U.S. patent application number 11/931869 was filed with the patent office on 2008-05-08 for apparatus for the controllable modification of compound concentration in a tube.
Invention is credited to Eldon H. Jr. Nyhart.
Application Number | 20080108935 11/931869 |
Document ID | / |
Family ID | 27388561 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108935 |
Kind Code |
A1 |
Nyhart; Eldon H. Jr. |
May 8, 2008 |
Apparatus For The Controllable Modification Of Compound
Concentration In A Tube
Abstract
A catheter for selective administration of a compound.
Inventors: |
Nyhart; Eldon H. Jr.;
(Zionsville, IN) |
Correspondence
Address: |
BAKER & DANIELS LLP
300 NORTH MERIDIAN STREET
SUITE 2700
INDIANAPOLIS
IN
46204
US
|
Family ID: |
27388561 |
Appl. No.: |
11/931869 |
Filed: |
October 31, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10045550 |
Oct 26, 2001 |
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11931869 |
Oct 31, 2007 |
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09692857 |
Oct 20, 2000 |
6738661 |
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10045550 |
Oct 26, 2001 |
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60161130 |
Oct 22, 1999 |
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60170051 |
Dec 10, 1999 |
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Current U.S.
Class: |
604/20 |
Current CPC
Class: |
A61B 18/20 20130101;
A61M 5/1407 20130101; A61M 2025/0057 20130101; A61M 39/08 20130101;
A61M 25/0043 20130101 |
Class at
Publication: |
604/020 |
International
Class: |
A61B 18/18 20060101
A61B018/18; A61N 1/30 20060101 A61N001/30 |
Claims
1. A catheter, comprising: a flexible outer sheath having an
interior surface and an exterior surface; a polymer matrix attached
to the interior surface of said sheath; a compound releasably
captured by the molecules of said polymer matrix; an energy source
for releasing said compound from said polymer matrix in response to
a signal from a sensor received by a controller that is operably
coupled to the energy source.
2. The catheter of claim 1, wherein said compound is releasably
captured by covalent bonding molecules of said compound to
molecules of said polymer matrix.
3. The catheter of claim 1, wherein said polymer matrix is a
hydrogel.
4. The catheter of claim 1, wherein the compound is a therapeutic
agent.
5. The catheter of claim 1, wherein said energy source is a laser
and said outer sheath transmits energy from said laser into said
polymer matrix.
6. The catheter of claim 5, wherein said energy source is a laser
irradiating the polymer matrix with laser pulses of varying time
duration.
7. The catheter of claim 5, wherein said energy source is a laser
irradiating the polymer matrix with laser pulses of varying
radiation intensity.
8. The catheter of claim 5, which further comprises a fiber optic
cable for optically coupling said laser to said sheath.
9. The catheter of claim 1, wherein said compound is a first
compound, and which further comprises a second compound intermixed
in said polymer matrix with said first compound, said second
compound being releasably captured by the molecules of said polymer
matrix.
11. The catheter of claim 1, wherein said controller includes a
cardiac monitor and said sensor responds to cardiac activity.
12. The catheter of claim 1, wherein said controller operates said
source of energy to provide energy to said polymer matrix in a
fractally-based pattern.
13. The catheter of claim 1, wherein said outer sheath includes a
first interior section and a second interior section, and which
further comprises a baffle separating said first section from said
second section, said first section and said second section each
including a portion of polymer matrix, and which further comprises
a first therapeutic agent releasably captured in said polymer
matrix of said first section and a second therapeutic agent
releasably captured in said polymer matrix of said second
section.
14. The catheter of claim 1 wherein said outer sheath includes an
opaque coating on the exterior surface for limiting the escape of
radiation from said outer sheath.
15. The catheter of claim 1 wherein said outer sheath includes a
reflective coating on the exterior surface for reflecting radiation
into said polymer matrix.
16. A catheter, comprising: a flexible outer sheath having an
interior surface and an exterior surface; a matrix material
attached to the interior surface of said sheath; a compound
releasably captured by the molecules of said matrix material; an
energy source for releasing said compound from said polymer matrix
in response to a signal from a sensor received by a controller that
is operably coupled to the energy source.
17. The catheter of claim 16, wherein the compound is a therapeutic
agent.
18. The catheter of claim 16, wherein said compound is releasably
captured by covalent bonding molecules of said compound to
molecules of said polymer matrix.
19. The catheter of claim 16, wherein the energy source is
configured to apply energy to said polymer matrix in a
fractally-based pattern.
20. The catheter of claim 16, wherein said energy source is
configured to release the compound from said polymer matrix in
response to a signal from a cardiac activity sensor received by a
cardiac monitor.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/045,550, filed Oct. 26, 2001 which is a
divisional of U.S. patent application Ser. No. 09/692,857, filed
Oct. 20, 2000. This application also claims priority to U.S.
Provisional Patent Application Ser. No. 60/161,130, filed Oct. 22,
1999, and to U.S. Provisional Patent Application No. 60/170,051,
filed Dec. 9, 1999. All of these applications are incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates generally to the field of a tube with
an internal layer comprising a polymer matrix and a captured
compound, and more particularly to an apparatus for releasing a
compound into an intravenous environment such as during intravenous
drug administration.
BACKGROUND OF THE INVENTION
[0003] Invasive drug administration can be a difficult procedure to
alter, once it is initiated. The dynamic nature of drug
administration can be difficult to anticipate. Feedback mechanisms
can be used to monitor drug administration and exert control
mechanisms on the system.
[0004] As drugs are becoming more sophisticated and endogenous
compounds continue to be discovered and synthesized, mechanisms to
deliver drugs in a more exact and versatile fashion will allow for
fuller drug utility to be realized.
[0005] Drugs have been released at the tip of solid catheters by
applying laser energy as an aid in tumor or local drug therapy.
Compounds have been encapsulated with the anticipation of releasing
them in a controlled way for many years in the form of timed
release capsules, matrix embedded tablets, or controlled release
granules. A catheter product exists whereby an interior coating of
antibiotic provides prophylactic protection against infection by
providing zero order release of drug from the interior surface.
[0006] Standard drug infusion consists of employing infusate of
constant concentration with respect to an active compound. The
volumetric flow rate determines the rate at which a drug or
compound is delivered to the systemic circulation or organ system.
Altering the rate of drug delivery necessitates altering the
volumetric flow rate of the infusate apparatus. Various catheter
designs and drug delivery systems are described in U.S. Pat. Nos.
5,304,121; 5,482,719; 6,086,558; 5,991,650; 5,795,581; 5,470,307,
5,830,539; 5,588,962; 5,947,977; 5,938,595; 5,788,678; 5,868,620;
5,843,789; 5,797,887; 5,773,308; 5,749,915; 5,767,288; and
5,665,077.
[0007] The present invention overcomes the shortcomings of previous
designs and systems in a novel and unobvious way.
SUMMARY OF THE INVENTION
[0008] One aspect of the present invention relates to a method for
providing a compound into a first flowing material. The method
includes providing a section of tubing having an interior with a
layer of a second matrix material bonded to the interior,
releasably capturing a first compound in the second matrix
material, and flowing the first material through the interior and
over the second matrix material. Energy is applied to the second
matrix material, and the first compound is released from the second
matrix material into the first flowing material.
[0009] In another aspect, the present invention includes a flexible
outer sheath with an interior surface and an exterior surface. A
polymer matrix is attached to the interior surface of the sheath,
the polymer matrix defining a lumen therethrough for flow of the
liquid. A therapeutic agent is releasably captured by molecules of
the polymer matrix.
[0010] Another aspect of the present invention includes a method
for manufacturing a catheter. The method includes providing a
sheath with an interior surface, and applying a layer of matrix
material onto the interior surface. The matrix material is in a
swelled condition. A rod is inserted into the interior of the
flexible sheath. The flexible sheath is formed into a predetermined
shape, and volume of the polymer matrix is shrunk. The rod is
removed.
