HK1147216A - Medical device for dispensing medicaments - Google Patents

Description

The invention relates to a medical device for the delivery of medicinal products for the selective therapy of certain tissue sections or parts of organs and a process for the manufacture of such medicinal product coated devices.

Many diseases do not affect the whole organism at the same time but are limited to certain tissue types, often to very limited individual tissue areas or organ parts.

The pharmacotherapy of these diseases is generally carried out by oral or intravenous administration of drugs that are distributed throughout the body and in many cases, especially in severe diseases, cause undesirable effects in healthy tissues and organs that limit therapeutic use. Selective therapy of diseased tissues has been achieved by means of specifically diseased tissue-binding drugs (e.g. antibodies) while maintaining the application pathway or by selective administration, e.g. by direct injection into diseased tissues or by supply via catheters to the diseased tissue-carrying blood vessels.

These problems have been addressed so far by various delayed-release pharmaceutical preparations, drug-releasing implants or selective access routes such as implanted catheters, etc.

It is already known that the surface of medical devices, especially catheters, placed in the body is coated with substances which improve the buoyancy or prevent blood clotting, but without therapeutic effect.

In addition, catheters are equipped with special devices to inject medicinal products into the artery wall, for example, by needles or high injection pressure through a perforation of the wall of the catheter adjacent to the vessel wall.

Other principles are based on extending the contact time between the artery wall and a catheter-applied active substance by either cutting off the blood flow for an appropriate period, e.g. double balloon catheters with chambers between the balloons filled with the medicinal solution or cavities between the e.g. bulbous outer wall, with a limited maintenance of blood flow through a channel passing through the balloon.

Under US 5 102 402, medicinal products in the form of microcapsules for delayed release are loosely placed in preformed recesses of balloon catheters. After the balloon expands, the microcapsules are to be pushed into the vessel wall, remain there and slowly release the active substance or substances.

The disadvantage of the products mentioned is in each case the complexity of their construction, with its problems of manufacture, quality control and costs, and the additional work steps involved in their use, which are burdensome for the doctor and the patient.

For completeness, reference is made to a device for the prevention of restenosis described in WO 01/24866, coated with a lipid ceramide substance derived from natural cell membranes, which is used because of its affinity for the cell walls of the artery wall, which is not found in common medicinal products.

The purpose of the invention is to provide a device for the delivery of medicinal products limited to certain areas of tissue or organ parts, which has a strong therapeutic effect without harmful effects on healthy tissue, which is of low patient load and which can be used and manufactured with little effort.

The present invention is solved by a device designed or manufactured in accordance with the characteristics of claims 1 and 15.

The invention provides, in a simple manufacturing process, improved drug-carrying balloon catheters or similar medical devices that are versatile and allow immediate drug release.Surprisingly, and contrary to popular belief, no continuous drug release from an inert matrix (polymer, hydrogel, microcapsules, etc.) or special chemical or physical states of the active substances are required or useful.Therefore, no elaborate techniques are required for the production or control of depot formulations.

Coating balloons on catheters with drugs of the present invention is particularly useful in that, after enlarging blood vessels or other cavities in the body with the balloons, therapeutic measures are often required to prevent narrowing or closing of the lumen pressurized with the balloon, limit tumor growth, or promote healing processes including collateral circuits. This can be achieved by means of devices that close their action in the immediate vicinity of the balloon surface. The drugs adhere to the target - usually through heavily bloodied arteries - until the balloon is unfolded, then only for a short time, often for a continuous period of time, while the blood is removed from the balloon immediately after contact with the deflated blood stream and the drug is released by a deflation of the balloon.

The coating is provided for wires, such as those used to guide catheters, needles and catheters or parts of catheters, which are pressed against diseased tissues with pressure for at least a short time. The preferred catheter materials are polyamides, polyamide-mixtures and copolymers, polyethylene terephthalate, polyethylene and copolymers, polyurethane, natural rubber and derivatives. The length and diameter of the areas intended for the pharmaceutical surface of the catheter or balloon is not relevant for the application, as the dosage is calculated in μg surface area/2 surface area. However, for example, the coronal surface is suitable for the balloon with a diameter of up to 2 mm. The diameter of the balloon is up to 4 mm. The length of the balloon is 1.0-4 mm. The structure of the balloon can be determined entirely by the size of the surface and the size of the balloon itself (if applicable) and can not be used for the specific application of the balloon.

