the
sterilization method is generally monitored by culturing a test
organism. For example, the remaining presence of the highly
heat-resistant bacterium, bacillus subtilis globigii, can be used
as a marker to measure the completeness of sterilization.
[0005] There are many different methods of sterilization, each of
which presents numerous advantages and disadvantages depending upon
the nature of the article or medium to be sterilized. Some of these
methods involve the application of heat, pressure, and/or moisture.
Moist heat sterilization, i.e., boiling, kills all vegetative
cells, most viruses, and fungi within 10 minutes. However, moist
heat sterilization is not suitable for many applications in biology
and medicine because it causes coagulation of proteins and breakage
of hydrogen bonds contained therein.
[0006] Another method of sterilization, known as steam
sterilization, is the application of steam under pressure within an
enclosed chamber known as an autoclave. This method subjects the
media to temperatures of typically 121.degree. C. at pressures of
15 pounds per square inch ("psi") above ambient. Autoclave
sterilization is capable of killing all microorganisms and their
endospores in about 15 minutes. The efficacy of autoclave
sterilization is measured by determining the presence or absence of
bacillus stearothermophilus spores. Media or substances stable in
heat may be sterilized at higher temperatures for shorter time
periods; conversely, sterilization at lower temperatures require
longer sterilization periods.
[0007] Dry heat sterilization may involve incineration, i.e.,
exposing media to high temperatures such as 180.degree. C., or
hot-air sterilization, i.e., exposing media to controlled time and
temperature conditions. This method is suitable for media such as
pharmaceutical products that do not contain water as their primary
solvent and cannot be sterilized by other methods. In this
instance, dry heat is applied to the media at temperatures of about
100.degree. C. to about 250.degree. C. and exposure times ranging
from about one to four hours. The temperature-time relationship is
similar to that of steam sterilization.
[0008] Sterilization can also occur through the filtration or the
physical retardation of microorganisms from a fluid medium by a
filter membrane.
[0009] Still other methods of sterilization involve the application
of radiation, either ionizing or non-ionizing, to sterilize the
media. Ionizing radiation involves the application of shorter
wavelength radiation, such as gamma rays, beta-rays, x-rays, or
high energy electron beams, to ionize the water particles contained
within the media to form reactive hydroxyl radicals. This method is
commonly used to sterilize pharmaceutical products or disposable
dental and medical supplies such as syringes, gloves, or sutures.
Activated resins such as those used in bone cements, however,
cannot be gamma sterilized because it effects the polymerization
process. Non-ionizing radiation involves the application of
ultraviolet rays to cause the formation of thymine dimers that
inhibit the replication of DNA. Although these rays are
non-penetrating to the media, some media can be destroyed in the
doses required for effective sterilization.
[0010] Another sterilization method is gas sterilization, in which
the media is exposed to a vapor or gas such as ethylene oxide
("EtO"). This method is suitable for media, such as foods,
pharmaceuticals, and medical equipment, that cannot withstand the
temperatures and moisture of steam sterilization or cannot be
exposed to radiation. A gaseous sterilant, such as ethylene oxide,
is applied under controlled temperature, time, gas concentration,
and relative humidity parameters that vary depending upon the
nature of the media to be sterilized. Important considerations in
the selection of a gas sterilant is the ability of the residue
remaining on the media after exposure to the sterilant to
volatilize quickly. Because gas sterilization may involve the use
of chlorofluorocarbons ("CFC"), plasma gas sterilization, which is
a low temperature gas sterilization process involving hydrogen
peroxide or other sterilants in the plasma state, is an alternative
that is generally safe for the environment. However, plasma
technology is currently even more limited than EtO sterilization in
terms of what media it can sterilize.
[0011] Once an article is sterilized, it needs to be packaged in a
manner that will not compromise its sterility until use.
Sterilization packaging typically takes place at one location prior
to use of the medium, or article, at another location. The main
purpose of this packaging is to protect the sterility of the
internal contents. Terminal sterilization describes the process of
placing an article within its protective container and subsequently
sterilizing the container and the article contained therein. On the
other hand, aseptic processing involves placing individually
sterilized components that have been sterilized by various
sterilized methods into a sterilized package that is sealed under
sterile conditions. The packaging containers used in these
processes are sterilized separately and remain in a sterile
environment prior to use. The packaging machinery that is used to
fill the packaging containers is also sterilized using steam,
sterile gases, or hydrogen peroxide.
[0012] Pharmaceutical products are typically rendered sterile by
aseptic processing. In aseptic processing, the separate ingredients
of a medium, such as a pharmaceutical, are available in sterile
form and compounded without microbial contamination.
Pharmaceuticals that are injectable may be comprised of aqueous or
oily solutions, suspensions or emulsions, and are prepared by
conventional manufacturing methods, with special care taken to
remove all extraneous particulate matter. Injections must be
sterilized by any of the methods given above or terminally
sterilized. Some aqueous injectables are not stable and need to be
prepared at the time of use by mixing some components prior to use.
In this instance, the end user is provided a kit and must assemble
the ingredients in a sterile environment immediately prior to
injection.
[0013] An example of a multi-component system, that must be
assembled by the end-user in a sterile environment prior to use,
are biocompatible, restorative compositions or biomaterials that
are used in orthopaedic and dental applications. Typically, these
biomaterials are comprised of a solid component and a liquid
component. The solid component may consist of a finely divided
polymer of acrylic and/or methacrylic esters and further additives
such as polymerization initiators, radiographic contrast agents,
and fillers. A typical example of such a powder may consist of
small spherical beads (usually about 75 .mu.m in diameter) of poly
(methyl methacrylate) (PMMA) and a small amount of a polymerization
initiator such as benzoyl peroxide. The liquid component may
consist of an acrylic and/or methacrylic ester monomer and further
additives such as polymerization accelerators and stabilizers. A
typical example of a liquid is a methyl methacrylate (MMA) monomer,
a polymerization activator such as N,N-dimethyl-para-toludine, and
an inhibitor such as hydroquinone. The solid and liquid components
are combined immediately prior to use to form a liquid to semisolid
paste. The paste may be formed into a desired shape or applied via
injection in a wide-mouth syringe or spatula to the implantation
site of a prosthesis where it polymerizes.
