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Description  |
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FIELD OF THE INVENTION
This invention relates to a novel method and apparatus for treating
fibrotic lesions, particularly to treating scar tissue wherever located,
and to treating strictures of tubular structures, hollow organs and the
like.
1. Background of the Invention
Whether created by disease, accident or therapeutic intervention, mammals
heal their wounds by formation of scar tissue. The healing process, namely
scar formation, often leaves mammals with limitations of motion,
constricting skin scars, frozen joints or restriction of organ function
such as in urethral stenosis or gastric outlet obstruction, for example.
For many years, medical practitioners and researchers have struggled
unsuccessfully with the difficult task of controlling scar formation by
either reducing scar production or promoting scar resorption in their
efforts to reduce limitations of motion, scarring, freezing of joints or
restriction of organ function. Their efforts prior to this time have not
been successful in alleviating these problems in human patients.
2. Description of the Prior Art
During the past quarter century much knowledge has been gained relative to
the biochemistry of scar formation. E.E. Peacock, Jr. & Walton VanWinkle
in Wound Repair. Sanders Company, Philadelphia, USA, 1976, among others,
have reported their work in this regard. In simple terms, scar is a woven
protein consisting primarily of special amino acid strands of fibers
called collagen. Collagen is formed in special wound cells (fibroblast)
which is extruded to mature in an extracellular matrix where eventual
strength is obtained by crosslinking of protein collagen fibers. The
cross-linking process, which gives scar its strength and hardness, is
facilitated by the enzyme lysyl oxidase.
U.S. Pat. No. 4,485,088 to Chvapil discloses that crosslinking can be
inhibited by altering several chemical pathways with compounds called
lathyrogens, such as D-Penicillamine and Beta-aninopropionitrile (BAPN).
These compounds have been administered systemically to insure their
incorporation into the healing process. Unfortunately, their therapeutic
and toxic concentrations are so close that they cannot be systemically
tolerated by humans, thereby precluding their application to human
patients.
The therapeutic effects of inhibiting or modifying collagen crosslinking
has been demonstrated with topical application to healing wound scars by
Chvapil. One of the lathyrogens, BAPN, penetrates the skin and other
surrounding tissues a few millimeters in thickness. The effective dose of
topical BAPN has been reported to be approximately 1/100th the
systemically effective dose, thereby reducing in importance, but not
eliminating, the issue of safety. Chvapil describes topical application to
burn scars, skin and chicken tendons at or near the time of injury and new
scar formation. However, Chvapil's technique is limited to topical
applications or applications where the lathyrogens may be injected into a
localized area, such as a joint or tendon.
Similar experimental work has been performed for treatment of dogs with
regard to burns in the esophagus; Davis et al in "A New Approach to the
Control of Esophageal Stenosis", Ann. Surg., Vol. 176, No. 4 (October
1972). However, serious toxicity problems were encountered with
systemically introduced Beta-aminopropionitrile fumarate (BAPN-F).
Moreover, during the treatment time, the subjects exhibited severe
problems in the ingestion of food.
Madden et al reported in "Experimental Esophageal Lye Burns", Ann. Surc.,
Vol. 178, No. 3 (September 1973), that although they believed that
mechanical splints should be applied continuously for many months to
achieve permanent correction in artificially induced esophaeal burns,
bougienage could only be performed intermittently.
OBJECTS OF THE INVENTION
It is accordingly an object of this invention to provide a method of
treatment of fibrotic lesions to reduce limitations of motion, scarring,
freezing of joints or restriction of organ function, all without
encountering problems as to systemic toleration.
A further object is to provide novel equipment for carrying the method into
effect.
SUMMARY OF THE INVENTION
This invention relates to a novel method of controlling scar formation in a
manner which preserves organ functions by the combination of biochemistry,
pharmacology and physics by (1) forceful resection or dilation of a
scarred area in a human patient to create a new wound, followed by (2)
continuous topical application of a lathyrogenic agent to the dilated
scarred area and (3) during healing of the new wound continuously
supporting the dilated scarred area in the desired configuration.
The invention further relates to a special catheter for controlling scar
formation, onto which a selected lathyrogen may be bonded prior to
insertion into generally tubular portions of the human or animal body,
followed by rehealing while supporting the tubular body portion in the
desired configuration.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a schematic front elevational view taken in section, of a
tubular organ exhibiting severe stenosis.
