CN101400384A

CN101400384A - Medical device with PH dependent drug release

Info

Publication number: CN101400384A
Application number: CNA2007800090006A
Authority: CN
Inventors: K·H·尼尔森; L·N·拉松; F·E·波尔森; S·G·彼得森; C·詹森; F·M·乌尔里克
Original assignee: MILLIMED AS
Current assignee: MILLIMED AS
Priority date: 2006-01-24
Filing date: 2007-01-24
Publication date: 2009-04-01

Abstract

The invention provides intravascular devices coated with a first domain comprising an alkali formulation of polyethylenimine diazeniumdiolate . The alkali ensures stabilisation of the polyethylenimine diazeniumdiolate during processing of the medical device, whilst allowing controlled release of nitric oxide upon use. The invention also provides medical devices coated with a first domain of polyethylenimine diazeniumdiolate, and an outer-layer which prevents or hinders the release of polyethylenimine diazeniumdiolate upon use in the body, particularly from the alkali first domain. In a preferred embodiment a balloon is coated with linear poly (ethylenimine) diazeniumdiolate (L-PEI-NONO) embedded in polyurethane (PU) and provided with a top coat of poly acrylic acid and PU.

Description

Medical apparatus with the dependent drug release of PH

Technical field

The present invention relates to nitrogenize nitrogen (nitric oxide) (NO) from the medical apparatus that comprises the polymine diazeniumdiolate, the especially release of medical apparatus in the blood vessel; Before the therapeutic of medical apparatus is used, the prevention of the too early release of nitrogenize nitrogen; In case dynamic (dynamical) optimization of using nitrogenize nitrogen in back to discharge from medical apparatus; With the prevention of in a single day using back polymine diazeniumdiolate from the release of medical science apparatus surface.

Background of invention

In the field of surgery, it often is useful that near the part of therapeutic agent affected therapentic part discharges in blood vessel.Usually, the release of therapeutic agent must be with regard to surgical intervention accurate timing not only in time send so that guarantee medicine, and send at correct position at correct time point.For example, before support had reached its target location in the patient vessel, the support of pharmaceutical pack quilt should not discharge medicine.Therefore, if, may wish that medicine is controlled from the speed that medical apparatus discharges through (for example several hours or even several days) the administering therapeutic agent of long-time section.On the other hand, for some treatment, drug release in a few minutes or several seconds, is that the optimization therapeutic efficiency is necessary for example fast.

Nitrogenize nitrogen is considered effective medium of many biological functions, plays the regulator of inhibitor, endothelium and leukocyte adhesion of vasodilation, neurotransmitter, inflammatory mediator, platelet activation and the regulator of macrophage and neutrophilic granulocyte.

But nitrogenize nitrogen is highly unsettled under physiological condition, can be by the rapid deactivation of the HbO2 Oxyhemoglobin in the Red blood corpuscle.

The for example nitroglycerin whole body use widely of nitrogenize nitrogen adduct for example is used for the treatment of angina pectoris.But the whole body application can cause the extensive dilution of adduct and away from the potential deleterious side effect in the position at therapeutical effect position.

Therefore, carried out the concerted effort of exploitation topical technology, this permission directly applies to intravital desired area with nitrogenize nitrogen, especially in vascular system, nitrogenize nitrogen can prevent or reduce thrombosis or the vasospasm in the vascular surgery process here, or prevention is implanted the restenosis that the back takes place at coronary angioplasty and support.With multiple being used for the treatment of property of chemical compound send NO.A kind of feasible material standed for that NO discharges is diazeniumdiolate (NONO ' ate), and it is being exposed to H ⁺Show the ability that discharges NO behind the ion.At U.S. Patent number 5,814, to describe NONO ' ate among 656 people such as () Saavedra and be used for the purposes that nitrogenize nitrogen discharges, described nitrogenize nitrogen is used for the treatment of and has damaged in sepsis or shock process or be in tissue in the damage danger.Obviously, at U.S. Patent number 5,519, among 020 (people such as Smith) insoluble polymer NONO ' ate has been described briefly also.These polymer have been used to send NO to particular organization, and the result shows that NO has reduced inflammation and quickened healing to the controlled release of specific part, it is said the illeffects that can avoid systemic delivery or release simultaneously.

At U.S. Patent number 5,770, the application of NONO ' ate as the coating on the implantable medical apparatus disclosed in 645.

PCT/DK2006/000714 incorporated by reference in this article provides and has measured the method and system of nitrogenize nitrogen from the release of nitrogenize nitrogen adduct.This method allow to consider or even eliminate nitrite level so that obtain the accurate measurement of attainable NO up to now.

EP 0 752 866 is disclosed that, discharges N ₂O ₂ ^-The bonded polymer of nitrogenize nitrogen of functional group can be used for the treatment of restenosis and associated disorders.Find that the polymine (polymine diazeniumdiolate) that nitrogenize nitrogen was handled can trigger vasodilation effectively.

WO2005037339 (it relates to the expansible balloon that is used for the angioplasty operation) is disclosed that, wrap up a kind of medicament can for the expandable stent that is used for the treatment of restenosis, nitrogenize nitrogen (NO) for example, the arteriospasm after such nitrogenize nitrogen release matrix also can loosen or prevent this medical apparatus in place.

US 2006/0008529 discloses and has added the position and be used for the purposes of controlled oxidation nitrogen from the release of the nitric oxide donor that is contained in polymer.

WO2005/039664 relates to a kind of medical apparatus, for example guide line, thromboembolism form device or are used for the guide shank of microtubular, its electricity that comprises by poly-(aziridine) diazeniumdiolate of polymeric linearity rotates the outer surface layer that nanofiber forms, it can be surrounded by outmost coating, for example the coating of polyacrylic acid and its copolymer.WO2005/039664 claims, it is favourable comprising acidizer in the outer surface layer that the electricity rotation nanofiber of poly-(aziridine) diazeniumdiolate of polymeric linearity forms.

WO 95/24908 discloses the NONOate polymer, comprises linear polyethylene imines diazeniumdiolate, and it can discharge nitrogen oxide partly to the position that is in restenosis danger.WO 95/24908 also is disclosed that, NONOate is unique in known drug at present, because they decompose at given arbitrarily pH by first order reaction, can predict to provide, quantitatively and the nitrogen oxide dosage of control.

US 6,885, and 366 (it relates to the electricity rotation of linear polyethylene imines diazeniumdiolate, with to the medical apparatus bag by the LPEI-NONO nanofiber) were disclosed that linear poly-(aziridine) diazeniumdiolate (LPEI-NONO) was a kind of water-insoluble polymer.

Summary of the invention

Embodiment of the present invention can be used in combination with following application invention disclosed incorporated by reference in this article: EP application number EP06023203 and U.S. Provisional Application 60/864,879, EP application number 06023223 and U.S. Provisional Application 60/864,886, EP application number 06023222 and U.S. Provisional Application 60/864,893, EP application number EP06075159 and U.S. Provisional Application 60/761,359.

Use is disclosed nitrogen oxide analytical method in our application PCT/DK2006/000714, we have carried out detailed research to the chemical property of the polymine diazeniumdiolate in formulation soln ((L) PEI-NONO), and embed in the polymeric matrices of spraying bag quilt.

Research has had been found that (L) PEI-NONO problem of unstable that has not identified in the past like this, this is embodied in the preparation of (L) PEI-NONO and uses preceding storage, for example in blood vessel the bag of medical apparatus by in, and be present in such medical apparatus or be coated on (L) PEI-NONO on such medical apparatus.Crucially, the application that disclosed nitrogen oxide is measured in PCT/DK2006/000714 has allowed us to measure the real-time release of nitrogen oxide, report the existence of nitrite and nitrate simultaneously, described nitrite and nitrate are otherwise can cause sizable experimental error and the pollutant of sizable excessive estimation of the NO that causes usually discharging from LPEI-NONO.

Solution provided by the invention be used for guaranteeing the preparation of (L) PEI-NONO and processing and with such (alkali) (L) the PEI-NONO preparation be applied to the medical apparatus process, (L) PEI-NONO remains in the alkaline environment.

By anatomize NO from linearity-release of polymine diazeniumdiolate, we also after testing after removing medical apparatus, NO is from the release of the solion that is exposed to medical apparatus.This finds us, opposite with former instruction, linear-polymine diazeniumdiolate dissolves in the deionized water solution, when using the medical apparatus of LPEI-NONO bag quilt, exists measurable LPEI-NONO to discharge (referring to Figure 12) to intravital whole body like this.

The dissolubility of LPEI-NONO in physiological solution proposed with it bag by the purposes of medical apparatus in medical apparatus, for example blood vessel relevant before the problem do not recognized, its be LPEI-NONO from the release of medical apparatus to blood flow will cause the whole body of LPEI-NONO to discharge and undesirable nitrogen oxide in release away from the position of therapentic part.

Think that also the release of LPEI-NONO in blood flow is undesirable, because it can cause foreign compound to intravital release.

By using the coat in LPEI-NONO layer outside, we have overcome the problem that this whole body discharges, and described coat can hinder the release of LPEI-NONO effectively when inserting body fluid, for example blood.

As if in addition, we have found that the application of the basic formulations of LPEI-NONO has proposed a shortcoming, its dissolubility that is LPEI-NONO is enhanced, cause the potentiality of the increase of polymer whole body release in use.In order to overcome this problem, we have adopted a kind of external coating (skin or outer coatings).In addition, described coat can have the kinetics useful effect of nitrogen oxide from the medical apparatus release of polymine diazeniumdiolate bag quilt.

Thus, before using medical apparatus, can control the release of NO effectively---this can greatly prolong the shelf life and the reliability of medical apparatus, and allows accurately to measure therapeutic release, thus the pharmacotoxicological effect that control is wished.

For example, in one aspect, after medical apparatus inserts in the body, has a controllable initial period, NO release at this moment is relatively low.This can prevent the too early release of NO, because anti--thrombosis effect of NO, release too early can cause the problem of bleeding from entry wound degree of making a slip of the tongue.The character that outer field character, and first, second and the 3rd territory of mentioning of this paper in some respects, the hydrophilic that especially uses in described territory are supported the polymer/polymer mixture is important for the character of this initial period of decision (i.e. control).

Therefore, use the present invention can carefully control the release dynamics of NO, guarantee release profiles best in operative process.Can limit simultaneously initial NO and discharge, the release stage that can the extended treatment effective dose, thus overcome the problem that prolonged operations operation back NO exhausts.

In one aspect, the present invention is based on following wonderful discovery, and promptly the knowledge with prior art is opposite, and (linearity) poly-(aziridine) diazeniumdiolate (LPEI-NONO) dissolves in for example blood of Ionized aqueous solution, most critical ground physiological solution.

The invention provides the solution of outer coatings form, described outer coatings is applied to LPEI-NONO layer (LPN layer, be also referred to as first territory in this article) the outside, this provides sterically hindered preventing or to reduce the release of LPEI-NONO from the medical science apparatus surface, allows water to diffuse into the LPN layer simultaneously and nitrogen oxide discharges from the LPN layer.

Skin can be used in combination with the polymer coating system, in this polymer coating system, nitric oxide adduct exists with the polymer architecture form that comprises structural polymer and hydrophilic polymer, thereby allow physiological fluid controllably directly near nitric oxide adduct, this depends on the ratio of the structural polymer, hydrophilic polymer and the nitric oxide adduct that exist in the polymer coating system.Consider that also the polymer coating system can be used to prevent or reduce the release of undesirable nitric oxide adduct from the surface of medical apparatus that coating is arranged, allow water and ion simultaneously to nitric oxide adduct with from the controlled spread of the nitrogen oxide of adduct.

The invention provides the medical apparatus that uses in the blood vessel, it comprises base material (basematerial), this base material comprises the polymine diazeniumdiolate or is enclosed with the interior coating that comprises the polymine diazeniumdiolate at least in part, wherein said medical apparatus comprises a skin in addition, it is positioned at the outside of described base material or described coating, and described skin comprises the polymer barrier between polymine diazeniumdiolate and external environment condition.

Therefore, skin comprises may command, reduces or prevents the polymer of polymine diazeniumdiolate release the course Physiological Medium in described.

The present invention also provides and has produced the method that is applicable to the medical apparatus that uses in the blood vessel, and described method comprises, and (a) selects to be applicable to the medical apparatus of vascular surgery, and described medical apparatus comprises base material; (b) randomly prime coat is applied to the surface of base material; (c) internal layer (being called first territory in this article) is applied on the surface of substrate material surface or prime coat, described internal layer (first territory) comprises the polymine diazeniumdiolate; (d) use skin, it comprises may command, reduces or prevents the polymer of polymine diazeniumdiolate from the release of described internal layer (first territory) to Physiological Medium.

The present invention also provides the method that is applicable to the medical apparatus that uses in the blood vessel of producing, described method comprises, (a) selection is applicable to the medical apparatus of vascular surgery, and described medical apparatus comprises base material or the internal layer (first territory) that contains the polymine diazeniumdiolate; (b) use outer (being also referred to as skin in this article), it comprises may command, reduces or prevents the polymer of polymine diazeniumdiolate release the course Physiological Medium in described.

The present invention also provides the purposes of (L) PEI-NONO compositions of coat and/or alkali stabilisation, the medical apparatus that it is used for producing in the blood vessel that comprises (L) PEI-NONO or neural blood vessel uses, be used to prevent one or more to be selected from following disease: vasospasm or vasoconstriction, the prevention of cerebral vasospasm, the diastole of smooth muscle, vasodilation, thrombosis, the platelet deposition or the gathering that reduce, restenosis alleviate hypertension, the oxygen-derived free radicals reperfusion injury, the treatment of cardiovascular disease, the prevention of the side effect relevant with the use of described medical apparatus prevents unusual cell proliferation.

The purposes of the speed that the polymine diazeniumdiolate discharged from the medical apparatus surface that comprises the polymine diazeniumdiolate when the present invention also provided outer (coating) to be used to control in described medical apparatus inserts body.

In one embodiment, outer can the release the course Physiological Medium in described of controlled oxidation nitrogen, and/or water is from the diffusion of Physiological Medium to internal layer under physiological condition, and/or small molecule by-product is from the seepage of described polymeric blends to Physiological Medium.

The present invention also provides the basic formulations of polymine diazeniumdiolate and has comprised the medical apparatus of the basic formulations (pH is greater than 7) of polymine diazeniumdiolate.

The invention provides the method that preparation is applicable to the polymine diazeniumdiolate preparation of (alkali) stabilisation in the medical apparatus coating in the blood vessel, described method comprises, and (LPEI-NONO) is dissolved in the alkali organic solvent with the polymine diazeniumdiolate.Described solvent can be the solvent of any appropriate, for example is selected from following solvent: alcohol, ethanol, methanol, aniline, benzaldehyde, cyclohexylamine dimethyl sulfoxide, particular methanol.The water content of organic solvent is preferably less than 1%, for example less than 0.5.The concentration that can be dissolved in the polymine diazeniumdiolate in the solvent depends on the solvent of use.But the level that is dissolved in the polymine diazeniumdiolate in the solvent usually is (by weight/weight) about 0.2% to about 20%, for example about 1% to about 10%, for example about 1% to about 5%, for example about 2%.

The present invention also provides the compositions that is applicable to the polymine diazeniumdiolate that comprises the alkali stabilisation in the medical apparatus coating in the blood vessel.Suitably, described compositions comprises the polymine diazeniumdiolate that is dissolved in the alkali solvent, and suitably, concentration is that about (w/w) 0.2% to about 20%, for example about 1% to about 10%, for example about 1% is to about 5%, for example about 2%.

The compositions that comprises the polymine diazeniumdiolate of alkali stabilisation can comprise another kind of polymer that this paper mentions for example hydrophilic polymer or structural polymer in addition, and polyether polyols with reduced unsaturation and/or hydrophilic that preferred this paper mentions are supported polymer or polymeric blends or coating system.

The invention provides a kind of medical apparatus, it comprises first territory of containing the polymine diazeniumdiolate at least, and the pH in wherein said first territory is greater than pH7.Suitably, when at least a portion on moistening medical apparatus surface, described medical apparatus can discharge nitrogen oxide (suitably, from the polymine diazeniumdiolate) to organism.

The present invention also provides and has produced the method that is applicable to the medical apparatus that uses in the blood vessel, and described method comprises, and (a) selects to be applicable to the medical apparatus of vascular surgery, and described medical apparatus comprises base material; (b) randomly prime coat is applied to the surface of base material; (c) internal layer (first territory) is applied to (or medical apparatus outer surface on the surface of substrate material surface or prime coat, for example another territory or the layer, the second or the 3rd territory mentioned of this paper for example), described internal layer (first territory) comprises the alkali preparation of polymine diazeniumdiolate; (d) randomly, use skin, it comprises may command, reduces or prevents the polymer of polymine diazeniumdiolate from the release of described internal layer (first territory) to Physiological Medium.

Therefore, production is applicable to that the method for the medical apparatus that uses in the blood vessel can comprise following step, (a) selection is applicable to the medical apparatus of vascular surgery, (b) first territory compositions of described preparation (or comprise) that will comprise the alkali preparation of polymine diazeniumdiolate is applied to described medical apparatus (being applied to outer surface usually, for example one of other territory of mentioning of base material or prime coat or this paper); (c) randomly, use skin, it comprises may command, reduces or prevents the polymer of polymine diazeniumdiolate from the release of described first territory to Physiological Medium.

In the method for producing according to medical apparatus of the present invention, can be before using first territory, in the process or afterwards, use second territory and/or the 3rd territory that this paper mentions.

