CN101511418A

CN101511418A - Implantable shunt or catheter enabling gradual delivery of therapeutic agents

Info

Publication number: CN101511418A
Application number: CNA2007800323241A
Authority: CN
Inventors: D·L·德拉古恩; J·M·科亨
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 2006-08-28
Filing date: 2007-08-27
Publication date: 2009-08-19
Also published as: MX2009002260A; AU2007290648A1; EP2056917A1; CA2659822A1; JP2010502279A; WO2008027322A1; BRPI0715656A2

Abstract

An implantable catheter or shunt (24) for draining fluid from a body cavity. The catheter or shunt body has a wall structure (28) that carries one or more therapeutic agents (26) in a manner enabling release of the therapeutic agent from the wall structure in situ after surgical implantation of the catheter or shunt body. The therapeutic agent can be gradually released over time to prevent infection, inhibit tissue ingrowths, and/or provide some other desired medicinal purpose. As an example, the therapeutic agent can be rapamycin or an mTOR inhibitor. According to some contemplated embodiments of the present invention, the therapeutic agent carried by the catheter/shunt is rechargeable or refillable in situ so that the therapeutic agent can be gradually released from the catheter/shunt over the expected useful life of the catheter/shunt.

Description

Implantable shunt or conduit that can gradual delivery of therapeutic agents

Technical field

The present invention relates generally to the operating equipment (surgical device) that is used for drain (drainingfluid) between the intravital zones of different of people, as implantable conduit and diverter, relate more specifically to make obstruction (blockage) and block (obstruction) and/or minimized conduit of infection risk and diverter.

Background technology

Diverter and conduit have been used to control body fluid flowing between each zone of human body in surgical use.For example, the implantable shunt system is used to overcome in hydrocephalus (hydrocephalus) treatment or controls the disappearance that freely circulate and/or absorb of cerebrospinal fluid (cerebrospinal fluid) in human brain.

Hydrocephalus is the nervous disorders that is caused by the abnormal accumulation of cerebrospinal fluid in the ventricles of the brain (ventricles) or encephalocoele (cavities).Cerebrospinal fluid surrounds brain and spinal cord (spinal cord) and provides buffering by the ventricular system circulation so that for brain and spinal cord.When the normal drainage of cerebrospinal fluid is obstructed so that choroid plexus (choroid plexus) produces Fluid Volume and this fluid suck between the speed of blood flow when unbalance the generation hydrocephalus.This unbalance raising cerebral also causes the ventricles of the brain to enlarge.

The treatment hydrocephalus generally includes the surgical placement cerebrospinal fluid shunt, and it provides valve and the pipe mechanical system that this fluid of controlled quatity is drawn cranial cavity (cranial cavity) and introduced another zone of health (can be absorbed at this this fluid).The near-end of ventricular catheter places Intraventricular so that the drainage pathway that is drawn out to the drainage shunt of band valve from brain to be provided, this diverter is the fluid peritoneal cavity (abdomino-peritoneal cavity) that for example leads, and can be absorbed in the peritoneal fluid (peritoneal fluid) and sucks blood flow at this cerebrospinal fluid.

The problem that the implantation of this class conduit and diverter runs into is that the inflow end of ventricular catheter may be blocked owing to the ingrowth of choroid (choroid) tissue or stop up.This makes this system can't discharge overvoltage, and needs surgical operation so that do not tearing cerebral tissue or causing and take out this system under the hemorrhage situation.

Another problem is to infect.As the exotic of health, the conduit of implantation or diverter provide the position of suitable growth of microorganism.Infect usually apparition in about seven to 90 days after implantation.Under situation about infecting, take out this shunt system usually.

The case description of cerebrospinal fluid shunt system is in following United States Patent (USP): 7,037,288 B2 that authorize people such as Rosenberg; Authorize 5,531,673 of Helenowski; Authorize 5,405,316 of Magram; Authorize people's such as Ruzicka 4,950,232; Authorize 4,655,745 of Corbett; With authorize 4,382,445 of Sommers.

Summary of the invention

The present invention relates to be used for implantable conduit or shunt system from the body cavity drain.This conduit or shunting body have load, and one or more are planted the wall construction of therapeutic agents back original position from wall construction is slowly defeated pass this one or more plant therapeutic agents so that can implant at the surgery of this conduit or shunting body.For example, can be with prevention infection, to suppress the tissue ingrowth thing and/or bring into play some other required medical science functions be that purpose provides this releases a kind of or more kinds of therapeutic agents.In expection embodiments more of the present invention, the contained therapeutic agent supply of wall construction of the catheter/shunt of implanting be original position can load (rechargeable) again and/or (refillable) that can recharge so that period that can be through prolonging, realize that (gradual) gradually of therapeutic agent discharges as the useful life time limit of the prolongation of the catheter/shunt implanted.

The invention provides the implantable shunt system that is used for from the body cavity drain, comprise conduit and by at least a therapeutic agent of the wall construction load of described conduit, described wall construction has outer rim (outer peripheral) surface and delimit out inner edge (inner peripheral) surface of inner chamber, fluid is drawn from body cavity through this inner chamber, and described wall construction can original position discharge described therapeutic agent gradually from described wall construction after described catheter body is implanted.