FIG. 2 shows a section of the tubular organ taken along the lines and
arrows II of FIG. 1.
FIG. 3 shows a section of the tubular organ taken along the lines and
arrows III of FIG. 1.
FIG. 4 is a schematic sectional view of a catheter having a lathyrogenic
agent applied thereto.
FIG. 5 is a schematic sectional view of a balloon catheter having a
lathyrogenic agent applied thereto.
FIG. 6 is a schematic view, taken in section, of a catheter inserted in a
tubular organ in accordance with aspects of the invention.
FIG. 7 is a schematic view, taken in section, of a balloon catheter
inserted in a tubular organ in accordance with aspects of the invention.
FIG. 8 shows a schematic view, taken in section, of a tubular organ after
treatment in accordance with the method of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Although a particular form of apparatus and method has been selected for
illustration in the drawings, and although specific terms will be used in
the specification for the sake of clarity in describing the apparatus and
method shown, the scope of this invention is defined in the appended
claims and is not intended to be limited either by the drawings selected
or the terms used in the specification or abstract. For example, although
fibrotic lesion on hollow organs have been illustrated in the drawings for
convenience, the method of the invention is not intended to be limited to
such hollow organs.
As shown in FIG. 1, which is a schematic of a tubular organ 10, a portion
of the tissue 12 exhibits severe stenosis. The portion exhibiting such
stenosis is designated by the numeral 14.
The stenotic portion 14 may be the result of any number of naturally
occurring or artificially induced occurrences. For example, portion 14 may
have been previously injured, such as by surgical operation, severe
injury, trauma or the like. Stenotic portion 14 resulted from the
formation of scar tissue, which grew into and toward the center portion of
tubular organ 10. The result of the formation of such scar tissue is the
severe narrowing of tubular organ 10.
Narrowing of tubular organ 10 can have severe consequences with regard to
the passage of fluids through the tube. For example, in the case where
tubular organ 10 represents the urethral canal, almost complete blockage
of flow can occur. This, of course, is highly undesirable. The same severe
consequences may result in instances where tubular organ 10 represents the
esophagus, blood vessels, intestinal passageways, fallopian tubes and the
like.
FIG. 2 of the drawings shows a portion of tubular organ 10 which is in a
normal, non-stenotic condition. Tissue 12 is of ordinary thickness. On the
other hand, FIG. 3 shows a stenotic portion 14 of tubular organ 10 wherein
tissue 12 has a far greater thickness, and reduces the interior diameter
of the tube.
Referring now to FIGS. 4 and 5, different forms of catheters are shown.
FIG. 4 illustrates a simple tubular catheter 16. Tubular catheter 16
includes a hollow tube 18 surrounded by lathyrogenic agent 20. Similarly,
FIG. 5 shows balloon catheter 22. .Balloon catheter 22 consists of a
central tube 24 and a balloon 26. Balloon 26 is coated with and is
surrounded by lathyrogenic agent 20.
FIG. 6 schematically illustrates insertion of one form of tubular catheter
16 into tubular organ 10. Tubular catheter 16, as shown, has an outer
diameter OD which is greater than the inner diameter ID of tubular organ
10. Tubular catheter 16 extends into tubular organ 10 for a distance
sufficient to engage stenotic portion 14. Tubular catheter 16 is inserted
to a point wherein lathyrogenic agent 20 directly and closely contacts
substantially all of stenotic portion 14.
FIG. 7 shows balloon catheter 22 in an inflated condition within tubular
organ 10. Balloon catheter 22 extends inwardly into tubular organ 10 to a
point wherein lathyrogenic agent 20, which surrounds balloon 26, directly
and closely contacts stenotic portion 14.
FIG. 8 shows tubular organ 10 after removal of either tubular catheter 16
or balloon catheter 22. Tissue 12 is in a normal condition and thickness
throughout the entire length of tubular organ 10. Stenotic portion 14 is
no longer present.