[0011] Another aspect of the present invention concerns a method
for manufacturing an internally coated tube. The method includes
providing a rod and a sheath with an interior surface and an
exterior surface. The method further comprises applying a layer of
a polymer matrix onto the surface of the rod, and placing the rod
within the interior of the sheath. The method includes forming the
sheath into a predetermined shape around the rod and removing the
rod from the formed sheath.
[0012] Another aspect of the present invention concerns a method
for providing a therapeutic agent to a biological unit. The method
includes providing a compound releasably captured within a matrix
material, the compound being releasable upon receiving an energy
input. The method includes placing the matrix material and captured
compound in fluid communication with a fluid which flows in a
biological space of the biological unit. Energy is provided to the
matrix material sufficient to release a portion of the compound,
and the compound is released into the biological unit in an
irregular pattern.
[0013] These and other aspects of the present invention will be
apparent from the description of the preferred embodiment, the
claims, and the drawings to follow.
DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a schematic representation of a prior art system
for delivering a drug by a catheter into a patient.
[0015] FIG. 2 is a schematic representation of one embodiment of
the present invention for providing a therapeutic agent into a
biological unit by a catheter.
[0016] FIG. 3 is a cross-sectional view of the catheter of FIG. 2
as taken along section 3-3 of FIG. 2.
[0017] FIG. 4 is a cross-sectional view of FIG. 3 including the
designation of diameters for calculation of the amount of
therapeutic agent within the polymer matrix.
[0018] FIG. 5A is a section of a catheter according to another
embodiment of the present invention.
[0019] FIG. 5B is a section of a catheter according to another
embodiment of the present invention.
[0020] FIG. 6 is a schematic representation of a closed-loop system
for providing a therapeutic agent to a biological unit.
[0021] FIG. 7 is a schematic representation according to another
embodiment of the present invention for providing a therapeutic
agent to a biological unit in a fractally-based pattern.
[0022] FIG. 8 is a perspective view according to another embodiment
of the present invention for manufacturing a catheter assembly.
[0023] FIG. 9 is a perspective view of the assembly of FIG. 8 with
the sheath closed around the rod.
[0024] FIG. 10 is a schematic representation according to another
embodiment of the present invention for withdrawal of fluid from a
biological unit and return of the fluid to the unit.
[0025] FIG. 11 is a schematic representation according to another
embodiment of the present invention for withdrawal of fluid from a
biological unit.
[0026] FIG. 12 is a schematic representation according to another
embodiment of the present invention.
[0027] FIG. 13A is a graphical representation of the log of a
spectral density verses the log of frequency.
[0028] FIG. 13B is a graphical representation of the quantity of
magnitude sampled at six regular intervals.
[0029] FIG. 13C is a graphical representation of the quantity of
duration sampled at six regular intervals.
[0030] FIG. 13D is a graphical representation of the quantity of
interval sampled at six regular intervals.
[0031] FIG. 13E is a graphical representation of a time history of
fractally derived pulses synthesized from the quantities
represented in FIGS. 13B, 13C, and 13D.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0032] For the purposes of promoting an understanding of the
principles of the invention, reference will now be made to the
embodiments illustrated in the drawings and specific language will
be used to describe the same. It will nevertheless be understood
that no limitation of the scope of the invention is thereby
intended, such alterations and further modifications in the
illustrated devices, and such further applications of the
principles of the invention as illustrated therein being
contemplated as would normally occur to one skilled in the art to
which the invention relates.
[0033] All documents, including patents, books and other
publications, named herein are incorporated herein to their
complete extent by reference.
[0034] Turning first to FIG. 1 there is shown a typical infusion
apparatus 1000 commonly in use in most modern hospital settings.
This apparatus administers infusate 1005 systemically to a patient
1007. Infusate fluid 1005 is contained in a plastic bag 1010, and
the fluid is allowed to pass at some predetermined volumetric flow
rate through plastic tubing and catheter setup 1015 and into an
appropriate biological space, usually vascular. This space could be
other body spaces or cavities capable of accepting positive
volumetric flow, such as the peritoneum or cerebral spinal fluid
space. This defines an "open" space or cavity as opposed to a
closed or site specific location. Examples of other open spaces
include the systemic circulation, the cerebral spinal fluid space,
the lymphatic space, synovial fluid spaces and urinary fluid
spaces.
[0035] Administration of a compound or drug 1020 is accomplished in
several ways. For example, the drug 1020 may be manually injected
by an attendant through a hand syringe 1025 that is in fluid
communication with catheter 1015. As another example, a pump 1030
containing a quantity of drug 1020 pumps a controlled quantity of
the drug into an apparatus that is in fluid communication with
catheter 1015. Maximum maintenance of the sterile environment of
the system is realized
[0036] The amount of drug administered is directly related to the
infusate flow rate and the concentration of compound (drug) in
solution with the infusate. Changing the rate of infusion of drug
necessitates changing the volumetric flow rate of infusate through
the catheter in direct proportion to the desired change in drug
administration. Once the infusion setup is operating, generally
under sterile conditions, changing the compound or drug for an
alternate compound or drug requires a new infusion setup to be put
into operation, with a new reservoir of infusate with drug in
solution.
[0037] The present invention relates to a system including a
catheter assembly and a source of energy for releasing a compound
into a biological space, such as the vascular system, peritoneum,
cerebral spinal fluid space, or other biological spaces which can
accept a volumetric flow rate of infusate. According to one
embodiment of the present invention, a therapeutic agent such as a
drug is linked by photolabile bonds to a polymer matrix surrounding
a lumen of a catheter. Infusate fluid such as normal saline, 5%
dextrose and water, lactated Ringer's solution, crystalloid
solution, plasma or blood flows through the lumen of the catheter
from a source of the infusate into the biological space. When it is
desired to release the compound into the biological space, the
polymer matrix surrounding the lumen and including the
photolabily-linked compound is exposed to the energy such as light
radiation. The radiation breaks the photolabile bonds, and the
compound is released from the material such that it can diffuse
into the infusate.
[0038] Changing the concentration of infusate without appreciably
changing the volumetric or mass flow rate is contemplated by this
invention. Some infusate apparatus only allow volume dependent
alteration of dosing rate, which may be prohibitive to the
recipient. It may be difficult to readily add or change
pharmacotherapy due to insufficient vein integrity. The immediacy
of emergency settings may dictate drug to be administered as
readily as possible, or discontinued in as immediate a fashion as
possible.
[0039] The present invention can provide an effective and efficient
mechanism to exert an infusate concentration change for a compound
delivery system with little or no volumetric changes. The clinical
setting is an immediate example where compounds can be introduced
by varying the concentration profile of a drug to alter the dose or
mass of drug administered. This is a departure from the traditional
manner of increasing the volume flow rate of intravenously
administered drugs. The ease and rapidity of introducing new
compounds to a given drug therapy provided by the present invention
may be unmatched for some settings. In-line prodrug-drug
interactions are possible. Developing drugs with previously
prohibitive delivery characteristics, such as extremely short
half-lives, may be delivered with this device.
[0040] In a preferred embodiment, the material forming the lumen of
the catheter is a polymer such as a hydrogel, and the one or more
compounds to be released are photolabily-linked to the molecules of
the hydrogel. The compound(s) to be released are preferably
therapeutic agents which are released systemically into the
biological space. The photolabile linkages between the compound and
the hydrogel are preferably broken by resonating the photolabile
bond with the proper wavelength of radiation. In a preferred
embodiment, the source of radiation is a laser tuned to a band of
wavelengths that will resonate with the photolabile links. However,
the present invention also incorporates those embodiments in which
the source of radiation includes lasers operating over wide ranges
of wavelengths and also incoherent light.