The invention provides can drain from body cavity the implantable shunt system, comprise conduit and by at least a therapeutic agent of the wall construction load of described conduit, described wall construction has outer fringe surface and delimit out the inner peripheral surface of inner chamber, fluid is drawn from body cavity through this inner chamber, and described wall construction can original position discharge described therapeutic agent gradually from described wall construction after described catheter body is implanted.

The invention provides the implantable shunt system that is fit to drain from body cavity, comprise conduit and by at least a therapeutic agent of the wall construction load of described conduit, described wall construction has outer fringe surface and delimit out the inner peripheral surface of inner chamber, fluid is drawn from body cavity through this inner chamber, and described wall construction is adapted at can original position discharging described therapeutic agent gradually from described wall construction after described catheter body is implanted.

This implantable shunt optimum system choosing further comprises the device that is used for loading or recharging at patient's internal in-situ the contained therapeutic agent of wall construction.

This implantable shunt system can further comprise the passage that at least one extends between interior and outer fringe surface in this wall construction, this passage contains at least one the therefrom releasable gradually therapeutic agent supply that sees through in interior and the outer fringe surface.This implantable shunt system can further comprise the passage that at least one extends between interior and outer fringe surface in this wall construction, this passage is fit to hold at least one that see through in interior and the outer fringe surface can releasable gradually therapeutic agent supply from this passage.This implantable shunt system can further comprise the passage that at least one extends between interior and outer fringe surface in this wall construction, this passage is fit to hold the therapeutic agent supply, and its suitable suitably at least one that sees through in interior and the outer fringe surface discharges this therapeutic agent gradually.

At least one passage comprises inlet suitably.This conduit can further comprise and be used to load the therapeutic agent supply, be positioned at the reservoir that wall construction is outside and be communicated with this inlet fluid.This implantable shunt system can further comprise pump suitably, and this pump can start (actuated) so that therapeutic agent is pumped into this passage via this inlet from reservoir.

This implantable shunt system can be included in the wall construction suitably along the substantially longitudinally extending a plurality of adjacency channels of the predetermined length of catheter body.The end of at least one this passage can be with the interconnection of the end of adjacency channel so that therapeutic agent can move and in adjacency channel, oppositely move with first direction along one of passage of certain-length.This reservoir can comprise a plurality of independent reservoirs.These can be separately and different channel connections.They can load the supply of different therapeutic agents separately.This implantable shunt system is applicable to the multiple different therapeutic agent of load in wall construction.This therapeutic agent can provide with the form of film that forms on the wall construction surface.This therapeutic agent can be immersed in and form in the material that wall construction uses and see through wall construction is diffusible.Wall construction can be the single-walled pipe of extruding, and wherein hollow channel extends in the single wall of this pipe.Wall construction can comprise the interior pipe of delimiting out inner chamber (fluid is drawn from body cavity through this inner chamber) and center on the outer tube or the shell (outer tube or jacket) of pipe support spaced apart in this, thereby delimit out the chamber that can be fit to hold the therapeutic agent supply between them.This wall construction can comprise in this at least one indoor regulator and maybe this chamber is divided into a plurality of independently chambers with the suitable spacing between pipe in keeping and outer tube or the shell.

The invention provides and have by the ventricular catheter of the direct or indirect interconnection of volume control device and the cerebrospinal fluid shunt system of drainage shunt, one of ventricular catheter and drainage shunt comprise elongate body, delimit the inner chamber of send as an envoy to the cerebrospinal fluid flow direction or outflow volume control device therein, this main body is formed by the wall construction of at least a therapeutic agent of load wherein or on it, and this wall construction is implanted back original position in this shunt system and discharged therapeutic agent.

The invention provides and comprise by the ventricular catheter of the direct or indirect interconnection of volume control device and the cerebrospinal fluid shunt system of drainage shunt, wherein one of ventricular catheter and drainage shunt comprise elongate body, delimit out therein and be fit in use make cerebrospinal fluid to flow to or flow out the inner chamber of volume control device, and this main body is formed by the wall construction of at least a therapeutic agent of load wherein or on it, and this wall construction can be implanted the back original position in this shunt system and discharge therapeutic agent.

This cerebrospinal fluid shunt system can further comprise the device that is used for loading or recharging at patient's internal in-situ the contained therapeutic agent of wall construction.This therapeutic agent provides maybe can be immersed in the form of film that forms on the wall construction surface suitably and constitutes in the material that wall construction uses.It preferably sees through wall construction is diffusible.

Wall construction can provide the outer fringe surface of this main body and the inner peripheral surface of this main body, wherein inner peripheral surface delimited out inner chamber, and preferably wherein at least one passage extends between interior and outer fringe surface in wall construction, this passage preferably contains the therapeutic agent supply, its in use see through in interior and the outer fringe surface at least one therefrom be slowly releasable.At least one passage can comprise that permission therapeutic agent supply flows (flushing), recharges, loads or the circulation entrance and exit again in this passage.This cerebrospinal fluid shunt system can further comprise at least one and load the therapeutic agent supply, is positioned at the implantable reservoir that wall construction is outside and be communicated with this entrance and exit fluid.