[0014] Presently known products feature deactivated resins which
are activated upon combination with other components immediately
prior to their delivery or use. These resins and other components
are individually wrapped and packaged in an overall aseptic package
or kit. An example of such a kit is SIMPLEX.RTM. bone cement
manufactured by Howmedica of Rutherford, N.J. SIMPLEX.RTM. bone
cement is comprised of an aseptically packaged ampule of a liquid
methyl methacrylate ("MMA") that is combined with an gamma
sterilized bag of powder which comprises pre-polymerized
MMA-styrene and barium sulfate (BaSO.sub.4). The end user opens the
outer packaging, the ampule, and the bag of powder and combines the
liquid and powder components. The user then fills a syringe with
the cement in order to deliver the cement to the patient. Some of
the disadvantages to this product include product variability; lack
of assurance that the components are used in compliance with the
manufacturer's instructions; concern over the integrity of the
sterilized components; and a shortened time window between
preparation of the cement and delivery to the patient. Traditional
terminal sterilization is not possible where unpolymerized
components must retain activation viability to be delivered to the
surgical suite.
[0015] There is a need to provide methods for the sterilization and
delivery of viscous, multi-component compositions without requiring
the end-user to pre-mix or assemble the components. Accordingly,
one object of the present invention is to provide a sterile,
multi-component, ready to use product that does not require
extensive pre-mixing or assembly.
[0016] Another object of the present invention is to provide a
method for the sterilization of products comprising activated
resins or monomers.
[0017] Yet another object of the present invention is to provide a
method for the sterilization of products comprising heat degradable
fillers.
[0018] A further object of the present invention is to provide
methods for the sterile manufacture and delivery of viscous,
multi-component compositions.
[0019] An additional object of the present invention is to provide
kits comprising the sterile, viscous restorative compositions of
the present invention and delivery vessels that allow mixing of
these compositions prior to use.
SUMMARY
[0020] The present invention overcomes the difficulties in the
sterilization and delivery of viscous, multi-component compositions
that require pre-mixing prior to usage by disclosing a sterile,
multi-component, ready-to-use product wherein each component is
sterilized independently and then assembled into a sterilized
delivery kit. These systems are suitable for, but not limited to,
medical or dental applications that utilize bone cement and
restorative compositions. The end products delivered from these
kits are sterile upon dispensing. The end user does not need a
separate sterile area to pre-mix or assemble the restorative
compositions prior to use. The present invention further provides
methods for the sterilization of the individual components that
comprise the paste compositions that will not adversely alter the
characteristics of these components. Moreover, the present
invention discloses unique delivery vessels that allow for the
pre-mixing of one or more paste compositions prior to and upon
delivery of the sterile end product.
[0021] The present invention provides one or more viscous, sterile
paste compositions, referred to herein as pastes, that are
pre-blended and sterile upon delivery to form one or more
homogeneous blends. Each sterile, viscous paste is comprised of one
or more polymerizable monomers or resin components and one or more
fillers. The monomers and fillers are initially and individually
sterilized, and then blended together to form one or more sterile
viscous pastes. The paste is packaged within a sterile delivery
vessel that contains one or more cartridges to house the paste. In
multiple paste systems, the pastes are dispensed from their
respective cartridges and blended together within the delivery
vessel to form at least one viscous, homogeneous blend immediately
prior to or upon dispensing.
[0022] The polymerizable monomer or resin components that comprise
the viscous, paste compositions are preferably ethylenically
unsaturated monomers, and more preferably, comprise an acrylate.
Examples of such monomers in one such composition include, but are
not limited to, bisphenol-A-diglycidyl methacrylate (bis GMA),
triethyleneglycol dimethacrylate (TEGDMA), diurethane
dimethacrylate (DUDMA), and bisphenol-A-ethyl methacrylate
(bis-EMA). In preferred embodiments, the monomers within the paste
are activated prior to sterilization. Further additions to the
paste may include, but are not limited to, polymerization
activators, polymerization initiators, radio pacifiers, reinforcing
components (i.e., fibers, particles, micro spheres, flakes, etc.),
bioactive fillers, neutralizing resins, diluting resins, antibiotic
agents, coloring agents, coupling agents, or radiographic contrast
agents. Examples of such additives include, but are not limited to,
butylhydroxytoluene (BHT), N,N-dimethyl-p-toluidine (DMEPT),
tetraethylene glycol dimethyaniline (TEGDMA),
dihydroxyethyl-p-toluidine (DHEPT), UV-9, and benzoyl peroxide
(BPO).
[0023] The monomers and other additives are combined to form a
paste composition precursor which is sterilized prior to adding one
or more fillers. The preferred method of sterilization of these
monomers and other additives that comprise the paste composition
precursor is via high pressure filtration. The monomers, which are
preferably activated, are passed through a filter such as a 0.22
.mu.m filter to exclude pathogens. The filtration process is
conducted under pressures which range between ambient and 200 psi
and more preferably between 2-40 psi. The housing and plumbing
fixtures used downstream in the filtration process (including the
filter itself) are also sterilized prior to use via steam
sterilization (i.e., steam sterilization in place ("SIP") or
autoclaving), or similar means, to eliminate or minimize
contamination.
