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Title: Methods for forming
regional tissue adherent barriers and drug delivery systems
United States Patent: 7,025,990
Issued: April 11, 2006
Inventors: Sawhney; Amarpreet S. (Bedford,
MA)
Assignee: Incept LLC (Lexington, MA)
Appl. No.: 266980
Filed: October 8, 2002
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Woodbury College's
Master of Science in Law
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Abstract
Methods are provided for forming hydrogel
barriers in situ that adhere to tissue and prevent the formation of
post-surgical adhesions or deliver drugs or other therapeutic agents to a
body cavity. The hydrogels are crosslinked, resorb or degrade over a
period of time, and may be formed by free radical polymerization initiated
by a redox system or thermal initiation, or electrophilic-neutrophilic
mechanism, wherein two components of an initiating system are
simultaneously or sequentially poured into a body cavity to obtain
widespread dispersal and coating of all or most visceral organs within
that cavity prior to gelation and polymerization of the regional barrier.
The hydrogel materials are selected to have a low stress at break in
tension or torsion, and so as to have a close to equilibrium hydration
level when formed.
DETAILED DESCRIPTION OF THE INVENTION
Preferred macromers suitable for practicing the methods of the present
invention include water soluble crosslinkable polymeric monomers that have
a functionality >1 (i.e., that form crosslinked networks on
polymerization) and that form biodegradable hydrogels. The in situ formed
hydrogels of the present invention may be crosslinked using several types
of initiating systems. Some of these initiating systems require an
external energy source, for example, in the form of radiation, focused
ultrasound, or other means. Photopolymerization using ultraviolet or
visible radiation has been widely used to polymerize free radically
crosslinkable materials.
Within an animal or human body, at the sites of localized disease, it is
useful to control the polymerization process to reduce or prevent
post-surgical adhesion. The location of post-surgical adhesion formation,
however, often is not predictable, and occurs not at the site of
iatrogenic intervention. Instead, the location of adhesions depends on
many factors, including pre-existing disease, ischemia etc.
In accordance with the present invention, methods are provided that permit
diffuse coating of wide and complicated tissue geometries to form
"regional" barriers, by coating essentially all tissues in the region of
intervention with an adherent crosslinked hydrogel barrier.
The process of the present invention is conceptually similar to "hydroflotation,"
which entails filling up a body cavity with a lubricious fluid to float
the organs within the cavity in isolation of each other. In hydroflotation,
the fluid is invariably rapidly absorbed and cleared, leading promptly to
organ apposition and adhesion formation.
In accordance with the principles of the present invention, an in situ
formed hydrogel is used to "float" the organs for substantially longer
than is possible with hydroflotation methods. Whereas hydroflotation has
been associated with fluidic imbalances in the patient resulting from the
use of hyperosmolar fluids, the method of the present invention does not
rely on osmolality. Instead, it is the crosslinked structure of the
hydrogel that prolongs residence of the barrier within the body cavity.
Thus, the precursor solutions and the resulting hydrogel barrier may be
iso-osmolar with the surrounding physiological fluids, and do not create
any fluidic imbalances.
For macromers that possess ethylenically unsaturated bonds, regional
barriers may be formed for example, by a free radically initiated
polymerization. This may be undertaken using chemically (such as a redox
system) and thermally activated initiating systems. Photopolymerization
processes may optionally be used, but such processes typically are better
suited for a local polymerization approach as opposed to a regional one.
This is so because some tissues and organs may not transmit light of the
wavelength being used. Also, photopolymerization generally is restricted
to a "spot-by-spot" approach, and is unsuitable when it may be difficult
to predict where the adhesions are likely to originate.
Other means for polymerization of macromers to form regional barriers may
also be advantageously used with macromers that contain groups that
demonstrate activity towards functional groups such as amines, imines,
thiols, carboxyls, isocyanates, urethanes, amides, thiocyanates, hydroxyls
etc. that may either be naturally present in, on, or around tissue or may
be optionally provided in the region as part of the instilled formulation
required to effect the barrier.
Materials Suitable for Formation of Regional Barriers
Absorbable polymers, often referred to as biodegradable polymers, have
been used clinically in sutures and allied surgical augmentation devices
to eliminate the need for a second surgical procedure to remove
functionally equivalent non-absorbable devices. See, e.g., U.S. Pat. No.
3,991,766 to Schmitt et al. and Encyclopedia of Pharmaceutical
Technology (Boylan & Swarbrick, Eds.), Vol. 1, Dekker, New York, p.
