DE102007030438A1 - Implant for use in modern medical technology, is made of bio-corrosive magnesium alloy and having coating of polyorthoester that is hydrophob and is wet by water such that hydrolytic dismantling of polymer in aqueous media is retarded - Google Patents

Abstract

The implant is made of a bio-corrosive magnesium alloy and having a coating of polyorthoester. The implant is provided as a stent. The coating has an active substance. The polyorthoester is a hydrophob, and is wet by water such that the hydrolytic dismantling of the polymer in aqueous media is retarded. An independent claim is also included for an application of polyorthoester as a coating material for a stent made of a bio-corrosive metallic material.

Description

Technical area

The The invention relates to (i) an implant of a biocorrodible Magnesium alloy having a coating consisting of a Poly (orthoester) consists of or contains, and (ii) a new use of poly (ortho esters).

Background of the invention and state of the art

implants have application in a variety of embodiments found in modern medical technology. They serve for example the support of vessels, hollow organs and duct systems (endovascular implants), for attachment and temporary fixation of tissue implants and tissue transplants, but also for orthopedic purposes, for example as a nail, Plate or screw.

So Implantation of stents, for example, has proven to be one of the most effective therapeutic measures in the treatment of vascular disease established. Stents have the purpose in hollow organs of a patient to take over a support function. Stents conventional Design have a filigree support structure made of metallic Strive for the introduction into the body first in a compressed form and at the place of application is widened. One of the main applications of such stents is the permanent or temporary widening and keeping open of vasoconstriction, especially of constrictions (Stenoses) of the coronary arteries. In addition, for example Also known as aneurysm stents, which in support of damaged Serve vessel walls.

stents have a peripheral wall of sufficient bearing capacity to the narrowed vessel to the desired extent keep open and a tubular body, through which the blood flow continues unhindered. The bearing Peripheral wall is usually of a grid-like support structure formed, which allows the stent in a compressed state with a small outer diameter to the treatment bottleneck to introduce the respective vessel and expand it there, for example with the help of a balloon catheter, that the vessel the desired, enlarged Inner diameter has. For unnecessary vascular damage To avoid, the stent should after dilating and after removal the balloon does not spring back elastically or only to a small extent, so that the stent widening only slightly beyond the desired End diameter must be widened out. Other criteria that with respect to a stent, for example, include a uniform area coverage and a structure that has some flexibility in terms of the longitudinal axis of the stent allowed. In practice, the Realization of the mentioned mechanical properties of the stent in usually formed from a metallic material.

Next The mechanical properties of a stent should this from a biocompatible material to rejection reactions submissions. Currently, about 70% of all percutaneous interventions Stents used, but in 25% of all cases it comes to an in-stent restenosis due to an overshoot neointimal growth, which is characterized by a strong proliferation of arterial smooth muscle cells and a chronic inflammatory response is caused. To reduce the restenosis rates are different Proposed solutions.

One Approach to reducing the rate of restenosis envisages on the stent to provide a pharmaceutically active substance (active substance), which counteracts the mechanisms of restenosis and supports the healing process. The active ingredient is in pure form or embedded in a carrier matrix applied as a coating or in cavities of the implant filled. Examples include the active substances sirolimus and Paclitaxel.

Another promising approach to solving the problem lies in the use of biocorrodible metals and their alloys, because usually a permanent support function through the stent is not required; regenerates the initially damaged body tissue. For example, in DE 197 31 021 A1 proposed to form medical implants of a metallic material whose main component is iron, zinc or aluminum or an element from the group of alkali metals or alkaline earth metals. Particularly suitable alloys based on magnesium, iron and zinc are described. Secondary constituents of the alloys may be manganese, cobalt, nickel, chromium, copper, cadmium, lead, tin, thorium, zirconium, silver, gold, palladium, platinum, silicon, calcium, lithium, aluminum, zinc and iron. Furthermore, from the DE 102 53 634 A1 the use of a biocorrodible magnesium alloy with a share of magnesium> 90%, yttrium 3.7-5.5%, rare earth metals 1.5-4.4% and remainder <1% known in particular for the preparation of an endoprosthesis, z. B. in the form of a self-expanding or balloon ex pandierbaren stents, is suitable. The use of biocorrodible metallic materials in implants should lead to a significant reduction of rejection or inflammatory reactions.