All surfaces may additionally have been or will be coated with substances that improve the viscosity of the products, prevent blood clotting on the surface or improve other properties of the medical devices, without the materials used for coating needing to be released into the environment and without the coating significantly restricting the release of the active substances to treat the target tissues and thus the efficacy.

Balloon catheters are formed from very thin plastic tubes by dilating a segment from 1 to about 10 cm in length. The enlarged, very thin-walled balloon membrane is then placed in several folds along the catheter axis and tightly wrapped around the catheter axis so that the enlarged area in the folded state has a diameter only minimally larger than the rest of the catheter.

The balloons of catheters may be coated in the folded and unfolded state, in any case ensuring an intact, sufficiently uniform coating of the surface and the active substances adhere sufficiently firmly to the surface of the unfolded coated balloon catheter.

The manufacture of a balloon coated in an unfolded state is carried out without affecting the coating, for example by using balloon shells with preformed folds and bends, whose structure in the material is not lost by expansion and which, after the pressure is released from the balloon, cause the balloon shell to fold back at least loosely without the need for an external force as a primary cause. Only after that, the preformed folds are compressed from the outside or by vacuum. In no case are folds necessary to retain the active substance. Furthermore, the folding can be affected by small mechanical forces by means of very smooth materials, whereby the tools can also be used, for example, with biocompatible fluids or in which we cannot dissolve well in any case.

According to another variant of the invention, the balloons of the finished folded balloon catheter are coated by immersion in low viscous active substance solutions, whereby the solvent and active substance penetrate between the extremely narrow folds and form a surprisingly uniform and dose-reproducible coating, which is not damaged by any further operation. The external adhesive solution or the external adhesive coating can be left there or removed in a further operation, so that only the active substance covered by the folds of the balloon remains.

After coating, a stent can be pushed onto the balloon catheter and pressed onto it, after which sterilization, e.g. with ethylene oxide, is required.

The procedure is extremely simple, has little interference and can be carried out with mechanically, chemically and physically sensitive coating materials.It has been shown that the coating procedure does not lead to undesirable loosening or adhesion of the fold and that the active substance applied in this way adheres firmly enough to prevent it from being worn away by the bloodstream, while the inflation of the balloon in the target tissue releases the active substance to a large extent.

The term 'lipophilic' refers to medicinal products with a coefficient of distribution of butanol: water buffer pH 7 = 0.5, preferably = 1 and particularly preferably = 5, and octanol: water buffer pH 7 = 1, preferably = 10, particularly preferably > 50. Alternatively or additionally, the drugs are intended to bind > 10%, preferably > 50%, and particularly > 80% irreversibly and/or irreversibly to the cell component.

The substances are preferably in the form of dry solids or oils on the surfaces of the various medical devices. Preference is given to particles of the smallest size (mostly < 5 μm, preferably < 1 μm, preferably < 0.1 μm), and in particular to amorphous, non-crystalline structures of the finest particle size which, due to their large surface area, dissolve rapidly in contact with tissue and do not act as microcapsules, i.e. dissolve spontaneously and rapidly.

Good adhesion to the surfaces of catheters, needles or wires in improving absorption into tissues is achieved by embedding highly lipophilic, poorly water-soluble active substances in a readily water-soluble matrix substance. As matrix substances, low molecular weight (molecular weight < 5000 D, preferably < 2000 D) hydrophilic substances such as contrast agents and dyes used in vivo for various diagnostic procedures in medicine, sugars and related substances such as sugar alcohols, low molecular weight polyethylene glycols, biocompatible organic and inorganic salts such as benzoates, salts and other derivatives of salicylic acid, etc. are suitable.

