CN108452368A - Sodium alginate drug-loaded embolism microsphere and preparation method and device thereof - Google Patents

Abstract

The invention provides a sodium alginate drug-loaded embolism microsphere and a preparation method and a device thereof. The preparation method comprises the following steps: (1) dissolving the drug liposome in sodium alginate solution, and stirring to uniformly disperse the drug liposome into mixed solution; (2) and (3) allowing the mixed solution to permeate into the curing solution under the action of pressure to obtain the sodium alginate drug-loaded embolism microsphere. The sodium alginate drug-loaded embolism microsphere provided by the invention has the advantages of uniform particle size, controllable size, simple and convenient operation of the preparation method, capability of completing solidification in situ, and great development prospect.

Description

Sodium alginate drug-loaded embolization microspheres and its preparation method and device

technical field

The invention relates to the field of biomedical engineering, and more specifically, relates to a sodium alginate drug-loaded embolic microsphere, a preparation method and a device thereof.

Background technique

Interventional radiology is a new discipline developed in recent years. It is a minimally invasive medical technology guided by imaging equipment. It has the characteristics of small trauma, fast recovery, and good curative effect. treatment pathway. Interventional embolization is an important part of interventional therapy, and it is increasingly playing an important role in the treatment of malignant tumors, vascular malformations, uterine fibroids and hemostasis.

Transcatheter vascular embolization (TACE) technology is a kind of interventional therapy. It mainly injects embolic agents into the supply vessels of the diseased target organs through arterial or intravenous catheters, so as to occlude the vessels and interrupt the blood supply, and finally achieve the purpose of treatment. .

The embolic materials currently used in clinic mainly include gelatin sponge, polyvinyl alcohol (PVA) microspheres, absolute alcohol, iodized oil, detachable balloons, coils, etc., which are commonly used in vascular intervention. Among them, drug-loaded microspheres are a new dosage form of drugs, which are micro-spherical solids formed by wrapping solid or liquid drugs and solidifying them by using polymer materials such as starch, chitosan, polylactic acid, and gelatin as carriers. Skeletons have different diameters, generally 1-300 μm, or even larger, and belong to matrix-type skeleton particles. The release of drugs in microspheres can slow down the release rate of drugs encapsulated in microspheres through methods such as skeleton erosion, surface erosion, overall disintegration, water vapor expansion, dissociation diffusion, and desorption. The number of medications can reduce the peak and valley phenomenon of drugs. It is currently the most concerned embolic agent. However, the microsphere embolic agents currently on the market are mainly PVA materials, which have the disadvantages of non-degradable, non-uniform particle size, and uncontrollable size.

The raw material used for sodium alginate microspheres is a natural polysaccharide extracted from natural plant brown algae, composed of β-D-mannose and β-L-gulose, with a molecular weight between 50,000 and 100,000, and has medicinal properties Stability, solubility, viscosity and safety required for formulation excipients. Sodium alginate has strong hydrophilicity and will form a viscous uniform solution when dissolved in water. In the presence of calcium ions (or other divalent metal salt ions), it will produce cross-linking and solidification between macromolecular chains. It can be processed into different types according to needs. specifications of solid microspheres.

Sodium alginate also has excellent biocompatibility, and is non-toxic and degradable within 6 months in a biological environment. Sodium alginate microsphere vascular embolism agent physically blocks the small arteries around the tumor or treatment site, causing corresponding vascular atresia, cutting off the nutrition and blood supply to the tissue at the site, resulting in its atrophy and necrosis due to ischemia and hypoxia; Or by reducing the blood supply of the target organ to create favorable conditions for surgery. This kind of microspheres can be used as a vascular embolism agent for the treatment of liver cancer or other solid tumors, and can be released to the local lesion tissue in a targeted and directional manner, so that the lesion tissue can be necrotic to achieve the purpose of embolization therapy; or it can be used in combination with chemotherapy drugs (putting the drug into In microspheres, drugs are carried by chemical bonding or physical adsorption) to improve the local efficacy of chemotherapy drugs and reduce the toxic and side effects of drugs.

Based on this, the prior art needs to be improved.

Contents of the invention

The object of the present invention is to provide a sodium alginate drug-loaded embolic microsphere and a preparation method and device thereof. The invention intends to use sodium alginate as a carrier to carry medicines to prepare embolism microspheres with uniform particle size and controllable size. The sodium alginate drug-loaded embolic microspheres provided by the invention have uniform particle size, controllable size, simple and convenient preparation method, and can be solidified in situ.

