KR101003204B1 - Solid lipid nanoparticles for drug delivery, a process for the preparatrion thereof, and an injection comprising the same - Google Patents

Abstract

The present invention includes a solid lipid nanoparticle for drug delivery, a method for preparing the same, and a solid lipid nanoparticle having a form in which a nano lipid nucleus consisting of a lipid matrix of a mixture of a cacaoter and a drug is present in a shell formed of poloxamer. To provide an injection.

Description

Solid lipid nanoparticles for drug delivery, a process for the preparatrion, and an injection comprising the same}

The present invention relates to solid lipid nanoparticles for drug delivery, a method for preparing the same, and an injection including the nanoparticles, and more particularly, do not cause toxicity and side effects in the body during administration while maintaining drug activity due to high stability. The present invention relates to solid lipid nanoparticles for drug delivery, a method for preparing the same, and an injection including the nanoparticles, which can induce sustained release of the drug and can be manufactured economically with high formulation stability.

The development of new active ingredients is also important in the pharmaceutical industry, but the development of drug delivery systems for how well they can be delivered to the body is also a very important technical field. The development of such a drug delivery system has been very active in recent years, and such a drug delivery system has been largely developed into implants, microparticles, and nanoparticles. Implants and microparticles, however, are easy for various parenteral administration of drugs, but are too large to be used for injection and are therefore limited. Thus, in recent years, nanotechnology has been in the spotlight to improve the drug delivery system for injection and increase efficiency.

Representative drug delivery systems using nanotechnology include polymer-drug conjugates, micelles, liposomes, nanosuspensions, nanoemulsions, solid lipid nanoparticles, and the like. There is this.

Solid lipid nanoparticles are agents in which a drug is supported in nano-sized microparticles composed of solid lipids instead of liquid lipids, and is for agents for targeted directed delivery of drugs or for sustained release of drugs. Solid lipid nanoparticles not only provide better drug release control, drug delivery efficiency, and drug stabilization effects than other nanotechnology drug delivery systems, but also have no biotoxicity of solid lipid nanoparticles themselves, and both hydrophilic and hydrophobic drugs. Applicable and easy to mass production (W. Mehnert et al., Adv. Drug. Del. Rev., 47, 165-196, 2001). Therefore, interest in solid lipid nanoparticles has recently increased and researched for various purposes.

Methods for making solid lipid nanoparticles include a method using a high pressure homogenizer, a method of preparing a microemulsion, and solvent emulsification / evaporation.

The high pressure homogenizer includes high temperature homogenization and low temperature homogenization. The high temperature homogenization technique is detrimental to supporting drugs due to heat caused by high temperature and high pressure. Compared with the high temperature homogenization technique, the supporting ratio of the drug is high and there is little concern about inactivating the drug, but the size of the particles is large and the manufacturing is not uniform. In addition, the biggest disadvantage of the method is that it requires expensive equipment such as a high pressure homogenizer.

The method by the preparation of the microemulsion can make particles using a small proportion of lipids as compared to the high pressure homogenizer and can change the size of the particles according to the nature of the solvent.

The solvent evaporation method is prepared by dissolving a lipid and a drug in an organic solvent which is not mixed with water, dispersing it in water with a surfactant, and solidifying the emulsion fine particles of the organic phase / water phase (o / w) formed by evaporating the organic solvent. Since all organic solvents are removed during the manufacturing process, there is no concern about toxicity due to the organic solvent, and there is an advantage in that the thermal stability is superior to the low temperature homogenization technique.

Until now, solid lipid nanoparticles composed of various lipid components and surfactants are known, but there is a need for development of solid lipid nanoparticles having improved drug stability, formulation stability, and economical cost of production.