In accordance with a preferred form of the invention, the physician locates
a stenotic portion of the tubular organ by ordinary means well known in
the art. Once the stenotic portion has been identified and located, it is
dilated, resected, incised or removed to create a fresh, open wound. Then
a lathyrogenic agent, preferably D-penicillinamine or
Beta-aminopropionitrile (BAPN), or Beta-aminopropionitrile fumarate
(BAPN-F), or aminoacetonitrile, for example, is applied to a catheter of
the physician's choice. Depending upon the tubular organ to which the
catheter is applied, various well known catheters may be utilized. In the
case where a balloon catheter is chosen, the lathyrogenic agent (sometimes
referred to hereinafter for convenience as BAPN-F) is applied in a coating
to the balloon portion of the catheter, such as shown in FIG. 5 of the
drawings.
The catheter is then inserted into the tubular organ by ordinary means well
known in the art. The balloon catheter is inserted to a point where the
BAPN is in position to directly and closely contact stenotic portion 14
upon expansion of the balloon. The balloon is then inflated and left in
position for the prescribed treatment time.
It has been discovered that the lathyrogenic agent should be applied to
target tissue in a dose of about 4.5 mM to about 8.5 mM for BAPN-F and
about 20 mM to about 40 mM for D-penicillamine. The preferred dose is
between about 5.0 mM and about 5.5 mM for BAPN-F and about 22mM to about
25 mM for D-penicillamine.
In another preferred form of the invention, the BAPN-F is ionically bonded
to a special catheter capable of ionically bonding the BAPN-F to the cuter
surface of the catheter. This ionic bonding permits insertion of the
catheter within the tube and up to the stenotic portion, without the
danger of BAPN-F being wiped off the catheter prior to contact with the
stenotic portion. In this manner, the coated catheter is inserted after
the stenotic portion has been expanded or resected to a degree which tears
or removes the existing scar tissue. The BAPN-F then directly contacts the
tissue in the new wound to soften the healing process. The resulting
formed tissue is substantially in the shape and size of the outer diameter
of the catheter and retains its normal pliant condition, and exhibits the
characteristics of normal, uninjured tissue.
In still another preferred form of the invention, the same steps may be
applied to non-tubular tissue. For example, the method of the invention
may be applied to exterior burns such as skin burns. However, it is
important that the same steps be followed t achieve the excellent results
achievable with this aspect of the invention. Examples of various
applications of the method of the invention are illustrated as follows:
EXAMPLE 1 --BURN SCAR-ELBOW
A patient with a full thickness dermal scar around the elbow, exhibits
complete contracture and cannot fully extend the elbow. This restricts
use. The hard scar is surgically "released" under general anesthesia by
cutting in several places with or without a skin graft. The patient then
has a lathyrogen applied and is placed in an elbow dynamic splint. This
allows the elbow to be protected and at the same time to fully exercise
the joint on a daily basis with or without the supervision of a physical
therapist.
A lathyrogen jelly with 5.0 mM of BAPN-F and/or 20-25 mM D-penicillamine or
a BAPN-F ]impregnated gauze (40 mg/100 cm.sup.2 of gauze) is continuously
applied to the wound during its healing phase beginning 4-8 days after
surgical treatment and continued for four to six weeks in combination with
physical therapy. At the end of healing, the splint is removed, the
lathyrogen discontinued and the patient resumes full range of motion at
the elbow due to the lack of cross-linking of newly formed collagen in
place of old scar tissue.
EXAMPLE 2 --FALLOPIAN TUBE STENOSIS-INFERTILITY
A patient having scarred and blocked fallopian tubes as a result of
infection has incisions made in the scar tissue and a BAPN- coated
silastic tube stint placed in the fallopian tube after one week and left
in place during the healing phase. The stint is continuously maintained in
contact with the fresh wound and is changed two or three times during the
four to six week healing phase as the lathyrogenic agent leaches off the
surface of the silastic stint and is incorporated into the newly healing
scar. The newly formed scar takes the shape of the stint. The stint is
removed, the opening of the fallopian tube is preserved and egg and sperm
transport can now cross the previously blocked fallopian tube.
