JPH07500523A - Polymer matrix drug delivery device and method - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Polymer Matrix Drug Delivery Apparatus and Method l Hadaki 11 1.1 The present invention provides a drug delivery device and device for selectively and locally administering drugs to body tissues. and methods. In particular, the present invention provides a polymeric matrix containing a drug; and a delivery means that actively transports the drug from the polymer matrix to body tissues. The invention relates to a catheter device.

2, l production strain 11 Various techniques are known for administering drugs and other pharmaceuticals to body tissues. Among these can be administered by mouth, by intramuscular injection directly into body tissues, or if the drug is applied to the skin or other surfaces. transdermal or topical medications that are passively absorbed through There are intravenous administrations that are injected directly into the body.

With the exception of transdermal dosing, the above dosing regimens are systemic.

In other words, the drug is administered throughout the body through the blood. For transdermal administration, the drug is selected. Although it can be called local medication because it is delivered locally to the affected area, this medication method also requires external administration. It is limited to administration through the patient's skin and other surface tissues.

Therefore, all of the above medications are generally suitable for local treatment of body tissues. Not yet. Because of these limitations in transdermal dosing and problems with systemic dosing, local Attention has been focused on the benefits of devices that deliver internal medication. In particular, local internal The drug device is designed to avoid overdosing associated with systemic medications, which can have adverse side effects. I can do it.

Additionally, systemic medications do not allow for the concentration of therapeutic agents in the local areas where they are most effective. stomach. Furthermore, by treating only the affected tissue with a local dispensing device, total drug usage is reduced. The dose can be drastically reduced, resulting in lower treatment costs. In addition, local medication is Although it is highly effective, it is thought to be highly toxic and lack specific efficacy when administered systemically. This allows for the use of therapeutic drugs.

percutaneous transluminal coronary angioplasty swelling in lcoronary angioplasty/PTCA) One example is the ability to treat dilated vessels, limiting or preventing restenosis. P.T.C.A. In the procedure, the catheter is inserted into the cardiovascular system under local anesthesia and then inflated. The inflatable balloon section inflates to compress the atherosclerotic area and widen the lumen of the artery. Geru. While PTCA treatment is generally successful, there is a high re-closure rate (reportedly 47%). ) remains a major problem. As a treatment for narrowed blood vessels, various treatments such as the use of lasers, the addition of heat, and the use of intravascular stents (5 tents). Placements have been tried. However, this and other treatments have failed. PTC In treatment A, drugs are administered to the dilated part of the artery without causing significant damage to other tissues. If administered locally, the problem of restenosis would be greatly alleviated.

A second example of the specific use of a topical dispensing device for administering drugs to body tissues is the use of cancer tumors. This is the case in the treatment of tumors, etc. In the treatment of such tumors, the aim is to The goal now is to administer anticancer drugs so that they concentrate as much as possible in cancerous tumors. child Drugs are generally administered systemically through the blood. Therefore, such drugs Many measures have been taken to focus on cancerous tumors. However, many of the drugs still circulate through the bloodstream and affect non-cancerous tissues, causing unwanted side effects. effects and limit the administration of drugs that can be safely used.

A catheter-based drug delivery device has been developed to enable the above treatment. ing. A double balloon catheter is used to seal the balloon inside a vessel or other conduit. Medication is administered to the chained area. However, this device has no communication between the balloons. The drawback is that the drug leaks out of the blood vessels. Also, by applying pressure A porous balloon that allows the drug solution to be administered directly into a hollow organ by passing through the wall of the porous balloon. A tone is also used.

Catheter-based local drug delivery devices are somewhat effective, but therapeutic Designed to deliver drugs in solution. This limitation is the source of some drawbacks. It becomes.

First, the desired therapeutic agent must be readily soluble in an appropriate solution. However, water soluble Many drugs are poorly soluble in liquids.

Second, the catheter is a conduit or tube for introducing and sometimes draining the solution. and terminal chemical reservoirs. These devices typically A bulge that acts as a drug reservoir or restricts drug movement to a specific part of a vessel or hollow organ. Use an inflatable balloon. Conduits are not required for the introduction or evacuation of liquid drugs. one or more for inflating or deflating the catheter balloon. It is necessary to provide another conduit above. With multiple conduits as described above, the catheter Not only is the cell complex and costly, but its shape is also large. This limits its use.

Third, defective or damaged conduits or Otherwise, there is a risk of the balloon leaking. The leak led to serious overmedication. This can result in wasted medication intended for topical administration.

Fourth, the drug solution must be prescribed by a physician and injected into the catheter. . This complicates steps, costs additional time and money, and prevents fraud. It could be a reliable medication.

U.S. Pat. No. 5,102.402 to Dror et al. The use of drugs contained in microcapsules placed on the outer surface of the tube-type catheter The purpose is described. This capsule is ruptured by sonic energy. Break When ruptured, the capsule delivers the drug inside. However, this patent does not allow the drug to be activated into surrounding tissues. There is no description of the sonic introduction method for transporting the air to the source. Instead, the drug is passively diffused. is carried by the plant, and its penetration is limited.

Therefore, prior art techniques include the application of non-liquid drugs selectively and locally to body tissues; What is needed is a device and method for active delivery without significant tissue impact. It will be done.

