Catheter with permeable hydrogel membrane

Drug delivery vehicles and catheter systems are disclosed for controlled release of therapeutic agents employing a permeable hydrogel membranes a reservoir for an inflation fluid carrying a therapeutic agent. The membrane devices of the present invention can be used in conjunction with a catheter or similar instrument having an elongated hollow body member and a lumen extending therethrough to permit fluid communication between a proximal infusion port and a permeable membrane disposed at the distal end of the catheter body. The membrane preferably comprises an expandable, hydrophilic polymer having a predetermined permeability with respect to an inflation fluid. One preferred hydrophilic polymer is a hydrogel capable of imbibing an aqueous solution to reach a state in which it comprises between 50% and 98% water by weight in equilibrium. In this state, the hydrogel membrane serves to control the rate of medicament delivery.

FIELD OF THE INVENTION
 This invention relates generally to medical devices for delivering
 therapeutic agents to selected tissue site through a hydrophilic membrane.
 More particularly the invention relates to catheter systems that have
 injection ports for delivery of therapeutic fluids and a membrane attached
 to a distal portion of the catheter into which the fluid is delivered,
 thereby inflating the balloon. The membrane is formed from a hydrophilic
 polymer that exhibits a predetermined permeability such that therapeutic
 solutions delivered through the injection port(s) into the membrane are
 contacted directly, which are in contact with the inflated membrane.
 BACKGROUND OF THE INVENTION
 Various forms of drug delivery catheters are known in the art. They
 generally comprise an elongated flexible catheter body having an
 inflatable member at a distal end portion thereof where the inflatable
 member or "balloon" has pores formed in the wall thereof through which a
 drug containing fluid can profuse. For example, U.S. Pat. No. 5,709,653 to
 Leone uses a balloon catheter with a porous balloon for allowing a
 photodynamic treatment fluid to pass through the pores and infuse into the
 wall of a body vessel in which the catheter is disposed. Other patents
 utilizing a porous balloon for drug delivery include Racchini et al. U.S.
 Pat. No. 5,458,568; Sahatjian et al. U.S. Pat. No. 5,674,192 and Shapland
 et al. U.S. Pat. No. 5,628,730.
 Unfortunately, porous balloons are difficult to manufacture (requiring
 precision drilling of an elastic material) and the minimum practical pore
 size is often much larger than desired. Moreover, the typical porous
 balloon system of the prior art has an undesirable release profile,
 characterized by rapid initial release of a drug or other agent followed
 by an exponential drop-off as the balloon deflates and the fluid pressure
 driving the agent through the pores becomes smaller and smaller.
 Accordingly, there exists a need for better drug delivery systems and, in
 particular, delivery systems with greater control over release rates.
 Balloon or other membrane-based drug delivery systems that can selectively
 pass molecules at a controlled and reproducible rate would satisfy a
 long-felt need in the art.
 SUMMARY OF THE INVENTION
 The present invention circumvents the problems described above by
 delivering a therapeutic agent, e.g., a medicament, into an area in need
 thereof, via a membrane that permits greater control of the application
 and release rates of the medicament. In a particular embodiment, the
 invention provides a device, which allows chemotherapeutic or
 radiosensitized treatment of a particular diseased tissue area with
 minimal if any exposure of non-diseased tissue to the treatment. Drug
 delivery vehicles and catheter systems of the invention are disclosed for
 controlled release of therapeutic agents, e.g., medicaments such as
 chemotherapeutic agents or radiosensitizers, employing a permeable
 hydrogel matrix, e.g., a membrane, and a reservoir for an inflation fluid
 carrying a therapeutic agent.
 The devices of the present invention can be used in conjunction with a
 catheter or similar instrument having an elongated hollow body member and
 a lumen extending therethrough to permit fluid communication between a
 proximal infusion port and a permeable membrane disposed at the distal end
 of the catheter body. The device preferably comprises an expandable,
 hydrophilic polymer membrane, e.g., a hydrogel membrane, e.g., a balloon,
 having a predetermined permeability with respect to an inflation fluid.
 One preferred hydrophilic polymer is a hydrogel capable of imbibing an
 aqueous solution to reach a state in which it comprises between 50% and
 98% water by weight in equilibrium. In this state, the hydrogel membrane
 serves to control the rate of medicament delivery.
 By injecting an inflation fluid comprising an aqueous solution containing a
 medicament, the membrane member can be inflated to engage body tissue
 (e.g., the interior surface of a blood vessel or other body lumen or
 tissue surrounding a natural or excised interstitial space within the
 body). The membrane can engage the body tissue over a substantial portion
 of its length and simultaneously exude the inflation fluid containing the
 medicament through the membrane so as to bathe the engaged tissue and
 surrounding tissues, e.g., a vessel wall, with the drug or other
 therapeutic substance.
 The invention is also drawn to methods for treating aberrant cells or
 cancer in a body cavity. The methods include inserting a catheter
 including an elongated tubular body member into a body cavity, the tubular
 body having a proximal end, a distal end and a lumen extending
 therebetween, with an inflation port extending through a wall of the
 tubular body member in fluid communication with the lumen. An expandable
 membrane member is affixed to the catheter body member near the distal end
 and in fluid communication with at least one inflation port.
