CN105832653A - Biological absorbable foamed magnesium adhesive-matrix type targeted drug slow-release carrier and preparation method - Google Patents

Abstract

The invention discloses a bioabsorbable foamed magnesium storage type targeted drug controlled release carrier and a preparation method. The carrier includes a cylinder with an open end and a cylinder cover matching the opening; the cylinder and the cylinder cover are threaded; the cylinder and the cylinder cover are made of foamed magnesium material, so Connected micropores with a pore size of 100-500 μm are evenly distributed in the foamed magnesium material for sustained release of drugs. After the carrier is loaded with drugs and implanted into diseased bone tissue, it can realize the controlled release of drugs at a fixed point, be biodegradable and absorbable, and help the growth of new bone tissue. The mechanical properties of foamed magnesium similar to natural bone enable it to be used in weight-bearing parts of the human body. Its preparation method selects polystyrene microspheres and magnesium powder to prepare foamed magnesium by powder metallurgy, and uses mechanical processing to process the foamed magnesium into a cylinder with a cylinder cover to form a capsule-shaped drug carrier, and the inner and outer surfaces of the carrier are formed 1 ~ ₂ μm thick MgF2 chemical conversion coating, the method is simple and reliable.

Description

Bioabsorbable foam magnesium storage type targeted drug controlled release carrier and preparation method

technical field

The invention belongs to the technical field of implantable biomedical drug carriers, and in particular relates to a bioabsorbable foam magnesium storage-type targeted drug controlled release carrier and a preparation method.

Background technique

The controlled-release drug delivery system is a new type of preparation that can provide stable and continuous drug delivery, effectively control the blood drug concentration, and overcome the peak-valley phenomenon. In the clinical treatment of human bone cancer, bone tuberculosis and other diseases, it is necessary to use drugs that are effective but highly toxic or prone to toxic side effects such as liver and kidney damage after a large amount of use, to study a bioabsorbable targeted drug control It is very necessary to release the carrier, which is loaded with drugs and implanted into the diseased part of the human body, and only directly and continuously releases the drug to the patient part, reducing side effects on other parts; at the same time, the carrier needs to be able to degrade in the body, improve the formation of bone tissue and recovery, thereby avoiding secondary surgery.

Chinese patent application number 200410060732.6 discloses polylactic acid and apatite depot-type drug carrier and its preparation method. The method can be used to prepare porous drug carriers with a pore size of 10-500 μm that can absorb and release drugs. However, apatite itself is brittle, the strength and elastic modulus of porous polylactic acid are lower than those of natural bone, and the interfacial bonding strength of composite materials composed of apatite and polylactic acid is low. Poor lactic acid drug carriers have poor mechanical properties, making it difficult to use them in load-bearing parts of the human body. In addition, the shaping and pore creation of special-shaped carriers are difficult, and the pore size distribution is wide and difficult to control. Therefore, the development of biodegradable and absorbable drug carriers with mechanical properties and porous structures similar to natural bone has important application value.

Other bioceramic or polymer reservoir-type porous drug carriers also have the problems of poor mechanical properties, shape-shaped carriers, and difficulties in pore formation.

Contents of the invention

In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a bioabsorbable foamed magnesium reservoir-type targeted drug controlled release carrier with good mechanical properties, easy to be degraded and absorbed by the human body, and capable of avoiding secondary operations. The preparation method is provided. When the carrier is prepared by the method, the forming and pore-making are simple and easy, and the pore diameter is controllable.

In order to achieve the above object, the technical scheme adopted in the present invention is as follows:

The bioabsorbable foam magnesium storage-type targeted drug controlled release carrier comprises a cylinder with one end open and a cylinder cover matching the opening; the cylinder and the cylinder cover are threaded; the The cylinder body and the cylinder cover are made of foamed magnesium material, and the connected micropores with a pore size of 100-500 μm are uniformly distributed in the foamed magnesium material, which is suitable for the diffusion-controlled sustained release of drugs.