[0041] Another embodiment of the present invention includes a
catheter assembly including a material defining a lumen, a
photolabily-linked compound within that material, a source of
infusate flowing through the lumen, and a source of energy. The
embodiment further includes a sensor for sensing a condition of a
biological subject and a controller for receiving the signal. As
one example, a source of radiation, such as a laser, is activated
to irradiate the material, break the photolabile bonds, and release
the compound into the biological subject upon the sensing of a
particular condition. As another example, the sensor generates a
signal corresponding to the activity of the heart. The controller
receives this signal and upon determination that the heart is
malfunctioning controls the laser to release a drug such as a
cardiac agent into the infusate, which then flows into the
biological space of the subject so as to address the heart
malfunction.
[0042] A wide range of therapeutic agents can be incorporated in
complexes for controlled release into the systemic circulation or
other body cavity of a biological subject. It is preferable that
the chemical structure of the therapeutic compound contain a
nucleophile group such as carboxylic acid, amino or hydroxyl, which
attaches to the light sensitive linkage of the polymer matrix
material defining the catheter lumen. Examples of such therapeutic
compounds include acetylsalicylic acid (aspirin), indomethacin,
nicotinic acid, naproxen, ibuprofen, cimetidine, ranitidine,
cycloserine, flucytosine, amantadine, benzocaine, penicillin V,
acetaminophen, and cortisone. Classes of drugs amenable to this
type of delivery include, but are not limited to antibiotics,
anesthetics, analgesics, cardiac agents, psychotropics, and
hormones.
[0043] Although what has been described is a catheter flowing
infusate, the present invention also contemplates the application
of a compound releasably captured in a matrix material applied to
the inside of tubing, where a flowing material flows through the
tubing and over the matrix material. The flowing material may be a
fluid, such as a liquid or a gas and can also be a flow of solid
particulate matter such as an aerosol or solid microparticles.
Further, the matrix material for releasably capturing a compound is
preferably a polymer material, but can also be other types of
matrix material. The compound releasably captured in the matrix can
be a therapeutic agent, but can also be any compound capable of
being releasably captured in the matrix.
[0044] As used herein, the term "catheter" includes those meanings
and definitions and understandings used by one of ordinary skill in
the art, but also includes tubing for withdrawal of bodily fluid
from a biological unit. Further, the term "therapeutic compound" as
used herein refers to drugs and compounds administered to
biological units, and also refers to drugs and compounds used to
condition fluids withdrawn from a biological unit. The use of a
prime (') designation with a number indicates that the element
shown or described is the same as the non-prime element, except as
shown or described differently.
[0045] Turning to FIGS. 2 and 3, a catheter is constructed to
release a therapeutic compound 65 into the infusate 24 flowing in
the catheter 20 during the infusion process. In one embodiment, the
catheter size is similar to conventional vascular catheters used in
hospitals of today. As used herein, the term catheter includes any
generally tubular medical device for insertion into canals,
vessels, passageways, or body cavities for the reception or
withdrawal of fluids through the catheter lumen. A catheter,
according to the present invention provides additional therapeutic
properties to the infusate 24 as it travels through the catheter
lumen space 60. Conventional catheter designs that may be adapted
for delivery of a therapeutic agent according to the inventions
described herein include, but are not limited to, percutaneous
transluminal angiography (PTA) catheters, percutaneous transluminal
coronary angioplasty (PTCA) catheters, vascular and peripheral
vascular catheters, thrombectomy catheters, renal catheters,
esophageal catheters, perfusion catheters, upper and lower
gastrointestinal catheters, bile duct and pancreatic duct
catheters, urogenital catheters, and similar catheters both with
and without dilation capabilities. Devices used for long-term
vascular access may be adapted for use with the present invention.
These catheters include, but are not limited to totally implantable
intravascular devices (TIDs), tunneled central venous catheters
including Hickman, Broviac, Groshong, and Quinton, which are
commonly used to provide vascular access to patients requiring
prolonged IV therapy (e.g., chemotherapy, home infusion therapy,
hemodialysis).
[0046] FIG. 2 schematically depicts a system 15 according to one
embodiment of the present invention. System 15 includes a catheter
assembly 20 which provides a flow of infusate 24 from an infusion
apparatus 25, such as a gravity drip bag, into the open biological
space of a biological unit 30, such as into the vasculature of a
patient. An energy source 35 is coupled by an appropriate conduit
40 into catheter 20. Energy source 35 provides energy through
conduit 40 to a polymer material within catheter 20. In one
embodiment of the present invention, energy source 35 includes a
laser, laser controller, and controller interface. The laser
provides coherent light energy to a conduit 40 such as a fiber
optic cable to transmit the laser energy into the catheter 20.
[0047] FIG. 3 shows a cross-section of catheter assembly 20.
Catheter 20 includes a sheath 50 forming the basic structure of
assembly 20 and capable of transmitting energy from source 35.
Located within the interior of sheath 50 is a polymer matrix 55
which forms a lumen 60 therein. Infusate 24 from infusion apparatus
25 flows through lumen 60 into the biological space. Polymer matrix
includes within it one or more therapeutic agents 65 that are held
within the polymer matrix 55 until released by energy from source
35. According to one embodiment of the present invention, the
linkage of the therapeutic agent 65 to the polymer matrix 55 is
accomplished by a covalent photolabile bond. The transmission of
laser energy through sheath 50 provides energy that breaks the
photolabile bond to release the therapeutic agent. The therapeutic
agent then defuses according to Fick's Law through the polymer
matrix and into the infusate flowing within lumen 60. In this
manner the therapeutic agent can be stored within polymer matrix 55
until it is desired to release therapeutic agent 65 into the
biological unit. For those embodiments of the present invention
utilizing a source of energy such as a laser, sheath 50 includes
one or both of a reflective coating 70 and/or an opaque coating
75.
[0048] Although what has been shown and described is a catheter 20
extending from a source 25 of infusate into the vasculature system
of a biological unit, the present invention also contemplates the
use of a catheter 20 which is linked as an input to a separate
catheter, such as catheter 1015. The separate catheter may be made
of any size and shape which facilitates entry of the separate
catheter into the biological unit. The separate catheter and
catheter 20 are joined in a union outside of the body of the
biological unit. This alternate embodiment permits catheter 20 to
have an outer diameter and/or use materials not compatible with
entry into a biological unit.
[0049] A catheter assembly 20 according to one embodiment of the
present invention has both drug storage and drug releasing
properties, and the ability to transmit appropriate energy from a
source of energy 35 into polymer matrix 55. A photo-activateable
therapeutic agent delivery material is used, in which a therapeutic
agent 65 is combined by covalent bonding, incorporation in a
matrix, or encapsulation, with a photosensitive macromolecule. In
this combination, the drug is inert. The macromolecule is large
enough to prevent migration of the combination within the catheter
body, so that the combination can be in place during infusion or
withdrawal of bodily fluids through the luminal space. A drug or
other compound is released from the combination, in an active form,
upon appropriate stimulation by the source of energy 35.
[0050] The drug may be combined with the polymer matrix using any
of several mechanisms including photolabile chemical bonding,
physical dispersion, or encapsulated or embedded in layers of
photodegradable polymers. In preparing the covalent chemical
complex of this aspect of the present invention, it is preferred to
link the photolabile compound to the polymer 55 first, and to link
the drug 65 to the photolabile groups thereon subsequently.
Coupling of the polymer 55 to the photolabile linking compounds
suitably takes place in solution, as does the subsequent coupling
of the photolabile linking compounds to the therapeutic agent.
[0051] A wide choice of polymers 55 are available for this purpose.
It is desirable that the polymer be biochemically acceptable and
inert. It is further desirable that the polymer should possess
chemical groups capable of reaction with a functional group of the
photolabile compound such as the carboxylic acid group of BNBA or
CPA, e.g. hydroxyl groups. It should also be capable of releasing
the active drug freely, once the covalent chemical bonding has been
broken. For example, the drug 65 should be able to diffuse out of
the residual polymer matrix in the presence of infusate fluid.