In another version, the pharmaceutical active substances can be adsorbed to particles or applied with a low molecular weight matrix to the surfaces of suitable medical devices.

Excipients of all kinds may be used at lower or higher doses than the active substances.

The coating of the medical devices shall be by means of solutions, suspensions or emulsions of the said medicinal products and excipients. Suitable media for the coating or emulsion are, for example, ethanol, isopropanol, ethyl acetate, diethyl ether, acetone, dimethyl sulfoxide, dimethyl formamide, glycerin, water or mixtures thereof. The choice of the solvents shall be based on the solubility of the active substances and additives and the benignity of the surfaces to be coated and the effect on the structure of the coating and particles remaining after evaporation of the solvent, their adhesion to the surface and the transfer of the active substance to the tissues in contact during very short periods.

The application may be carried out, for example, by dipping, coating, application by volume measuring devices or spraying at different temperatures and, where appropriate, vapour saturations of the solvents in the atmosphere.

The balloons of the pre-folded balloon catheters can be coated with a remarkably uniform, reproducible, dose-controlled coating by immersion in active solutions or other measures without affecting the function of the catheters.

Excess solution or excess loosely adhering substances from the coating solution can be removed by simple methods without affecting the effectiveness of the coating.

The medical devices of different types designed and manufactured in accordance with the invention come into contact with the tissue for a short time, i.e. for seconds, minutes or a few hours. In some cases it is desirable to treat the tissue in the immediate vicinity of the medical device pharmacologically, for example to prevent overgrowth in response to injury or to reduce tumor growth or to promote the puncturing of blood vessels or to reduce inflammatory reactions. In all these cases, the above procedure can achieve a high local drug concentration for an astonishingly long time. One major advantage is the exceptional variety of applications of the products and procedures described.

A preferred application is to reduce hyperproliferation of the vascular walls induced by vascular dilation by means of balloon catheters. This is also achieved in the area of implanted vascular supports (stents) if necessary by coating the stents with medicinal products, but only in the vascular area immediately covered by the stent.

Several embodiments of the invention are described below, using the example of the coating of balloon catheters, and with respect to the adhesion of the coating in the blood, the inhibition of residues and the active substance content of the catheters.

Example 1:

Coating of an expanded balloon catheter with paclitaxel in ethyl acetate

Balloon catheters from Fa. BMT, Oberpfaffenhofen/ Munich, Germany, named Joker Lite, balloon size 2.5 mm x 20 mm, after maximum expansion for 1 min over the entire length of the balloon, are immersed in ethyl acetate, 18.8 mg paclitaxel/ ml, + 1% pharmaceutical olive oil, dried: Paclitaxel content 39 μg (after extraction with ethanol, HPLC).

Example 2:

Coating of a folded balloon catheter with paclitaxel in ethyl acetate Balloon catheters from Fa. BMT, Oberpfaffenhofen/ Munich, Germany, named Joker Lite, balloon size 2.5 mm x 20 mm, are folded and dipped for 1 min over the entire length of the balloon in ethyl acetate, 18.8 mg paclitaxel/ ml, + 1% pharmaceutical olive oil, dried: paclitaxel content 69 μg.

Example 3:

Coating of a folded balloon catheter with paclitaxel in ethyl acetate (a) The balloon catheter of the Fa. BMT, Oberpfaffenhofen/ Munich, Germany, named Joker Lite, balloon size 2.5 mm x 20 mm, is immersed in ethyl acetate, 16.6 mg paclitaxel/ ml, for 1 min. over the entire length of the balloon, in the folded state, and dried for 4 h: paclitaxel content 54 μ g) Similarly but 2 times 5 sec. with 1 hour drying time after each immersion in solution A (= 3.33 ml ethyl acetate + 100.0 mg paclitaxel): paclitaxel content 126 μ gc) Similarly but 4 times 5 sec. with 1 h with each immersion in the same solution: paclitaxel 158 μ g

Example 4:

Coating a balloon catheter with paclitaxel in acetone 350 mg paclitaxel is dissolved in 9.0 ml acetone; balloon catheter from Fa. BMT, Oberpfaffenhofen/ Munich, Germany, named Joker Lite, balloon size 2.5 mm x 20 mm, is immersed in the maximum expanded state for 1 min over the entire length of the balloon, withdrawn, the solvent is dried at room temperature for 12 h.