Cerebrospinal fluid shunt system can further comprise the implantable pump that is arranged in the wall construction outside and is fit to therapeutic agent is pumped into from reservoir this passage.This wall construction can be suitably be the flexible single-walled pipe of extruding of the passage with a series of (a array of) that form therein independent longitudinal extension.This wall construction can comprise interior pipe of delimiting out inner chamber and the shell of delimiting out at least one passage.

The present invention further provides the method for drawing undesired body fluid in the patient of the long-term drain of needs, this method comprises implants step among the patient who needs it with aforesaid implantable shunt system.This conduit is adjacent with biocompatible matrix suitably, and this substrate can be failed delivery of therapeutic agents for a long time.This fluid comprises cerebrospinal fluid suitably.This fluid can comprise carrier and at least a therapeutic agent or its metabolite.

The present invention further provides the method to the defeated delivery of therapeutic agents of hydrocephalic, this method comprises the step of aforesaid cerebrospinal fluid shunt system surgery being implanted the patient.

The present invention further provides the purposes of therapeutic agent in the manufacturing of above-mentioned implantable shunt system.The present invention further provides the purposes of therapeutic agent in the manufacturing of above-mentioned cerebrospinal fluid shunt system.

According to the following specific embodiment, other aspects and advantages of the present invention are apparent.

Description of drawings

According to the following description that connection with figures is considered, the features and advantages of the present invention should become obviously, wherein:

Fig. 1 is the sketch map of shunt system of the present invention;

Fig. 2 is the amplification sectional view of first embodiment of conduit of the present invention or diverter;

Fig. 3 is the amplification sectional view of second embodiment of conduit of the present invention or diverter;

Fig. 4 is the amplification sectional view of the 3rd embodiment of conduit of the present invention or diverter;

Fig. 5 is the amplification sectional view of the 4th embodiment of conduit of the present invention or diverter;

Fig. 6 is the sectional view of the catheter/shunt 6-6 along the line shown in Fig. 5;

Fig. 7 is the sketch map that has the catheter/shunt system that can load again of reservoir according to of the present invention; And

Fig. 8 is the sketch map that has another the catheter/shunt system that can load again of reservoir according to of the present invention.

The specific embodiment

The present invention relates to implant used conduit or diverter in patient's body as the part of the shunt system of drain between the patient body zones of different.Be used for the treatment of hydrocephalic shunt system an example is provided.But implantable catheter/shunt of the present invention can be used in other drain or the similar applications.

Implantable catheter/shunt of the present invention can be used on especially and need be delivered to the interior of catheter/shunt and/or outer surface is adjacent and/or in catheter/shunt in the purposes of the position of intracavity with therapeutic agent, medicine or similar utility are defeated.For example, catheter/shunt of the present invention can be used for discharging gradually one or more kinds and makes the obstruction of catheter/shunt inner chamber or block risk minimization or make the minimized therapeutic agent of infection risk.Certainly, catheter/shunt of the present invention also can be used for discharging other utility for other desired use.

Typical marrowbrain shunt system 10 is illustrated schematically in Fig. 1 in patient " P " body.This system 10 comprises the ventricular catheter 12 that extends through the boring (burr hole) that operation forms in patient's skull.This conduit 12 has the near-end that is arranged in patient's ventricles of the brain or flows into end 14 and the inner chamber that the longitudinal extension of the drainage pathway that makes cerebrospinal fluid flow to volume control device or check valve 16 is provided.Valve 16 connects to drainage shunt 18, and its company of providing is to the flow path 20 of patient's peritoneal cavity, and in peritoneal cavity, the cerebrospinal fluid of discharge can see through peritoneum (gastrointestinal organ's inner lining film) and absorb in the blood.Perhaps, diverter 18 can the company of providing to the path 22 (showing) of the right atrium that directly enters sanguimotor heart with mirage phantom.

Whole shunt system 10 is positioned at or implants subcutaneous.For example, conduit 12 and diverter 18 can be embedded in patient's subcutaneous tissue and can be made by the organosilicon or the similar polymer that are tolerated by human body well.Valve 16 is subcutaneous to be inserted on the skull (cranium) behind the ear, or inserts in the pectoral region (pectoral region) or in the rib abdomen (flank).

First embodiment of catheter/shunt 24 of the present invention is presented among Fig. 2 with cross section.This catheter/shunt 24 can be used as ventricular catheter, drainage shunt or both, or can be used in other drain or the similar applications.At least the catheter/shunt 24 of predetermined length is made as organosilicon by the polymer that wherein contains therapeutic agent 26.For example, can be before making catheter/shunt with therapeutic agent 26 and this polymer mixed so that after making catheter/shunt, therapeutic agent 26 evenly spreads all over the shaping wall of catheter/shunt.Correspondingly, the wall 28 of catheter/shunt 24 is flooded by therapeutic agent 26, and therapeutic agent 26 can through predetermined period therefrom original position slowly discharge with the defeated therapeutic agent 26 of controlled quatity of passing in patient's body.