Technical scheme of the present invention is as follows:

According to the present invention, there is provided a preparation method of sodium alginate drug-loaded embolic microspheres, comprising the following steps:

(1) dissolving the drug liposome in the sodium alginate solution, stirring to make it uniformly dispersed into a mixed solution;

(2) The mixed solution is permeated through the membrane under the action of pressure, and permeates into the solidification solution to obtain the sodium alginate drug-loaded embolic microspheres.

According to an embodiment of the present invention, in step (1), the drug liposome is one of liposomes of doxorubicin, liposomes of sorafenib, and liposomes of paclitaxel.

According to an embodiment of the present invention, in step (2), the membrane is a microporous membrane,

According to an embodiment of the present invention, the pore diameter of the microporous membrane is 100-200 μm, and the membrane thickness of the microporous membrane is 1-3 mm.

According to an embodiment of the present invention, the pressure in step (2) is 120-150KPa.

According to an embodiment of the present invention, in step (1), the concentration of the sodium alginate solution is 1-5 wt%.

According to an embodiment of the present invention, in step (1), the stirring is mechanical stirring, and the condition is: stirring for 10 minutes at a rotating speed of 5000 rpm.

According to an embodiment of the present invention, in step (2), the solidification liquid is a calcium chloride solution with a concentration of 10-30 wt%. Wherein, in step (2), sodium alginate and calcium ion are cross-linked and solidified to obtain sodium alginate drug-loaded embolic microspheres.

According to an embodiment of the present invention, in step (2), the flow rate of the solidification liquid is controlled at 0.5-8 mL/h.

According to the present invention, there is provided a sodium alginate drug-loaded embolic microsphere, which is prepared by the above-mentioned preparation method.

According to an embodiment of the present invention, the particle size distribution of the sodium alginate drug-loaded embolic microspheres is 120-500 μm, and the particle size of the sodium alginate drug-loaded embolic microspheres is adjustable, specifically according to the pore size of the microporous membrane, curing The concentration of the liquid and the flow rate of the solidified liquid are adjusted.

According to the present invention, there is provided a device for preparing sodium alginate drug-loaded embolic microspheres, comprising:

The first container, the first container includes a pressurizing device, and is used to hold a mixed solution of drug liposome and sodium alginate solution;

a second container, the second container is used to make the solidification liquid flow therein at a constant speed;

The first container is arranged on the upper part of the second container, and the first container communicates with the second container through the membrane.

According to an embodiment of the present invention, the flow direction of the mixed solution in the first container is vertically downward, that is, the mixed solution flows into the second container through the membrane arranged at the lower part of the first container.

According to an embodiment of the present invention, the flow direction of the solidification liquid in the second container is a horizontal direction, that is, the flow direction of the solidification liquid is perpendicular to the flow direction of the mixed solution.

According to an embodiment of the present invention, the second container further includes an outlet, which is used to discharge the solidification solution and the sodium alginate drug-loaded embolic microspheres formed therein.

Compared with the preparation technology of the existing embolic microspheres, the preparation method of the present invention has the following advantages:

1) The present invention uses degradable sodium alginate as a material, which has excellent biocompatibility. For the first time, the present invention uses drug liposomes combined with sodium alginate to form microspheres; the microspheres are loaded with drugs at the same time. Degradation of sodium, slow drug release, clinically reduce drug dosage and side effects.

2) The sodium alginate drug-loaded microspheres of the present invention have a drug-loading capacity of 2-10% and an encapsulation efficiency of 86.7-95.3%.

3) The preparation method of the present invention is simple, and the sodium alginate drug-loaded embolization microspheres can be obtained only by using the mixed solution to permeate through the microporous membrane into the solidification liquid under the action of pressure. The particle size of the obtained embolization microspheres is controllable, which avoids the disadvantage of obtaining microspheres of suitable size through screening in the traditional method, and can complete in-situ solidification, which has great development prospects.

Description of drawings

Fig. 1 is the schematic diagram of the principle of preparing sodium alginate drug-loaded embolic microspheres of the present invention;

Fig. 2 is the illustration under the microscope of preparing sodium alginate drug-loaded embolic microspheres by the preparation method of the present invention;

Fig. 3 is a flowchart of the preparation method of sodium alginate drug-loaded embolic microspheres.