465 (1988). Interest in using such absorbable systems, with or without
biologically active components, in medical applications has grown
significantly over the past few years. Such applications are disclosed in
Bhatia, et al., J. Biomater. Sci., Polym. Ed., 6(5):435 (1994);
U.S. Pat. No. 5,198,220 to Damani; U.S. Pat. No. 5,171,148 to Wasserman,
et. al.; and U.S. Pat. No. 3,991,766 to Schmitt et al.
Absorbable hydrogels that may be formed and crosslinked in situ to form a
network are preferred materials for practicing the current invention.
Synthesis and biomedical and pharmaceutical applications of absorbable or
biodegradable hydrogels based on covalently crosslinked networks
comprising polypeptide or polyester components as the enzymatically or
hydrolytically labile components, respectively, have been described by a
number of researchers. See, Jarrett et al., "Bioabsorbable Hydrogel Tissue
Barrier: In Situ Gelatin Kinetics," Trans. Soc. Biomater., Vol.
XVIII, 182 (1995); Sawhney et al., "Bioerodible hydrogels based on
photopolymerized poly(ethylene glycol)-co-poly(α-hydroxy acid) diacrylate
macromers", Macromolecules, 26:581-587 (1993); Park, et al.,
Biodegradable Hydrogels for Drug Delivery, Technomic Pub. Co.,
Lancaster, Pa., 1993; Park, "Enzyme-digestible swelling hydrogels as
platforms for long-term oral drug delivery: synthesis and
characterization," Biomaterials, 9:435-441 (1988).
Hydrogels described in the literature include, for example, those made of
water-soluble polymers, such as polyvinyl pyrrolidone, which have been
crosslinked with naturally derived biodegradable components such as those
based on albumin.
Totally synthetic hydrogels are based on covalent networks formed by the
addition polymerization of acrylic-terminated, water-soluble chains of
polyether-poly(α-hydroxyester) block copolymers. These materials are among
those preferred for practicing the present invention because they have
been used for in vivo applications and have been demonstrated to be
biocompatible. Details of compositions and methods to synthesize such
materials have been described in U.S. Pat. No. 5,410,016 to Hubbell et
al., which is incorporated herein by reference.
Preferred macromers for use in forming regional barriers for prevention of
adhesion in accordance with the principles of the present invention
include any of a variety of in situ polymerizable macromers that form
hydrogel compositions absorbable in vivo. These macromers, for example,
may be selected from compositions that are biodegradable, polymerizable,
and substantially water soluble macromers comprising at least one water
soluble region, at least one degradable region, and statistically more
than 1 polymerizable region on average per macromer chain, wherein the
polymerizable regions are separated from each other by at least one
degradable region. The individual regions that comprise such macromers are
described in detail below.
Water Soluble Regions
The water soluble region is selected from any of a variety of natural,
synthetic, or hybrid polymers the group consisting of poly(ethylene
glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(allyl alcohol),
poly(vinylpyrrolidone), poly(ethyleneimine), poly(allylamine), poly(vinyl
amine), poly(aminoacids), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propyleneoxide)
block copolymers, polysaccharides, carbohydrates, proteins, and
combinations thereof.
Random copolymers of monomers that form water soluble polymers also may be
used, for example, copolymers of vinyl amine and allyl alcohol. These
types of random copolymers are preferred when the crosslinking reaction is
mediated by nucleophilic or electrophilic functional groups. The water
soluble region also may be selected from species that are capable of being
rendered hydrophilic in a post-polymer reaction. For example, vinyl esters
of carboxylic acids such as vinyl formate, vinyl acetate, vinyl
monochloroacetate, and vinyl butyrate, may be copolymerized with the
afore-described copolymerizable macromolecular monomers. Subsequent to the
copolymerization reaction, the polymeric backbone (containing repeating
monomeric units of these vinyl esters of carboxylic acids) may be rendered
hydrophilic by hydrolysis to the resulting polyvinyl alcohol. In other
words, the polymeric backbone comprises a polyvinyl alcohol.
