KR20090123328A - alpha-LIPOIC ACID NANO FORMULATION HAVING ENHANCED STABILITY AND MANUFACTURING METHOD THEREOF - Google Patents

Abstract

PURPOSE: A nanoparticle formulation of alpha-lipoic acid with improved stability is provided to maintain the formulation in a nanoparticle when dispersing in water and improve bioavailability. CONSTITUTION: An alpha-lipoic acid nanoparticle formulation with improved stability has polymer stabilizing agent for suppressing coagulation of lipoic acid with a dispersing agent by low temperature moisturization pulverizing. The alpha-lipoic acid nanoparticle formulation is dispersed in 0.1-100um. The alpha-lipoic acid nanoparticle formulation is dispersed again in 0.1-0.4um. The alpha-lipoic acid nanoparticle formulation has powder form of freeze-dry type and is administered through oral administration and parenteral administration. The alpha-lipoic acid nanoparticle formulation has suspension solution and is administered through oral and injection administration.

Description

Nanoparticle formulation of alpha-lipoic acid with enhanced stability and its preparation method {α-LIPOIC ACID NANO FORMULATION HAVING ENHANCED STABILITY AND MANUFACTURING METHOD THEREOF}

The present invention relates to a nanoparticle formulation of alpha-lipoic acid having improved stability and a method for preparing the same, and more particularly, to a nano-lipoic acid drug and a polymer stabilizer for inhibiting coagulation between the alpha-lipoic acid and low-temperature wet grinding. It is a formulation prepared by homogenizing the particles, and the dispersant is mixed, the alpha-lipoic acid nanoparticles formulation and method for preparing the alpha-lipoic acid drug to improve the bioavailability of the alpha-lipoic acid drug since it is maintained as the nanoparticles when redispersed in water It is about.

Alpha-Lipoic Acid (ALA) represented by the following Chemical Formula 1 is an essential element of the mitochondria, is biosynthesized in all cells, and optical isomers of R-ALA and S-ALA forms are present in the human body. It consists of the coenzyme form of R form.

Such alpha-lipoic acid has long been used as an important drug in various diseases in the pharmaceutical field, such as diabetes [Ziegler D. et al., Diabetologia , 38: 1425-1433, 1995 ], liver disease [Bode J. Ch. . et al. , DMW, 112 (9): 349-352, 1987 ], appetite suppressing effect [German Patent No. 19,818,563], Asthma [Korean Patent Publication No. 2004-97820], Pyeon headache [Korean Patent Publication No. 2002-60168] There is a report applied to the back.

Conventional method for preparing alpha-lipoic acid is in the form of tablets, salt substitution, soft capsules and the like. As an example, Korean Patent Laid-Open Publication No. 2006-100117 discloses a pharmaceutical composition for oral administration including alpha-lipoic acid, including alpha-lipoic acid, an oil and a surfactant, and alpha-lipoic acid of a free acid. In the form, the oil has been reported to improve the stability of the pharmaceutical composition by presenting a combination of synthetic oils or natural oils alone or in combination of two or more synthetic oils in the pharmaceutically usable synthetic oils.

In addition, Korean Patent Laid-Open Publication No. 2004-43171 suggests that the preparation of tromethanemol salt using tromethamol in alpha-lipoic acid can be used for injection.

U. S. Patent No. 6,348, 490 discloses a soft capsule composition comprising a tromethamine salt of alpha-lipoic acid, a medium-chain triglyceride (MCT) and a hardfat.

In preparing a conventional alpha-lipoic acid in a pharmaceutical formulation, the alpha-lipoic acid has a very low solubility in water, which affects bioavailability, and there are many limitations in drug formulation due to the low melting point.

In addition, when tableting to produce tablets, alpha-lipoic acid is melted by tableting pressure and tablets are cracked during the pressure release. Tablets are attached to a tablet press to which pressure is applied, causing various defects. Therefore, continuous purification is therefore not possible.