 The membrane member includes a hydrophilic polymer having a predetermined
 permeability to migration of inflation fluid therethrough. An inflation
 solution containing a medicament is injected into the expandable membrane
 such that the medicament permeates through the membrane over a period of
 time treating the aberrant.
 In one embodiment, the method further includes slidably positioning an
 insertion tube with radioactive pellet(s), e.g., seed(s), into a lumen of
 the catheter, such that ionizing radiation strikes the medicament,
 preferably a chemotherapeutic agent or a radiosensitizer, thereby treating
 the aberrant cells with an activated medicament.
 In another embodiment, the methods include inflating a second membrane,
 which is fixedly attached to the catheter and proximate to the first
 membrane with a solution containing a radioactive isotope. Preferably, the
 radioactive solution emits ionizing radiation that interacts with a
 chemotherapeutic agent or a radiosensitizer forming activated molecules
 useful for treating aberrant cells or cancer.
 The invention will next be described in connection with illustrated
 embodiments. However, it should be clear that various additions,
 subtractions and substitutions can be made without departing from the
 spirit or scope of the invention. For example, the membranes of the
 present invention can be bonded to the catheter in many different ways so
 long as a fluid pathway exists between an inflation fluid source and the
 membrane. The membrane can be multi-walled or multi-layered so long as the
 overall structure has a predefined permeability.
 The membrane can be affixed or otherwise joined to the catheter body
 without the need for defined inflation ports and can also be stored in a
 collapsed or recessed state prior to use, e.g., an open-ended catheter.
 The membrane and catheter components can be sold separately and permeable
 membranes according to the invention can be designed or adapted to connect
 to various conventional medical instruments. Broadly, the invention
 encompasses each of the various elements, methods and features described
 herein alone or in combination with any other element, method or feature.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS
 The features and other details of the invention will now be more
 particularly described and pointed out in the claims. It will be
 understood that the particular embodiments of the invention are shown by
 way of illustration and not as limitations of the invention. The principle
 features of this invention can be employed in various embodiments without
 departing from the scope of the invention.
 In one aspect, the present invention pertains to a biocompatible drug
 delivery catheter that includes an elongated tubular body member and an
 expandable biocompatible membrane member affixed to the catheter body. The
 elongated tubular body member has a proximal end, a distal end and a lumen
 extending therebetween, with at least one inflation port extending through
 a wall of the tubular body member. In a preferred embodiment of the
 invention, the inflation port(s) is in fluid communication with the lumen.
 In one embodiment the inflation port can be the open end of the catheter
 where the membrane is affixed to the end of the catheter and acts as a
 capping feature.
 The expandable membrane member, e.g., a biocompatible membrane balloon, is
 affixed to the catheter body member near the distal end and is in fluid
 communication with at least one of the inflation ports. The membrane
 member consists of a hydrophilic polymer having a predetermined
 permeability for migration of inflation fluid therethrough. Upon injection
 of an inflation fluid, e.g., a pharmaceutically acceptable carrier and a
 medicament, the expandable membrane inflates forming a "reservoir" between
 the catheter body and the outerwall of the membrane.
 In FIGS. 1A and 1B a drug delivery catheter 10, constructed in accordance
 with the present invention, is depicted in its unexpanded and expanded
 form within a body cavity such as a lumen of a blood vessel 12. The
 catheter 10 is somewhat conventional in its construction in that it
 includes an elongated flexible tubular body 14 having at least one lumen
 16 extending the length thereof from a proximal end to a distal end.
 Openings in the side wall of the body member 14 define one or more
 inflation ports 18 that provide fluid communication between the lumen 16
 and an outer membrane 20, which can be bonded at its proximal end 22 and
 distal end 24 to the tubular body 14. As shown in FIG. 1B, injecting an
 inflation fluid into the proximal end of the catheter body 14, it is
 forced to flow through the lumen 16 and out the inflation ports 18 to fill
 the chamber 26 within the membrane 20, thereby inflating outer membrane
 20. Generally the inflation fluid includes a therapeutic agent, e.g., a
 medicament, which is a chemotherapeutic agent or a radiosensitizer. In a
 preferred embodiment, the membrane is a hydrogel and is hydrophilic.
 By injecting an inflation fluid comprising an aqueous solution containing a
 medicament, membrane member 20 can be inflated to engage body tissue
 (e.g., the interior surface of a blood vessel or other body lumen or
 tissue surrounding a natural or excised interstitial space within the
 body). Membrane 20 can engage the body tissue over a substantial portion
 of its length and simultaneously exude the inflation fluid containing the
 medicament through the membrane so as to bathe the engaged tissue and
 surrounding tissues, e.g., a vessel wall, with the drug or other
 therapeutic substance.