Suitable species that may be polymerized and used in preparing the
hydrophilic polymeric backbone of the macromers useful in the present
invention include:
acrylic and methacrylic acid;
water-soluble monoesters of acrylic and
methacrylic acid in which the ester moiety contains at least one
hydrophilic group such as a hydroxy group, i.e., the hydroxy lower alkyl
acrylates and methacrylates, typical examples of which include:
- 2-hydroxyethyl acrylate,
2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl
methacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate,
diethylene glycol monomethacrylate, diethylene glycol monoacrylate,
dipropylene glycol monomethacrylate, and dipropylene glycol monoacrylate;
water-soluble vinyl monomers having at
least one nitrogen atom in the molecule, examples of which include:
- acrylamide, methacrylamide,
methylolacrylamide, methylolmethacrylamide, diacetone acrylamide N-methylacrylamide,
N-ethylacrylamide, N-hydroxyethyl acrylamide, N,N-disubstituted
acrylamides, such as N,N-dimethylacrylamide, N,N-diethylacrylamide, N-ethylmethylacrylamide,
N,N-dimethylolacrylamide, and N,N-dihydroxyethyl acrylamide
heterocyclic nitrogen containing
compounds such as N-pyrrolidone, N-vinyl piperidone, N-acryloylpyrriolidone,
N-acryloylpiperidine, and N-acryloylmorpholene; and
cationic functional monomers, for
example, vinyl pyridene quaternary ammonium salts and dimethyl aminoethyl
methacrylate quaternary ammonium salts.
Suitable hydrophobic copolymerizable monomers also may be interpolymerized
with hydrophobic copolymerizable macromolecular monomers and the
aforementioned hydrophilic copolymerizable comonomers, so long as the
ultimate products of biodegradation are water soluble. Hydrophobic species
may include the alkyl acrylates and methacrylates, e.g., methylacrylate or
methylmethacrylate, ethylacrylate or ethylmethacrylate, propylacrylate or
propylmethacrylate, butylacrylate or butylmethacrylate, butylacrylate
being preferred. Other suitable hydrophobic copolymerizable comonomers
include vinyl chloride, vinylidene chloride, acrylonitrile,
methacrylonitrile, vinylidene cyanide, vinyl acetate, vinyl propionate,
and vinyl aromatic compounds such as styrene and alpha-methylstyrene, and
maleic anhydride.
Degradable Regions
The degradable region is selected from any of a variety of polymers that
undergo either hydrolytic, enzymatic, or thermal decomposition by bond
scission of linkages so as to produce ultimately soluble and
physiologically cleared molecules. Preferable biodegradable polymers,
oliogomers or even single moieties can be selected from the group
consisting of poly(α-hydroxy acids), poly(lactones), poly(amino acids),
peptide sequences, oligonucleotides, poly(saccharides), poly(anhydrides),
poly(orthoesters), poly(phosphazenes), and poly(phosphoesters),
poly(urethanes), poly(amides), poly(imines), poly(esters), phosphoester
linkages and combinations, copolymers, blends, etc. In some cases the
water soluble and the degradable region may be one and the same, for
example, in the case of proteins and poly(saccharides) that are degraded
by naturally existing enzymes within the body.
Polymerizable Regions
The polymerizable end groups in these macromers may consist of groups that
either react within themselves, with added excipients, or with the surface
of tissue to form tissue protective coatings that function as regional
barriers. Preferable end groups that mainly react within themselves may be
selected from ethyleneically unsaturated functional groups such as
acrylate, allyl, vinyl, methacrylate, cinnamate, or other ethylenically
unsaturated functional groups.
Polymerizable groups may be selected from nucleophilic groups and their
salts that react further, for example, with acylating agents. Useful
nucleophilic groups may include primary, secondary, tertiary, or
quaternary amino, amide, urethane, urea, hydrazide or thiol groups. These
functional groups may be present along the main chain of the water soluble
macromer or present only at the end groups. When they are present along
the main chain of the macromer, they may be evenly spaced, as in a block
copolymer, or they may be randomly spaced.
For example, Shearwater Polymers, Huntsville, Ala., sell p-PEGs which
contain pendant functional groups. optionally these groups may be spaced
from the polymeric main chain (either at the chain ends or along the
backbone) by spacer groups that may contain ester linkages. The
preparation of macromers containing amino acid esters of PEG is described,
for example, in Zalipsky et al., "Esterification of Polyethylene Glycols,"
J. Macromol. Sci. Chem., A21:839 (1984). The presence of such
linkages can impart desirable properties such as speed of polymerization
and predictable instability of the linkage.
Nucleophilic functional group-containing macromers optionally may be mixed
with electrophilic group-containing macromers to rapidly initiate
polymerization. It should be noted that several nucleophilic and
electrophilic functional groups are naturally present in proteins,
polysaccharides, glycosaminoglycans, and oligonucleotides that constitute
tissue, cells, and organs and thus both nucleophilic and electrophilic
macromers may react with appropriate naturally occurring functional groups
in the absence of any additional externally added macromers.
For purposes of the present invention, however, reaction rates are more
predictable and the resulting hydrogel will have more predictable
properties if both components are added externally so as to initiate
polymerization and formation of the hydrogel. Electrophilic groups that
may be useful to react with the aforementioned nucleophilic groups may
include carboxyl groups that may or may not be separated from the
polymeric main chain (either at the chain ends or along the backbone) by
spacer groups that may contain ester linkages (for example esters of
succinic acid, carboxymethyl esters, esters of propionic, adipic, or amino
acids), among others.