Detailed ways

In order to make the object, technical solution and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described here are only used to explain the present invention, not to limit the present invention.

The invention provides a device for preparing sodium alginate drug-loaded embolic microspheres, comprising:

The first container, the first container includes a pressurizing device, and is used to hold a mixed solution of drug liposome and sodium alginate solution;

The second container is used to make the solidification liquid flow therein at a constant speed; the second container also includes an outlet, and the outlet is used to discharge the solidification liquid and the sodium alginate drug-loaded embolic microspheres formed therein.

The first container is arranged on the upper part of the second container, and the first container communicates with the second container through the membrane.

The flow direction of the mixed solution in the first container is vertically downward, that is, the mixed solution flows into the second container through the membrane arranged at the lower part of the first container. The flow direction of the solidified liquid in the second container is the horizontal direction, that is, the flow direction of the solidified liquid is perpendicular to the flow direction of the mixed solution.

Example 1

This embodiment provides a sodium alginate drug-loaded embolic microsphere, which is prepared through the following steps (as shown in Figure 3):

A liposome solution with a concentration of 1 g/L of doxorubicin was mixed with a sodium alginate solution with a concentration of 4 wt %, mechanically stirred at 25° C. at a speed of 5000 rpm for ten minutes, and dispersed uniformly into a mixed solution.

As shown in Figure 1, the mixed solution is passed through the microporous membrane under pressure, and penetrates into the solidified solution (calcium chloride solution) with a concentration of 10wt%, wherein the microporous membrane aperture is 100 μm, the thickness is 1mm, and the pressure is 120KPa, the solidification liquid flow rate is 2mL/h. Droplets are generated through the pore outlet of the microporous membrane, and at the same time, they are cross-linked with calcium ions at a concentration of 10wt%, and solidified to form sodium alginate drug-loaded embolization microspheres; the particle size of sodium alginate drug-loaded embolization microspheres is 120 μm, and the size The deviation is 4%.

Sodium alginate drug-loaded embolic microspheres were dissolved in acetonitrile, degraded overnight after ultrasonication for 20 min, and the supernatant was collected by centrifugation for HPLC (high performance liquid chromatography) determination to obtain the drug concentration of the drug. The drug loading capacity of the sodium alginate drug-loaded embolic microspheres is 2.5%, and the encapsulation efficiency is 90.6%.

Example 2

This embodiment provides a sodium alginate drug-loaded embolic microsphere, which is prepared through the following steps (as shown in Figure 3):

Take the liposome solution of Sorafenib with a concentration of 1g/L and mix it with a sodium alginate solution with a concentration of 4wt%, mechanically stir for ten minutes at 25°C and a speed of 5000rpm, and evenly disperse into a mixed solution.

As shown in Figure 1, the mixed solution is passed through the microporous membrane under pressure, and penetrates into the solidified solution (calcium chloride solution) with a concentration of 10wt%, wherein the microporous membrane aperture is 120 μm, the thickness is 2mm, and the pressure is 130KPa, the solidification liquid flow rate is 2mL/h. Droplets are generated through the pore outlet of the microporous membrane, and at the same time, they are cross-linked with calcium ions at a concentration of 10wt%, and solidified to form sodium alginate drug-loaded embolization microspheres; the particle size of sodium alginate drug-loaded embolization microspheres is 160 μm, and the size The deviation is 4%.

Sodium alginate drug-loaded embolic microspheres were dissolved in acetonitrile, degraded overnight after ultrasonication for 20 min, and the supernatant was collected by centrifugation for HPLC (high performance liquid chromatography) determination to obtain the drug concentration of the drug. The drug loading capacity of the sodium alginate drug-loaded embolic microspheres is 4%, and the encapsulation efficiency is 86.7%.

Example 3

This embodiment provides a sodium alginate drug-loaded embolic microsphere, which is prepared through the following steps (as shown in Figure 3):

A liposome solution of paclitaxel with a concentration of 1 g/L was mixed with a sodium alginate solution with a concentration of 3 wt %, mechanically stirred at 25° C. at a speed of 5000 rpm for ten minutes, and dispersed uniformly into a mixed solution.