 "Interstitial cavity," as the term is used herein, encompasses interstices
 in a tissue or structure of a natural body structure, spaces and gaps
 existing between layers of tissue or existing within organs, and can
 include interstices within the interior of the ureter, bladder,
 intestines, stomach, esophagus, trachea, lung, blood vessel or other organ
 or body cavity, and will be further understood to include any surgically
 created interstice that defines an interior cavity surrounded by tissue.
 The term "catheter" as used herein is intended to encompass any hollow
 instrument capable of penetrating body tissue and providing a conduit for
 a fluid to an inflatable membrane with controlled permeability, including
 without limitation, venous and arterial conduits of various sizes and
 shapes, endoscopes, cystoscopes, culpascopes, colonscopes, trocars and
 laparoscope. Catheters of the present invention can be constructed with
 biocompatible materials known to those skilled in the art, e.g., silastic,
 polyethylene, Teflon, polyurethanes, etc.
 The terms "into" and "onto" are used interchangeably and are intended to
 include treatment of tissue by delivering a medicament to the afflicted
 area. In some instances the medicament penetrates the tissue and in other
 instances the medicament only superficially treats the surface of the
 tissue, e.g., contacts or coats. An ordinary skilled artisan would
 understand what depth(s) of penetration are required and are dependent
 upon the application, tissue type, area to be treated and severity of
 condition. Accordingly, the amount of medicament used to treat the
 afflicted area would be attenuated based upon the disease or condition
 being treated.
 One skilled in the art would recognize those medicaments that would be
 useful for interstitial treatment of aberrant cell growth, e.g., cancerous
 tissue (malignant or benign), tumors, etc., by the present invention. The
 medicaments of interest would include chemicals known in the art which are
 useful for treating disease states, e.g., cancer, including but not
 limited to, radiosensitizers and chemotherapeutic agents.
 The term "radiosensitizer" is art recognized and is intended to include
 those agents which, when present during irradiation, enhance the cytotoxic
 effects of radiation, e.g., ionizing radiation. For example, the hypoxic
 radiosensitizer Misonidazole, enhances the cytotoxic effect of X-ray and
 gamma ray radiation. Although studied for many years, the interaction(s)
 between radiation and a radiosensitizer is complex and difficult to
 predict. Moreover, as both the radiosensitizer and the radiation are
 cytotoxic per se, their use in therapy is limited in conventional
 techniques.
 Radiosensitizers are often easily degraded by ionizing radiation into
 reactive fragments. For example, incorporation of a bromine or iodine atom
 into DNA using bromodeoxyuridine, e.g., 5'-bromo-2'-deoxyuridine (BUdR) or
 5'-iodo-2'-deoxyuridine (IUdR), is known to sensitize DNA to breakage by
 ionizing or ultraviolet radiation. The sensitization is mediated by the
 uracilyl free radical formed by dissociation of the carbon-halogen bond in
 the BUdR or lUdR by UV and the same free radical is formed by a reaction
 of hydrated electrons produced by ionizing radiation. It has been proposed
 that the uracilyl free radical initiates strand cleavage by abstraction of
 the hydrogen atom from the 2'-deoxyribose carbon on the adjacent
 nucleotide.
 The term ionizing radiation is used herein to include photons having enough
 energy to ionize a bond, such as, alpha (.alpha.), beta (.beta.) and gamma
 (.gamma.) rays from radioactive nuclei and x-rays.
 Various heterocyclic compounds, in particular, those with oxidized nitrogen
 moieties, have been used for the purpose of radiosensitizing aberrant
 cells, e.g., tumor cells. Indeed, it has been postulated that the oxidized
 nitrogen functionality is responsible for this activity. Nitroimidazoles,
 particularly misonidazole (MIS) and metronidazole have been extensively
 studied, and MIS is commonly used as a standard in in vitro and in vivo
 tests for radiosensitizing activity. (See, e.g., Asquith, et al.,
 Radiation Res (1974) 60:108-118; Hall, et al., Brit J Cancer (1978) 37:
 567-569; Brown, et al., Radiation Res (1980) 82:171-190; and U.S. Pat. No.
 4,371,540). The radiosensitizing activities of certain 1-substituted
 3(5)-nitro-s-triazoles, various quinoxaline-1,4-dioxide derivatives,
 diamines such as diaminetetrametronidazoles (DATMs) (See for example U.S.
 Pat. No. 5,700,825), and texaphyrins (See U.S. Pat. No. 5,622,946), for
 example, have also been disclosed as radiosensitizing agents.
 The term "chemotherapeutic agent" is art recognized and is intended to
 include those chemical and biological agents, including small molecules
 and larger molecules, such as peptides, proteins, lymphokines, antibodies,
 tumor necrosis factor, conjugates of antibodies with toxins, and other
 chemical or biological molecules which have an antitumor effect which is
 oxygen dependent.