• (i) Der Zutritt von Wasser an die degradierbare Implantatsoberfläche sollte in den ersten Wochen vollständig verhindert werden, um den Beginn des Abbaus des Implantats zu verzögern.
• (ii) Der alkalische pH-Wert, der sich während der Degradation des Implantats aus einer biokorrodierbaren Magnesiumlegierung bildet, darf den Abbau der Beschichtung nicht wesentlich beschleunigen.
• (iii) Wirkstoffe, die in der Beschichtung eingebettet sind, sollten kontinuierlich abgegeben werden und nach Möglichkeit auch nach 14 Tagen noch merklich eluieren.
• (iv) Das Beschichtungsmaterial sollte biokompatibel sein und im Körper langsam abgebaut werden.

The combination of drug release and biocorrodible metallic drug appears particularly promising. The active ingredient is applied as a coating or introduced into a cavity in the implant - usually embedded in a carrier matrix. For example, stents made of a biocorrodible magnesium alloy with a coating of a poly (L-lactide) are known. Regardless of the progress achieved, however, the following problems still have to be solved for implants made of a biocorrodible magnesium alloy:

• (i) The access of water to the degradable implant surface should be completely prevented in the first few weeks to delay the onset of degradation of the implant.
• (ii) The alkaline pH, which forms during the degradation of the implant from a biocorrodible magnesium alloy, must not significantly accelerate the degradation of the coating.
• (iii) Active agents embedded in the coating should be delivered continuously and, if possible, should elute noticeably even after 14 days.
• (iv) The coating material should be biocompatible and slowly degraded in the body.

Summary of the invention

Of the Invention is based on the object, one or more of the described To mitigate or overcome problems.

One The first aspect of the invention is the provision of an implant made of a biocorrodible magnesium alloy and with a coating consisting of or containing a poly (orthoester).

Poly (orthoesters) have been known for about 30 years. Meanwhile, specific poly (orthoesters) have been developed that can serve as an implant material or carrier material for drug depots. Provide an overview of the current state of development J. Heller and J. Barr, Biomacromolecules, Vol. 5, (2004), 1625-1632 , Particularly suitable for the purposes of the present invention are poly (ortho esters) which can be obtained by polymerization of a specific diketene acetal with a diol and (optionally) a diol having a polyester segment (as a latent acid function) according to the following scheme:

Poly (orthoesters) are hydrophobic and wetting by water is thus low so that the hydrolytic degradation of the polymer in aqueous media is retarded. The rate of erosion of the polymer can be moderated by incorporation of the illustrated latent acid function (see the above article by J. Heller and J. Barr ). Poly (orthoesters) are very stable in the alkaline medium, so that the basic degradation products of the magnesium alloy do not accelerate the degradation of the polymer, but rather have a retarding effect.

A Coating according to the invention is an at least in sections Application of the components to the basic body of the implant, especially stents. Preferably, the entire surface of the Basic body of the implant / stent of the coating covered. The coating consists of poly (orthoesters) or they contains poly (orthoester). The proportion by weight of poly (orthoester) on the carrier matrix forming components of the coating is at least 30%, preferably at least 50%, especially preferably at least 70%. The components of the coating include the materials acting as support matrix, ie materials those for the functional properties of the carrier matrix necessary, z. B. also adjuvants to improve the viscosity properties, Gel formation and processability. These components do not include optionally added active ingredients or marker materials.

The Poly (orthoester) used according to the invention are highly biocompatible and biocorrodable. The processing can be done by standard methods of coating. The biocompatibility of poly (orthoesters) is usually limited by the fact that while the degradation acidic by-products arise. When dismantling the implant However, magnesium hydroxide forms as a degradation product, which is the stabilizing the polymer, i. H. slows down the degradation. To the Others, the acid decomposition product of the polymer neutralizes the high pH in the tissue surrounding the implant. Otherwise, this one can high pH to an unwanted alkalosis and a Cause vascular reaction. Poly (orthoester) and degradable implant thus have a synergistic effect on biocompatibility.