Limiting restenosis after PTCA, treating cancer tumors, and a variety of other medical conditions There is also a need for devices and methods for localized treatment of internal tissue for treatment.

1 person and 1 person According to the present invention, a polymer matrix incorporated into a catheter-based delivery device Actively deliver drugs or drug combinations selectively and locally to body tissues using Apparatus and methods for dispensing have been provided. This invention applies to blood vessels, ureters, intestinal tracts, reproductive tracts. active delivery of a drug or drug combination generally widthwise relative to the longitudinal axis of a body passageway, such as device or device that treats the passageway itself or a local area or tissue adjacent to the passageway. and methods. Furthermore, the present invention enables the application of drugs or mixed drugs directly to body tissues. Also relates to sexual dispensing devices and methods.

In a preferred embodiment, the device is designed for insertion into a body passageway or tissue. a flexible member coupled to the flexible member for application to a passageway wall or local tissue; and drug delivery means for delivering the drug via the drug. The drug delivery means is a polymer - Contains drug stored within the matrix. Treatment from polymer matrix Also included is a delivery means that cooperates with the drug delivery means to actively transport the drug to the area. There is. The means of transport typically involves iontophoresis or uses phonophoresis.

The method according to the invention comprises a drug comprising a polymeric matrix containing a drug. disposing the delivery member in the body passageway such that the delivery member traverses the predetermined local dosing area; Including. Once the drug delivery member is in place, the drug is actively absorbed into the polymer. - Carried from the matrix and delivered to the desired area of the passageway. Drug delivery to body tissues The method of delivery involves the placement of a drug delivery member into the desired area of body tissue and the use of a polymer matrix. involves the active transfer of selected agents from the drug to the target area of the body's tissues.

Polymer matrix containing drug can be used as a pluggable slow sustained release device has been used. However, the present invention provides an active delivery means, i.e., the drug is transferred to a polymer. Iontophoresis or sonic guidance for rapid and effective transfer from the matrix to the target area An entry method has been added.

The present invention also relates to conventional catheter-based local drug delivery devices. solve many problems. A conduit that delivers and drains a drug solution because the drug is not in liquid form. There is no need to provide one. This reduces catheter size and thus costs. limit is possible. The matrix is pre-filled with a known amount of drug and and active delivery methods such as iontophoresis or sonophoresis to enable controlled dosing. Distributed by stages. The polymer matrix also prevents drug solution leakage and This also avoids the problems associated with this. Finally, the drug is transferred to the polymer matrix. The catheter is prefilled, allowing for easy preparation, injection, and circulation into the catheter. It can be inserted without any additional steps, saving time and making it easy to use. make it easier.

These and other advantages of the present invention are illustrated in the drawings, preferred embodiments and method description. This becomes clear from the statement of the claim.

K Bloody Evil 11 FIG. 1 shows a catheter comprising a polymer matrix and a delivery means; Partial cross section showing the state before expansion of the first embodiment of the drug delivery device according to the present invention Figure 2 shows the transfer means positioned within the polymer matrix. , a partial cross-sectional view of the drug delivery device of FIG. 1; FIG. 3 shows, after removing the transport means from the polymer matrix: A partial cross-sectional view of the device of FIG. 1; FIG. 4 shows another implementation of the drug delivery device according to the invention. Example partial cross-section, FIG. 5 shows a portion of the drug delivery device with the polymer matrix expanded. Partial sectional view, Figure 6 shows the embodiment of Figures 4 and 5 in a state where the catheter is ready for removal. A partially sectional view, FIG. 7A, shows a manually loaded wire basket used in this invention. Schematic diagram of the cut electrode, Figure 7B shows the manually loaded wire basket electrode of Figure 7A in an expanded state. Schematic diagram, FIG. 8A shows a balloon for inflating the polymer matrix and the balloon for inflating the polymer matrix. incorporating an expandable electrode between the tube and the polymer matrix; However, FIG. 8B is a partial cross-sectional view of another embodiment of the drug delivery device according to the present invention. a partial cross-sectional view of the catheter of FIG. 8A in a state; FIG. 9A shows a drug delivery system according to the invention incorporating a balloon for inflation and a central electrode. A partial sectional view of another embodiment of the feeding device, FIG. 9B is a partial cross-sectional view of the catheter of FIG. 9A in an inflated state; FIG. 10 shows a drug according to the invention incorporating a balloon for inflation and a sonic transducer. A partial cross-sectional view of another embodiment of the dispensing device, Figure 11 requires expansion of the polymer matrix to achieve a close-fitting structure. Other embodiments of the drug delivery device according to the invention for use in internal body tissues A partial cross-sectional view of FIG. 12A shows the assembly of a movable sheath to protect the polymer matrix. Figures illustrating other embodiments of the drug delivery device according to the present invention, including FIG. 12B shows the sheath retracted and the polymer matrix removed to deliver drug. 12B shows the catheter of FIG. 12A with the catheter exposed; Figure 13 shows a porous outer thin film to protect the polymer matrix. FIG. 6 is a diagram illustrating another embodiment of the drug delivery device according to the present invention incorporated therein;

Dislocation of the beautiful 1 to 13 show preferred embodiments and various modifications of the drug delivery device according to the present invention. Give an example. This device has minimal, if any, effect on other body tissues. by delivering a drug or combination of drugs to a limited area of the body's internal passageways. , means for treating a restricted area of said passageway or a restricted area adjacent to said passageway. and systems. Catheters used in this application The term refers to the opening of internal passageways in the body for the purpose of injecting and expelling fluids into and out of the body. to be inserted into a body passageway for maintenance or for any other purpose. It broadly encompasses all designed medical devices. Drug according to this invention Delivery devices are suitable for various body passageways such as blood vessels, urinary tract, intestinal tract, reproductive tract, respiratory tract, etc., among others. It can be used for

Many of the embodiments disclosed herein apply drugs or compounds to limited areas of internal body tissue. Mixed medicines can also be distributed.