On the other hand, proton pump inhibitors are widely used as gastric acid secretion inhibitors to suppress the activity of the hydrogen / potassium pump (H ⁺ / K ⁺ ATPase pump) in the last stage of gastric acid production in the body to treat various diseases caused by gastric acid, It performs the function of mitigation. It is also available in terms of anticancer drug development that is being studied. As cancer cells expand blood vessels for proliferation, they consume a lot of energy, and the oxygen used for energy generation is converted to carbon dioxide and released outside the cell, increasing the concentration of hydrogen ions in body fluids and blood and consequently acidifying surrounding tissues. By this mechanism, cancer cells develop hydrogen / potassium pumps of extracellular membranes compared to normal cells (A De Milito et al., Future oncology, 1 (6), 779-786, 2005). Therefore, the proton pump inhibitor has recently been reported as the potential anticancer agent for cancer has been attracting attention. It has been reported that proton pump inhibitors such as pantoprazole selectively kill cancer cells and maintain normal cells (Yeo M et al., Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells, Clin Cancer Res. 15: 8687- 8696, 2004), proton pump inhibitors have been reported to have high potential as anticancer agents (Fais S et al., Targeting vacuolar H + -ATPase as a new strategy against cancer, Cancer Res. 67: 10627, 20).

Proton pump inhibitors have also been reported to be useful in the treatment of osteoporosis. One of the major etiologies of osteoporosis is balanced destruction by the increase in bone-breaking cells while the decrease in bone-forming cells. In the case of proton pump inhibitors, osteoblasts function by selectively killing only osteoclasts. It has been reported to result in hyperstimulation and can be used clinically for the treatment of osteoporosis (Haji Dib E et al., Imatinib mesylate (Gleevec) enhances mature osteoclast apoptosis and suppresses osteoclast bone resorpting activity, Cur J pharmacol 551: 27-33, 2006; Woo JT et al., Reveromycin A, an agent for osteoporosis inhibits bone resorption by inducing apoptosis specifically in osteoclasts, Pro Natl Acad Sci 103: 4729-4734, 2006).

Pantoprazole, a representative proton pump inhibitor, is hydrophilized by connecting sodium to pantoprazole to obtain an injection, which is faster than oral administration. Such injections are already commercially available. However, pantoprazole has a drawback in that it does not continuously show an effect because it has a very short half-life of 1 hour in the body. In addition, in order to obtain a sufficient effect as a cancer treatment agent, the active ingredient must exist for a long time around the cancer cells, but the half-life is very short, which is a problem. In addition, in order for a proton pump inhibitor to be effective as a therapeutic agent for osteoporosis, a preparation in a form capable of penetrating into osteoblasts is required. Therefore, in order for a proton pump inhibitor such as pantoprazole to have a sufficient therapeutic effect, there is an urgent need for the development of a drug delivery system that can continue to work in the blood for a longer time.

Accordingly, the present inventors have tried to develop more improved solid lipid nanoparticles that can be applied to efficient drug delivery of drugs with short blood half-lives, such as proton pump inhibitors. Can be varied in size and can be applied to both hydrophilic drugs, hydrophobic drugs, and protein drugs, as well as novel solids that can be manufactured economically and more stable than conventional solid lipid nanoparticles. Lipid nanoparticles have been developed.

Accordingly, it is an object of the present invention to provide solid lipid nanoparticles for drug delivery, which have high stability and safety, can be applied to hydrophilic drugs, hydrophobic drugs, and protein drugs, and have high formulation stability and economy.

Another object of the present invention is to provide a method for producing the solid lipid nanoparticles.

Another object of the present invention to provide an injection comprising the solid lipid nanoparticles.

In order to achieve the above object, the present invention provides a method for treating cacao butter and drug in a shell formed of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer (hereinafter also referred to as its representative trade name 'poloxamer'). Provided are solid lipid nanoparticles for drug delivery, in the form of a nano lipid nucleus consisting of a lipid matrix of the mixture.