Examples of suitable polymers 55 include, but are not limited to
polyvinyl alcohol (PVA), polyethylene oxide (polyethylene glycol
PEG), acrylamide copolymers, vinylpyrrolidone copolymers, hydroxyl
functionalized polylactides, poly (hydroxyethyl methacrylate)
(HEMA), copolymers of two or more such monomers, e.g. copolymers of
vinylpyrrolidone and HEMA, and copolymers of ethylene oxide and
propylene oxide. The hydrogel polymer may also be selected from the
group consisting of polycarboxylic acids, cellulosic polymers,
gelatin, polyvinylpyrrolidone, maleicanhydride polymers,
polyamides, polyvinyl alcohols, and polyethylene oxides or
polyacrylic acid.
[0052] The catheter sheathing material is a homogeneous fiber optic
material that is transparent to and is able to conduct the
controlling energy, preferably laser light, throughout the extent
of the molded sheath. The fiber optic material is of a type known
to the art of laser catheters and is configured to transmit laser
energy. A person of ordinary skill in the art can readily adapt
known fiber optic materials for incorporation into the apparatus of
the present invention. A hydrogel matrix forms a large portion of
the body of the catheter tubing and is tenaciously affixed to the
inner surface of the energy-conducting sheath. This matrix provides
the storage space for photolabily linked compound to remain in a
soluabilized and bound state prior to compound release via
controlled delivery of energy through the sheathing material.
[0053] The hydrogel polymer matrix 55 deposition and affixation to
the inner surface 52 of the catheter sheath 50 can be accomplished
by the following example according to U.S. Pat. No. 5,304,121,
incorporated herein by reference. The inner surface 52 of the
catheter sheath 50 is coated with a solution of 4,4'
diphenylmethane diisocyanate (MDI) in methylethylketone for 30
minutes. After drying in an air oven at 85.degree. C. for 30
minutes, the sheath is dipped in a 1.7% solution of poly(acrylic
acid) homopolymer having a molecular weight of about 3,000,000 in
dimethylformamide (DMF) and tertiarybutyl alcohol. After drying at
about 85.degree. C. for 30 minutes, a smooth coating is obtained.
The sheath is oven dried for 8 hours at 50.degree. C. One function
of the drying steps is to remove solvent from the coating. The
polyisocyanate solution is at a concentration of about 0.5 to 10%
by weight. The polyacrylic acid is at a concentration of about 0.1
to 10% by weight. The poly(carboxylic acid) to polyisocyanate molar
ratio is generally about 1:1. The formation of the hydrogel is well
known in the art, such as the hydrogel further described in U.S.
Pat. No. 5,091,205, incorporated herein by reference.
[0054] The rate of drug release is controlled by exposure of the
catheter body to a source 35 of transmissible energy, such as the
energy of a laser. Persons of ordinary skill in the art know
readily available electronic devices which can be used for laser
energy generation and computer control. Through suitable optical
coupling 40, the laser energy enters the catheter sheath or casing
50, and in a preferred embodiment, is reflected off of the
reflective outer coating 70 and is transmitted into and through the
catheter body when it is desired for drug to be released from
catheter matrix material storage. Photolabile bonds are broken and
the freed therapeutic agent 65' is released and traverses across
the infusate soluble polymer matrix material 55, and into the
catheter lumen 60 as free therapeutic agent in infusate solution
24. An outer opaque coating 75 with reflective properties prevents
extraneous light from entering the catheter body and also directs
the controlled laser light into the catheter body to provide energy
exposure.
[0055] Energy for release of the drug in its active form from the
drug-polymer combination can be by one of a variety of means
depending upon the photosensitivities of the chosen photolabile
bond, the polymer 50, and the drug 65. For example, the source 35
of energy can be radiation such as infrared, visible, or
ultraviolet radiation, supplied from incandescent sources, natural
sources, lasers including solid state lasers, or even sunlight. In
one embodiment, the present invention contemplates the use of a
source 35 of coherent light of wavelengths from about 300 nm to
about 1200 nm. This includes UV, visible and infrared light. The
choice of wavelength is based on the photolabile characteristics of
the bonds holding 65 within 55 and is selected to match the
wavelength necessary to break the photolabile bond between 65 and
55. Since body tissues tend to absorb radiation in the ultraviolet
region of the electromagnetic spectrum, it is preferred to choose a
photolabile bond sensitive to red and infrared wavelengths. The
amount of drug released is proportional to the dosage of the
radiation. Various agents for producing the photoliable bonds are
described in related are such as U.S. Pat. No. 5,767,288,
incorporated herein by reference.
[0056] Administration of the radiation can be by use of fiber optic
light pipes or sheathing included within the catheter assembly.
Fiber optic light pipes 40 are known and used in various types of
medical treatments, for example irradiation treatment of internal
body organs such as bladder irradiation. In some embodiments of the
present invention, a fiber optic light pipe also acts as the main
source of energy into matrix 55, the light pipe providing light
down the length of catheter 20 and transmitting the light radially
or longitudinally through the catheter sheath. These light pipes
can be used to couple energy of particular wavelengths to distinct
sections of the sheathing material.
[0057] Preferably, the apparatus comprises an optically
transmitting fiber optic outer sheath 50 having a proximal end and
a distal end. The material can be either transparent or
translucent. The preferred material is transparent and
non-distendable. The fiber optic sheath 50 is of a type known in
the art of laser catheters and is configured to transmit laser
energy. The intensity and overall uniformity of the light
transmitted can be dramatically increased by using a coating 70
that reflects and/or scatters light into the lumen 60. The sheath
50 preferably includes a reflective outer coat 70 that reflects and
scatters light into and through the polymer matrix 55 and into the
lumen 60, providing a diffuse reflection of the light striking the
matrix 55 and agent 65. The function of the reflective material is
to provide increased uniformity and efficiency in the light
transmitted through polymer matrix 55. Examples of material for
coating 70 include, but are not limited to, titanium dioxide,
aluminum, gold, silver, and dielectric films. A person of ordinary
skill in the art can readily adapt known reflective materials for
incorporation into the outer portion of the apparatus of the
present invention. The preferred reflective material will reflect
and scatter light and prevent from about 20% to 100% of light
striking the material from passing through the material. The most
preferred will reflect and scatter over 70% of the light. The
reflective material can be incorporated onto the outer portion of
the sheath 50 in a variety of ways. For example, the reflective
material can be applied to the outer surface of catheter sheath 50
after the catheter is formed, by using a dipping process.
Alternatively, the reflective material can be directly incorporated
into the material used to form the catheter sheath 50 during the
manufacturing. The method used to incorporate the reflective
material into the catheter is based primarily on the reflective
material used, the material the catheter is made of, and the method
used to manufacture the catheter. A person of ordinary skill in the
art can readily employ known procedures for incorporating a
reflective material within or onto the surface of the catheter
sheath 50.
[0058] In addition to a reflective coating, the catheter may
further have an additional opaque coating 75 over the reflective
coating 70. An opaque coating 75 is used to further prevent light
from exiting the catheter exterior surface or extraneous light from
entering the body of the catheter. Some catheters, such as those
disclosed by Overholt et al. Lasers and Surgery in Medicine
14:27-33 (1994), utilize an opaque absorbing coating, such as black
Color Guard supplied by Permatex Industrial Corp. Avon, Conn., to
prevent the light from being transmitted through portions of the
catheter.
[0059] Some embodiments of the present invention further include
one or more optical sensors 80. Optical sensors 80 are integral to
the catheter and used to measure the intensity of illumination when
the catheter is used therapeutically. Optical sensors 80, such as a
fiber optic probe or a photodiode as part of a balloon catheter,
have been described in U.S. Pat. No. 5,125,925, incorporated herein
by reference. By monitoring, with a sensing fiber on the wall of
the fiber optic sheath, the light to which the sensing fiber and,
hence, the catheter matrix are exposed, can be determined.