EXAMPLE 3 --ESOPHAGEAL STRUCTURE
A young teenager, who as a child swallowed a drain cleaning solution, has a
lye burn to the lower esophagus and has great difficulty with maintaining
proper nutrition. The result is stunted growth. The scar formed from the
burn is dilated under direct endoscopic vision with a dilator or
surgically resected to create fresh wound tissue. A Cellestin tube is
immediately attached across the new wound area and continuously maintained
in position for the duration of healing. The outer lining of the Cellestin
tube consists of silicone to which a combination of D-Penicillamine and
BAPN-F is bonded, which leaches into the healing area. When healing is
complete the tube is removed and a normal esophageal diameter remains
because the 5.0 mM solutions of the lathyrogens have been incorporated
into the new scar allowing it to form itself around the tube without
further stenosis.
EXAMPLE 4 --URETHRA-PROSTATIC CANCER
A patient with prostatic cancer detected with sonography and a candidate
for total prostatectomy has the prostate removed and the cuff of the
bladder sewn to the most proximal remaining portion of the urethra. This
circumferential suture line often progresses to heavy scarring preventing
complete emptying of the bladder. The scar is cut away under anesthesia
and direct resectoscope vision and immediately stinted with a silicone
catheter coated with 5.0 mM BAPN-F. The catheter remains in continuous
direct contact with the new wound tissue during healing. The BAPN-F
leaches from the surface of the catheter, thereby inhibiting hardening of
the healing scar during the next three weeks. The catheter is changed on a
weekly basis to renew the BAPN-F supply. Once healing is complete and the
newly formed scar is laid down around the stint of the indwelling bladder
urethra catheter, no new scarring takes place.
EXAMPLE 5 --BURN SCAR-HAND
A patient with a well healed full thickness burn of the hand has severe
scarring of the fingers and hand in a claw-like form. The old scars are
surgically released to create full mobility of the joints. The hand is
placed in a "dynamic splint." The splint contains rubber band fixation to
a rigid frame allowing the patient to exercise his fingers through a full
range of motion. During the healing phase and on a daily basis, a jelly
containing 5 mM/L of the lathyrogenic agent BAPN-F is continuously applied
to the surgically "released" areas. The patient continues to exercise and
use the dynamic splint during the healing phase over the next four to six
weeks. Once re-epithelialization and healing is complete, the newly formed
scar, being softened by the continuous application of BAPN-F, has full
range of motion without further restriction of hand motion. The dynamic
splint is removed. Healing is complete and range of motion restored.
EXAMPLE 6 --BURN SCAR-NECK
A patient with severe third degree burn of the neck has completed healing,
but the resulting scar is so severe that the head cannot be straightened.
The sca is surgically released (incised) with or without a skin graft,
thereby creating a new wound. A stiff plastic collar having a soft lining
is applied to the neck to hold it in a new desired position. A combination
of 5.0 mM BAPN-F and 20-25 D-Penicillinamine jelly or a BAPN-F impregnated
gauze (40 mg/100 cm.sup.2 of gauze) is continuously applied to the newly
created wound tissue so that as new scar is formed, it will be soft,
plastic-like, and uncross-linked until healing is complete in four to six
weeks. A the end of that time no new medication need be applied, the
collar is removed and the patient has been restored to full range of
motion of the neck.
EXAMPLE 7 --URETHRA-INFECTION
A patient with urethral stenosis (narrowing of the tube between the bladder
and the end of the penis) secondary to a gonococcal infection exhibits
bladder outlet obstruction. The old scar in the urethra is opened under
direct surgical resection. Immediately afterward a silicone urethral
bladder catheter is inserted. After one week, this catheter is exchanged
for one with the lathyrogenic agent BAPN-F bonded onto its surface. The
coated catheter is continuously maintained in place and changed ever week
for about six weeks during the healing phase. During the healing phase new
scar tissue is laid down. However, its strength is beneficially altered by
the lathyrogen BAPN-F which inhibits the bonding of one protein scar fiber
to the next protein scar fiber allowing the wound to be molded in the
shape of the intraluminal stint (urinary bladder catheter). At the end of
the healing phase, the stint is removed and normal unobstructed urination
can proceed.