Example 5:

Coating a balloon catheter with paclitaxel in acetone (a) Dip folded balloon catheters of the Fa. BMT designation Allegro, balloon size 2.5 x 20 mm in a mixture of 0.15 ml ethanol + 4.5 μl Ultravist 300 (X-ray contrast agent from Schering AG, Berlin, Germany) + 1.35 ml acetone + 0.8 mg of Sudan red + 30.0 mg of paclitaxel: The folded balloon sections of the catheters are immersed 5 times, first for 1 minute, then 3 hours drying time, then 4 times for 5 sec each, 1 hour apart; then a stent is crimped and the catheter with stent is sterilised in the usual way with ethylene oxide: paclitaxel content 172 μg, no HPLC detectable degradation products of the active substance (b) a saturated aqueous mannitol solution is added instead of Ultravist 300c) a saturated aqueous sodium salicylate solution, pH 7.5, is added instead of Ultravist 300d) 5 mg acetylsalicylic acid is added to the solution after (5a) 5 mg Glycerin is added to the solution (5a)

Example 6: Adhesion of the active substance to blood

12 balloon catheters of Fa. BMT, named Allegro, balloon size 2.5 x 20 mm, were used. Each of the 6 folded balloon sections of the catheters were either dipped in [0.15 ml ethanol + 4.5 μ l Ultravist 300 + 1.35 ml acetone + 0.8 mg Sudanrot + 30.0 mg paclitaxel] or in [1.5 ml ethyl acetate + 0.8 mg Sudanrot + 31.0 mg paclitaxel] 5 x, first for 1 minute, then 3 h drying time, then 4 times for 5 sec each at 1 h interval; then each of the 3 folded balloons were lightly moved in a series of 50 ml Human blood for 5 min at 37 °C and then incubated for 3 minutes in a control blood treatment, not in the control blood, to analyse the Paclitaxel-containing blood sample: the mean values (n=3 by weight) were obtained in 5 minutes. Other

Aceton:	12 %
Ethylacetat:	10 %

Example 7:

Testing of restenosis inhibition following angioplasty and stent implantation in the coronary arteries of pigs

Folded balloon catheters of the type Joker Lite, BMT 3.5 x 20 mm or BMT 3.0 x 20 mm were used in either The following information is provided in the Annex to this Regulation: The test chemical was immersed in water for 1 min and dried overnight at room temperature, followed by a further (low dose = L) and 4 (high dose = H) dips, each for only 5 seconds, at intervals of 1 h on the following day.

The active substance content after 2 malignant dips in solution (B) is on average 250 μg, after 5 malignant dips in solution (B) 500 μg, in solution (A) 400 μg.

A total of 22 pigs were implanted into the left anterior or lateral coronary artery by means of either the paclitaxel-coated catheters or uncoated catheters, with the vessels slightly stretched to stimulate restenosis by tissue hyperplasia.

Quantitative coronary angiography 5 weeks after stent implantation with uncoated and coated catheters; stenosis = percentage reduction in lumen diameter in the stent area compared to lumen diameter immediately after stent implantation mean and statistical significance of treatment effect.

Example 8:

The active substance content of the catheters after vasodilation and stenting

The balloons from example 8 were removed from the balloon catheters after stenting and removal from the animals to a length of approximately 3 cm and transferred to 1.5 ml of ethanol.