 There are a variety of known classes of small molecule chemotherapeutic
 agents. These include alkylating agents, such as Melphalan (PAM),
 Cyclophosphamide (CTX), cis-Diammminedichloroplatinum (II) (CDDP),
 nitrosoureas such as N,N'-bis(II-chloroethyl)-N-nitrosourea (BCNU),
 nitrogen mustards, ethyleneimine compounds, alkyl sulphonates, cisplatin
 and dacarbazine. Another general class of antitumor chemotherapeutic
 agents are the antimetabolites, such as folic acid, purine or pyrimidine
 antagonists, 6-Mercaptopurine, 5-fluorouracil (5-FU), fluorodeoxyuridine,
 cytosine arabinoside, methotrexate and thioquinone. Antibiotics are
 another general class of antitumor chemotherapeutic agents including drugs
 such as actinomycin, daunorubicin, Adriamycin and bleomycin. Still yet
 another class are mitotic inhibitors, such as the vinca alkaloids,
 including etoposide, vincristine and vinblastine and derivatives of
 podophyllotoxin.
 Particular examples of chemotherapeutic agents are described, for instance,
 by D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical
 Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Fla.,
 U.S.A. (1991) pages 177-203. Commonly used chemotherapeutic agents include
 Adriamycin (doxorubicin), Bleomycin Sulfate, 5-Fluorouracil, Paraplatin
 (Carboplatin), Methotrexate, Taxol (Paclitaxel), Etoposide, Cytosine
 Arabinofuraoside (Are-C), Dacarbazine (DTIC), Dactinomycin,
 Mechlorethamine (nitrogen mustard), Streptozocin, Cyclophosphamide,
 Carmustine (BCNU), Lomustine (CCNU), Daunorubicin, Procarbazine,
 Mitomycin, Cytarabine, Etoposide, Methotrexate, 5-fluorouracil,
 Vinblastine, Vincristine, and Chlorambucil (See, for example, R. J. Gralla
 et al in Cancer Treatment Reports (1984) 68(1), 163-172).
 Mixtures of more than one chemotherapeutic or radiosensitizer agent or
 combinations thereof can, of course, be administered. Indeed, it is often
 preferred to use mixtures or sequential administration of different
 chemotherapeutic or radiosensitizer agents to treat aberrant tissue sites,
 e.g., tumors, cancerous growths, especially agents from the different
 classes of agents. For example, mixtures of methotrexate and a
 cis-platinum compound are often used to treat various afflicted tissue
 sites.
 The term "biocompatible" is art recognized and as used herein, means
 exhibition of essentially no cytotoxicity while in contact with body
 fluids or tissues. "Biocompatibility" also includes essentially no
 interactions with recognition proteins, e.g., naturally occurring
 antibodies, cell proteins, cells and other components of biological
 systems.
 The terms "treat," "treatment," or "treating" are intended to include both
 prophylactic and/or therapeutic applications. The methods of the invention
 can be used prophylatically to protect a subject from damage or injury
 caused by a disease state or condition, or can be used therapeutically to
 treat the subject after the onset of the disease or condition.
 The term "subject" is intended to include mammals susceptible to diseases,
 including one or more disease related symptoms. Examples of such subjects
 include humans, dogs, cats, pigs, cows, horses, rats and mice.
 The term "tissue" is art recognized and is intended to include
 extracorporeal materials, such as organs, e.g., mesentery, liver, kidney,
 heart, lung, brain, tendon, muscle etc., and corporeal materials, such as
 blood cells, e.g., red and white blood cells and extracellular components.
 The term "disease" is associated with an increase of a pathogen within a
 subject such that the subject often experiences physiological symptoms
 which include, but are not limited to, release of toxins, gastritis,
 inflammation, coma, water retention, weight gain or loss, ischemia and
 immunodeficiency. The effects often associated with such symptoms include,
 but are not limited to fever, nausea, diarrhea, weakness, headache and
 even death. Examples of diseases that can be treated by the present
 invention include undesirable cell proliferation or cancer, e.g., bladder,
 urethral, brain mammarian, ovarian cancer, or, ischemia, and benign
 prostatic hypertrophy or hyperplasia (BHP).
 The language "undesirable cell proliferation" is intended to include
 abnormal growth of cells that can be detrimental to a subject's
 physiological well being. Effects of undesirable cell proliferation can
 include the release of toxins into the subject, fever, gastritis,
 inflammation, nausea, weakness, coma, headache, water retention, weight
 gain or loss, immunodeficiency, death, etc. The undesired cells that
 proliferate can include cells that are either benign or malignant.
 Examples of undesirable cell proliferation include aberrant cell division
 and/or proliferation of foreign cells, such as in cancer cells.
 The terms "aberrant cell" or "aberrant tissues" as used herein, is art
 recognized and is intended to include aberrant cell division and/or
 proliferation where cells are generated in excess of what is considered
 typical in physiologically similar environment, such as in cancers.
 The language "control of undesirable cell proliferation" or "controlling
 undesirable cell proliferation" is intended to include changes in growth
 or replication of undesired cells or eradication of undesired cells,
 cancer, or those cells associated with abnormal physiological activity.