Therefore, due to the physical properties of alpha-lipoic acid, liquid and injectables using the derivative of alpha-lipoic acid are currently on the market, but the present invention does not provide other formulations except tablets.

Accordingly, the present inventors have tried to solve the conventional physical problems of alpha-lipoic acid and improve the bioavailability, and as a result, the preparation of nanoparticles by selecting the alpha-lipoic acid drug and the optimal polymer stabilizer and dispersant, The present invention has been completed by optimizing the preparation process of the nanoparticle formulation, thereby providing a formulation suitable for oral and parenteral administration since it remains stable at nano-level particle size upon redispersion in water.

It is an object of the present invention to stabilize alpha-lipoic acid nanoparticle formulations in which the optimal polymer stabilizer and dispersant are uniformly dispersed in the alpha-lipoic acid drug such that the nanoparticle size of the drug is maintained even during redispersion in water. To provide.

Another object of the present invention is to provide a method for preparing the alpha-lipoic acid nanoparticle preparation prepared by low temperature milling.

In order to achieve the above object, the present invention, after the alpha-lipoic acid and the polymer stabilizer for inhibiting the aggregation of the alpha-lipoic acid is prepared as nanoparticles by low temperature wet grinding, the dispersing agent is mixed, the dispersion when water is redispersed Provided are alpha-lipoic acid nanoparticle formulations with enhanced stability characterized in that they are retained as nanoparticles.

The polymer stabilizer used in the present invention uses any one selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone and Pluronic F-127.

In addition, the preferred dispersant used in the present invention is any one selected from the group consisting of sucrose, polyethylene glycol, lactose and chitosan, more preferably using sucrose.

The alpha-lipoic acid nanoparticle formulation of the present invention is a form in which the alpha-lipoic acid drug is optimally mixed with an optimal polymer stabilizer and a dispersant, and maintains a nano-level particle size when redispersed in water. It is done.

At this time, the particle size is dispersed in 0.1 to 100㎛, more preferably in the case of the alpha-lipoic acid nanoparticle formulation prepared by using sucrose as a dispersant dispersed in water to 0.1 ~ 0.4㎛ particle size do.

The alpha-lipoic acid nanoparticle formulation of the present invention is provided in lyophilized powder form after dispersant mixing and can be administered for oral and parenteral use.

In addition, the alpha-lipoic acid nanoparticles formulation may be provided in the form of a suspension that is not lyophilized after mixing the dispersant, and is a formulation that can be administered orally and for injection.

According to the present invention, alpha-lipoic acid is mixed with a polymer stabilizer-containing solution at low temperature and wet grinding, followed by mixing a dispersant-containing aqueous solution to prepare a slurry, and lyophilizing the slurry to recover the powder in powder form. Provided is a method for preparing Iksan nanoparticle powder formulation.

At this time, the low temperature wet milling is performed by a low temperature milling method, and the low temperature milling method is performed by milling for 5 to 120 hours in a range of 4 ° C.

As the polymer stabilizer used in the preparation method of the alpha-lipoic acid nanoparticle powder formulation of the present invention, any one selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, and pluronic F-127 is used. As the dispersant, any one selected from the group consisting of sucrose, polyethylene glycol, lactose and chitosan is used.

For 100 parts by weight of the alpha-lipoic acid, the polymer stabilizer is to be mixed 1 to 40 parts by weight.

At this time, the preferred content of the dispersant is 30 to 80% by weight based on the weight of the dry powder.

According to the present invention, the alpha-lipoic acid drug nanoparticles are functionalized using a polymer stabilizer and homogenized with a dispersant, thereby maintaining the drug as nanoparticles when redispersed in water, thereby increasing the bioavailability of the drug, It is possible to provide alpha-lipoic acid nanoparticle formulations with enhanced stability.

