KR20160101231A - Metal Implant Capable of Multiple-Release of Drugs and Method for Preparing the same - Google Patents

Abstract

The present invention relates to a metal implant capable of multiple releases of a drug, and to a manufacturing method thereof. According to the present invention, a pore size and the porosity of a used metal support are easily adjustable, and the drug can be discharged from a single bio-implantable implant while exhibiting multiple release conditions. Thus, an effect of delivering the drug to a site to which the implant is transplanted within certain time is maximized.

Description

Technical Field [0001] The present invention relates to a metal implant capable of multiple release of a drug and a method for manufacturing the metal implant.

The present invention relates to a metal implant capable of multiple release of a drug and a method of manufacturing the same.

(I) a metal material such as titanium, a stainless steel alloy, a cobalt-chromium alloy, (ii) a bio-inactive material such as alumina or zirconia, and (iii) a metal- Bioactive ceramic materials such as hydroxyapatite are now widely used.

Among the materials of these implantable implants, titanium has a high biocompatibility, strong mechanical properties, high corrosion resistance, and particularly a low elastic modulus as compared with other metal materials, so that the implantable implant material .

On the other hand, in the case of implanting a living implant for implantation into a human body through a procedure, it is possible to shorten the time for the injured portion to be recovered by the implantation of the implant for implantation and the time for the implant to stably bind to the bone or tissue , It is important to prevent acute inflammation that may occur after the procedure.

For this purpose, recently, it has been proposed to improve the biocompatibility by surface-treating the implant for implantation, or to prevent the inflammation by coating a drug such as antibiotics or a protein such as growth factor or insulin on the implant for implantation, (Korean Patent Laid-Open No. 10-2008-0016780).

However, when a therapeutic drug or protein is coated on a living implant, it is necessary to 1) limit the amount and type of therapeutic drug or protein that can be coated, 2) to coat an expensive therapeutic drug, And it is very inefficient in terms of cost and treatment, and 3) it controls the release rate of the therapeutic drug or protein coated on the surface of the implant for implantation And the performance of the therapeutic drug or protein can not be effectively exerted.

In addition, since the route of injecting body fluids varies depending on the implant site, it is necessary to construct a drug delivery system suitable for the site of treatment, and the release pattern of the drug should be changed depending on the type of drug to be administered.

For example, antibiotics should be released within one week to prevent acute inflammation after implantation, while proteins such as growth factors should be short in order to increase the degree of binding between the implant and tissue and bone. It is required to be released continuously for several months. However, according to the conventional technique, there is no multi-emissive implant that allows each of these drugs to be released for a desired period of time so that the performance of each drug can not be sufficiently exhibited.

Therefore, it is necessary to develop an implant that is suitable for the treatment site and can be adjusted so that the drug to be administered is appropriately released.

The present inventors have studied to develop a metal implant capable of multi-drug release in one implant to solve the above problems. As a result, the present inventors have found that a metal implant having a porosity and / , And the interface of the metal supports was engaged with each other to produce a single metal implant showing various drug release patterns.

SUMMARY OF THE INVENTION In order to solve the above problems, the present invention provides a porous medical device comprising: a first porous metal support containing a first drug; And a second porous metal support containing a second drug, wherein the first porous metal support and the second porous metal support are in a compressed and meshed state, Lt; / RTI >

The present invention also relates to a pharmaceutical composition comprising at least one first porous metal support comprising a first drug; And a second porous metal support comprising a second drug, wherein the first porous metal support and the second porous metal support are interlocking to each other at an interface, Wherein the first porous metal support containing the first drug and the second porous metal support containing the second drug are compressed and integrated after the interfacial physical irregularities are bonded to each other.

Further, the present invention provides a method of preparing a porous medical support comprising: 1) immersing a first porous metal support in a solution comprising a first drug; 2) immersing the second porous metal support in a solution comprising the second drug; 3) maintaining each of the metal supports carrying the drug in the pores in vacuum; And 4) attaching the first porous metal support and the second porous metal support to each other and then applying pressure to the metal support to engage with each other.

Hereinafter, the present invention will be described in detail.

The present invention utilizes the property that the interfaces can be engaged when the adjacent metal supports are compressed and the porosity and / or pore size at the time of interfacial bonding by the compression between the porous metal supports containing the drug or during production of each porous metal support The present invention provides an integrated metal implant that exhibits various drug release patterns.