[0024] In addition to the monomer, the viscous paste or pastes
further comprise one or more fillers. These fillers may possess a
variety of morphologies such as, but not limited to, needles,
particulate, flakes, cylinders, long fibers, whiskers, or spherical
particles. In preferred embodiments, the filler is comprised of
particles with an average particle size ranging from about less
than 1.0 .mu.m up to several millimeters (mm). Preferably, the
average particle size distribution ranges from 5 to 20 .mu.m.
[0025] The filler may be comprised of an inorganic or organic
material. In preferred embodiments, the filler is comprised of an
inorganic material. Examples of suitable fillers include, but are
not limited to, barium glass, barium-boroaluminosilicate glass,
silica, 45S5 glass, bioactive glass, ceramics, glass-ceramics,
bioactive synthetic combeite glass-ceramic or combinations thereof.
The filler or fillers are generally pre-dried prior to blending
with other fillers. In preferred embodiments, one or more fillers
are coated with silane prior to sterilization.
[0026] The filler may be sterilized by dry heat, E beam, bright
light, gamma or EtO methods. The filler is preferably sterilized
via dry heat sterilization, i.e., exposed to dry heat at a time and
temperature sufficient to render it sterile. If the filler is
coated with silane, the sterilization method selected should
maintain the integrity of the silane coating. In certain
embodiments wherein one or more fillers are coated with silane, the
filler is dry heat sterilized with minimal heat penetration to
yield a minimally degraded silane surface chemistry. The filler is
preferably heated to a temperature of about 140.sup..andgate.C or
less for a period of between about 6 hours to about 12 hours, or
more preferably, heated to a temperature of about
121.sup..andgate.C for at least 8 hours. In alternative
embodiments, the filler can be heated to higher temperatures, such
as, but not limited to, temperatures of from about
10.sup..andgate.C to about 250.degree. C. for inversely
proportional time periods or shorter periods of time at higher
temperatures.
[0027] After the filler and the monomer are sterilized, the filler
and monomer are combined to form one or more paste compositions. In
preferred embodiments, the monomer and filler are combined to form
one or more pastes in an aseptic process, i.e., using equipment
that has been pre-sterilized and combining the components of the
paste in a class 100 or greater clean room. The equipment used to
blend the paste or pastes, such as the mixing equipment, spatulas,
blades etc., are preferably pre-sterilized using steam or autoclave
sterilization.
[0028] The paste is preferably contained within a primary packaging
which comprises one or more cartridges, caps, O-ring pistons, and
external pouches. Each of these components are sterilized prior to
the aseptic filling of the paste or pastes. In preferred
embodiments, the primary packaging components are sterilized via
gamma sterilization.
[0029] One or more pastes are aseptically filled into individual
cartridges that further comprise a cap and an O-ring piston. The
pastes are fed into their respective cartridge barrels using an
aseptic filling process as described herein. Air is removed from
the cartridge prior to piston insertion. The piston is then
assembled into the cartridge to form an air-tight seal. The filled
cartridge and piston are then packaged within at least one external
pouch. In preferred embodiments, the filled cartridges and piston
assemblies are packaged within a dual pouch arrangement, or an
inner and outer pouch. The cartridges are then thermally sealed and
labeled. The previous steps, of filling the cartridges, assembling
the piston into the cartridge, encapsulating the cartridges into
one or more pouches and then thermo-sealing the cartridges, are
conducted within an isolated system referred to herein as an
isolator. The isolator preferably employs vaporous hydrogen
peroxide (VHP) to ensure a sterile environment for the preceding
process steps.
[0030] Further components, that may comprise the delivery system
and kit, include a delivery gun and one or more tips, referred to
herein as "mix tips", that enable mixing and dispensing of the
paste or pastes. Additional components to the systems of the
present invention may include a micro delivery system. All of these
components are sterile or sterilized and packaged prior to use. In
preferred embodiments, these components are sterilized via gamma
sterilization. After sterilization is completed, the components are
placed with an external package to ensure sterility. An example of
this external package may include an oxygen permeable membrane such
as a TYVEK.RTM./polyester pouch manufactured by Tolas Healthcare
Packaging of Feasterville, Pa. Still other external packages may
include, but not be limited to, foil pouches, opaque pouches for
light sensitive materials, or other breathable or permeable
pouches.
[0031] The present invention also discloses methods of preparing a
sterile, polymerizable blend. This method comprises the steps of:
applying dry heat under time and temperature conditions sufficient
to sterilize at least one filler; passing a plurality of
polymerizable monomers (or dimers or trimers) through a filter; and
combining the monomers and the filler together to form at least one
homogeneous blend contained within a first vessel wherein the
combined monomers and fillers are dischargeable from a final
sterile delivery vessel.
[0032] The present invention also discloses sterile, biologically
compatible restorative compositions that comprise: a plurality of
polymerizable monomers, the monomers having been sterilized by
passing them through a filter; at least one filler which has been
exposed to conditions of time and temperature effective to render
the filler sterile; and the monomers and the filler being blended
together to form at least one homogeneous composition contained
within a sterile delivery vessel wherein the combined monomers and
fillers are dischargeable from the sterile delivery vessel.
[0033] Further embodiments disclosed are methods for preparing a
sterile, biologically compatible restorative composition. This
method comprises the steps of: applying dry heat under time and
temperature conditions sufficient to sterilize at least one filler;
passing a plurality of polymerizable monomers through a filter,
preferably sized to exclude pathogens; and combining the monomers
and filler together to form at least one homogeneous composition
contained within a sterile delivery vessel. Yet further embodiments
of the present invention include sterilization methods for the
activated monomer and the silane-coated filler that comprise the
paste.