For example, therapeutic agent 26 can be rapamycin (rapamycin), mTOR inhibitor, antimicrobial (antimicrobial), antibiotic (antibiotic) or other activating agent or utility.Shown in the arrow among Fig. 2, the inner peripheral surface 30 that therapeutic agent 26 can see through wall 28 be discharged in the inner chamber 32 of catheter/shunt 24 and/or the outer fringe surface 34 that sees through wall 28 discharges.The diffusion gradually that therapeutic agent 26, thunderous handkerchief mycin see through

surface

30 and 34 can effectively prevent in the catheter/shunt 24 and bacterial growth on every side and prevent to stop up or to hinder tissue ingrowth thing through inner chamber 32 drains.As instantiation, therapeutic agent 26 can be used for preventing that undesired choroid plexus is attached on the catheter/shunt 26.

Second embodiment of catheter/shunt 36 of the present invention is presented among Fig. 3 with cross section.Wall 38 with thin film that contains therapeutic agent 26 or coating 40 coating catheter/shunt 36.This thin film or coating 40 can be made by the solution of one of the inner peripheral surface 42 that is applied to wall 38 by dip-coating, spraying, brushing, spin coating or similar techniques and outer fringe surface 44 or the mixture that comprises therapeutic agent 26 and polymer supported liquid solution on both.When catheter/shunt 36 is implanted the patient, therefrom discharge therapeutic agent 26 gradually through predetermined period.Therapeutic agent 26 can be above-mentioned any therapeutic agent.

Catheter/shunt 24 shown in Fig. 2 can be by coating shown in Fig. 3 or thin film 40 coatings.In this case, can rely on thin film 40 that prominent (burst)/release, the more long-term then therapeutic agent 26 that is immersed in the catheter/shunt wall that discharges released of initial short-term of therapeutic agent 26 is provided.Perhaps, thin film 40 can contain one type therapeutic agent, and floods dissimilar therapeutic agents in wall.For example, the therapeutic agent in the thin film 40 can be the chemical compound of prevention infection, and the therapeutic agent that is immersed in the wall can prevent the tissue ingrowth thing.Certainly, also can adopt other combination of utility.

The 3rd embodiment of catheter/shunt 46 of the present invention is presented among Fig. 4 with cross section.The advantage of this specific embodiments is that it can load and/or recharge the contained therapeutic agent of catheter/shunt again, prolongs the time limit that can fail delivery of therapeutic agents from the catheter/shunt of implanting thus.This time limit can comprise the whole useful life of the catheter/shunt of implantation.

The inner peripheral surface 48 of the wall 50 of catheter/shunt 46 delimited out the inner chamber 52 that extends at the center, and one or more hollow channel 54 in wall 50 between the inner peripheral surface 48 of wall 50 and outer fringe surface 56 longitudinal extension.This hollow channel 54 is equipped with therapeutic agent 26, and it is allowed to move gradually with one of

outer fringe surface

48 and 56 or both through interior.Specific embodiments shown in Fig. 4 is preferably extruded flexible pipe, wherein forms inner chamber 52 and passage 54 in the extruding pipe forming process.Passage 54 can extend the length of catheter/shunt, or only in its predetermined length.

Can be around the end of the catheter/shunt 46 point annular substantially end cap of assembling or adapter (not shown) to clog the terminal of passage 54 or to provide the 54 terminal interconnection of one or more passage and the U-shape passages of backward channel are provided.For example, can allow to make therapeutic agent to flow with first direction, then reverse flow in the adjacent interconnection passage along the length of first passage.Therapeutic agent 26 can be that above-mentioned any therapeutic agent and catheter/shunt 46 can contain polytype therapeutic agent in wall 50 in the different passages of (unconnected) passage that does not connect.Wall 50 also can be flooded by therapeutic agent according to the embodiment shown in Fig. 2, and/or can have the thin film that contains therapeutic agent according to the embodiment shown in Fig. 3.

The 4th embodiment of catheter/shunt 62 of the present invention is presented in Fig. 5 and 6.Catheter/shunt 62 has wall construction 64, and it comprises interior pipe 66 of delimiting out inner chamber 68 and outer tube or the shell 70 of sealing interior pipe 66.Between interior pipe 66 and shell 70, have the gap, between them, provide one or more to be used to hold the passage 72 of therapeutic agent 26 supply.Can provide one or more regulator with the suitable spacing between pipe 66 and the shell 70 in guaranteeing.Regulator 74 also is used in the passage 72 of delimiting and being separated out independent longitudinal extension in the wall construction 64.Regulator 74 can be designed to allow the cross flow one between the adjacency channel or prevent cross flow one between the adjacency channel.The use of individual passage is for guaranteeing that the uniform distribution of therapeutic agent along catheter/shunt 62 may be that desirable maybe can allowing loads in each passage 72 different therapeutic agents separately.

Therapeutic agent 26 supply in the passage 72 see through one of interior pipe 66 and shell 70 or both and move gradually or spread.This provides the therapeutic agent slow release for a long time.Can be on catheter/shunt 62 end points mounting ring female cap, adapter or analog (not shown) with the end of seal channel 72.Manage in pipe 66 and/or the shell 70 and/or during being applied in identical or different therapeutic agent can be immersed in 66 and/or shell 70 on coating in provide.