The present invention also provides the alkali preparation of polymine diazeniumdiolate or has comprised the purposes of the compositions of preparation according to the present invention (for example this paper mention first territory), the medical apparatus that it is used to produce in the blood vessel or neural blood vessel uses, for example be used to prevent or treat one or more be selected from following disease: vasospasm or vasoconstriction, the prevention of cerebral vasospasm, the diastole of smooth muscle, vasodilation, thrombosis, the platelet deposition of minimizing or gathering, the alleviating of restenosis, hypertension, the oxygen-derived free radicals reperfusion injury, the treatment of cardiovascular disease, the prevention of the side effect relevant with the use of described medical apparatus, prevent unusual cell proliferation

And/or

The present invention also provides according to outer field purposes of the present invention, the medical apparatus that it is used to produce in the blood vessel or neural blood vessel uses, for example be used to prevent or treat one or more be selected from following disease: vasospasm or vasoconstriction, the prevention of cerebral vasospasm, the diastole of smooth muscle, vasodilation, thrombosis, the platelet deposition or the gathering that reduce, restenosis alleviate hypertension, the oxygen-derived free radicals reperfusion injury, the treatment of cardiovascular disease, the prevention of the side effect relevant with the use of described medical apparatus prevents unusual cell proliferation.

Therefore, the present invention also provides one or more to be selected from following treatment of conditions (comprising preventing/prevent) method, for example Therapeutic Method (operation, get involved in vascular surgery or the blood vessel): vasospasm or vasoconstriction, the prevention of cerebral vasospasm, the diastole of smooth muscle, vasodilation, thrombosis, the platelet deposition of minimizing or gathering, alleviating of restenosis, hypertension, oxygen-derived free radicals reperfusion injury, the treatment of cardiovascular disease, the prevention of the side effect relevant with the use of described medical apparatus prevents unusual cell proliferation.

The invention provides use and carry out getting involved in the blood vessel method of (or vascular surgery) according to medical apparatus in the blood vessel of the present invention, for example one or more are selected from following treatment of conditions (comprising preventing/prevent) method: vasospasm or vasoconstriction, the prevention of cerebral vasospasm, the diastole of smooth muscle, vasodilation, thrombosis, the platelet deposition or the gathering that reduce, alleviating of restenosis, hypertension, oxygen-derived free radicals reperfusion injury, the treatment of cardiovascular disease, the prevention of the side effect relevant with the use of described medical apparatus prevents unusual cell proliferation.

The present invention also provides multilamellar (territory) coating system to be used to wrap purposes by medical apparatus in medical apparatus, for example blood vessel.In one aspect, described coating system comprises territory, first territory and second (tart), described first territory comprises the basic formulations of (L) PEI-NONO, (for example performing the operation between the operating period in blood vessel) when the moistening medical apparatus and can cause proton from the transfer of second territory to first territory in described second territory, thereby causes H in first territory ⁺And OH ^-The change of local equilibrium between the ion reduces the pH in first territory effectively, thereby makes (L) PEI-NONO of ' alkali ' stabilisation go to stablize, and causes the therapeutic of NO to discharge.

Can spread the concentration of proton in the buffer capacity by regulating alkali first territory and/or second territory, can guarantee to reduce or prevent the too early release of NO and control NO timing and release effectively from the medical science apparatus surface.

Usually, for temporary medical apparatus, for example intubate sheath, guide line, conduit, microtubular and balloon catheters, preferably the alkali of Shi Yonging does not have significant buffer capacity.But for implant, for example support and thromboembolism form device, and preferably described alkali is the form of ealkaline buffer, because this can guarantee the long-time release of NO.

Therefore, a purpose of the preferred embodiments of the invention provides a kind of medical apparatus and a kind of method that allows the speed that controlled oxidation nitrogen discharges from such medical apparatus (for example balloon catheters system, guide line or intubate sheath).Another purpose of the preferred embodiments of the invention provides a kind of medical apparatus, and balloon, guide line or the intubate sheath of coating for example arranged, and it has the high mechanical properties of the mechanical integrity of keeping it in surgical procedures.Another purpose of the preferred embodiments of the invention provides a kind of medical apparatus and its using method, and the release of the therapeutic agent that its permission contains from the device moistening to this device is through the preset time section.Another purpose of the preferred embodiments of the invention provides a kind of balloon catheters that coating is arranged, its have can fold, store, sterilization and unfolded balloon, can adhesion between the surface that coating is arranged of balloon.Another purpose of the preferred embodiments of the invention provides a kind of multiple coatings on medical apparatus, and it allows the whole coating of moistening immediately basically, even the surface is folding before use.Another purpose of the preferred embodiments of the invention is for the medical apparatus with low skin resistance provides a kind of coating, places for example placement of balloon before inflation to guarantee the convenient of this device.

In one aspect, the invention provides a kind of medical apparatus, it is used for when at least a portion on moistening (for example using body fluid) medical apparatus surface, discharges therapeutic agent (nitrogen oxide) to organism, and described medical apparatus comprises first territory and second territory at least, wherein:

● described first territory can discharge therapeutic agent with rate of release;

● described second territory can influence the pH at least one territory in first territory and second territory, and this is by changing H when at least a portion of moistening medical apparatus ⁺And OH ^-Local equilibrium between the ion realizes;

And wherein:

● therapeutic agent depends on the pH at least one territory first territory and second territory from the rate of release in first territory.

In yet another aspect, the invention provides a kind of medical product, it comprises medical apparatus of the present invention, and this medical apparatus is wrapped in the packing, and this packing prevents that moisture, oxygen and/or light from entering in the packing.

In yet another aspect, the invention provides the application of therapeutic agent in the disposable medical apparatus of preparation, described disposable medical apparatus is used for the treatment of the cell obstacle of bodily conduit, and described medical apparatus comprises first territory and second territory at least, wherein:

And wherein:

In yet another aspect, the invention provides the method that discharges therapeutic agent from medical apparatus, described medical apparatus comprises 2 territories at least, first territory and second territory, wherein said first territory can discharge therapeutic agent with rate of release, and described second territory can influence the pH in first territory, and this is by changing H when at least a portion of moistening medical apparatus ⁺And OH ^-Local equilibrium between the ion realizes, and wherein said therapeutic agent depends on the pH at least one territory first territory and second territory from the rate of release in first territory, and this method comprises following step:

● make the biological body fluid of medical apparatus contact;

● the moistening medical apparatus, thus H caused ⁺Or OH ^-Ion is from the transportation of one of first and second territories to another territory, thus the speed that the raising therapeutic agent discharges to bodily tissue from first territory.

In yet another aspect, the invention provides the method that coating is applied to the medical apparatus surface, described coating comprises at least a therapeutic agent, and this method comprises following step:

● medical apparatus is placed in the qualification environment, for example the production space; Subsequently:

● coating is applied to the medical apparatus surface, and control simultaneously limits the pH of environment, with the release of suppression therapy agent from medical apparatus, for example in alkaline environment.

As a replacement scheme that limits environment, coating solution can contain the buffer agent of controlling pH.For example, can be with US 6,737,447 disclosed poly-(aziridine) diazeniumdiolate, for example linear poly-(aziridine) diazeniumdiolate (L-PEI-NONO) are dissolved in the pH-controlling agent for example among the NaOH, are dissolved in organic solvent usually and (mention as this paper, for example pyridine or alcohol, for example methanol).Another replacement scheme is to supply with for example ammonia of pH-control gas to the spray pistol of for example using coating.Having in the presence of the liquid, ammonia can make spraying become alkalescence.When suitable, can use other alkali gas.

Therefore, the invention provides and treat smooth muscle cell proliferation for example reducing the method for restenosis, prevention or reduce inflammation, for example insert method, anticoagulant and/or the vasodilative method of the inflammation that causes among the patient by foreign body or device.Such method is included in operation technique, for example blood vessel and uses according to medical apparatus of the present invention in the operation/intervention.

Detailed Description Of The Invention

NO adduct (therapeutic agent)

Proposed to discharge multiple nitrogen oxide (NO) compound donator and the polymer composition of nitrogen oxide in the prior art, for example US 5,519,020, and US 5,691,423, US 5,770,645, US 5,814, and 656, US 5,962,520, and US 5,958,427, US 6,147,068, and US6,737,447 B1 (corresponding EP 1220694 B1).

Poly-imines is represented different types of polymer, and they can have diazeniumdiolate part covalently bound with it.Poly-imines comprises poly-(thiazolinyl imines) for example gathers (aziridine).For example, described polymer can be poly-(aziridine) diazeniumdiolate (L-PEI-NONO) of disclosed linearity among the US 6,737,447 incorporated by reference in this article.Can change nitric oxide donor at the loading of linearity poly-(aziridine) on (PEI), make the amine groups of 5-80% (for example 10-50%, for example 33%) of PEI carry the diazeniumdiolate part.According to the condition of using, (L)-PEI-NONO can discharge the different marks of releasable nitrogen oxide total amount.

Poly-imines with diazeniumdiolate part (especially linear poly-(aziridine) diazeniumdiolate) can for example be used as the polymer of electric rotary course, because such polymer has suitable hydrophilic usually, also (with the therefore loading of potential NO molecule) can change in wide region because the loading of diazeniumdiolate part, with reference to the above-mentioned example of PEI-NONO.

A kind of most preferred nitric oxide adduct polymer is the polymine diazeniumdiolate, for example linear polyethylene imines diazeniumdiolate (LPEI-NONO).PEI-NONO also exists as branched polymer, and it also can use, although LPEI-NONO (linearity) form is preferred.

US 6,855, and 366 provide the method for preparing LPEI-NONO.Can change nitric oxide donor at the loading of linearity poly-(aziridine) on (PEI), make the amine groups of 5-80% (for example 10-50%, for example about 20 to about 40%, for example about 30%) of PEI carry the diazeniumdiolate part.According to the condition of using, L-PEI-NONO can discharge the different marks of releasable nitrogen oxide total amount.

In one embodiment, for example when the NO adduct is LPEI-NONO, the molecular weight of nitric oxide adduct polymer depends on the size of the raw material that is used to prepare the NO adduct and at the branch degree of polymer in some cases.Usually, with regard to dissolubility in reducing body, bigger polymer sizes is preferred, and still, big polymer also may hinder dissolving and bag by the ability of medical apparatus.Under the situation of LPEI-NONO, the application of the precursor of branching can cause molecular structure in the fracture of branch point place, is reduced in the mean molecule quantity of the polymer molecule that exists in the final NO polymer adduct.Therefore whether be linear to molecular weight if can be used to define LPEI-NONO.

In a preferred embodiment, the nitric oxide adduct for example mean molecule quantity of LPEI-NONO polymer is that about 5kDa is to about 200kDa, for example about 10kDa is to about 100kDa, for example more preferably from about 30kDa to about 70kDa, for example about 55kDa, preferred polydispersity is about 1 to about 3, more preferably from about 2.

Use has the different Polyethylene Glycol (PEG) of known molecular amount as standard substance, measures mean molecule quantity by the molecular-exclusion chromatography (SEC) of main polymer chain linear polyethylene imines (L-PEI).Can measure the total amount of the NO in the polymer (L-PEI-NONO) that NO loads by elementary analysis (EA).Therefore, can calculate the mean molecule quantity of the polymer (L-PEI-NONO) of NO loading based on result from molecular-exclusion chromatography (SEC) and elementary analysis (EA).

In a preferred embodiment, the nitric oxide adduct that can form coating (be NO discharge coating) is or based on the linear polyethylene imines (L-PEI) with pendant NONO group.

Each NONO group covalently bind on one of N atom of L-PEI polymer chain, thereby forms N*-N ⁺(O ^-)=N-O ^-Group, wherein N* is one of L-PEI backbone atoms.This group by with the L-PEI main chain in vicinity-NH ₂ ⁺-amine groups forms the amphion complex and stabilisation.

Provide (H when being exposed to proton ⁺) when environment such as Ionized water or blood, the linear polyethylene imines (L-PEI-NONO) that nitrogen oxide loads can discharge nitrogen oxide.

For auxiliary stabilisation coating, this device is stored in usually noble gas (N for example is housed ₂Atmosphere) in the sealed aluminum bag.Protect product in storing process, to avoid moisture, light and oxygen thus.Usually, for example when using N ₂(g) during atmosphere, moisture is 6% or lower, O ₂(g) be about 2% or lower.Use moisture and oxygen absorbent (for example this paper mention those) can further reduce moisture and O ₂(g) level, thereby in a preferred embodiment, the level of moisture is about 0.1% or lower, O ₂(g) level is about 0.01% or lower.

L-PEI-NONO is mixed the controlled release that can realize nitrogen oxide in the polymeric matrix.In the time of in importing vascular system, nitrogen oxide arrives blood vessel wall by transdermal delivery.

The nitrogen oxide dosage that is delivered to blood vessel wall (being target position) is by rate of release and the time decision that contacts arterial wall.The dosage that is delivered to the target thing and is smooth muscle cell (SMC) also depends on the existence of the thickness of blood vessel wall, potential speckle, blood/hemoglobin, the existence and the diffusion constant (D) of oxygen.

Have realized that polymeric NONOate, those that for example contain the diazeniumdiolate group can produce undesirable small molecule by-product, for example nitrosamine (referring to US 6,875,840).The present invention has overcome the generation and/or the release of undesirable small molecule by-product, can realize simultaneously the controlled release of nitrogen oxide under physiological condition, this supports to realize in polymer or the polymeric blends by polymeric NONOate (for example polymine diazeniumdiolate) being mixed hydrophilic.

In one embodiment, with the NO adduct for example the polymine diazeniumdiolate to be applied to the lip-deep density of medical apparatus be about 0.05 to about 100mg/cm ², for example about 0.1 to about 10mg/cm ², for example preferred about 0.2 to about 0.5mg/cm ²

In one embodiment, with the NO adduct for example the polymine diazeniumdiolate to be applied to the lip-deep density of medical apparatus be about 0.05 to about 200 μ mol NO/cm ², for example about 0.1 to about 20 μ mol NO/cm ², for example preferred about 0.3 to about 1 μ mol NO/cm ²

In one embodiment, the invention provides for example alkali stabilized preparations of linear polyethylene imines diazeniumdiolate of polymine diazeniumdiolate, with comprise the medical apparatus that for example is coated with such alkali stabilized preparations, for example comprise the medical apparatus in described at least first territory as herein described.

We have found that, although use nonaqueous solvent for example methanol as the solvent of polymine diazeniumdiolate, NO takes place too early from the release meeting of polymine diazeniumdiolate, for example in preparation, storage and the course of processing of polymine diazeniumdiolate, cause the nitrogen oxide providing capability of suboptimum.For the situation (for example in the spray coating process at medical apparatus) in preparation and the processing of carrying out nitric oxide adduct in the presence of the aerobic, the formation of nitrite is the inevitable effect that spontaneous nitrogen oxide discharges.

Therefore the present invention provides the method for the basic formulations of preparation polymine diazeniumdiolate, and it comprises the polymine diazeniumdiolate is dissolved in alkali organic solvent, alcohol for example, for example ethanol and methanol, oxolane, pyridine etc.

Usually be prepared as follows the alkali solvent: before adding (L) PEI-NONO polymer, suitable alkali cpd (alkali) is dissolved.The OH that adds ^-Should be that about 0.1 μ M is to about 2mM OH ^-, for example 0.001mM is to about 1mM OH ^-, for example about 0.01mM is to about 0.5mM, and for example about 0.05mM is to about 0.2mM, about 0.1mM.By regulating the amount of the alkali that adds, regulate the pH of solvent.

Can use many suitable base reagents, inorganic base for example, NaOH for example, KOH, Ca (OH) ₂, and LiOH, or organic base, for example diisopropylamino lithium and methylamine.Alkali can be organic or inorganic alkali buffer agent, phosphate (pK2) for example, ethanolamine, ADA; carbonate (pK1), ACES, PIPES, MOPSO; imidazoles, BIS-TRIS propane, BES, MOPS; HEPES, TES, MOBS, DIPSO; TAPSO, triethanolamine (TEA), pyrophosphate, HEPPSO; POPSO, tricine, hydrazine, glycylglycine (pK2); tromethane (tris), EPPS, HEPPS, BICINE; HEPBS, TAPS, 2-amino-2-methyl-1, ammediol (AMPD); TABS, AMPSO, taurine (AES), borate; CHES, 2-amino-2-methyl-1-propanol (AMP), glycine (pK2), ammonium hydroxide; CAPSO, carbonate (pK2), methylamine; piperazine (pK2), CAPS, CABS and piperidines.

Suitably, the pH in first territory is such, OH ^-Concentration is that about 0.02mM is to about 2mM OH ^-, for example 0.05 to about 1mM OH ^-, for example about 0.1mM.

Alkali methanol most preferably for example is dissolved in NaOH in the methanol (concentration is 0.1 to 10 μ g/ml usually, 1 to 2 μ g/ml for example, for example about 1.67 μ g/ml).

The critical aspects that controlled oxidation nitrogen discharges too early from the polymine diazeniumdiolate is that the pH of polymine diazeniumdiolate (local environment-for example first territory) is brought up to more than 7, and for example pH 8 to 13.

First territory

First territory is a discrete domain, and it does not form homogeneous phase with second territory (if existence).In a preferred embodiment, first territory can be the conforming layer form of roughly uniform thickness.But those skilled in the art are apparent, and first territory can be many other forms.

First territory can comprise and one or more base reagents or bonded hydrophilic support polymer of alkaline side group or polymeric blends.Be applicable to that hydrophilic support polymer or polymeric blends in first territory are described in EP application number 06023223 and the U.S. Provisional Application 60/864,886.

In one embodiment, first territory can form discrete particle, nano-particle for example, and they are embedded in another territory for example in second territory.Perhaps, second territory can form discrete particle, and they are embedded in for example outer and/or first territory, another territory.

In one embodiment, first territory is the form of LPEI-NONO fiber, for example electricity rotation fiber or nanofiber.

But in one embodiment, first territory is not for example electricity rotation fiber or a form of nanofibers of LPEI-NONO fiber, or does not comprise LPEI-NONO fiber for example electricity rotation fiber or nanofiber.

Preferably, first territory forms homogeneous phase.

Can control the pH in first territory in many modes known in the art.With regard to being applied to medical apparatus, (L) PEI-NONO is dissolved in the nonaqueous solvent usually.