As shown in Figure 1, the mixed solution is passed through the microporous membrane under pressure, and penetrates into the solidified solution (calcium chloride solution) with a concentration of 10wt%, wherein the microporous membrane aperture is 120 μm, the thickness is 2mm, and the pressure is 150KPa, the solidification liquid flow rate is 3mL/h. Droplets are generated through the pore outlet of the microporous membrane, and at the same time, they are cross-linked with calcium ions at a concentration of 10wt%, and solidified to form sodium alginate drug-loaded embolization microspheres; the particle size of sodium alginate drug-loaded embolization microspheres is 380 μm, and the size The deviation is 4%.

Sodium alginate drug-loaded embolic microspheres were dissolved in acetonitrile, degraded overnight after ultrasonication for 20 min, and the supernatant was collected by centrifugation for HPLC (high performance liquid chromatography) determination to obtain the drug concentration of the drug. The drug loading capacity of the sodium alginate drug-loaded embolic microspheres is 3%, and the encapsulation efficiency is 88.4%.

Example 4

This embodiment provides a sodium alginate drug-loaded embolic microsphere, which is prepared through the following steps (as shown in Figure 3):

Take the liposome solution of Sorafenib with a concentration of 1g/L and mix it with a sodium alginate solution with a concentration of 5wt%, mechanically stir at 25°C and a speed of 5000rpm for ten minutes, and evenly disperse into a mixed solution.

As shown in Figure 1, the mixed solution is passed through the microporous membrane under pressure, and penetrates into the solidification solution (calcium chloride solution) with a concentration of 10wt%, wherein the microporous membrane aperture is 150 μm, the thickness is 3mm, and the pressure is 120KPa, the solidification liquid flow rate is 3mL/h. Droplets are generated through the pore outlet of the microporous membrane, and at the same time, they are cross-linked with calcium ions at a concentration of 10 wt%, and solidified to form sodium alginate drug-loaded embolization microspheres; the particle size of sodium alginate drug-loaded embolization microspheres is about 230 μm ( As shown in Figure 2), the size deviation is 4%.

Sodium alginate drug-loaded embolic microspheres were dissolved in acetonitrile, degraded overnight after ultrasonication for 20 min, and the supernatant was collected by centrifugation for HPLC (high performance liquid chromatography) determination to obtain the drug concentration of the drug. The drug-loading amount of the sodium alginate drug-loaded embolic microsphere is 3%, and the encapsulation efficiency is 90.8%.

Example 5

This embodiment provides a sodium alginate drug-loaded embolic microsphere, which is prepared through the following steps (as shown in Figure 3):

A liposome solution with a concentration of 1 g/L of doxorubicin was mixed with a sodium alginate solution with a concentration of 1 wt%, mechanically stirred for ten minutes at 25° C. at a speed of 5000 rpm, and dispersed uniformly into a mixed solution.

As shown in Figure 1, the mixed solution is passed through the microporous membrane under pressure, and penetrates into the solidified solution (calcium chloride solution) with a concentration of 10wt%, wherein the microporous membrane aperture is 200 μm, the thickness is 2mm, and the pressure is 120KPa, the solidification liquid flow rate is 0.4mL/h. Droplets are generated through the pore outlet of the microporous membrane, and at the same time, they are cross-linked with calcium ions at a concentration of 10 wt%, and solidified to form sodium alginate drug-loaded embolization microspheres; the particle size of sodium alginate drug-loaded embolization microspheres is 500 μm, and the size The deviation is 4%.

Sodium alginate drug-loaded embolic microspheres were dissolved in acetonitrile, degraded overnight after ultrasonication for 20 min, and the supernatant was collected by centrifugation for HPLC (high performance liquid chromatography) determination to obtain the drug concentration of the drug. The drug-loading capacity of the sodium alginate drug-loaded embolic microspheres is 10%, and the encapsulation efficiency is 95.2%.

Example 6

This embodiment provides a sodium alginate drug-loaded embolic microsphere, which is prepared through the following steps (as shown in Figure 3):

A liposome solution with a concentration of 1 g/L of doxorubicin was mixed with a sodium alginate solution with a concentration of 2 wt %, mechanically stirred at 25° C. and a speed of 5000 rpm for ten minutes, and dispersed uniformly into a mixed solution.