In addition, the method for preparing the alpha-lipoic acid nanoparticle formulation of the present invention may provide a nanoparticle powder formulation of the final alpha-lipoic acid by a process by low temperature wet grinding, more preferably low temperature milling.

Hereinafter, the present invention will be described in detail.

The present invention provides an alpha-lipoic acid nanoparticle formulation in which the alpha-lipoic acid drug is uniformly mixed with an optimal polymer stabilizer and dispersant so that it is stably maintained at the nano-level particle size of the drug when redispersed in water. do.

The polymer stabilizer of the present invention serves to prevent aggregation between the cohesive alpha-lipoic acid drug particles.

At this time, the preferred polymer stabilizer used in the present invention is a group consisting of hydroxypropyl cellulose (HPC, hydroxypropyl cellulose), polyvinylpyrrolidone (PVP, polyvinyl pyrrolidone) and Pluronic F-127 (Pluronic F-127) Any one selected from the above is used, and the polymer stabilizer is prepared in the form of a solution dissolved in a bioapplicable solvent and mixed with alpha-lipoic acid drug to prepare nanoparticles by low temperature wet grinding method. At this time, distilled water is preferably used as a solvent.

Therefore, the powder form of the alpha-lipoic acid prepared by lyophilizing the slurry form [ FIG. 1 ] and the slurry form immediately after low temperature wet grinding according to the type of the polymer stabilizer of the present invention [ FIG . In the dispersion, the particle size of each of the alpha-lipoic acid drugs was compared, and in the case of the suspension in the form of a slurry, the particle size was uniform according to the polymer stabilizer, whereas the slurry was lyophilized to prepare a powder formulation. Later, when it was redispersed in water, the particle size was larger than the alpha-lipoic acid drug particle size.

However, for formulations prepared using the polymer stabilizer used in the present invention, it can still be identified as nanoparticle size upon redispersion in water. More preferably, when hydroxypropyl cellulose is used as the polymer stabilizer, the drug particle size change is less than 20%, and the aggregation phenomenon between the alpha-lipoic acid drug particles is suppressed and the nanoparticle size is maintained [ Table 1 ], By increasing the solubility, dissolution rate, gastrointestinal absorption of the alpha-lipoic acid drug can improve the bioavailability of the drug.

Figure 3 is when the drug particles in the suspension of the alpha-lipoic acid prepared according to the type of polymer stabilization of the present invention and the powder formulation of the alpha-lipoic acid, respectively, redispersed in water, the drug particles were observed by electron microscopy As a photo, the powder formulation showed the result of agglomeration upon redispersion in water, but still confirmed by the nanoparticle size. In particular, when prepared using hydroxypropyl cellulose as the polymer stabilizer, when redispersion of the suspension and powder formulation, aggregation was minimized to maintain the initial particle size.

The dispersant used in the present invention is prepared after the alpha-lipoic acid drug and the polymer stabilizer are prepared as nanoparticles by low temperature wet grinding, so that the dispersant is uniformly dispersed in the alpha-lipoic acid drug, and when the redispersed in water Keep the drug stable at the nanoscale particle size.

In this case, the dispersant may be used without particular limitation as long as it is well soluble in water and harmless to the human body. Examples of the dispersant include sucrose, polyethylene glycol (PEG, polyethylene glycol), lactose, and chitosan. ) Is any one selected from the group consisting of, more preferably sucrose is used.

When the alpha-lipoic acid nanoparticle formulation of the present invention prepared using the dispersant is redispersed in water, the particle size is dispersed to 0.1 to 100㎛, more preferably prepared using sucrose as a dispersant. In the case of the formulation, it is dispersed in water at a particle size of 0.1 to 0.4 탆.

For the alpha-lipoic acid nanoparticle preparation prepared according to the type of dispersant of the present invention, when the particle size change was observed upon redispersion in water, when the particle size in the form of slurry before initial lyophilization was 0.32 μm, freezing The powder formulation after drying had a small particle size change of less than 20% for formulations prepared using sucrose with redispersion, and the nanoparticles were still re-dispersed even with other dispersants. The result is maintained in size [ Table 2 and Figure 4 ].