Usually, first territory is alkaline territory, promptly when the suitable solvent of its contact for example during water, the pH of local field is greater than pH 7, for example greater than about pH 7.5, for example greater than about pH 8, for example greater than about pH9, for example greater than about pH 10, for example greater than about pH 11, for example greater than about pH 12, for example greater than about pH 13, for example about pH 14, or for example greater than pH 7 to about pH 14.In a preferred embodiment, the pH in first territory be about pH 9 to about pH 12, most preferably from about pH 8 is to about pH11, for example about pH 9 is to about pH 10.We have been noted that high pH, for example 12 and more than, polymer system for example hydrophilic is supported the polymer/polymer mixture, high pH can change the physical property of polymer, and this may be deleterious in some cases, and for example high pH can influence the stability of coating system.

Therefore, first territory comprises the alkali compounds of organic or inorganic usually.Suitable inorganic alkali compound comprises for example NaOH, KOH, Ca (OH) ₂And LiOH.Suitable alkali organic compound comprises for example diisopropylamino lithium and methylamine.Alkali cpd can be an ealkaline buffer, for example is selected from following buffer agent: phosphate (pK2), ethanolamine, ADA; carbonate (pK1), ACES, PIPES, MOPSO; imidazoles, BIS-TRIS propane, BES, MOPS; HEPES, TES, MOBS, DIPSO; TAPSO, triethanolamine (TEA), pyrophosphate, HEPPSO; POPSO, N-(methylol) methylglycine, hydrazine, glycylglycine (pK2); tromethane (tris), EPPS, HEPPS, BICINE; HEPBS, TAPS, 2-amino-2-methyl-1, ammediol (AMPD); TABS, AMPSO, taurine (AES), borate; CHES, 2-amino-2-methyl-1-propanol (AMP), glycine (pK2), ammonium hydroxide; CAPSO, carbonate (pK2), methylamine; piperazine (pK2), CAPS, CABS and piperidines.

Alkali compounds also can be an alkaline polymer, for example contains inorganic or organic base, the polymer of alkaline side group for example.

The alkali compounds that comprises the alkali polymer preferably has the pKb less than 6, is more preferably less than 5 pKb.

Alkali cpd or group can be selected from primary amine, secondary amine and tertiary amine.

Alkali cpd or group can be selected from diisopropylamino lithium, methylamine, chloroquine.

Except (alkali preparation) (L) the PEI-NONO, first territory comprises another kind of polymer usually, hydrophilic structure polymer that for example polyurethane, or this paper is mentioned or polymeric blends (under the coating system).

In one embodiment, first territory can comprise and is selected from following polymer: polyolefin, polystyrene for example, polypropylene, polyethylene, politef, Kynoar, polrvinyl chloride, deutero-polyolefin is polymine for example, polyethers, polyester, polyamide is nylon for example, polyurethane, silicone.

In one embodiment, first territory can comprise and is selected from following polymer: aromatic polyurethane, and the vinyl acrylate polyolefin, hydrophilic aliphatic urethane or silicone, they all have high water conduction/water absorptance.These polymer can be selected from: tecophilic, estane, EMAC and EBAC polyolefin family or high water vapor conduction silicone.

In one embodiment, first territory can comprise and is selected from following polymer: polyolefin, for example polystyrene, polypropylene, polyethylene, politef, Kynoar, polrvinyl chloride, deutero-polyolefin is polymine for example, polyethers, polyester, polyamide is nylon for example, has the polyurethane of good adhesion and structural stability, and they satisfy the aforementioned stable standard.But the polyurethane that is preferably based on aliphatic polyether is Tecoflex SG 85A for example.

Second territory

Second territory is a discrete domain, and it does not form homogeneous phase with first territory.In a preferred embodiment, second territory can be the conforming layer form of roughly uniform thickness.But those skilled in the art are apparent, and second territory can be many other forms.

Second territory can comprise and one or more acidizers or bonded hydrophilic support polymer of acidic pendant groups or polymeric blends.Be applicable to that hydrophilic support polymer or polymeric blends in second territory are described in EP application number 06023223 and the U.S. Provisional Application 60/864,886.

Second territory can form discrete particle, nano-particle for example, and they are embedded in another territory for example in first territory.Perhaps, second territory can form discrete particle, and they are embedded in for example outer and/or first territory, another territory.

Second territory also can comprise (L) PEI-NONO in one embodiment.But in a preferred embodiment, second territory does not comprise (L) PEI-NONO.

In one embodiment, the second layer is not for example electricity rotation fiber or a form of nanofibers of LPEI-NONO fiber, or does not comprise LPEI-NONO fiber for example electricity rotation fiber or nanofiber.

Preferably, second territory forms homogeneous phase.

Can control the pH in second territory in many modes known in the art.For example, second territory can comprise for example ascorbic acid, polyacrylic acid, and lactic acid, acetic acid and/or oxylic acid (oxylicacid) are as H ⁺-releasing agent is used to influence the release of therapeutic agent from first territory.Second territory can comprise tart polymer, or comprises tart side group, and they can discharge proton when contact water.

Other acidizer or the side group that can be used for second territory comprise lactic acid or vitamin C, and/or are selected from following sour reagent: ascorbic acid, polyacrylic acid, oxylic acid, acetic acid and lactic acid.

Acidizer can have the pKa less than 6, more preferably has any organic acid less than 5 pKa.

In one embodiment, acidizer is a mineral acid, for example hydrochloric acid, sulphuric acid, nitric acid or hydrobromic acid.

Acidizer can be or comprise acid buffer agent, for example be selected from following buffer agent: maleate (pK1), phosphate (pK1), glycine (pK1), citrate (pK1), glycylglycine (pK1), malate (pK1), formates, citrate (pK2), succinate (pK1), acetate, propionate, malate (pK2), pyridine, piperazine (pK1), Cacodylate, succinate (pK2), MES, citrate (pK3), maleate (pK2), histidine, bis-tris, phosphate (pK2), ethanolamine, ADA and carbonate (pK1).

In one embodiment, acid compound can be to contain inorganic or the organic acid polymer of side group for example.In a preferred embodiment, for example tart polymer of acid compound comprises carboxyl.

Therefore, acid compound can be fruit acid or equivalent, for example hydroxy acid or its acid derivant.

Therefore think that second territory can be in the inside or the outside in first territory.

Second territory can influence the pH in first territory, and this is by changing H when at least a portion of moistening medical apparatus ⁺And OH ^-Local equilibrium between the ion realizes that promptly second territory can reduce the pH in first territory when at least a portion of moistening medical apparatus.Therefore, nitrogen oxide depends on the pH in second territory in one embodiment from the pH at least one territory of rate dependent in first territory and second territory of first territory release.

Usually, second territory is an acidic domain, and promptly when the suitable solvent of its contact for example during water, the pH of local field is lower than pH 7, for example be lower than about pH 6.5, for example be lower than about pH 6, for example be lower than about pH5, for example be lower than about pH 4, for example be lower than about pH 3, for example be lower than about pH 2, for example about pH 1, or for example be lower than pH 7 to about pH 1.The pH in second territory can be for example about pH 2 to about pH 6 or about pH 3 to about pH 5.

We have been noted that also and for example are lower than pH 2 in low-down acidity that this acidity can influence the physical property of the polymer that uses in second coating, and this can influence the stability of described coating nocuously.

First and second territories

In one embodiment of the invention, medical apparatus is coated with first and second territories at least in part.

In one embodiment, first territory comprises first coatings of device, and it is applied to or is being close to the base material or the prime coat of medical apparatus.Therefore second territory can comprise second coatings of device, and it is applied to or is being close to described first coating.

Suitably, nitrogen oxide is from the pH at least one territory of rate dependent in first territory and/or second territory of first territory release.

First and second territories can have form or shape arbitrarily, and still, stratified structure is preferred, make the territory of winning form a coatings, and second territory form another coatings.For example, medical apparatus can be coated with a kind of material, and it forms second territory as initial surface coatings, and this initial surface coatings is capped another kind of material subsequently, and it forms first territory as another coatings on initial surface coatings.For some application, preferably use the layer (i.e. first territory) that contains donor-chemical compound before, and, preferably use pH decorative layer (i.e. second territory) before in donor layer (i.e. first territory) for other application at pH decorative layer (i.e. second territory).Also can predict, 2 layers can be used simultaneously, for example by 2 independent stratums of extruding, or by coating comprise first and second territories the layer, for example when first and/or second territory is particle form, a territory can form ' substrate ', and another territory is formed on discrete (the being non-homogeneous) granule in ' substrate ' territory, for example nano-particle, or first and second territories all is the form of the discrete particle in suitable base composition (for example this paper mention hydrophilic support polymer or polymeric blends).

In the embodiment that has first territory and second territory at least, first territory can discharge one or more therapeutic agents, and rate of release depends on for example pH in this territory.Because H can be passed through in second territory ⁺Ionic release influences the pH in first territory, and when at least a portion of moistening medical apparatus, the pH in first territory increases when this device of moistening a part of, therefore triggers or strengthen the release of therapeutic agent.Because H ⁺Ion is from the transportation of second territory to first territory, and the pH in first territory changes when moistening second territory.

Therefore, in a preferred embodiment, the invention provides the controlled release of therapeutic agent (nitrogen oxide usually), it depends on the humidity or the water content of the part of medical apparatus, for example water content in second territory.In a typical use of medical apparatus, after entering the vascular system of human or animal body, second territory is by the blood moistening.The arrangement in first and second territories and another layer for example interpolation of outer coating can further influence release opportunity of nitrogen oxide.In one embodiment, outer coating provides the another kind protection that prevents that NO from discharging too early, and this realizes by the too early hydration that prevents first and/or second territory.This can realize by using outer coating, described outer coating is that for example only part is permeable, but or permeate water steam only, the outer coating of being made by hydrophobic polymer for example---such outer coating is useful especially for postponing to discharge, for example in implant for example under the situation of support.Suitable hydrophobic polymer is known in the art, comprise multiple polymers for example silicone (it can for example pass through steam, but waterproof) and polrvinyl chloride (PVC) polyurethane (PU), polyacrylate or have other polymer or its mixture of limited water conduction.

In a preferred embodiment, second territory is applied in before first territory, promptly in inside, first territory.This guarantees that they must pass first territory along with proton spreads to external environment condition from second territory, thereby guarantees that maximum NO discharges.

In this article, described first territory is also referred to as biologically active domain, and described second territory is also referred to as the active territory of pH.But, will be appreciated that first territory also is that pH is active, but opposite with second territory, the pH in first territory (or the potential pH when moistening) is alkaline, and the pH in second territory (or the potential pH when moistening) is tart.

The 3rd territory

Described medical apparatus can comprise the 3rd territory.

The 3rd territory can be another territory between first territory and second territory.

In one embodiment, medical apparatus can comprise first territory and the 3rd territory.

The 3rd territory can be a neutral line, and it is controlling the speed of water (and proton) from body fluid (randomly, by second territory) inflow first territory.In one embodiment, the 3rd territory can comprise buffer agent, its restriction proton inflow in first territory, thus ' long and low ' NO release dynamics is provided.

By using between first and second territories roughly the 3rd territory of neutral pH (7), can further avoid or reduce the too early degraded (NO release) of (L) PEI-NONO, in the procedure of processing that comprises in the preparation of medical apparatus (production) process, this is specially suitable.

In one embodiment, the 3rd territory comprises hydrophilic support polymer or the polymeric blends that this paper mentions, or form those disclosed in EP application number 06023223 and U.S. Provisional Application 60/864/886 for example by hydrophilic support polymer or polymeric blends that this paper mentions.

In one embodiment, the 3rd territory is made up of hydrophilic polymer, or comprises hydrophilic polymer.

In one embodiment, the 3rd territory is made up of hygroscopic polymer, or comprises hygroscopic polymer.

The 3rd territory can comprise buffer agent, for example near the buffer agent of pH 7 when contact water.Like this, by playing the proton quencher, proton diffuses into first territory from second territory speed can be controlled in the 3rd territory.When medical apparatus may contact water or water vapour before needs or best therapeutic discharges constantly, this was useful.Equally, the 3rd territory can be used as-the OH quencher, prevents the alkalization of undesirable acidic layer.

The thickness in the 3rd territory can be extremely about 10 μ m of for example about 0.1 μ m, and for example 1 μ m is to about 5 μ m.

In one embodiment, the 3rd territory does not comprise buffer agent.In one embodiment, the pH in the 3rd territory is about 7.

Recognize that outer coatings can be identical with trilaminar composition in one embodiment.

Interior prime coat

Priming paint normally is used to first coating that seals coarse surface and hold follow-up flush coat.

In a preferred embodiment, base material (being the surface of outer surface and/or the contact Physiological Medium) bag of giving medical apparatus is by interior prime coat, and it is between the basal layer of medical apparatus and described first or second territory (or this paper mention coating system) or nitric oxide adduct.

In one embodiment, interior prime coat can be selected from: polyolefin, polystyrene for example, polypropylene, polyethylene, politef, Kynoar, polrvinyl chloride, deutero-polyolefin is polymine for example, polyethers, polyester, polyamide is nylon for example, polyurethane.

Suitably, interior prime coat has good adhesion and structural stability, to resist about 4-100 newton cm ^-2, about 8-50 newton cm for example ^-2, preferred 10-20 newton cm for example ^-2Be applied to pull strength on the polymer-coated surface.

A kind of preferred priming paint polymer is based on the polyurethane of aliphatic polyether, for example Tecoflex SG85A.

In one embodiment, the thickness of prime coat is 0.2 to 5 μ m.Prime coat thickness from the teeth outwards needs not be uniformly, because its effect is to make coating and/or NO adduct strong bonded on medical apparatus.Therefore, need provide enough anchor points to use the strong platform that adds coating to provide.Preferably, prime coat has covered the base material that will wrap quilt effectively fully, and this can guarantee the max architecture integrity of succeeding layer.

Other layer

As mentioned above, about producing the method for the medical apparatus of sterilizing, can be with one or more layers be applied to nitric oxide adduct (first territory), for example coating system or fibrous layer in addition.Other layer like this comprises second territory and the 3rd territory and coat disclosed herein (skin).

In one embodiment, at least one territory in first, second, third territory comprises polyurethane, for example first and second territories, for example the first and the 3rd territory.

Therefore, in one embodiment, medical apparatus according to the present invention comprises can be at the nitric oxide adduct (first territory) that discharges nitrogen oxide under the physiological condition as herein described and can influence at least one other layer (second territory), for example nitric oxide adduct coating system or fiber of material of the pH of nitric oxide adduct (first territory) after inserting Physiological Medium.

In one embodiment, preferably other layer (comprising the skin of mentioning below) is soft enough, allowing the movable and crooked of medical apparatus, and the integrity of other layer of entail dangers to not.Suitably, other layer can be moisture absorption, and water expands in use.Therefore, for example conventional submergence of intubate sheath mechanism in isosmotic solution of medical apparatus before using allows the enough water of other layer absorption, to guarantee enough flexibilities and the lower resistance after insertion.Some polymer for example is used for the tecophillic polymer of coat, and about 60% of their volumes can expand in the time of in inserting aqueous medium.Use another advantage of other coating of expanded polymer to be, expansion will hide any needle pore defect or the shortcoming in other coating, therefore guarantee the integrity of coating system in use.

Simultaneously, in one embodiment, preferably externally be applied to described nitric oxide adduct (promptly between the Physiological Medium of nitric oxide adduct and use) with other one or more layers, recognize that also other layer can be used as the base material of medical apparatus and the layer between the nitric oxide adduct is used.

In a preferred embodiment, also use coat as herein described.Coat can directly apply to the coating system layer, or is applied to one or more other layers on the coating system layer.

Outer (coat)

Preferably, medical apparatus comprises the skin of any other the overseas portion that is positioned at first territory and may exists.Usually, skin comprises is controlling following one or more polymer: i) (L) PEI-NONO release the course Physiological Medium in described, for example, by forming the diffusion barrier between nitrogen oxide release adduct and the Physiological Medium, or by high diffusional resistance is applied to spread molecule, thereby significantly slow down diffusion process; Ii) release the course Physiological Medium in described, this is by reducing the conduction of nitrogen oxide molecule; Iii) water is from the diffusion of Physiological Medium to internal layer under physiological condition, and this passes the water mobile (conduction) of top layer according to the needs of given purposes by promotion or restriction; And/or iv) small molecule by-product from the leakage of described polymeric blends to Physiological Medium.Discharge in order to ensure controlled nitrogen oxide, in one embodiment, compare with the nitrogen oxide release of nitrogen oxide coatings self, outer activation and/or continuous release that should limit nitrogen oxide release, the factor is about 1-20, for example about 1.5-10, for example preferred 2-5.

Suitable coat and be coated with the production method of medical apparatus of coat and medical apparatus and application thereof are disclosed in European application number 06023222 and U.S. Provisional Application 60/864,893.

Skin also can provide structural stability to remain on original position to guarantee NO adduct and/or coating system in production, storage, preparation and the use of intubate sheath mechanism.

As mentioned above, outer coatings can be by forming by expansible polymer after inserting aqueous medium, or comprise such polymer.Use an advantage of expanded polymer to be, expansion will hide any needle pore defect or the shortcoming in other coating, therefore guarantee the integrity of coating system in use.

Can measure swelliong power by following simple experiment: the polymer (for example with particle form) of known volume is added in the excessive pure water, water is absorbed reach balance.Take out expansible granule from aqueous medium then, remove unnecessary water, and the variation of evaluation volume.Usually, the swelliong power that is applicable to the polymer in the outer coatings is at least 1% volume, for example at least 5%, for example at least 10%, for example at least 20%, for example at least 30%, for example at least 40%, for example at least 50%, for example about 60%.Such polymer is called hygroscopic polymer.But will be appreciated that, should use hygroscopic polymer carefully, thereby do not hinder functional or medical apparatus the removing from the patient of medical apparatus.