The solid lipid nanoparticles are

Preparing a reaction mixture by mixing a solution of cacao butter with an aqueous solution of poloxamer;

Dispersing the reaction mixture to prepare an o / w emulsion; And

The emulsion may be prepared by a process comprising cooling the emulsion to form solid lipid nanoparticles dispersed in water.

In another aspect, the present invention provides an injection comprising the solid lipid nanoparticles.

Hereinafter, the present invention will be described in more detail.

The solid lipid nanoparticles provided by the present invention are characterized by having a form in which a nano lipid nucleus consisting of a lipid matrix of a mixture of a cacaoter and a drug is present in a shell formed of poloxamer.

The shell constituting the solid lipid nanoparticle of the present invention is a part constituting the surface of the lipid nucleus of the nanoparticle, and is made of poloxamer. Poloxamer is a substance that forms the surface of the lipid nucleus of the nanoparticles by acting as an emulsifier to enable the formation of nanoparticles in the production of solid lipid nanoparticles. Poloxamer is a nonionic triblock copolymer with hydrophilic ethylene oxide bonded to both ends of hydrophobic propylene oxide. It has a temperature-sensitive characteristic, which converts sol and gel according to concentration and temperature. This is possible and has already been demonstrated by the FDA in the development of pharmaceuticals (G. Dumortier et al., Pharm. Res. 23 (12), 2709-2728, 2006). The properties of poloxamers vary depending on the proportion of polyoxypropylene and polyoxyethylene. Poloxamer 407 is solid at room temperature and soluble in water and ethanol. As the poloxamer constituting the nanoparticles according to the present invention, poloxamers selected from the group consisting of poloxamers 407, 124, 188, 235, 237, 238, 338, and combinations thereof may be used, but poloxamer 407 is preferred. Do. Poloxamers may be prepared and used by those skilled in the art according to methods described in the known literature, or may be purchased and used commercially available products.

The solid lipid nanoparticles according to the present invention have a form in which a nano lipid nucleus consisting of a lipid matrix of a mixture of a cacaoter and a drug is present in a shell formed of poloxamer. The cacao butter is composed of more than 40% unsaturated fatty acids and has very good biocompatibility and low biotoxicity compared to semisynthetic lipids (BD Kim et al., Eur. J. Pharm. Sci., 24, 199-205 , 2005). For complete dissolution of the cacao butter, a nonpolar organic solvent containing no hydroxyl group (-OH) should be used. Examples of solvents that can be used at room temperature include ethyl acetate, ether, n-hexane, cyclohexane, tetrahydrofuran and methylene chloride. Etc. Formamide, dimethylsulfoxide, isopropanol and the like are available as solvents for dissolving cacao butter, and methanol, ethanol, propanol, 1.3-butylene glycol, propylene glycol and glycerin in polar organic solvents , 1,2-pentanediol, di-panthenol, dipropylene glycol, acetone, etc., do not show complete solubility but may form an o / w emulsion in the temperature range of 40 to 70 ° C. In addition, organic solvents having four or more saturated carbon chains, including organic solvents and hydroxyl groups not limited to the above-mentioned organic solvent and not containing a hydroxyl group (-OH), may be organic solvents having nonpolar properties. It is also possible to mix two or more solvents.

The poloxamer and cacao butter constituting the solid lipid nanoparticles according to the present invention may be contained in the range of 5 to 30 parts by weight of the cacao butter with respect to 100 parts by weight of poloxamer. If it is out of the above range, the aggregation of the cacao butter may occur to increase the size of the particles, and there is a fear that the ability to carry the drug in terms of efficiency may decrease. The solid lipid nanoparticles of the present invention may have an average diameter of 50 to 300 nm, preferably 100 nm to 200 nm. 50 to 300 nm can be suitably used for injection administration. Cancer lesions have increased permeability of capillary walls. Targeting drugs to these sites requires controlling the physicochemical properties of the particles so that their transition to target organs is relatively faster than transition to nontarget organs such as urinary excretion or uptake into the liver. Therefore, the particle size is very important in the targeting of drugs. Particles with a size of μm can cause embolism in the capillaries of the lungs initially reaching intravenous administration and embolism in the basin organs during arterial injection. In addition, when the diameter exceeds 300 nm, intravenous administration may accumulate in reticulum endothelial tissue, including hepatic Kupffer cells. Therefore, only 300 nm or less particles can be used to avoid the hepatic hyperpass and penetrate into blood vessels of cancer lesions and accumulate in cancer tissues. On the other hand, the production of nanoparticles with a size of 50 nm or less not only makes the nanoparticle manufacturing process very difficult, but also difficult to obtain a uniform particle size and may increase the initial release amount during drug administration.