Catheter/

shunt

46 and 62 with

passage

54 and 72 allows to make the therapeutic agent supply of load thus to load, flow, recharge and/or circulate.But this has prolonged the useful life and the defeated time limit of passing the patient of therapeutic agent original position of this implantable shunt device system.For this reason, passage can have inlet (entry port) 76 and outlet (exit port) 78, and they are interconnected to separately contains on the reservoir 80 that appends the therapeutic agent supply.For example, reservoir 80 can be implanted subcutaneous behind patient's ear and can contain the therapeutic agent of instantaneous bolus dose (transient bolus dose).This reservoir itself can recharge by syringe or analog.In addition, can provide implantable pump (not shown) to order about the circulation of therapeutic agent from reservoir to the catheter/shunt passage.For example, this pump can be a mechanical pump, and when the skin of wherein implanting this pump was exerted pressure, this pump was by pressure-activated.Fig. 7 has shown a kind of system, and wherein, along the unidirectional boot cycle of the predetermined length of conduit 82, and Fig. 8 has shown a kind of system, and wherein, circulating in the catheter/shunt 84 of therapeutic agent reverses so that entrance and exit is close to each other and with reservoir.

In all above-mentioned embodiments of the present invention, these one or more therapeutic agents can be considered in patient's body next-door neighbour's catheter/shunt inner chamber or in catheter/shunt intracavity can be used for the defeated any material passed of original position.The useful especially material of the present invention's imagination is the mTOR inhibitor, thunderous handkerchief mycin.Rapamycin is can prevent to organize and bacterial growth and macrolide (macrolide) antibiotic with anti-inflammatory activity.Correspondingly, by discharging rapamycin wherein gradually, can prevent that tissue ingrowth thing, inner chamber to the catheter/shunt inner chamber from stopping up or block and tissue is attached on the catheter/shunt.Perhaps, therapeutic agent can be forms of rapamycin analogs or other mTOR inhibitor.Also can use material as medicine, biocide (sterilants), plasticizer (plasticizers), antimicrobial and so on as therapeutic agent.

Although described preferred shunt system and catheter/shunt in detail, can under the situation that does not deviate from the spirit and scope of the invention specified, make various modifications, change and change as appended claims.

Drainage method

On the other hand, the invention provides the implantable shunt system and be used in patient's body, drawing undesired fluidic purposes.This implantable shunt system provides capacity mTOR inhibitor inwardly to grow to avoid the cell in the shunt system.Thus, this shunt system makes the attached of bacterial growth and cell and diverter, and for example choroid plexus is attached minimizes or eliminate.

Term used herein " mTOR inhibitor " is meant by the blocking-up cell cycle and proceeds to chemical compound or part or its medicinal acceptable salt that S suppresses cellular replication from G1.This term comprises neutral tricyclic compound rapamycin (sirolimus (sirolimus)) and other rapamycin compounds, comprise rapamycin derivative for example, forms of rapamycin analogs, active other Macrocyclic lactone compounds of inhibition mTOR and contained all chemical compounds in the following definitions of term " rapamycin ".These comprise the chemical compound that has structural similarity with " rapamycin ", for example have been modified to improve the chemical compound with similar macrocyclic structure of treatment benefit.FK-506 is also in the method for the invention available.

Term defined herein " rapamycin " is meant that a para-immunity that contains following rapamycin nucleus suppresses (immunosuppressive) chemical compound:

Rapamycin

Term " demethyl rapamycin (desmethylrapamycin) " is meant basic rapamycin nucleus shown in containing but does not contain the immunosuppressive compounds class of one or more methyl.In one embodiment, rapamycin nucleus loses the methyl at position 7,32 or 41 places, or its combination.Can lose methyl with other position from rapamycin nucleus with synthetic other demethyl rapamycin of genetic engineering.The manufacturing of demethyl rapamycin has been described.Referring to, for example 3-demethyl rapamycin [U.S. Patent No. 6,358,969] and 17-demethyl rapamycin [U.S. Patent No. 6,670,168].

Unless indicate separately, term " demethyl rapamycin " and " O-demethyl rapamycin " are used interchangeably in the literature and in this manual.

Rapamycin used according to the invention comprises derivatives chemical or the bio-modification that can be used as rapamycin nucleus, still keeps the chemical compound of inhibitive ability of immunity simultaneously.Correspondingly, term " rapamycin " comprises ester, ether, oxime, hydrazone and the azanol of rapamycin, and the functional group on the nuclear for example passes through the rapamycin of reduction or oxidizing process modification.Term " rapamycin " also comprises the medicinal acceptable salt of rapamycin, and it can form this class salt owing to containing acidity or basic moiety.

Medicinal acceptable salt used herein includes but not limited to hydrochlorate, hydrobromate, hydriodate, hydrofluoride, sulfate, citrate, maleate, acetate, lactate, nicotine hydrochlorate (nicotinic), succinate, oxalates, phosphate, malonate, Salicylate, phenylacetic acid salt, stearate, piperidinium salt, ammonium salt, piperazine salt, the diethyl amine salt, nicotinoyl amine salt (nicotinamide), formates, urea salt (urea), sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, lithium salts, cinnamate (cinnamic), methylamino salt (methylamino), methane sulfonates, picrate (picric), tartrate (tartaric), triithylamine base salt, dimethylamino salt and three (methylol) aminomethane salt.Other medicinal acceptable salt is well known by persons skilled in the art.