Simultaneously, the disclosure of prior art mention LPEI-NONO insoluble (referring to US6,855,366 for example), we are surprised to find, and (linearity) polymine diazeniumdiolate dissolves in Physiological Medium, although thought in the past that it was insoluble to the aqueous medium.This dissolubility is seemingly because the existence of ion in Physiological Medium lacks described ion in the insoluble pure water of polymine diazeniumdiolate.Coating system and/or outer field application can reduce or prevent the inappropriate release of LPEI-NONO from the medical apparatus of coating.

In one embodiment, skin comprises hydrophilic polymer, for example hygroscopic polymer.

The polymer that can be used for outer coatings can be selected from: polyolefin, polystyrene for example, polypropylene, polyethylene, politef, Kynoar, polrvinyl chloride, deutero-polyolefin is polymine for example, polyethers, polyester, polyamide is nylon for example, polyurethane, silicone or cellulose.More specifically, they can be aromatic polyurethanes, vinyl acrylate polyolefin, hydrophilic aliphatic urethane or silicone.In one embodiment, these polymer can be selected from: tecophilic, estanes.

Also can use high water vapour conducting polymer for example EMAC and EBAC polyolefin family or high water vapor conduction silicone.Use ASTM method E96B-50%RH, 23 ℉ can identify the water vapour conducting polymer, and the scope of preferred water vapour conducting polymer is therefrom isopneustic about 350g/m ²About 760g/m of the paramount breathing of MVT in/24 hours ²/ 24 hours HMVT.In one embodiment, such polymer also can be with the hydrophilic polymer that acts in polymeric blends disclosed herein/coating system.

In a preferred embodiment, outer layer copolymer forms the hygroscopicity gel after inserting Physiological Medium.

Preferably, select the ability of the promotion medical apparatus of outer coatings from blood vessel insertion and extraction.In this respect, moisture absorption or hydrophilic polymer may be preferred in some purposes because their form smooth surface inserting aquatic environment (for example Physiological Medium) back.Therefore, preferably make the suitable aqueous solution of medical apparatus contact isotonic water a period of time for example before use, for example 1-3 minute.

In a preferred embodiment, outer layer copolymer comprises Hdyrophilic polyurethane.

Be surprised to find, so outer field application can the release the course Physiological Medium in described of controlled oxidation nitrogen adduct.For medical apparatus in the blood vessel, medical apparatus in the temporary transient blood vessel for example, this is suitable especially, and wherein the release of nitric oxide adduct can cause low-level undesirable systemic effect, therefore also needs the control method of stricter approval.

Therefore preferably, use first territory (with randomly, the second and/or the 3rd territory) and outer because they the two can control the release of undesirable nitric oxide adduct in Physiological Medium.

Skin also can be used for controlled oxidation nitrogen from nitric oxide adduct (for example disclosed herein coating system) to speed and opportunity that Physiological Medium discharges.In this respect, skin can only partly or unevenly be used, thereby allows a part of nitric oxide adduct to contact Physiological Medium fast, begins to discharge NO, and the adduct that has coat simultaneously can discharge the longer time more enduringly.

Also can predict, skin can prevent that small molecule by-product from leaking into Physiological Medium from described polymeric blends.

In one embodiment, outer (coating) do not comprise acidizer.Such skin can be used for having used other one or more layers the coating of medical apparatus, and described one or more layers comprises the reagent (being the pH decorative layer) of the regulation and control pH that this paper mentions in addition.

Outer field pH can be suitably physiological pH roughly, for example about pH 7 is to about pH 8, for example about pH 7.4.Skin can comprise the buffer agent of keeping such pH, for example phosphate buffer.By keeping the roughly pH of physiological pH, skin can protect the cell of contact medical apparatus to avoid the pH in first and/or second territory.

Nitrogen oxide discharges

One of advantage process in the blood vessel is that hemoglobin is removed nitrogen oxide.In 60-100% oxygen saturation environment, most of nitrogen oxide can form metahemoglobin in conjunction with HbO2 Oxyhemoglobin, forms nitrate subsequently.In the hypoxia saturated environment, nitrogen oxide can form nitrosylhemoglobin in conjunction with deoxyhemoglobin, and the latter forms nitrogen oxide and metahemoglobin in the presence of aerobic.The end-product that enters the nitrogen oxide of systemic circulation is metahemoglobin and nitrate subsequently.Nitrate is transferred to serum then, and more most nitrate advances in the urine by renal secretion.

The typical half-life of nitrogen oxide in blood is several milliseconds.The half-life of nitrogen oxide in tissue is than long number Radix Achyranthis Bidentatae in blood.The biological half-life of hemoglobin-bonded nitrogen oxide is about 15min.

The active physiological concentration scope of nitrogen oxide

Find to cause the concentration in the smooth muscle cell of diastole based on document, then the big 200nM of expection, but significantly be lower than 1mM.Lower limit (200nM) is by activating the required concentration decision of soluble guanylate cyclase, and described guanylate cyclase works to produce the enzyme that causes the loose second message,second messenger's cyclic GMP of smooth muscle.The upper limit (1mM) is by the concentration decision that produces significant oxidative stress and sudden change.

In order to contrast, the scope of the physiological level of nitric oxide concentration is 100-500nM in the described tissue of document.Physiological concentration in the healthy endotheliocyte is about 100 μ M.

Dosage-nitrogen oxide discharges

According to people such as Vaughn, Am J Physiol.1998 Jun; 274 (6Pt2), 0.32nmol/min/cm ²It is one of flank speed that discharges from natural endothelium of report.For the biological response value that obtains wishing, therefore may need higher.For example, consider and the contacting in short-term and nitrogen oxide need pass before reaching the blood vessel medium thickness of tissue of blood vessel wall that the rate of release of hope should be preferably higher to obtain best vasodilation response.

In order to support mensuration, on people and rat artery, carried out vitro study to suitable rate of release.The purpose of research is the effect of research from the nitrogen oxide of the test tube release of nitrogen oxide release polymers bag quilt.Confirmed that the nitrogen oxide release polymers can induce the strong diastole (relaxation) of tremulous pulse.The rate of release of using is to being up to 3nmol/min/cm 0.5 ²Magnitude.In PBS and in blood, test.

Find according to document, activate between the concentration level (1mM) of the required concentration of soluble guanylate cyclase (200nM) and significant oxidative stress of generation and sudden change and have about 5000 the factor.

Find according to preclinical test and document, effectively install rate of release and have broad scope.For toxicity risk is minimized, the upper limit preferably is set in 40nmol/min/cm ²Lower limit preferably is set in 0.5nmol/min/cm ²Compare 0.5nmol/min/cm ²Lower rate of release even be low to moderate 0.2nmol/min/cm ²Also may induce diastole, but their effectiveness may be lower.

Suitably, NO can be greater than about 0.1nmol/min/cm from (maximum) speed of medical apparatus release according to the present invention ², for example greater than 0.25nmol/min/cm ², be preferably greater than about 0.32nmol/min/cm ², for example greater than 0.5nmol/min/cm ², for example greater than 1nmol/min/cm ²

Suitably, NO is no more than about 40nmol/min/cm from the maximum rate that medical apparatus according to the present invention discharges ², for example be no more than about 60nmol/min/cm ², for example be no more than about 80nmol/min/cm ²

In one embodiment, (maximum) speed that discharges from medical apparatus according to the present invention is about 0.5 to being up to about 3nmol/min/cm ²

When using top layer (skin/coating), the release of nitrogen oxide significantly departs from 1 grade of release usually.This is because the barrier of top layer: its restriction water absorption and nitrogen oxide are by the diffusion of coating.

Preferably, nitrogen oxide discharge from the peak of medical science outside of deivce face and/or after inserting isosmotic solution the release after 5 minutes be about 0.5 to about 40nmol/min/cm ²This can use the dynamic head space chamber that is connected on the chemiluminescence NO detector to measure: will be coated with the object that described nitrogen oxide discharges the coating system and be placed in the head space chamber that the pbs buffer agent (pH7.4) that contains 0.00004% polysorbas20 is housed, and remain on 37 ℃.Use 250mL N ₂The continuous rinse solution of gas is guaranteed oxygen free condition.The nitrogen oxide that is discharged in the oxygen-free environment by coating breaks away from from solution by NO gas, and is carried to chemiluminescence NO detector.This example provides a NO test that is used to measure the rate of release of nitrogen oxide.

In one embodiment, in moistening or after inserting device in preceding 10 minutes, for example in moistening or after inserting device in preceding 5 minutes, for example in preceding 3 minutes, obtain the peak rate of release.

Whether can discharge nitrogen oxide in order to measure potential nitric oxide adduct, can use above-mentioned test at ' under the physiological condition ' used herein.

Preferably, nitrogen oxide from the half-life that is released in the Physiological Medium of medical science outside of deivce face be at least 30 minutes, for example at least 60 minutes, for example at least 90 minutes or at least 2 hours for example at least 4 hours, at least 6 hours or at least 12 hours.

In one embodiment, behind the maximum rate point that obtains NO release, the maximum rate of the decline that NO discharges is less than pact-0.015nmol/min/min, for example less than pact-0.03nmol/min/min, for example less than pact-0.06nmol/min/min.

Other therapeutic agent

Medical apparatus can discharge one or more other therapeutic agents.These other therapeutic agents can be provided in first, second and/or the 3rd territory and/or the outer coatings.Perhaps, therapy equipment can provide the alternate manner of sending other therapeutic agent.As the release of NO from the polymine diazeniumdiolate, the release of other therapeutic agent also can be that pH is dependent, the acidify in such first territory can cause the release of therapeutic agent, or can trigger the release of other therapeutic agent to the second or the 3rd territory or outer field alkalization from first territory.

Except the polymine diazeniumdiolate (or in one embodiment, a replacement scheme as the polymine diazeniumdiolate), medical apparatus can be coated with one or more other therapeutic agents, human growth factor for example, and anti-agglomerating agent is heparin for example, antibiotic agent is antibiotic for example, chemotherapeutics, another kind of inhibitors of smooth muscle cell proliferation, for example nitrogen oxide (NO) or nitric oxide donor, and/or vasodilation, for example NO or NO donor.Ascorbic acid (vitamin C) can be used as antioxidant or discharges catalyst (promptly in second territory) as nitrogen oxide and provides.In one embodiment, rate of release itself at other therapeutic agent does not rely under the situation of pH, therapeutic agent can in conjunction with or be encapsulated in the carrier compound, it is characterized in that, seal the dependent rate of release of pH-or the dependent degradation rate of pH-of the carrier material of therapeutic agent.

Other therapeutic agent can be immobilized in the hydrogel (for example hydrogel).Some hydrogel expands under acid condition.Production is expanded in blood, still a kind of feasible mode of non-bloating this hydrogel is with glucoseoxidase (GOD) codeposition therapeutic agent in pure water.When glucose when blood diffuses into hydrogel, GOD can become conversion of glucose gluconic acid and hydrogen peroxide.

Other therapeutic agent can comprise for example following at least a: heparin or another kind of thrombin inhibitor, and hirudin, hirulog, argatroban, D-phenylalanyl-L-is poly--L-arginyl-chloromethyl ketone or another kind of antithrombotic agent, or its mixture; Streptokinase, urokinase, tissue plasminogen activator, or another kind of thrombolytic agent, or its mixture; Paclitaxel; Estrogen or oestrogen derivatives; Fibrinolytic agent; The vasospasm inhibitor; Calcium channel blocker, nitrate, nitrite, nitrogen oxide, nitrogen oxide promoter, for example ascorbic acid, or another kind of vasodilation; Antimicrobial or antibiotic; Aspirin, ticlopidine or another kind of anti-platelet agents; Colchicine or another kind of antimitotic agent, or another kind of microtubule inhibitor; Cytochalasin or another kind of actin inhibitor; The remodeling inhibitor; GPllb/Illa, GPIb-IX or another kind of inhibitor or surface glycoprotein receptor; DNA (deoxyribonucleic acid), the another kind of reagent that antisense nucleotide or molecular genetic are intervened; Methotrexate or another kind of antimetabolite or antiproliferative agents; Anti-cancer chemotherapeutic agents; Dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate or another kind of dexamethasone derivant, or another kind of anti-inflammatory steroid; Dopamine, bromocriptine methanesulfonate, pergolide mesylate or another kind of dopamine agonist; ⁶⁰Co (half-life) with 5.3 years, ¹⁹²Ir (73.8 days half-life), ³²P (14.3 days half-life), ¹¹¹Ln (68 hours), ⁹⁰Y (64 hours), ^99mTc (6 hours) or another kind of radiotherapeutic agents; Contain iodine compound, containing barium compound, gold, tantalum, platinum, the another kind of heavy metal of a tungsten or a contrast agent function; Peptide, albumen, enzyme, extracellular matrix component, cellular component or another kind of biological preparation; Captopril, enalapril or another kind of angiotensin converting enzyme (ACE) inhibitor; Ascorbic acid, alpha tocopherol, superoxide dismutase, deferoxyamine, 21-amino steroid (lasaroid) or another kind of free radical scavenger, iron chelating agent or antioxidant; Angiopeptin; ¹⁴C-, ³H-, ¹³¹I-, ³²P or ³⁶S-radio-labeled form or aforementioned any other radio-labeled form.Also predict in them mixture arbitrarily.

Recognize that in one embodiment, one or more therapeutic agents of listing above can be under the situation that does not have (L) PEI-NONO or having under the situation of (L) PEI-NONO and use.They may reside in first territory, second territory, the 3rd territory or the outer coatings and/or other layer that this paper mentions.

Medical apparatus

In one embodiment, described medical apparatus is medical apparatus or a neural blood vessel medical apparatus in the blood vessel.

In one embodiment, described medical apparatus is temporary transient medical apparatus, it is not retained in the patient after operation technique finishes, for example intubate sheath or its set and component, for example crown guiding tube of conduit or nerve trachea, guide line, syringe needle/trocar, the angioplasty balloon, crown lead.

Medical apparatus can be disposable.

Medical apparatus can comprise intermittently or permanent blood vessel implant.

Medical apparatus can be selected from: neuromedicine device, for example neural guiding tube, neural microtubular, neural little line, neural stent delivery system, neural balloon; Crown medical apparatus, for example crown lead, crown guiding tube, PTCA angioplasty balloon; Stent delivery system, crown lead, crown guiding tube, PTA angioplasty balloon; The intubate sheath, dilator, guide line, syringe needle/trocar, the set of intubate sheath, dialysis sheath.

Medical apparatus for example can comprise intermittently or permanent blood vessel implant, support for example, and stent graft, balloon, conduit, guiding tube, seal wire, thromboembolism forms device, for example tinsel or coil.

Under the situation of balloon, this device can comprise for example distensible angioplasty balloon that coating is arranged, PTA (angioplasty that passes the chamber wall of percutaneous) balloon for example, PTCA (coronary angioplasty that passes the chamber wall of percutaneous) balloon or PTNA (the neural blood vessel angioplasty that passes the chamber wall of percutaneous) balloon.

In one embodiment, described medical apparatus is an implant, for example support.

In one embodiment, described medical apparatus is a prosthese, for example breast implant or penile implant.

In one embodiment, described medical apparatus can be applicable to operation in the blood vessel, can comprise for example balloon, ballon catheter, conduit, support, stent graft or seal wire.

In one embodiment, described medical apparatus is not by polytetrafluoroethylene (PTFE) (Teflon ^TM) or fluorizated polyethylene (FEP) make.Have 2 benefits when the alternative substrate of the base material of selecting to be used to produce medical apparatus, at first, its allows to use based on the routine of radiating sterilization technology, and secondly, it can promote the coating of medical apparatus.

Therefore, preferably, described medical apparatus for example intubate sheath (or dialysis sheath) by using the material of sterilizing to make based on radiating technology (for example gamma-radiation or electron beam (e-beam)).Nylon is a kind of suitable base material.Other suitable material can be selected from, for example, and polyurethane, aromatic polyester, Merlon, polyethylene, polystyrene and polysulfones.

Described medical apparatus can be made by the high density polyethylene (HDPE) base material.

Described medical apparatus for example can comprise intermittently or permanent blood vessel implant, support for example, and stent graft, balloon, conduit, guiding tube, seal wire, thromboembolism forms device, for example tinsel or coil.Under the situation of balloon, this device can comprise for example distensible angioplasty balloon that coating is arranged, PTA (angioplasty that passes the chamber wall of percutaneous) balloon for example, PTCA (coronary angioplasty that passes the chamber wall of percutaneous) balloon or PTNA (the neural blood vessel angioplasty that passes the chamber wall of percutaneous) balloon.

In one embodiment, described medical apparatus is the intubate sheath, for example the intubate sheath of mentioning in European application EP06023203 and U.S. Provisional Application 60/864,879 and its component.

The intubate sheath

Discharging medical apparatus according to nitrogen oxide of the present invention can be the intubate sheath, or intubate sheath set (parts bag).The parts bag comprises at least 2 key components: comprise the intubate sheath of dilator and the nitrogen oxide that is applied on the distal portions at least of sheath discharges coating.The basic role pattern of this device is identical with traditional intubate sheath: be used to get involved and/or the blood vessel of the diagnostic equipment in insert.The assosting effect that nitrogen oxide discharges be prevention get involved and/or the diagnostic equipment by vasospasm and obstruction in the intubate sheath insertion process.The application of predicting intubate sheath of the present invention also can reduce the probability of clot formation, thrombosis and associated conditions.

A kind of preferred device is to be coated with the intubate sheath that nitrogen oxide discharges coating, and the end that described coating is applied to described sheath is the 10cm place at least.

In one embodiment, the near-end 1cm of intubate sheath does not wrap quilt.

This device indentation is used to get involved/imports in the radial blood vessel of the diagnostic equipment, and the basic role pattern of this device is identical with traditional intubate sheath.

The assosting effect of medical apparatus is that nitrogen oxide discharges, and to strengthen the clinical safety in the operating process, for example reduces vasospasm or thrombotic risk.