In addition, in the present invention, in manufacturing a single implant for implantation by compressing and bonding two or more units of metal supports, pressure is applied differently to each unit of the metal support, or the height, surface area, etc. of each metal support are different It was confirmed that the porosity / pore size in each metal support also differs when the same pressure is applied to vary the compression ratio, and furthermore, the release pattern of the loaded drug is also different. Specifically, it has been confirmed that as the metal support is compressed more, the porosity of the metal support decreases, the pore size decreases, and the release rate of the drug decreases. As a result, a metal implant was first designed to exert a drug delivery effect on a site to be implanted by releasing the drug in several implantation modes in one implantable implant.

In the present invention, "metal support" is a structure that forms the basic framework of a metal implant, and carries a drug or the like to be delivered into the body through the implant. Therefore, the metal support is preferably a biodegradable metal and decomposed in the human body after a lapse of a predetermined time.

On the other hand, the metal may have porosity, and the drug may be carried in the pores of the metal by the porosity. The porosity of the metal support may be 60 to 80%, more specifically 70%. The porous metal support may be, but is not limited to, titanium, magnesium, iron, aluminum, copper, tantalum, or an alloy thereof.

In the present invention, two or more units of metal supports are combined by being engaged with each other by compression. Thus, the metal implant of the present invention may comprise more than two units of metal support. The metal supports of each unit may be the same metal or may be different metals. That is, in the present invention, the first porous metal support and the second porous metal support may be the same or different.

The metal support of two or more units of the metal implant of the present invention can be engaged by compression. This may be a physical bond such as bonding or attachment between the metals, in which pores in the metal atoms or in the metal support are mechanically engaged. Thus, the two or more metal supports coupled by compression as described above may be separated again. When the metal implant of the present invention is to be implanted into a body and then removed from the body, it may be separated and removed by each unit of the metal support. In addition, since the surgical site can be minimized when the size of each unit of the metal support is smaller than that of the entire implant, if the destruction occurs in some units in the body or when additional drug loading is required, Replaceable.

The pressure required for the separation of the separable metal unit support can be controlled through the bonding area of the supports. In the case where separation is not to be made, it is possible to increase the required pressure (force) by increasing the bonding area between the supports, and when the separation is necessary, the bonding range between the supports is reduced, can do.

In addition, when the metal support is compressed and joined together, the compression ratio (degree of compression) for each unit of metal support may be different, and thus the porosity and / or pore size in the metal support may vary.

Specifically, in the experimental example of the present invention, it was confirmed that the higher the compressibility of the metal support, the lower the porosity in the metal support and the smaller the pore size (Experimental Example 1).

Also, the porous metal support of the present invention can be used without limitation in its form, but preferably the first porous metal support is in the form of a hollow, and the second porous metal support is in the hollow of the first porous metal support By having an insertable form, it is possible to more clearly distinguish the release pattern of the loaded drug (Fig. 1).

"Drug" in the present invention is a substance to be delivered into the body through the implant of the present invention. Specific examples of drugs that can be included in the implant of the present invention include an immune response modifying factor, an anti-proliferative agent, an anti-mitotic agent, an anti-platelet agent, a platinum coordination complex, a hormone, an anticoagulant, An antioxidant, an angiogenesis inhibitor, an angiotensin receptor blocker, a nitric oxide donor, an antisense oligonucleotide and a complex thereof, a cell cycle inhibitor, a corticosteroid, a hemostatic steroid, an anti-glaucoma agent, But are not limited to, drugs, antibiotics, differentiation regulators, antiviral agents, anticancer agents, anti-inflammatory agents and growth factors.

In the case of the "growth factor" of the drug, it can function to help the implant implanted in the living body stably bind to the bone or the tissue. Therefore, it is desirable to regulate the implant so that it can be released gradually over a long period of time (for example, several weeks to several months) after in vivo implantation. Specific examples of the growth factor include bone morphogenetic proteins (BMPs), epidermal growth factor (EGF), erythropoietin (EPO), fibroblast growth factor FGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), myostatin (GDF-8), nerve growth factor (NGF) (TGF-beta), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor (VEGF). growth factor (VEGF), placental growth factor (PlGF), adrenomedullin (AM), autocrine motility factor, granulocyte-colony stimulating factor (G- CSF), granulocyte macrophage colony stimulating factor (Gr IL-2, IL-4, IL-5, IL-6, IL-6 and IL- -7, but are not limited thereto.

The "antibiotic" of the drug also functions to inhibit the initial inflammatory response due to the in vivo rejection reaction according to the implantation of the metal implant of the present invention. Since inflammation is particularly likely to occur early in the transplantation, it is desirable to regulate such drugs to be released early (e.g., within a week).

The drugs to be carried on each metal support of the present invention may be the same drug or may be different drugs. That is, the first drug and the second drug of the present invention may be the same or different. In the present invention, the drug may be a single drug or a mixture of two or more drugs.