In one embodiment, the ester of rapamycin and ether are at the hydroxyl of the 42-of rapamycin nucleus and/or 31-position, at the ester and the ether (after the electronation of 27-ketone) of the hydroxyl of 27-position, and oxime, hydrazone and azanol are at the 27-ketone of (after the oxidation of 42-hydroxyl) of the ketone of 42-position and rapamycin nucleus.

In another embodiment, the 42-of rapamycin and/or 31-ester and ether are described in the following patent: Arrcostab (U.S. Patent No. 4,316,885); Aminoalkyl ester (U.S. Patent No. 4,650,803); Fluorinated esters (U.S. Patent No. 5,100,883); Carboxylic acid amide esters (U.S. Patent No. 5,118,677); Carbamate (U.S. Patent No. 5,118,678); Silyl ether (U.S. Patent No. 5,120,842); Amino ester (U.S. Patent No. 5,130,307); Acetal (U.S. Patent No. 5,51,413); Amino diester (U.S. Patent No. 5,162,333); Sulphonic acid ester and sulfuric ester (U.S. Patent No. 5,177,203); Ester (U.S. Patent No. 5,221,670); Alkoxy ester (U.S. Patent No. 5,233,036); The O-aryl ,-alkyl ,-alkenyl and-alkynyl ether (U.S. Patent No. 5,258,389); Carbonic ester (U.S. Patent No. 5,260,300); The carbamate of aryl carbonyl and alkoxy carbonyl (U.S. Patent No. 5,262,423); Carbamate (U.S. Patent No. 5,302,584); Hydroxy ester (U.S. Patent No. 5,362,718); Ester (U.S. Patent No. 5,385,908) is obstructed; Heterocyclic ester (U.S. Patent No. 5,385,909); The dibasic ester of gem-(U.S. Patent No. 5,385,910); Amino-alkane acid esters (U.S. Patent No. 5,389,639); Carbamic acid phosphorylic ester (U.S. Patent No. 5,391,730); Carbamate (U.S. Patent No. 5,411,967); Carbamate (U.S. Patent No. 5,434,260); Carbamic acid amidine ester (U.S. Patent No. 5,463,048); Carbamate (U.S. Patent No. 5,480,988); Carbamate (U.S. Patent No. 5,480,989); Carbamate (U.S. Patent No. 5,489,680); N-oxide ester (U.S. Patent No. 5,491,231) is obstructed; Biotin ester (U.S. Patent No. 5,504,091); O-alkyl ether (U.S. Patent No. 5,665,772); PEG ester (U.S. Patent No. 5,780,462) with rapamycin.The preparation of these esters and ether has been described in above-listed patent.

In an embodiment again,, rapamycin 27-ester and ether have been described in 790 in U.S. Patent No. 5,256.The preparation of these esters and ether has been described in above-listed patent.

In an embodiment again, at United States Patent(USP) Nos.: oxime, hydrazone and the azanol of having described rapamycin in 5,373,014,5,378,836,5,023,264 and 5,563,145.The preparation of these oximes, hydrazone and azanol has been described in above-listed patent.In U.S. Patent No. 5,023, the preparation of 42-oxo rapamycin has been described in 263.

In another embodiment, rapamycin comprises rapamycin [U.S. Patent No. 3,929,992], with the rapamycin 42-ester [U.S. Patent No. 5 of 3-hydroxyl-2-(methylol)-2 Methylpropionic acid, 362,718] and 42-O-(2-hydroxyl) ethyl rapamycin [U.S. Patent No. 5,665,772].At United States Patent(USP) Nos. 5,362, the hydroxy ester of rapamycin has been described in 718 and 6,277,983, comprise preparation and the purposes of CCI-779.

Term used herein " CCI-779 " is meant the rapamycin 42-ester (temsirolimus) with 3-hydroxyl-2-(methylol)-2 Methylpropionic acid, and comprises its prodrug, derivant, medicinal acceptable salt or analog.

The example of rapamycin comprises, rapamycin for example, 32-deoxidation rapamycin (deoxo-rapamycin), 16-penta-2-alkynes (ynyl) oxygen base-32-deoxidation rapamycin, 16-penta-2-alkynes (ylyl) oxygen base-32 (S)-dihydro-rapamycin, 16-penta-2-alkynes (ylyl) oxygen base-32 (S)-dihydro-40-O-(2-ethoxy)-rapamycin, 40-O-(2-ethoxy)-rapamycin, rapamycin 42-ester (CCI-779) with 3-hydroxyl-2-(methylol)-2 Methylpropionic acid, 40-[3-hydroxyl-2-(methylol)-2 Methylpropionic acid ester]-rapamycin or its medicinal acceptable salt is (as U.S. Patent No. 5,362, open in 718), ABT578 or 40-(tetrazole radical)-rapamycin, 40-epi-(tetrazole radical)-rapamycin (as disclosed among the open No.WO 99/15530 of international monopoly) or as international monopoly disclosed forms of rapamycin analogs, for example AP23573 among No.WO 98/02441 and the WO 01/14387 disclosed.In another embodiment, this chemical compound is Certican ^TM(everolimus, 2-O-(2-hydroxyl) ethyl rapamycin, Novartis, U.S. Patent No. 5,665,772).