Term used herein ' intubate sheath ' is to be used for medical apparatus is imported for example device of blood vessel or neural blood vessel system of human body.It comprises the blank pipe of being made by flexible material usually, and other medical apparatus passes this blank pipe and imports blood vessel or neural blood vessel system.The intubate sheath often is coated with lubricated surface or by lubriation material Teflon for example ^TMMake.The near-end of intubate sheath is external, and most of length of intubate sheath is in the intravascular space of vascular system simultaneously.The intubate sheath has about length of 10 to about 30cm, the diameter of 5 or 6 french usually.French is with the internal diameter of intubate sheath and inserts for example corresponding unit of external diameter of the medical apparatus in the conduit of intubate sheath subsequently.1 french be 1 millimeter 1/3.Although the wall thickness of intubate sheath can change, preferably have thin as far as possible wall, keep the property firm in structure of intubate sheath simultaneously.

Usually, the insertion of intubate sheath comprises, and uses empty needle (trocar) to insert arterial wall (venipuncture) produces otch in human body first element.Subsequently soft guide line passed this pin, and take out pin.Make the intubate sheath that comprises dilator in inside pass guide line then.Take out dilator, make the medical apparatus that comprises conduit usually pass guide line, and take out guide line.

Preferably, the outer surface of intubate sheath near-end does not wrap by described nitric oxide adduct.This be because, this is the zone that contacts with damage location (insertion position) moment of blood vessel, here may wish partial vasospasm, be connected with the tight of intubate sheath guaranteeing, thereby the prevention Physiological Medium leaks into surrounding tissue and external from inserting the position, also promotes to heal faster along with blood condenses at the insertion position after taking out the intubate sheath.

Therefore, preferably, the outer surface region of intubate sheath near-end is not fully wrapped quilt, to compare with the sheath of the near-end bag quilt that is equal to, reduces from the seepage of inlet point to blood vessel or neural blood vessel system.

Usually, the intubate sheath has the length of 10-30cm.

Usually, the intubate sheath has the internal diameter of 4-12 French.Other size may suit, and this depends on patient's size of (with their tremulous pulse), and the size that will pass through the medical apparatus of intubate sheath insertion.For example, diameter can be 4-7 French, and for example 5-6 French can for example be used for radial artery (radial arteries).4French intubate sheath goes for child.8 or 9 French can be used for the more bigger device that will enter by femoral artery, even are used for devices such as aortic stents up to 12-14French.But 5-6 French is enough for common heart operation usually.

In one embodiment, the intubate sheath is the dialysis sheath.Such dialysis sheath is particularly useful because the release of NO can reduce with the sheath that is used for conventional dialysis repeat to insert and take out relevant vasospasm.In some patient, vasospasm is such problem: all suitable vascular access sites become unavailable, like this life of entail dangers to dialysis patient.

The parts bag

The intubate sheath is made into the parts bag usually, and it also comprises dilator except the intubate sheath.

Term used herein ' dilator ' is the device that inserts in the intubate sheath, and it guarantees the firm in structure property of intubate sheath after inserting vascular system, and takes out before inserting the medical apparatus that will insert in the intubate sheath.The external diameter of dilator allows to closely cooperate with the intubate sheath, can not hinder its taking-up simultaneously.Internal diameter permission guide line after inserting the patient of dilator passes therethrough.Dilator is also made by flexible material, and in the time of in inserting the intubate sheath fully, they can extend beyond the far-end of intubate sheath usually, and comprise tapered distal end usually, and this tapered distal end can promote the insertion of intubate sheath/dilator in blood vessel.Dilator also can comprise the remote area of radial opaque material, and it is used to locate the end of intubate sheath set to guarantee correct insertion when using radioscopic image.

Term ' guide line of intubate sheath ' is specific term, is used for describing the guide line that the guide cannula sheath inserts to blood vessel.Preferably, the diameter of guide line is about 0.018 to about 0.038 " (about 0.4572 to about 0.9652mm), length is about 35 to about 80cm.Different with the guide line that is used for conduit, the guide line of intubate sheath can not reach gets involved the position, and in fact, in one embodiment, guide line does not need to extend beyond the far-end of intubate sheath or dilator.

Term ' set of intubate sheath ' is meant a kind of parts bag, and it comprises the intubate sheath and the intubate sheath is being inserted at least a other medical apparatus that uses in vascular system (for example the passing through seldinger technique) process.Intubate sheath set also can comprise and be used to promote for example valve that imports of conduit of other medical apparatus at its intravital near-end that do not insert.The intubate sheath also can comprise and be used to realize for example valve of the insertion of therapeutic agent of fluids administration.Suture ring on the valve body can provide the safe grappling of sheath.

At US 5,409, disclose in 463 and be applicable to that bag can be discharged the oxidation nitrogen compound under physiological condition intubate sheath gathers.The intubate sheath that is applicable to use method bag quilt of the present invention can be from Thomas Medical Products Inc., Malvern, Pennsylvania obtains, and can by spraying bag for example by, for example with the coat system bag by and/or for example rotated with the nanofiber bag and to be prepared that (US 6 by electricity, 382,526, US6,520,425).

In one embodiment, the parts bag comprises according to dilator of the present invention, and wherein said dilator can insert the intubate sheath, for example according to intubate sheath of the present invention, or does not wrap the intubate sheath of oxidized nitrogen adduct.Dilator also can preferably can pass through intubate sheath guide line (for example according to intubate sheath guide line of the present invention) and insert.

Preferably, when dilator inserts in the described intubate sheath fully, it extends beyond the far-end of described intubate sheath, and the dilator zone that extends beyond the far-end of described intubate sheath comprises tapered distal end, and this tapered distal end is coated with and describedly can discharges the oxidation nitrogen compound under physiological condition.

In one embodiment, when inserting fully, do not extend beyond the described dilator zone of the far-end of intubate sheath, be not coated with and describedly can under physiological condition, discharge the oxidation nitrogen compound.

The parts bag also can comprise intubate sheath guide line, and it randomly is coated with the nitric oxide adduct that can discharge nitrogen oxide under physiological condition, for example this paper nitric oxide adduct and/or the coating system mentioned.

The trocar that is used to produce initial insertion also can be coated with nitric oxide adduct.Trocar is a hollow, passes therethrough in the intravasation inner chamber to allow guide line.Think that simultaneously the extremity bag at trocar is useful by nitric oxide adduct and/or the coating system that this paper mentions, in one embodiment, trocar near-end (i.e. the part of contact wound location after inserting the patient) does not wrap nitric oxide adduct or the coating system mentioned by this paper.

The coating system

One preferred aspect, first territory, second territory, the 3rd territory and/or outer coatings are the forms that is applied to according to the coating at least a portion of medical apparatus outer surface of the present invention.The coating system that is applicable to each territory in first, second and/or the 3rd territory is being described in European application number 06023223 and the U.S. Provisional Application 60/864,886.

In a preferred embodiment, medical apparatus according to the present invention comprises first territory of containing nitric oxide adduct, described nitric oxide adduct is the coating system form that comprises polymeric blends, wherein said polymeric blends comprises described nitric oxide adduct and hydrophilic support polymer or polymeric blends, and wherein said nitric oxide adduct and support polymer or polymeric blends formation homogeneous phase.

The coating optimum system choosing comprises antioxidant, for example the phenolic antioxidant of steric restriction (octadecyl-3-(3,5-di-t-butyl-4-hydroxyphenyl)-propionic ester for example, trade name Irganox 1076, Ciba specialty chemicals), for example about 0.01 to 1%; For example about 0.1% to 0.5% (w/w).The application of such antioxidant can increase the stability in the radiation sterilization process, and improves the shelf life of medical apparatus.

Term ' hydrophilic ' refers to the dissolubility ratio higher material in oil or other hydrophobic solvent in water.Hydrophilic molecules can form hydrogen bond, and described hydrogen bond makes their not only water solubles but also dissolve in other polar solvent.

Be surprised to find, the application of such polymeric blends can the release the course Physiological Medium in described of controlled oxidation nitrogen adduct.Discharge ratio between adduct and other polymeric blends by regulating nitrogen oxide, can improve the embodiment that nitrogen oxide discharges adduct, minimize oxidation nitrogen and discharge the adduct release in the environment towards periphery.This is relevant especially for for example temporary transient medical apparatus of medical apparatus, and wherein the release of nitric oxide adduct can cause low-level undesirable systemic effect, and therefore also can need the stricter adjusting technology through approval.Also can predict, the application of polymeric matrix can prevent that small molecule by-product is from the leakage of described polymeric blends to Physiological Medium.

Being applied in the speed that controlled oxidation nitrogen discharges the course Physiological Medium in described and also being crucial in opportunity of polymeric blends.This can followingly control: telomerized polymer or polymeric blends are with the level of balance holder with respect to hydrophilic feature, thereby the structure of set up wishing, this structure can provide water under physiological condition from the controlled spread of Physiological Medium to internal layer to discharge nitrogen oxide.

As mentioned above, important parameters is a good stable for nitrogen oxide discharges adduct, the quick active that nitrogen oxide discharges, the continuous release in the physiology related concentrations and guarantee not have or the minimum release of nitrogen oxide release polymers in external environment condition.

In order to ensure good stable, polymeric blends, polymer mixed liquid, coating system and/or single polymers should withstand and be applied to the lip-deep pull strength of polymeric layer, and this pull strength is about 4-100 newton cm ^-2, for example about 8-50 newton cm ^-2, for example preferred 10-20 newton cm ^-2

In order to ensure the quick active that nitrogen oxide discharges, polymeric blends should show good water conductive performance.In one embodiment, this parameter can be measured from the rate of release of the NO adduct that is coated with polymer and suitable nitric oxide adduct by measuring nitrogen oxide.This can recently realize by polymer and high water conduction/expansion with high water conduction are provided to nitrogen oxide release polymers layer.Polymeric blends (polymer mixture), blend polymer (polymerblend), coating system and/or hydrophilic polymer should allow water to transport into NO adduct layer fast enough, and per minute about 0.05 is to about 50nmol cm when inducing the maximum rate that discharge to increase at NO to measure ^-2Min ^-1, for example per minute about 0.25 is to about 20nmol cm ^-2Min ^-1, for example preferred per minute 0,5 is to about 10nmol cm ^-2Min ^-1Nitrogen oxide discharge to increase (referring to Fig. 6).This can followingly measure: for example prepare 30%LPEI-NONO, 70% hydrophilic polymer (or polymeric blends or blend polymer) on the nylon at the inertia base material, and measure NO rate of release in time when 7.4,37 ℃ of insertion phosphate buffered saline (PBS) pH.Suitably, being used to measure nitric oxide adduct that NO discharges can be LPEI-NONO as embodiment 1 preparation.

In one embodiment, the polymeric blends that exists in the coating system and the ratio of described nitric oxide adduct are about 5/95 to about 95/5, and for example 40/60 to 90/10, preferred about 50/50 to about 80/20, and be for example about 70/30, is measured as w/w).

In one embodiment, NO donor self can form hydrophilic or support polymer or blend polymer, and such NO adduct is suitable for the coating system itself that does.In a such embodiment, the coating system can comprise and be up to 100% NO adduct.

In a preferred embodiment, blend polymer comprises the mixture of supporting polymer and hydrophilic polymer.

Hydrophilic polymer can be selected from: polyolefin, and polystyrene for example, polypropylene, polyethylene, politef, Kynoar, polrvinyl chloride, deutero-polyolefin is polymine for example, polyethers, polyester, polyamide is nylon for example, polyurethane, silicone.

More specifically, they can be selected from: aromatic polyurethane, and the vinyl acrylate polyolefin, hydrophilic aliphatic urethane or silicone, they all have the height ratio that water conduction/water absorbs.These polymer can be selected from: tecophilic, estane, EMAC and EBAC polyolefin family or high water vapor conduction silicone.

Described support polymer can be selected from: polyolefin, polystyrene for example, polypropylene, polyethylene, politef, Kynoar, polrvinyl chloride, deutero-polyolefin is polymine for example, polyethers, polyester, polyamide is nylon for example, polyurethane with good adhesion and structural stability, they satisfy above-mentioned stability criterion.But, be preferably based on the polyurethane of aliphatic polyether, for example Tecoflex SG 85A.

In one embodiment, the support polymer that uses in the coating system and the weight ratio of hydrophilic polymer can be about 95/5 to about 35/65, and this depends on the feature of the polymer of use.In a system, use polyurethane and aromatic polyurethane based on aliphatic polyether, this weight ratio can be about 90/10 to about 50/50.

In one embodiment, the support polymer that uses in the coating system and the weight ratio of hydrophilic polymer are about 70/30.

Support that the polymer and the ratio of hydrophilic polymer are the ratios of getting rid of the NO adduct that also exists in the coating system.

Predict, in one embodiment, described NO adduct self can be hydrophilic and/or support any part in the polymer.But in a preferred embodiment, the NO adduct is not support polymer or the hydrophilic polymer of mentioning in the coating system, supports and/or hydrophilic nmature although can comprise.Be applicable to that preparation is hydrophilic and/or support the method for polymer nitric oxide adduct to be disclosed in US 5,405,919 or synthetic other document about the NO polymer in, those that mention in this article for example.

In one embodiment, the thickness of coating system is about 1 to about 100 μ m, for example when drying regime 5 to about 20 μ m.

In one aspect,, coating or coating system are applied to (for example comprising nitric oxide adduct-first territory) outer surface of described medical apparatus by one or more following methods: spray coating, smear dipping and extruding.Second territory can comprise acidizer or acidic pendant groups, the latter is the coating system form that comprises polymeric blends, wherein said polymeric blends comprises acidizer (for example chemical compound or acidic-group) and hydrophilic support polymer or blend polymer, and wherein said acidizer and support polymer or blend polymer formation homogeneous phase.Recognize that the polymer that uses can be a natural acidic in the coating system, or be modified into and comprise acidic pendant groups.The coating system that uses in first territory can comprise the polymer of natural alkalescence, or has been modified into the polymer that comprises alkaline side group.

The 3rd territory can comprise the coating system that contains polymeric blends, and wherein said polymeric blends comprises hydrophilic support polymer or blend polymer, and the latter forms homogeneous phase.

Fiber

In one embodiment, the coating that will comprise nitric oxide adduct is applied to the outer surface of described medical apparatus, described medical apparatus is a fibers form, nanofiber for example, for example electricity rotation nanofiber is (for example at US 6,382,526, US 6,520, disclosed polymine diazeniumdiolate nanofiber in 425).

Predict, such fibers/nanofibers also can be packaged in the polymer system as herein described.Fibers/nanofibers can directly apply to medical apparatus surface or prime coat as herein described.Fibers/nanofibers can further be coated with skin as herein described.

But in one embodiment, described nitric oxide adduct is applied to wrap the medical apparatus zone that is become conforming layer, coating system form for example as herein described.

In one embodiment, be the form of fiber or nanometer-fiber or electricity rotation nanofiber or electricity rotation fiber.

Production method

Predict, can make by the base material that comprises nitric oxide adduct, or comprise such base material according to medical apparatus of the present invention.In this case, first territory forms at least a portion of the base material of medical apparatus.

But, in a preferred embodiment, produce medical apparatus in advance, and wrap subsequently by NO adduct-for example by using at least the first territory.

(best target thing release scope is about 0.5nmol/min/cm in order to ensure producing the clinical impact of wishing ²To about 40nmol/min/cm ²) the specific target thing discharge, nitric oxide donor is mixed in the polymeric matrices coating system that for example this paper mentions.

In a preferred embodiment, coating is formed by 3 layers: (i) optional prime coat, and it is guaranteed and optimizes the adhesion of coating to device; (ii) nitrogen oxide supplying layer (first territory), it can be for example other polymer (under the coating system) of mentioning of polyurethane or this paper and L-PEI-NONO (LPN) mixture (it can for example be dissolved in suitably the alkali organic solvent for example pyridine or regulate pH methanol (for example by add suitable alkali for example NaOH prepare), be used for spray applications in medical apparatus).The prescription of nitrogen oxide (for example LPN) releasing layer can comprise the solvent (for example the alkali organic solvent is for example pure as methanol or pyridine) of regulating pH, to guarantee that nitrogen oxide (for example LPN) is stable in the course of processing.Base reagent preferably is retained in first territory, remains on greater than 7 with the pH that guarantees first territory; (iii) Ren Xuan top layer coating (skin/coating), it is used to guarantee the suitable speed that coating integrity, water absorb and the suitable speed (and the whole body that prevents LPEI-NONO discharges) of NO diffusion.

The pH in first territory also can followingly control: guarantee that coating carries out in limiting environment, described qualification environment comprises suitable base reagent, usually (alkali) gas, for example ammonia.With regard to the adding in second territory, when suitable, usually medical apparatus is transferred to neutral environment then.

Coating (i) and (iii) can choosing wantonly, but preferred.Usually, preparation is made up of following step according to the method for the medical apparatus of coating of the present invention: first optional step of application of primer layer (i), use nitric oxide adduct layer (first territory) second step and application top layer coating the 3rd optional step (iii) (ii).Other coating, second territory and the 3rd territory mentioned of this paper for example, can use nitric oxide adduct layer (first territory) before, in the process or use afterwards.

When using top layer coating (outer coatings), the release of nitrogen oxide significantly departs from 1 grade of release usually.This is because the barrier of top layer: absorption of restriction water and nitrogen oxide cause more constant release in time by the diffusion of coating.

Using NO adduct coating (first territory) before, can use prime coat as herein described.Prime coat can be used by the mode of any appropriate, for example dipping, spray coating or extruding.

In the production process of device, described layer (territory) can be by dipping-coating for example, spray, smear, printing, vapor deposition, extruding or its make up and form.In one embodiment, described layer is not to form by electric rotation technique.Have been found that spray coating is the mode very easily to medical apparatus application domain and layer.