 The language includes preventing survival or inhibiting continued growth
 and replication of an undesired cell. In one preferred embodiment, the
 control of the undesired cell is such that an undesired cell is
 eradicated. In another preferred embodiment, the control is selective such
 that a particular targeted undesired cell is controlled while other cells
 which are not detrimental to the mammal are allowed to remain
 substantially uncontrolled or substantially unaffected, e.g., lymphocytes,
 red blood cells, white blood cells, platelets, growth factors, etc.
 The term "cancer" is art recognized and is intended to include undesirable
 cell proliferation and/or aberrant cell growth, e.g., proliferation.
 The term "modulate" includes effect(s) targeted tissue(s) that prevent or
 inhibit growth of diseased tissue, which may ultimately affect the
 physiological well being of the subject, e.g., in the context of the
 therapeutic methods of the invention.
 The term "inflation fluid" is intended to include those solutions, e.g.,
 aqueous solutions, which can be administered to a subject through a device
 of the present invention without subsequent adverse effects. In general,
 the inflation fluid is considered a pharmaceutically acceptable carrier or
 vehicle. The phrase "phannaceutically acceptable carrier" as used herein
 means a pharmaceutically acceptable material, composition or vehicle, such
 as a liquid, diluent, excipient, or solvent, involved in carrying or
 transporting a medicament useful in the present invention within or to the
 subject such that it can performs its intended function.
 Each carrier must be "acceptable" in the sense of being compatible with the
 other ingredients of the formulation and not injurious to the patient.
 Some examples of materials which can serve as pharmaceutically acceptable
 carriers include excipients, such as cocoa butter and suppository waxes;
 oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive
 oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols,
 such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such
 as ethyl oleate and ethyl laurate; agar; buffering agents, such as
 magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free
 water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer
 solutions; and other non-toxic compatible substances employed in
 pharmaceutical formulations.
 Besides inert diluents, the inflation fluid can also include adjuvants such
 as wetting agents, emulsifying and suspending agents, lubricants, such as
 sodium lauryl sulfate and magnesium stearate, as well as coloring agents,
 release agents, coating agents, preservative agents and antioxidants can
 also be present in the compositions.
 Examples of pharmaceutically acceptable antioxidants useful in the
 inflation fluids include: water soluble antioxidants, such as ascorbic
 acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
 sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl
 palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
 lecithin, propyl gallate, alpha-tocopherol, and the like; and metal
 chelating agents, such as citric acid, ethylenediamine tetraacetic acid
 (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
 The medicament may conveniently be presented in unit dosage form and may be
 prepared by any methods well known in the art of pharmacy. The amount of
 active ingredient that can be combined with a carrier material, e.g., an
 inflation fluid, to produce a single dosage form will generally be that
 amount of the medicament that produces a therapeutic effect. Generally,
 out of one hundred per cent, this amount will range from about 1 percent
 to about ninety-nine percent of active ingredient, preferably from about 5
 percent to about 70 percent, most preferably from about 10 percent to
 about 30 percent.
 Methods of preparing these formulations include the step of bringing into
 association a medicament with the carrier and, optionally, one or more
 accessory ingredients. In general, the formulations are prepared by
 uniformly and intimately bringing into association a medicament with
 liquid carriers.
 Formulations of the invention suitable for administration may be in a
 solution or a suspension in an aqueous or non-aqueous liquid, or as an
 oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,
 each containing a predetermined amount of a medicament as an active
 ingredient.
 Liquid dosage forms for administration of the compounds of the invention
 include pharmaceutically acceptable emulsions, microemulsions, solutions,
 suspensions, syrups and elixirs. In addition to the medicinal ingredient,
 the liquid dosage forms may contain inert diluents commonly used in the
 art, such as, for example, water or other solvents, solubilizing agents
 and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
 carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene
 glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut,
 corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl
 alcohol, polyethylene glycols and fatty acid esters of sorbitan, and
 mixtures thereof.
 Suspensions, in addition to the medicament, may contain suspending agents
 as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol
 and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide,
 bentonite, agar-agar and tragacanth, and mixtures thereof.
 Actual dosage levels of the medicament in the inflation fluids used in
 conjunction with this invention may be varied so as to obtain an amount of
 the medicament which is effective to achieve the desired therapeutic
 response for a particular patient without being toxic to the patient.
 The selected dosage level will depend upon a variety of factors including
 the activity of the particular medicament, the time of administration, the
 rate of excretion of the particular medicament being employed, the
 duration of the treatment, other drugs, compounds and/or materials used in
 combination with the particular medicament employed, the age, sex, weight,
 condition, general health and prior medical history of the subject being
 treated, and like factors well known in the medical arts.
 A physician or veterinarian having ordinary skill in the art can readily
 determine and prescribe the effective amount of medicament required. For
 example, the physician or veterinarian could start doses of the medicament
 employed in the pharmaceutical composition at levels lower than that
 required in order to achieve the desired therapeutic effect and gradually
 increase the dosage until the desired effect is achieved.