Individual light doses and accurate measurement of the cumulative
light doses are measured by processor 85 and provide an accurate
measurement of the cumulative light dose and relates to released
compounds from various sections of the catheter matrix or
associated sections of the catheter matrix. Light power output is
also monitored and alarm may be given in the event of abnormal
light conditions.
[0060] In accordance with the present invention, therapeutic agent
65 is stored within the polymer matrix 55. Once the infusate is
flowing through lumen 60 at a constant rate and the matrix is in a
hydrated condition, the therapeutic agent 65 is in a soluablilized
state within the polymer matrix, with respect to the surrounding
infusate fluid infiltrate. A barrier to complete drug solution in
the infusate are laser liable bonds holding the therapeutic agent
65 within the polymer matrix 55. These bonds can be broken when
exposed to the proper frequency and intensity of laser energy,
thereby freeing the drug to enter the catheter lumen 60.
[0061] The amount of storage volume is adequate to incorporate a
substantial amount of drug to be used for various procedures. As
best seen in FIG. 4, in one embodiment of the present invention the
inner wall 52 of sheath 50 has a diameter D.sub.2 of about 3.6 mm,
and the lumen formed by polymer matrix 55 has a diameter D.sub.1 of
about 2.6 mm. The total length L.sub.1 of the portion of the
catheter 20 incorporating the polymer matrix is 1.7 meters. The
cross-sectional area A.sub.1 is calculated as
.pi.(D.sub.2.sup.2-D.sub.1.sup.2)/4 and is 4.84 mm.sup.2. The total
volume V.sub.1 of the polymer matrix is 8.23 cm.sup.3. This is a
representative volume calculation and provides an estimate of a
catheter body matrix 55 volume that would be available for drug
incorporation for the present invention. There is no general
restriction of the tubing diameter of the portion of the present
invention that resides outside the vasculature. It is anticipated
that an 8-12 cm.sup.3 volume of catheter matrix material 55 would
be sufficient to incorporate substantial amounts of drug(s) into
the polymer matrix for delivery into the infusate and further into
the systemic circulation or receiver space. Much larger reservoirs
for drug storage can be realized for portions of the present
designed to be extravascular in nature. By controlling the
concentration of the therapeutic agent 65 within matrix 55, the
total amount of therapeutic agent 65 available for infusion can be
limited by control of the thickness and length of the polymer
matrix. For example, the total amount of therapeutic agent stored
in a particular catheter assembly 20 can be limited to an amount
that is safe for delivery under any conditions. Jacketed
conditioning of the tubing extravascularly, such as for temperature
or radiation exposure, can also be provided for extravascular
portions of the present invention to allow for better inline
processing of fluids or for maintaining the integrity of the
catheter body matrix or compounds stored therein.
[0062] FIG. 6 depicts a system 100 for the automatic administration
of a therapeutic agent based on a sensed response from a biological
unit. A biological unit 30 such as an animal produces a response
which can be sensed by a sensor 105. The response elicits an output
signal 107 which is provided to a signal processor 110. Signal
processor 110 preferably accepts analog signal 107, and includes
suitable A/D processing and an internal digital processor which
produces a control signal 112 to energy source 35, such as a laser.
In response to control signal 112, energy source 35 produces an
energy output 120 which is coupled into catheter 20. Energy
response 120, which is preferably a controlled amount of laser
light, is transmitted down the fiber optic sheath 40 of catheter
assembly 20 and fractures the bonds between the therapeutic agent
65 and polymer matrix 55. The release of the therapeutic agent into
the infusate and subsequently into the biological unit 30 changes
the response of the biological unit that resulted in the signal 107
generated by sensor 105. Another example, sensor 105 measures the
brain activity of a person during anesthesia and provides a signal
to an electroencephalographic monitor 110. If the depth of
anesthesia is determined through brain wave activity to be
aberrant, then a signal is sent to a power supply to fire a laser
and release a therapeutic anesthetic agent from the catheter into
the blood stream of the patient.
[0063] As one example, sensor 105 measures the cardiac activity of
a person and provides a signal to a cardiac monitor 110. If the
cardiac monitor 110 determines that the patient is in cardiac
distress, then a signal is sent to a power supply to fire a laser
and release a therapeutic cardiac agent from the catheter into the
blood stream of the patient.
[0064] The present invention may be used during outflow of bodily
fluids from a body cavity. FIGS. 10 and 11 schematically depict
systems for the withdrawal of bodily fluids from a biological unit.
The exit of fluid from the body during kidney or peritoneal
dialysis would be examples of this use. A device 310 for withdrawal
of fluids, such as dialysis machine, is in fluid communication with
catheter 20a. A compound captured within the polymer matrix of
catheter 20a is released by energy from energy source 35a as
transmitted along conduit 40a. The bodily fluid is further
conditioned within conditioning unit 310, which is in fluid
communication with a catheter 20b for return of the fluid into the
biological unit. Another therapeutic agent captured in the polymer
matrix of catheter 20b is released into the bodily fluid by
activation of energy source 35b which provides energy through
conduit 40b into the sheath of catheter 20b.
[0065] The catheter or tubing 20 would release compound into
contents of body fluid, such as, blood, cerebral spinal fluid,
cardiac pericardial fluid, lymph, during outflow, adding
pretreatment compounds, such as anticoagulant, antibiotic,
anti-thrombotic or other conditioning or treatment agents proximal
to entrance into the dialysis or other equipment. Upon exit from a
treatment apparatus, such as dialysis or chemotherapy devices, and
prior to return into the living system, further conditioning
compounds could be released into the luminal tubing space to
deactivate or activate functionalities in the treated body fluids.
The advantage of maintaining sterile or otherwise separate
conditions during such extra-corporal closed loop treatments is
realized. It is anticipated that the tubing designed from the
present invention could be incorporated into the interior of an
apparatus for dialysis or other inline treatment regimen, such as
during lymphatic or lucemic cancer treatment or other disease
amenable to fluid treatment modalities
[0066] The permanent withdrawal of fluids for diagnostic sample
collection can be pretreated during collection with another
embodiment of the present invention. As seen in FIG. 11, system 400
withdraws bodily fluid from a biological unit and conditions that
fluid for subsequent use during testing or analysis of the fluid.
Fluid is withdrawn from a biological unit 30 through a catheter 20
which is in fluid communication with a fluid receiver 410, receiver
410 including a suction pump or other means for withdrawing fluid.
As the fluid passes through catheter 20, energy source 35 provides
energy through conduit 40 into the polymer matrix of catheter 20,
such that a compound releasably captured in the polymer matrix is
released into the bodily fluid flowing into receiver 410. For
example, the bodily fluid can be blood, and the compound released
from the polymer matrix can be an anticoagulant. Addition of
anticoagulant, antibodies, or dyes prior to sample preparation can
aid in the accuracy, reliability and speed of such clinical
testing. This sample conditioning could extend to any sample fluid
obtained through such tubing, including lymph, CSF, certain biopsy
material and urine. It is also anticipated that various laboratory,
experimental, industrial or non-biological processes or settings
can incorporate the present invention and method thereof for the
purposes of adding compounds to an inline process.
[0067] It has been shown (U.S. Pat. No. 5,482,719) that a shape
retaining non-flowing aqueous hydrogel polymer and drug compound
PEG 6000-BNBA-nicotinic acid released unchanged nicotionic acid
upon irradiation with light. The anti-viral drug adamantamine was
coupled to a polymer via a photolabile chemical linkage utilizing
the amino group of the drug, and then released in unchanged form by
photolysis 8 mg of the 10 mg of adamantamine combined with the
hydrogel-photolinker present in the formed hydrogel-linker-drug
yield of ADANABA-Et. This complex released unchanged adamantamine
over a ten minute period with most of the drug being released
within 5 minutes and with only a trace amount left complexed after
ten minutes of irradiation.