In addition, the drug release pattern may vary depending on the porosity and / or pore size of the metal support depending on the compression ratio (degree of compression) of the metal support.

Specifically, in the experimental example of the present invention, it was confirmed that as the compressibility of the metal support increases, the lowered final porosity decreases the loaded drug release rate and the longer the drug release time (Experimental Example 2).

Therefore, when the metal support and / or the drug loaded thereon are different, the release rate and release rate of the drug are controlled according to the compression ratio (degree of compression) of each unit of the metal support, The duration can be different and can be adjusted. It is also possible to adjust the release rate and duration of the drug contained by adjusting the position of the metal support.

Preferably, (i) in the case of immediate-release drugs requiring rapid release into the body, the compressibility may be lowered to increase the porosity and pore size, and the drug-loaded metal scaffold may be located outside the implant, On the contrary, (ii) in the case of sustained-release sustained release drug, the compression rate can be increased to reduce the porosity and pore size, and the drug release pattern can be controlled by positioning the drug-loaded metal support on the inside of the implant have.

On the other hand, the contact portion of the metal support, that is, the interfacial bonding portion having the pore size and porosity different from the pore size and porosity in each metal support, Other drug release patterns may be seen.

The thickness of the interfacial region can be controlled according to the degree of compression (compression ratio) of the metal support, so that three drug release patterns can be derived from a metal implant including two metal supports.

The present invention also relates to a pharmaceutical composition comprising at least one first porous metal support comprising a first drug; And a second porous metal support comprising a second drug, wherein the first porous metal support and the second porous metal support are interlocking to each other at an interface, Wherein the first porous metal support containing the first drug and the second porous metal support containing the second drug are compressed and integrated after the interfacial physical irregularities are bonded to each other.

The metal implant according to the present invention is formed by joining two or more units of metal supports together, and may have a concavo-convex form so as to facilitate joining or bonding between the metal supports. In this case, since the area of the interface (contact surface) to be meshed with each other is widened, it is advantageous to be more strongly bonded or bonded under the same pressure condition. In addition, the bonding strength can be adjusted through the uneven shape to change the bonding strength according to each unit of the metal support. In the case of units with relatively small concavities and convexities, it is possible to separate after bonding because the bonding strength is low, and the units having relatively large concavities and convexities can reduce the separation risk because of high bonding strength.

The material, pore size, or porosity of the first porous metal support and the second porous metal support, and the types of the first and second drugs may be the same or different.

When the number of the first porous metal supports is two or more, the first drugs contained in each first porous metal support may be the same or different from each other, or when two or more of the second porous metal supports are contained, The second drug may be the same or different from each other.

Meanwhile, the metal implant may include at least one first porous metal support containing the first drug; And a second porous metal support containing the second drug may be assembled to have the desired structural form.

It is possible to provide an integrated metal implant having a certain structure like a block by engaging with several metal supports as shown in FIG. The metal implants may be prepared by compressing and bonding one unit at a time, or may be manufactured by positioning several metal supports at a time and compressing the metal supports at a time.

The present invention also provides a method of making a metal implant comprising the steps of:

1) immersing a first porous metal support in a solution comprising a first drug;

2) immersing the second porous metal support in a solution comprising the second drug;

3) maintaining each of the metal supports carrying the drug in the pores in vacuum; And

4) attaching the first porous metal support and the second porous metal support, and then applying pressure to the metal support to engage with each other.

Step 1 and Step 2 are the steps of immersing each metal support in a solution containing the drug, which is a step for supporting the drug in the pores of each metal support. The order of steps 1 and 2 may be reversed, and both steps may be performed at the same time.

Step 3 is a step of maintaining each of the metal supports on which the drug is supported in the pores in vacuum, which removes the air bubbles remaining in the pores to carry the drug to the pores in the metal support to the maximum.

Step 4 is a step of attaching the metal supports to each other and then applying pressure to the both metal supports to join the metal supports to each other to strengthen the bonding between the metal supports on which the drug is loaded, Compressing the support.

In step 4, the pressure is applied to each metal support differently, or the height, surface area, etc. of each metal support are made different, so that even if the same pressure is applied, the compression ratio can be changed, and the porosity / pore size Can be adjusted differently. The pressure for deformation of the metal support can be applied until the support is deformed to a maximum compressibility of about 5%. Specifically, the range of pressure that can be applied to the metal support may be from 0.1 to 2 GPa, but is not limited thereto. For example, in the case of titanium, compression can be applied up to 5% when 2 GPa pressure is applied in 70% porous body. Care should be taken when applying pressure, as compression of the porous body may occur in compression above this.