EXAMPLE 8 --URETHRA-TRAUMA
Following fractured hips, 5-10% of human males suffer transection of the
membranous urethra as it leaves the bladder. This transection requires
primary anastamosis with catheter stinting, often resulting in severe scar
formation and secondary bladder outlet obstruction. Balloon dilation
(pressure balloon) to create new wound tissue may be performed or direct
surgical resection removes the narrowed scar tissue. After one week, the
original bladder catheter is exchanged for a silicone catheter coated with
either BAPN-F or another lathyrogenic agent such as D-Penicillamine, which
inhibits cross-linking (strong bonding) between scar collagen fibers. The
coated catheter is continuously maintained in place and changed once a
week for about six weeks during the healing phase. After catheter removal
a normal sized opening is present, with the new scar being molded to the
shape of the intraluminal stint (bladder urethral catheter.)
EXAMPLE 9 --URETHRA-PROSTATE RESECTION
Following partial prostatic resection for bladder neck obstruction in human
males, approximately 10% of patients develop tubal narrowing at the origin
of the urethra. The scar is resected to reopen the under direct surgical
endoscopic vision. After one week, the lumen is protected with a catheter
stint of silicone coated with a combination of D-Penicillamine and BAPN-F
to inhibit cross-linking or hardening of the newly formed scar tissue. The
catheter is continuously maintained in place and changed once a week for
six weeks as healing is completed and new soft scar is layered around in
the shape of the intraluminal stint. Once the stint is removed, the
opening between the bladder and the beginning of the urethra is protected
by the shape of the mature collagen scar which now progresses to slow
cross-linking or hardening without narrowing the lumen.
EXAMPLE 10 --TRACHEA
The patient suffering tracheal injury either due to a tracheostomy on an
emergency basis or secondary to an automobile accident has primary
anastomosis of the trachea resulting in a severe scar and impairment of
the airway. The scar is excised and an endotracheal silastic stint coated
with 5.0 mM BAPN-F or D-Penicillamine is put in place after one week and
continuously maintained and changed on a weekly basis for five or six
weeks during the healing phase. The lathyrogen is incorporated in the
newly formed and healing wound where it allows the newly formed scar to be
soft, plastic-like and conform to the diameter of the endotracheal stint.
Once healing is complete no further scarring takes place, the medication
and stint is discontinued and the patient returns to normal airway
dynamics.
EXAMPLE 11 --COMMON BILE DUCT STENOSIS
A patient who has had an injury of the common bile duct secondary to a
complicated gallbladder operation is jaundiced. The scar is partially
resected and after one week an original silastic stint is exchanged for an
intraluminal silastic tube coated with BAPN-F with one arm of the tube
protruding into the duodenum. The BAPN-F leaches off the silastic tube and
is incorporated into the newly formed scar, which is soft because BAPN-F
blocks cross-linking. The tube is continuously maintained in place and on
a weekly basis the patient returns to the gastroenterology lab where,
under direct manipulation, the tube is exchanged every week for six weeks.
Once healing is complete the tube is removed and the new lumen of the
common bile duct is preserved. The patient is no longer jaundiced and
fluids from the liver can pass into the duodenum uninhibited.
In many of the foregoing examples it is beneficial to use a special
catheter containing directly bonded BAPN-F. This provides the advantage
that the BAPN-F will be delivered directly to the desired tissue without
the danger of being partially or completely wiped off the catheter during
insertion into the tubular organ.
Linking a drug such as BAPN-F to a polymer forming a catheter or wound
dressing may be achieved by several methods including:
a. direct binding of the drug to available functional binding groups in the
polymeric surface of the catheter;
b. linking the drug to newly created functional binding sites after
chemical or physical modification of the polymeric surface;
c. direct incorporation of the drug into the polymeric surface either
during the catheter manufacturing process or into the final catheter
product by programmed, controlled soaking in the appropriate solution of
the drug;
d. deposition of a drug in another polymeric substance (hydrogel, gelatin,
collagen and the like) which is then chemically attached to the polymeric
surface of the device. By this method large quantities of the drug can be
associated with the effective surface of the device. The drug can be
linked chemically to this coating material as well as physically sorbed if
added in quantities exceeding the binding capacity of the coating polymer
(hydrogel). An additional advantage of this process is that the coating
polymer may add new properties to the device polymer, such as
slipperiness, biocompatibility to tissue cells, reduction of mineral
crystal formation when in contact with some biological fluids (urine).