For this purpose, the device of the invention comprises a polymer matrix surrounding the transport means. a flexible catheter connected to a drug delivery element having a catheter. Said The means for transporting the polymeric matrix to the target area of internal body tissue. , used for active delivery of drugs.

Catheters are percutaneous caliber catheters used to dilate narrowed blood vessels or arteries. Canaloplasty (percutaneous transluminal colon) Commonly used in angioplasty (PCT A)) has been done. These catheters include the patent disclosed in U.S. Patent No. 4,323,071 “over-the-wire” of the type shown ``catheter and catheter disclosed in U.S. Patent No. 4,582,181. Includes “fixed-wire” catheters . These catheters may be modified in accordance with this invention.

The present invention is used to describe a method for treating restricted areas of body passageways to prevent recurrence of strictures. An example applied to suppress this will be explained. And an explanation of this suppression of restenosis Next, an example in which the present invention is applied to tumor treatment will be described.

As mentioned above, PCTA is used to treat atherosclerosis and other arterial passageway narrowings. It has proven to be a highly successful procedure in the treatment of certain diseases. normal In PCTA, a dilation catheter is advanced along an artery to a desired location in the arterial system. be made to proceed. This catheter has an inflatable balloon at its tip. and means for inflating the balloon. the balloon is in the stenotic area Once in position across the area, the balloon is inflated to cause atherosclerosis. Compress the area of arteriosclerosis and dilate the artery in a direction approximately perpendicular to the arterial wall; thereby expanding the caliber of the artery. After this treatment, the balloon is deflated; The catheter is retracted.

Although the above-mentioned PCTA generally produced excellent results, the incidence of restenosis was relatively high (dilated The rate at which arteries close again remains a major problem. This kind of restenosis In addition to the common gradual restenosis, these include thrombotic occlusion and vascular spasm. .

According to the method of the present invention, reactions leading to reocclusion can be prevented or suppressed. To biologically inactivate the walls of carious vessels, drugs called fixatives or fixatives are used. , delivered exclusively to the dilated portion of the blood vessel. The nature of the fixative and the The fixative inactivates the living cells and the tissues it comes in contact with are biologically active. Due to their ability to inactivate the arterial wall, these fixatives are recommended only for dilated arterial wall areas. It is necessary to be exposed.

Preferred method and device for delivering fixative in a limited manner to dilated blood vessels The positioning is achieved by a catheter designed according to the present invention. said medicine The catheter delivering the agent may be the same as the catheter dilating the blood vessel. , thus one catheter performs two functions. with an alternative The blood vessel is then dilated by a catheter specifically designed for dilatory function, A second catheter may then be inserted for drug delivery function. Izu Modified catheters useful in both methods are shown in FIGS. 1-3, FIG. It is shown in FIG.

In the embodiment shown in FIG. 1, the impervious end cap 17 is a generally cylindrical polyester. provided at both ends of the polymer matrix 12, and 12 is prevented from moving longitudinally along catheter body 11. deer However, the end cap 17 is optional and prevents the drug from moving in the axial direction during drug transfer. Depending on the extent of the leak and the undesirable effects that drug leaks may have on the patient, May be added or removed.

Electrode passages 14 are arranged on both sides of the polymer matrix 12 to accommodate the catheter. It extends along the main body 11.

The wire 16 is attached to an electrode 18 provided at the tip of the passage 14. Ru. The wire 16 extends from the proximal end of the catheter body 11 to the distal end. It is attached to the electrode 18 at a portion.

The embodiments described with reference to Figures 1 to 10 (all of which are radially expanded) Polymer matrices used as drug reservoirs in Rix materials should be pliable and expandable, ideally incompressible or The material should have minimal compressibility. The expansion means is as shown in FIG. electrode 18, wire basket 5 as shown in FIG. 5, wire as shown in FIG. 7A. Basket 70. Or, regardless of whether it is a balloon as shown in FIG. The material is pliable and expandable such that it can be expanded sufficiently by said expansion means. Must be material.

The compressibility of the material determines the diameter of the catheter when the material is expanded. and thereby maximize the distance between the polymer matrix and the target tissue. Preferably, the compression ratio is limited to such that it ensures intimate contact and increases drug transfer efficiency. stomach. Furthermore, regardless of the compressibility of the polymer matrix material, the expansion means said polymer matrix material as long as it is designed to ensure intimate contact. The material may be compressible.

In embodiments that do not expand radially, such as the one shown in FIG. The polymer matrix material need not be expandable or incompressible; In practice, it may be rigid if desired.