The alpha-lipoic acid nanoparticle formulation of the present invention is preferably in the form of a powder prepared by lyophilization after mixing the dispersant, and can be used as a formulation for easy oral and parenteral administration.

Accordingly, the alpha-lipoic acid nanoparticle powder formulation of the present invention is uniformly mixed with alpha-lipoic acid, a polymer stabilizer, and a dispersing auxiliary material, and maintains a nano-level particle size when water is redispersed by impurities. It can improve bioavailability with few side effects.

In addition, the alpha-lipoic acid nanoparticle formulations of the present invention may be provided in the form of a lyophilized suspension after mixing the dispersant, such formulations may be administered orally and for injection.

In the present invention, alpha-lipoic acid is mixed with a polymer stabilizer-containing solution, followed by low temperature wet grinding, followed by mixing a dispersant-containing aqueous solution to prepare a slurry, and lyophilizing the slurry to recover the powder in powder form. Provided is a method for preparing a lipoic acid nanoparticle formulation.

At this time, the production method of the present invention is mixed and pulverized by using mechanical energy to reduce the particle size of the alpha-lipoic acid drug and homogenize the dispersion mixture of alpha-lipoic acid in the solution containing the polymer stabilizer. At this time, the grinding method of the present invention uses a wet grinding method such as ball low temperature milling.

When the alpha-lipoic acid is mixed with the polymer stabilizer-containing solution, 1 to 40 parts by weight of the polymer stabilizer is mixed with respect to 100 parts by weight of the alpha-lipoic acid. At this time, if the polymer stabilizer is less than 1 part by weight, there is a problem in stabilization of the drug nanoparticles, and if it exceeds 40 parts by weight, the viscosity increases too much to be processed, which is not preferable.

Preferred polymer stabilizers used in the preparation method of the present invention serve to prevent aggregation of alpha-lipoic acid particles having strong cohesion, and preferred examples thereof include hydroxypropyl cellulose, polyvinylpyrrolidone and pluronic F. Any one selected from the group consisting of -127 is used, more preferably hydroxypropyl cellulose is used.

In the low temperature wet grinding method of the present invention, the polymer stabilizer-containing solution and alpha-lipoic acid are mixed and homogenized through a grinding process, and the preferred low temperature wet grinding method is performed by a ball low temperature milling method. In addition, the low temperature milling method is performed by milling for 5 to 120 hours, more preferably 5 to 15 hours in the 4 ℃ range.

At this time, the temperature is higher than the room temperature due to the low melting point of the alpha-lipoic acid, or low temperature enough to not freeze the water of about 4 ℃ than at room temperature. On the other hand, in order to maintain a lower temperature than 4 ℃ additional equipment or cost compared to the efficiency is not preferable.

In addition, the grinding time can be widely applied depending on the size of the desired particle. For example, when a nano-sized particle size is desired, the ball cold milling time is preferably milled for 5 to 120 hours, more preferably 5 to 15 hours, and for 2 to 5 days when micro-sized particles are desired. Can be done.

In the preparation method of the alpha-lipoic acid nanoparticle formulation of the present invention, the particle size of the alpha-lipoic acid was observed according to the low temperature milling time, and the wet grinding, that is, the milling time at 4 ° C. was 10, 48, and 120. As a result, the longer the time, the larger the particle size was than the initial particle size, but the redispersed formulation in water retained the nanoparticles. Most preferably, the low temperature milling time of 4 ° C. was performed for 10 hours. As a result, aggregation of the alpha-lipoic acid drug particles was minimized to minimize particle size [ Table 3 ].

In the production method of the present invention, after the homogenization step by the low-temperature milling method, a dispersant-containing aqueous solution is mixed to prepare a slurry, and the slurry is lyophilized and recovered in powder form.