The solid lipid nanoparticles according to the present invention can be used as a drug delivery medium by supporting a drug in a nano lipid nucleus present in a shell formed of poloxamer. The drug constitutes the nano lipid nucleus as a lipid matrix in admixture with a cacao butter. As used herein, "lipid matrix" means a solid that is homogeneously mixed with a drug and a lipid that is a cacaoter. Drugs supported on the nanolipid nucleus and applicable to the solid lipid nanoparticles according to the present invention include hydrophilic drugs, hydrophobic drugs, peptides or protein drugs. The hydrophobic drug is well mixed with the fat-soluble cacao butter, so it can be easily supported in the nano lipid nucleus. In the case of protein drugs, the formulation may be prepared by adding an additive that forms an ionic complex to prevent and stabilize protein denaturation. For example, in the case of lysozyme, the formulation is formed by stabilizing and forming an ionic complex with chondroitin sulfate (K. na. Et al., J. Biomaterials, 28, 2754-2762, 2007). Can be. In the case of hydrophilic drugs, there may be a method of supporting a liquid hydrophilic drug concentrated in cacao butter by a method of w / o / w emulsion.

Representative drugs that can be applied to the solid lipid nanoparticles of the present invention include pantoprazole, omeprazole, lansoprazole, rabeprazole and the like. Such drugs are known to have a proton pump inhibitory effect and can be used as a treatment for gastritis and gastric ulcers, and may also be used for the treatment of anticancer drugs and osteoporosis.

Still other drugs that can be applied to the solid lipid nanoparticles of the present invention include insulin, progesterone, cotisone, betamethasone, vitamins, coenzyme Q10, cyclosporin, acyclovir, diazepam, oxazelpam, doxorubicin, taxol, paclitaxel, or camptothecin, and the like. There is, but is not limited to this. In addition, the above-mentioned drugs are examples of drugs that may be used in the present invention, but are not limited thereto.

The solid lipid nanoparticles may be administered by injection, oral or transdermal, preferably as an injection. In order to administer the solid lipid nanoparticles as an injection, the size of the diameter of the nanoparticles is preferably in the range of 50 to 300 nm, more preferably 100 nm to 200 nm. Solid lipid nanoparticles according to the invention may have a size range of the diameter. In addition, the solid lipid nanoparticles according to the present invention can adjust the size of the diameter according to the content of the cacao butter, it can be obtained as a solid lipid nanoparticles having a diameter of the desired size when used as an injection. In addition, the solid lipid nanoparticles according to the present invention are capable of sustained release of the drug, thereby enabling continuous drug delivery of drugs (eg pantoprazole) which have a short half-life when administered by injection and are rapidly removed from the blood.

In addition, the solid lipid nanoparticles according to the present invention support the drug in the solid lipid matrix, the drug can reduce the extent of the drug activity decreases due to ambient conditions such as light, oxygen, heat, etc. over time It is in the form of a formulation which is very advantageous for improving the stability of the drug. In addition, the solid lipid nanoparticles according to the present invention has the advantage that the drug is supported in the solid lipid matrix to enable continuous release of the drug, thereby reducing the number of administration of the drug. In addition, compared to the conventional solid lipid nanoparticles, the solid lipid nanoparticles are less likely to cause agglomeration between particles, resulting in high stability of the agent, thereby reducing the variation in drug content between the preparations, The risk of side effects can also be reduced.