Of the Poly (orthoester) can be used as a carrier matrix for pharmaceutical Actives, x-ray markers or magnetic resonance markers act. The x-ray marker can be made from a biocorrodible implant metallic material is not applied directly to the product be because he z. B. the degradation of the stent by formation of Would affect local elements. In the matrix of poly (orthoester) on the other hand, the marker is shielded from the main body.

When biocorrodible in the context of the invention are metallic or polymeric Materials called, in which a physiological environment Degradation takes place, which ultimately leads to that entire implant or the part formed from the material Implantates loses its mechanical integrity.

Under a biocorrodible magnesium alloy according to the invention is understood as a metallic structure whose main component Magnesium is. The main component is the alloy component whose Weight content of the alloy is highest. A share the main component is preferably more than 50% by weight, in particular more than 70% by weight. Preferably, the biocorrodible magnesium alloy yttrium and other rare earth metals, because such an alloy due to their physico-chemical Properties and high biocompatibility, in particular also its degradation products, distinguishes. Particularly preferred a magnesium alloy of the composition rare earth metals 5.2-9.9 % By weight, of which yttrium 3.7-5.5 wt.%, And balance <1 wt.%, Where Magnesium occupies the 100% by weight missing proportion of the alloy, used. This magnesium alloy already confirmed experimental and in first clinical trials their special Suitability, d. H. shows a high biocompatibility, favorable Processing properties, good mechanical properties and a for the purposes of adequate corrosion behavior. Under the collective term "rare earth metals" are present Scandium (21), yttrium (39), lanthanum (57) and the 14 on lanthanum (57) the following elements, namely cerium (58), praseodymium (59), neodymium (60), promethium (61), samarium (62), europium (63), gadolinium (64), terbium (65), dysprosium (66), holmium (67), erbium (68), Thulium (69), ytterbium (70) and lutetium (71).

Poly (orthoester) and the magnesium alloys are to be chosen in their composition so that they are biocorrodible. As a test medium for testing the corrosion behavior of polymeric materials or alloys used artificial plasma, as according to EN ISO 10993-15: 2000 for biocorrosion tests (composition NaCl 6.8 g / l, CaCl ₂ 0.2 g / l, KCl 0.4 g / l, MgSO ₄ 0.1 g / l, NaHCO ₃ 2.2 g / l, Na ₂ HPO ₄ 0.126 g / l, NaH ₂ PO ₄ 0.026 g / l). A sample of the material to be examined is stored in a sealed sample container with a defined amount of the test medium at 37 ° C. At intervals - adjusted to the expected corrosion behavior - from a few hours to several months, the samples are taken and examined in a known manner for traces of corrosion. The artificial plasma after EN ISO 10993-15: 2000 corresponds to a blood-like medium and thus represents a possibility to reproducibly reproduce a physiological environment within the meaning of the invention.

implants within the meaning of the invention are via a surgical procedure incorporated into the body devices and include fasteners for bones, such as screws, plates or nails, surgical sutures, intestinal staples, vascular clips, Prostheses in the area of hard and soft tissue and anchor elements for electrodes, in particular pacemakers or defibrillators.

Preferably the implant is a stent. Stents of conventional design have a filigree support structure of metallic struts on that for introduction into the body first is present in a non-expanded state and at the place of Application is then expanded into an expanded state. Due to the way of use, they are brittle coating systems not suitable; By contrast, poly (orthoesters) have particularly suitable material properties. as a viscosity sufficient for the purpose and flexibility. The stent may be before or after crimping to be coated on a balloon.

One second aspect of the invention relates to the use of Poly (ortho esters) as coating material for a stent made of a biocorrodible magnesium alloy.

The Invention will be described below with reference to embodiments explained in more detail.

Example 1: Coating of Absorbable metal stents

A stent of the biocorrodible magnesium alloy WE43 (97% by weight of magnesium, 4% by weight of yttrium, 3% by weight of rare earth metals except yttrium) is coated as follows:
A 0.1% by weight solution of a poly (ortho ester) in dry THF is provided (the concentration range should preferably be in the range of 0.05 to 0.4% by weight). The poly (ortho ester) was prepared from a 100/70/30 mixture of 3,9-diethylidene-2,4,8,10-tetraoxaspiro [5.5] undecane, 1,10-decanediol, and 1,10-decanediactactide.