At this time, as the dispersant of the present invention, it is preferably to use any one selected from the group consisting of sucrose, polyethylene glycol, lactose and chitosan, preferably after low-temperature milling for 10 hours in the step, According to the application of the dispersant of the invention, upon redispersion in water, the alpha-lipoic acid drug is dispersed to a particle size of 0.1 to 100 μm.

In particular, in the case of the alpha-lipoic acid nanoparticle preparation prepared by using sucrose as a dispersant, it is found that an alpha-lipoic acid drug having a particle size distribution of 0.1 to 0.4 µm exists in the powder when redispersed in water. Can be.

In the production method of the present invention, as a result of observing the change of the nanoparticle size of the alpha-lipoic acid drug according to the dispersant content, the higher the content of the dispersant was minimized the aggregation between drug particles [ Table 4 and Figure 5 ].

Therefore, after the low temperature wet grinding in the production method of the present invention, a slurry is prepared by mixing a dispersant-containing aqueous solution, wherein the dispersant is 30 to 80% by weight, more preferably 30 to 60% by weight based on the final dry powder weight Contains% If the content of the dispersant is less than 30% by weight, the dispersion is not sufficient to cause a problem in the redispersion is not preferable, if the content exceeds 80% by weight, the drug content is too low to eliminate the advantage of performing the nanoparticle formulation It is not desirable to have.

In the production method of the present invention, it will be understood that the stirring process may be further performed for several minutes to several tens of minutes when preparing a slurry by mixing alpha-lipoic acid in a solution containing a polymer stabilizer and mixing a dispersant in a homogenized dispersion. will be.

After the above step, the slurry is lyophilized to be recovered in powder form, thereby limiting the production method of the present invention to powder formulation.

Thus, the powder formulation prepared by the manufacturing method of the present invention is prepared in a solid formulation in which alpha-lipoic acid, a polymer stabilizer, and a dispersion aid are uniformly mixed, so that the particle size of the drug when redispersed in an aqueous solution Maintaining the nanoscale size to increase the solubility, dissolution rate, gastrointestinal absorption, etc. to improve the bioavailability of the drug.

Powder formulations are also easy to store and can be used in formulations intended for oral and parenteral administration.

Hereinafter, the present invention will be described in more detail with reference to Examples.

This embodiment is intended to illustrate the present invention in more detail, and the scope of the present invention is not limited to these examples.

Example 1 Alpha-Lipoic Acid Nanoparticles Formulation 1

0.6 g of alpha-lipoic acid, 0.1 g of polyvinyl pyrrolidone (PVP) as a polymer stabilizer, and 6.8 g of distilled water were added, and zirconia beads were wet-pulverized by ball-chilling about 30 ml at 4 ° C for 10 hours. To prepare a slurry. A dispersant-containing aqueous solution in which 1.0 g (60 wt% of the total dry powder) of the dispersant was dissolved in 6.5 g of distilled water was mixed with the slurry mixture.

Thereafter, the slurry mixture was lyophilized in liquid nitrogen and lyophilized for at least 24 hours, and finally an alpha-lipoic acid nanoparticle powder formulation was obtained.

Example 2 Alpha-Lipoic Acid Nanoparticles Formulation 2 According to Polymer Stabilizer

An alpha-lipoic acid nanoparticle formulation was prepared in the same manner as in Example 1, except that hydroxypropyl cellulose (HPC) was used instead of the polyvinyl pyrrolidine as the polymer stabilizer. It was.

Example 3 Alpha-Lipoic Acid Nanoparticles Formulation 3 According to Polymer Stabilizer

An alpha-lipoic acid nanoparticle formulation was prepared in the same manner as in Example 1, except that fluoric F127 (Pluronic F127) was used instead of polyvinyl pyrrolidine as the polymer stabilizer.