The present invention can easily adjust the pore size and porosity of a metal support to be used so that a drug can be released with a few release patterns in a single implant, The drug delivery effect can be maximized.

In addition, since the shape is manufactured in accordance with the structure of the site to be treated, it is possible to effectively reduce the stress shielding phenomenon in the conventional metal implant treatment, and it is possible to prevent the drug from being damaged And can effectively prevent the inflammation that may occur after the initial stage.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagrammatic view illustrating a process of manufacturing a metal implant according to the present invention; FIG.
FIG. 2 is a photograph of an electron microscope showing the state of pores after simultaneously compressing metal supports having different heights in the process of manufacturing the metal support of the present invention.
FIG. 3 is a table for measuring the pore size and the porosity after the metal support of the present invention is bonded and compressed.
FIG. 4 is a graph showing the behavior of BMP-2 released from implants prepared by compression at different compression rates.
5 is a view illustrating an example in which several metal supports having a concavo-convex shape are assembled to form a single structure.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are provided for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1: Preparation of Implant

Example 1-1: Preparation of test piece of metal support

A titanium support having a porosity of about 70% as a metal support was prepared. Specifically, 10 g of titanium (Alfa Aesar, Ward Hill, Ma, USA) as a metal powder, 11 g of camphine (C ₁₀ H ₁₆ ) as a freezing medium and 0.2 g of an oligomer polyester (Hypermer KD-4, UniQema, Everburg, Belgium) g were mixed, and the slurry was prepared by ball milling for 24 hours at a temperature of about 60 캜.

Then, the slurry was injected into a mold made of aluminum, the mold was rotated at a rotation speed of 30 rpm, and held at a temperature of about 44 캜 for about 24 hours to form a freeze-molded body. The frozen formed body was separated from the mold, and a freeze medium was removed by holding a temperature of about 50 ° C under a vacuum of 5.0 × 10 ^-3 Torr to remove the freezing medium from the frozen body.

The porous body was heat-treated at about 1300 ° C for about 2 hours to prepare a titanium support having a porosity of about 70%. (Ii) an outer diameter of 12 mm, an inner diameter of 8 mm, a height of 18 mm, a weight of 1.5 (g), a diameter of 8 mm, a height of 18 mm, a weight of 1.2 g and a diameter of 8 mm, g, and an outer diameter of 12 mm, an inner diameter of 8 mm, a height of 14 mm, and a weight of 1.2 g.

Example 1-2: Immersion (coating) and drying step

An internal specimen having a diameter of 8 mm, a height of 18 mm, and a weight of 1.2 g was immersed in 10 ml of a PBS solution in which 1 mg of BMP-2 was dissolved in the titanium support sample prepared in Example 1-1, and then vacuum of about 70 cmHg Lt; / RTI > The vacuum was then released and allowed to stand at normal pressure for 2 hours and then dried for 24 hours.

An external specimen having an outer diameter of 12 mm, an inner diameter of 9 mm, a height of 14 mm, and a weight of 1.2 g was immersed in 10 mL of a PBS solution containing 1 mg of TCH (Tetracycline-hydrochloride) dissolved in the titanium support sample prepared in Example 1-1 , And the vacuum was maintained at a vacuum degree of about 70 cmHg for about 20 minutes. Thereafter, the vacuum was released, allowed to stand at normal pressure for 2 hours, and then dried for 24 hours.

Examples 1-3: Compression and molding steps

As shown in FIG. 1, (i) the BMP-2-supported titanium support prepared in Example 1-2 and (ii) the TCH-supported titanium support prepared in Example 1-2 were bonded together and compressed by applying a pressure of about 1 GPa Implant and drug delivery implants were prepared.

The height (18 mm) of the specimen inside the titanium support carrying the BMP-2 was made larger than the height (14 mm) of the specimen supporting the specimen of the titanium support, thereby making the compression ratio of the titanium support bearing the BMP-2 relatively high The upper end A). Further, different implants were prepared by differently arranging the two supports inside and outside (lower end B in Fig. 1).

Experimental Example 1: Measurement of porosity and pore size of implants

The internal and external porosity and pore size of the implants prepared in Example 1 were observed and measured using a scanning electron microscope.

2 and 3 show the cross-section of the upper end structure of FIG. 1, and A and C, which are portions bearing the TCH with a low compression ratio, are BMP- The porosity is higher than the porosity of B and D,

As shown in FIG. 3, the porosity of the portion bearing the relatively low compressibility TCH is still 70%, while the porosity of the portion having relatively high compressibility BMP-2 is about 60% Respectively.

