TWI423820B - Drug carrier - Google Patents

Description

Drug carrier

The invention relates to a pharmaceutical carrier, in particular to a pharmaceutical carrier having a magnetic target, a photothermal therapy function, a drug release and a cancer calibration.

In general, a conventional drug carrier coats a drug having a specific function with a specific drug to form a conventional drug carrier, for example, a temperature-sensitive polymer, an acid-base sensitive polymer, or a light-sensitive one. A material such as a polymer coats a specific drug so that the conventional drug carrier releases the drug in a living body.

Conventional drug carrier, as described in the invention patent of "Temperature Sensitive Nanostructure for Magnetocaloric Treatment", No. I314465, which is coated with a temperature-sensitive polymer coated with paramagnetic iron oxide nanoparticles and a drug. The lower critical solution temperature (LCST) of the temperature sensitive polymer is between 40 and 45 °C. Thus, by applying a high-intensity magnetic field, the paramagnetic iron oxide nanoparticle can generate heat, and the temperature reaches 42 to 45 ° C for magnetocaloric treatment, and at the same time, when the temperature reaches the lower critical dissolution of the temperature-sensitive polymer. At the temperature, the structure of the temperature-sensitive polymer will also produce a phase change, and the coated drug will be released to achieve the effects of magnetocaloric therapy and drug treatment.

Another conventional drug carrier, such as the Chinese Patent Publication No. 200900082, "Controlling Thermosensitive Lipid Release Drugs by Applying an AC Magnetic Field", uses a thermosensitive lipohydrate composed of a lipid layer. The body is coated with paramagnetic iron oxide nanoparticles and a drug to form a conventional drug carrier. In this way, by sending the thermosensitive liposome containing the paramagnetic iron oxide nanoparticles to the target in the body, and then applying an alternating magnetic field to the target in the body, the paramagnetic iron oxide nanoparticle can be caused by the magnetocaloric effect. The heat is generated so that the overall temperature reaches the heat-sensitive temperature of the thermosensitive liposome, so that the thermosensitive liposome can release the coated drug to achieve a therapeutic effect.

However, the pharmaceutical carriers of the patents No. I314465 and No. 200900082 require a magnetic field with a higher strength to cause a magnetocaloric effect of the paramagnetic iron oxide nanoparticles, which is usually required to be provided in a large medical institution. A device with a high-intensity magnetic field, so that a general user cannot perform the aforementioned magnetocaloric effect in a personal residence, which causes inconvenience in use; and, further, a magnetic field that causes a magnetocaloric effect of the paramagnetic iron oxide nanoparticle. The intensity is high. If other auxiliary electronic instruments (such as a heart rate adjuster) are provided in the user's body, the operation of the auxiliary electronic device may be affected by the high-intensity magnetic field, thereby causing a threat to the user's life.

Another conventional drug carrier, as described in the invention patent of "Core-shell structure with magnetic, thermal and optical properties and its manufacturing method" of the Republic of China Publication No. 200623170, is a drug carrier having a core-shell structure, Magnetic particles (such as iron or iron oxide) are used as a magnetic core, and a seed layer is formed on the outer surface of the magnetic particles as a bonding agent, and then a metal is transmitted through the seed layer to form a surface of the magnetic particles through a reduction reaction. In order to form a shell layer (for example, gold, platinum or silver) having light absorbing properties on the surface of the magnetic core. In this way, the magnetic core can be applied to magnetic resonance imaging (MRI), guided to a target area to be treated by a magnetic field, or generated by a magnetic field to generate magnetocaloric treatment effect; The shell portion of the light absorbing property can also generate heat in the form of heat by absorbing light of a specific wavelength, and can be applied to heat treatment of tumor cells.

However, the conventional pharmaceutical carrier of the patent No. 200623170 requires a seed layer on the surface of the magnetic core to be further subjected to a reduction reaction to form the gold shell layer on the surface of the magnetic core, thereby causing an increase in manufacturing complexity; Moreover, if the particles of the magnetic core reach 40 nm or more, the gold shell layer is easily detached, and the effect of photothermal therapy cannot be achieved; further, after the conventional drug carrier reaches the target area, the structure of the gold shell layer will still be The drug is coated so that the drug cannot be released directly in the target region; further, the gold shell layer has a uniform thickness, so that only a single wavelength of light can be absorbed, so that the heat generation rate of the gold shell layer is slow.

For the above reasons, it is necessary to further improve the above various conventional drug carriers.

The object of the present invention is to improve the above disadvantages to provide a pharmaceutical carrier having the functions of magnetic target, photothermotherapy, drug release and cancer calibration, for the purpose of its invention.