Coronary artery

3.0 x 20 mm, Beschichtung:	Ac hoch	38 ± 4 µg (n=4)
Ac niedrig	22 ± 5 µg (n=2)
EEE hoch	41 (n=1)
3.5 x 20 mm, Beschichtung:	Ac hoch	37 ±10 µg (n=8)
Ac niedrig	26 ± 6 µg (n=8)
EEE hoch	53 ± 9 µg (n=9)
Unbeschichtet (unabhängig von Größe und Gefäßgebiet)
0.9 ± 1.0 µg (n=7)

Example 6 shows that a maximum of 10% of the dose is lost before the balloon expands and approximately 10% of the dose remains on the balloon.

Example 9:

Probucol is injected into acetone at a concentration of 100 mg/ ml and the solution is used to coat the balloon catheters as described in the previous examples.

Example 10:

The balloon portions of the catheters are coated as described in the previous examples, and the balloons should be positioned horizontally as soon as possible after removal from the coating solution and rotated continuously along their longitudinal axis.

Example 11:

Epothilone B is dissolved in ethyl acetate at a concentration of 2 mg/ ml and used as described in the previous examples to coat the balloon catheters.

The following items are also part of the invention: 1. a medical device for the selective administration of medicinal products for the treatment of certain diseased tissue or organ parts, characterised by the presence on the surface of devices which, at least briefly, come into contact with diseased tissue under pressure with lipophilic, largely insoluble, binding medicinal products to any tissue component and which release their active substance immediately after tissue contact.2. a device referred to in point 1 characterised by the presence of balloon catheters without or in conjunction with stents, catheters and/or parts thereof, needles and conductors and stents.3. a device referred to in point 2 characterised by the presence of a coating of medicinal products with a balloon shape,The device referred to in point 2 is characterised by the fact that the balloons are made of a very smooth material on which the medicinal products adhere well enough to withstand the forces necessary for their application, essentially intact.5. The device referred to in point 2 is characterised by the fact that, in the finished folded state, it is provided with balloons coated by immersion in a low viscosity active substance solution.6. The device referred to in one of the points 2 to 5 is characterised by the fact that only the area covered by the folds is covered by the medicinal product carried after application.7. The device referred to in point 1 is characterised by the fact that the lipophilic substances are pro-inflammatory or anti-inflammatory agents.Device described in section 7 is characterised by the presence of the lipophilic medicinal products as dry solids or oils on the surface of the product concerned.Device described in claim 9 is characterised by the presence of amorphous structures in the dose of the medicinal products in a particle size of between 0,1 μm and 5 μm, which, despite their high solubility in water, are rapidly dissolved in solution.The device described in paragraph 1 is characterised by the incorporation of the lipophilic medicinal products into a matrix substance which is readily soluble in water and which is incorporated into the device surface to achieve good adhesion to the device surface and to improve tissue uptake.12 The device described in paragraph 11 is characterised by the fact that the matrix substance is composed of a low molecular weight hydrophilic substance with a molecular weight < 5000 D.13. The device described in paragraph 1 is characterised by the fact that the lipophilic medicinal products are either absorbed in particles or applied to the surface of the device with a low molecular weight matrix.14. The device described in paragraph 1 is characterised by the fact that the surfaces are additionally coated with substances intended to influence certain properties, such as the device's ability to reduce the blood pressure or to reduce blood flow.The method described in paragraph 15 is characterised by the coating process, which is repeatedly performed in order to reproducibly increase the active substance content with the same or different solution, suspension or emulsion media and/or excipients, in a solvent, suspension or emulsion medium, by immersion, smearing, spraying or by means of a volume measuring device on the surface of the device, removing excess media and loosely adhering substances.18. procedure in one of the points 15 to 17 characterised by the use of bulbs, which are largely ready for application, coated with or without applied stent before or after sterilisation.19. procedure in point 18 characterised by coating the bulbs with the relevant lipophilic medicinal products in the unfolded state and the folding of the bulbs with a particularly flexible tool, where appropriate moistened with biocompatible lubricants.20. procedure in point 15 characterised by the installation of stents connected to a balloon catheter before or after a coating procedure.21. procedure in point 15 characterised by the coating of the finished device with ethylene oxide.22. use of medical devices designed and manufactured in accordance with points 1 to 21 for the treatment of vascular disease or circulatory disorders.