In another aspect of the invention, the invention also

Mixing a solution of cacao butter and drug with an aqueous solution of poloxamer to prepare a reaction mixture;

Dispersing the reaction mixture to prepare an o / w emulsion; And

It provides a method for producing a solid lipid nanoparticles for drug delivery, comprising the step of cooling the emulsion to form solid lipid nanoparticles dispersed in water.

The cacao butter and the mixed solution of the drug may be an organic solvent capable of dissolving both the cacao butter and the drug, and is not particularly limited as long as it can satisfy such conditions, typically ethyl acetate, ether, n- Hexane, cyclohexane, tetrahydrofuran, methylene chloride, formamide, dimethyl sulfoxide, isopropanol, methanol, ethanol, propanol, 1.3-butylene glycol, propylene glycol, glycerin, 1,2-pentanediol, di-panthenol, di Propylene glycol, acetone and the like can be used. Since the cacao butter is solid at room temperature (20 to 30 ° C.), in order to prepare a mixed solution of the cacao butter and the drug, ethyl acetate, ether, n-hexane, cyclohexane, tetrahydrofuran, methylene chloride, etc. Formamide, dimethyl sulfoxide, isopropanol and the like can be used at room temperature and can be used in the temperature range of 40 to 80 ℃, methanol, ethanol, propanol, 1.3- butylene glycol, propylene glycol, glycerin, 1,2-pentanediol, di-panthenol, dipropylene glycol, acetone, etc., do not show complete solubility but are capable of forming an o / w emulsion in the temperature range of 40 to 70 ° C., so that they are carried out within the appropriate temperature range depending on the solvent. shall. The content of the drug mixed with the cacao butter may be 40% by weight or less, preferably 10% by weight or less, based on the total lipid matrix of the mixture of the cacao butter and the drug. When the content ratio of the drug in the lipid matrix is high, the drug having a concentration higher than that of the lipid matrix may not be supported by the solid lipid nanoparticles, and thus the effect to be obtained by formulating the solid lipid nanoparticles may not be sufficiently obtained.

The aqueous solution of poloxamer may be an aqueous solution of 5-15% by weight with water as a solvent. If the above range is exceeded, gelation of poloxamer may occur at room temperature and gelation by body temperature when injected into the body. Can be a problem. The amount of poloxamer used may be 5 to 30 parts by weight of the cacao butter relative to 100 parts by weight of the poloxamer compared to the content of the cacao butter used.

The mixture solution of the cacao butter and the drug is mixed with an aqueous solution of poloxamer to prepare a reaction mixture, and then dispersed to prepare an oil-in-water (o / w) emulsion. The dispersion may be performed by sonication, and the organic solvent used for dissolving the cacaoter and the drug may be evaporated and removed while the ultrasonic wave is added to the mixed solution, which may cause toxicity problems to the human body due to the organic solvent. none. The sonication conditions are not particularly limited as long as it can form an oil-in-water emulsion, but the repetition period of the ultrasonic waves can be used at 0.4-0.8 seconds, preferably 0.5-0.6 seconds, and the amplitude is 50-80%, preferably May be used in 60-70%, the total number of uses is 5-7 times, preferably 6 times based on 10 minutes at a time. When the ultrasonic wave is added to the mixed solution, the diameter of the oil particles present in the water can be made 100-300 nm. Since the method can produce the solid lipid nanoparticles according to the present invention by a solvent evaporation method by ultrasonication, the method can reduce the waste of cost due to expensive equipment such as a high pressure homogenizer.