Other useful groups include isocyanate, thiocyanate, N-hydroxy succinamide
esters such as succinamide as well as succinamide groups that are spaced
by groups such as esters or amino acids, among others such as succinimidyl
succinates, succinimidyl propionates, succinimidyl succinates,
succinimidyl esters of carboxymethylated water soluble polymers,
benzotriazole carbonates, and any of a variety of carbodiimides also may
be selected. PEG succinimidyl succinates, PEG succinimidyl propionates,
succinimidyl esters of amono acid or carboxymethylated PEG, and PEG
succinamidyl succinamides are particularly suitable as electrophilically
active macromers that react with nucleophilic group-containing macromers
due to their high reactivity at physiological pH and speed of
polymerization.
Other useful electrophilic macromers may contain functional groups such as
glycidyl ethers (or epoxides) or hydroxyl group containing polymers that
have been activated with 1,1,-carbonyl diimidazole (for example PEG-oxycarbonylimidazole)
or p-nitrophenyl chlorocarbonates (e.g., PEG nitrophenyl carbonate),
tresylates, aldehydes and isocyanates. Other groups reactive towards
nucleophilic moieties may include for example anhydrides.
Thus, for example, a polymer of maleic anhydride when copolymerized with
allyl or vinyl group containing water soluble polymers (such that the
vinyl or allyl or other ethylenically unsaturated functionality is 1 per
molecule or lower) forms a water soluble co-polymer that contains
anhydride groups along the backbone. These anhydride groups are reactive
towards any of the various nucleophilic groups mentioned hereinabove.
Other electrophilic groups, that are more selective towards specific
nucleophiles (such as sulfahydryl groups), also may be used, such as
vinylsulfone, maleimide, orthopyridyl disulfide or iodoacetamide
containing macromers.
It is to be understood that more than one type of electrophilic group or
nucleophilic group may be present as a part of a macromer chain, so that
multiple levels of reactivities may be built into the materials. In fact,
both electrophilic and nucleophilic groups may be built into the same
molecule and the solution prepared at a pH where the reactivity between
these functional groups is low. A second solution that restores the
appropriate pH upon mixing then may be added to initiate the crosslinking
reaction.
Also, the concentration and number of the functional groups may be varied
to obtain different rates of reactivity. The pH of the solutions may be
varied to control rates of reaction, and the properties of the resulting
crosslinked hydrogel also may be tailored by appropriate selection of the
reactive macromers. For example, a higher molecular weight between
crosslinks may lead to the formation of a lower modulus and more flexible
hydrogel.
Delivery of Bioactive Species
The regional barriers of the present invention further may have bioactive
molecules either dissolved or dispersed within them. The dispersed or
dissolved drugs may be present as a particulate suspension, that either
may or may not further be contained in a secondary containment membrane or
coating, microspheres, or microcapsule. The materials for such secondary
coating and containment also may be selected from any of a variety of
biodegradable natural or synthetic hydrophobic materials that provide
resistance to diffusion of small molecules, especially water soluble small
molecules.
The biologically active molecules may include proteins (including growth
factors and enzymes that may demonstrate bioactivity), carbohydrates,
nucleic acids (both sense and antisense as well as gene fragments for gene
therapy), organic molecules, inorganic biologically active molecules,
cells, tissues, and tissue aggregates. Biologically active molecules may
include any of the beneficial drugs as are known in the art, and
described, for example, in Pharmaceutical Sciences, by Remington,
14th Ed., 1979, published by Mack Publishing Co.; The Drug, The Nurse,
The Patient, Including Current Drug Handbook, by Falconer et al.,
1974-1976, published by Saunder Company; and Medicinal Chemistry,
3rd Ed., Vol. 1 and 2, by Burger, published by Wiley-Interscience Co.
The drugs selected may serve to act against an underlying pathological
condition that is suspected to contribute to the formation of adhesions,
such as drugs that interfere with the polymerization of fibrin, serve as
anticoagulants (such as heparin, hirudin, etc.) or act to dissolve fibrin
clots or disrupt the native fibrinogen (such as tissue plasminogen
activator, urokinase, streptokinase, streptodornase, ancrod, etc). Drugs
having an antiinflammatory effect may be used, such as medroxyprogestrone
acetate, which has been observed to reduce postoperative adhesion
formation in animal studies. Other antiinflammatory compounds such as
antibodies to IL-6, IL-1, TNF-α, and TGF-β have demonstrated efficacy as
well.