[0068] The present invention also contemplates non-biological
embodiments. FIG. 12 is a schematic representation of system 500
according to another embodiment of the present invention for
releasing a compound into a fluid flowing from one container into
another container. A fluid 524 held within a container 525 is
removed from container 525 by a pump 521. The pump 521 provides the
fluid to a section of tubing 520 which contains an internal layer
of a matrix material which includes a releasably captured compound.
Application of energy from source 535 through conduit 540 into the
matrix material results in the release of the compound into the
flowing fluid 524. The released compound is added to the flowing
fluid without appreciably changing the volumetric or mass flow rate
of the flowing fluid 524. The mixture 527 of the flowing fluid and
compound flows into container 526.
[0069] The section of tubing 520 containing the releasably captured
compound and the matrix material is the same as catheter assembly
20, except as shown and described differently. The sheath material
for tubing 520 does not need to be either biocompatible nor
flexible and may be constructed from any material which transmits
the energy into the matrix material. The compound releasably
captured within the matrix of tubing assembly 520 does not need to
be biocompatible or provide therapeutic affect, and may be any
material which can be releasably captured within the matrix
material and subsequently released by the application of energy to
the matrix material. Energy source 535 is the same as energy source
35, except as shown and describe differently. Energy source 535
does not need to be biocompatible in terms of the quantity or
quality of energy released.
[0070] Another embodiment of the present invention relates to a
method for manufacturing a catheter assembly. The catheter includes
one end that is readily attachable to a laser or non-laser light
source. FIGS. 8 and 9 depict a molded outer sheath 50' of laser
light conductible fiber optic material and incorporating multiple
baffles 253 and 254 to center an inner rod 252 used during assembly
of the catheter. Baffles 253 and 254 are semicircular in shape and
are integrally molded into sheathing 50'. Each baffle preferably
includes a semicircular cut out 257 and 258, respectively. These
cut outs are shaped to accept and support a form coated with
polymer matrix, such as rod 252 coated with hydrogel 55.
[0071] The light carrying section of the outer fiber optic sheath
50 and 50' can be of any thickness that conducts the proper
intensity of light. The preferred fiber optic sheath will have a
cross sectional area from about 200 to about 3000 microns and
preferably about 1200 microns. The choice of the sheath cross
sectional area depends on the brightness of the light source and
the optical power output required for release of the drug from
polymer matrix. In some embodiments, the sheath provides the
structural integrity and flexible characteristics of the overall
catheter tubing. This material is readily available to one of
ordinary skill in the art
[0072] As shown in FIGS. 8 and 9, the catheter sheath 50' is a
split cylinder, with the split occurring lengthwise along the
sheath. The sheath includes only a single split 251, such that the
sheath 50' preferably remains one piece. In some embodiments of the
present invention, the molded sheath includes a hinge section 280,
such as and area of weakened material, on the side of the sheath
opposite the split. This hinged area 280 facilitates a bending
apart of the two lengthwise sections of the molded sheath 50'. The
two sections can be hinged away from one another so as to
facilitate the later insertion of a rod 252 in the central cut out
of the baffles.
[0073] A biocompatible hydrogel polymer matrix 55 which includes
the photolabily bonded therapeutic agent 65 is deposited upon a rod
252 designed to loosely bind the gel material. The rod is composed
of a material such as a hard plastic. The surface does not bind
tightly to the gel, which may be property of the hard plastic
itself or a property of a rod coating substance such as TEFLON.RTM.
provided to coat the surface of the rod. The polymer 55 thickness
is allowed to build up in the hydrated state around the rod 252 to
a thickness such that the volume of the matrix 55 and rod 252
together become greater than the internal volume of the closed
catheter sheathing. Various sections of hydrogel material may be
included such that each section might incorporate unique compounds
or groups of compounds distinct from other sections with regard to
their confinement properties and releasing characteristics.
[0074] The sheath is formed around the rod-hydrogel section, as
seen in FIG. 9. The bent-apart sheath sections are brought back
into contact, which may result in a partial squeezing out of some
of the hydrogel in therapeutic agent. The lengthwise split 251 is
sealed by a method such as adhesion with a bonding agent or
ultrasonic welding. The inner surface 52' of the sheath 50',
including the baffles 253 and 254, are preferably prepared to
accept the hydrogel via adhesive preparation according to U.S. Pat.
No. 5,304,121 and designed to accept the hydrogel 55 and affix it
to the catheter sheath interior prior to assembly with the rod-gel
section.
[0075] The assembly is allowed to dry, the subsequent dehydration
causing the thickness of the hydrogel to decrease by as much as a
factor of 6-10. This substantial reduction in volume permits the
hydrogel to pull away from the surface of rod 252, since the
adhesion of the hydrogel to the rod surface is less than the
adhesion of the hydrogel to the inner surface 52' of the sheathing
50'. The rod 252 is then removed, and the sheath is coated on the
outer surface with an opaque and reflective coating combination 70
and 75. These coatings can also incorporate a sealer to provide a
means to close the seam 251 remaining after the sheath
circumscribes the rod-hydrogel section, or a separate step may be
needed to close the seam prior to coating. When rehydrated during
use the polymer matrix 55 swells and reforms to a shape that allows
a lumen 60 to form with a diameter generally determined by the
central cut-outs of the baffle and the outer diameter of the rod.
Appropriate sterile procedures are followed for tubing that is
manufactured for parenteral use, such that either suitable
sterilization techniques compatible with the catheter materials are
followed for components prior to assembly or appropriate
post-manufacturing sterilization procedures are carried out, such
as radiation bombardment.
[0076] Another embodiment of the present invention contemplates a
catheter assembly incorporating two different therapeutic agents 65
and 66 which are not mixed within the polymer matrix, and are
separated into different sections of the catheter. As best seen in
FIG. 8, a portion 55a of the polymer matrix including captured
therapeutic agent 65 coats a first portion of rod 252. A portion
55b of the polymer matrix including captured therapeutic agent 66
coats a second portion of rod 252. As coated road 252 is placed
within the baffle cut outs, therapeutic agent 65 is largely
confined to section 259a of sheath 50', defined between baffles
254a and 254b, and between baffles 253a and 253b. Therapeutic agent
66 is largely confined to section 259b of sheath 50', defined
between baffles 254b and 254c, and between baffles 253b and 253c.
An arbitrary number and placement of such said sections can be
incorporated into the sheath of the present invention. Further,
these sheath sections can be supplied by separate laser light pipes
capable of transmitting multiple distinct wavelengths of laser
energy
[0077] According to another embodiment of the present invention,
catheter 20 is manufactured using a split, bent-apart, molded
sheath 50', Sections of a polymer matrix such as 55a and/or 55b are
placed within the interior sections 259a or 259b of sheath 50'. A
rod 252 which is preferably not coated with a polymer matrix is
placed within sheath 50', preferably being supported within the
cutouts 257 or 258 of the baffles. The interior surface 52' of
sheath 50' is preferably coated as previously described to improve
the adhesion of the polymer matrix to surface 52'. Sheath 50' is
then formed around rod 252, with split 251 being adhered closed as
previously described. The polymer matrix is then shrunk in volume,
such as by dehydrating. Rod 252 is removed from the closed sheath.
Sheath 50' can include a first section 259a containing a first
releasably captured compound 65, and a second section 259b
containing a second releasably captured compound 66.
[0078] According to another embodiment of the present invention,
catheter 20 is manufactured using an injection method. A sheath 50
which is not split along its length is preferably supported along
the outer diameter of its length in a straight, linear fixture. A
rod 252 is held by its ends in the approximate center of the
sheath. A quantity of polymer matrix 55a and/or 55b is injected
into the annulus between the interior wall 52 of the sheath and the
outer diameter of rod 252. The interior surface 52 of sheath 50 is
preferably coated as previously described to improve the adhesion
of the polymer matrix to surface 52. The polymer matrix is then
shrunk in volume, such as by dehydrating. Rod 252 is removed from
the sheath.
