WO1998003160A1

WO1998003160A1 - Pharmaceutical releasing corpuscle

Info

Publication number: WO1998003160A1
Application number: PCT/EP1997/003886
Authority: WO
Inventors: Anton HÄRLE
Original assignee: Haerle Anton
Priority date: 1996-07-23
Filing date: 1997-07-19
Publication date: 1998-01-29
Also published as: AU4011497A

Abstract

Pharmaceutical releasing corpuscles are linked by wires/threads to each other to form chains and are characterised by a shape which deviates from that of an ellipsoid of revolution. The flattening of the corpuscles along at least one axis gives a more favourable surface-volume relation which can be utilised to increase the packing density and improve the release of pharmaceutical substances. Handling in the area of implantation sites close to the skin and in association with other implants is also favourably influenced. Finally, the flattening of the corpuscles along at least one axis makes it easier to remove them again.

Description

"Pharma-releasing bodies"

The invention relates to pharmaceutical release bodies for local treatment and use in or on the body tissue, consisting of a biologically inert carrier material such as e.g. Polymethyl methacrylate, one or different pharmaceuticals being releasably present in the carrier material in a uniform distribution and the bodies being connected to one another.

From DE-OS 23 20 373 an antibiotic-containing agent in spherical form is known, in which the spheres are connected to one another by means of threads or wires. Such antibiotic-containing aids are widely used in the treatment of bone and soft tissue infections. The particular advantage is that the antibiotics used are introduced directly into the focus of infection and are used; adverse effects on parts of the body or organs not affected by the infection can thus be almost completely avoided.

EP 0 157 909 proposed corpuscles in the form of an ellipsoid of revolution. Theoretically, a more favorable surface / volume ratio could be achieved with this, but it was very difficult to manufacture this shape. Even in clinical use, this configuration was not always able to achieve the required concentration of active substance in the diseased tissue, which is necessary for therapeutic success. An increase in the controlled release of pharmaceuticals in particular The local conditions in the operating area were therefore desirable.

In addition, the production of a relatively tapered particle is still associated with many difficulties for reasons of production technology.

Another disadvantage of the previously known configurations of pharmaceutical-releasing bodies with a spherical or ellipsoidal configuration was that they are heavily applied in the tissue and therefore e.g. could hardly be inserted in the area of bone directly under the skin. The addition of the pharmaceutical-release particles to or under osteosynthesis aids was also made difficult or hindered because of their circular cross-section. But even when filling bone cavities, the pharmaceutical-releasing bodies with spherical or ellipsoidal design could not be packed tightly, so that there remained large free spaces between them that could not be used to release antibiotics.

Since pharmaceutical release is a surface dependent process, i.e. that initially only the pharmaceuticals lying in the superficial layers are released, the clinically relevant release in the first few days of use is not influenced by the pharmaceutical depot lying in the core. Spherical bodies or bodies that are circular in several right-angled sectional planes therefore only ever make part of the incorporated pharmaceuticals available for clinical use.

The circular cross-section of the pharmaceutical release bodies connected to one another in chains according to the prior art also hindered their removal if these chains had to be removed from the body tissue under tensile action, since granulation tissue had formed around the body during healing and then that when the chains were pulled out Slipping through the particles having a relatively large cross section is difficult. This object of improving the pharmaceutical release, increasing the local pharmaceutical concentration and easier handling on which the invention is based is achieved by the features mentioned in the claims.

By designing the pharmaceutical-releasing bodies with a flattened cross-section e.g. In the sense of an ellipsoid, the release of pharmaceuticals can be increased considerably by increasing the surface area per unit volume. In the proposed shape designs, the central pharmacological depot in cross-section or longitudinal section of circular particles, which has hardly any clinical effects, is largely dispensed with, thus economizing on the amount of pharmaceutical used. It is particularly important, however, that the local pharmaceutical concentration can be increased by denser packing and more favorable surface / volume ratio, which is particularly important in the treatment of tissue infections. The increase in resistant infectious agents that has been observed in recent years requires the highest possible local concentration of antibiotics in order to bring about a successful healing.

The development of new antibiotics has more or less come to a standstill in the past few years and the threat of antibiotic resistance can best be counteracted by preventing the development of resistant bacterial strains by immediately suppressing this process through an initially high concentration of active substances.

The task is therefore based on the task of creating pharmaceutical-releasing bodies which have such a shape that a maximum concentration of active substance in the diseased tissue can be achieved by means of their surgical insert, even in tissue areas which have hitherto hardly been accessible to such therapy were.

This object on which the invention is based is achieved by the teaching of the main claim. Advantageous configurations are explained in the subclaims.

