Medical device for dispensing medicaments
Abstract
A drug delivering medicinal device (A) for selective therapy of particular diseased tissue segments or organ parts comprises a device to be contacted (for at least a short period) under pressure with the diseased region, carrying on the surface a lipophilic, water-insoluble drug (I) which bonds with tissue components, such that (I) is released immediately on contact with tissue. An independent claim is included for the preparation of (A).
Term
Term ended
Expired 26 August 2023, 3.1 years ago.
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22 claims: 1 independent, 21 dependent
- 1Zastrzeżenia patentowe 1. Cewnik balonikowy, znamienny tym, że balonik ma wstępnie wykonane wzdłużne pofałdowania, przy czym powierzchnia z pofałdowaniami powleczona jest paklitakselem, wysuszonym po naniesieniu na powierzchnię balonika, wiążącym substancję zawartą w matrycy niskocząsteczkowej o masie cząsteczkowej < 5000 D z powierzchnią balonika i uwalniającym natychmiast substancję czynną po zetknięciu się z tkanką, gdy balonik jest rozkładany.
- 2Cewnik według zastrz. 1, znamienny tym, że jest cewnikiem balonikowym bez stentów lub w połączeniu ze stentami, cewnikami i/lub ich elementami, igłami i przewodami prowadzącymi, jak również samymi stentami.
- 3Cewnik według zastrz. 1, znamienny tym, że balonik ma gładką powierzchnię.
- 4Cewnik według zastrz. 1, znamienny tym, że balonik, w postaci całkowicie sfałdowanej jest powleczony roztworem paklitakselu o niskiej lepkości.
- 5Cewnik według dowolnego z zastrz. 1-4, znamienny tym, że jedynie obszar sfałdowany powleczony jest paklitakselem wysuszonym po naniesieniu.
- 6Cewnik według zastrz. 1, znamienny tym, że paklitaksel występuje w postaci suchych ciał stałych na powierzchni cewnika balonikowego.
- 7Cewnik według zastrz. 6, znamienny tym, że skuteczna dawka paklitakselu obejmuje struktury amorficzne o rozmiarze cząstek od <0,1 mikrona do 5 mikronów, które szybko ulegają rozpuszczeniu ze względu na dużą powierzchnię i pomimo niskiej rozpuszczalności w wodzie substancji czynnej. PL 217 416 B1
- 8Cewnik według zastrz. 1, znamienny tym, że substancja matrycy jest ciałem stałym, łatwo rozpuszczalnym w wodzie, o niskiej masie cząsteczkowej, dla uzyskania dobrej przyczepności do powierzchni urządzenia oraz poprawy absorpcji przez tkankę.
- 9Cewnik według zastrz. 8, znamienny tym, że substancję matrycy stanowi niskocząsteczkowa substancja hydrofilowa.
- 10Cewnik według zastrz. 9, znamienny tym, że substancję matrycy wybrano z grupy obejmującej środki kontrastowe i barwniki stosowane in vivo podczas różnych diagnostycznych zabiegów medycznych, cukry i podobne substancje, w szczególności alkohole cukrowe, sole organiczne i nieorganiczne biokompatybilne, zwłaszcza benzoesany oraz sole i inne pochodne kwasu salicylowego.
- 11Cewnik według zastrz. 10, znamienny tym, że substancję matrycy stanowi jeden lub więcej jodowanych środków kontrastowych stosowanych w badaniach rentgenograficznych i/lub chelatów paramagnetycznych.
- 12Cewnik według zastrz. 1, znamienny tym, że paklitaksel jest pochłaniany przez cząstki lub nanoszony na powierzchnię urządzenia z zastosowaniem niskocząsteczkowej matrycy.
- 13Cewnik według zastrz. 1, znamienny tym, że powierzchnie są dodatkowo powlekane substancjami, które wpływają na szczególne właściwości, takie jak poślizg urządzenia, lub przeciwdziałają krzepnięciu krwi.
- 14Sposób powlekania cewnika balonikowego określonego w zastrz. 1 - 13, znamienny tym, że paklitaksel i zaróbki zawarte w roztworze, zawiesinie lub emulsji nanosi się na drodze zanurzania, rozprowadzania, rozpylania lub nanoszenia z zastosowaniem przyrządów, które doprowadzają określoną ilość substancji na powierzchnię cewnika balonikowego, przy czym usuwa się nadmiar ośrodka oraz substancje, które luźno przywierają do powierzchni.