In addition, the pore size of the TCH-loaded portion having a relatively low compression ratio shows a large pore size of about 340 μm, while the portion having a relatively high compression rate of BMP-2 has a pore size of about 260 μm It is confirmed that the difference is about 80 ~ 100μm.

EXPERIMENTAL EXAMPLE 2: Emission Behavior According to Compression Ratio of Implant

The behavior of releasing BMP-2 in the implant of Example 1 prepared by compression at different compression ratios was measured, and the results are shown in FIG.

As a result, as shown in FIG. 4, it was confirmed that as the compression ratio increases and the final porosity decreases, the drug release rate decreases and the drug release time increases. Thus, it was confirmed that the release rate of BMP-2 (growth factor) and the release rate of TCH (drug) can be controlled by controlling the compression ratio of the carrier.

From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.

Claims (17)

A first porous metal support containing a first drug; And
A second porous metal support containing a second drug, the metal porous support comprising:
Wherein the first porous metal support and the second porous metal support are compressed and engagingly coupled.
The method of claim 1, wherein the first porous metal support is in the form of a hollow, and the second porous metal support is in a form insertable into the hollow of the first porous metal support. Implant.
The metal implant according to claim 1, wherein the first porous metal support and the second porous metal support are each compressed at different compression ratios.
The metal implant according to claim 1, wherein porosities of the first porous metal support and the second porous metal support are different from each other.
2. The metal implant according to claim 1, wherein the pores of the first porous metal support and the second porous metal support are different from each other.
2. The metal implant of claim 1, wherein the release of the first drug and the release of the second drug respectively from the first porous metal support and the second porous metal support are different.
The metal implant according to claim 1, wherein the porous metal support is titanium, magnesium, iron, aluminum, copper, tantalum or an alloy thereof.
The method of claim 1, wherein the drug is selected from the group consisting of an immune response modifier, an anti-proliferative agent, an anti-mitotic agent, an anti-platelet agent, a platinum coordination complex, a hormone, an anticoagulant, An antibiotic, an antibiotic, an anti-glaucoma drug, an angiogenesis inhibitor, an angiogenesis drug, an angiotensin receptor blocker, a nitric oxide donor, an antisense oligonucleotide and a combination thereof, a cell cycle inhibitor, a corticosteroid, a hemostatic steroid, Wherein the drug is at least one selected from the group consisting of an anti-inflammatory agent, a regulatory substance, an antiviral agent, a growth factor, an anti-cancer agent, and an anti-inflammatory agent.
9. The method of claim 8, wherein the growth factor is selected from the group consisting of bone formation inducing protein, epidermal growth factor, erythropoietin, fibroblast growth factor, hepatocyte growth factor, insulin like growth factor, myostatin, nerve growth factor, neurotrophin, A granulocyte macrophage colony-stimulating factor, a growth differentiation factor, IL-1, a growth factor, a growth factor, an angiogenic growth factor, a placental growth factor, adrenomedullin, Wherein the drug is at least one selected from the group consisting of IL-2, IL-3, IL-4, IL-5, IL-6 and IL-7.
The metal implant according to claim 1, wherein the porosity of the porous metal support is 60 to 80%.
At least one first porous metal support containing a first drug; And
A second porous metal support comprising a second drug, wherein the second porous metal support is a bonded and integrated metal implant,
The first porous metal support and the second porous metal support have an irregular shape interlocking with each other at an interface,
Wherein the first porous metal support containing the first drug and the second porous metal support containing the second drug are compressed and integrated after physical interfacial bonding.
The metal implant according to claim 11, wherein the first porous metal support and the second porous metal support are characterized in that at least one of material, pore size and porosity are the same or different from each other.
12. The metal implant according to claim 11, wherein the first drug and the second drug are the same or different.
12. The method of claim 11, wherein if the number of the first porous metal supports is two or more, the first drug contained in each first porous metal support is the same or different,
Wherein the second medicament contained in each second porous metal support is the same or different from each other if there are more than one second porous metal support.
12. The method of claim 11, wherein the at least one first porous metal support comprises a first drug; And a second porous metal support comprising a second drug, and having a predetermined structure.
1) immersing a first porous metal support in a solution comprising a first drug;
2) immersing the second porous metal support in a solution comprising the second drug;
3) maintaining each of the metal supports carrying the drug in the pores in vacuum; And
4) attaching the first porous metal support and the second porous metal support, and then applying pressure to engage the metal support;
A method of manufacturing a metal implant capable of multiple release of the drug of claim 1.
17. The method of claim 16, wherein in step 4), the first porous metal support and the second porous metal support are compressed at different pressure ratios, respectively.

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