In one embodiment, one or more parts of shunt system, for example next-door neighbour such as conduit, pump can fail the biocompatible matrix insertion of delivery of therapeutic agents for a long time.

Thus, the shunt system that the invention provides the accommodating substrate of use own or next-door neighbour's substrate is drawn undesired fluidic method in patient's body, this substrate provides the long-acting release that is enough to prevent the inside growth of cell or organize the mTOR inhibitor of the amount on one or more parts that are attached to this shunt system maybe can refill and carries the source.Can use biocompatibility, biodegradable, can resorbent host material, as collagen (collagen), fibrin (fibrin) or chitosan (chitosan).Perhaps, also can use the not biodegradable substrate of suitable biocompatibility.Suitable biocompatible matrix has been described in the literature.Many these class substrate can be available from for example Advanced Nanotechnology,

Drug delivery system [QLTUSA] also uses the method for manufacturer to load required compound.Perhaps, this mTOR inhibitor is passed by shunt system itself is defeated, for example by in the parts that are immersed in shunt system, or via bolus dose (bolus dose).

The supply of mTOR inhibitor can be regarded as in the curative scope for some indication, and is about 10 for example at about 5 to about 175 milligrams, or about 5, about 20, or to about 25 milligrams scope.But, because the present invention is used for local supply mTOR inhibitor, consider preferably to make the defeated minimized fact of fluidic amount of passing, this mTOR inhibitor can be with in one or more parts that still are enough to suppress this shunt system, and particularly low amount of the growth of the cell in the drainage catheter provides.For example, about 0.0001 milligram to 1 milligram of can discharge for every day, weekly of suitable amount, or otherwise provide by long-acting delivery system.

Usually, the undesired fluid source that draw will become with the purposes of this diverter.For example, in the hydrocephalic, this diverter will be drawn cerebrospinal fluid.In another example, when shunt system was used for glaucoma (glaucoma) patient, this diverter can be drawn vitreous humor (intravitreal fluid).

In addition, when using the defeated bolus dose of passing treatment effective dose chemical compound of shunt system or other dosage, this fluid can comprise other inactive component of the metabolite and the pharmaceutical composition of carrier, reactive compound.

Can via shunt system defeated pass or via the treatment examples for compounds of shunt system drain include but not limited to treat effective dose mTOR inhibitor, antibiotic, can be used for treatment and Alzheimer's disease (Alzheimer ' s Disease) and other deficiency disorder (for it, to defeated the passing of brain is desirable) medicine of relevant symptom, can be used for treating the oculopathy medicine of (comprising glaucoma, degeneration of macula (macular degeneration) etc.).

In one embodiment, the invention provides the method to the defeated delivery of therapeutic agents of hydrocephalic, described method comprises implants described patient's step with cerebrospinal fluid shunt system surgery of the present invention.

All patents of quoting herein, patent disclosure, article and other file are incorporated herein by this reference.It will be clear to someone skilled in the art that and to modify specific embodiments as herein described in the case without departing from the scope of the present invention.

Claims

1. be used for implantable shunt system from the body cavity drain, comprise conduit and by at least a therapeutic agent of the wall construction load of described conduit, described wall construction has outer fringe surface and delimit out the inner peripheral surface of inner chamber, fluid is drawn from body cavity through this inner chamber, and described wall construction can original position discharge described therapeutic agent gradually from described wall construction after described catheter body is implanted.

2. according to the implantable shunt system of claim 1, further comprise the device that is used for loading again or recharging the contained therapeutic agent of described wall construction at patient's internal in-situ.

3. according to the implantable shunt system of claim 2, further comprise at least one in described wall construction in described and the passage that extends between the outer fringe surface, described passage contain can see through described in and at least one the described therapeutic agent supply that therefrom discharges gradually in the outer fringe surface.

4. according to the implantable shunt system of claim 3, wherein said at least one passage comprises inlet, and wherein said conduit further comprises the reservoir that loads described therapeutic agent supply, is positioned at described wall construction outside and is communicated with described inlet fluid.

5. according to the implantable shunt system of claim 4, further comprise pump, this pump can start so that described therapeutic agent is pumped into the described passage via described inlet from described reservoir.

6. according to the implantable shunt system of claim 5, wherein said at least one passage is included in the described wall construction along the substantially longitudinally extending a plurality of adjacency channels of the predetermined length of described catheter body.

7. according to the implantable shunt system of claim 6, wherein said passage selected at least those in its terminal interconnection so that described therapeutic agent move and in adjacency channel, oppositely move with first direction along one of described passage of certain-length.

8. according to the implantable shunt system of claim 6, wherein said reservoir comprises a plurality of independent reservoirs, and they are separately with different channel connections and load the supply of different therapeutic agents.