[0034] Additional embodiments of the present invention may include
shaped bodies made of a sterile polymerizable blend, wherein the
blend comprises a plurality of polymerizable monomers, the monomers
having been sterilized by passing them through a filter preferably
sized to exclude pathogens; at least one filler which has been
exposed to conditions of time and temperature effective to render
the filler sterile; and the monomers and the filler being blended
together to form at least one homogeneous blend contained within a
sterile delivery vessel.
[0035] Lastly, embodiments of the present invention include methods
of restoring tissue in an animal wherein the method comprises the
steps of: applying dry heat under time and temperature conditions
sufficient to sterilize at least one filler; passing a plurality of
polymerizable monomers through a filter sized so as to exclude
pathogens; combining the monomers and the filler together to form
at least one homogeneous composition contained within a sterile
delivery vessel; and applying the composition to an animal whereby
the tissue may be restored.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] The foregoing, as well as the following description of
certain preferred embodiments, is better understood when read in
conjunction with the appended drawings. For the purpose of
illustrating the invention, there is shown in the drawings an
embodiment that is presently preferred, it being understood,
however, that the invention is not limited to the specific methods
and apparatuses disclosed.
[0037] FIG. 1 provides a flow diagram for the steps that comprise
the assembly of the sterile, polymerizable paste composition.
[0038] The present invention overcomes the difficulties in the
sterilization and delivery of viscous multi-component compositions
that require pre-mixing prior to usage by disclosing a sterile,
multi-component, ready-to-use product wherein each component is
sterilized independently and then assembled into a sterilized
delivery system. These systems are suitable for, but not limited
to, medical or dental applications such as viscous, restorative
bone cement compositions. The end-products delivered from these
kits are considered sterile upon dispensing. The end-user does not
need a separate sterile area to pre-mix or assemble the restorative
compositions prior to use. The present invention further provides
methods for sterilization of the individual components that will
not significantly alter the characteristics of these components.
Lastly, the present invention discloses a unique delivery system
that allows for the pre-mixing of these components prior to, and
upon delivery of, the sterile end-product.
[0039] The present invention provides one or more viscous, sterile
compositions, or pastes, that are pre-blended and sterile upon
delivery to form one or more homogeneous blends. Each sterile,
viscous paste is comprised of one or more polymerizable monomers
and one or more fillers. Further additions to these paste
compositions may include, but are not limited to, polymerization
activators, polymerization initiators, radio pacifiers, reinforcing
components (i.e., fibers, particles, micro spheres, flakes, etc.),
bioactive fillers, neutralizing resins, diluting resins, antibiotic
agents, or polymerization catalysts. The monomers and the fillers
are initially and individually sterilized, and then blended
together to form one or more viscous pastes. The paste or pastes
are packaged within cartridges and loaded into a sterile delivery
vessel. In multiple paste systems, the pastes are dispensed from
their respective cartridges and blended together within the
delivery vessel to form at least one viscous, homogeneous blend
immediately prior to or upon dispensing.
[0040] FIG. 1 provides a flow diagram of a presently preferred
embodiment of the assembly method for the sterile, polymerizable
paste composition. Steps 10, 20, and 30 denote the sterilization of
the manufacturing equipment, cleaning equipment, and primary
packaging, respectively. These steps occur prior to the blending
and packaging of the pastes of the present invention. In step 10,
the manufacturing equipment, such as the mixing vessel, blades, and
other equipment used to blend and contain the paste, is sterilized
prior to use, preferably through steam or EtO sterilization.
Similarly, in step 20, the cleaning supplies and equipment and
processing equipment such as the sterilization filters, housing and
plumbing fixtures, and mixing blades, are preferably sterilized via
steam sterilization in an autoclave. Lastly, in step 30, the
primary packaging for the paste composition, such as the
cartridges, caps, O-ring pistons, and pouches, is preferably
sterilized via gamma, EtO, electron beam ("E-beam") or other
sterilization methods. The selection of the sterilization processes
for steps 10, 20, and 30 will vary depending upon the nature of the
item to be sterilized. Regardless of the sterilization process, a
sterility level of at least about 10.sup.-6, and more preferably at
least about 10.sup.-3, is required prior to the use of the
equipment in the manufacturing process or prior to contact of the
composition precursors or paste prior to packaging.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0041] As mentioned previously, the sterile compositions of the
present invention are comprised of one or more polymerizable
monomers and one or more fillers. These compositions are referred
to herein as pastes to denote that the compositions are viscous
liquids. The viscosity of these pastes range from about 40,000
centipoise to about 400,000 centipoise, as measured, for example,
by an Brooksfield viscometer.
[0042] Relatively low viscosity, syringable pastes are best suited
for the filling of bony defects, fracture repair, and implant
fixation and revision. Syringable pastes flow to fill voids, and
crevices, and adhere tightly to the surface of the bone, tissue, or
implant. Flowability can be important for tight adherence and
removal of micromotion when implant securing is being achieved. The
lack of implant motion can reduce inflammation and determine the
success of the implant system over time. Higher viscosity pastes
are desirable for larger, load bearing bone defects and easily
accessible fracture sites. A "putty" can be manipulated, sculpted
and cured in place with immediate high strength capability.
Oncological bony defects are well-suited for highly loaded, highly
bioactive composites. The use of hand mixed pastes can also
facilitate the addition of medicaments, antibiotics, or bone growth
factors.
[0043] The polymerizable monomer or monomers (or dimers or trimers)
that comprise the viscous, paste compositions are preferably
ethylenically unsaturated monomers, and more preferably comprise an
acrylate functional group. The term "monomers", as used herein, can
also represent dimers, trimers, resins, resin components, or any
other polymerizable component. Examples of the monomers include,
but are not limited to, bisphenol-A-diglycidyl methacrylate (bis
GMA), triethyleneglycol dimethacrylate (TEGDMA), or
bisphenol-A-ethyl methacrylate (bis-EMA). In preferred embodiments,
the monomers within the paste composition are activated prior to
sterilization. The monomers may be activated, for example, by the
addition of benzoyl peroxide (BPO) or other free radical formers
and tertiary amines, or other reducing agents, such as but not
limited to DHEPT, DMAPE, DMEPT, ascorbic acid, that may provide an
electron withdrawing group that initiates free radical
polymerization.