When in use, the medicine is put into the cylinder and the cylinder cap is screwed tightly, and then the carrier is implanted into the bone disease site of the human body. The drug will continuously penetrate directly into the affected area through the connected micropores. If the connected micropores are too large, the effect of sustained release cannot be achieved, and if they are too small, it will affect the penetration of the drug and cause the dosage to fail to meet the requirements.

Further, the total volume of the interconnected micropores accounts for 30-60% of the total volume of the foamed magnesium material. Only when the proportion of the total volume of the connected micropores is appropriate can the mechanical properties of the material and the bone tissue be guaranteed while meeting the dosage. If the ratio is too large, the mechanical strength of the material may be difficult to match with the host bone tissue, and if the ratio is too small, it will lead to insufficient dosage.

Further, the inner and outer surfaces of the cylinder body and the cylinder cover are covered with a MgF2 chemical conversion film with a thickness of _1-2 μm to delay the degradation rate of the foamed magnesium material.

Further, the wall thickness of the cylinder is 2-5mm. The thickness of the cylinder is directly related to the drug release effect and mechanical strength of the carrier. If it is too thin, the carrier will be easily deformed or even broken, which will lead to early disintegration of the drug and cannot achieve the sustained release effect; if it is too thick, the filling volume of the drug will be limited and the speed of administration will be excessively reduced, which will affect the curative effect.

The preparation method of the above-mentioned bioabsorbable foamed magnesium storage type targeted drug controlled release carrier comprises the following steps:

1) Billet making: Put the microsphere pore-forming agent with a particle size of 150~800μm and magnesium powder into a ball mill tank, mix evenly on a roller ball mill to form a billet-making raw material, and then put the billet-making raw material into the mold and press The tablet machine is pressed into a cylindrical green body under 50~100MPa. The particle size of the microsphere pore-forming agent directly affects the size of the connected micropores of the finished product. Since the pore-forming agent will have a linear shrinkage rate of 30% to 40% during the compression molding and subsequent thermal degradation process, its particle size should be larger than The average pore diameter of the connected micropores of foamed magnesium is about 50% to 60%.

2) Preparation of foamed magnesium: place the green body in a vacuum atmosphere tube electric furnace with a pressure lower than 5×10 ^-3 Pa, raise the temperature to 200°C at 2°C/min and keep it for 2h; then raise the temperature to 500°C at 5°C/min ℃ and keep warm for 2~5h; then let the green body cool down to room temperature naturally under vacuum condition with the vacuum atmosphere tube-type electric furnace, and make the foamed magnesium cylinder. During the heating process, the microsphere pore-forming agent will be thermally degraded at a temperature of 300-450°C and the magnesium powder will be sintered into a solid matrix in the vacuum heating environment at the above temperature, so that the original microsphere-formed body in the cylindrical green body Micropores are formed in the place where the porogen is added, and then the cylindrical green body is heated to form a porous structure.

3) Machining and molding: Cut the foamed magnesium cylinder into two sections along its radial direction, so that the busbar length of one section is longer than the other section, forming a long section and a short section; then process the long section into a cylinder with one end open, And process the internal thread at the opening of the cylinder; process the external thread matching the internal thread on the short section to make the cylinder cover; pour absolute ethanol for cooling during the processing to prevent thermal deformation of the cylinder and the cylinder cover or thermal oxidation; and then ultrasonically cleaned with absolute ethanol for 15 minutes to remove the debris generated during processing, thereby obtaining the bioabsorbable foamed magnesium storage-type targeted drug controlled release carrier.

It also includes the following step of covering the obtained bioabsorbable foam magnesium storage type targeted drug controlled release carrier: soaking the cylinder body and cylinder cover in 40wt% hydrofluoric _acid for 48 hours to form MgF2 Chemical conversion coating; then ultrasonically cleaned with deionized water for 5 minutes, and dried in a blast drying oven at 105-110°C for 0.5-1 hour.