Examples of manufacturing procedures for the above outlined processes are
shown below:
A latex polymer may be partially hydrolyzed-depolymerized, for instance, in
a strong oxidizing environment to provide free carboxyl, hydroxyl or amino
groups when the polymer does not contain available functional groups. The
groups then serve as sites for chemical binding of BAPN. In the case of
BAPN binding, the availability of COO- groups is optional.
In practice, the latex polymer may be dipped into an aqueous solution of 2%
sodium hypochlorite, wherein the solution contains 0.5% sulfuric acid.
After 5-10 minutes of incubation at 25.degree. C., the solution is
decanted and the latex polymer incubated for another 5-10 minutes in 5%
ammonium hydroxide solution. Removed polymer is then excessively washed in
iced water. Activation of the COO- groups of the latex is achieved at 25oC
in the presence of carbodiimide (10 mg/ml) at pH 4.75 of 0.1 M MES buffer.
The incubation lasts 30 minutes, followed by quick ice water washing and
then exposing the activated polymer to the solution of BAPN for 12 hours
in 0.1 M MES at pH 4.75.
After completion of the reaction, the final product is not washed from the
excess of the drug, which under these conditions contains both chemically
and physically linked BAPN to the device polymer. In this medium, the
carboxyl groups are activated and these react with the .beta.-amino group
of the BAPN-F to form a rather strong linkage. Carbodiimide having the
chemical formula (1- ethyl-3 (3-dimethylamine-propyl) carbodiimide-HCl
(EDC) has been recognized as a potent coupling agent activating the
available carboxyl groups in hydrogel, collagen or gelatin.
When the device is made of inert or substantially inert silicones, known
for their low polarity group content, the surface of the device may be
modified to render more binding sites. The methods of modifying the
silicone may be either chemical or physical. The example of using strong
oxidizing agents was described above. Another method of forming reactive
side groups in the silicone (activating the surface) is exposing a
silicone surface to high energy ionizing radiation such as high energy
electrons, X-ray or gamma radiation first and then interacting such a
surface with BAPN-F under similar conditions as shown above. The radiation
exposure total dose corresponds to 0.20 to 0.45 Merads. The principles of
this method are the object of U.S. Pat. Nos. 3,453,194 or 3,826,678.
There is another method of bringing larger amounts of BAPN-F onto the
surface of a polymer, such as latex or silicone. Either polymer is
partially hydrolyzed as described above. To the activated surface of a
polymer (a hydrogel, collagen or gelatin soluble in ethanol) is interacted
to form a uniform coating. A reasonable amount of BAPN-F can be
incorporated in such a coating of hydrogel, collagen or gelatin. The
release of BAPN-F will then depend o the rate of diffusion of this
molecule from the hydrogel, collagen or gelatin. This then will be
controlled by the swellability of the hydrogel, collagen or gelatin. There
are various types of hydrogels, based on polyacrylonitrile or
polyurethanes, where hydration can vary from a few weight percent of water
to almost 90% of water.
A purified collagen similar to hydrogels can be used to link with the
functional groups of the polymer device, using known, described various
procedures known in the art.
Selection of the appropriate hydrogel, collagen or gelatin will allow the
desired release of BAPN-F. For instance, hydrogel based on polyurethane is
available with free carboxyl groups (for example, see U.S. Pat. No.
4,255,550), lactone or hydroxyl groups (for example, see U.S. Pat. Nos.
4,156,066 and 4,156,067). In general, hydrophilic polymers or hydrogels
are useful carriers for pharmaceutical agents (U.S. Pat. Nos. 3,975,350 or
4,439,585). Another factor controlling the rate of drug release from the
hydrogel, collagen or gelatin coat (besides diffusibility) is the option
of chemical binding of the drug to the functional (mainly carboxyl) groups
of the hydrogel, collagen or gelatin.
It is known that lysyl oxidase, an enzyme essential for cross-linking of
collagen (which results in strictures and contractures), is effectively,
and irreversibly inhibited at 10.sup.16 M BAPN tissue concentration. Given
that a) this concentration of BAPN, released every hour to reach a steady
state in the tissue, is the safe and effective inhibitory dose and b) the
treatment will last 10 days, the dose of BAPN deposited within the device
to obtain zero order sustained release should exceed 24 mg of BAPN/device.