 In general, a suitable dose of the medicament will be that amount of the
 medicament that is the lowest dose effective to produce a therapeutic
 effect. Such an effective dose will generally depend upon the factors
 described above. Generally, doses of the medicament for a subject, when
 used for the indicated analgesic effects, will range from about 0.0001 to
 about 100 mg per kilogram of body weight per day, more preferably from
 about 0.01 to about 50 mg per kg per day, and still more preferably from
 about 0.1 to about 40 mg per kg per day.
 If desired, the effective daily dose of the medicament may be administered
 as two, three, four, five, six or more sub-doses administered separately
 at appropriate intervals throughout the day, optionally, in unit dosage
 forms.
 In accordance with the present invention, the membrane 20 is formed from a
 hydrophilic polymer exhibiting a predetermined permeability to migration
 of the inflation fluid through its wall. A suitable hydrophilic polymer is
 one that will contain between about 50% and about 98% water by weight in
 equilibrium following imbibition of an inflation fluid and have a
 permeability coefficient P.times.10.sup.7 (cm.sup.2 sec.sup.-1) of at
 least 150 in its inflated state.
 In a preferred embodiment, the membrane permits passage of molecules having
 molecular weight between about 100 MW to about 85,000 MW, for example
 between about 100 MW and 500 MW, between about 400 MW and 1000 MW,
 preferably between about 1000 MW and about 5000 MW, more preferably
 between about 3000 MW and about 10,000 MW and most preferably between
 about 25,000 MW and about 85,000 MW. The ranges of molecular weight
 intermediate to those listed are also intended to be part of this
 invention, e.g., about 100 to 1000 and about 1000 to about 2000 MW and
 about 15,000 MW to about 20,000 MW. For example, ranges of molecular
 weight values using a combination of any of the above values recited as
 upper and/or lower limits are intended to be included.
 In one embodiment, the membrane polymer has an elongation coefficient of at
 least 1000% upon inflation, preferably at least 500%, more preferably at
 least 300%, most preferably 200%, such that the membrane matrix swells
 into a shape which conforms within or to the body cavity and contacts the
 surrounding tissue, e.g., a balloon, sausage or ball shape. The term
 "elongation coefficient" is intended to mean that the membrane can expand
 in any of the x, y, z coordinates to at least 10 times the uninflated
 dimensions, preferably at least 5 times, more preferably at least 3 times,
 most preferably at least 2 times its uninflated dimensions without tearing
 or spilling the contents of the inflation fluid into the body cavity. The
 elongation coefficient ranges intermediate to those listed are also
 intended to be part of this invention, e.g., at least about 150% to about
 250%, at least about 350% to about 650%. For example, ranges of elongation
 coefficients using a combination of any of the above values recited as
 upper and/or lower limits are intended to be included.
 The term "hydrophilic" is art recognized and is intended to include those
 organic and/or inorganic functional groups which are more soluble in water
 than in nonpolar or hydrocarbon solvents, e.g., water wettable or
 dissolvable. Suitable examples of hydrophilic polymers include those which
 have alkoxides, such as phenols, hydroxybiphenyls, polyalkylene oxides
 (polyethers), polyamines, biphenyls, hydroxylated acrylates and
 methacrylates, e.g., hydroxylated alkyl acrylates and methacrylates, e.g.,
 hydroxyethyl acrylates, hydroxyethyl methacrylates,
 hydroxypropylacrylates, hydroxypropylmethacrylates, polyalkylene oxide
 acrylates and methacrylates and sugar based derivatives, e.g.,
 cellulosics.
 The term "hydrogel" is art recognized and is intended to include those
 polymers that swell with an aqueous solution, e.g., water, between two
 weight percent and 60 weight percent per volume of gel. Hydrogels are
 typically 80 to 90% water, preferably between about 50% and 98%, having
 indices of refraction close to 1.3. Mechanically, the hydrogels should be
 able to support a breaking tensile stress of between 40,000 and 60,000
 dynes/cm2. Chemically, the hydrogels should remain stable and not degrade
 in vivo. Hydrogel membranes utilized in the present invention can be
 crosslinked with known crosslinking agents.
 The term "membrane" is art recognized and is intended to include those
 polymeric materials which selectively facilitate the diffusion of small
 molecules in preference over larger molecules. The membrane can be
 selected so that molecules of a given molecular weight can pass through
 the polymeric matrix and molecules with larger molecular weights are
 retained and do not pass through the polymeric matrix. Preferably the
 membrane polymeric matrix is a hydrogel.
 The membrane polymeric matrix can be crosslinked via those cross-linkers
 known in the art. For example, di, tri, or tetra acrylates can be used
 with those monomers listed above to form a crosslinked matrix. Typically,
 the hydrogel membrane is lightly crosslinked, having a cross-link density
 of less than 25%, preferably less than 15%, more preferably less than 10%,
 still more preferably less than 5%, and most preferably less than 2%,
 e.g., between about 0.1% and 0.5%. The resulting crosslinked membrane
 still retains the elongation coefficient of expansion as described above.
 The degrees of cross-link density intermediate to those listed are also
 intended to be part of this invention, e.g., between about 0.2% and about
 0.75%, between about 0.8% to about 1.5% and between about 1.75% to about
 2.5%. For example, ranges of cross-link density using a combination of any
 of the above values recited as upper and/or lower limits are intended to
 be included.