Example 4 Alpha-Lipoic Acid Nanoparticles Formulation 1 According to Dispersant

0.6 g of alpha-lipoic acid, 0.1 g of polymer stabilizer (HPC), and 6.8 g of distilled water were added, and about 30 ml of zirconia beads were ball milled at 4 ° C. for 10 hours in a wet mill to prepare a slurry. After dissolving 1.0 g of dispersant sucrose in 6.5 g of distilled water, an aqueous solution containing a dispersant was mixed with the slurry mixture.

Thereafter, the slurry mixture was lyophilized in liquid nitrogen and lyophilized for at least 24 hours, and finally an alpha-lipoic acid nanoparticle powder formulation was obtained.

Example 5 Alpha-Lipoic Acid Nanoparticles Formulation 2 According to the Dispersant

An alpha-lipoic acid nanoparticle formulation was prepared in the same manner as in Example 4, except that polyethylene glycol (PEG) was used instead of sucrose as the dispersant.

Example 6 Alpha-Lipoic Acid Nanoparticles Formulation 3 According to Dispersant

An alpha-lipoic acid nanoparticle formulation was prepared in the same manner as in Example 4 except that chitosan was used instead of sucrose as the dispersant.

Example 7 Alpha-Lipoic Acid Nanoparticles Formulation 4 According to Dispersant

As the dispersant, alpha-lipoic acid nanoparticle formulations were prepared in the same manner as in Example 4, except that instead of sucrose, lactose was used.

Examples 8 to 10 Alpha-lipoic acid nanoparticle formulations 1 to 3 according to cold milling time

0.6 g of alpha-lipoic acid, 0.1 g of polymer stabilizer (HPC), and 6.8 g of distilled water were added thereto, and zirconia beads were wet-pulverized by ball milling at about 30 ml at 4 ° C. according to the times shown in Table 3 to prepare slurry. After dissolving 1.0 g of dispersant sucrose in 6.5 g of distilled water, an aqueous solution containing a dispersant was mixed with the slurry mixture.

Thereafter, the slurry mixture was lyophilized in liquid nitrogen and lyophilized for at least 24 hours, and finally an alpha-lipoic acid nanoparticle powder formulation was obtained.

Example 11 Alpha-Lipoic Acid Nanoparticles Formulations 1-3 According to Dispersant Content

Depending on the concentration of the dispersant, it was carried out to see how it affects the particle size of the redispersed alpha-lipoic acid, wherein sucrose was used as the dispersant.

0.6 g of alpha-lipoic acid, 0.1 g of polymer stabilizer (HPC), and 6.8 g of distilled water were added, and about 30 ml of zirconia beads were ball milled at 4 ° C. for 10 hours in a wet mill to prepare a slurry. Dissolved sucrose content of 1.0 g in 6.5 g of distilled water was dissolved as shown in Table 4 , and then mixed with the prepared slurry mixture to give a concentration change of the powder.

Thereafter, the slurry mixture was lyophilized in liquid nitrogen and lyophilized for at least 24 hours, and finally an alpha-lipoic acid nanoparticle powder formulation was obtained.

Experimental Example 1 Particle Size Change of Nanoparticle Formulations According to Polymer Stabilizer

Particle size changes were observed for the alpha-lipoic acid nanoparticle formulations prepared according to the polymer stabilizers in Examples 1 to 3.

After low-temperature milling the alpha-lipoic acid using the polymer stabilizer in Examples 1 to 3, the particle size of the prepared slurry mixture was laser diffraction particle size analyzer (Horiba, Japan, model name LA 910, Mie & Fraunhofer, Relative Refraction) Index = 1) was used to measure in aqueous conditions.

At this time, the decomposition power of the ultrasonic disperser used when measuring the particle size was 40W (39 kHz), the stirring speed and the circulation rate was 340 ml / min. The particle size was measured after performing 1 minute ultrasonic dispersion, and when the slurry mixture was redispersed in distilled water, the particle size of alpha-lipoic acid is shown in Table 1 below.