Internal layer can veining, for example by sand milling before using skin, so that obtain veining or the coarse outer surface of internal layer, so that the skin combination of improvement to be provided.

NO adduct (first territory) directly applies to the base material of medical apparatus suitably, or is applied to prime coat or other layer, for example the second or the 3rd territory.NO adduct (first territory) self can be used, for example, in one embodiment, the LPEI-NONO nanofiber can be used.Perhaps, can adopt the coating system of as herein described comprising of (L) PEI-NONO.

The coating system can comprise the polymeric blends that is applied on the described medical apparatus outer surface, wherein said polymeric blends comprises at least a nitric oxide adduct and hydrophilic support polymer or polymeric blends, and wherein nitric oxide adduct forms homogeneous phase with support polymer or blend polymer.

Other layer can be applied on the coating system layer then.For example, can be applied in second territory (being described second territory) of the material that inserts the pH that can influence first territory behind the Physiological Medium.

The pH decorative layer generally includes the pH dressing agent, and it can comprise in a wide embodiment can be by changing H ⁺And OH ^-Local equilibrium between the ion influences arbitrary atom, molecule or the ion of pH, comprises H ⁺And OH ^-The variation of pH can be derived from the H that causes that enters owing to acid or alkali ⁺Or OH ^-Ionic direct increase or minimizing, or be derived from the molecule or ionic the entering of triggering the chemical reaction that causes the pH variation.NO normally to the pH sensitivity, helps the release of NO from the release of NO adduct under acid condition.Therefore, (for example in Physiological Medium) can change H when moistening ⁺And OH ^-The application of other layer of the local equilibrium between the ion allows the rate of release of control NO from nitric oxide adduct.Therefore second territory can comprise, and for example acidizer or acidic pendant groups for example are selected from the acid of ascorbic acid, polyacrylic acid, oxylic acid, acetic acid and lactic acid.Described acid can be mixed in the stand-by polyether polyols with reduced unsaturation.

In a preferred embodiment, also use outer coating as herein described.Described outer coating can directly apply to the coating system layer, or be applied on the coating system layer one or more other the layer on.

If avoid the too early release of therapeutic agent, the coating that contains donor-chemical compound is preferably used under the condition that is unfavorable for discharging, for example the condition of low temperature, low pressure, low water content or low humidity.More specifically, be therapeutic agent by (suitably pH greater than 7 alkali condition under) deposition donor-chemical compound under the pH condition that discharges in the suppression therapy agent, realize the too early release of therapeutic agent.

Thereby, preferably occur in maximum 40%, maximum 30%, maximum 25%, maximum relative humiditys of 20%, for example maximum 15% or 10% for example for example for example in accordance with the present production process.Equally, in the product of a second aspect of the present invention, maximum 40% relative humidity can maintain in the packing, and for example maximum 30%, for example maximum 25%, for example maximum 20%, for example maximum 15% or 10%.Similarly,, can produce and store medical apparatus at the pH that suppresses such release for the too early release of prophylactic treatment agent, for example at least 7 pH, for example at least 8,9,10,11,12,13 or 14.The combination of other parameter that can use humidity and pH and choose wantonly is with the too early release of further suppression therapy agent.

The medical apparatus of can packing and sterilize then.

Because discharging from the NO of NO adduct is moisture-sensitive, preferably, be packaged in to limit in the environment and carry out, in described qualification environment, it is about 40% that relative humidity is no more than, and for example is no more than approximately 30%, for example is no more than about 20% or about 10%.In one embodiment, relative humidity (in room temperature) is less than about 1%, or is substantially devoid of water (promptly less than 0.1% water).In one embodiment, O ₂(g), or be substantially devoid of O less than about 0.1% ₂(g) (promptly less than 0.1% water).Preferably, described medical apparatus or parts collation package for example are filled with N in airtight bag ₂The alumiseal bag of gas.Described packing should prevent preferably that moisture, oxygen and light from entering packing.

In packaging material, comprise oxygen and/or water absorbent, with the hypoxia in guaranteeing to pack with water environment-this not only can prolong the shelf life of sealed product, and can protect the top layer coating in sterilization process highly beneficially.Suitably, can obtain in packing, being low to moderate 0.01% the vaporous water and the level (www.mgc-a.com) of molecular oxygen.

In one embodiment, use radiation sterilization, for example gamma-emitting electron beam is sterilized.

In one embodiment, production method comprises the whole medical apparatus outer surface of coating.But, as described herein, advantageously be coated with the only a part of of medical apparatus usually, promptly the possibility contact need receives the part of the cell of NO.

In the production process of device, described layer can prepare by for example following manner: dipping-coating, and the electricity rotation, the auxiliary electricity rotation of gas, spraying is smeared, printing, vapor deposition or its combination.Internal layer can be formed on to be used before the skin, so that obtain veining or the coarse outer surface of internal layer, so that the skin combination of improvement to be provided.

First territory can comprise at least a polymer and at least a compound donator, and described compound donator can discharge therapeutic agent, and has the feature that rate of release is associated with the pH in this territory.

Therapeutic agent can be used as discrete molecule and is present in the polymer, maybe can pass through covalent bond, by ionic interaction, by hydrogen bond or by the polymer of hydrophobic interaction in conjunction with first territory.In the latter of both of these case, described therapeutic agent need discharge from polymer molecule before its biological effect can be had an effect usually.In the former of both of these case, polymer self can be used as compound donator.Discharge when often occurring in moistening second territory, promptly by contacting physiological solution (for example blood) to cause H ⁺Ion is to the transfer in first territory, thus the release therapeutic agent.

When the moistening first and/or second territory, second territory can obtain being different from the pH of the first territory pH, so the phase counterdiffusion meeting between first and second territories influences the pH in first territory, thereby and influences the release of therapeutic agent.

According to the bioactive and definite character active territory of pH, different mechanism can cause the release of therapeutic agent.

First mechanism is that the pH modified compound diffuses into the active territory of pH from biologically active domain, thereby exhausts the biologically active domain of pH modified compound.

Second mechanism is that the pH modified compound diffuses into biologically active domain from the active territory of pH, thereby influences the pH in the biologically active domain.

The 3rd mechanism is that compound donator diffuses into the active territory of pH from biologically active domain.By entering the active territory of pH, pH changes, thereby triggers the release of therapeutic agent from compound donator.

The pH dressing agent can comprise can be by changing H ⁺And OH ^-Local equilibrium between the ion influences arbitrary atom, molecule or the ion of pH, comprises H ⁺And OH ^-The variation of pH can be derived from the H that causes that enters owing to acid or alkali ⁺Or OH ^-Ionic increase or minimizing, or be derived from the molecule or ionic the entering of triggering the chemical reaction that causes the pH variation.

In the embodiment that first and second territories of the present invention provide as eclipsed coatings; medical apparatus can comprise the 3rd coatings in addition; it forms the outer surface layer of medical apparatus, for example protect first and/or second territory to avoid damaging or postpone blood or other body fluid enter and/or control the rate of release that therapeutic agent is organized towards periphery from ground floor (first territory).H between first and second territories ⁺Or OH ^-Ionic transportation can be postponed by the 4th coatings that provides between first and second coatings (i.e. the layer in first and second territories).The 4th layer can prevent or reduce the undesirable diffusion between first and second territories in this device storage process, the diffusion under the low humidity of promptly undesirable environment around.In the first, second, third and the 4th coatings at least one can comprise polyurethane.Because outer surface layer i.e. providing of the 3rd coatings, can improve the mechanical integrity and the intensity of device, can avoid for example wrapping the adhesion between the surface portion of balloon of quilt, and can realize low surface friction power.

Therapeutic Method

Can be used to realize in the blood vessel or the neural blood vessel operation according to medical apparatus of the present invention/parts bag, for example blood vessel is got involved.

Therefore the present invention provides the method that discharges nitrogen oxide from medical apparatus, and described medical apparatus comprises that at least this method comprises following step according to each first and second territories in the aforementioned claim:

● make the biological body fluid of medical apparatus contact;

● the moistening medical apparatus, thus H caused ⁺Or OH ^-Ion increases the speed that nitrogen oxide discharges to bodily tissue from first territory thus from the transportation of one of first and second territories to another territory.

In one embodiment, the entry site of medical apparatus can be selected from: femoral artery, radial artery, carotid artery, brachial artery, auxilliary tremulous pulse (auxiliary artery).

In one embodiment, the entry site of medical apparatus is selected from: radial artery, brachial artery and auxilliary tremulous pulse.When using according to intubate sheath of the present invention, such inlet point is particularly preferred.

Other embodiment: following particular can be combined with other embodiment that this paper mentions.

Embodiment 1. is when at least a portion on moistening medical apparatus surface, and to the medical apparatus of organism release therapeutic agent, described medical apparatus comprises first territory and second territory at least, wherein:

● described second territory can influence the pH at least one territory in first territory and second territory, and it is by changing H after at least a portion of moistening medical apparatus ⁺And OH ^-Local equilibrium between the ion realizes;

And wherein:

2. the medical apparatus of embodiment 1, wherein said therapeutic agent comprise following at least a: human growth factor, and anti-agglomerating agent, antibiotic agent, chemotherapeutics, vasodilation and smooth muscle cell proliferation reduce agent.

3.

embodiment

1 or 2 medical apparatus, and comprise intermittently or permanent blood vessel implant.

4. the medical apparatus of any among the embodiment 1-3, wherein said first territory comprises first coatings of this device.

5. the medical apparatus of embodiment 4, wherein said second territory comprises second coatings of this device.

6. the medical apparatus of any of previous embodiments, wherein said second territory comprise following at least a: ascorbic acid, polyacrylic acid, oxylic acid, acetic acid and lactic acid.

7. the medical apparatus of embodiment 5, wherein the one deck in first and second coatings be provided at another layer above.

8. the medical apparatus of embodiment 7, wherein said first coatings be provided at second coatings above.

9.

embodiment

7 or 8 medical apparatus also comprise the 3rd coatings, and it forms the outer surface layer of medical apparatus.

10. the medical apparatus of any among the embodiment 7-9 also comprises the 4th coatings, and it is provided between first and second coatings.

11. the medical apparatus of embodiment 9 or 10, wherein the one deck at least in the first, second, third and the 4th coatings comprises polyurethane.

12. the medical apparatus of any of previous embodiments, wherein said therapeutic agent is fixed in the hydrogel.

13. the medical apparatus of embodiment 12, wherein said hydrogel mixes mutually with glucoseoxidase (GOD).

14. comprise any medical product of medical apparatus of previous embodiments, described medical apparatus is wrapped in the packing, it prevents that moisture from entering this packing.

15. the medical product of embodiment 14, wherein said packing are kept in the packing the highest 40% relative humidity under room temperature.

16. keeping, the medical product of embodiment 14 or 15, wherein said packing be up to 7 pH.

17. therapeutic agent is used for the treatment of application in the disposable medical apparatus of cell obstacle of bodily conduit in preparation, described medical apparatus comprises first and second territories at least, wherein:

● described second territory can influence the pH at least one territory in first territory and second territory, and it is by changing H when at least a portion of moistening medical apparatus ⁺And OH ^-Local equilibrium between the ion realizes;

And wherein:

18. discharge the method for therapeutic agent from medical apparatus, described medical apparatus comprises first and second territories at least, wherein first territory can discharge therapeutic agent with rate of release, and second territory can influence the pH at least one territory in first territory and second territory, and this is by changing H when at least a portion of moistening medical apparatus ⁺And OH ^-Local equilibrium between the ion realizes, and wherein said therapeutic agent depends on the pH at least one territory first territory and second territory from the rate of release in first territory, and this method comprises following step:

● make the biological body fluid of medical apparatus contact;

19. coating is applied to the method on medical apparatus surface, and described coating comprises at least a therapeutic agent, this method comprises following step:

● medical apparatus is arranged in the qualification environment; And subsequently:

● coating is applied to the medical apparatus surface, and control simultaneously limits the pH of environment, with the release of suppression therapy agent from medical apparatus.

20. the method for embodiment 19, wherein said qualification environment maintain and are up to 40% relative humidity.

21. the method for embodiment 19 or 20, wherein said qualification environment maintain the pH that the suppression therapy agent discharges from medical apparatus.

Description of drawings

Fig. 1: synthetic L-PEI also further is processed into the sketch map of LPEI-NONO ' ate.Poly-(the 2-ethyl-2-oxazoline) that uses by Polymer Chemistry Innovation Inc. produce (

500), and mean molecule quantity be 500.000g/mol.

Fig. 2: available from the sketch of the intubate sheath of U.S. Thomas Medical Products.

Fig. 3: the principle of spray pattern analyser.Spraying thread stream is illuminated by the laser sheet, and is caught by high-speed camera.

Fig. 4: the simplicity of explanation of notion: the release of nitrogen oxide is subjected to water absorption, pH and nitrogen oxide to pass the influence of the diffusion rate of coatings.

Fig. 5: their releasing mechanism of diazeniumdiolate and proposition.

Fig. 6: use priming paint/(alkali) NO adduct coating system/outer field nitrogen oxide release dynamics.

Fig. 7: explained the medical apparatus according to multiple coating of the present invention as herein described.OL refers to skin, 1 ^StRefer to first territory, 2 ^NdRefer to second territory, 3 ^RdRefer to the 3rd territory, BM refers to the outer surface before the coating of the base material of medical apparatus-normally.All embodiments shown also can be included in the prime coat above the base material.The pH in first territory is preferably at embodiment A, B, and C, D, F, G is alkaline among H and the I, and also can be alkaline in E.The pH in second territory is tart in all embodiments that show.The pH in the 3rd territory is usually near neutral.The pH of outer coating is usually near physiological pH.Sketch F, G, H and I represent the granule in first and/or second territory, and it randomly is coated with the 3rd territory, and is embedded in first, second or the 3rd territory of explanation.

Fig. 8: be embedded in the polyurethane and the bag that is provided pure top polyurethane layer coating by US6, the balloon of poly-(aziridine) diazeniumdiolate (LPEI-NONO) of 737,447 disclosed linearities is immersed in the head space chamber.Nitrogen oxide discharges basically and begins immediately after expansible balloon is immersed the head space chamber, and increases to about 1.5nmol/min/cm gradually in about 50 minutes ²Level.Because the high capacity of NO in LPEI-NONO, the remaining measuring phases that is released in of NO is kept constant (about 140 minutes) basically.

Fig. 9: the bag that is embedded in the polyurethane and is supported by the coatings of 90% polyacrylic acid and 10% polyurethane is by US6, and the balloon of poly-(aziridine) diazeniumdiolate (LPEI-NONO) of 737,447 disclosed linearities is immersed in the head space chamber.Nitrogen oxide discharges basically and begins immediately after expansible balloon is immersed the head space chamber, and its level is measured (10nmol/min/cm greater than the max-thresholds of nitrogen oxide analytical equipment ²).Before interrupting measurement after about 82 minutes, observe to about 1.2nmol/min/cm ²The reduction gradually of level.

Figure 10: be embedded in the polyurethane and by the coatings support of 80% polyacrylic acid and 20% polyurethane and the bag that comprises the top polyurethane layer coating in addition by US 6, the balloon of poly-(aziridine) diazeniumdiolate (LPEI-NONO) of 737,447 disclosed linearities is immersed in the head space chamber.Nitrogen oxide discharges basically and begins immediately after expansible balloon is immersed the head space chamber, and its level is measured (10nmol/min/cm greater than the max-thresholds of nitrogen oxide analytical equipment ²).Before interrupting measurement after about 105 minutes, observe to about 0.4nmol/min/cm ²The reduction gradually of level.

Figure 11: A and B represent the bag that is embedded in the polyurethane and does not have the top layer coating by US6, the balloon of poly-(aziridine) diazeniumdiolate (LPEI-NONO) of 737,447 disclosed linearities.(A) with the prescription of (B) with process identically, difference is the pH that is used to dissolve the methanol of LPEI-NONO.Two kinds of balloons are dissolved in alkaline methanol (A) and neutral methanol (B) respectively.Balloon is immersed in the head space chamber.Represent nitrite to measure (for contrast sample being carried out index revises) at about 15-17 minute and peak when measure finishing.2,005 1102 SGP E1-B2 #710 are pH regulator, and 20051102 SGP E1-B1 #719 do not regulate pH.

Figure 12: A and B representative from bag by US 6,737, poly-(aziridine) diazeniumdiolate (LPEI-NONO) of 447 disclosed linearities and be embedded in improved nylon (pebax in the polyurethane ^TM) nitrogen oxide that discharges of test tube.(A) with the prescription of (B) with process identically, difference is that A exists the top layer coating, B lacks the top layer coating.The arrow indication has been removed the test tube of bag quilt and has been reentered the place of measuring chamber.Nitrogen oxide signal between the arrow discharges identical (for contrast is carried out the index revision with sample) with the nitrogen oxide of the LPEI-NONO that leaks from coating.

Embodiment

Embodiment 1: the production of nitric oxide donor (L-PEI-NONO ' ate)

In this embodiment, the nitrogen oxide that is applied to medical apparatus discharges coating and is based on and has the linear polyethylene imines (L-PEI) that side is hung the NONO group.

Each NONO group covalently bind on one of N atom in the L-PEI polymer chain, thereby forms N*-N ⁺(O ^-)=N-O ^-Group, wherein N* is one of L-PEI backbone atoms.This group is had vicinity-NH in the L-PEI main chain ₂ ⁺The formation institute stabilisation of the amphion complex of-amine groups.

The production of L-PEI-NONO ' ate can be divided into following basic step:

1.L-PEI synthetic (from poly-(2-ethyl-oxazolines) synthetic-method is referring to Warakomski and Thill, J.Polymer Science 1990; 28:3551-63)

2.L-PEI the preparation of powder.