9. according to each implantable shunt system of claim 1 to 8, wherein said therapeutic agent is the mTOR inhibitor.

10. according to the implantable shunt system of claim 9, wherein said therapeutic agent is a rapamycin.

11. according to the implantable shunt system of claim 10, wherein said therapeutic agent is selected from rapamycin and CCI-779.

12. according to each implantable shunt system of claim 1 to 11, the multiple different therapeutic agents of wherein said wall construction load.

13. according to each implantable shunt system of claim 1 to 12, wherein said therapeutic agent provides with the form of film that forms on described wall construction surface.

14. according to each implantable shunt system of claim 1 to 13, wherein said therapeutic agent is immersed in and forms in the material that described wall construction uses and can see through described wall construction diffusion.

15. according to each implantable shunt system of claim 1 to 14, wherein said wall construction is the single-walled pipe of extruding, wherein hollow channel extends in the single wall of this pipe.

16. according to each implantable shunt system of claim 1 to 15, wherein said wall construction comprises delimit the fluid of sening as an envoy to through the interior pipe of this described inner chamber of drawing with manage the outer tube or the shell of support spaced apart in described from body cavity, thereby delimit out the chamber that is used to hold described therapeutic agent supply between them.

17. according to the implantable shunt system of claim 14, wherein said wall construction comprise described indoor at least one regulator with keep described between pipe and outer tube or the shell suitable spacing or described chamber is divided into a plurality of independently chambers.

18. have by the ventricular catheter of the direct or indirect interconnection of volume control device and the cerebrospinal fluid shunt system of drainage shunt, one of described ventricular catheter and drainage shunt comprise elongate body, delimit the cerebrospinal fluid of sening as an envoy to therein and flow to or flow out the inner chamber of described volume control device, described main body is formed by the wall construction of at least a therapeutic agent of load wherein or on it, and described wall construction is implanted the back original position in described shunt system and discharged described therapeutic agent.

19., further comprise the device that is used for loading again or recharging the contained therapeutic agent of described wall construction at patient's internal in-situ according to the cerebrospinal fluid shunt system of claim 18.

20. according to the cerebrospinal fluid shunt system of claim 18, wherein said therapeutic agent is the mTOR inhibitor.

21. according to the cerebrospinal fluid shunt system of claim 20, wherein said mTOR inhibitor is a rapamycin.

22. according to the cerebrospinal fluid shunt system of claim 21, wherein rapamycin is selected from rapamycin and CCI-779.

23. according to each cerebrospinal fluid shunt system of claim 18 to 22, wherein said therapeutic agent provides with the form of film that forms on described wall construction surface, or is immersed in and constitutes in the material that described wall construction uses and can see through described wall construction diffusion.

24. according to each cerebrospinal fluid shunt system of claim 18 to 23, wherein said wall construction provides the outer fringe surface of described main body and the inner peripheral surface of described main body, wherein said inner peripheral surface delimited out described inner chamber, and wherein at least one passage extends in described and between the outer fringe surface in described wall construction, described passage contains described therapeutic agent supply, and it can be through at least one the therefrom slowly release in described and in the outer fringe surface.

25. according to the cerebrospinal fluid shunt system of claim 24, wherein said at least one passage comprises that the described therapeutic agent supply of permission flows, recharges, loads or the circulation entrance and exit again in described passage.

26., further comprise at least one and load described therapeutic agent supply, be positioned at the implantable reservoir that described wall construction is outside and be communicated with described entrance and exit fluid according to each cerebrospinal fluid shunt system of claim 18 to 25.

27., further comprise the implantable pump that is arranged in described wall construction outside and is fit to described therapeutic agent is pumped into from described reservoir described passage according to the cerebrospinal fluid shunt system of claim 26.

28. according to the cerebrospinal fluid shunt system of claim 27, wherein said wall construction is the flexible single-walled pipe of extruding that has therein a series of independent longitudinally extending channels that forms.

29. according to the cerebrospinal fluid shunt system of claim 27, wherein said wall construction comprises interior pipe of delimiting out described inner chamber and the shell of delimiting out described at least one passage between them.

30. draw the method for undesired body fluid in the patient of the long-term drain of needs, this method comprises the step that will implant according to each implantable shunt system of claim 1 to 17 among its patient of needs.

31. according to the method for claim 30, wherein this conduit and biocompatible matrix are adjacent, described substrate can be failed delivery of therapeutic agents for a long time.

32. according to the method for claim 30, wherein this fluid comprises cerebrospinal fluid.

33. according to the method for claim 30, wherein this fluid comprises carrier and at least a therapeutic agent or its metabolite.

34. according to each method of claim 30 to 33, wherein therapeutic agent is the mTOR inhibitor.

35. according to each method of claim 30 to 34, wherein therapeutic agent is an antibiotic.

36. to the method for the defeated delivery of therapeutic agents of hydrocephalic, described method comprises and will implant described patient's step according to each cerebrospinal fluid shunt system surgery of claim 18 to 29.

37. therapeutic agent is being made according to the purposes in each the implantable shunt system of claim 1 to 17.

38. therapeutic agent is being made according to the purposes in each the cerebrospinal fluid shunt system of claim 18 to 29.