[0044] The pastes of the present invention may further comprise,
but are not limited to, polymerization inhibitors, polymerization
activators, polymerization initiators, radiopacifiers, reinforcing
components (i.e., fibers, particles, micro spheres, flakes, etc.),
bioactive fillers, neutralizing resins, diluting resins, antibiotic
agents, coloring agents, plasticizers, coupling agents, free
radical generators, radiographic contrast agents, and
antibiotics.
[0045] Polymerization inhibitors may be added to the composition to
minimize polymerization during storage. Examples of polymerization
inhibitors include hydroquinone, and various functional equivalents
such as butylhydroxytoluene (BHT), UV-9, methyl ether hydroquinone
(MEHQ), 4-benzyloxy phenol and 3,5-diisopropyl phenol.
[0046] Polymerization activators are typically amines and are used
to promote free radical generation from organic peroxide initiators
in addition polymerizations. The free radicals are generated at
temperatures around room temperature or below by chemical reduction
of the peroxide. Examples of such activators are,
N,N-dimethyl-p-toluidine (DMEPT), dihydroxyethyl-p-toluidine
(DHEPT), and functional equivalents such as
N,N-deimethyl-meta-toluidine, N,N-dimethyl-ortho-toluidine, and
N-ethyl-N-hydroxyethyl-meta-toluidine.
[0047] Color agents may be added to the composition to impart color
and may include dyes, paint pigments, or reduced metal
particles.
[0048] Plasticizers may be added to the composition to facilitate
processing and increase the flexibility of the final product.
Examples of plasticizers include TEGDMA, HEMA and phthalates such
as diethyl phthalate, benzylbutyl phthalate, dibutyl phthalate, and
dibenzyl phthalate.
[0049] Coupling agents are used to link the filler within the
composition to the polymer matrix. Typical coupling agents include
silanes such as .gamma.-methyacryloxypropyltrimethoxysilane or
other cationic coupling agents.
[0050] Free radical generators are substances within the
composition that decompose to form free radicals that begin the
process of polymerization in addition reactions. Examples of free
radical generators include benzoyl peroxide, tert-butyl peroxide,
and diethyl peroxide.
[0051] Radiographic or diagnostic contrast agents may be added to
the composition to enable the composition to be discerned upon
X-ray or other diagnostic means. Examples of such agents include
barium boroaluminosilicate glasses and glass-ceramics, barium
sulfate (BaSO.sub.4), zirconium dioxide (ZrO.sub.2), chromium oxide
(CrO), Ta, Gd or other heavy metal particulate, or bismuthic
compounds such as Bi.sub.2O.sub.3 and Bi(OH).sub.3.
[0052] In preferred embodiments, the polymerizable systems are
comprised of two pastes designated as pastes A and B. In certain
preferred embodiments, paste A is comprised of at least one or more
fillers and at least one or more resins. Exemplary resin components
contained within paste A may include from about 0 to about 25% by
weight bisphenol-A glycidyl dimethacrylate (BisGMA), from about 0
to about 18% by weight triethylene glycol dimethacrylate (TEGDMA),
from about 0 to about 25% by weight diurethane dimethacrylate
(DUDMA), from about 0 to about 2% by weight DHEPT, and from about 0
to about 0.009% by weight butylhydroxytoluene (BHT). In certain
preferred embodiments, paste B is also comprised of at least one or
more fillers and at least one or more resins. Exemplary resin
components contained within paste B may include from about 0 to
about 15% by weight bisphenol-A glycidyl dimethacrylate (BisGMA),
from about 4 to about 15% by weight triethylene glycol
dimethacrylate (TEGDMA), from about 0 to about 25% by weight
diurethane dimethacrylate (DUDMA), from about 0-0.07% by weight
butylhydroxytoluene (BHT), and from about 0 to about 0.70% by
weight of BPO.
[0053] Various combinations of the amine:BPO:BHT additives within
the paste will yield specific working and set times. Within the
composition variables given above, the 2.25:1:0.12 ratio gives the
preferred long work time of 5 minutes and the slow set time of 8 to
10 minutes. The more preferred 3 minutes working time and 5 to 7
minutes set time is obtained with a 2.5:1:0.1 amine:BPO:BHT ratio.
Each set character will depend on the mass of material used, energy
imparted upon mixing, and the temperature of the body (normally
37.degree. C.) at the implant site.
[0054] The monomers and other additives are blended together to
form one or more paste composition precursors. The duration of the
blending operation will vary depending upon the constituents that
comprise the paste composition precursors. In preferred
embodiments, the blending of the monomers and other additives
within the paste composition precursors activates the
polymerization of the composition.
[0055] Referring again to FIG. 1, step 40 relates to the
sterilization of the paste composition precursor. The preferred
method of sterilization of the paste composition precursor is via
high pressure filtration. In a preferred method, the filter is
sized so as to exclude pathogens. The monomers, which are
preferably activated during the blending operation, are passed
through a filter, such as the 0.22 .mu.m filter manufactured by
Millipore, Corporation of Bedford, Mass. The filtration process is
conducted under pressures which range between ambient and 200 psi
and more preferably between from about 2 to about 40 psi. The
housing and plumbing fixtures used downstream in the filtration
process (including the filter itself) are also sterilized prior to
use via steam sterilization (i.e., steam sterilization in place
("SIP") or autoclaving), or similar means, to eliminate or minimize
contamination. The SAL of these paste composition precursors after
sterilization is preferably about 11, more preferably about
10.sup.-3. The precursors are processed and stored within a sterile
environment, such as a class 100 or greater clean room, to maintain
this SAL prior to forming one or more sterile paste
compositions.