 Membranes are often associated with pore structure, e.g., an effective
 opening for passage of molecules. In one embodiment, membranes useful in
 this invention can be considered ultrafiltration membranes. In other
 embodiments, the pore sizes, in cases where there are distinct pore sizes,
 range from between about 0.01 microns to about 50 microns, preferably
 between about 0.02 microns to about 10 microns, more preferably between
 about 0.05 microns to about 5 microns, most preferably between about 0.1
 microns to about 2 microns and between about 0.2 microns to about 2.5
 microns. The ranges of pore sizes intermediate to those listed are also
 intended to be part of this invention, e.g., about 100 to 1000 and about
 1000 to about 2000 MW and about 15,000 MW to about 20,000 MW. For example,
 ranges of molecular weight values using a combination of any of the above
 values recited as upper and/or lower limits are intended to be included.
 In FIG. 2A, a drug delivery catheter 10, constructed in accordance with the
 present invention, is depicted in its deflated position. Membrane 20
 resides within lumen 16 of tubular body 14 and is fixedly attached at
 distal end 24. As an inflation fluid is injected through lumen 16,
 membrane 20 expands outwardly from tubular body 14 as shown in FIG. 2B.
 The expansion of membrane 20 is dependent upon the length of membrane 20
 and the applied pressure of inflation fluid. By this method, membrane 20
 can conform to the body cavity to which it is proximate.
 FIG. 3, a drug delivery catheter 28, is shown as an elevational view of the
 device. Membrane 20 is shown in a partially inflated position. The device
 includes control handle 29 for positioning of the catheter within a body
 cavity. In one embodiment, an inflation fluid containing a therapeutic
 agent is injected through a lumen or inflation port(s) (not shown) to
 inflate membrane 20 within a body cavity. Insertion tube 30 can be
 slidably positioned within a lumen of catheter 28 such that a radioactive
 pellet(s), e.g., seed(s), 32 irradiate the inflation fluid and therapeutic
 agent within membrane 20, thereby inducing a radiosensitizing or a
 chemotherapeutic effect on the surrounding tissue in contact with membrane
 20 and the therapeutic agent exuding therefrom.
 In a preferred embodiment, a distal portion of the membrane/catheter and a
 distal portion of the insertion tube can be detached from the main body of
 the catheter and insertion tube such that the detached portions remain in
 the body cavity for an extended period of time, e.g., 1 day to several
 weeks. It should be understood that the detached membrane/catheter portion
 retains a reservoir of inflation fluid containing a therapeutic agent,
 e.g., a radiosensitizer or a chemotherapeutic agent. In one embodiment,
 only the membrane/catheter portion and inflation fluid is left in the body
 cavity. In another embodiment, a portion of the insert tube is also
 detached, thereby allowing radioactive seeds in the lumen to continue to
 irradiate the therapeutic agent(s), e.g., a radiosensitizer, in the
 inflation fluid.
 FIG. 4A depicts another embodiment of a drug delivery catheter 28,
 constructed in accordance with the present invention. Membrane 20 is shown
 in a partially inflated position. The device includes control handle 29
 for positioning of the catheter within a body cavity. As shown in FIG. 4B,
 an inflation fluid containing a therapeutic agent is injected through
 inflation ports 18 to inflate membrane 20 within a body cavity.
 Separately, a second membrane 33, abutting membrane 20 is inflated with a
 radioisotopic solution or a second inflation fluid via a lumen (not shown)
 or inflation ports (not shown) so that inner chamber reservoir 34 expands.
 The radioisotope solution produces ionizing radiation that interacts with
 the therapeutic agent contained within membrane 20, thereby inducing a
 radiosensitizing or a chemotherapeutic effect on the surrounding tissue in
 contact with membrane 20 and the therapeutic agent exuding therefrom. In
 one embodiment, the second membrane 33 does not permit passage of the
 radioisotope solution through the second membrane, e.g., the membrane is
 impermeable to fluids. Preferably, injection of inflation fluid containing
 a radioisotope into the second membrane 33 pressurizes the outer membrane
 balloon 20, such that a constant stream of first inflation fluid is
 delivered to the tissue.
 In instances where a radioisotopic solution is not utilized in the
 inflation fluid in reservoir 34, the inflation fluid serves as a means to
 pressurize the outer inflated membrane balloon 20, thereby facilitating
 delivery of the first inflation fluid containing a therapeutic agent to
 the site for application. The second inflation fluid and second chamber
 34, thereby serve to keep the outer membrane pressurized such that a
 constant stream of first inflation fluid is delivered to the tissue. It is
 to be understood that any of the devices of the invention can include a
 second membrane, as described above, to pressurize or maintain pressure in
 a first outer membrane and reservoir, thereby delivering the therapeutic
 agent at a constant rate, for example, in the presence of ionizing
 radiation supplied by an injection rod as described above. In certain
 embodiments, the second membrane does not allow passage of fluids into or
 out of the membrane, e.g., it is impermeable and can be considered a
 barrier.
