WO2011070189A1

WO2011070189A1 - Bone implant provided with porous edges for the controlled release of therapeutically active compounds

Info

Publication number: WO2011070189A1
Application number: PCT/ES2010/000500
Authority: WO
Inventors: Manuel Arruebo Gordo; Silvia Irusta Alderete; Luis Manuel Perez Puentes; Patricia Lalueza Valero; José Antonio PUERTOLAS RAFAEL; Luis Gracia Villa; Felicito Enrique GARCIA-ÁLVAREZ GARCIA; Marta Monzon Garces; Jesús SANTAMARIA RAMIRO
Original assignee: Universidad De Zaragoza
Priority date: 2009-12-11
Filing date: 2010-12-09
Publication date: 2011-06-16
Also published as: ES2362228A1; ES2362228B1

Abstract

The invention comprises a hollow carrier (2) including a wall (6) which has at least one porous area and which defines a primary chamber (3) inside the carrier (2). A filler material (4) is disposed inside the chamber, said filler material comprising ordered identical pores (7) in which particles of a drug (5) are absorbed. The particles of the drug (5) are released to the exterior first by means of diffusion from the pores (7) of the filler material (4) into the primary chamber (4) and, subsequently, from the primary chamber (3) to the exterior through the porous wall (6), such as to allow dual control of the release profile of the drug (5).

Description

BONE IMPLANT. GIVEN WITH POROUS LIMITS. FOR THE CONTROLLED RELEASE OF THERAPEUTICALLY COMPOUNDS

ASSETS D E S C R I P C I Ó N

OBJECT OF THE INVENTION The present invention can be included in the technical field of the development of implants, screws, scaffolds, fixings, etc. employees in traumatology and orthopedic surgery.

The present invention can also be included in the technical field of the administration of therapeutically active compounds, in particular in the administration from the inside of the body in a controlled manner of drugs or any therapeutically active substance.

The object of the present invention is a bone implant, provided with porous limits, for the controlled release of therapeutically active compounds, for use in traumatology and orthopedic surgery, adapted to release a therapeutically active compound contained therein in a controlled manner and Lasting over time. BACKGROUND OF THE INVENTION

There are hollow implants or medical devices on the market that release a drug contained inside. Said release of drug contained as a liquid inside the device can be done from a small window of said device. In this regard, the Journal of Controlled Relay 2005, number 102, pages 123-133 describes a device or implant provided with a nanoporous membrane. It comprises a cylindrical methacrylate carrier equipped with two rubber rings. A nanoporous membrane of 2x3 mm. It is fixed on a small hole that passes through the carrier by means of general purpose silicone that is allowed to cure at 55 ^Q C for 3 hours to achieve its fixation. The entire carrier is inserted into a titanium container until the membrane is fully aligned. At each end of the titanium vessel, methacrylate lids are sealed, containing releasable rubber septum, using silicone adhesive and allowed to cure. The implant is oriented vertically, and a 27-gauge Luer-Lock needle is inserted into the upper septum for use as an air inlet. A pharmacological liquid suspension is slowly injected into the implant through the lower septum until all the air inside the implant is removed, as indicated by fluid exudation from the needle. Needles are removed under pressure to prevent air ingress. The implants are rinsed by immersion before being placed in a control vessel or during surgical implantation.

Likewise, implants or other perforated mechanical models that release a drug previously encapsulated in a polymer are known. In this regard, in FASEB Journal 2008, number 22, pages 1-10, bone growth is described in vivo by means of a titanium implant with TGF-βΙ release. A porous titanium implant was developed. Next, encapsulated placebo or TGF-βΙ were placed in a negative pressure jelly sponge and placed in the porous titanium implant for unicortical implantation in the humerus of a rabbit.

Porous matrices that release an encapsulated drug therein are also known, as can be seen from the Journal of the Chemical Society, Dalton Translations, 2006, pages 521 1-5220. The technical problem to be solved is to describe a bone implant provided with porous limits for the release of a therapeutically active compound capable of releasing said pharmacological compound that is contained within it in a controlled and lasting manner.

DESCRIPTION OF THE INVENTION

The present invention solves the technical problem posed by means of a bone implant provided with porous limits for the controlled release of a therapeutically active compound, preferably a percutaneous screw or a centromedular nail, comprising a hollow carrier, preferably in a cylindrical shape, manufactured in a porous material, or at least with some porous areas, preferably a metal suitable for implantation inside a human or animal body, such as steel or titanium, for example.