Claims (21)

1. Balloon delivery catheters for the selective therapy of certain diseased tissue or organ parts, characterised by the presence on the surface of the balloon of lipophile, largely water-insoluble, free-binding medicinal products with immediate release of active substance after at least brief pressure contact with diseased tissue, the medicinal products being paclitaxel and other taxanes, rapamycin and related substances, tacrolimus and related substances, corticosteroids, sex hormones, estradiol, androgen and related substances, anti-cyclics, epos, statin, proticolol, prostaglandins or angioedema.
2. Balloon catheters as described in claim 1, characterised by the fact that the balloon catheter is provided without or in conjunction with stents, catheters and/or parts thereof, needles and guide wires and stents.
3. Balloon catheter according to claim 2, characterised by the fact that the balloon is designed to be coated with the drug with preformed longitudinal folds, the tendency of which to fold back is not lost by stretching.
4. Balloon catheter according to claim 2, characterised by the fact that the balloon is made of a very smooth material on which the medicinal products adhere well enough to withstand the forces necessary for the application, essentially intact.
5. Balloon catheter according to claim 2, characterised by the finished folded balloon being coated by immersion in a low viscosity active substance solution.
6. Balloon catheter according to one of claims 2 to 5, characterised by only the area covered by the wrinkles being covered with the medicinal product dried after application.
7. Balloon catheters as claimed 1, characterised by the presence of the lipophilic medicinal products as dry solids or oils on the surface of the product concerned.
8. Balloon catheters as claimed 1, characterised by the effective dose of the medicinal products comprising amorphous structures with a particle size between < 0,1 μm and 5 μm which, due to their large surface area, dissolve rapidly despite low water solubility of the active substances.
9. Balloon catheters as claimed 1, characterised by the incorporation of the lipophilic medicinal products into a readily water-soluble matrix substance to achieve good adhesion to the surface of the balloon and to improve tissue uptake.
10. Balloon catheter according to claim 9, characterised by the matrix substance being a low molecular weight hydrophilic substance with a molecular weight < 5000 D.
11. Balloon catheter according to claim 1, characterised by the absorption of the lipophilic medicinal products in particles or by application of a low molecular weight matrix to the surface of the balloon.
12. Balloon catheters as described in claim 1, characterised by the addition of coating on the surfaces of substances to influence certain properties, such as the gliding ability of the balloon catheter or the reduction of blood clotting.
13. A process for the manufacture of the balloon catheter according to any of claims 1 to 12 characterised by the application of the lipophilic medicinal products and excipients in a solvent, suspension or emulsion medium to the surface of the balloon by immersion, painting, spraying or by means of a volume measuring device, removing excess media and loosely adhering substances on the surface.
14. The method described in claim 13 is characterised by repeated coating operations with the same or different solvent, suspension or emulsion media and/or excipients to reproducibly increase the active substance content.
15. The method described in claim 14 is characterised by the use of ethanol, isopropanol, ethyl acetate, diethyl ether, acetone, dimethyl sulfoxide, dimethyl formamide, glycerol, water or mixtures thereof as solvent, suspension and emulsion media.
16. A procedure according to one of claims 13 to 15 characterised by the use of bulbs, which are largely ready to be used, folded and coated with or without an applied stent before or after sterilisation.
17. The method described in claim 16 is characterised by coating the balloons in the unfolded state with the relevant lipophilic medicinal products and folding the balloons with a particularly flexible tool moistened with biocompatible glue, if applicable.
18. The method described in claim 13 is characterised by the installation of stents connected to a balloon catheter before or after a coating procedure.
19. The method described in claim 13 is characterised by sterilisation of the finished balloon catheter with ethylene oxide.
20. Use of the balloon catheter designed and manufactured in accordance with claims 1 to 19 for the manufacture of a medical device for the treatment of vascular disease or circulatory disorders.
21. Use of the balloon catheter designed and manufactured in accordance with claims 1 to 19 to manufacture a medical device for creating open passages in the body.