Of the Stent is cleaned of dust and residues and into a suitable stent coating apparatus (DES Coater, Eigenentwicklung Fa. Biotronik) clamped. With the help of an airbrush system (Fa. EFD or Spraying System), the rotating stent is under constant Ambient conditions (room temperature, 42% humidity), half-sided coated. With a nozzle distance of 20 mm is an 18 mm long stent after about 10 min coated. After reaching the intended layer mass, the stent is dried for 5 min at RT, before turning the stent and re-clamping the uncoated Side is coated in the same way. The finished coated Stent is incubated for 24 h at 80 ° C in a vacuum oven (Vakucell, MMM) dried.

Example 2: Coating of a stent made of a CoCr alloy

A stent made of a CoCr alloy is coated as follows:
A 0.1% by weight solution of a poly (ortho ester) in ethyl acetate is provided (the concentration range should preferably be in the range of 0.05 to 0.4% by weight). The poly (ortho ester) was prepared from 3,9-diethylidene-2,4,8,10-tetraoxaspiro [5.5] undecane and 1,6-hexanediol.

Of the Stent is cleaned of dust and residues and into a suitable stent coating apparatus (DES Coater, Eigenentwicklung Company BIOTRONIK). With the help of an airbrush system (EFD or Spraying System), the rotating stent is under constant Ambient conditions (room temperature, 42% humidity), half-sided coated. With a nozzle distance of 20 mm is an 18 mm long stent after about 10 min coated. After reaching the intended layer mass, the stent is dried for 5 min at RT, before turning the stent and re-clamping the uncoated Side is coated in the same way. The finished coated Stent is incubated for 24 h at 80 ° C in a vacuum oven (Vakucell, MMM) dried.

Example 3: Coating of an Absorbable Metal stents with a drug-loaded poly (orthoester)

A stent made of the biocorrodible magnesium alloy WE43 is coated as follows:
A 0.1% by weight solution of a poly (ortho ester) in dry THF is provided (the concentration range should preferably be in the range of 0.05 to 0.4% by weight). The poly (ortho ester) was prepared from a 15/40/40/5 mixture of 3,9-diethylidene-2,4,8,10-tetraoxaspiro [5.5] undecane, 1,6-hexanediol, triethylene glycol and triethylene glycol glycolide.

Of the Stent is cleaned of dust and residues and into a suitable stent coating apparatus (DES Coater, Eigenentwicklung Company BIOTRONIK). It becomes a clear, concentrated solution of a pharmacological agent in THF thus becomes the polymer solution added that polymer and active ingredient in a weight ratio from 20/80 to 80/20 (preferred: 60/40). With the help of an airbrush Systems (EFD or Spraying System) becomes the rotating stent under constant ambient conditions (room temperature, 42% humidity) coated on one side. At a nozzle distance of 20 mm is a 18 mm long stent after about 10 min coated. After reaching the intended layer mass, the stent is dried for 5 min at RT, before turning the stent and re-clamping the uncoated Side is coated in the same way. The finished coated Stent is incubated for 24 h at 80 ° C in a vacuum oven (Vakucell, MMM) dried.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• DE 19731021 A1 [0007]
• - DE 10253634 A1 [0007]

Cited non-patent literature

• J. Heller and J. Barr, Biomacromolecules, Vol. 5, (2004), 1625-1632 [0011]
• J. Heller and J. Barr [0012]
• - EN ISO 10993-15: 2000 [0018]
• - EN ISO 10993-15: 2000 [0018]

Claims (4)

Implant made of a biocorrodible magnesium alloy and with a coating consisting of or containing a poly (orthoester). Implant according to claim 1, wherein the implant a stent is. Implant according to claim 1 or 2, wherein the coating contains an active substance. Use of a poly (ortho ester) as a coating material for a stent made of a biocorrodible metallic Material.