A filling material is arranged inside the carrier. The filler material is a nanoporous inorganic silica material of ordered pores, preferably the same. There is a possibility that the filler material consists of both a fixed bed composed of microparticles and a continuous membrane-like film. An example of nanoporous material is mesoporous silica, preferably one of the materials selected from MCM-41, MCM-48, and SBA-15. Said filling material partially occupies the interior space of the carrier, called the primary chamber.

Inside the pores of the filler material a therapeutically active compound is adsorbed, such as a drug, a protein, a plasmid, etc. The case of a drug is especially preferred. A preferred type of pharmacological compound capable of being adsorbed in said pores is antibiotics, for example Linezolid (Zyvoxid ®).

Through the use of the implant of the present invention, an exhaustive control of the release profile of the therapeutically active compound contained is achieved, because there are two physical barriers to the release of the therapeutically active compound. Indeed, the therapeutically active compound particles adsorbed in the pores of the mesoporous filler material are first released into the primary chamber by diffusion and then accessed through the pores of the carrier's porous wall into the bloodstream .

The kinetic process that regulates the release of the therapeutically active compound particles into the primary chamber depends on the characteristics of the particles (diameter, porosity, packing density), as well as on the concentration of said particles within the primary chamber The kinetics of the outward release of the primary chamber depends on the concentration on both sides of the porous wall of the carrier, and on the characteristics of said porous wall of the carrier, such as permeation area, thickness, porosity. By properly defining the characteristics of the packing in the primary chamber and the permeation characteristics in the corresponding windows, it is possible to independently regulate the kinetics associated with the release from the porous material towards the primary chamber and the release towards the outside of the primary chamber.

The advantage of having the therapeutically active compound adsorbed inside the pores of the filler material (intra distribution) with respect to the distribution between the pores (inter distribution) is related to the need to protect the therapeutically active compound against the degradation by chemical or enzymatic action (nucleases, proteases, etc.), as well as with the need to minimize the incidence of sudden release (burst relée) that is often associated with adsorbed compounds on the external surface of materials. The fact of selecting fillers with ordered pores allows a better control of the release process, with respect to the situation in which the material has a wide distribution. The degradation of a biodegradable organic material is via erosion of the matrix and, therefore, the release profiles are difficult to reproduce. Since the invention does not contemplate the use of biodegradable materials, the encapsulating matrix (the carrier) remains unchanged in the processes of loading therapeutically active compound into the filler material and releasing said therapeutically active material.

The invention allows different sizes of carriers and, therefore, of bone implants to be released for the release of the therapeutically active compound, depending on the dose of therapeutically active compound necessary in each case.

According to a preferred claim of the invention, the carrier comprises a porous part and a non-porous part, there being in the non-porous part a window sealed with a nanoporous inorganic material, preferably with zeolite. This window is in contact with the primary chamber. From said primary chamber the therapeutically active compound can be diffused out of the carrier through the sealed window, according to a controlled release. DESCRIPTION OF THE DRAWINGS

To complement the description that is being made and in order to help a better understanding of the features of the invention, according to a preferred example of practical implementation thereof, a set of drawings is attached as an integral part of said description. where for illustrative and non-limiting purposes, the following has been represented:

Figure 1.- Shows a longitudinal sectional view of the first embodiment of the invention.

Figure 2.- Shows an enlarged view of the interior of the filler material where the pores and the therapeutically active compound particles adsorbed in said pores are appreciated.

Figure 3.- Shows the release of a hospital solution (line

A) commercial linezolid® from inside the carrier through the porous wall.

Figure 4.- Shows the release of linezolid® (line B) from a bed of MCM48 filler material.

Figure 5.- Shows the difference between the release of linezolid® from a carrier loaded with hospital solution (line A) and from a carrier loaded with a set of filler material plus drug (line

B).

Figure 6.- Shows a comparison between the concentrations of linezolid® reached by 400 nm particles. (line C1) with respect to 1500 nm particles. (line D1) in 50 mi. from SBF to 37 ^Q C. Figure 7.- Shows a comparison between linezolid® flows from 400 nm particles. (C2) and 1500 nm. (D2) in 50 mi. from SBF to 37

° -C.

Figure 8.- Shows a comparison of four of the forms of release studied (lines A, B, C1 and D1).

Figure 9.- Shows a longitudinal sectional view of the third embodiment of the invention.

PREFERRED EMBODIMENTS OF THE INVENTION

FIRST PREFERRED EMBODIMENT

In a first preferred embodiment of the invention, a bone implant (1) for the release of a therapeutically active compound (5), according to a percutaneous screw, is described with the aid of Figures 1 and 2. As can be seen in Figure 1, the implant (1) comprises a steel carrier (2) in the form of a hollow cylinder, with a porous wall (6) in which a primary chamber (3) is defined.