In other words, it is proposed to create pharmaceutical-releasing bodies with a surface / volume ratio which is as favorable as possible or with a flat shape and which do not apply very much.

Since the corpuscles are now more flat, they are no longer so bulky and can also be placed on bone sections directly under the skin without fear of internal pressure ulcers.

The attachment to or under osteosynthesis aids such as plates, rods and endoprostheses is thus considerably improved, since no substantial weakening of the given implants is required in order to create space for the pharmaceutical-containing bodies to be attached. Such particles according to the invention can now also be attached to implants lying close to the skin without spatial problems occurring.

Finally, the removal from soft tissue and bone tissue is also made easier, since the greater packing density means that the granulation tissue lying between the particles is less pronounced, which opposes the slipping of the particles depending on the thickness of the tissue.

These exemplary embodiments of the shape of the pharmaceutical release bodies according to the invention are explained below with reference to the drawings. The drawings show in

1 is a view of interconnected particles as a chain,

2 to 5 longitudinal sectional images of various For configurations, Fig. 6 to 9 cross-sectional images of various shape configurations.

The following definitions are used in the description and in the claims:

Chains designate pharmaceutical-releasing bodies connected by threads / wires,

Particles and bodies denote the pharmaceutical-releasing bodies according to the invention as a whole,

Sections denote parts of the bodies in the longitudinal sectional view,

Segments denote the parts of the segments lying above or below the axis of symmetry (wire / thread) in the longitudinal sectional view.

^• In the example shown in Fig. 1 chain section, denote 1 2 and 3 similar Drug delivering corpuscles as chain links which are interconnected by means of a thread or wire (7). The pharmaceutical-releasing bodies are shown in an axial longitudinal sectional view and have a tapered shape at both ends of the wire outlet. In this projection, the corpuscles can be divided into three sections according to the dotted lines, 4 and 6 denoting the final tapering sections and 5 defining the middle section.

The bodies shown in FIG. 1 accordingly have two circular, tapered sections in the axial longitudinal section, between which a rectangular center piece is connected. If the particles are formed as a rotating body around the axial longitudinal axis, ie around the wire / thread 7, the tapered sections have a spherical shape and the central section has a cylindrical shape. Completely different forms of the bodies according to the invention arise when the axis of rotation is not central but eccentric.

In particularly advantageous configurations, the cross-sectional images have other formations corresponding to FIGS. 7 to 9 instead of the circular outer contour; The three-dimensional shape of such bodies according to FIG. 1 can therefore be very different, depending on the selected dimensioning and configuration of the third axis.

A cross-sectional plane of the body is designated by 12, the various configurations of which are shown in FIGS. 7 to 9.

2 shows an axial longitudinal sectional view of a body; the dotted lines again define the three sections, here different tapering sections are present which are divided into two segments by the wire / thread 7. The left tapered section is formed by the two segments 8a and 8b, which are mirror images in the case shown, and has a circular outer contour. The right-hand tapered section is composed of the likewise mirror-image segments 10a and 10b, so that the outer contours of this second tapered section correspond to an ellipse segment.

It should be expressly pointed out here that the configurations according to the invention are not limited to the fact that the tapered sections consist of mirror-image or similar segments, rather the tapered sections can be composed of different segments.

Between the two tapered sections there is the bulbous central section, the two outer contours 9a and 9b of which in this case are mirror images and represent ellipse segments. A cross-sectional plane of the body is designated by 12, the different configurations of which are shown in FIGS. 7 to 9.

In FIG. 3, the dotted lines in the axial longitudinal sectional view again divide the pharmaceutical-releasing body into three sections, and 12 denotes a cross-sectional plane of the body, the different configurations of which are shown in FIGS. 7 to 9. The left-hand tapered section consists of the conical segment 13a and the concave segment 13b, is not mirror-inverted with respect to the thread / wire axis and forms a stump cut off at right angles to the wire-thread axis. The right-hand tapered section is formed by the two conical segments 15a and 15b and tapers to a point. Between the two tapering segments is the central section with a reduced cross-section, which is defined by the different outer contours 14a and 14b.

In this embodiment, both a tapered section and the central section are composed of two different and non-mirror-image segments.

The body shown in the axial longitudinal sectional view in FIG. 4 corresponds to an ellipse in this projection, the outer contours of the particle halves 16a and 16b being mirror images. The outer contours 16a and 16b of the bodies can also be asymmetrical and represent segments of different functions.

The three main axes a, b and c, which describe the spatial formation, are drawn into the body, slightly offset from the center.