When an oil-in-water emulsion of oil particles of sufficiently small size is formed by the ultrasonic treatment, the emulsion can be cooled to solidify the oil particles of the emulsion. The cooling temperature is preferably at room temperature, where the room temperature refers to a temperature in the range of 20 to 30 ° C. Since the melting point of the cacao butter is about 33 ° C, the oil particles of the emulsion of which the cacao butter is the main component may be solidified upon cooling to room temperature to form solid lipid nanoparticles dispersed in water.

The solid lipid nanoparticles dispersed in the water can separate only the solid lipid nanoparticles by filtration. Filtration may be carried out by conventional filtration means known in the art, for example by a syringe filter.

The separated solid lipid nanoparticles may be lyophilized for commercialization. In order to perform lyophilization, it is preferable to add a lyoprotectant to the solid lipid nanoparticles and then perform lyophilization. In freeze-drying, a problem arises in that the size becomes larger than the size of the nanoparticles originally formed due to the cracking and agglomeration of the particles due to the evaporation of moisture present in the solid lipid nanoparticles. It can reduce the stress of the particles generated due to the size of the nanoparticles can be kept more stable. As the cryoprotectant, sucrose, lactose, glucose, trehalose, glycerol, fructose, maltose, mannitol, sorbitol, dextran, polyethylene glycol, glycine, alanine, lysine and the like may be used. Mannitol can be used in amounts of 5-15% by weight.

In another aspect of the invention, the invention also provides an injection comprising the solid lipid nanoparticles according to the invention.

Injectables comprising the solid lipid nanoparticles provided by the present invention can be prepared according to conventional methods for preparing injectables known in the art. According to one embodiment, the injection according to the present invention may be prepared by dissolving a drug in powder form in distilled water or ethanol. Injectables according to the present invention may be in a form dispersed in a sterile medium so that it can be used as it is when administered to a patient, or may be administered in a form in which distilled water for injection is added and dispersed in an appropriate concentration. When the injection according to the present invention is applied to a drug having a short half-life, such as pantoprosol, the half-life is short, and thus the drug which has been rapidly removed from the blood can maintain a therapeutically effective concentration in the blood for a long time.

As described above, the solid lipid nanoparticles according to the present invention have high agglomeration stability between the nanoparticles as compared with the conventional solid lipid nanoparticles, and thus have high stability of the preparation, no toxicity to the human body, and by adjusting the ratio of each component. In addition to varying the size of the particle size, it can be applied to both hydrophilic drugs, hydrophobic drugs, and protein drugs, and can be manufactured very economically.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention is not limited by them in any sense.

Example  1: Preparation of Solid Lipid Nanoparticles (1)

In the present embodiment, the solid lipid nanoparticles without the drug were prepared by using different concentrations of the cacao butter, and thus the degree of particle change according to the content of the cacao butter of the nanoparticles was examined.

A solution of 0.5, 1, 2, and 3% by weight was prepared at room temperature using methylene chloride as a solvent for the cacaoterus constituting the nano lipid nucleus of the solid lipid nanoparticles. Then, a solution of poloxamer 407 (Poloxamer 407; Pluronic-F127) was prepared in distilled water at a concentration of 10% by weight. Then, the poloxamer 407 solution and the cacao butter solution were mixed while maintaining the temperature at room temperature, and then, using an Ultrasonic processor (UP200S, hielscher, Germany) at 10 cycles of 0.6 cycles and 70% amplitude. By sonication for 6 minutes, nanoparticles were prepared by solvent evaporation.

The particle size of the nanoparticles prepared by the above method was measured using a Zetasizer (ZEN3600, MALVERN instrument Ltd, U.K), and the results are shown in Table 1 and FIG. 1. Table 1 further shows the polydisperse index.

TABLE 1

According to the results shown in Table 1 and FIG. 1, the diameter of the nanoparticles was changed depending on the content of the cacao butter present in the solid lipid nanoparticles of the present invention. In addition, when checking the polydispersity coefficient, it can be seen that particles of a very uniform size are made through the ultrasonic technique described above. Therefore, it can be seen that the diameter of the solid lipid nanoparticles according to the present invention can be changed by changing the content of the cacao butter and the size is very uniform.