As shown in Figure 1, the mixed solution is passed through the microporous membrane under pressure, and penetrates into the solidified solution (calcium chloride solution) with a concentration of 30wt%, wherein the microporous membrane aperture is 180 μm, the thickness is 2mm, and the pressure is 140KPa, the solidification liquid flow rate is 8mL/h. Droplets are generated through the pore outlet of the microporous membrane, and at the same time, they are cross-linked with calcium ions at a concentration of 30wt%, and solidified to form sodium alginate drug-loaded embolization microspheres; the particle size of sodium alginate drug-loaded embolization microspheres is 200 μm, and the size The deviation is 4%.

Sodium alginate drug-loaded embolic microspheres were dissolved in acetonitrile, degraded overnight after ultrasonication for 20 min, and the supernatant was collected by centrifugation for HPLC (high performance liquid chromatography) determination to obtain the drug concentration of the drug. The drug loading capacity of sodium alginate drug-loaded embolic microspheres is 4%, and the encapsulation efficiency is 87.7%.

Example 7

This embodiment provides a sodium alginate drug-loaded embolic microsphere, which is prepared through the following steps (as shown in Figure 3):

Take the liposome solution of Sorafenib with a concentration of 1g/L and mix it with a sodium alginate solution with a concentration of 4wt%, mechanically stir for ten minutes at 25°C and a speed of 5000rpm, and evenly disperse into a mixed solution.

As shown in Figure 1, the mixed solution is passed through the microporous membrane under pressure, and penetrates into the solidified solution (calcium chloride solution) with a concentration of 20wt%, wherein the microporous membrane aperture is 100 μm, the thickness is 1mm, and the pressure is 120KPa, the solidification liquid flow rate is 0.5mL/h. Droplets are generated through the pore outlet of the microporous membrane, and at the same time, they are cross-linked with calcium ions at a concentration of 20 wt%, and solidified to form sodium alginate drug-loaded embolization microspheres; the particle size of sodium alginate drug-loaded embolization microspheres is 430 μm, and the size The deviation is 4%.

Sodium alginate drug-loaded embolic microspheres were dissolved in acetonitrile, degraded overnight after ultrasonication for 20 min, and the supernatant was collected by centrifugation for HPLC (high performance liquid chromatography) determination to obtain the drug concentration of the drug. The drug-loading amount of the sodium alginate drug-loaded embolic microsphere is 3%, and the encapsulation efficiency is 95.3%.

The above description is only a preferred embodiment of the present invention, and is not intended to limit the implementation scope of the present invention; if it does not depart from the spirit and scope of the present invention, any modification or equivalent replacement of the present invention shall be covered by the claims of the present invention. within the scope of protection.

Claims (10)

1. a kind of sodium alginate carries the preparation method of medicine embolism microball, which is characterized in that include the following steps：

(1) medicinal liposome is dissolved in sodium alginate soln, stirring keeps its evenly dispersed at mixed solution；

(2) mixed solution is penetrated into film under pressure, penetrated into solidify liquid, it is micro- to obtain sodium alginate load stype plug Ball.

2. preparation method according to claim 1, which is characterized in that in the step (1), the medicinal liposome be Ah The liposome of mycin, the liposome of Sorafenib, taxol liposome in one kind.

3. preparation method according to claim 1, which is characterized in that in the step (2), the film is microporous barrier.

4. preparation method according to claim 3, which is characterized in that the aperture of the microporous barrier is 100-200 μm, described The film thickness of microporous barrier is 1-3mm.

5. preparation method according to claim 1, which is characterized in that the pressure in the step (2) is 120- 150KPa。

6. preparation method according to claim 1, which is characterized in that in the step (1), the sodium alginate soln is dense Degree is 1-5wt%.

7. preparation method according to claim 1, which is characterized in that in the step (2), the solidify liquid is a concentration of The calcium chloride solution of 10-30wt%.

8. preparation method according to claim 1, which is characterized in that in the step (2), the solidify liquid flow control In 0.5-8mL/h.

9. a kind of sodium alginate carries medicine embolism microball, prepared using such as claim 1-8 any one of them preparation method.

10. a kind of device for preparing sodium alginate and carrying medicine embolism microball, which is characterized in that include：

The first container, the first container include pressue device, and for containing medicinal liposome and sodium alginate soln Mixed solution；

Second container, the second container is for making solidify liquid at the uniform velocity flow wherein；

The first container setting is on the second container top, and the first container is connected by film and the second container It is logical.