A second object of the present invention is to provide a pharmaceutical carrier that prevents high-intensity magnetic fields from affecting the actuation of other auxiliary electronic devices in the body.

Still another object of the present invention is to provide a pharmaceutical carrier that is convenient for the user to operate by himself.

It is still another object of the present invention to provide a pharmaceutical carrier that simultaneously absorbs light of two wavelengths to produce a photothermotherapy effect.

Another object of the present invention is to provide a pharmaceutical carrier to increase heat production efficiency.

The pharmaceutical carrier according to the present invention comprises: a carrier portion, a magnetic particle, a rod-shaped light absorbing particle, and a drug. The magnetic particles, the rod-shaped light absorbing particles, and the drug are embedded in the carrier portion; the rod-shaped light absorbing particles are used to absorb light to generate thermal energy.

The above and other objects, features, and advantages of the present invention will become more apparent from the aspects of the appended claims. The pharmaceutical carrier 1 of the preferred embodiment of the present invention comprises a carrier portion 11, at least one super-paramaganetic particle 12, at least one rod-shaped light absorbing particle 13 and at least one drug 14 for transmitting through the carrier portion 11 The magnetic particles 12, the rod-shaped light absorbing particles 13, and the drug 14 are covered.

Referring to FIG. 1, the carrier portion 11 of the present embodiment can be selected from various polymer materials having specific functions, such as temperature-sensitive polymers, acid-base sensitive polymers, or light-sensitive polymers. It is an implementable material, for example, polyethylene glycol (PEG), polylactic acid-glycolic acid (PLGA), polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL) Polymethyl methacrylate (PMMA) or a copolymer of the above materials may be used as the material of the carrier portion 11. For example, in this embodiment, polycaprolactone/polylactic acid-glycolic acid (PCL/PLGA) is selected. As the material of the carrier portion 11. Wherein, the glass transition temperature of the carrier portion 11 is preferably slightly higher than the temperature of the target region to be administered, so as to avoid a phase change before the carrier portion 11 reaches the target region, and the particle size of the carrier portion 11 is preferably At 50-500 nm, the excessive particle size is caused to cause aggregation and precipitation of the drug carrier 1, thereby affecting the delivery of the drug carrier 1.

Referring to Fig. 1, the magnetic particles 12 of the present embodiment are embedded in the carrier portion 11. The magnetic particle 12 can be selected from materials such as iron, cobalt, nickel, iron oxide, cobalt oxide or nickel oxide, and is preferably made of a material having superparamagnetism, and generates magnetic properties in an external magnetic field environment. In the absence of a magnetic field, no magnetic properties are generated, so that the magnetic particles 12 can be controlled by the strength of the applied magnetic field. For example, in this embodiment, iron oxide (Fe ₃ O ₄ ) having superparamagnetism is selected as the The magnetic particles 12. The magnetic particles 12 preferably have a particle diameter of 5 to 50 nm to prevent the magnetic particles 12 from being easily aggregated and precipitated by an excessively large particle diameter. Thus, by providing the magnetic particles 12 in the carrier portion 11, the drug carrier 1 of the present invention can be concentrated and concentrated in the body by magnetic guidance, and can be accurately moved to the target region to achieve the magnetic target. For example, in this embodiment, iron oxide (Fe ₂ O ₄ ) is selected as the material for fabricating the magnetic particles 12, and can be used as an MRI magnetic resonance contrast agent to detect the distribution of the drug carrier 1 in the body to further establish The drug controlled release dosage form image analysis system can not only achieve the role of magnetic targets, but also further utilize magnetic target methods for cancer calibration, and selectively achieve direct effects on cancer cells at specific locations.

Referring to Fig. 1, the rod-shaped light absorbing particles 13 of the present embodiment are embedded in the carrier portion 11. The rod-shaped light absorbing particles 13 have light absorbing properties, for example, having characteristics of absorbing light such as ultraviolet light (UV), near infrared light (NIR), far infrared light, or visible light (VIS), which are absorbed by the light heat effect. The energy of light is converted into heat. The rod-shaped light absorbing particles 13 may be made of a metal such as gold, platinum or silver. The rod-shaped light absorbing particles 13 have a rod length L and a rod diameter R, and the ratio of the rod length L to the rod diameter R (the rod length L/the rod diameter R) is preferably between 2 and 5, due to the rod shape. The light absorbing particles 13 have two different lengths of the rod length L and the rod diameter R, so that light of two different wavelengths can be simultaneously absorbed, thereby increasing the heat generation rate of the rod-shaped light absorbing particles 13. For example, the rod-shaped light absorbing particles 13 of the present embodiment are selected from a nanometer gold rod having a rod length L of 37.2±5.4 nm and a rod diameter R of 9.4±1.8 nm, and a rod length L/rod diameter R ratio. It is 3.9, so it can absorb near-infrared light with wavelengths of 480~550nm and 760~820nm at the same time to increase the heat generation rate.