Preferably, the drugs are directed to a process unique to adhesion
formation, and which does not disrupt normal healing. For example,
pentoxifylline, a drug used to treat intermittent claudication, and
calcium channel blockers, such as verapamil, have been shown to reduce
postoperative adhesion formation. It is thus expected that the delivery of
one or more therapeutic compounds in a hydrogel-based regional barrier
capable of controlled release may further enhance the prevention of
postoperative adhesions. Thus, drugs that may be advantageously delivered
using the regional barrier of the present invention include
antiinflammatory compounds, antifibrinolytics, targeted modulators that
interfere with the pathways of adhesion formation, such as IL-10 and
antibodies to various cytokines, and immunomodulators.
Drugs delivered by the regional barrier also may serve to supplement the
overall therapeutic regimen for the particular patient by delivering a
drug or a combination of drugs that address another disease state. For
example, physiologically active materials or medicinal drugs, such as
agents affecting the central nervous system, antiallergic agents,
cardiovascular agents, agents affecting respiratory organs, agents
affecting digestive organs, hormone preparations, agents affecting
metabolism, antitumor agents, antibiotic preparations, chemotherapeutics,
antimicrobials, local anesthetics, antihistaminics, antiphlogistics,
astringents, vitamins, antifungal agents, peripheral nervous anesthetics,
vasodilators, crude drug essences, tinctures, crude drug powders,
immunosuppressants, hypotensive agents, and the like may be delivered.
Drugs that are delivered using the regional barriers of the present
invention may include both water soluble as well as partially water
soluble or even lipophilic drugs. The drugs may be small molecules or
macromolecular in nature. Particular water-soluble polypeptides which may
be used in this invention are, for example, oxytocin, vasopressin, tissue
plasminogen activator, urokinase, and other fibrinolytic enzymes,
adrenocorticotrophic hormone (ACTH), epidermal growth factor (EGF),
transforming growth factor antagonists, prolactin, luliberin or
luteinizing hormone releasing hormone (LH-RH), LH-RH agonists or
antagonists, growth hormone, growth hormone releasing factor, insulin,
somatostatin, bombesin antagonists, glucagon, interferon, gastrin,
tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins,
endomorphins, angiotensins, renin, bradykinin, bacitracins, polymyzins,
colistins, tyrocidin, gramicidines, and synthetic analogues and
modifications and pharmaceutically-active fragments thereof, monoclonal
antibodies and soluble vaccines.
The water-soluble drugs that may be delivered by this method are not
specifically limited. Examples include peptides having biological
activities, other antibiotics, antitumor agents, antipyretics, analgesics,
anti-inflammatory agents, antitussive expectorants, sedatives, muscle
relaxants, antiepileptic agents, antiulcer agents, antidepressants,
antiallergic agents, cardiotonics, antiarrhythmic agents, vasodilators,
hypotensive diuretics, antidiabetic agents, anticoagulants, hemostatics,
antituberculous agents, hormone preparations, narcotic antagonists, bone
resorption inhibitors, angiogenesis inhibitors and the like.
Examples of antitumor agents include bleomycin hydrochloride, methotrexate,
actinomycin D, mitomycin C, vinblastine sulfate, vincristine sulfate,
daunorubicin hydrochloride, adriamycin, neocarzinoszatin, cytosine
arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil krestin,
picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin, poly
I:C, poly A:U, poly ICLC, cisplatin and the like.
The terms "cytokine" and "growth factor" are used to describe biologically
active molecules and active peptides (which may be either naturally
occurring or synthetic) that aid in healing or regrowth of normal tissue,
including growth factors and active peptides. The function of cytokines is
two-fold: (1) to incite local cells to produce new collagen or tissue, or
(2) to attract cells to a site in need of correction. For example, one may
incorporate cytokines such as interferons (IFN), tumor necrosis factors (TNF),
interleukins, colony stimulating factors (CSFs), or growth factors such as
osteogenic factor extract (OFE), epidermal growth factor (EGF),
transforming growth factor (TGF) alpha, TGF-β (including any combination
of TGF-βs), TGF-β1, TGF-β2, platelet derived growth factor (PDGF-AA, PDGF-AB,
PDGF-BB), acidic fibroblast growth factor (FGF), basic FGF, connective
tissue activating peptides (CTAP), β-thromboglobulin, insulin-like growth
factors, erythropoietin (EPO), nerve growth factor (NGF), bone morphogenic
protein (BMP), osteogenic factors, and the like.