[0056] As mentioned previously, the viscous paste or pastes further
comprise one or more fillers. Fillers, which may be inorganic or
organic compounds, but preferably are inorganic compounds, are
added to the paste to enhance, inter alia, the mechanical or the
rheological properties of the paste composition. Examples of
suitable fillers include, but are not limited to, barium glass,
barium-boroaluminosilicate glass, silica, 45S5 glass, bioactive
glass, ceramics, glass-ceramics, bioactive synthetic combeite
glass-ceramic or combinations thereof. These fillers may possess a
variety of morphologies such as, but not limited to, needles,
particulate, flakes, cylinders, long fibers, whiskers, or spherical
particles. In preferred embodiments, the filler is comprised of
particles with an average particle size ranging from less than
about 1.0 .mu.m up to a range of from 2 to 3 millimeters (mm).
Preferably, the average particle size distribution ranges from 5 to
20 .mu.m.
[0057] Optionally, the filler or fillers may be pre-dried and
screened prior to sterilization as needed. In preferred
embodiments, one or more fillers are coated with silane which acts
as a coupling agent prior to sterilization.
[0058] In a presently preferred embodiment, paste composition A
comprises a silane-coated, glass-ceramic filler that is combined in
a blending step with a silane-coated silica to form filler A. An
example of a silane-coated, glass-ceramic filler is one
manufactured by Mo-Sci, Corp. of Rolla, Mo. and comprised of from
52 to 56% by weight by weight SiO.sub.2, from 16 to 25% by weight
of CaO, from 12 to 16% by weight of Al.sub.2O.sub.3, from 0 to 2%
by weight of Na.sub.2O, from 0 to 5% by weight of MgO, from 0.05 to
0.4% by weight of Fe.sub.2O.sub.3, from 0 to 0.08% by weight of
TiO.sub.2, and <1% F. The glass filler may, optionally, be
pre-dried and screened prior to dry-heat sterilization or,
alternatively, gamma-sterilized. Paste composition B comprises a
silane-coated barium glass, such as, for example, the
barium-boroaluminosilicate glass manufactured by Sci-Pharm, Inc. of
Pomona, Calif. and comprised of 52% by weight SiO.sub.2, 30% by
weight of BaO, 8.5% by weight of Al.sub.2O.sub.3, 7.5% by weight of
B.sub.2O.sub.3 with trace amounts of Na.sub.2O, CaO,
Cr.sub.2O.sub.3, Fe.sub.2O.sub.3, and P.sub.2O.sub.5. The
silane-coated barium glass is further combined with a
silane-coated, synthetic Combeite glass-ceramic and a silane-coated
silica in a blending step to form filler B.
[0059] In preferred embodiments, the filler level of pastes A and B
can vary from 65 to 85% by weight total filler content with the
preferred bioactive glass-ceramic, such as the Combeite
glass-ceramic ("CGC") filler and composition disclosed in U.S. Pat.
No. 5,681,872, and assigned to Orthovita, Inc., the assignee of the
present invention which is incorporated herein in its entirety by
reference. The content of the preferred bioactive glass-ceramic
preferably ranges from about 10 to about 99% by weight of that
filler. It is preferred that the particle size distribution of the
fillers be broad, bimodal, or preferably trimodal, also of which
being less than about 300 micrometers, even more preferably less
than 50 .mu.m, with less than about 5% by weight being sub 0.1
microns in size.
[0060] Referring again to FIG. 1, step 50 discloses one embodiment
of the sterilization of the fillers prior to combining with the
paste composition precursors. Methods for sterilizing the fillers
may include dry heat, gamma, E beam, bright light or EtO. If the
filler is coated with silane, the sterilization method selected
should maintain the integrity of the silane coating.
[0061] In step 50, the filler or fillers are preferably sterilized
via dry heat sterilization or exposed to dry heat at a time and
temperature sufficient to render the filler sterile. The filler is
typically heated to a temperature of about 140.degree. C. or less
for a period of between about 6 to about 12 hours, or more
preferably, heated to a temperature of about 121.degree. C. or less
for at least 8 hours. In alternative embodiments, the filler can be
heated to higher temperatures, such as, but not limited to,
temperatures of from about 100.degree. C. to about 250.degree. C.
for inversely proportional time periods or shorter periods of time
at higher temperatures. Process variables that effect the length of
time and temperature that the filler is sterilized at are the
volume of filler, the loading of the filler within the oven or
kiln, the ramp rate of the oven or kiln, the dwell time, and
atmosphere in the dry heat operation. In embodiments wherein one or
more fillers are coated with silane, the filler is distributed in a
thin layer on a fluidized bed, such as a rotary kiln, to allow
sufficient heat penetration of the filler without degrading the
silane coating. The SAL of the filler after sterilization is about
10.sup.-6, or more preferably about 10.sup.-3. The filler is
maintained within a sterile environment, such as a class 100 or
greater clean room, to ensure its SAL prior to combining with the
paste composition precursor.