The term "polymer matrix" as used in connection with this invention refers to hydroxylated Aluminum gel, polyvinyl alcohol, polyvinylpyrrolidone, polymer Reacrylamide, polyethylene oxide, polyhexamethylene aziboamide (2 - other porous or drug-permeable materials such as (hydroxyethyl methacrylate) Synthetic polymers consisting of structures; natural polymers such as rubber and starch; silico This term includes synthetic elastomers such as rubber; and natural rubber. the above The examples are for reference only; other suitable polymer matrix materials may be used. You may.

Furthermore, as long as the above-mentioned physical characteristics are met, the polymer matrix The box material may be hydrophilic or hydrophobic.

Drugs can be injected into the polymer matrix material by various methods. I can do it. The drug is formed into an annular form, preferably a polymer solution or dispersion. It can be injected at the same time. Further, the drug may be formed into the desired shape. Later (e.g. by iontophoresis/ontophoresis) can be passively or actively injected into the polymer matrix material. Wear. The agent may also be present in a solvent (e.g., water, propylene, glycol, etc.). The resulting solution can be dissolved in the polymer matrix material. Can be injected into food. Alternatively, drug molecules can be directly added to the polymer matrix. It can be injected into the trix material.

FIG. 2 shows that the polymer matrix 12 is expanded within an arterial blood vessel having a wall 15. 2 shows the drug delivery device of FIG. 1 in a state shown in FIG. In PTCA treatment, catheter The catheter, having a body 11 and a polymer matrix 12, is used in the arterial system. is advanced to a desired location, at which point the polymer matrix 12 is Cross the stenotic area. Then, the electrode 1 is placed in the inner chamber 13 of the matrix 12. By pulling in 8, said matrix 12 is expanded. like this wires 16 so that electrodes 18 can be drawn into said matrix 12 is attached to a handle (not shown) at the proximal end of the catheter. preferable. Wires 16 draw electrodes 18 into said matrix 12 (this (expanding the matrix 12) and expanding the electrode 18 after drawing it in. Used to energize pole 18.

When the above-described expansion is performed, the outer surface of the matrix 12 becomes similar to that of the blood vessel wall 15. The inner surface is pushed outward to dilate the narrowed area of the blood vessel. And said matric The fixative or other agent in the iontophoresis (i.

delivered into the surrounding tissue using nitophoresis.

Alternatively, the catheter according to the invention may dilate said blood vessel and Fixatives or other agents may be used to deliver the target tissue.

Generally, the preferred drug delivery means are ionic fixatives, by voltage or electric current. or driving drugs, or non-ionic fixatives or drugs in ionic solutions. This is an iontophoresis method. The iontophoresis method uses solids from the matrix 12. In this invention, it facilitates the delivery and penetration of drugs or drugs into tissues. In this case, it is preferable to use iontophoresis.

In iontophoresis, two electrodes are used to generate the required voltage or current. is used. In particular, one electrode 18 (the "catheter electrode") is The other electrode is placed inside the matrix 12, while the other electrode is placed at a distance on the patient's skin. It is preferable that they be provided at a location far apart. In some applications, the other electrode may be placed elsewhere on the patient, including appropriate internal areas; provided along the catheter body at a location away from the catheter electrode 18; Good too.

In addition to constant direct current, other waveforms (e.g., frequencies of 100 Hz or higher) The iontophoretic delivery process may be performed using a continuous square wave (number of consecutive square waves). this A more complete description of iontophoresis and DC waveforms useful in the invention can be found in Jam es E, by 5hapland and Keith Hildebrand. INTERNAL l0NTOPHORE filed on October 6, 1992 SIS ELECTRICAL CIRCUIT AND WAVE FORMS No. 077,957,209, entitled Ru.

To use iontophoresis, the solid inside the polymer matrix 12 must be It is necessary for a fixative or drug to have certain properties. Ideally, polymer - to facilitate iontophoretic transfer or transport from the matrix 12. The fixative or drug may be ionic or bound to the active component of the fixative or drug. It is necessary to have other ionic molecules combined. For the iontophoresis process in Figure 2 Current is applied to the electrodes 18. by an external power source 30 via electrical leads 22.24. Generated between 20.

The polarity of the iontophoresis electrode is determined by the excess solidity supplied to the blood vessel wall after the above procedure. It may be inverted to recapture the fixing agent.

As mentioned above, the fixative is a composition known in the art as a fixative. It is. Fixatives primarily kill fresh tissue, penetrate the tissue, and harden the tissue. to ensure that its function and structure are not altered by subsequent biological or other treatments. It functions to immobilize and render cellular components insoluble. of body tissue so that systematic slippage is prevented or body tissue is preserved for examination. Fixatives stabilize and immobilize body tissues as soon as they are exposed to the fixative. It is commonly used to

The particular fixative or fixative fluid used in this invention may It is necessary to penetrate quickly into the larks and bone tissue. The fixative hardens the bone tissue The tissue must be killed or preserved quickly while still allowing the tissue to survive. stiff Immobilization maintains the vessel in an "open" or dilated state, preventing vasospasm or its likeness. prevent or inhibit reocclusion by other acute reocclusion mechanisms.

Such immobilization also slows down the biological process that leads to gradual restenosis. or stop it. Preferred fixatives have rapid specific action at high concentrations and low At low concentrations it exerts virtually non-toxic effects.