Suitable biologically-active agents for use in the present invention also
include oxygen radical scavenging agents such as superoxide dismutase or
anti-inflammatory agents such as hydrocortisone, prednisone and the like;
antibacterial agents such as penicillin, cephalosporins, bacitracin and
the like; antiparasitic agents such as quinacrine, chloroquine and the
like; antifungal agents such as nystatin, gentamicin, and the like;
antiviral agents such as acyclovir, ribavirin, interferons and the like;
antineoplastic agents such as methotrexate, 5-fluorouracil, adriamycin,
taxol, taxotere, tumor-specific antibodies conjugated to toxins, tumor
necrosis factor, and the like; analgesic agents such as salicylic acid,
acetaminophen, ibuprofen, flurbiprofen, morphine and the like; local
anesthetics such as lidocaine, bupivacaine, benzocaine and the like;
vaccines such as hepatitis, influenza, measles, rubella, tetanus, polio,
rabies and the like; central nervous system agents such as a tranquilizer,
β-adrenergic blocking agent, dopamine and the like; growth factors such as
colony stimulating factor, platelet-derived growth factors, fibroblast
growth factor, transforming growth factor B, human growth hormone, bone
morphogenetic protein, insulin-like growth factor and the like; hormones
such as progesterone, follicle stimulating hormone, insulin, somatotropins
and the like; antihistamines such as diphenhydramine, chlorphencramine and
the like; cardiovascular agents such as digitalis, nitroglycerine,
papaverine, streptokinase and the like; vasodilators such as theophylline,
niacin, minoxidil, and the like; and other like substances.
The regional hydrogel barriers also may be used to delivery antitumor,
antineoplastic, or anticancer agents to the body cavity, wherein multiple
tumor sites exist and it may not be possible to accurately identify all
sites of disease.
Physical and Mechanical Characteristics of Materials Suitable for
Formation of Regional Barriers
Materials suitable for use in forming the regional barriers in accordance
with the present invention preferably have certain physical and mechanical
attributes. These include safety, effectiveness at adhesion prevention,
absorbability, non-inflammatoriness, compatibility with laparoscopic use,
ease of use, efficacy at sites distant to surgery, lack of interference
with normal healing, suitability as a pharmaceutical carrier, and
conformity to tissue. While no adhesion barrier material may possess all
of these properties, the materials described hereinabove satisfy many of
these criteria.
In addition to the foregoing criteria, crosslinked materials suitable for
use as regional tissue adherent adhesion barriers or drug delivery systems
in accordance with the present invention should exhibit the following
characteristics: (1) the materials should not obstruct the normal
functioning of internal organs; and (2) these materials should not cause a
substantial hydraulic imbalance after instillation and polymerization.
The first requirement ensures that, despite the extensive regional
presence of the barrier throughout a body cavity, it will not impede
normal tissue movement. Thus, even though the hydrogel barrier is
crosslinked, it should not have the structural strength to adhere or bind
organs together tenaciously. It is instead preferable that the barrier
have weak cohesive strength and fail within the bulk of the material,
rather than constrict organs to which it is applied. Desirable materials
are expected to have stress at shear or tensile loading failure of less
than 1 MPa. More preferably, the stress at failure should be between less
than 300 KPa, and more preferably, less than 100 KPa.
The regional barriers need not form bulk hydrogels, but may form coatings
on tissue upon instillation that may be thin and of the order of 1-1000
microns in thickness. In fact, the coating even may be formed as a surface
modification of the tissue by instillation of macromers that have a
reactivity to functional groups found on the surface of the tissues at
risk for formation of adhesions. The instillation of the precursor
solutions may be simultaneous or sequential, with a first solution coating
tissue for some period of time and the subsequent solution being
administered just prior to completion of the surgical procedure and
closure of the surgical access points or incision.
The quantity of water contained within a hydrogel may be evaluated as "%
Water Content," defined as:
##EQU1## (see Original Patent)
Hydrogels continue to absorb water from surrounding aqueous fluids until
they reach an equilibrium level of hydration. During this process the
addition increase in water content can be determined by measuring the %
Hydration, which is defined as:
##EQU2## (see Original Patent)
The requirement that the barrier material not create a hydraulic imbalance
in situ arises from the relatively large volumes of such materials that
are needed to form regional barriers as opposed to local barriers. It is
expected, for example, that a typical use of regional barrier material in
accordance with the present invention will involve the instillation of
precursor materials in excess of 200 ml, possibly in excess of 500 ml, and
in some cases, even as high as 3000 ml. Due to such relatively large
volumes of instillates, it is important that the resulting regional
barrier be relatively isotonic and near equilibrium hydration, i.e. it
will not continue to absorb fluid from within the body cavity and induce
fluid imbalance in the patient.