[0062] After the filler and monomer are sterilized, the filler and
the monomer are combined to form one or more paste compositions. In
preferred embodiments such as the process disclosed in step 60 of
FIG. 1, the paste composition precursor comprising the monomer and
filler are combined to form one or more pastes in an aseptic
process, i.e., using equipment that has been pre-sterilized and
combining the components of the paste compositions in a class 100
or greater clean room. Depending upon the components of the paste
composition, a vacuum that ranges from 0 to 29.5 in Hg may be
pulled to prevent auto polymerization during compounding and/or to
minimize macro-sized air bubbles. For example, in certain presently
preferred embodiments, the A paste composition that will fill the
A-side cartridge has an applied vacuum of 20 in Hg pulled whereas
the B paste composition that will fill the B-side cartridge has an
applied vacuum of 5 in Hg. The equipment used to blend the monomer,
filler, or other constituents to form the paste compositions, such
as the mixing equipment, spatulas, blades etc., are preferably
pre-sterilized using steam (referring to step 10) or autoclave
sterilization (referring to step 20).
[0063] The paste is preferably contained within a primary packaging
that comprises one or more cartridges, caps, O-ring pistons, and
external pouches. Each of the primary packaging components are
sterilized prior to the aseptic filling of the paste or pastes (see
step 30 of FIG. 1). In preferred embodiments, the primary packaging
components are sterilized via gamma sterilization or other
sterilization techniques such as EtO, or E-beam sterilization (see
step 30 of FIG. 1).
[0064] Referring to step 70 of FIG. 1, one or more pastes are
aseptically filled into cartridges that further comprise a cap and
an O-ring piston. In preferred embodiments, paste compositions A
and B are loaded into the a monolithic, double-chambered cartridge
such as the double-chambered cartridge that is manufactured by
Mixpac Systems AG of Rothreuz, Switzerland. Preferably, the
double-chambered cartridge has two chambers that keep the pastes
separated from each other. Further embodiments of the present
invention may include, but are not limited to, multiple-chambered,
i.e., triple- or quadruple-chambered cartridges for three or four
paste compositions. The cartridge preferably has a dispensing
nozzle and cap to seal the contents prior to use.
[0065] Referring to FIG. 1, step 80, or the steps, of filling the
cartridges, assembling the piston into the cartridge, encapsulating
the cartridges into one or more pouches and then thermo-sealing the
cartridges, is conducted within an isolated system or isolator (see
step 70). The isolator preferably employs vaporous hydrogen
peroxide (VHP) to obtain a sterile environment or SAL of from about
10.sup.-6 to about 10.sup.-5. However, other methods of rendering
the area sterile may be used without departing from the spirit of
the invention. Air is removed from the cartridge prior to the
filling process and platen insertion. A platen is then inserted
into each individual chamber of the cartridge. The paste is
aseptically filled into the cartridge using filling equipment which
is selected to minimize the risk of contamination of the sterile
material. Preferably, non-product contact filling equipment such as
the Trideck filler manufactured by Trideck, Inc. of Brookfield,
Conn. is used. Depending upon the composition of the paste or
pastes, the filling may further be conducted under hot or cold
temperatures (hot filled or cold filled) or conducted under vacuum.
After the cartridge or chambers of the cartridge are filled, the
O-ring piston assembly is assembled into the cartridge to form an
air-tight seal. The filled cartridge and piston may then be
packaged within an external pouch. In preferred embodiments, the
filled cartridges and piston assemblies are packaged within a dual
pouch arrangement, or an inner and outer pouch. Examples of the
external packaging for the filled cartridges my comprise a
TYVEK.RTM./polyester pouch manufactured by Tolas Healthcare
Packaging of Feasterville, Pa. and/or polyvinyl pouch. Still other
external packages may include, but not be limited to, foil pouches,
opaque pouches for light sensitive materials, or other permeable
pouches. The cartridges are then thermally sealed. In certain
preferred embodiments, the cartridge is inserted into an internal
polyvinyl pouch which is then placed within a TYVEK.RTM./polyester
pouch. Both internal and external packages are thermally sealed
simultaneously.
[0066] Referring to FIG. 1, step 90 occurs when the packaged
cartridge is labeled and placed in stock in an environment that
maintains the integrity and sterility of the paste or pastes
contained therein. The filled cartridges are then inspected for
sterility and other parameters such as, but not limited to, pouch
seal integrity dye test, pouch test integrity pull test, composite
set time, polymerization stability, prior to release. In preferred
embodiments, the sterility may be tested on each production lot of
pastes or other components of the system in accordance with the
procedures provided in the following test references: Test
Procedure PSI SOP LP074 (Bacterial Endotoxin Inhibition/Enhancement
Test), Test Procedure PSI SOP LP012 (Bacterial Endotoxin Limit
Test) found in the FDA Guidelines on Validation of the Limulus
Amebocyte Lystate Test as an End-Product Endotoxin Test for Human
and Animal Parenteral Drugs, Biological Products, and Medical
Devices (FDA, December 1987) and Bacterial Endotoxins Test, Chap.
85 of the United States Pharmacopeia 24. Further tests may include
the Biological Indicator Sterility Test provided in U.S.
Pharmacopeial Guidelines for Biological Indicators and ANSI/AAMI
ST-34: 1991. The sterility levels of the system components such as
the paste or pastes, inner pouch, cartridges, and fillers are
preferably tested on a lot-by-lot basis to subscribe to or exceed
the FDA sterility guidelines.
[0067] The filled cartridges may be packaged along with accessories
for the presently preferred embodiment of the present invention.
These accessories are individually sterilized and packaged into a
single-use kit. This kit may comprise a delivery gun and one or
more tips, or "mix tips" of various sizes and configurations. In
preferred embodiments, a single-use delivery gun, such as the gun
manufactured by Mixpac Systems AG of Rothreuz, Switzerland, may be
used that accommodates a dual-chambered cartridge that contains two
different paste compositions. Still further accessories to the kit
of the present invention includes the straight and tapered mix tip
of the present invention. In preferred embodiments, these mix tips
are also manufactured by Mixpac Systems AG of Rothreuz,
Switzerland, and are sized to fit the nozzle end of the cartridge.