- 15Sposób według zastrz. 14, znamienny tym, że powlekanie przeprowadza się wielokrotnie do uzyskania powtarzalnego wzrostu zawartości substancji czynnej z zastosowaniem tego samego lub różnych roztworów, zawiesin emulsji i/lub zaróbek.
- 16Sposób według zastrz. 15, znamienny tym, że jako roztwory, zawiesiny i emulsje stosuje się następujące substancje:etanol, izopropanol, octan etylu, eter dietylu, aceton, wodę lub ich mieszaniny.
- 17Sposób według jednego z zastrz. 14-16, znamienny tym, że stosuje się sfałdowany balonik gotowy do użytku, stanowiący nośnik paklitakselu, który powleka się przed lub po przeprowadzeniu procesu wyjaławiania z zaciśniętym stentem lub bez niego.
- 18Sposób według zastrz. 17, znamienny tym, że balonik w postaci niesfałdowanej powleka się paklitakselem i tym, że balonik fałduje się przy użyciu urządzenia smarującego, opcjonalnie nawilżanego środkami poślizgowymi biokompatybilnymi.
- 19Sposób według zastrz. 14, znamienny tym, że stenty łączone z cewnikiem balonikowym mocuje się przed lub po powlekaniu.
- 20Sposób według zastrz. 14, znamienny tym, że całkowicie powleczony cewnik balonikowy wyjaławia się przy użyciu tlenku etylenu.
- 21Cewnik balonikowy określony w zastrz. 1-13 do zastosowania w urządzeniu do wytwarzania wysokich lokalnych stężeń leku.
- 22Cewnik balonikowy określony w zastrz. 1-13 do zastosowania w urządzeniu do wytwarzania otwartych przejść w organizmie.
Independent claims22
123 paragraphs in 3 sections, as filed
Description of the invention
The present invention relates to a balloon catheter, a method of coating a balloon catheter and the use of a balloon catheter.
Many diseases do not affect the entire body at the same time, but only selected tissues, often a very limited area or parts of organs. Examples include neoplasms, joint diseases and vascular diseases.
Pharmacotherapy for this type of disease usually involves the oral or intravenous administration of drugs delivered inside the body, with undesirable side effects affecting healthy tissues and organs, particularly in severe conditions, limiting the therapeutic use of drugs. Meanwhile, diseased tissues could be subjected to selective therapy with drugs that bind specifically to the diseased tissue (e.g. antibodies) using the usual route of administration, or using a selective route of administration, for example by direct injection at the site of the diseased tissue or by means of a catheter inserted into the blood vessels that supply blood to the diseased tissue. When drugs are administered selectively, problems may arise due to the short period during which the drugs are effective and due to the invasive route of administration; the possibility of multiple drug administration is not available here. When drugs are selectively administered via the bloodstream, when the drug is delivered with the blood supplying the diseased tissue, an additional problem is observed, that drugs are insufficiently extracted during rapid flow of blood or active ingredient solution along the blood vessels.
Attempts have been made to address the above problems with the use of various pharmaceutical compositions for delayed release of the active ingredient, drug-releasing implants, or selective access routes allowing sustained drug administration, such as implanted catheters and the like.
The prior art discloses solutions according to which medical equipment introduced into the body, in particular catheters, can be coated with agents that help to lubricate or prevent blood clotting without affecting the course of therapy.
Moreover, catheters are provided with special devices for introducing drugs into the arterial wall, for example by means of a needle or perforation of the catheter wall, which is adjacent to the vessel wall and through which the drug is injected by injection under high pressure.
Other methods rely on extending the contact time between the arterial wall and the active agent composition administered via a catheter while blocking the blood flow for a sufficient period, for example by means of double balloon catheters where the active ingredient solution is contained in a chamber between the balloons, or by using void spaces between external balloons. balloon walls, equipped with, for example, a roller, which allows for limited blood flow through the channel passing through the balloon.