Delivery of the fixative or drug from the polymer matrix 12 was performed. Thereafter, as shown in FIG. It is removed from the matrix 12 and preferably drawn into the holding chamber 19. Said By removing electrode 18 from polymer matrix 12, the matrix The tube 12 has a narrower caliber, which makes it easier to remove the catheter from the blood vessel. It becomes easier to

As will be understood by those skilled in the art, after use the electrode 18 is pushed into the original holding chamber 14. If means are provided, the electrode 18 may be stored in the original holding chamber 14. stomach.

However, in a preferred embodiment, a wire 16 for energizing said electrode 18 is provided. applies a compressive force sufficient to extrude the electrode 18 from the polymer matrix 12. It has become impossible to give. As a result, the wire 16 18 into the holding chamber 19, the holding chamber 19 stores the electrode 18. used for

4-6 show other alternative variations of catheters according to the invention. this catheter The main difference between the catheters of FIGS. 1-3 and FIGS. The use of a spring-loaded wire basket housed in a holding chamber 48.

The construction of the polymer matrix 42 is similar to that described for the embodiments of FIGS. 1-3. It is almost the same as .

Polymer matrix 42 is generally cylindrically disposed in catheter body 46. There is. Similar to the preferred embodiment described above, an optional impermeable end cap 4 3, the drug encapsulated in the polymer matrix is distributed along the catheter body 46. They are provided at both ends to prevent it from being carried in the axial direction. polymer matrix Box 42 also includes an inner cavity for housing a spring-loaded basket 56. 50 is provided. The opposing retention chambers 48 of the catheter body 46 are made of polyethylene. used to store the spring-loaded basket 56 after expansion of the mer matrix 42. It holds a chamber 52 in which Compressed wire bar in holding chamber 52 Storage of the sket 56 is shown in FIG.

In a preferred embodiment, spring loaded basket 56 is comprised of polymer matrix 42. In addition to being used to expand the used. Wire 54 also protects basket 56 during iontophoresis operations. The holding chamber 48, the cavity 50 of the polymer matrix 42 and the holding chamber Current is supplied to the basket 56 while moving between the baskets 52.

Referring to FIGS. 4-6, the active spring loaded basket 56 is The polymer matrix is drawn into the polymer matrix chamber 50 where it expands. be caught. After expansion, the conveying process begins to remove the proper volume from the polymer matrix 42. Electric current is applied to the electrode/wire via wire 54 to transfer fixative or other agents to the area. Loading basket 56 is fed. After the transfer process is completed, the spring-loaded basket will By compressing the spring-loaded basket 56 through the catheter body 46 A retention chamber 52 that allows the polymer matrix 42 to return to its pinched shape is further retracted to assist in removal of the catheter from the blood vessel.

As in the embodiment shown in FIGS. 1-3, the basket 56 is placed in the basket during an iontophoresis run. into position using the wire 54 which is also used to supply current to the socket 56. be drawn into. Therefore, the wire 54 is inserted into the cabinet after using the basket 56. Sufficient force cannot be applied to the basket 56 to return it to the tee 48. death However, if a suitable mechanism is used to do so, chamber 52 is unnecessary.

7A and 7B are wire baskets for use in the embodiments shown and illustrated in FIGS. 4-6. shows an alternative embodiment. Basket 70 was hand loaded rather than spring loaded. It differs from the basket 56 of the embodiment shown in FIGS. 4-6 in that it is different from the embodiment shown in FIGS. hand loading Using basket 70, holding chambers 48 and 52 shown in FIGS. The basket can be manually inflated or deflated as desired by the user. It will no longer be necessary.

FIG. 7A shows hand-loading basket 70 in a deflated or uninflated condition. In contrast, FIG. 7B shows the basket 70 in an inflated state. this basket uses a force along a wire 72 that extends through the basket to its tip 74. and inflate it. The connection of the basket at point 76 along wire 72 is such that the force A slide that, when applied to wire 72, allows movement of point 76 along wire 72. It is a push-in fit. As a result, the distance between points 74 and 76 is reduced. This translates into an expansion of the diameter of the basket 70.

Like the spring-loaded basket, the hand-loaded basket 70 is made of a polymer matrix. Ion conductor to provide a transport mechanism to transport the drug or fixative from the It also acts as an electrode when the method is used.

One advantage of the hand-loading basket 70 is that it allows you to load a specific length of wire 72 from the catheter. The user can adjust the amount of expansion of the basket by pulling. suitable In some embodiments, the wire 72 may have a length to indicate the degree of expansion of the basket 70. Maring is provided along the direction.

The polymer matrix of the present invention can provide forces that dilate blood vessel walls and In order to bond the impregnated polymer matrix sox to the blood vessel wall, it is used together with a balloon. It can be used for. Referring to FIGS. 8A and 8B, the implementation shown therein Examples include a polymer matrix disposed along the cross section of the catheter body 80. 82 included.

Optional impermeable end cap 83 is a generally cylindrical polymer of the preferred embodiment. - are arranged at both ends of the matrix 82. polymer matrix 82 The center of the is substantially cylindrical and expandable, which may be in the form of an expandable wire mesh. includes an inflatable balloon surrounded by possible electrodes.

In use, balloon 84 is inflated via lumen 85 using a suitable liquid or gas. Ru. As shown in FIG. 8B, in the inflated state, electrode 86 connects with balloon 84. expand together and release the drug or fixative contained within the polymer matrix 82. Used to provide electrical current that transports to surrounding tissue. The current flows along lumen 85. An extending wire 87 is used to feed the electrode 86 .