In order to obtain zero order (linear) release of a drug from a matrix, it
is important to combine at least two different mechanisms of a drug
sorption (binding) in a polymer or matrix. These mechanisms include a)
chemical binding of moderate strength providing slower release of a drug
after its dissociation from the chemical bond and b) physical sorption,
which is a very weak bond and allows immediate release of the drug once
the device is exposed to tissue fluid and moisture. The kinetics of the
release for each mechanism differ for various polymers and drugs.
One important factor favoring using hydrogels, collagens or gelatins as
carrier for BAPN-F and other lathyrogenic substances is the similarity of
hydrogel characteristics with tissue composition (same content of water,
absence of toxic elements, similarity to collagen molecule chain in
physical and physico-chemical aspects). Thus, hydrogel-drug implants or
coatings of other polymer devices provides for better tissue tolerance.
Although several classes of hydrophilic polymers swellable in tissue fluids
are available, the selection of the most appropriate hydrogel, collagen or
gelatin is directed by criteria of safety, reflecting nontoxicity,
noncarcinogenicity, mutagenicity, teratogenicity, etc. Furthermore,
chemical reactions which lead to establishing a polymer (hydrogel)-drug
complex, or which require additional cross-linking agents or activators,
or which may cause difficulty in washing out the final product without
compromising the stability of the linked drug, must be considered in the
selection of an adequate coating polymer to be used as the reservoir for
BAPN-F or other lathyrogen.
Other drug delivery systems for time release of lathyrogenic medications
have been developed. Such delivery systems use biodegradable vehicles
which are biologically safe, induce minimal local tissue reaction without
any side toxic effects, are easy to handle, and are economically feasible.
For several years, gelatin-resorcinol-glutaraldehyde (G-R-Gl) tissue
adhesive showed to be one of the least toxic tissue adhesives used in
various surgical applications. The glue quickly polymerizes and
efficiently adheres the tissue surfaces together when in contact with
tissue and when reacted with formaldehyde or glutaraldehyde. The adhesive
capacity depends on the content of R- which usually is 30% of total solids
and on the concentration of the tanning agent used in the concentrated
form. G-R-Gl as tissue adhesive has been applied to tissues in only
minimal amounts, because the strength of the bonds is indirectly
proportional to the thickness of the polymer in between the tissue
surfaces.
Use of earlier tissue adhesive G-R-Gl polymers a vehicles for delivering
lathyrogenic agents in the method of this invention is disadvantageous
because the polymer consists of gelatin and resorcinol in weight ratio
3:1, G forms 33% and R forms 10% of the nonpolymerized solution. In other
words, the original tissue adhesive mixture is a 60% aqueous solution
consisting of 45 weight volumes of gelatin, 15 weight volumes of
resorcinol and 40 volumes of water. After polymerization with 37%
formaldehyde or 25% glutaraldehyde, a firm polymer is formed which
undergoes, in biological environment, minimal swelling and slow
resorption. High content of gelatin, resorcinol and tanning agent are
essential to obtain solid tissue adhesion of high tensile strength. Thus,
the lathyrogenic agent added to this earlier system would be released at
an extremely slow rate.
We have found that by decreasing the content of the individual components
and by varying the content of G, R and the concentration of tanning agent,
mainly of Gl, it is possible to control the consistency and hydrophility
of the final form of gel-polymer to release the lathyrogenic agent at a
beneficial rate.
We have also found that if the lathyrogenic agent is added to the G-R-water
mixture in appropriate concentration, then after quick mixing with
selected concentrations of Gl in a syringe, the still fluid gel may be
applied to the subject to form a polymer.
We have also found that in case faster drug release is desirable, R need
not be present or added to the collagen solution during crosslinking by
any tanning agent.
We found that a mixture consisting of 15 to 30 parts of G, 0.1-2 parts of
R, 20 to 30 parts of water component and using 5 to 30 fold dilution of
the Gl as polymerizing agent are optimal for long-term release of BAPN or
other lathyrogenic agents over the period of several weeks or months.
A polymer consisting of only 1 to 5 parts of gelatin, 20 parts of water, of
appropriate concentration of the lathyrogenic agent and polymerization
induced by 0.05 ml of 0.5 to 3% glutaraldehyde per 1 milliliter of the
mixture is optimal for short time relea | | |