3. load nitrogen oxide for the L-PEI powder.Be loaded under the nitrogen oxide pressure and occur in the reative cell, wherein LPEI is suspended in the acetonitrile.Nitrogen-atoms on nitrogen oxide and the L-PEI forms covalent bond, thereby forms L-PEI-NONO ' ate.This reaction proceeds to reaction and reaches balance, does not have more NO to be consumed (4-6 days, this depends on a batch scale).Subsequently, L-PEI-NONO ' ate is discharged any solvent, grind to form very thin powder then.

In Fig. 1, explained whole chemical reaction.

Nitrogen oxide (NO) is colourless, tasteless lipophilic gas, and its air: water partition coefficient is 20:1, is 1.7 x 10 at the maxima solubility of 25 ℃ in 1 atmospheric pressure ^-3M makes it can extend across the film diffusion easily.NO has a unpaired electron, thereby is characterized as being free radical, and this allows it and other to have the material (O for example of unpaired electron ₂ ^-With other root material) reaction.In addition, NO has for example ability of hemoglobin of high connection hemoprotein.

Be used to produce the NO that NO discharges the intubate sheath and contain the NO of 99%V/V at least.The impurity of NO comprises following gas: carbon dioxide, nitrogen, nitrogen dioxide, nitrous oxide (nitrous oxide) and water.

Nitrogen oxide is available from Linde Gas.Purity is greater than 99% weight.Impurity is appointed as unspecific NOX＜0.5% weight (N ₂O, N ₂O ₃, N ₂O ₄, NO ₂, N ₂O ₅) and nitrogen＜0.5% weight (N ₂).

To gather (2-ethyl-oxazolines) boiled in sulphuric acid 24 hours.Reach needed〉poly-(2-ethyl 2-oxazoline) hydrolysis of 90% level, need in sulfuric acid solution, boil.In the lock out operation of the product polymine that forms, distill out the propanoic acid of formation, use the sodium hydroxide neutralisation of sulphuric acid, then in water recrystallization several times with removal salt impurity, i.e. sodium sulfate and propanoic acid residue.

Produce LPEI from poly-(2-ethyl-oxazolines) and eliminated the monomeric danger of remaining aziridine.

The mean molecule quantity of finding L-PEI-NONO ' ate is 25-30kDa, and for example about 28kDa has narrow relatively distribution.

Embodiment 2: the intubate sheath

The intubate sheath that wraps quilt is in batches available from U.S. Thomas Medical Products.(percutaneous) intubate sheath is used to get involved/import (referring to Fig. 2) in the blood vessel of the diagnostic equipment.

Table 1: the material that is used for intubate sheath bag quilt

Component material

Sheath coating: L-PEI-NONO ' ate

The trade name of the polymer that uses: Tecoflex SG85A, Estane 58237, Tecophillic SP-93A.

Embodiment 3: the 100%Tecoflex in pyridine (prime coat)

Solution: 2% solid (w/w) Tecoflex in pyridine (80g altogether).

1. 75 ℃ of dry 2g Tecoflex SG85A4 hour.

2. after the drying, hermetic container is placed on room temperature.

3. the exsiccant Tecoflex SG of 1.6g 85A is mixed with the 78.4g pyridine, be incubated overnight at 75 ℃.Use is from Riedel-de

" exsiccant " pyridine 34945.

4. before use, solution is homogenized.

Embodiment 4: consumption is that 70/30 Tecoflex/Estane 70/30 makes the LPN preparation

1. reach 4 hours at 75 ℃ of dry 2g Tecoflex and SG85A 1g Estane 58237.

2. after the drying, hermetic container is placed on room temperature.

3. the preparation of mixture A: mix the exsiccant Tecoflex SG85A of 0.48g, exsiccant Estane 58237 of 0.12g and the exsiccant pyridine of 29.4g.Sealed mixture is incubated overnight at 75 ℃.In the incubation process, acutely shake container several times.

4. in order to prepare the methanol of pH regulator, 50mg NaOH is added in 30ml anhydrous (promptly about 99.8% methanol or the more than) methanol.

5. the preparation of mixture B: the methanol that in bottle, mixes 0.3g LPN and 14.7g (18.6ml) pH regulator.Shake mixture simply.Sealed container, lucifuge is at room temperature incubation 1 hour under agitation.Through 0.45 μ m filter mixture is filtered into new bottle.

6. the preparation of mixture C: mixture A and B are mixed into a new bottle with ratio 7:3 (for example 7ml+3ml), are sealed in the light resistant container.

7. mixture C is used for downstream processing.Maximum time from the final preparation of mixture C to the downstream process finishing is 9 hours.Agitation of solutions before being about to carry out downstream processing.

Embodiment 5: the 100%Tecophillic SP-93A-100 in pyridine

Solution: 2% solid (w/w) Tecophillic in pyridine (amounting to 80g).

1. reach 4 hours at 75 ℃ of dry 2g Tecophillic SP-93A-100.

2. after the drying, airtight Tecophillic SP-93A-100 is stored in room temperature.

3. mix 1.6g Tecophillic and 78.4g pyridine, be incubated overnight at 75 ℃.In the incubation process, acutely shake container several times.

4. before the processing of downstream, solution is homogenized.

Embodiment 6: coating

In 3 step spray coating technologies, use coating.The first step is to use the priming paint of USP level VI test on sheath.Spray coating on sheath is dissolved in pyridine with priming paint.

Second step was that spraying is dissolved in polyurethane in methanol and the pyridine and the mixture of L-PEI-NONO on the intubate sheath.

The 3rd step was to use the top layer coating.

Describe 3 kinds of different spray coating mixture below in detail.

Carry out spray coating with conventional air-atomizing device for rill body stream and low pressure design.Monitor and control spray coating process, send level and smooth conforming layer to guarantee spray process, and deviation does not take place layer thickness.

The variation of most critical source is the variation in the spraying thread stream in the spray coating scheme.Variation can comprise that granular size changes and the spraying thread flows geometric variation, and for example in spraying-coating process, spraying thread stream no longer concentrates on the central authorities of rotation sheath.

The variation of spray coating process is normally because the spraying fluid is dry on spray nozzle, thus the change air-flow.An approach controlling this problem is to optimize the design of spray nozzle, thereby avoid spraying the residue accumulation.In addition, optimize the prescription of spraying mixture, dry on spray nozzle with the prevention spray solution.

Use senior laser technology and high-speed camera can check and optimize spray process.This equipment can be measured the angle and direction of spraying thread stream and analyze and change.In addition, this equipment can be analyzed drop size and different parameters (for example air-flow and the apart from) influence to apparatus surface.In Fig. 3, explained the operation principle of this spray coating analytical equipment.

Described technology type is similar to the spraying of checking mouth and nose spraying and flows the required method of geometry in detail.

Discharge in order to ensure the particular target of the clinical impact that produces described expectation that (target release scope is 0.5nmol/min/cm ²-40nmol/min/cm ²), nitric oxide donor is mixed polymeric matrices (Fig. 4).Coating is formed by 3 layers:

Priming paint:

Be used to guarantee and optimize the adhesion of coating to device.

The nitrogen oxide supplying layer:

The nitrogen oxide supplying layer is to be dissolved in polyurethane in pyridine and the methanol and the mixture of L-PEI-NONO (LPN) on the medical apparatus.

The prescription of nitrogen oxide supplying layer comprises the solvent (methanol) of pH regulator, is stable in the course of processing to guarantee LPN.

The top layer coating

Polymeric top layer coating is used to guarantee the barrier solubilization of coating integrity, LPN polymer, the suitable speed of water absorption and the suitable speed of NO diffusion.

When using top layer, the release of nitrogen oxide significantly departs from 1 grade of release.This is because the barrier of top layer coating: absorption of restriction water and nitrogen oxide are by the diffusion of coating.

Embodiment 7: layer thickness

When using confocal fluorescent microscopy, the LPN layer has strong relatively autofluorescence (blue/green).Other layer can not detect by this method, may be because they do not have or have very weak autofluorescence, and because top layer and prime coat too thin (less than 0.6-0.7 μ m).When using the LPN (common spraying-coating parameter) in 44 cycles, recording the thickness of LPN layer when the drying by this method is the magnitude of 4-5 μ m.When using the LPN of the only application in 22 cycles and suppose ratio on device, the LPN coating is the magnitude of 2 μ m.

When using 22 cycles, think that total coated is the magnitude of 3 μ m.But the coating that is up to 40 μ m may suit, and can realize by increasing coating numerical example such as spray cycles.

In the time of in immersing isosmotic solution, the water absorption can cause that coating expands.We measure in experiment, and expansion can make coating thickness increase about 0.03mm (30 μ m).

Embodiment 8: nitrogen oxide is measured

Using chemiluminescence NO analyser (Sievers NO analyser NOA 280i-2) to carry out nitrogen oxide measures.But the total amount of passing the NO (g) of detector after this NO analyser test sample injection.Detection is based on following reaction:

NO+O ₃→NO ₂*+O ₂

NO ₂*→NO ₂+hv

In photomultiplier tube, detect emission light (hv), and with the amount direct correlation of NO.

Principle is, NO discharged sample place the pickling bottle (called after head space chamber) that contains PBS buffer agent (pH 7.4), adds 0.0004 ‰ polysorbas20s and covers sample, uses N ₂Gas washes continuously, N ₂Gas is carried into the NO analyser with the NO gas that discharges.Because N ₂Continuous-flow, thereby avoided the existence of oxygen, also avoided nitrite (NO ₂ ^-) formation.This method guarantees to detect all NO, and only detects NO.

Embodiment 9: packing and sterilization

Packaging product then, and be sealed in the aluminum bag, it is applicable to the electron beam irradiation sterilization.

Through the subcontractor who confirms, Ster igenics for example, Espergade, DK can be by the sterilize medical apparatus of coating of electron beam sterilization.

Requirement according to EN552 (Sterilization of medical devices-Validation androutine control of sterilization by irradiation) and ISO11137 (Sterilization of health care products-Radiation), verify and conventional sterilization, and according to EN 556 (Sterilization of MedicalDevices), (SAL 10 to carry out degerming (sterile) ^-6).

Embodiment 10:

8-10 has explained that in the following embodiments nitrogen oxide (NO) is from the release according to medical apparatus of the present invention with reference to the accompanying drawings.The balloon that will have the bag quilt of different coatings immerses to contain and maintains pH=7.4 and body temperature promptly in 37 ℃ the head space chamber of phosphate-buffer saline (PBS).Use N ₂Gas washes head space chamber, N continuously ₂Gas is carried into the nitrogen oxide analytical equipment with the NO that discharges.The nitrogen oxide analytical equipment comprises the so-called high sensitivity detector that is used to measure nitrogen oxide, and it is based on the gas chemistry luminescence-producing reaction between nitrogen oxide and the ozone:

NO+O3->NO2*+O2

NO2*->NO2+hv

Because the emission from the nitrogen dioxide of electron excitation is in spectrographic red and near infrared region, it can be detected by photomultiplier tube thermoelectric-cooled, red sensitivity.The analytical equipment of using be by

Boulder, the nitric oxide analyzer NOA that Colorado, USA provide ^TM280i.

In Fig. 8-10, the irregular interruption of NO output signal is derived from NO to the mobile interruption of analytical equipment.

Embodiment 10a (Fig. 8): be embedded in the polyurethane and the bag that is provided pure top polyurethane layer coating by US 6,737, the balloon of poly-(aziridine) diazeniumdiolate (LPEI-NONO) of 447 disclosed linearities is immersed in the head space chamber.Nitrogen oxide discharges basically and begins immediately after expansible balloon is immersed the head space chamber, and increases to about 1.5nmol/min/cm gradually in about 50 minutes ²Level.Because the high capacity of NO in LPEI-NONO, the remaining measuring phases that is released in of NO is kept constant (about 140 minutes) basically.

Embodiment 10b (Fig. 9): the bag that is embedded in the polyurethane and is supported by 90% polyacrylic acid and 10% polyurethane coatings is by US 6,737, and the balloon of poly-(aziridine) diazeniumdiolate (LPEI-NONO) of 447 disclosed linearities is immersed in the head space chamber.Nitrogen oxide discharges basically and begins immediately after expansible balloon is immersed the head space chamber, and its level is measured (10nmol/min/cm greater than the max-thresholds of nitrogen oxide analytical equipment ²).Before interrupting measurement after about 82 minutes, observe to about 1.2nmol/min/cm ²The reduction gradually of level.

Embodiment 10c (Figure 10): be embedded in the polyurethane and by 80% polyacrylic acid and 20% polyurethane coatings support and the bag that comprises the top polyurethane layer coating in addition by US 6, the balloon of poly-(aziridine) diazeniumdiolate (LPEI-NONO) of 737,447 disclosed linearities is immersed in the head space chamber.Nitrogen oxide discharges basically and begins immediately after expansible balloon is immersed the head space chamber, and its level is measured (10nmol/min/cm greater than the max-thresholds of nitrogen oxide analytical equipment ²).Before interrupting measurement after about 105 minutes, observe to about 0.4nmol/min/cm ²The reduction gradually of level.

List of references

[1]Iganarro?et?al.

Oxidation?of?nitric?oxide?in?aqueous?solution?to?nitrite?butnotnitrate：Comparison?with?enzymatically?formed?nitric?oxidefrom?L-argininePharmacology，Vol.90，pp.8103-8107，September?1999

[2]L.K.Keefer?et?al.

Chemistry?of?the?Diazeniumdiolates.2.Kinetics?and?Mechanismof?Dissociation?to?Nitric?Oxide?in?Aqueous?Solution.J.Am.Chem.Soc.2001，123，5473-5481

[3]Keith?M.Davies，*，David?A.Wink，Joseph?E.Saavedra，§and?Larry?K.Keefer.Chemistry?of?the?Diazeniumdiolates.2.Kinetics?and?Mechanism?of?Dissociation?to?Nitric?Oxide?inAqueous?Solution.J.Am.Chem.Soc.2001，123，5473-5481

[4]Dennis?K.Taylor，Ian?Bytheway，Derek?H.R.Barton，Craig?A.Bayse，and?Michael?B.Hall.Toward?the?Generation?of?NO?inBiological?Systems.Theoretical?Studies?of?the?N?202?Grouping.J.Org.Chem.1996，60，435-444

[5]Andrew?S.Dutton，Jon?M.Fukuto?and?K.N.Houk.The?Mechanismof?NO?Formation?from?the?Decomposition?of?DialkylaminoDiazeniumdiolates：Density?Functional?Theory?and?CBS-QB3Predictions.Inorganic?Chemistry，Vol.43，No.3，2004.

Claims

1. can discharge the medical apparatus of nitrogen oxide when at least a portion on moistening medical apparatus surface to organism, described medical apparatus comprises first territory of containing the polymine diazeniumdiolate, and wherein the pH in first territory is greater than pH 7.

2. according to the medical apparatus of claim 1, the pH in wherein said first territory is that about pH8 is to about pH 13.

3. according to the medical apparatus of claim 1, the pH in wherein said first territory is that about pH9 is to about pH 10.

4. according to each medical apparatus among the claim 1-3, wherein said first territory comprises alkali compounds.

5. according to the medical apparatus of claim 4, wherein said alkali compounds is an inorganic compound, and for example pKb is less than 6 inorganic compound, and for example pKb is less than 5 inorganic compound.

6. according to the medical apparatus of claim 5, wherein said inorganic compound is selected from: NaOH, KOH, Ca (OH) ₂And LiOH.

7. according to the medical apparatus of claim 4, wherein said alkali compounds is an organic compound, and for example pKb is less than 6 organic compound, and for example pKb is less than 5 organic compound.

8. according to the medical apparatus of claim 7, wherein said organic compound is selected from: primary amine class, secondary amine class, tertiary amines, chloroquine, diisopropylamino lithium or methylamine.

9. according to each medical apparatus in claim 4 or 8, wherein said alkali compounds is the organic or inorganic ealkaline buffer.

10. according to the medical apparatus of claim 9, wherein said ealkaline buffer is selected from: phosphate, ethanolamine, ADA; carbonate, ACES, PIPES, MOPSO; imidazoles, BIS-TRIS propane, BES, MOPS; HEPES, TES, MOBS, DIPSO; TAPSO, triethanolamine (TEA), pyrophosphate, HEPPSO; POPSO, N-(methylol) methylglycine, hydrazine, glycylglycine; tromethane (tris), EPPS, HEPPS, BICINE; HEPBS, TAPS, 2-amino-2-methyl-1, ammediol (AMPD); TABS, AMPSO, taurine (AES), borate; CHES, 2-amino-2-methyl-1-propanol (AMP), glycine, ammonium hydroxide; CAPSO, carbonate, methylamine; piperazine, CAPS, CABS and piperidines.

11. medical apparatus according to claim 4-10, wherein said alkali compounds is the polymer that contains inorganic or organic base, for example pKb is less than 6 inorganic or organic base, and more preferably pKb for example is selected from the alkali of primary amine class, secondary amine class and tertiary amines less than 5 any inorganic or organic base.

12. according to each medical apparatus in the aforementioned claim, the molecular weight of wherein said polymine diazeniumdiolate be about 5kDa to about 200kDa, for example about 10kDa is about 100kDa extremely, 20kDa about 60kDa extremely more preferably from about for example, for example about 30kDa.

13. according to each medical apparatus in the aforementioned claim, wherein the polymine diazeniumdiolate is linear.

14. according to each medical apparatus in the aforementioned claim, use as the coatings that is applied on the medical apparatus outer surface in first territory that wherein comprises the polymine diazeniumdiolate, or form the coatings that is applied on the medical apparatus outer surface.

15. according to each medical apparatus in the aforementioned claim, wherein said polymine diazeniumdiolate be not as fiber for example nanofiber for example electricity rotation nanofiber use, or do not form for example nanofiber electricity rotation nanofiber for example of fiber.

16. according to the medical apparatus of claim 14 or 15, wherein said polymine diazeniumdiolate forms homogeneous phase in described first territory.

17. according to the medical apparatus of claim 16, the described polymine diazeniumdiolate in wherein said alkali compounds and described first territory forms homogeneous phase.