The mix tip has mixing elements contained therein that allow the
paste compositions in the separate chambers to mix and delivery a
substantially homogeneous blend. Other components to the systems of
the present invention may include a micro delivery system. All of
the components are pre-sterilized and packaged prior to use. In
preferred embodiments, the components are sterilized via gamma
sterilization. After the components are sterilized, the components
are placed into an external package to ensure sterility. An example
of this external package may include a TYVEK.RTM./polyester pouch
manufactured by Tolas Healthcare Packaging of Feasterville, Pa. The
present invention may further include additional kits that comprise
refills of the paste compositions, preferably in cartridge form,
and mix tips.
[0068] In certain preferred embodiments, the end-user opens the
external and internal pouches that house the dual-chambered
cartridge and loads the cartridge into the delivery gun within a
sterile environment, such as a surgical operating room. The plunger
of the gun uniformly engages the platens within each chamber to
dispense the pastes. The individual caps covering the outlets on
each chamber of the cartridge are removed and the mix tip is
installed. The mix tip is preferably shaped to allow the pastes to
flow through their respective outlets on each chamber and
ultimately to flow through one central orifice into a mixing
element. The mix tip further has an mixing element that is shaped
like an auger to combine the pastes into a homogeneous blend prior
to dispensing. For best results, the first inch of the blend is
discarded to ensure uniform mixing of both pastes. Depending upon
the composition of the pastes, the blended, restorative composition
should be used approximately 5-8 minutes after dispensing.
[0069] By way of example, three sterile polymerizable systems were
made from three different production lots in accordance with the
methods of the present invention. These systems were comprised of
two pastes designated A and B, both of which were comprised of at
least one sterile filler and at least one sterile polymerizable
monomer. The pastes were filled into separate chambers of a dual
chambered cartridge as disclosed herein and packaged within an
internal and external pouch that was sealed simultaneously. Each
system was subjected to the following tests: bacterial endotoxin
inhibition/enhancement tests and bacterial endotoxin limit tests.
These tests were performed in accordance with following FDA
Guideline--Validation of Limulus Amebocyte Lysate as an End-Product
Endotoxin Test for Human and Parenteral Drugs, Biological Products,
and Medical Devices ("LAL"). These tests showed that the paste
compositions were compliant with or exceeded FDA Guidelines.
Further testing and analysis was performed for the following:
endotoxin tests on the paste compositions; product sterility
testing on the paste compositions; product sterility testing on
swabs of the outside of the inner pouch to insure that the inner
pouch is sterile; and product sterility testing on swabs of the
outside of the cartridges; biological indicator sterility test
certificate for the filler comprised within the paste compositions.
All of these tests showed that the systems met or exceeded FDA
and/or ASTM guidelines.
[0070] The present invention also discloses methods of preparing
sterile, polymerizable blends. This method comprises the steps of:
applying dry heat under time and temperature conditions sufficient
to sterilize at least one filler; passing a plurality of
polymerizable monomers through a filter; and combining the monomers
and the filler together to form at least one homogeneous blend
contained within a sterile delivery vessel wherein the combined
monomers and fillers are dischargeable from the sterile delivery
vessel.
[0071] The present invention also discloses sterile, biologically
compatible restorative compositions that comprise: a plurality of
polymerizable monomers, the monomers having been sterilized by
passing them through a filter; at least one filler which has been
exposed to conditions of time and temperature effective to render
the filler sterile; and the monomers and the filler being blended
together to form at least one homogeneous composition contained
within a sterile delivery vessel wherein the combined monomers and
fillers are dischargeable from the sterile delivery vessel.
[0072] Further embodiments disclosed are methods for preparing a
sterile, biologically compatible restorative composition. This
method comprises the steps of: applying dry heat under time and
temperature conditions sufficient to sterilize at least one filler;
passing a plurality of polymerizable monomers through a filter; and
combining the monomers and filler together to form at least one
homogeneous composition contained within a sterile delivery vessel.
Yet further embodiments of the present invention include
sterilization methods for the activated monomer and the
silane-coated filler that comprise the paste.
[0073] Additional embodiments of the present invention may include
shaped bodies made of a sterile polymerizable blend, wherein the
blend comprises a plurality of polymerizable monomers, the monomers
having been sterilized by passing them through a filter; at least
one filler which has been exposed to conditions of time and
temperature effective to render the filler sterile; and the
monomers and the filler being blended together to form at least one
homogeneous blend contained within a sterile delivery vessel.
[0074] Lastly, embodiments of the present invention include methods
of restoring tissue in an animal wherein the method comprises the
steps of: applying dry heat under time and temperature conditions
sufficient to sterilize at least one filler; passing a plurality of
polymerizable monomers through a filter; combining the monomers and
the filler together to form at least one homogeneous composition
contained within a sterile delivery vessel; and applying the
composition to an animal whereby the tissue may be restored.
[0075] Thus, there had been described presently preferred
embodiments of a sterile, polymerizable kit and/or system and
methods for the manufacture and use thereof that are comprised of
one or more sterile compositions and a delivery system or kit.
Although the present invention has been described with reference to
restorative biomaterials, it should be understood that aspects of
the present invention, such as the sterile compositions themselves,
the sterilization methods of the constituents that comprise the
compositions, and their methods of use for a restorative bone
composition, are not limited to the particular embodiments
disclosed. While the present invention has been particularly shown
and described with reference to the presently preferred embodiments
thereof, it is understood that the invention is not limited to the
embodiments specifically disclosed herein. Numerous changes and
modifications may be made to the preferred embodiment of the
invention, and such changes and modifications may be made without
departing from the spirit of the invention. It is therefore
intended that the appended claims cover all such equivalent
variations as they fall within the true spirit and scope of the
invention.
* * * * *