Wherein, the microsphere pore-forming agent described in step 1) is polystyrene microspheres, and the microsphere pore-forming agent accounts for 20 to 50% of the total weight of the billet raw materials, and if the weight ratio of the pore-forming agent is too small, it will It leads to low porosity and pore connectivity, and if the ratio is too high, the size of the connected pores is too large and the mechanical strength is reduced.

The median diameter of the magnesium powder described in step 1) is less than 200 μm and the purity is greater than 99.9%. The particle size and purity of the magnesium powder directly affect the performance of the finished product: too thick magnesium powder will reduce the sintered density and mechanical strength of the magnesium matrix ; High purity prevents the introduction of impurities or toxic elements with poor biocompatibility.

The ratio of the bus length of the long section to the short section described in step 3) is 3:1. This not only facilitates mechanical processing, but also ensures that the cylinder body and the cylinder cover can be fully rotated and have sufficient drug-loading volume.

Foamed magnesium has a connected porous structure and mechanical properties close to natural bone. It has good biocompatibility, is easy to degrade and absorb, and magnesium is an essential element for the human body. The foamed magnesium storage-type targeted drug-controlled release carrier can realize the controlled release of drugs and nutrition. The transmission of substances helps the growth of new bone, so as to realize the targeted treatment of orthopedic diseases and the regeneration of bone tissue.

Compared with the prior art, the present invention has the following beneficial effects:

1. The bioabsorbable foam magnesium storage-type targeted drug controlled-release carrier provided by the present invention is filled with drugs and implanted into diseased bone tissue to achieve targeted drug release, biodegradable absorption, and beneficial to bone tissue regeneration. The porous structure of magnesium foam is similar to that of natural bone, which helps the carrier to release drugs in a controlled manner, deliver nutrients and grow into new bone tissue.

2. Magnesium foam has mechanical properties similar to natural bone, so it can be used in the weight-bearing parts of the human body. _The MgF2 chemical conversion coating can delay the degradation rate of foamed magnesium, thereby ensuring that the carrier has proper mechanical properties before the bone tissue grows into it.

3. Polystyrene microspheres with different weight ratios of polystyrene in the mixture and different particle sizes can be selected to control the porosity and pore size of the carrier, and the shape and capacity of the carrier can be customized by mechanical processing; the preparation process is simple and easy OK, high reliability.

detailed description

The present invention will be described in further detail below in conjunction with specific embodiments.

Embodiment one

The following steps are adopted to prepare the bioabsorbable foamed magnesium storage type targeted drug controlled release carrier:

1) Take 10.5g of polystyrene with a particle size of 300μm as a microsphere pore-forming agent, put it into a polyurethane ball mill tank together with 19.5g of magnesium powder with a median diameter of 120μm and a purity of 99.9%, and put it on a roller ball mill well mixed. Weigh 10 g of the mixture and put it into a mold and press it with a tablet press at 50 MPa to form a compact cylindrical green body with a diameter of φ15×40 mm.

2) Put the green body in a vacuum atmosphere tube-type electric furnace with a pressure lower than 5×10 ^-3 Pa, raise the temperature to 200°C at 2°C/min and keep it for 2h; then raise the temperature to 500°C at 5°C/min and keep it for 4h ; Then allow the green body to be naturally cooled to room temperature under vacuum conditions with the vacuum atmosphere tube-type electric furnace to make a foamed magnesium cylinder;

3) Cut the obtained foamed magnesium cylinder into long and short sections at a ratio of 3:1. Use a micro machine tool to bore out the inner hole of φ11×28mm in the long section, process it into a cylinder with a wall thickness of 2mm and one end closed, and tap the internal thread at the opening, and process the corresponding external thread in the short section to form The cylinder cover is poured with absolute ethanol for cooling during processing, and then ultrasonically cleaned with absolute ethanol for 15 minutes after processing, thereby obtaining the bioabsorbable foamed magnesium storage-type targeted drug controlled release carrier.

The cylinder and the cylinder cover can be screwed together to form a capsule-like sealed foam magnesium cylinder for filling targeted drugs.

4) Soak the cylinder and cylinder cover in 40wt% hydrofluoric acid for 48 hours, then take them out, ultrasonically clean them with deionized water for 5 minutes, and put them in a blast drying oven at 105°C for 0.5 hours.

Embodiment two

1) Take 6.0g of polystyrene with a particle size of 800μm as a microsphere pore-forming agent, put it into a polyurethane ball mill tank together with 24.0g of magnesium powder with a median diameter of 180μm and a purity of 99.9%, and put it on a roller ball mill well mixed. Weigh 11 g of the mixture and put it into a mold with a tablet press under 50 MPa to form a dense cylindrical green body with a diameter of φ15×40 mm.

2) Put the green body in a vacuum atmosphere tube-type electric furnace with a pressure lower than 5×10 ^-3 Pa, raise the temperature to 200°C at 2°C/min and keep it for 2h; then raise the temperature to 500°C at 5°C/min and keep it for 2h ; Then allow the green body to be naturally cooled to room temperature under vacuum conditions with the vacuum atmosphere tube-type electric furnace to make a foamed magnesium cylinder;

3) Cut the obtained foamed magnesium cylinder into long and short sections at a ratio of 3:1. Use a micro machine tool to bore out the inner hole of φ5×25mm in the long section, process it into a cylinder with a wall thickness of 5mm and one end closed, and tap the internal thread at the opening, and process the corresponding external thread in the short section to form The cylinder cover is poured with absolute ethanol for cooling during processing, and then ultrasonically cleaned with absolute ethanol for 15 minutes after processing, thereby obtaining the bioabsorbable foamed magnesium storage-type targeted drug controlled release carrier.

The cylinder and the cylinder cover can be screwed together to form a capsule-like sealed foam magnesium cylinder for filling targeted drugs.

4) Soak the cylinder and cylinder cover in 40wt% hydrofluoric acid for 48 hours, then take them out, ultrasonically clean them with deionized water for 5 minutes, and put them in a blast drying oven at 105°C for 0.5 hours.

Embodiment three

1) Take 15.0 g of polystyrene with a particle size of 153 μm as a microsphere pore-forming agent, put it into a polyurethane ball mill tank together with 15.0 g of magnesium powder with a median diameter of 110 μm and a purity of 99.9%, and place it on a roller ball mill well mixed. Weigh 9.3 g of the mixture, put it into a mold, and press it under 50 MPa with a tablet machine to form a dense cylindrical body with a diameter of φ15×40 mm.

2) Put the green body in a vacuum atmosphere tube-type electric furnace with a pressure lower than 5×10 ^-3 Pa, raise the temperature to 200°C at 2°C/min and keep it for 2h; then raise the temperature to 500°C at 5°C/min and keep it for 5h ; Then allow the green body to be naturally cooled to room temperature under vacuum conditions with the vacuum atmosphere tube-type electric furnace to make a foamed magnesium cylinder;

3) Cut the obtained foamed magnesium cylinder into long and short sections at a ratio of 3:1. Use a micro machine tool to bore out the inner hole of φ9×27mm in the long section, process it into a cylinder with a wall thickness of 3mm and one end closed, and tap the internal thread at the opening, and process the corresponding external thread in the short section to form The cylinder cover is poured with absolute ethanol for cooling during processing, and then ultrasonically cleaned with absolute ethanol for 15 minutes after processing, thereby obtaining the bioabsorbable foamed magnesium storage-type targeted drug controlled release carrier.

The cylinder and the cylinder cover can be screwed together to form a capsule-like sealed foam magnesium cylinder for filling targeted drugs.

4) Soak the cylinder and cylinder cover in 40wt% hydrofluoric acid for 48 hours, then take them out, ultrasonically clean them with deionized water for 5 minutes, and put them in a blast drying oven at 105-110°C for 1 hour.