18. medical apparatus according to claim 16 or 17, wherein said first territory that comprises the polymine diazeniumdiolate is the coating system form that comprises polymeric blends, wherein said polymeric blends comprises polymine diazeniumdiolate and hydrophilic support polymer or polymeric blends and optional alkali compounds, and wherein the polymine diazeniumdiolate forms homogeneous phase with support polymer or polymeric blends with optional alkali compounds.

19. according to the medical apparatus of claim 18, the hydrophilic support polymer that wherein exists in the coating system is about 5% to about 80%, for example 10% to 50%, preferred about 20% to about 50%, for example about 30% with the ratio of polymine diazeniumdiolate.

20. according to each medical apparatus among the claim 17-19, wherein the first territory neutral and alkali compound concentrations makes OH ^-Concentration is that about 0.1 μ M is to about 2mM OH ^-, for example 0.001mM is to about 1mM OH ^-, for example about 0.1mM.

21. according to each medical apparatus among the claim 18-20, wherein said polymeric blends comprises the mixture of supporting polymer and hydrophilic polymer.

22. according to each medical apparatus among the claim 18-21, wherein the polymeric blends of homogenizing provides about 0.5 to about 40nmol/min/cm ²Rate of release, this can use the dynamic head space chamber that is connected on the chemiluminescence NO detector, in inserting phosphate buffered salt solution pH7.4,37 ℃, discharges the maximum rate point mensuration that increases at nitrogen oxide.

23. according to each medical apparatus among the claim 18-22, wherein said support polymer and/or hydrophilic support the polymeric blends of polymer or polymeric blends and/or coating system and/or homogenizing to withstand and are applied to the lip-deep pull strength of polymer coating that this pull strength is about 4-100 newton cm ^-2, for example about 8-50 newton cm ^-2, for example preferred 10-20 newton cm ^-2

24. according to each medical apparatus among the claim 18-23, the support polymer that wherein uses in the coating system and the weight ratio of hydrophilic polymer are about 95/5 to about 35/65.

25. according to each medical apparatus among the claim 18-24, wherein the thickness of coating system is about 1 to about 100 μ m, for example when drying regime 5 to about 20 μ m.

26. according to each medical apparatus among the claim 1-25, wherein use the coating system for example before first or second territory (promptly in inside) to the base material bag by interior prime coat.

27. according to the medical apparatus of claim 26, wherein said interior prime coat is a polyurethane primer.

28. according to the medical apparatus of claim 26 or 27, wherein the thickness of prime coat is about 0.2 to about 5 μ m.

29. according to each medical apparatus in the aforementioned claim, wherein use the dynamic head space chamber that is connected on the chemiluminescence NO detector to record, nitrogen oxide is about 0.5 to about 40nmol/min/cm from the release of medical science outside of deivce face ²

30. according to each medical apparatus in the aforementioned claim, wherein use the dynamic head space chamber be connected on the chemiluminescence NO detector to record, nitrogen oxide has at least 30 minutes, for example at least 60 minutes, half-life of at least 90 minutes for example from being released in of medical science outside of deivce face under the physiological condition.

31. according to each medical apparatus in the aforementioned claim, wherein use the dynamic head space chamber be connected on the chemiluminescence NO detector to record, nitrogen oxide has from the release of medical science outside of deivce face and is no more than 6 hours, for example is no more than 4 hours, for example is no more than half-life of 3 hours.

32. according to each medical apparatus in the aforementioned claim, wherein said medical apparatus is a medical apparatus in the blood vessel.

33. according to the medical apparatus of claim 32, wherein said medical apparatus is selected from: neuromedicine device, for example neural guiding tube, neural microtubular, neural little line, neural stent delivery system, neuron balloon; Crown medical apparatus, for example crown lead, crown guiding tube, PTCA angioplasty balloon; Stent delivery system, crown lead, crown guiding tube, PTA angioplasty balloon; The intubate sheath, dilator, guide line, syringe needle; With the dialysis sheath.

34. according to each medical apparatus in the aforementioned claim, wherein the base material of medical apparatus is selected from following chemical compound by one or more and forms, or comprises one or more and be selected from following chemical compound: metal, rustless steel for example, titanium, gold, platinum; Plastics, PVC for example, PA, PS, epoxy resin, silicone rubber, natural rubber, polyurethane, PE, PP, polyester, nylon, polyester, PET, PMMA, polysulfones, Polyphosphazenes, thermoplastic elastomer (TPE) polydimethylsiloxane (PDMS).

35. according to each medical apparatus in the aforementioned claim, wherein the polymine diazeniumdiolate is that about 0.05mg/cm2 is to about 100mg/cm2 in the lip-deep application density of medical apparatus.

36. according to each medical apparatus in the aforementioned claim, its comprise can be in first territory inner or second outside territory, wherein said second territory can influence the pH in first territory, it is by changing H when at least a portion of moistening medical apparatus ⁺And OH ^-Local equilibrium between the ion realizes.

37. according to the medical apparatus of claim 36, wherein said second territory can reduce the pH in first territory when at least a portion of moistening medical apparatus.

38. according to the medical apparatus of claim 36 or 37, the pH in rate dependent at least one territory in first territory and second territory that wherein said nitrogen oxide discharges from first territory.

39. according to each medical apparatus among the claim 1-38, wherein said first territory comprises first coatings of this device, it is applied to or is being close to the base material of medical apparatus or according to each prime coat among the claim 26-28.

40. according to the medical apparatus of claim 39, wherein said second territory comprises second coatings of this device, it is applied to or is being close to described first coating.

41. according to each medical apparatus among the claim 36-40, wherein the pH in second territory is that about pH 1 is to being lower than pH 7.

42. according to the medical apparatus of claim 36-40, wherein the pH in second territory is that about pH 2 is to about pH 6.

43. according to the medical apparatus of claim 36-40, wherein the pH in second territory is that about pH 3 is to about pH 5.

44. according to each medical apparatus among the claim 36-43, wherein said second territory comprises acid compound.

45. according to the medical apparatus of claim 44, wherein said acid compound is an inorganic compound.

46. according to the medical apparatus of claim 45, wherein said inorganic compound is selected from: pKa is less than 6 mineral acid, and pKa is less than 5 mineral acid, hydrochloric acid, sulphuric acid, nitric acid and hydrobromic acid.

47. according to the medical apparatus of claim 44, wherein said acid compound is an organic compound.

48. according to the medical apparatus of claim 47, wherein said organic compound is selected from: pKa is less than 6 organic acid, and pKa is less than 5 organic acid, ascorbic acid, polyacrylic acid, oxylic acid, acetic acid and lactic acid.

49. according to each medical apparatus among the claim 44-48, wherein said acid compound is the organic or inorganic acid buffer agent.

50. according to the medical apparatus of claim 49, wherein said acid buffer agent is selected from: maleate, phosphate, glycine, citrate, glycylglycine, malate, formates, citrate, succinate, acetate, propionate, pyridine, piperazine, Cacodylate, succinate, MES, histidine, bis-tris, ethanolamine, ADA and carbonate.

51. medical apparatus according to claim 44-50, wherein said acid compound is tart polymer, for example be selected from following polymer: the polymer that contains mineral acid, contain the organic acid polymer, pKa is less than 6 inorganic or organic acid, pKa contains the polymer of carboxyl less than 5 inorganic or organic acid.

52. according to the medical apparatus of claim 51, wherein said acid compound is polyacrylic acid or polylactic acid polymer.

53. according to each medical apparatus among the claim 36-52, a territory in wherein said first and second territories be provided at another territory above.

54. according to the medical apparatus of claim 53, wherein said first territory be provided at second territory above.

55. according to each medical apparatus among the claim 1-54, wherein said medical apparatus comprises in addition and is positioned at a skin of described first overseas, and described skin is included in the polymine diazeniumdiolate that exists in described first territory and the polymer barrier between the external environment condition (for example body fluid).

56. according to the medical apparatus of claim 55, wherein when described medical apparatus be when aqueous ionic medium is for example in the serum, described skin prevents or reduces the release of polymine diazeniumdiolate from described first territory.

57. according to the medical apparatus of claim 55 or 56, wherein said outer controlled oxidation nitrogen is release the described Physiological Medium of course in described.

58. according to each medical apparatus among the claim 55-57, wherein said skin is controlled under the physiological condition water from the diffusion of described Physiological Medium to internal layer.

59. according to each medical apparatus among the claim 55-58, wherein said outer can reduce or the prevention small molecule by-product leaks to described Physiological Medium from described polymeric blends.

60. according to each medical apparatus among the claim 55-59, wherein said skin comprises hydrophilic polymer.

61. according to the medical apparatus of claim 60, wherein said hydrophilic polymer forms the hygroscopicity gel when inserting Physiological Medium.

62. according to each medical apparatus among the claim 55-61, wherein said skin comprises and is selected from following hydrophilic polymer: polyurethane, polyolefin, polystyrene for example, polypropylene, polyethylene, politef, Kynoar, polrvinyl chloride, deutero-polyolefin is polymine for example, polyethers, polyester, polyamide is nylon for example, polyurethane, silicone or cellulose.

63. according to the medical apparatus of claim 62, wherein said skin comprises and is selected from following hydrophilic polymer: aromatic polyurethane, vinyl acrylate polyolefin, hydrophilic aliphatic urethane or high water vapor conduction silicone or cellulose.

64. according to each medical apparatus among the claim 55-63, wherein said skin is not buffered layer, it allows skin to be adjusted to physiological pH in use.

65. according to each medical apparatus among the claim 55-64, wherein said outer field pH is near physiological pH, for example near pH 7.4.

66. according to each medical apparatus among the claim 55-65, wherein said outer field thickness is about 0.3 to about 5 μ m.

67. according to each medical apparatus among the claim 36-66, the 3rd territory (the 4th coatings) that provides between first and second territories is provided wherein said medical apparatus.

68. according to the medical apparatus of claim 67, wherein said the 3rd territory is not buffered polymer layer.

69. according to the medical apparatus of claim 67 or 68, wherein the 3rd territory comprises hydrophilic support polymer or polymeric blends.

70. preparation is applicable to the method for the polymine diazeniumdiolate preparation of (alkali) stabilisation in the medical apparatus coating in the blood vessel, described method comprises polymine diazeniumdiolate (LPEI-NONO) is dissolved in the alkali organic solvent.

71. according to the method for claim 70, wherein said solvent is selected from: alcohol, ethanol, methanol, aniline, benzaldehyde and cyclohexylamine dimethyl sulfoxide.

72. according to the method for claim 72, wherein said organic solvent is a methanol.

73. according to the method for claim 73, the water content of wherein said organic solvent is less than 1%, for example less than 0.5%.

74. according to each method among the claim 70-73, the concentration of wherein said polymine diazeniumdiolate is about 0.2% to about 20%, for example about 1% to about 10%, for example about 1% to about 5%, for example about 2%.

75. be applicable to the compositions of the polymine diazeniumdiolate that comprises the alkali stabilisation in the medical apparatus coating in the blood vessel, it is about 0.2% to about 20% that wherein said compositions comprises concentration, for example about 1% to about 10%, for example about 1% to about 5%, for example about 2% polymine diazeniumdiolate, it is dissolved in according in each the alkali solvent among the claim 70-73.

76. according to the compositions of claim 75, wherein said compositions comprises polyether polyols with reduced unsaturation in addition and/or supports polymer or polymeric blends according to each hydrophilic among the claim 18-25.

77. produce the method that is applicable to the medical apparatus that uses in the blood vessel, described method comprises:

A. select to be applicable to the medical apparatus of vascular surgery, described medical apparatus comprises base material,

B. use first territory at least a portion of described base material, it is according to each first territory among the claim 1-35.

78. according to the method for claim 77, it comprises uses at least one second territory, this second territory can be applied to inside, first territory (before) or outside (afterwards), and each defines among wherein said second territory such as the claim 36-54.

79. according to the method for claim 77 or 78, wherein before using first territory, will be according to each primer applications among the claim 26-28 in the base material of described medical apparatus.

80., wherein use the 3rd territory between first territory and second territory using, to be provided at the barrier territory between first and second territories according to each method among the claim 77-79.

81. 0 method according to Claim 8, each defines among wherein said the 3rd territory such as the claim 67-69.

82. according to each method among the claim 77-81, in case described first territory and the described second and the 3rd optional territory have wherein been used, each skin in medical apparatus is used according to claim 55-66.

83. according to each method among the claim 77-82, wherein by spray application, dipping, push or smear and use described prime coat, first territory, second territory, the 3rd territory and/or skin.

84. according to each method among the claim 77-83, wherein before being applied on the medical apparatus, be prepared as follows first territory: mix according to the compositions of claim 75 or by the preparation of each method preparation among the claim 70-74 with according to each hydrophilic among the claim 18-25 and support polymer or polymeric blends.

85. comprise the medical apparatus that uses in the blood vessel of base material, described base material comprises the polymine diazeniumdiolate, or be coated with the interior coating (or first territory) that contains the polymine diazeniumdiolate at least in part, wherein said medical apparatus comprises a skin that is positioned at described base material or described coating (or first territory) outside in addition, and described skin comprises the polymer barrier between polymine diazeniumdiolate and external environment condition.

86. 5 medical apparatus according to Claim 8, each defines among wherein said skin such as the claim 55-66.

87. 5 or 86 medical apparatus according to Claim 8, wherein said medical apparatus comprise according to each first territory among the claim 1-25.

88. each medical apparatus among the 5-87 according to Claim 8, wherein said medical apparatus comprise according to each second territory among the claim 36-54.

89. each medical apparatus among the 5-88 according to Claim 8, wherein said medical apparatus comprise according to each interior prime coat among the claim 26-28.

90. each medical apparatus among the 5-89 according to Claim 8, wherein said medical apparatus comprise according to each the 3rd territory among the claim 67-69.

91. each medical apparatus among the 5-90 according to Claim 8, wherein said medical apparatus are selected among the claim 32-34 each medical apparatus.

92. each medical apparatus among the 5-91 according to Claim 8, wherein said nitrogen oxide from the release of medical science outside of deivce face as the claim 29-31 as described in each.

93. each medical apparatus among the 5-92 according to Claim 8, wherein said polymine diazeniumdiolate is 0.05 to about 100mg/cm2 in the lip-deep application density of medical apparatus.

94. produce the method that is applicable to the medical apparatus that uses in the blood vessel, described method comprises:

A. select to be applicable to the medical apparatus of vascular surgery, described medical apparatus comprises base material or the internal layer (or first territory) that contains the polymine diazeniumdiolate;

B. use skin to described medical apparatus, each defines among described skin such as the claim 55-66.

95. according to the method for claim 94, it comprises uses at least one second territory, this second territory can be applied to internal layer (or first territory) inner (before) or outside (afterwards), and each defines among wherein said second territory such as the claim 36-54.

96. according to the method for claim 94 or 95, wherein before using first territory, will be according to each primer applications among the claim 26-28 in the base material of medical apparatus.

97., wherein use the 3rd territory between first territory and second territory using, to be provided at the barrier territory between first and second territories according to each method among the claim 94-96.

98. according to the method for claim 97, each defines among wherein said the 3rd territory such as the claim 67-69.

99. according to each method among the claim 94-98, wherein by spray application, dipping, push or smear application of primer layer, first territory, second territory, the 3rd territory and/or skin.

100. a medical product, it comprises among the claim 1-69 among each or the claim 85-93 each medical apparatus, and described medical apparatus is wrapped in the packing, and this packing prevents that moisture, oxygen and/or light from entering in the packing.

The medical product of claim 100, wherein said packing are kept in the packing under room temperature less than about 0.01% relative humidity.

Claim 100 or 101 medical product, wherein said packing is the sealing bag form that contains inert gas atmosphere.

Each medical product among the claim 100-102, the oxygen (O in its intermediate package ₂) content is less than about 0.1%.

Carry out in the blood vessel or the method for neural blood vessel operation, its comprise in patient's blood vessel or neural blood vessel system, insert according to claim 1-69 in each or according to Claim 8 among the 5-93 each according to claim 77-84 in each the method preparation or according to claim 94-99 in each the medical apparatus of method preparation.

According among the claim 1-69 each, or according to Claim 8 among the 5-93 each, or prepare according to each method among the claim 77-84, or according to the medical apparatus of each method preparation among the claim 94-99, it is used in the blood vessel or the neural blood vessel purposes, be used to prevent one or more to be selected from following disease: vasospasm or vasoconstriction, the prevention of cerebral vasospasm, the diastole of smooth muscle, vasodilation, thrombosis, the platelet deposition or the gathering that reduce, alleviating of restenosis, hypertension, the oxygen-derived free radicals reperfusion injury, the treatment of cardiovascular disease, the prevention of the side effect relevant with the use of described medical apparatus prevents unusual cell proliferation.

The outer coatings of each definition is used to prevent the polymine diazeniumdiolate from being applicable to the purposes of the medical apparatus release of using in the blood vessel among claim 55-66 or the 83-91, and described medical apparatus comprises substrate coating and/or the internal layer (or first territory) that contains the polymine diazeniumdiolate.

Alkali cpd or compositions are used to prevent the nitrogen oxide purposes that discharges of the polymine diazeniumdiolate of the medical apparatus that uses of self application always in blood vessel, described medical apparatus comprises the substrate coating and/or first territory of containing described polymine diazeniumdiolate and described alkali cpd or compositions.

The polymine diazeniumdiolate of alkali stabilisation is used for the treatment of purposes in the disposable medical apparatus of cell obstacle of bodily conduit in preparation, described medical apparatus comprises first territory and optional one or more according to each other territory or layer in the aforementioned claim at least.

Coating is applied to the method on medical apparatus surface, and described coating comprises the polymine diazeniumdiolate at least, and this method comprises following step:

● polymine diazeniumdiolate coating is applied to the medical apparatus surface, and control simultaneously limits the pH of environment, with the release of inhibited oxidation nitrogen from medical apparatus.

110. the method for claim 109, wherein said qualification environment maintains the pH greater than 7.