9A and 9B show a cover including a balloon 92 and a polymer matrix 94. An alternative embodiment of the tether 90 is shown. In this embodiment, catheter body 96 is , a core 98 extending through the balloon 92 around which the electrode 100 is coiled. including. Catheter body 96 also includes a central guidewire lumen 105.

Balloon 92 is attached along each side of catheter body 96 by adhesive or heat welding. Consisting of a substantially cylindrical cross-section of attached porous, elastic material. polymer· The matrix material 94 is placed on the outside of the balloon 92 so as to be in close contact with the blood vessel wall 101 after inflation. (See Figure 9B).

In use, balloon 92 is inflated with liquid supplied via liquid supply lumen 102. , wire lumen 104 houses a wire 106 that provides electrical current to the electrode. balloon The liquid used to inflate 92 preferably facilitates drug delivery to the target tissue. A weak electrolyte that facilitates current flow through the polymer matrix material 94 liquid or water.

FIG. 10 shows a catheter similar to catheter 90 shown in FIGS. 9A and 9B. The electrode transducer 108 of this catheter 90 has been replaced.

Transducer 108 converts the polymer matrix using sonophoresis instead of iontophoresis. The sonic energy that transports the drug from the box material 110 is generated. electricity wire supply Transducer 108 is fed using a wire 109 extending through the lumen.

The preferred liquid used to inflate balloon 112 is a polymeric liquid from transducer 108. ・Sonic energy is transmitted to the matrix 110 and further to the target tissue for drug transfer. Any material that has physical properties that facilitate the transmission of nothing.

The embodiments of FIGS. 1-10 are primarily shown as delivering fixation material to a blood vessel wall. However, the catheter according to the present invention does not allow any drug to be delivered to or through the blood vessel wall. It may be used for administration. In particular, each of the above embodiments of FIGS. It may be used for drug therapy, and each example may be used to treat tumors or other tumors in the vicinity via blood vessels. It can be used to administer drugs such as antitumor agents and antiproliferative agents to body tissues.

For example, using iontophoresis to pass through body passage walls and surrounding or adjacent tissues. generally width relative to the longitudinal axis of the passageway to treat a localized area of tissue adjacent to the passageway; The drug may be delivered in the direction. Any of the alternative embodiments of the apparatus seen in Figures 1-10 can also be used for such drug administration.

In particular, tumors require certain drugs to be administered to adjacent tumor locations, such as from blood vessels or intestinal tracts. Treat by. The invention further provides for the administration of sensitizer agents and immunomodulators. It fits well.

Administration of drugs to localized tissues or areas within the body, such as solid tumors, abscesses, and localized lymph nodes. For primary or adjuvant treatments and other situations in which it is desired to provide Another embodiment according to the invention as shown in FIG. 11 is preferred. As shown in Figure 11 The tissue delivery system includes a drug delivery device 120 that is placed within a specific tissue, such as a tumor. including.

A preferred drug delivery device 120 for use in body tissue treatment includes a flexible catheter body. 121 and a generally cylindrical polymer matrix 124. polymer ma Disposed in the trix 124 is a catheter 120 that extends to the proximal end of the catheter 120. Electrode 128 connected to wire 130.

In use, catheter body 121 moves into position. The drug is then applied to the electrode 12 Polymer matrix 124 by voltage gradient (iontophoresis) using 8 consists of The device 120 may be of large size (with a sleeve) depending on the type and location of the body tissue to be treated. Dimensions vary from pipes) to small ones (1 mm).

The embodiment of FIG. 11 preferably allows drug addition from polymer matrix 124. Use iontophoresis for extraction. Fixative, i.e. facilitates the transport of drugs and also aids in assembly. Iontophoresis is preferred because it increases textile penetration. If iontophoresis is used, the Similar to the configuration shown in FIG. 4, whereas other electrodes (not shown) are preferably placed on the patient's body. It is placed. Other electrodes may also be used in certain applications, including appropriate internal areas. may be placed in other areas of the body, and indeed at locations remote from catheter electrode 128. It may be placed along the catheter body.

For treatment of body tissue according to the present invention, an inductor (not shown) mechanically locates the lesion. after being identified visually, radiographically, thermally, ultrasonically, or by other similar methods. It is then inserted into the target area, such as a tumor. The cannula/probe is easily inserted into the tumor. It should be designed to increase the This can be done by placing bends in the cannula or other conventional This is achieved by applying mechanical design techniques.

The activation device 120 is then inserted directly above the inductor or through the space after withdrawal of the inserter. The guiding element is located within or on the guiding element. device 120 by one of the methods described above. Once the active compound is in place, the active compound is locally extracted from the polymer matrix 124. distributed to local organizations. Using an embodiment of a device 120 of the type seen in FIG. Delivery is achieved by iontophoresis. delivered to body tissue using device 120. The active compounds include, without limitation, the vinca alkaloids (vinca a lkaloids), anthracyclin antibiotics e antibiotics), platinum-like compounds, antimetabolites (ant imetabolites) (e.g. methotrexate), antibiotics, sensitizers and other compounds.