[0079] In accordance with another embodiment of the present
invention, FIG. 5A shows a cross-section of an apparatus 220 which
is the same as catheter 20, except as herein described and
depicted. In apparatus 220, polymer matrix 55 includes molecules
photolabily bonded to two different therapeutic agents 65 and 66.
These agents 65 and 66 may represent distinctly different drugs
with regard to, but not limited to, such properties as drug
pharmacological classification and storage concentration within the
catheter body. Further, the laser liable bonds holding drugs 65 and
66 may or may not be characterized by different frequency or
intensity of laser liabilities. The use of a coherent laser light
source will be preferable in many applications because the use of
one or more discrete wavelengths of light energy that can be tuned
or adjusted to the particular photolytic reaction occurring in the
photolytic linker necessitates only the minimum power (wattage)
level necessary to accomplish a desired release of agents such as
65 and 66.
[0080] Multiple releases of different therapeutic agents or
multiple-step reactions can be accomplished using coherent light of
different wavelengths. Intermediate linkages to dye filters may be
utilized to screen out or block transmission of light energy at
unused or antagonistic wavelengths (particularly cytotoxic or
cytogenic wavelengths), and secondary emitters may be utilized to
optimize the light energy at the principle wavelength of the laser
source. Preferably, light radiation refers to light of wavelengths
from about 300 nm to about 1200 nm. This includes UV, visible and
infrared light. The choice of wavelength will be based on the
intended use, namely being selected to match the activation
wavelength for the cleavage of the photolabile linkage between the
catheter matrix material 55 and compounds 65 and 66 to be released.
The art pertaining to the transmission of light energy through
fiber optic conduits or other suitable transmission or production
means to the remote biophysical site is extensively developed.
[0081] This embodiment affords a means of providing selective
multi-drug therapies on demand. The present invention also
contemplates the storage of multiple drugs within the matrix. For
example, drug 65 and drug 66 can be released within the infusate 24
at times which would allow interaction within the infusate prior to
release into the systemic circulation.
[0082] In accordance with another embodiment of the present
invention, FIG. 5B shows a cross-section of an apparatus 222 which
is the same as catheter 20, except as herein described and
depicted. In apparatus 222, polymer matrix 55 includes molecules
photolabily bonded to two different therapeutic agents 65 and 66.
These agents 65 and 66 may represent distinctly different drugs
with regard to such properties as drug pharmacological
classification and storage concentration within the catheter body.
Further, the laser liable bonds holding drugs 65 and 66 may or may
not be characterized by different frequency or intensity of laser
liabilities. This interaction could result in a prodrug effect,
where drug 65 activates or alters drug 66, or drug 65 and drug 66
interact to produce a new drug 67. Then altered drug 66 or drug 67
would be available to the systemic circulation for therapy. This
allows for inline synthesis of drugs or compounds that would be
otherwise difficult to produce and administer effectively by other
means.
[0083] The advantages of this device are increased safety to the
recipient of infused drug through decreased trauma of infusion site
innervations and for maximum maintenance of sterile conditions.
Catheters can be used for either short-term or long-term vascular
access. Factors associated with infusion-related phlebitis among
patients with peripheral venous catheters including site of
catheter insertion, experience of personnel inserting the catheter,
frequency of dressing change, catheter-related infection, skin
preparation, host factors, and emergency-room insertion could all
be decreased from use of the present invention. The present
invention provides increased safety for general catheter use by
providing a drug or other compound to be made immediately available
for use when needed for adjunctive therapy without adding any extra
equipment into the sterile infusion set environment. This is in
contrast to the necessity with current practices for an additional
catheter to be inserted, a drug solution to be changed, or any of
various other alterations necessary to add adjunctive drug therapy
using catheter or tubing system. The present invention provides
quicker and accurate drug delivery of on-demand doses of new or
concurrent multi-drug therapies. The present device can be
programmed to release drug at a specified time and in a controlled
amount with a degree of accuracy based upon the high degree of
accuracy available through computer control of an energy source.
The computer control allows administration of a specified and
appropriate amount of intensity and duration of energy exposure,
preferably coherent light, to the catheter sheath for subsequent
release of agents 65 and 66 into infusate solution.
[0084] The drug is also released into the catheter lumen which may
extend up to and sometimes inside the vasculature setting. A more
immediate entrance into a positive flow body cavity space, such as
the systemic circulation can be realized with the present device,
where drug is stored and released at the opening of a catheter
inside the vasculature. This is in contrast to a current adjunctive
processes including providing drug into a port which has to travel
down the catheter tubing and then enter the systemic circulation.
In such cases an attendant is necessary to mix a drug and inject it
into the infusion set port, which takes time and adds an element of
human error to the process. In some situations a common syringe
pump apparatus in place to administer the adjunctive drug therapy.
The present invention has few mechanical parts to fail. The
infusion pump apparatus involves many moving parts which increases
the risk of malfunction. Both attendant and syringe pump apparatus
therapy modifiers inject an added volumetric input to the flow of
infusate, thereby limiting their effectiveness if the total flow
rate into the biological unit must be limited to a maximum amount.
Both adjunctive processes also use a constant concentration of
added infusate, so that dynamic changes in dose require dynamic
changes in injected infusate volume.
[0085] Some embodiments of the present invention incorporate a
therapeutic agent 65 with a short half-life into the polymer matrix
55. Because of the short time lag from release of the drug from the
matrix into the vasculature of the patient, there is increased
effectiveness of the short, half-life agent. Examples of these type
of drugs would include short acting anesthetic agents such as
xylocaine and cardiac agents such as nitrous oxide derivatives, and
prostaglandin derivatives. An operator may afford effective
feedback control of short acting cardiac drugs, analeptics,
neurotransmitters, analgesics, or hormones. During the monitoring
of an EKG of a patient in the intensive care unit of a hospital,
when arrhythmias are detected or cardiac arrest is indicated, a
drug can immediately be released into the systemic circulation for
therapy. While monitoring the EEG during anesthesia, drugs can be
released into the systemic circulation by the present invention to
decrease or increase the depth of anesthesia through proper release
of drugs.
[0086] The present invention can be used to administer drug in an
automatic, easily controlled manner. Traditional drug regimens have
included administering drugs orally, sublingually, rectally,
subcutaneously, intramuscularly, occularly and parenterally. The
regimens with respect to time have included rapid injections,
constant rate infusions and combinations thereof. The present
invention can be used to administer drug or compound when that drug
or compound is administered by a tubing or a catheter system. To
deliver any arbitrarily administered drug regimen, a computer
controller is programmed control energy source 35 to administer a
defined energy magnitude or duration to the tubing matrix of the
present invention so that a proportional amount of stored compound
is released into the tubing lumen in a controlled manner. The ease
of input profile generation used to control drug release from the
present inventions, coupled with their potentially complex
characteristics with respect to time represent a very flexible
means of drug delivery when traditional methods of drug delivery
are considered. A patient can in many instances self-administer the
radiation to release drug on an "as required" arbitrary basis, e.g.
for hypertension treatment or for pain relief.
[0087] Many natural systems exhibit structure characterized by
chaotic behavior. Various patterns in nature have been described by
fractal geometric curves, surfaces and volumes. There is ample
evidence to suggest that many biological systems incorporate
chaotic mechanisms in their structure. These chaotic structural
mechanisms result in observational data that can be interpreted as
fractal in form. Among many biological systems, such systems
studied have included cardiac function and neural stimulation.