Referring to FIG. 1 , the drug 14 is also embedded in the carrier portion 11 and can be appropriately selected according to the disease to be treated. The drug 14 of the present embodiment is selected but not limited to an anticancer drug (for example, cisplatin). The drug 14 (such as cisplatin) can be magnetically guided to accurately move the drug 14 to the target affected part by the magnetic particles 12 provided in the carrier portion 11, and then irradiated with light such as near-infrared light to induce the drug. Release of 14 to achieve the role of cancer calibration.

As described above, the carrier portion 11 includes the magnetic particles 12, the rod-shaped light absorbing particles 13, and the drug 14. The drug carrier 1 of the present invention can magnetically attract the magnetic particles 12 in the carrier portion 11 by applying a magnetic field to guide the drug carrier 1 to the target region, thereby achieving the function of the magnetic target. The target region is irradiated with light such as near-infrared light, so that the rod-shaped light absorbing particles 13 can absorb light energy of two wavelengths, and rapidly generate heat energy to raise the temperature, thereby achieving the effect of photothermal therapy; After the glass transition temperature of the carrier portion 11, the carrier portion 11 can be disintegrated, and the coated drug 14 is released in the target region to achieve the effect of selective drug treatment. Thereby, the pharmaceutical carrier 1 of the present invention is a multifunctional drug carrier having magnetic targets, photothermal therapy, drug release and cancer calibration.

Further, the present invention disintegrates the carrier portion 11 by photothermal means to release the drug 14, instead of causing the magnetic particle 12 to generate a magnetocaloric effect by the magnetocaloric effect to disintegrate the carrier portion 11, without using a super-strong magnetic field. The effect of drug release can be achieved, so that the action of other auxiliary electronic devices in the body can be avoided due to the ultra-strong magnetic field, and the user only needs a slightly stronger electromagnet to perform the magnetic guiding action in the home environment, thereby improving the convenience of use. Sex.

The detailed preparation process of the pharmaceutical carrier 1 of the preferred embodiment of the present invention is disclosed below. In this embodiment, an organic phase solution and an aqueous phase solution are first disposed, and if the drug 14 to be coated is a fat-soluble drug, it can be dissolved in the organic In the phase solution, if it is a water-soluble drug, it is soluble in the aqueous phase solution. In this embodiment, a fat-soluble anticancer drug (Tamoxifen), polycaprolactone/polylactic acid-glycolic acid (PCL/PLGA), and iron oxide (Fe ₃ O ₄ ) are dissolved in a chloroform solvent. Caprolactone/polylactic acid-glycolic acid and iron oxide are used as the material of the carrier portion 11 and the magnetic particles 12, respectively. In this embodiment, the weight ratio of the fat-soluble drug: polycaprolactone/polylactic acid-glycolic acid: iron oxide is selected but not limited to 2:27:4.95, and the ratio can be appropriately adjusted according to the type of drug and actual needs. .

In this embodiment, a water-soluble anticancer drug (epirubicin) and a nanogold rod are dissolved in deionized water (ddH ₂ O) in a ratio of 1:1 to prepare the aqueous phase solution, and the nanometer is prepared. The rod system is used as the rod-shaped light absorbing particles 13 with a rod length L of 37.2 ± 5.4 nm and a rod diameter R of 9.4 ± 1.8 nm. The rod length L / rod diameter R ratio is about 3.9. .

Next, the configured organic phase solution and the aqueous phase solution are mixed by a homogenizer at a volume ratio of 1:10 to produce a single emulsion reaction to obtain a mixed solution. Then, 1 ml of the mixed solution was dropped into 10 ml of a solution containing 1% polyvinyl alcohol (PVA), and continuously shaken with a sonicator for 15 minutes to carry out a second emulsification reaction, wherein the polymerization was carried out. Vinyl alcohol is used as a surfactant to assist in the progress of the secondary emulsification reaction. After the shaking, the mixture was stirred with a stirrer until the organic solvent was volatilized to obtain a suspension containing the uncoated drug and the carrier.

Next, an aqueous solution is added to the suspension for rinsing, and after rinsing, the supernatant is removed by centrifugation to remove the residual organic solvent, and the precipitate obtained after repeating three times is the pharmaceutical carrier 1 of the present invention. Thus far, the preparation of the pharmaceutical carrier 1 of the present invention is completed, wherein it is preferred to dissolve the precipitate back into 1 ml of deionized water as a drug carrier solution for subsequent use.