 The invention is also drawn to methods for treating aberrant cells or
 cancer in a body cavity. The methods include inserting a catheter
 including an elongated tubular body member into a body cavity, the tubular
 body having a proximal end, a distal end and a lumen extending
 therebetween, with an inflation port extending through a wall of the
 tubular body member in fluid communication with the lumen. An expandable
 membrane member is affixed to the catheter body member near the distal end
 and in fluid communication with at least one inflation port.
 The membrane member includes a hydrophilic polymer having a predetermined
 permeability to migration of inflation fluid therethrough. An inflation
 solution containing a medicament is injected into the expandable membrane
 such that the medicament permeates through the membrane over a period of
 time treating the aberrant.
 In one embodiment, the method further includes slidably positioning an
 insertion tube with one or more radioactive pellets, e.g., seeds, into a
 lumen of the catheter, such that ionizing radiation strikes the
 medicament, preferably a chemotherapeutic agent or a radiosensitizer,
 thereby treating the aberrant cells with an activated medicament.
 In another embodiment, the methods include inflating a second membrane that
 is fixedly attached to the catheter and proximate to the first membrane
 with a solution containing a radioactive isotope. Preferably, the
 radioactive solution emits ionizing radiation that interacts with a
 chemotherapeutic agent or a radiosensitizer forming activated molecules
 useful for treating aberrant cells or cancer.
 In a preferred embodiment, the distal portion of the
 membrane/catheter/inner chamber can be detached from the main body of the
 catheter such that the detached portions remain in the body cavity for an
 extended period of time, e.g., 1 day to several weeks. It should be
 understood that the detached membrane/catheter/inner chamber portion
 retains a reservoir of inflation fluid containing a therapeutic agent,
 e.g., a radiosensitizer or a chemotherapeutic agent and a solution having
 at least one radioisotope.
 To prepare the balloon/membrane structure 20, the catheter body stock 14
 and membrane 20 are bonded and when inflated by an aqueous solution
 containing a water soluble drug, the inflation fluid is found to permeate
 through the polymeric membrane with the rate of flow being governed by the
 composition and thickness of the membrane and the pressure differential
 across the polymer wall. Membrane thickness range from between about 0.01
 mm to about 1 mm, preferably between about 0.05 mm to about 0.8 mm, more
 preferably between about 0.1 mm to about 0.5 mm.
 For example, membrane materials made of polyacrylates useful in the present
 invention are commercially available from SKY Polymers, Inc (Rocky Hill,
 N.J.). In fabricating the membranes, an acrylic acid-derived hydrophilic
 polymer is dissolved in a water soluble solvent to yield a final solution
 of 10% polymer and 90% solvent. The polymer solution can then be applied
 by dipping to an appropriately shaped mandrel and solidified, via water
 coagulation. The polymer and the mandrel can then be placed in deionized
 water for at least two hours until about a 95% water content is reached.
 The solidified polymer is then removed from the mandrel and placed into a
 solution of 0.9% NaCl for about 24 hours to equilibrate to a final water
 content of about 90% as shown in FIG. 5.
 The membrane can be secured to the proximal end of the catheter by a
 variety of means, which are known in the art. The membrane and catheter
 can be formed integrally or unitarily, or may be bonded together. The
 membrane, in an uninflated or collapsed state, can be positioned
 substantially surrounding the outer proximal surface of the catheter, as
 is conventional for balloon catheters. Alternatively, the uninflated or
 collapsed membrane can be positioned within a recess at the proximal end
 of the catheter. The membrane can be inflated in response to a supply of
 fluid under pressure through the first catheter lumen, and in an inflated
 state extends outwardly from the recess(es) in the catheter to fill the
 interstitial body cavity. In the collapsed condition, the membrane can be
 dimensionally adapted for fitting within the interstitial cavity, and in
 the inflated condition can be dimensionally adapted to volumetrically
 substantially fill the interstitial cavity and thereby forcibly cause the
 tissue wall surrounding the cavity to stretch or expand. Additionally, the
 membrane can be dimensionally adapted to extend into the interstitial
 cavity a select distance and thereby contact, in the inflated condition,
 only a portion of the interstitial.
 It is important to recognize that the hydrophilic polymer (a hydrogel) is
 not merely a coating layer on a permeable or impermeable membrane as known
 in the art as a surface treatment to enhance lubricity. In contrast, the
 polymeric compositions (e.g., hydrogels) of the present invention comprise
 the permeable membrane itself.
 This invention has been described herein in considerable detail in order to
 comply with the patent statutes and to provide those skilled in the art
 with the information needed to apply the novel principles and to constrict
 and use such specialized components as are required. However, it is to be
 understood that the invention can be carried out by specifically different
 equipment and devices, and that various modifications, both as to the
 equipment and operating procedures, can be accomplished without departing
 from the scope of the invention itself. All publications and references
 cited herein, including those in the background section, are expressly
 incorporated herein by reference in their entirety.