The advantage of this method is that if the vasculature in the target area is severely affected and the cells are not sensitive to the drug, Allows drug delivery to cells and interstitial spaces in the area, even if not absorbed well . These are well-known attributes of solid tumors and represent one of the outstanding obstacles to cancer treatment. ing.

In addition to injecting highly cancerous drugs into body tissues, this device can be used to treat other diseases of body tissues. and the utility of the method is within the skill of those skilled in the art.

Both the vascular delivery example (FIGS. 1-9) and the tissue delivery example (FIG. 11) Sound can be used instead of iontophoresis to transport drugs from polymer matrices to surrounding tissues. Wave introduction (phonophoresis; also called 5onophoresis) ) can be used.

Sonication is a technique that uses ultrasound, or radiofrequency waves, to transport drugs. certain cure For therapy, sonophoresis has advantages over iontophoresis, one of which is that it It can be easily distributed in its molecular form, rather than in a closed state, and can be delivered deeper into the body. There are several points that can be mentioned. Traditional sound induction has been used to treat lateral epicondylitis, sinusitis, bursitis, and osteoarthritis. Medications such as anti-inflammatories and local anesthetics that are injected through the skin to treat arthritis. Its use was limited to skin distribution.

Sonication also facilitates the delivery of fixatives, i.e. drugs, while at the same time allowing for tissue penetration. Due to its enhanced permeability, the polymer matrix materials of the present invention can be used to It is also perfect for delivering chemicals to textiles.

In addition to drug delivery, ultrasound can reduce the increased capillary permeability associated with ultrasound. It is advantageous to utilize catheters of the present invention based on tissue temperature and tissue hyperemia.

These effects enhance interstitial drug transport and cellular uptake, and here Vasodilation/relaxation advantageous for vascular medication using catheter embodiments of the type described cause to occur.

Sonication may be used in the vascular delivery embodiment or tissue delivery embodiment of the catheter of the present invention. When used in either case, the cathode electrode is an ultrasonic piezoelectric transducer connected to an external power source. (barium titanate, red zirconate titanate, etc.).

Once the catheter is in place, the ultrasound transducer is activated to deliver the drug or A fixative is delivered into the tissue surrounding the catheter.

The rate of diffusion of drugs delivered by sonic introduction depends on the ultrasound range and intensity. Conventional The transdermal method of introducing sound waves is 0°1~6 watts/crr? using the strength of A direct correlation between the amount of drug dispersed and the intensity of the ultrasound field is involved. The catheter of the present invention The internal application of sonic induction (which does not require transdermal delivery) in the Tel Example uses the same amount of drug. It is believed that significantly less intensity is required to deliver the agent. Various wavelengths available It is Noh. A frequency of about IMHz was arbitrarily used for transcutaneous sound wave introduction. Here's the explanation For internal use of the disclosed catheter embodiments, approximately IMHz or less may be required. I think that the.

In addition to using sonophoresis instead of iontophoresis as described above, the present invention Additional features that may be added to the catheter include overlying the polymer matrix material. It is a protective cover. Protective covers are not as dimensionally stable as others and may be difficult to insert and/or for polymer matrix materials that are particularly sensitive to shear and/or abrasion during removal. Beneficial to use. Shear and/or abrasion can affect polymer matrix materials. This causes some to remain in the patient's body after surgery.

To prevent this from occurring, the catheter according to the invention is equipped with various forms of protection. Equipped with a cover. The first version of the protective cover is shown in Figures 12A and 12B. The catheter 132 shown here includes a polymer matrix during its insertion. Includes an outer sheath 134 surrounding the trix 136. Placement of catheter 132 Sheath 134 is then withdrawn to extrude polymer matrix 136. and drug delivery is possible (polymer matrix as shown in Figure 12B). with or without expansion). After treatment, the sheath 134 is re-catheterized. 132 to protect the polymer matrix 136 during withdrawal. Ru.

The sheath 134 according to this embodiment of the protective cover preferably has a constant withdrawal and made of a hard material to provide elongation properties. Another advantage of sheath 134 The material used to form the drug is incorporated into the polymer matrix 136. It is generally impermeable to water. This impermeability is due to the polymer matrix. The drug in the catheter spreads inertly into the tissue during insertion or removal of the catheter 132. This prevents dispensing due to dispersion and thus ensures accurate dosing of the catheter 132. materialize.

An alternative protective cover is shown in FIG. 13 in which the outer membrane 144 covers the catheter 14. 0 polymer matrix (not shown). The catheter 140 , any form of the catheter described above.

Thin film 144 is formed using a polymer matrix by either iontophoresis or sonophoresis. The membrane 144 is porous so that the drug within the box migrates through the membrane 144.

If the outer membrane 144 is formed of a flexible material, the polymer matrix material 14 2 with electrodes, transducer, wire basket or inner balloon (all detailed) Can be used for catheters that are inflated. When expandable, membrane 144 is made of a polymer. - Can be placed with plenty of room around the matrix to provide expansion space. Ru. Alternatively, if membrane 144 is elastic or stretchable, an expanding polymer ・The thin film can also expand around the matrix, so it can expand around the polymer matrix. The arrangement may be made tighter.

Like a hard retractable sheath, the porous membrane 144 also resists shear and abrasion. While protecting the polymer matrix (even if thin film 144 is porous) ) provide some protection from inert diffusion during insertion and removal of catheter 140; .