The drug carrier 1 prepared by the above steps can have multiple functions such as magnetic target, photothermal therapy, drug release and cancer calibration as described above.

In the present example, the following animal test was carried out to verify that the pharmaceutical carrier 1 of the present invention does have the above effects.

The animal test of the present embodiment was selected for the mouse, and the analysis chart of the non-invasive live imaging system (IVIS Imaging System) before the administration of the drug carrier solution was as shown in Fig. 2. In this embodiment, the mouse is administered with 100 μl of the drug carrier solution by subcutaneous injection, and is extracted by an electromagnet. Providing a magnetic field having an intensity of 5000 gauss, and attracting the magnetic particles 12 in the drug carrier 1 through the magnetic field, and attracting the drug carrier 1 to the target region, as shown in FIG. 3, to reach the role of the magnetic target; After the drug carrier reaches the target area, the target area is irradiated with near-infrared light for 20 minutes. Since the near-infrared light has a short wavelength and a strong penetrating power, the drug carrier 1 can be irradiated through the mouse skin to make the drug. The rod-shaped light absorbing particles 13 (nano gold rod body) coated in the carrier 1 can simultaneously absorb the near-infrared light of two wavelengths, and release the heat to raise the temperature, thereby achieving the effect of the photothermal treatment, and further, when the temperature is raised to a high level After the glass transition temperature of the carrier portion 11 (polycaprolactone/polylactic acid-glycolic acid), the structure of the carrier portion 11 can be disintegrated, and the coated drug 14 (such as an anticancer drug) can be released. The effect of drug release and cancer calibration is achieved, as shown in Fig. 4, so that the drug carrier 1 of the present invention can simultaneously have multifunctional functions such as magnetic target, photothermal therapy, drug release and cancer calibration.

The present invention provides a pharmaceutical carrier for providing magnetic particles, rod-shaped light absorbing particles and a drug through a drug carrier to achieve magnetic target, photothermal therapy and drug release.

The present invention provides a drug carrier for rapidly absorbing heat by absorbing light energy of two wavelengths through the rod-shaped light to generate a photothermal treatment effect to increase the rate of heat generation.

The present invention provides a pharmaceutical carrier for dispersing a carrier portion through the absorption of heat by absorption of light by the rod-shaped light absorbing particles, thereby releasing the drug. Therefore, it is not necessary to use a high-strength magnetic field to generate a magnetocaloric effect to disintegrate the carrier, and to avoid the influence of a high-intensity magnetic field on other auxiliary electronic devices in the body.

While the invention has been described in connection with the preferred embodiments described above, it is not intended to limit the scope of the invention. The technical scope of the invention is protected, and therefore the scope of the invention is defined by the scope of the appended claims.

〔this invention〕

1‧‧‧ drug carrier

11‧‧‧ Carrier Department

12‧‧‧Magnetic particles

13‧‧‧ rod-shaped light absorbing particles

14‧‧‧ drugs

L‧‧‧ rod length

R‧‧‧ rod diameter

Figure 1 is a perspective view showing the structure of a drug carrier in accordance with a preferred embodiment of the present invention.

Fig. 2 is a diagram showing the analysis of a non-invasive live imaging system before the administration of the drug carrier of the present invention.

Fig. 3 is a diagram showing the analysis of a non-invasive live imaging system after the mouse was administered the drug carrier of the present invention.

Figure 4: Non-invasive live imaging system analysis of mice after exposure to near-infrared light for photothermal therapy and drug release.

1. . . Drug carrier

11. . . Carrier department

12. . . Magnetic particle

13. . . Rod light absorbing particle

14. . . drug

L. . . Rod length

R. . . Rod diameter

Claims (6)

A pharmaceutical carrier comprising: a carrier portion comprising polyethylene glycol (PEG), polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL), polymethacrylic acid a methyl ester (PMMA) or a copolymer of the materials; a magnetic particle embedded in the carrier portion, the magnetic particle being made of cobalt, nickel, cobalt oxide or nickel oxide; a rod-shaped light absorption The particles are embedded in the carrier portion for absorbing light to generate thermal energy. The rod-shaped light absorbing particles are made of gold, platinum or silver; and a drug is embedded in the carrier portion. The pharmaceutical carrier according to claim 1, wherein the rod-shaped light absorbing particles have a rod length/rod diameter of 2 to 5. The pharmaceutical carrier according to claim 1, wherein the magnetic particles are made of a material having superparamagnetism. The pharmaceutical carrier according to claim 1, wherein the magnetic particles have a particle diameter of 5 to 50 nm. The pharmaceutical carrier according to claim 1, wherein the carrier portion has a particle diameter of 50 to 500 nm. The pharmaceutical carrier according to claim 1, wherein the drug is an anticancer drug.