Example  2: Preparation of Solid Lipid Nanoparticles (2)

In Example 1, the content of the cacao butter was fixed to 1% by weight of the whole formulation, and pantoprazole was added together when preparing the cacao butter solution to prepare drug-supported solid lipid nanoparticles.

First, methylene chloride is used as a solvent so that the sum of the cacaoter and pantoprazole is 1% by weight based on the total formulation, and the pantoprazole is 5% by weight and 10% by weight, respectively, based on the lipid matrix of the cacaoter and pantoprazole. , And 20% by weight, each of the cacao butter and pantoprazole were quantified and added to dissolve. As the pantoprazole, hydrophilic pantoprazole sodium was added with 0.1 mol of hydrochloric acid to remove sodium to form hydrophobic pantoprazole.

Then, a solution of poloxamer 407 (Poloxamer 407; Pluronic-F127) was prepared in distilled water at a concentration of 10% by weight. Then, the poloxamer 407 solution and the respective cacao butter solution were mixed and then sonicated six times for 10 minutes at 0.6 cycles and 70% amplitude using an Ultrasonic processor (UP200S, hielscher, Germany). Nanoparticles were prepared by solvent evaporation.

The particle size of the nanoparticles prepared by the above method was measured using a Zetasizer (ZEN3600, MALVERN instrument Ltd, U.K), and the results are shown in Table 2 and FIG. 2. Table 2 further shows the polydisperse index.

TABLE 2

According to the above results, in comparison with the particle size of the solid lipid nanoparticles prepared in Example 1 without the drug in the concentration of the cacao butter 1% by weight, the nanoparticles of the It can be seen that the particle diameter increases.

Example  3: Preparation of Solid Lipid Nanoparticles (3)

The change in the particle size of each solid lipid nanoparticles prepared in Example 2 when lyophilized and the change of the particle size when 10 wt% Mannitol was added as a lyoprotectant were compared. Lyophilization was carried out in an EYELA FDU-2100, TOKOY RIKAKIKAI CO., LTD (Japan) apparatus under conditions of atmospheric pressure 9-10 Pa within a temperature of -70 to -80 ° C.

The results are shown in Fig. According to the results of Figure 3, the solid lipid nanoparticles can be seen that the particle size increases compared to the nanoparticles before lyophilization. In addition, when mannitol is added and then lyophilized, it can be seen that the change in size of the particle size is relatively smaller than that of lyophilization without addition of mannitol.

Test Example  1: dissolution test of the drug

Each solid lipid nanoparticle prepared in Example 2 was subjected to in vitro dissolution of the drug.

Take 10% by weight of each solid lipid nanoparticles obtained in Example 2, dissolve in 5 mL of PBS (phosphate buffer saline) and put it in a cutoff 10000 50 mL vial containing 30 mL of PBS The sample was sampled by time to confirm the release of the drug until the final 90 hours. The amount of drug released was determined using an UV / Vis spectrophotometer (UV-2450, SHIMADZU Co, Japan). The results are shown in FIG.

According to the results shown in Figure 4, it can be seen that the most stable and sustained release of the drug occurs in the solid lipid nanoparticles having a drug concentration of 5% by weight. In contrast, the solid lipid nanoparticles having 10 wt% and 20 wt% concentrations of the drug showed a high initial drug release, indicating that the drug incorporation into the solid lipid nanoparticles was relatively low. . The inclusion rate of the drug and the ratio of drug to the total formulation are shown in Table 3.

[Table 3]

According to Table 3, it can be seen that the solid lipid nanoparticles have the highest content of drug when the ratio of the drug to the lipid matrix of 1% by weight is 5% by weight. This means that more than 5% by weight of the drug is beyond the range that the lipid matrix can contain, which means that high concentrations of drugs, such as 10% and 20% by weight, cannot be encapsulated. It means that the intrusion of is possible.