The above-mentioned embodiments of the present invention are only examples for illustrating the present invention, rather than limiting the implementation of the present invention. For those of ordinary skill in the art, other changes in various forms can also be made on the basis of the above description. All the implementation manners cannot be exhaustively listed here. All obvious changes derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims (9)

1. the foam magnesium depot targeted drug controlled release carrier of biological absorbable, it is characterised in that include the cylinder of open at one end And with this uncovered cover matched；It is threaded between described cylinder and cover；Described cylinder and cover are by foam Magnesium material is made, and is evenly distributed with the connection micropore that aperture is 100 ~ 500 μm, for slow releasing medicinal in described foam magnesium material Thing.

The foam magnesium depot targeted drug controlled release carrier of biological absorbable the most according to claim 1, it is characterised in that The cumulative volume of described connection micropore accounts for 30 ~ 60% that described foam magnesium all materials is long-pending.

The foam magnesium depot targeted drug controlled release carrier of biological absorbable the most according to claim 1, it is characterised in that Described cylinder and the inner and outer surfaces of cover are all covered with the MgF that thickness is 1 ~ 2 μm₂Chemical composition coating, in order to delay foam magnesium The degradation rate of material.

The foam magnesium depot targeted drug controlled release carrier of biological absorbable the most according to claim 1, it is characterised in that The wall thickness of described cylinder is 2 ~ 5mm.

5. the preparation method of the foam magnesium depot targeted drug controlled release carrier of biological absorbable as claimed in claim 1, its It is characterised by, comprises the following steps:

1) base: microballoon pore creating material and magnesium powder that particle diameter is 150 ~ 800 μm are put in ball grinder, mixes on roll-type ball mill Uniformly, base raw material is formed；Base raw material loading mould tablet press machine is pressed under 50 ~ 100MPa the base of cylinder again Body；

2) foam magnesium is prepared: base substrate is placed in pressure less than 5 × 10^-3In the vacuum atmosphere tube type electric furnace of Pa, heat up with 2 DEG C/min To 200 DEG C and be incubated 2h；It is warming up to 500 DEG C with 5 DEG C/min again and is incubated 2 ~ 5h；Then allow described base substrate with vacuum atmosphere tube type Electric furnace naturally cools to room temperature under vacuum, prepares foamed magnesium cylinders；

3) machining shaping: foamed magnesium cylinders is radially cut in two so that it is in the bus length of a section more than another One section, form long section and short section；Long section is processed into the cylinder of open at one end, and spiral shell in the open-mouth of this cylinder is processed again Line；Short section is processed the external screw thread mated with internal thread, makes cover；Process is watered pouring absolute ethyl alcohol cool down； Then with absolute ethyl alcohol ultrasonic cleaning 15min, to remove the chip that processing produces, the bubble of described biological absorbable is thus obtained Foam magnesium depot targeted drug controlled release carrier.

Preparation method the most according to claim 5, it is characterised in that also include the bubble of the following biological absorbable to obtaining The step of foam magnesium depot targeted drug controlled release carrier overlay film:

Described cylinder and cover are placed in 40wt% hydrofluoric acid immersion 48h, to form MgF₂Chemical composition coating；Use deionization again Water ultrasonic cleaning 5min, and put in air dry oven in 105 ~ 110 DEG C of baking 0.5 ~ 1h.

Preparation method the most according to claim 5, it is characterised in that microballoon pore creating material described in step 1) is polystyrene Microballoon, described microballoon pore creating material accounts for the 20 ~ 50% of base raw material gross weight.

Preparation method the most according to claim 5, it is characterised in that meso-position radius ＜ 200 μ of the magnesium powder described in step 1) M, purity are more than 99.9%.

Preparation method the most according to claim 5, it is characterised in that the long section described in step 3) is long with the bus of short section The ratio of degree is 3:1.