The prior art publication WO 02/076509 relates to a preparation for the prophylaxis of restenosis, in which, unlike the known preparations, in which it was not possible to obtain a sufficient concentration of the active substance in the corresponding fragments of the vessel walls because higher doses caused undesirable side effects. at least one lipophilic anti-hyperplastic active agent having a segregation index between butanol and water> 0.5 was added. The lipophilic active substance is rapidly and in sufficient quantity absorbed into the vessel wall. The preparation may be fluid and passable through a capillary and may contain a contrast agent, so that with the substantially required contrast images, the active ingredient passes into the vessel wall without additional expenditure. In accordance with the solution disclosed in WO 02/076509, the formulation can also be applied to a catheter.
According to US 5,102,402, microcapsulated drugs are introduced into a pre-formed cavity in balloon catheters to achieve delayed release of the active ingredient. When the balloon is expanded, the microcapsules that are intended to press against the walls of the vessel remain in place, gradually releasing the active ingredient (s). Many authors propose to place drugs contained in a hydrogel on balloon catheters, while not specifying the role of the hydrogel, i.e. without pointing to its role as an adhesive, a lubricant, or a drug release regulating agent.
The disadvantage of the above-mentioned products is their complicated structure, which is associated with problems during the production process, quality control, as well as high costs,
This involves forcing doctors and patients to take additional steps in administering the drug. Some of the above-mentioned modes of administration may result in undesirable vascular damage from excessive vasodilatation. Another weakness of the above solutions is that any measure used to extend the contact period entails a further reduction in the process of supplying the tissues with blood and oxygen.
For the sake of completeness, mention should also be made of an anti-restenosis device, as described in WO 01/24866, and which is coated with a substance based on lipid ceramides derived from natural cell membranes. This substance is used because of its affinity to the cell walls of the artery wall, which is not observed with commonly used drugs. At the same time, experts in the field maintain that preventing restenosis with drugs requires the active ingredient to be released over a period of several days.
The object of the present invention is therefore to provide a device for delivering drugs to selected tissue areas or parts of organs which allows for an effective therapeutic effect, while not posing a threat to healthy tissues, which is sufficiently well tolerated and which can be manufactured and used at low cost.
This goal was achieved by presenting a solution in the independent claims. The dependent claims present further features and advantages of the use of the present invention.
The essence of the invention is a balloon catheter, the balloon of which has pre-made longitudinal folds, the surface with folds being coated with paclitaxel, dried after being applied to the balloon surface, binding the substance contained in a low-molecular matrix with a molecular weight <5000 D to the balloon surface and immediately releasing the active substance after tissue contact when the balloon is deployed.
Preferably, the catheter is a stentless balloon catheter or in combination with stents, catheters and / or components thereof, needles and guide lines as well as the stents themselves.
Preferably the balloon has a smooth surface.
Preferably, the fully folded balloon is coated with a low viscosity paclitaxel solution.
Preferably, only the folded area is coated with paclitaxel dried after application.
Preferably, paclitaxel is in the form of dry solids on the surface of the balloon catheter.
Preferably, an effective dose of paclitaxel comprises amorphous structures with a particle size of <0.1 microns to 5 microns which dissolve rapidly due to the large surface area and despite the low water solubility of the active ingredient.
Preferably, the matrix material is a solid, readily soluble in water, of low molecular weight, to obtain good adhesion to the device surface and to improve tissue absorption.
Preferably, the matrix material is a low molecular weight hydrophilic material.
Preferably, the matrix substance is selected from the group consisting of contrast agents and dyes used in vivo during various diagnostic medical procedures, sugars and the like, in particular sugar alcohols, organic and inorganic biocompatible salts, especially benzoates and salts and other derivatives of salicylic acid.
Preferably, the matrix material is one or more iodinated X-ray contrast agents and / or paramagnetic chelates.
Preferably, paclitaxel is absorbed by the particles or applied to the surface of the device using a low molecular weight matrix.
Preferably, the surfaces are additionally coated with substances that contribute to specific properties, such as device glide, or prevent blood from clotting.
The invention also relates to a method of coating a balloon catheter in which paclitaxel and excipients contained in a solution, suspension or emulsion are applied by dipping, spreading, spraying or application by means of devices which deliver a given amount of substance to the surface of the balloon catheter, whereby excess medium and substances that loosely adhere to the surface are removed.
Preferably, coating is carried out repeatedly to obtain a reproducible increase in the active ingredient content using the same or different solutions, emulsion suspensions and / or excipients.
PL 217 416 B1
Preferably, the following substances are used as solutions, suspensions and emulsions: ethanol, isopropanol, ethyl acetate, diethyl ether, acetone, water or mixtures thereof.
Preferably, a ready-to-use pleated balloon is used which is a paclitaxel carrier which is coated before or after the sterilization process is carried out with or without a clamped stent.
Preferably, the unfolded balloon is coated with paclitaxel and the balloon is folded using a lubricating device, optionally moistened with biocompatible lubricants.
Preferably, the stents connected to the balloon catheter are secured before or after coating.
Preferably, the fully coated balloon catheter is sterilized with ethylene oxide.
The invention also relates to the use of a balloon catheter in a device for generating high local concentrations of a drug and in a device for generating open passageways in the body.
The subject of the invention is simply improved catheters with a drug delivery balloon or similar medical devices which are very versatile and enable immediate release of the active ingredient. Surprisingly and contrary to current opinion, continuous release of the active ingredient from an inert matrix (polymer, hydrogel, microcapsule, etc.) as well as a specific chemical or physical form of the active ingredients is not required or desirable. Accordingly, no specific techniques are required for the preparation or regulation of drug compositions administered in sustained-release aliquots embedded in tissues from where the drug is slowly absorbed.
Coating catheter balloons with drugs according to the invention is particularly advantageous as there is often a need for post-balloon-expansion therapy for blood vessels or other cavities inside the body to thereby prevent the lumen of the tube obtained under the pressure of the balloon from narrowing or occluding. limit the development of neoplastic disease or to support the treatment process, including the process of creating collateral circulation. This can be done with the help of drugs that are activated in the immediate vicinity of the balloon surface. The drugs stick permanently to the balloon carried along the artery with the intense blood flow until the balloon is stretched at the target and an effective dose of the drug is released in a short time (often in just a few seconds). This happens when the taut balloon is in contact with the tissue. The medicine will be absorbed into the tissue in such a way that the blood flow as soon as the balloon is expanded will not rinse it out.
According to the invention, wires used to guide catheters, needles, and catheters or catheter components that press against diseased tissue for at least a short period of time are coated. Preferably, the materials from which the catheters are made are polyamides, polyamide mixtures and copolymers, polyethylene terephthalate, polyethylene and copolymers, polyurethane, natural rubber and its derivatives. The length and diameter of the areas of the catheter or balloons for pharmacological treatment are not critical to their use as the drug dose is calculated in pg of active substance per mm<sup>2</sup> surface. For example, balloons with a diameter of 2 to 4 mm and a length of 1.0 to 4.0 cm are commonly used to dilate the coronary vessels. On the other hand, balloons> 20 mm in diameter and> 10 cm in length can be used in other vessels. The surface to be coated may be smooth (ie, not having any particular surface structure for absorbing the active ingredients), rough, or may include any surface structure. And although the use of surface structures is not required to ensure the adherence of the active ingredients, such structures do not impede adhesion.
The adherence of the active ingredients to the balloon surface is solely due to the selection of suitable solvents and, if appropriate, the addition of adhesion promoters. This sticking is surprisingly strong even with a completely smooth balloon surface.
All surfaces can be additionally coated with substances that improve the glide of the products, prevent blood clotting on the surface or improve other properties of medical products, while the materials used for the coating do not have to be released into the environment, and this additional coating does not significantly reduce the release of active substances used in the therapy of a given tissue, and thus does not affect the effectiveness of the product.
Balloon catheters are made by expanding a fragment of a thin plastic tube from about 1 cm to about 10 cm long. Then the balloon's expanded, thin-walled diaphragm
It is folded several times along the axis of the catheter, and then it is tightly wrapped around the axis of the catheter, as a result of which the enlarged area, after its folding, has a slightly larger diameter than the rest of the catheter. The close folding of the balloon membrane is necessary so that the balloon catheter can be inserted through access points, guide catheters and, for example, along significantly constricted sections of blood vessels.
The balloons in the catheters can be coated after or before they are crimped. This process always results in an intact and sufficiently uniform coating, and the active ingredients adhere to the balloon surface even when the balloon is refolded in an unfolded form after the coating process.
A coated balloon in the unfolded form is produced without affecting the coating, for example by using coatings with pre-shaped folds which are not disturbed by expansion and which allow the coating to re-fold - at least loosely - when the pressure inside the balloon is lowered, while this happens without the need to apply external force as the primary stimulus for the folding. After the coating has been pre-folded, the previously formed folds are compressed by applying pressure from the outside or under vacuum conditions. Such bends are not necessary to retain the active ingredient. Moreover, the refolding of the balloon envelope can be achieved with low mechanical force using very smooth materials, and the tools used can also be moistened with slippery biocompatible liquids in which the active substances do not dissolve or dissolve with difficulty.
In a further embodiment of the invention, the balloons of the puckered balloon catheters are coated by dipping them in low-viscosity solutions of the active ingredient. The solvent and the active substance penetrate between the very densely spaced folds where they form a surprisingly uniform coating containing a reproducible dose without being damaged in any of the following steps. The solution or - after the solvent has dried - the coating adhering to the outer surface may remain there or be removed at another stage, with the result that only the portion of the active ingredient inside the folds will remain there.
After coating has been performed and the balloon is folded, the stent used to maintain patency can be pulled over the balloon catheter and pressed down firmly. The only thing left to do is sterilize, for example with ethylene oxide.
This type of work cycle is extremely simple, rarely error-prone, and can also be carried out with coating materials that are sensitive to mechanical, chemical and physical influences. It has been found that coating using the above-described method does not undesirable loosening or sticking of the folds, and furthermore, that the active ingredient applied in this way adheres sufficiently tightly without being washed away by the bloodstream. Most of the active ingredient is released as the balloon is stretched into the tissue proper.
Drugs of use here are lipophilic drugs, usually water-insoluble, having a potent effect that binds to any tissue component. Drugs are defined as lipophilic when the butanol: aqueous buffer solution (pH 7) partition coefficient is 0.5, preferably 1, particularly preferably 5, or when the octanol: aqueous buffer solution (pH 7) is 1, preferably 10 and particularly preferably greater than 50. According to an alternative solution, or additionally, it must be ensured that the drugs bind reversibly and / or irreversibly to the cell components in an amount greater than 10%, preferably greater than 50% and particularly preferably greater than 80%. It is advantageous to use substances which inhibit the cell proliferation or inflammatory processes or antioxidants, such as paclitaxel and other taxanes, rapamycin and the like, tacrolimus and the like, corticosteroids, sex hormones (estrogen, estradiol, antiandrogens) and the like. substances, statins, epothilones, probucol, prostacyclins, vascular stimulants and others.
These substances are preferably contained in the form of a dry solid or oil on the surface of various medicinal products. Preferably, particles of the smallest possible size are used (typically <5 microns, preferably <1 microns and particularly preferably <0.1 microns), with particularly preferred being used amorphous non-crystalline structures with the smallest possible particle size which dissolve rapidly upon contact. with tissue for the sake of
They have a large surface area, and despite the substantially low water solubility of the drugs, they are not microcapsules, that is, they dissolve spontaneously and rapidly. It is sufficient that the effective dose be contained in the form of the smallest or amorphous particles; larger particles have almost no effect on the active ingredient content, and at the same time are not a hindrance. The size of the dose depends on the desired effect and the effectiveness of the drug used. It can be up to<sub>2</sub> pg / mm, with this value not being an upper limit. However, it is easier to administer smaller doses.
Advantageous adhesion properties to catheters, needles or tubing surfaces with favorable tissue absorption properties are achieved by incorporating highly lipophilic active substances with low water solubility in a readily water-soluble matrix. The matrices that can be used are low molecular weight (MW <5000 D, preferably <2000 D) and are hydrophilic substances such as contrast agents and dyes used in vivo in various diagnostic medical procedures, sugar and similar substances such as such as sugar alcohols, low molecular weight polyethylene glycols, organic and inorganic salts with biological compatibility, e.g. benzoates, salts and other derivatives of salicylic acid and others. Examples of contrast agents are iodine X-ray contrast agents and paramagnetic chelates; exemplary dyes are indocyanine green, fluorescein and methylene blue. The excipients, which allow for additional pharmacological effects or quality control, can also extend the shelf life of the drug.
According to a further embodiment of the invention, the pharmaceutical active ingredients can also be absorbed by the particles or applied to the surface of suitable medical products using a low molecular weight matrix. The particles referred to herein are biocompatible agents such as ferrites and various sonographic contrast agents.
Excipients in amounts less than or greater than the amount of the active ingredients are used.
Medical products are coated with solutions, suspensions or emulsions of the above-mentioned drugs and excipients. Suitable substances as solutions, suspensions or emulsions are, for example, ethanol, isopropanol, ethyl acetate, diethyl ether, acetone, dimethyl sulfoxide, dimethyl formamide, glycerin, water or mixtures thereof. The choice of solvent depends on the solubility of the active ingredients and adjuvants, the wetting of the surfaces to be coated and the effect achieved in the structure of the coating, as well as the particles present in it after evaporation of the solvent, the properties of their adherence to the surface and the transfer of the active ingredient to the tissue during a short contact period.
The coating process can be carried out by dipping, spreading, applying by means of devices which bring a given amount of the substance to the surface, or by spraying at different temperatures, as well as, optionally, impregnating with solvent vapor in the atmosphere. This process can be repeated many times with the use of various solvents and excipients, as needed.
The balloons used in the corrugated balloon catheters can be provided with a surprisingly uniform, reproducible, dose-controlled coating without adversely affecting the performance of the catheter by dipping them in solutions containing the active ingredient (s) or otherwise. When the balloons are repeatedly dipped in unsaturated solutions of the active ingredient, the previously applied active ingredient is not completely removed; instead, the active ingredient content of the balloons increases in a reproducible manner.
Excess solution or substances derived from the coating solution, which are bound loosely to the outside, can be removed by simple means without thereby adversely affecting the effectiveness of the coating.
Briefly, for a few seconds, minutes or hours, various types of devices designed and manufactured in accordance with the invention come into contact with tissues. In selected cases, it is preferable to apply pharmacological tissue therapy with drugs in the immediate vicinity of the medicinal product, for example to prevent excessive tissue growth due to tissue damage or to prevent tumor growth, to aid neovascularization or to reduce inflammatory responses. In all these cases, using the method according to the invention, it is possible to obtain a high local concentration of the drug for an unexpectedly long period
Time. The main advantage of using the solution according to the invention is the unique versatility of applications of the described products and methods.
A preferred application is to limit the hyperproliferation of vessel walls caused by their dilatation with the aid of balloon catheters. This can be done with drug-coated vessel supports (stents), but only for those vessel portions that are covered by the stent. Coated balloon catheters also allow the treatment of any areas in close proximity to and immediately behind the stent that require treatment. They enable the treatment of the section where the stent is applied, without the need to insert another stent, or the treatment of the vessels in which the stent is not or cannot be inserted. The advantage of this solution in combination with stents that allow the release of the drug over a long period of time is the improvement of the treatment process while advantageously limiting the hyperproliferation and limiting the risk of thrombosis.
Particular embodiments of the invention will be described below with reference to the coating of balloon catheters, adherence of the coating in the bloodstream, inhibition of restenosis, and the active ingredient content of the catheters.
Example 1:
Coating of a stretched balloon using paclitaxel in ethyl acetate
Balloon catheters manufactured by BMT, Oberpfaffenhofen / Munich, Germany, trade name Joker Lite, 2.5mm x 20mm balloon dimensions, were stretched to the maximum extent and then immersed for 1 minute in ethyl acetate, 18.8 mg paclitaxel / ml, + 1% pharmaceutical oil, then dried:
Paclitaxel content: 39 micrograms (after extraction with ethanol, HPLC).
Example 2:
Coating a pleated balloon catheter with paclitaxel in ethyl acetate
Balloon catheters manufactured by BMT, Oberpfaffenhofen / Munich, Germany, trade name Joker Lite, balloon dimensions 2.5 mm x 20 mm, were immersed over their entire length in a folded form for 1 minute in ethyl acetate, 18.8 mg paclitaxel / ml , + 1% pharmaceutical oil, then dried:
Paclitaxel content: 69 micrograms
Example 3:
Coating a pleated balloon catheter with paclitaxel in ethyl acetate
a) Balloon catheters manufactured by BMT, Oberpfaffenhofen / Munich, Germany, trade name Joker Lite, balloon dimensions 2.5 mm x 20 mm, immersed over the entire length in a folded form for 1 minute in ethyl acetate, 16.6 mg paclitaxel / ml and then dried for four hours:
Paclitaxel content: 54 micrograms.
b) The same procedure was used, except that an additional 5 second dipping and 1 hour drying were performed after each immersion in solution A = (3.33 ml of ethyl acetate + 100.0 mg of paclitaxel):
Paclitaxel content: 126 micrograms.
c) The same procedure was used, except that a 5 second dipping and a drying time of 1 hour were additionally carried out after each dipping in the same solution:
Paclitaxel content: 158 micrograms.
Example 4:
Coating a balloon catheter with paclitaxel in acetone
Dissolve 350 mg of paclitaxel in 9.0 ml of acetone; balloon catheters produced by
BMT, Oberpfaffenhofen / Munich, Germany, trade name Joker Lite, balloon size 2.5mm x 20mm, fully tensioned and immersed over its entire length for 1 minute, then taken out. The solvent was dried for 12 hours at room temperature. The balloon was then expanded and then crimped in the usual manner using a PTEE coated tool. As an optional solution, the balloon can be crimped with a stent of appropriate dimensions: 29 micrograms of paclitaxel on the balloon.
Example 5:
Coating a balloon catheter with paclitaxel in acetone
PL 217 416 B1
a) Immersion of catheters with a pleated balloon manufactured by BMT, trade name Allegro, balloon dimensions 2.5 x 20 mm in a mixture of 0.15 ml ethanol + 4.5 μΐ Ultravist 300 (and X-ray contrast agent, manufacturer Schering AG , Berlin, Germany) + 1.35 ml acetone + 0.8 mg Sudan red dye + 30.0 mg paclitaxel:
The folded areas of the balloon in the catheter were immersed 5 times, the first time for 1 minute, followed by drying for 3 hours, then 4 times every hour for 5 seconds each; then the stent was compressed, then the catheter and the stent were sterilized in the traditional way with the use of ethylene oxide: paclitaxel content 172 micrograms; using HPLC, no active substance degradation products were found.
b) A saturated aqueous mannitol solution was used in place of the Ultravist 300.
c) In place of Ultravist 300, a saturated aqueous sodium salicylate solution (pH 7.5) was used.
d) 5 mg of acetylsalicylic acid was added to the obtained solution according to (5a).
e) 5 mg of glycerol was added to the resulting solution according to (5a).
Example 6:
Adhesion of the active substance in the bloodstream
12 catheters with balloon manufactured by BMT were used, trade name Allegro, balloon dimensions 2.5 x 20 mm. 6 catheter fragments with a folded balloon were immersed each 5 times in [0.15 ml of ethanol + 4.5 μl of Ultravist 300 + 1.35 ml of acetone + 0.8 mg of Sudan red dye + 30.0 mg of paclitaxel] and in [1.5 ml of ethyl acetate + 0.8 mg of Sudan red dye + 31.0 mg of paclitaxel], first for 1 minute with a 3-hour drying period, and then 4 times, each time for 5 seconds, with one-hour breaks; then 3 of the folded balloons in each group were gently displaced for 5 minutes at 37 ° C in 50 ml of human blood and then removed to test paclitaxel content: reduction of mean values (n = 3 for a given coating method) with 5 minutes blood movement versus 3 control catheters each not incubated in blood.
Acetone: 12%
Ethyl acetate: 10%
Example 7:
Study of the inhibition of restenosis after vascular plasticization and stent implantation in the coronary arteries of pigs.
Balloon catheters (model: Joker Lite, manufacturer: BMT, dimensions: 3.5 x 20 mm or 3.0 x 20 mm) were immersed for 1 minute in one of the following solutions: solution A) 3.33 ml of ethyl acetate ( EA) + 100.0 mg paclitaxel;
solution B) 0.45 ml of ethanol + 100 μl of Ultravist-37 0 + 4.5 ml of acetone (ac) + 150.0 mg of paclitaxel and then allowed to dry at room temperature overnight. The next day, one (low dose = L) or 4 additional dipping operations (high dose = H) were performed for only 5 seconds at intervals of one hour.
The content of active substance after two dips in solution (B) was on average 250 µg, after five dips in solution (B) 500 µg, in solution (A) 400 µg.
In 22 pigs, stents were applied to the left anterior or lateral coronary artery using paclitaxel coated or uncoated catheters, and the vessels were slightly dilated above normal, thereby stimulating restenosis following tissue proliferation. The animals were angiographically again after 5 weeks and the vasoconstriction seen in the angiograms was measured using an appropriate computer program.
<td>Group</td><td>Constriction (%)</td>
<td>Uncoated</td><td> 50,49</td>
<td>AcL</td><td> 20,22</td>
<td>EAH</td><td> 36,01</td>
<td>AcH</td><td> 0,86</td>
<td>P.</td><td> 0,004</td>
PL 217 416 B1
Quantitative angiography of coronary vessels 5 weeks after stent implantation using coated and uncoated catheters; stenosis = restriction of the diameter in percent around the stent placement versus the diameter measured immediately after stent implantation; mean values and statistical significance of the treatment effect.
Example 8:
Active substance content in the catheter after vasodilation and stent implantation
After the stent was implanted and removed from the animals, the balloons described in Example 8, about 3 cm in length, were separated from the catheters and placed in 1.5 ml of ethanol. The paclitaxel content was determined using HPLC. All available coated balloons and selected uncoated balloons were tested.
Coronary vessels,
3.0 x 20 mm, coating: high Ac 38 ± 4 pg (n = 4) low Ac 22 and 5 pg (n = 2) high EEE 41 (n = 1)
3.5 x 20 mm, coating: high Ac 37 ± 10 pg (n = 8) low Ac 26 ± 6 pg (n = 8) high EEE53 ± 9 pg (n = 9)
No coating (regardless of the size and area of the vessel)
0.9 ± 1.0 pg (n = 7)
From Example 6, it can be seen that at most 10% of the dose was lost before balloon tension, and about 10% of the dose was retained on the balloon.
Example 9:
Probucol was added to acetone to obtain a concentration of 100 mg / ml; the resulting solution was used to coat balloon catheters as described in the above examples.
Example 10:
Rapamycin was dissolved in diethyl ether to give a concentration of 10 mg / ml. Portions of catheters where the balloons were placed were coated as described in the examples above; after removal from the coating solution, the balloons are positioned horizontally and then continuously rotated about the longitudinal axis as soon as possible.
Example 11:
Epothilone B was dissolved in ethyl acetate to give a concentration of 2 mg / ml; the solution was used to coat balloon catheters as described in the above examples.
Contents3
99 members in 23 offices
Priority claims4
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| 10244847 | Germany | A | |
| 10244847 | Germany | A | |
| 102448477 | – | – | – |
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Numbers
- Publication
- 217416
- Publication, DOCDB
- 217416
- Publication, EPODOC
- PL217416B
- Application
- 374330
- Application, DOCDB
- 37433003
- Application, EPODOC
- PL20030374330
Titles2
- English
- MEDICAL DEVICE FOR DISPENSING MEDICAMENTS
- Polish
- Cewnik balonikowy, sposób powlekania cewnika balonikowego i zastosowanie cewnika balonikowego
Classification
- CPC, 26
- A61L29/085
- A61L29/16
- A61M25/1002
- A61L2300/41
- A61L2300/412
- A61L2300/416
- A61L2300/43
- A61M25/10
- A61M25/1027
- A61M25/1038
- A61M25/104
- A61M2025/0057
- A61M2025/1031
- A61M2025/105
- A61M2025/1075
- A61M2025/1086
- A61P29/00
- A61P35/00
- A61P39/06
- A61P9/00
- A61L31/16
- A61L27/54
- A61M2025/1004
- A61L31/08
- A61M25/0045
- A61L29/08
- IPC, 6
- A61B17 00
- A61L29 16
- A61F2 958
- A61L31 16
- A61M25 00
- A61M25 10