In part of the primary chamber (3) a bed of filler material (4) of the MCM-41 mesoporous silica type is distributed, with pores (7) (see Figure 2) ordered and equal in nanometric size.

Inside the pores (7) of the filler material (4) a therapeutically active compound (5) of the drug type is adsorbed, which can be released by diffusion from the filler material (4) to the primary chamber (3) in a first step, and outward from the primary chamber (3) through the porous wall (6) of the carrier (2).

As just mentioned, there are two physical barriers to the release of the therapeutically active compound (5): First, there is the relationship between the characteristics of the therapeutically active compound itself (5) and the filler material (4) and, in second, there is the porous wall (6) of the carrier (2).

The factors that regulate the diffusion between the filler material (5) and the primary chamber (3) are the diameter of the particles of therapeutically active compound (5), as well as the diameter of the pores (7) and the density of packing of the filling material (4), in addition to the concentration of said particles inside the primary chamber (3). The factors that regulate the release of the therapeutically active compound particles (5) through the porous wall (4) are the concentration of said particles on both sides of the porous wall (6) and the characteristics of said wall (6) porous, such as permeation area, thickness and porosity of the porous wall material (6).

The invention allows the control of diffusion to the primary chamber (3) and of the release through the porous wall (6) independently, providing a control of the release profile more customized to the needs of each specific case.

SECOND PREFERRED EMBODIMENT

In a second preferred embodiment, the results of a drug release (5) arranged directly in solution inside a carrier (2) are compared with respect to a release using a filler material (3) in which the drug is adsorbed ( 5).

The experimental system used for the study of drug release (5) comprises:

- a plurality of hollow cylindrical carriers (2) of porous steel, by way of percutaneous screws, of length equal to 2.7 cm. and of inside diameters equal 0.24 cm. and outside equal to 0.67 cm.,

- a hospital solution of drug (5) linezolid® with a concentration of 2mg / ml.,

- a set of porous filler material (4) plus drug (5) linezolid®,

- a 50 ml beaker,

- 50 mi. of SBF (simulated biological fluid), and

- a UV-visible spectrophotometer.

Inside the carriers (2) the hospital solution or the set of porous filler material (4) plus drug (5) is introduced. The filler material (4) used is mesoporous silica type MCM-48. The carrier (2) with the hospital solution or with the filling material set

(4) more drug (5) is introduced in 50 ml. of SBF and the release of the drug (5) is studied as a function of time by means of the spectrophotometer for each case: carrier (2) with solution or carrier (2) with filling material set (4) plus drug (5 ). Figure 3 shows as line A the release of the drug (5) from the hospital solution to the FBS.

In the aforementioned figure 3 it can be seen that almost all of the drug (5) is released in the first three hours of the test. In this example the drug (5) as a liquid is filling the entire primary chamber (3).

An example of the regulation on the drug release rate that can be obtained by introducing a filler into whose pores the molecule to be released is loaded is shown in Figure 4. Line B in the figure shows the release of drug (5) from a filler material (4) MCM-48 previously loaded with linezolid®. In this case, the filler material (4) is previously contacted with the hospital solution, the pores (7) of the stuffed material of said drug (5) remaining. 37.6 mg are introduced into the carrier (2). with 6.17% by weight of linezolid®.

In Figure 4, unlike in Figure 3, it can be seen that the release is not instantaneous and that there is therefore a period of stabilization of the system until the release of linezolid® of about two hours begins, which corresponds to the time It takes water to enter the pores (7) of the filler material, and drag the linezolid® that diffuses from the pores (7) of the filler material (4) to the outside of the carrier (2). This stabilization period is observed for all experiments performed and can be modulated by selecting the characteristics of the filling used (pore size, particle size, degree of packaging).

Figure 5 shows an example illustrating the difference in drug release (5) from a carrier (2) loaded with hospital solution (line A) and from another carrier (2) loaded with the filling material set (4) plus drug (5) (line B). As seen in view of Figure 5, it has been possible to slow down the release of linezolid® only by adsorbing it in a bed of mesoporous filler material (4). The release profile and kinetics of the pre-adsorbed drug (5) in said porous filler material (4) have been achieved.

Another study was carried out in which the same filler material (4) MCM48 was prepared with different particle sizes (400 nm. And 1500 nm.) And a study of the release of Linezolid® was performed. In this case, the release profile was controlled using different sizes of adsorbent particles. The result is shown in figures 6 and 7.