Similarly, the materials used to form the regional barriers of the present
invention also should be close to the equilibrium level of hydration.
Thus, the barrier will not appreciably increase in size by hydrating
substantially after formation and thus will not impose undesirable
mechanical obstructions within the body cavity. Accordingly, materials
that hydrate less than 100% beyond their own weight in physiological
aqueous solutions, at time of formation, are preferred. More preferable
are materials that hydrate less than 50% of their own weight, and more
preferably, materials that hydrate less than 20% beyond their initial
weight at time of formation.
It is to be understood, based upon the foregoing discussion, that
materials suitable for practicing the present invention should have many
of the other beneficial properties expected of adhesion barrier materials,
such as not eliciting an inflammatory response. If the barrier material
generates a significant inflammation, it may enhance the formation of
adhesions, rather than reducing or eliminating them. For example talc,
which is considered to be an inflammatory material, is often used to
create adhesions within the chest cavity by a regional instillation.
The hydrogel barriers formed in accordance with the methods of the present
invention preferably are absorbed over time by natural physiological
processes, so that the organs within the region of interest ultimately
return to their original conformations. Absorption of the barrier material
is defined herein as a lack of physical evidence of presence of the
barrier at the application site. Preferably, the regional barriers of the
present invention should absorb within 6 months, more preferably within 2
months, and most preferably within 1 month.
Free Radical Initiating Systems
Many previously known chemical systems that use free radical
polymerization do not depend on external energy sources such as
photoexcitation. Such systems advantageously may be used at physiological
conditions of temperature and do not create physiologically toxic effects
at the concentrations used. For example, Roland et al., "Recent
Developments in Free-Radical Polymerization-A Mini Review," Progress in
Organic Coatings, 21:227-254 (1992), presents an overview of the free
radical polymerization process, with an emphasis on recent developments.
U.S. Pat. No. 4,511,478 to Nowinski et al. describes several types of
oxidation-reduction initiators, including: (1) peroxides in combination
with a reducing agent, e.g., hydrogen peroxide with ferrous ion or other
transition metal ions, or benzoyl peroxide with an N,N-dialkylaniline or
toluidine, and (2) persulfates in combination with a reducing agent, such
as sodium metabisulfite or sodium thioslfate.
Specifically, ammonium persulfate, benzoyl peroxide, lauryl peroxide, tert-butyl
hydroperoxide, tert-butyl perbenzoate, cumene hydroperoxide, dibenzoyl
peroxide, tert-butyl peroctoate, tert-butyl peracetate, di-tert-amyl
peroxide, di-tert-butyl peroxide, tert-amyl perpivalate, butyl
per-2-ethyl-hexanoate, tert-butyl perpivalate, tert-butyl perneodecanoate,
tert-butyl perisononanoate, tert-amylperneodecanoate, di-2-ethyl-hexyl
peroxydicarbonate, dicyclohexyl peroxydicarbonate, cumyl perneodecanoate,
tert-butyl permaleate, 1,3-bis-(t-butylperoxyisopropyl)benzene, succinic
acid peroxide, bis(1-hydroxycyclohexyl)-peroxide, isopropyl percarbonate,
methyl ethyl ketone peroxide, and dicumyl peroxide, potassium ferricyanide,
potassium permanganate, ceric sulfate, pinane hydroperoxide,
di-isopropylbenzene hydroperoxide and other oxidizing compounds including
combinations thereof with reducing agents, such as transition metal ions,
sodium hyposulfite, sodium metabisulfite, sodium sulfide, sodium
thiosulfate, hydrazine hydrate, sodium bisulfite or sodium thiosulfate,
may be used. Sodium bisulfite alone may be used for polymerization.
Other initiators suitable for use in accordance with the methods of the
present invention include, but are not limited to azo initiators.
Preferred thermally active free radical polymerization initiators for use
in the present invention may include, but are not limited to,
diazodiisobutyrodinitrile, 2,2′-azobis-(isobutyronitrile),
2,2′-azobis(2,4-dimethylvaleronitrile), 2,2′-azobis(cyclohexanenitrile),
2,2′-azobis-(2-methylbutyronitrile), 2,2′-azobis(2,4-dimethyl
4-methoxyvaleronitrile), mixtures thereof and several like azo initiators
such as those sold by Wako Chemical Co., Richmond, Va. Mixtures of two or
more initiators also may be used, if desired.
Another group of catalysts, useful mainly for low temperature
polymerization, include redox systems such as potassium persulfate-riboflavin,
potassium persulfate-sodium bisulfite. Various compounds such as N,N,N′,N-tetramethylethylenediamine
and dimethyl toluidine may be used to accelerate the effect of the
catalysts. Other suitable catalyst(s) and accelerant(s) may be used to
catalyze the polymerization.