1 is a particle size of the solid lipid nanoparticles prepared while fixing the concentration of poloxamer 407 to 10% by weight and changing the concentration of the cacao butter to 0.5, 1, 2, and 3% by weight according to one embodiment of the present invention. Is a graph showing the results of the measurement.

2 is a concentration of poloxamer 407 in accordance with an embodiment of the present invention to 10% by weight, the concentration of the sum of the cacao butter and pantoprazole to 1% by weight, the pantoprazole of the cacaoter and pantoprazole It is a graph which shows the result of measuring the particle diameter of the solid lipid nanoparticles prepared by 5, 10, and 20 weight% with respect to the lipid matrix.

3 is 10 wt% of poloxamer 407 according to one embodiment of the present invention, the concentration of the sum of the cacao butter and pantoprazole is 1 wt%, and pantoprazole is added to the lipid matrix of cacao butter and pantoprazole. It is a graph showing the result of measuring the particle size after freeze-drying the solid lipid nanoparticles prepared at 5, 10, and 20% by weight with or without mannitol.

Figure 4 is prepared according to one embodiment of the present invention poloxamer 407 to 10% by weight, the concentration of the cacao butter to 1% by weight, pantoprazole to 5, 10, and 20% by weight relative to the lipid matrix A graph showing the dissolution test results for one solid lipid nanoparticle.

Claims (16)

In a shell formed of a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer (poloxamer) in which a nano lipid nucleus consisting of a lipid matrix of a mixture of a cacao butter and a drug is present, The cacao butter is included in a ratio of 5 to 30 parts by weight based on 100 parts by weight of the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, Average diameter is 100-300 nm, The drug may be a hydrophilic drug, a hydrophobic drug, or a protein drug. Solid lipid nanoparticles for drug delivery, characterized in that. delete delete delete delete The method according to claim 1, wherein the drug is pantoprazole, omeprazole, lansoprazole, labeprazole, insulin, progesterone, cortisone, betamethasone, vitamin, coenzyme Q10, cyclosporine, acyclovir, diazepam, oxazelpam, doxorubicin, taxol, paclitaxel, or Solid lipid nanoparticles, characterized in that it is camptothecin. The solid lipid nanoparticle of claim 1, wherein the solid lipid nanoparticle is used as an anticancer agent. The solid lipid nanoparticles according to claim 1, which is used as a therapeutic agent for osteoporosis. delete The solid lipid nanoparticles of claim 1, wherein the solid lipid nanoparticles are administered by injection, oral or transdermal. Adding cacao butter and drug together to prepare a mixed solution of cacao butter and drug with nanoparticles consisting of cacao butter and drug, Preparing a reaction mixture by mixing the cacao butter and the mixed solution with a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer aqueous solution; Dispersing the reaction mixture to prepare an o / w emulsion; And A method for preparing solid lipid nanoparticles for drug delivery according to any one of claims 1, 6 and 7, comprising cooling the emulsion to form solid lipid nanoparticles dispersed in water. The method of claim 11, wherein the ratio of the drug to the sum of the cacao butter and the drug in the mixed solution of cacao butter and drug is 40% by weight or less. The method of claim 11 or 12, further comprising the step of filtering the solid lipid nanoparticles dispersed in the water to separate the solid lipid nanoparticles, then adding a lyoprotectant and lyophilizing. The method of claim 11 or 12, wherein the cryoprotectant is sucrose, lactose, glucose, trehalose, glycerol, fructose, maltose, mannitol, sorbitol, dextran, polyethylene glycol, glycine, alanine, or lysine Method characterized in that. 12. The method of claim 11, wherein said dispersing is by sonication. An injection comprising the solid lipid nanoparticles according to any one of claims 1, 6, 7 and 8.

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