[0088] Unpredictable changes over time t of a quantity V is known
as noise V(t). The spectral density of V(t), S.sub.v(f), gives an
estimate of the mean square fluctuations of the quantity at a
frequency f. As seen in FIG. 13A, by plotting log S.sub.v(f) as a
function of log f, a slope can be calculated, and this slope can be
interpreted as having a functional form 1/f.sup..beta.., where
.beta. is a spectral exponent. Plot 605 of FIG. 13A plots the
spectral density of a variable where .beta. equal to 1. Graph 610
represents the log of the spectral density of a variable for .beta.
equal to 2. A particular finding has included the discovery that
almost all musical melodies mimic 1/f noise, where 1 is equivalent
to "white" noise, and 1/f.sup.2 corresponds to Brownian motion.
[0089] Fractional Brownian motion (fBm) is a mathematical model for
many random fractals found in nature, including 1/f noise.
Formally, it is the increments of fBm (the differences between
successive values) that produce values corresponding to various
1/f.sup..beta. noise series. Traces of fBm are characterized by a
parameter H in the range of 0<H<1. The value H.apprxeq.0.8 is
empirically a good choice for many natural phenomena. Fractal
Brownian motion has been studied and various methods of generating
trains of 1-, 2- and 3-dimensional data sets have been developed;
see: The Science of Fractal Images, Eds. Heinz-Otto Petigen and
Dietmar Saupe, 1988. These include spatial approximation methods
and, approximation by spectral synthesis. These methods can readily
be carried out by ordinary computer analysis. According to another
embodiment of the present invention, the application of energy to
the catheter assembly is applied according to a 1-dimensional
algorithm to synthesize fBm fractal Brownian motion.
[0090] FIG. 7 schematically depicts a system 150 for delivering
therapeutic agent in a fractally-based pulsatile manner to a
biological unit 30. An electronic controller 155 produces a
fractally derived signal 157 to control an energy source 35', such
as a laser. Various methods of generating fBm numerical time series
can be used to calculate fractally-based signal 157 by controller
155, such as with fast Fourier Transform filtering, random midpoint
displacement methods, or other methods described in The Science of
Fractal Images, Eds. Heinz-Otto Petigen and Dietmar Saupe, 1988.
FIG. 13B-D represent three distinct fBm curves Vi(t) synthesized
using the midpoint displacement method to produce fBm, where H=0.8.
The fractally derived control signal 157 can also be generated by
choosing a value of .beta. preferably between the values of 0.5 and
1.5. From selection of either H or .beta., the log of the spectral
density of a pulse parameter such as magnitude, duration, and
separation interval can be predicted. FIGS. 13B, 13C, and 13D
represent three distinct fBm curves 620, 630, and 640,
respectively, for Vi(t) synthesized using the midpoint displacement
method for a selected value of H. Curve 620 of FIG. 13B represents
a fractally derived series of laser pulse magnitudes at 6
intervals. FIG. 13C represents a series of fractally derived laser
pulse durations at 6 intervals. FIG. 13D represents a series of 6
fractally derived laser pulse spacing intervals. These series have
been sampled at regular intervals, Si, to determine the value of
the quantity at the particular sampling time. These value are used
to assign values to laser pulse parameters. Each pulse is
characterized by the parameters of pulse magnitude, (V.sub.1),
duration, (V.sub.2) and separation interval, (V.sub.3), from the
immediately preceding pulse in the series, Sp(i).
[0091] Numerically, each of these values conforms independently to
a fractally-based algorithm for each pulse to produce a fractally
derived, time domain pulse train signal at the series sampling
times as shown in FIG. 13E. A time domain pulse train is shown in
FIG. 13E, and is synthesized by combining the pulse series of FIGS.
13B, 13C, and 13D. As shown in FIG. 13E, there is a first pulse 645
with a magnitude of 5, duration of 5, and an interval spacing of 5
from the origin. A second pulse 650 from sampling interval 2 has a
magnitude of 6, a duration of 2, and is spaced 6 units from pulse
645. Pulse 655 has a magnitude of 3, a duration of 3, and is spaced
9 units from pulse 650. The pulse train represented in FIG. 13E
represents a model for the laser control signal 157. The pulse
train of FIG. 13E is scaled by the appropriate intensity and time
factors to take into account the specific embodiment of the
invention, considering factors such as the effect of the chosen
releasable compound, the volumetric flow rate of the infusate, the
rate at which the particular laser breaks the particular
photolabile bonds, and other factors. For example, with certain
specific therapeutic agents, the time interval shown could be
minutes, where as for other specific therapeutic agents the time
interval could be hours. As an alternate to the method described
above, the present invention contemplates using the difference
between successive magnitudes are used to assign values to pulse
parameters. For example of this alternate embodiment, the
difference between successive values of FIGS. 13B, 13C, and 13D
would be used to generate the time domain pulse train, instead of
the values themselves.
[0092] Compound fractally-based pulse train signals can be obtained
by combining several single pulse series together through
superposition and applying this compound pulse series to derive a
fractally based signal 157. The signal 157 is provided to energy
source 35' to generate a fractally-based stream of energy 160 that
enters catheter assembly 20 so as to fracture the bonds between the
therapeutic agent and the polymer matrix. These bonds are
fractured, and the therapeutic agent is subsequently released in a
pulsatile manner. This pulsatile release of therapeutic agent can
include predetermined amounts of agent released at variable
intervals, variable amounts of therapeutic agents released at
predetermined intervals, or variable amounts of therapeutic agent
released at variable intervals. Since there is a time lag for the
therapeutic agent to defuse out of the polymer matrix and into the
infusate flow stream, and further a time lag for the mixture of
therapeutic agent and infusate to mix within the biological unit,
it is preferable that the frequency content of the pulsed energy
160 be less than about 1 Hz.
[0093] Since there is evidence that neuronal systems and cardiac
systems exhibit chaotic behavior which can be described in fractal
terms, one embodiment of the present invention administers a drug
in a pulsatile input train, where the pulse separation and/or pulse
magnitude relates to a fractally derived input signal. As one
example, the present invention contemplates treatment of an acute
cardiac event such as heart arrest or fibrillation in an intensive
care ward, where intravenous tubing of the present invention would
release a therapeutic agent in a fractally based pattern to the
patient in distress. As another example, the present invention
contemplates delivery of intravenous anesthesia, where there is an
anesthetic response from a fractally based pattern drug delivery.
As another example, the present invention contemplates the
administration of morphine to a post-operative patient in a fBm
pattern. It is anticipated that short acting neurotransmitters or
other psychoactive agent may be used in this fashion, such as
norepinephrine, epinephrine, and dobutamine
[0094] On a longer time scale, administration of hormones, such as
hGH (human growth hormone), can be administered as a fBm pulsatile
input to growth deficient patients.
[0095] The delivery of drug or compound therapy using routes other
than parenteral administration in a fBm profile can also be
expected to engender beneficial responses when compared to
traditional compound treatment regimens. Traditional dosage forms
which could incorporate these fractally-based timed release
regimens of drug release include, but are not limited to,
intramuscular matrix embedded depot, subcutaneous depot injections
and various suppository preparations.
[0096] Input stimulus other than chemical modifiers when
administered as fBm regimens, for example through pulsatile light
stimulation to the eye or other non-drug means, may elicit a
potentiated or a muted evoked response when compared to a steady
application of an effector stimuli. Such fBm treatment may include
cancer radiation treatments, audible stimulation or any other
stimuli sensed by a living system. The frequency content of the
pulsed energy can be greater or less than 1 Hz.
[0097] It is contemplated that the various embodiments described
heretofore are combinable. For example, the release of compound in
a fractally-based pattern can be incorporated into system 500.
[0098] While the invention has been illustrated and described in
detail in the drawings and foregoing description, the same is to be
considered as illustrative and not restrictive in character, it
being understood that only the preferred embodiments have been
shown and described and that all changes and modifications that
come within the spirit of the invention are desired to be
protected.
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