It is observed that the 400 nm particles. (line C1) are capable of loading more Linezolid® (8.02% by weight) compared to 1500 nm. (line D1) (5.71% by weight) while releasing more drug (5). But on the contrary, comparing the proportion of Linezolid® released with respect to the amount that they have been able to adsorb, what is observed is that larger particles (line D2) have a higher ratio, than smaller ones ( line C2) as shown in figure 7.

A common characteristic in all graphs except in graph 7 (hospital dissolution) is that the maximum release slope lasts up to approximately 50 hours of experiment.

Finally, comparing four of the forms of release studied according to lines A, B, C1 and D1, Figure 8 is obtained, where it can be seen that the fastest release of all is that in which it was introduced into the carrier (2 ) the hospital solution of linezolid®, in just 3 hours almost 100% of the drug has been released (5), while it is achieved that the release of Linezolid® is much slower by introducing Linezolid® into the pores (7) of the filler material (4) CM48. The fastest release is extended in these cases to 50 hours, followed by a slower release. In the three cases in which the drug (5) is loaded in the porous filler material (4), there is an induction period until the drug (5) begins to diffuse outside for about 2 hours, a period that does not exist in the case of hospital dissolution. These examples are intended to demonstrate that it is possible to control the release kinetics of a drug (5) previously adsorbed in the pores (7) of a siliceous filler material (4).

THIRD PREFERRED EMBODIMENT

Figure 9 shows a sectional view of the third preferred embodiment, where a bone implant (1) can be seen for the release of a therapeutically active compound (5), (see figure 2). The implant (1) comprises a steel carrier (2) in the form of a hollow cylinder, inside which a primary chamber (3) is defined.

Inside the primary chamber (3) a bed of filler material (4) of the MCM-41 mesoporous silica type is distributed, with pores (7) (see Figure 2) ordered and equal in nanometric size.

The carrier (2) has a wall (6) in which there is a window (8) that communicates with the primary chamber (3). Said window (8) is sealed with a zeolite membrane (9). Inside the pores (7) of the filler material (4) a therapeutically active compound (5) of the drug type is adsorbed, which can be released by diffusion from the filler material (4) to the primary chamber (3 ) in a first step, and outwards of the primary chamber (3) through the membrane (9).

Claims

1. - Implant (1) in bone, provided with porous limits, for the release of therapeutically active compounds (5), comprising:

- a hollow carrier (2) with a wall (6) comprising at least one porous area, said wall (6) defining a primary chamber (3) inside said carrier (2), and

- a therapeutically active compound (5) contained within the primary chamber (3),

characterized in that it additionally comprises:

- a nanoporous filler material (4) provided with pores (7) arranged and substantially equal, located in part of the primary chamber (3), containing at least some of said pores (7) adsorbed particles of the therapeutically active compound (5) susceptible of being transmitted by diffusion to the primary chamber (3), as well as susceptible of being released from the primary chamber (3) to the outside of the carrier (2) through the porous area of the wall (6).

2. - Implant (1) in bone, provided with porous limits, for the release of therapeutically active compounds (5), according to claim 1, characterized in that said element (1) is a percutaneous screw or a centromedular nail.

3. - Implant (1) in bone, provided with porous limits, for the release of therapeutically active compounds (5), according to claim 1, characterized in that the nanoporous filler material (4) is a mesoporous siliceous material.

4. - Implant (1) in bone, provided with porous limits, for the release of therapeutically active compounds (5), according to claim 3, characterized in that the nanoporous filler material (4) is mesoporous silica.

5. - Implant (1) in bone, provided with porous limits, for the release of therapeutically active compounds (5), according to claim 4, characterized in that the nanoporous filler material (4) is selected from MCM-41, MCM-48, SBA-15.

6. - Implant (1) in bone, provided with porous limits, for the release of therapeutically active compounds (5), according to claim 1, characterized in that the therapeutically active material (5) is a drug.

7. Implant (1) in bone, provided with porous limits, for the release of therapeutically active compounds (5), according to claim 6, characterized in that the therapeutically active material (5) is an antibiotic.

8. - Implant (1) in bone, provided with porous limits, for the release of therapeutically active compounds (5), according to claim 1, characterized in that the non-porous area of the wall (6) additionally comprises a connected window with the primary chamber, said window being sealed with a nanoporous material that allows the release of the therapeutically active compound through said window.

9. - Implant (1) in bone, provided with porous limits, for the release of therapeutically active compounds (5), according to claim 8, characterized in that the window is sealed with zeolite.