Fig. 5 shows a pharmaceutical-releasing body, which is circular in longitudinal section, ie the axes a and b indicating length and height are of equal size. A particle with this longitudinal sectional image only falls under the bodies according to the invention if the third axis c is not equal to a and b.

FIG. 6 shows a circular cross section of a pharmaceutical-releasing body according to the cross-sectional planes 12 in FIGS. 1 to 3. The central wire / thread is designated 7.

FIG. 7 shows a cross section of a flattened pharmaceutical-releasing body according to the cross-sectional planes 12 in FIGS. 1 to 5. In the cross-sectional image, the two ends are characterized by arcs, which are followed by a rectangular intermediate piece. The long axis can be either a or b according to the three-dimensional axis system in FIG. 4. The central wire / thread is designated 7.

FIG. 8 shows an elliptical cross-section of a pharmaceutical-releasing body according to the cross-sectional planes 12 in FIGS. 1 to 5. The long axis can be either a or b according to the three-dimensional axis system in FIG. 4. The central wire / thread is designated 7.

FIG. 9 shows an almost rectangular cross-section of a pharmaceutical-releasing body according to the cross-sectional planes 12 in FIGS. 1 to 5, in which only the corners are rounded. The long axis can be either a or b according to the three-dimensional axis system in FIG. 4. The central wire / thread is designated 7.

The shape configurations of the pharmaceutical-releasing bodies according to the invention result from the possible combinations. the different sections in the longitudinal section with different cross-sectional shapes. The tapered sections can in turn be composed of a large number of different segments which can be freely combined with one another. These combination options also apply to the middle sections.

At this point, it is expressly pointed out once again that the configurations according to the invention are not limited to the forms shown in the drawings.

Claims

"Pharma-releasing bodies"

Claims:

1) Pharmaceutical release bodies for local use in or on the body tissue, consisting of a biologically inert carrier material in which one or different pharmaceuticals are present in a uniform distribution and releasable form, the bodies being connected to one another by threads or wires, characterized in that the Bodies have a shape that deviates from the pure ellipsoidal shape and tapers at both wire or thread exit points and has a curved outer contour in at least one cross-sectional plane in both terminal tapers.

2) Pharmaceutical-releasing bodies according to claim 1, characterized in that the bodies in at least one axial longitudinal sectional view are composed of at least two different sections (4; 5), the outer contours of which are defined by curves of different functions.

3) Pharmaceutical-releasing bodies according to claim 2, characterized in that the bodies in at least one axial longitudinal sectional view are composed of at least three different sections (4; 5; 6), the outer contours of which are defined by curves with at least two different functions. 4) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies are composed in at least one axial cross-sectional image from at least two different sections, the outer contours of which are defined by curves of different functions.

5) Pharmaceutical release body according to claim 4, characterized in that the body is composed in at least one axial cross-sectional image from at least three different sections, the outer contours of which are defined by curves with at least two different functions.

6) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies between the two terminal tapering sections (4; 6) have a central section (5) which is essentially cylindrical in longitudinal section.

7) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies between the two terminal tapering sections (8; 10) have a substantially barrel-shaped bulging central section (9) in the longitudinal sectional view.

8) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies have a central section (14a) concave in the longitudinal section between the terminal tapering sections.

9) Pharmaceutical release bodies according to one or more of the preceding claims, characterized in that the bodies between the terminal tapered sections have a substantially elliptical central section in the longitudinal sectional view.

10) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies in the longitudinal sectional image are essentially characterized by a second-order curve (14; 15).

11) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that at least one segment of at least one terminal tapering section (8; 10) can be described essentially by a curve of second or higher order.

12) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that at least one segment of at least one terminal tapering section (13a; 15a; 15b) is conical or conoid in at least one longitudinal section.

13) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that at least one of the terminal tapering sections (13) is concave.

14) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies have different outer contours in two axial longitudinal sectional planes offset at right angles to one another.

15) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies are flattened in the longitudinal axis (1; Fig. 2; Fig. 3; Fig. 4). 16) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies in cross-section (Fig. 7; Fig. 8; Fig. 9) have a shape deviating from the circular shape.

17) Pharmaceutical-releasing bodies according to claim 12, characterized in that the bodies represent triaxial (a; b; c) ellipsoids with at least two different main axes.

18) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies represent ellipsoids with three different main axes (a; b; c).

19) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies have a grooved or furrowed surface.

20) Pharmaceutical-releasing bodies according to one or more of the preceding claims, characterized in that the bodies as pharmaceuticals have anti-inflammatory and / or anti-tumor agents, such as e.g. Antibiotics, antseptics, chemotherapy drugs, corticoids, anti-inflammatory drugs, cytostatics.