Inhibitors of Free Radical Polymerization
Free radical-inhibitors are generally used in the production,
transportation and/or storage of systems that are reactive via free
radicals to definitely exclude that the system will undergo premature
reaction. With respect to the foregoing polymerizable materials, the
addition of numerous compounds and/or systems that function as free
radical-inhibitors are known, including, for example, hydrides such as
lithium aluminum hydride, calcium hydride or sodium borohydride.
Further known examples serving this purpose are phenols, phenol
derivatives, hydroquinone and hydroquinone derivatives or, especially,
phenothiazine. As typical examples there may be mentioned cumene,
hydroquinone, 2,6-di-tert-butyl-p-cresol, BHT, BRA, anisole,
2,6-di-tert-butyl-4-methoxyphenol,
bis(2-hydroxy-3-tert-butyl-5-methylphenyl)methane,
bis(3,5-di-tert-butyl-4-hydroxyphenyl)methane,
bis(2-hydroxy-3-tert-butyl-5-methylphenyl)sulfide,
bis(3-tert-butyl-4-hydroxy-5-methyl-phenyl)sulfide, or also amines such as
diphenylamine, N,N′-diphenyl-p-phenylene diamine, 2-phenylbenzimidazole,
aniline, dinitrobenzene, 2-nitro-α-naphthol, tetraphenylethylene,
triphenylmethane and vitamin E.
Methods of Instillation
In accordance with the methods of the present invention, macromer
solutions used in forming regional barriers may be instilled by pouring,
spraying (e.g., using two or more spray nozzles that simultaneously spray
more than one solution into the region of interest), or by devices such as
infusion catheters (e.g., dual lumen catheters or nozzles with mixing
tips), funnel like devices, syringes, or bellows like devices with either
dual chambers with a distal mixing tip, which is optionally attached, or
with two separate devices that are either simultaneously or sequentially
employed, etc.
The solutions may be selected so as to have active ingredients separated
in two or more solutions that enable the polymerization upon mixing or on
contact. Thus, for example, elements of a redox initiating system may be
present in separate macromer solutions that either may be used
simultaneously, sequentially or separately after an intervening interval
of time to effect polymerization. In order to provide control of hydrogel
formation, the barriers of the present invention may also include colored
indicator substances such as phenol red (0.04-0.008%), thymol blue
(0.04-0.1%), furoxone (0.02-0.4%), rivanol (0.45-0.75%) or picric acid
(0.01-0.03%); or antibiotics such as tetracycline (0.7-0.17%), mithramycin
(0.1-0.4%), or chlortetracycline (0.1-0.4%). (All percentages are w/v.)
As a result, a color change, such as a green color, will be observed after
mixing or penetration of these colored substances (e.g., one is blue,
other is yellow). The color changes also may be usefully observed as a
result of pH change when two macromeric solution streams that are
instilled into the body cavity are mixed, such macromeric solutions being
selected such that the crosslinking reaction only occurs when an
appropriate pH is reached, which is indicated by the presence of the pH
sensitive calorimetric indicator.
Colored species also may be generated as part of the in situ reaction
process. For example, the use of p-nitrophenyl activated PEG as a
crosslinking molecule with a poly(amine) such as poly(ethyleneimine) will
result in the generation of a yellow color due to the formation of p-nitrophenol
as a reaction byproduct. This attribute of color appearance may be used to
monitor successful deployment of the regional adhesion barrier.
The macromer solutions will typically be used at the end of the particular
surgical procedure but may also be used during or even before undertaking
the particular surgical procedure so as to serve as tissue protectants
during the surgical procedure by hydrating and lubricating such tissues
during the surgery. If thermal initiating systems are used, premature
polymerization may be prevented by maintaining the solutions at low
temperature so that polymerization occurs when physiological temperatures
are attained upon instillation.
Claim 1 of 33 Claims
1. A method for forming a
regional hydrogel barrier in a patient, the method comprising:
instilling a first component within a patient, wherein the first component
comprises a pharmaceutically acceptable macromer having statistically more
than one polymerizable region on average per molecule; and
instilling a second component within the patient so that the second
component contacts the first component, wherein the second component
comprises an initiator selected from the group consisting of peroxides,
persulfates, azo initiators, thermal initiators and redox initiators,
thereby initiating the polymerization of the macromer in situ to form a
regional hydrogel barrier that hydrates less than 100% in physiological
solution compared to an initial weight of the hydrogel barrier.
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