A portion of the membrane 144 is provided to further control drug delivery in the polymer matrix. Therefore, it may be made non-permeable (non-porous). In particular, the non-permeable part is preferably to prevent or limit axial drug delivery along the body of the catheter 140; located at each end of the membrane 144.

This design allows for expansion of the polymer matrix and associated thin film 144. After tensioning, the porous portion of the thin film 144 comes into close contact with the blood vessel wall or target tissue; The remaining portion of membrane 144 that has not been This is particularly beneficial for catheter inflation as drug movement is restricted.

FIG, 8A international search report 11 moromi＾11 ryo--NII PCT/υs 92/10839AN)-I AN Cl　M　hJ　I　11JE:　X　A　hJ　NE:　X　E Front Page Continuation of Ji (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, SN, TD.

TG), AT, AU, BB, BG, BR, CA, CH.

C3, DE, DK, ES, FI, GB, HU, JP, KP, KR, LK, LU, MG, MN, MW, NL, N.

, NZ, PL, RO, RU, SD, SE, UA (72) Inventor: Shabrand, James Yee United States 55126 Shoreview, LA, Minnesota Tic Plane 4322 (72) Inventor Jin Shimada United States 55113 Minnesota, Falcon Heights, Simpson's Treat (72) Inventor Knudson, Mark Bee United States 55126 130 West Royal Aurus Drive, Shoreview, Minnesota 9

Claims (21)

[Claims] 1. It has a distal end and a proximal end to locally deliver the drug to the body tissue, i.e. the target area. A drug delivery device comprising: (a) a flexible catheter inserted into an internal target area of the body; Tell and (b) proximate the tip of the drug delivery device for delivering the drug to the target area; a polymer matrix connected to the catheter of the invention and holding the drug; a drug delivery means including a drug; (c) delivering said drug from said polymer matrix to said target area inside the body; a drug delivery device comprising: a transport means for actively transporting; 2. The polymer matrix is concentric about the longitudinal axis of the catheter. The drug delivery device according to claim 1, wherein the drug delivery device is arranged in a. 3. 2. The drug delivery device of claim 1, wherein the catheter includes an integral introducer. 4. A drug delivery device according to claim 1, wherein said transport means comprises iontophoresis means. . 5. The iontophoresis means includes an electric current located inside the polymer matrix. 5. A drug delivery device according to claim 4, comprising poles. 6. 2. The drug delivery device of claim 1, wherein said transport means comprises sonophoresis means. 7. The sonication method means includes ultrasonic waves located inside the polymer matrix. 7. A drug delivery device according to claim 6, comprising a wave transducer. 8. expansion for expanding the drug delivery means in a generally radial direction of the catheter; The drug delivery device of claim 1 further comprising means. 9. Claim wherein said expansion means comprises a wire basket biased into an expanded configuration. The drug delivery device according to item 8. 10. 9. The inflation means comprises a wire basket biased into a relaxed position. The drug dispensing device described in. 11. 9. A drug delivery device according to claim 8, wherein said inflation means comprises a balloon. 12. The polymer matrix is physically exposed during insertion and removal of the device. 2. The drug delivery device of claim 1, further comprising protection means for protecting against physical deterioration. 13. 13. The drug delivery device of claim 12, wherein said protection means comprises a movable sheath. 14. The protective means further comprises a porous thin film covering the polymer matrix. 13. The drug delivery device of claim 12. 15. localized delivery of drug to a body passageway with elongated passageway walls, i.e., to a target area; A drug delivery device for: (a) a flexible catheter having a distal end and a proximal end; (b) the distal end of the drug delivery device for delivering drug to the target area; a polymeric matrix connected to the catheter near the catheter and carrying the drug; a drug delivery means comprising Trix; (c) delivering said drug from said polymer matrix to said target area inside the body; (d) a means for actively transporting said catheter in a generally radial direction relative to said catheter; A drug delivery device comprising: an expansion means for inflating the drug delivery means. 16. A method of delivering a drug to a target area inside the body, the method comprising: (a) a polymer matrix having a tip and holding said drug; a step for inserting the distal end portion of the catheter included near the distal end portion into the inner target region; and (b) located near the tip of the catheter and actively transporting the drug; from the polymer matrix to the target area within the body using a delivery means for transporting the drug; A drug delivery method consisting of: 17. 4. The method of claim 1, wherein the step of transferring comprises transferring the drug by iontophoresis. 17. The drug delivery method according to 16. 18. 2. The step of transferring comprises transferring the drug by sonophoresis. 6. The drug distribution method according to 6. 19. the polymer matrix at a generally radius relative to the longitudinal axis of the catheter; 17. The method of claim 16, further comprising the step of directional expansion. 20. protecting the polymer matrix from physical deterioration during the insertion step; 17. The method of claim 16, further comprising the step of protecting. 21. A method of delivering a drug to a target area inside the body, the method comprising: (a) a polymer matrix having a tip and holding said drug; a step for inserting the distal end portion of the catheter included near the distal end portion into the inner target region; and (b) the polymer matrix in a generally radial direction relative to the longitudinal axis of the catheter; (c) inflating a catheter near the distal end of the catheter; the drug to the target region within the body using a delivery means for actively transporting the drug; transporting the drug from the polymer matrix; A drug delivery method consisting of: