Medical device for dispensing medicaments

p0001The invention relates to a balloon catheter for drug delivery for the selective therapy of certain tissue sections or organ parts and to a method for the production of such drug-coated devices.

p0002Numerous diseases do not affect the whole organism at the same time, but are limited to certain tissue types, frequently also to very limited individual tissue districts or organ parts. Examples of this can be found in tumor, joint and vascular diseases.

p0003Pharmacotherapy of these diseases is generally by oral or intravenous administration of drugs which spread throughout the body and in many cases, especially in severe diseases, cause undesirable effects in healthy tissues and organs which limit the therapeutic use. A selective therapy of the diseased tissue was made by means of drugs (eg antibodies) specifically binding to diseased tissue, while maintaining the route of administration or by selective administration, for example by direct injection into the diseased tissue or by delivery via catheters to the blood vessels supplying the diseased tissue , reached. In the case of selective administration, the usually short duration of action of the drugs and the invasive routes of administration result in problems, since an arbitrarily repeated administration is prohibited. When administered selectively via the blood stream supplying the diseased tissue, there is the additional problem of insufficient extraction of the drugs during the rapid passage of the blood or active substance solution through the blood vessels.

p0004Until now, these problems have been counteracted by different pharmaceutical preparations with delayed drug release, drug-releasing implants, or for long-term, selective access routes such as implanted catheters, etc.

p0005It is already known to coat the surface of medical devices, in particular catheters, introduced into the body, with means for improving the gliding ability or for preventing blood coagulation but without a therapeutic effect.

p0006In addition, catheters are provided with special devices for injecting drugs into the arterial wall, for example, by means of needles or high injection pressure, via a perforation of the catheter wall adjacent to the vessel wall.

p0007Other principles are based on extending the contact time between the arterial wall and an active substance preparation applied via the catheter by either preventing the flow of blood for a corresponding period of time, for example a double balloon catheter with a chamber or cavities filled between the balloons and the drug solution Balloon outer wall, wherein the flow of blood through a passage passing through the balloon can be maintained to a limited extent.

p0008According to the <patcit id="pcit0001" dnum="US5102402A"><text>US 5,102,402</text></patcit> Medicaments in the form of microcapsules for the delayed release of active ingredients are loosely accommodated in preformed depressions of balloon catheters. After expansion of the balloon, the microcapsules are to be pressed into the vessel wall, remain there, and the active substance or agents are released slowly. Numerous authors also propose to apply drugs in hydrogel embedded on balloon catheters, with the function of the hydrogel remaining open as an adhesive, to improve the lubricity or delay in the release of the drugs.

p0009The disadvantage of these products is, in any case, the complex design with corresponding problems during manufacture, quality control and costs, as well as additional work steps which are a burden on the physician and the patient. A part of the methods mentioned leads to a completely unwanted vessel injury which goes beyond the intended vessel dilatation. On the other hand, any measure envisaged to extend the contact time results in an additional shortage of the downstream tissue with blood and oxygen.

p0010For the sake of completeness, reference is also made to one in the <patcit id="pcit0002" dnum="WO0124866A"><text>WO 01/24866</text></patcit> Described device for preventing restenosis, which are coated with a lipid ceramide substance derived from natural cell membranes. This substance is used for the cell walls of the arterial wall because of its affinity, which is not found in conventional drugs. In the literature, however, it is still considered that a drug prophylaxis of restenosis requires a release of the necessary active substances over days.

p0011The invention is based on the object of providing a balloon catheter for a drug delivery limited to certain tissue regions or organ parts which has a strong therapeutic effect without damaging influence on healthy tissue, the patient is only slightly stressed and can be applied and produced with little effort.

p0012According to the invention, the object is achieved with a balloon catheter designed or manufactured according to the features of claims 1 and 14. Further features and advantageous further developments of the invention result from the subclaims.

p0013By the invention, improved drug-bearing balloon catheters are provided in a simple manufacturing process, which can be used in many ways and enable an immediate release of active substance. Surprisingly and contrary to the teaching, no sustained release of active ingredient from an inert matrix (polymer, hydrogel, microcapsules, etc.) or specific chemical or physical states of the active ingredients is necessary or useful. Therefore, no expensive techniques for the production or control of depot formulations are required.

p0014The coating of balloon-containing balloons with drugs according to the present invention is of particular use in that, after the expansion of blood vessels or other cavities in the body with the balloons, there is often the need for therapeutic measures to prevent a constriction or closure of the balloon Pressurized lumens, to limit tumor growth, or to promote healing processes, including the formation of collateral cycles. This can be achieved by drugs which unfold their action in the immediate vicinity of the balloon surface. The medicaments adhere to the tissue in effective doses on the way to the target, usually through intensely perfused arteries, until the development of the balloon, and are then released in an effective dose during the short, often only second, contact time of the unfolded balloon , Which avoids the rinsing of the blood stream immediately after the deflation of the balloon.

p0015For coating, balloons of catheters according to the invention are provided, which are pressed at least for a short time with pressure against diseased tissue. Preferred catheter materials are polyamides, polyamide blends and copolymers, polyethylene terephthalate, polyethylene and copolymers, polyurethane, natural rubber and its derivatives. The length and the diameter of the areas of the catheters or balloons intended for pharmacotherapy is not critical for the application since the dosage in μg of active substance / mm² Surface is calculated. For example, balloons in the range of 2 to 4 mm in diameter and of 1.0 to 4.0 cm in length are common to the coronary dilatations. For other vessels, balloons up to> 20 mm in diameter and lengths up to> 10 cm can also be used. The surfaces to be coated can be smooth (ie without a special structure for absorbing the active ingredients), roughened or provided with structures in any desired manner, special surface structures being not a prerequisite for the adhesion of the active ingredients, but also not hindering the adhesion. The adhesion of the active ingredients to the balloon surfaces is effected exclusively by the choice of suitable solvents and, if appropriate, the additives influencing the adhesion. It is surprisingly solid even on externally completely smooth balloon surfaces.

p0016All surfaces may additionally be coated with substances which improve the lubricity of the products, prevent the coagulation of blood on the surface, or improve other properties of the medical products without the materials used for the coating having to be delivered to the environment and without The coating substantially restricts the release of the active ingredients for the treatment of the target tissues and thus the effectiveness.

p0017Balloon catheters are formed from very thin plastic tubing by widening a segment of 1 to about 10 cm in length. The widened, very thin-walled balloon membrane is then placed in several folds arranged along the catheter axis and wound tightly around the catheter axis so that the widened area in the folded state has only a minimally larger diameter than the rest of the catheter. The close folding of the balloon envelope is a prerequisite for the problem-free passage of the balloon catheter through introductory sluices, guide catheters and, for example, severely constricted sections of blood vessels.

p0018The balloons of catheters are coated in the folded state, in which case an intact, sufficiently uniform coating of the surface is achieved, and the active substances also adhere sufficiently firmly to the surface during the folding of a balloon catheter coated in the unfolded state.

p0019The manufacture of a balloon coated in unfolded state is carried out in accordance with the prior art without impairing the coating, for example, by the use of balloon sheaths with preformed folds and bends, the structure of which is not lost in the material by stretching and which after pressure release from the balloon, That the balloon sheath once again folds at least loosely, without the need for an external force as the primary cause. Only then are the preformed folds compressed from the outside or by vacuum. In no case, wrinkles are required to hold the active ingredient. Furthermore, the folding can be effected by low mechanical forces by means of very smooth materials, wherein the tools can also be wetted, for example, with slippery biocompatible liquids in which the active ingredients do not dissolve or do not dissolve well.

p0020According to a further variant of the invention, the balloons of ready-folded balloon catheters are coated by dipping into low-viscosity active substance solutions. Solvents and active substances penetrate between the extremely narrow folds and form a surprisingly even and reproducible coating which is not damaged by any further step. The externally adhering solution or the coating adhering to the outside after drying of the solvent can be left there or removed in a further working step so that only the active substance concealed by the folds of the balloon is retained.

p0021After the coating, a stent can be pushed onto the balloon catheter and pressed onto the balloon catheter when the balloon is folded. Only sterilization, for example by means of ethylene oxide, is then required.

p0022The thus designed operation is extremely simple, little susceptible to faults and also with mechanically, chemically and physically sensitive coating materials. It has been shown that the coating does not lead to undesirable loosening or adhesive bonding of the fold according to this method, and that the active substance applied in this manner adheres firmly enough not to be abraded on the way through the blood, and on the other hand when the balloon is inflated in the target tissue Active ingredient.

p0023Suitable medicaments are highly lipophilic, largely water-insoluble, highly effective drugs which bind to any tissue constituents. Lipophilic drugs are those whose distribution coefficient is butanol: aqueous buffer pH 7 = 0.5, preferably 1 and more preferably 5 or octanol: aqueous buffer pH 7 = 1, preferably 10, more preferably> 50. As an alternative or in addition, the medicaments should be reversibly and / or irreversibly bound to cell components by> 10%, preferably> 50%, particularly preferably> 80%. Preferred substances are substances for inhibiting cell proliferation or else inflammatory processes or antioxidants such as paclitaxel and other taxanes, rapamycin and related substances, tacrolimus and related substances, corticoids, sex hormones (estrogen, estradiol, antiandrogens) and related substances, statins, epothilones, probucol, prostacycline , Angiogenesis inductors, etc.

p0024The substances are preferably present as a dry solid substance or as an oil on the surfaces of the different medical products. Preference is given to particles of the smallest size (in the majority &lt;5 μm, preferably &lt;1 μm, particularly preferably &lt;0.1 μm). Particularly preferred are amorphous, noncrystalline structures of very fine particle size Drugs rapidly dissolve and do not function as microcapsules, ie spontaneously and rapidly dissolve. It is sufficient that an effective dose is in the form of small or amorphous particles; Although larger particles do not contribute to the concentration of active substance in the tissue, but do not interfere with it. The dosage depends on the desired effect and the effectiveness of the medicament used. It can be up to 5 μg / mm² Which is not an upper limit. Lower dosages are easier to implement.

p0025Good adhesion to the surfaces of the catheters, needles, or wires to improve the uptake into the tissues is achieved by embedding highly lipophilic, poorly water-soluble active ingredients in a slightly water-soluble matrix substance. As matrix substances, low molecular weight (molecular weight &lt;5000 D, preferably &lt;2000 D) are hydrophilic substances such as contrast agents and dyes used in vivo for different diagnostic methods in medicine, sugars and related substances such as sugar alcohols, low molecular weight polyethylene glycols, biocompatible organic and inorganic salts, For example, benzoates, salts and other derivatives of salicylic acid, etc. For contrast, reference is made to the iodinated x-ray contrast media and the paramagnetic chelates. Examples of dyes are indocyanine green, fluorescein and methylene blue. Auxiliaries can also serve to improve the shelf life of the products, cause specific complementary pharmacological effects or serve for quality control.

p0026In a further embodiment, the pharmaceutical active ingredients can be adsorbed onto particles or applied to the surfaces of suitable medical products by means of a low-molecular-weight matrix. As particles are again suitable biocompatible diagnostic agents such as ferrites and various contrast agents for sonography.

p0027Auxiliaries of all types can be used at a lower or higher dose than the active ingredients.

p0028The coating of the balloon catheters is carried out by means of solutions, suspensions or emulsions of the said drugs and excipients. Suitable solution suspending or emulsion media are, for example, ethanol, isopropanol, ethyl acetate, diethyl ether, acetone, dimethylsulfoxide, dimethylformamide, glycerol, water or mixtures thereof. The selection of the solvents follows according to the solubility of the active ingredients and additives as well as the wetting of the surfaces to be coated and the effect on the structure of the coating and particles remaining after evaporation of the solvents, their adhesion to the surface and the transfer of active substance into the tissue during very short contact times .

p0029The application can be carried out, for example, by dipping, brushing, application by means of volume measuring devices or spraying, in each case at different temperatures and, if appropriate, steam saturations of the solvents in the atmosphere. The process can be repeated several times, if appropriate also using various solvents and auxiliaries.

p0030The balloons of prefolded balloon catheters can be controlled in a dose-controllable manner by dipping into active substance-containing solutions or other measures astonishingly uniformly, reproducibly, without affecting the function of the catheters. In the case of repeated dipping in unsaturated drug solutions, contrary to expectations, not a complete detachment of the previously applied active ingredient but a reproducible increase in the active substance content of the balloons occurs.

p0031Excess solution or excess, externally adherent substances from the coating solution can be removed by simple methods without impairing the effectiveness of the coating.

p0032The balloon catheters of different types according to the invention are manufactured and produced in a short time, ie, in contact with the tissue for seconds, minutes or a few hours. In some cases, it is desirable to treat the tissue in the immediate vicinity of the medicinal product by pharmacological treatment, for example, to prevent over-growth in response to injury or to reduce tumor growth, or to promote the infiltration of blood vessels or to reduce inflammatory responses. In all of these cases, a high local drug concentration can be achieved for an astonishingly long time by the method described above. A major advantage is the extraordinary variety of possible applications of the described products and processes.

p0033A preferred application is the reduction of the hyperproliferation of the vessel walls induced by vessel dilatation by means of balloon catheters. This can be achieved in the area of ​​implanted vascular supports (stents), if desired, by coating the stents with drugs, but only in the vessel region directly covered by the stent. The coated balloon catheters also treat the areas requiring treatment shortly before and just behind the stent, they can treat the area within existing stents without re-implanting the stent, or vessels into which a stent is not intended to be implanted. Advantageously compared to the stent releasing drug over a long period of time, the better healing is accompanied by a good inhibition of hyperproliferation and the lower risk of thrombosis.

p0034In the following, several embodiments of the invention are described with the example of the coating of balloon catheters as well as with regard to the adhesion of the coating in the blood, the restenosis inhibition and the active substance content of the catheters.

Example 1:

Coating an expanded balloon catheter with paclitaxel in ethyl acetate

p0035Balloon catheters from the company BMT, Oberpfaffenhofen / Munich, Germany, with the designation Jokerlite, balloon size 2.5 mm × 20 mm, are filled after maximal expansion for 1 min. Over the entire length of the balloon in ethyl acetate, 18.8 mg paclitaxel / ml, + 1% pharmaceutical olive oil, dipped, dried:<ul><li>Paclitaxel content 39 μg (after extraction with ethanol, HPLC).</li></ul>

Example 2:

Coating a folded balloon catheter with paclitaxel in ethyl acetate

p0036Balloon catheters of the company BMT, Oberpfaffenhofen / Munich, Germany, with the designation Jokerlite, balloon size 2.5 mm × 20 mm, are folded in the folded state for 1 min. Over the entire length of the balloon in ethyl acetate, 18.8 mg paclitaxel / ml, + 1% pharmaceutical olive oil, dipped, dried: Paclitaxel content 69 μg.

Example 3:

Coating a folded balloon catheter with paclitaxel in ethyl acetate

p0037<ul><li>A) balloon catheters of the company BMT, Oberpfaffenhofen / Munich, Germany with the designation Jokerlite, balloon size 2.5 mm x 20 mm, are folded in the folded state for 1 min. Over the entire length of the balloon in ethyl acetate, 16.6 mg paclitaxel / ml, dipped, dried for 4 h: paclitaxel content 54 μg</li><li>B) Immediately, but still 2 times 5 seconds with 1 h drying time after each immersion in Solution A (= 3.33 ml ethyl acetate + 100.0 mg paclitaxel): paclitaxel content 126 μg</li><li>C) Immediately, however, immersed in the same solution after each dipping operation in the same solution, 4 times 5 seconds with 1 h of drying time: Paclitaxel content 158 ​​μg</li></ul>

Example 4:

Coating a balloon catheter with paclitaxel in acetone

p0038Dissolve 350 mg paclitaxel in 9.0 ml acetone; Balloon catheters from the company BMT, Oberpfaffenhofen / Munich, Germany with the designation Jokerlite, balloon size 2.5 mm × 20 mm, are used in the maximally expanded state for 1 min. Over the entire length of the balloon, the solvent is dried at room temperature for 12 h. Thereafter, the balloon is deflated and unfolded with a PTFE-coated tool in the usual way. Optionally, a stent of suitable size can be trimmed to the balloon: 29 μg paclitaxel on the balloon.

Example 5:

Coating a balloon catheter with paclitaxel in acetone

p0039<ol><li>A) Diving folded balloon catheters from BMT, named Allegro, balloon size 2.5 x 20 mm into a mixture of 0.15 ml ethanol + 4.5 μl Ultravist 300 (X-ray contrast medium from Schering AG, Berlin, Germany) + 1.35 ml acetone + 0.8 mg Sudanrot + 30.0 mg Paclitaxel: The folded balloon sections of the catheters are immersed 5 times, the first time for 1 minute, then 3 hours of drying time, then 4 times for 5 seconds each at intervals of 1 hour; After which a stent was crimped and the catheter was sterilized with stent in conventional manner with ethylene oxide: paclitaxel content 172 μg, no HPLC detectable decomposition products of the active ingredient</li><li>B) Instead of Ultravist 300, a saturated aqueous mannitol solution is added</li><li>C) A saturated aqueous sodium salicylate solution, pH 7.5, is added instead of Ultravist 300.</li><li>D) 5 mg acetylsalicylic acid is added to the finished solution according to (5a).</li><li>E) 5 mg of glycerol are added to the final solution according to (5a)</li></ol>

Example 6:

Adhesion of the active substance in blood

p004012 balloon catheters from BMT, designated Allegro, balloon size 2.5 × 20 mm, were used. In each case 6 pieces of the folded balloon sections of the catheters were immersed in [0.15 ml of ethanol + 4.5 μl of Ultravist 300 + 1.35 ml of acetone + 0.8 mg of Sudanrot + 30.0 mg Paclitaxel] or in [1.5 ml of ethyl acetate + 0.8 mg of Sudanrot + 31.0 mg of paclitaxel] 5 × , The first time for 1 minute, then 3 hours of drying time, then 4 times for 5 seconds each at intervals of 1 hour; Then 3 folded balloons of each series were easily agitated in 50 ml of human blood for 5 min at 37 ° C. and then taken for analysis of the paclitaxel content: reduction of mean values ​​(n = 3 per coating method) by 5 minutes of movement in blood compared to each 3 control catheters not incubated in blood.<tables id="tabl0001" num="0001"><table frame="none"><tgroup cols="2" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="22mm" /><colspec colnum="2" colname="col2" colwidth="12mm" /><tbody><row><entry>Acetone:</entry><entry>12%</entry></row><row><entry>ethyl acetate:</entry><entry>10%</entry></row></tbody></tgroup></table></tables>

Example 7:

Examination of restenosis inhibition after angioplasty and stent implantation on the coronaries of pigs

p0041Folded balloon catheters of the firm BMT Type Jokerlite, BMT 3.5 x 20 mm or 3.0 x 20 mm were used either in<ul><li>Solution A) 3.33 ml ethyl acetate (EA) + 100.0 mg paclitaxel or in</li><li>Solution B) 0.45 ml ethanol + 100 μl Ultravist-370 + 4.5 ml acetone (Ac) + 150.0 mg paclitaxel</li></ul>Dipped for 1 min and dried overnight at room temperature. A further (low dose = L) or 4 additional (high dose = H) dipping operations were carried out only for 5 seconds on the next day at intervals of 1 h.

p0042Active ingredient content after immersion twice in solution (B) on average 250 μg, with 5 times dipping in solution (B) 500 μg, in solution (A) 400 μg.

p0043A total of 22 pigs were implanted into the left front wall or side wall coronary artery by means of the paclitaxel-coated catheters or by means of uncoated catheter stents, the vessels being slightly overstressed for stimulation of restenosis by tissue hyperplasia. After 5 weeks, the animals were re-angiographed and the degree of vessel narrowing on the angiograms was measured with an automatic computer program.<tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="26mm" /><colspec colnum="2" colname="col2" colwidth="22mm" /><thead><row><entry valign="top">group</entry><entry valign="top">Stenosis (%)</entry></row></thead><tbody><row><entry>Uncoated</entry><entry>50.49</entry></row><row><entry>AcL</entry><entry>20.22</entry></row><row><entry>EAH</entry><entry>36.01</entry></row><row><entry>Oh</entry><entry>0.86</entry></row><row><entry>p</entry><entry>.004</entry></row></tbody></tgroup></table></tables>

p0044Quantitative coronary angiography 5 weeks after stent implantation with uncoated and coated catheters; Stenosis = percentage reduction of the lumbar diameter in the area of ​​the stent compared to the lumbar diameter immediately after stent implantation Mean value and statistical significance of the treatment effect.

Example 8:

Drug content of the catheters after vascular dilatation and stent implantation

p0045The balloons from Example 8 were separated from the balloon catheters after stenting and removal from the animals for about 3 cm length and transferred into 1.5 ml of ethanol. The paclitaxel content was determined by HPLC. All available coated balloons and a selection of uncoated balloons were examined.

Coronary,

p0046<tables id="tabl0003" num="0003"><table frame="none"><tgroup cols="3" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="48mm" /><colspec colnum="2" colname="col2" colwidth="20mm" /><colspec colnum="3" colname="col3" colwidth="30mm" /><tbody><row><entry>3.0 x 20 mm, coating:</entry><entry>Ac high</entry><entry>38 ± 4 μg (n = 4)</entry></row><row><entry>Ac low</entry><entry>22 ± 5 μg (n = 2)</entry></row><row><entry>EEE high</entry><entry>41 (n = 1)</entry></row><row><entry>3.5 x 20 mm, coating:</entry><entry>Ac high</entry><entry>37 ± 10 μg (n = 8)</entry></row><row><entry>Ac low</entry><entry>26 ± 6 μg (n = 8)</entry></row><row><entry>EEE high</entry><entry>53 ± 9 μg (n = 9)</entry></row><row><entry namest="col1" nameend="col3" align="left">Uncoated (independent of size and vascular area)</entry></row><row><entry>0.9 ± 1.0 μg (n = 7)</entry></row></tbody></tgroup></table></tables>

p0047From Example 6, a maximum of 10% of the dose is lost before the balloon is expanded and about 10% of the dose remains on the balloon.

Example 9:

p0048Probucol is introduced into acetone at a concentration of 100 mg / ml; The solution is used to coat the balloon catheters as described in the preceding examples.

Example 10:

p0049Rapamycin is dissolved in diethyl ether at a concentration of 10 mg / ml. The coating of the balloon portions of the catheters is performed as described in the preceding examples; After removal from the coating solution, the balloons should be aligned horizontally as far as possible and rotated constantly about their longitudinal axis.

Example 11:

p0050Epothilone B is dissolved in ethyl acetate at a concentration of 2 mg / ml; The solution is used to coat the balloon catheters as described in the preceding examples.