In addition, the particle size of the alpha-lipoic acid when the nanoparticle powder formulation prepared by lyophilizing the slurry mixture is redispersed in water is shown in Table 1 below.

As shown in Table 1, when the nanoparticle powder formulation prepared by lyophilizing the slurry form prepared according to the polymer stabilizer of the present invention and redispersed in water, each alpha-lipoic acid silver nanoparticle size It was confirmed.

More specifically, in the case of the suspension in the form of a slurry before lyophilization according to the type of the polymer stabilizer of the present invention, the alpha-lipoic acid drug was confirmed to have a uniform particle size upon redispersion in water [FIG. 1]. In addition, when the powder formulation of alpha-lipoic acid prepared by lyophilization of the slurry form was redispersed in water, the drug particle size of alpha-lipoic acid was increased than that of the suspension, but was still confirmed as nanoparticle size [Fig. 2].

In this case, the electron microscope observation results of the suspension of the alpha-lipoic acid and the nanoparticle powder formulation of the alpha-lipoic acid are shown in FIG. 3, so that aggregation between the drug particles on the suspension is minimized and when dispersed in water, the nano The particle size was maintained.

At this time, more preferably, when hydroxypropyl cellulose is used as the polymer stabilizer, in the case of the slurry mixture and the powder formulation, the particle size change upon redispersion in water is less than 20%, and the aggregation between the alpha-lipoic acid drug particles is performed. It was confirmed that the nanoparticle size was maintained while the phenomenon was minimized. Therefore, the alpha-lipoic acid nanoparticle formulation of the present invention can adjust the particle size upon redispersion according to the selection of the polymer stabilizer.

Experimental Example 2 Particle Size Changes of Nanoparticle Formulations According to Dispersants

The particle size of the alpha-lipoic acid nanoparticle preparation prepared according to the dispersant in Examples 4 to 7 using a laser diffraction particle size analyzer (Horiba, Japan, model name LA 910, Mie & Fraunhofer, Relative Refraction Index = 1) Change was observed.

When the alpha-lipoic acid nanoparticle formulations prepared in Examples 4 to 7 were redispersed in water, the alpha-lipoic acid particle sizes are shown in Table 2 and FIG. 4.

At this time, after low-temperature milling of alpha-lipoic acid using HPC used as a polymer stabilizer, the particle size of the prepared slurry mixture was laser diffraction particle size analyzer (Horiba, Japan, model name LA 910, Mie & Fraunhofer, Relative Refraction Index = As a result of measurement under aqueous conditions using 1), the particle size was 1 minute after ultrasonic dispersion, and the particle size of the alpha-lipoic acid adsorbed with the polymer stabilizer was 0.32 μm. The decomposition power of the ultrasonic disperser used for particle size measurement was 40 W (39 kHz), and the stirring speed and circulation rate were 340 ml / min.

For the alpha-lipoic acid nanoparticle preparation prepared according to the type of dispersant of the present invention, the particle size change was observed when redispersed in water, and still observed as the nanoparticle size.

In particular, in the case of nanoparticle powder formulations prepared using dispersant sucrose, the smallest change in size of the nanoparticles was observed, and the nanoparticle size was still maintained even when other dispersants of the present invention were used. Therefore, the alpha-lipoic acid nanoparticle formulation of the present invention can adjust the particle size upon redispersion, depending on the choice of dispersant.

Experimental Example 3 Particle Size Changes of Nanoparticles Formulated by Cold Milling Time

When the alpha-lipoic acid nanoparticle formulations prepared according to the low temperature milling time in Examples 8 to 10 were redispersed in water, the alpha-lipoic acid particle sizes are shown in Table 3 below.

After low-temperature milling alpha-lipoic acid using the polymer stabilizer in Examples 8 to 10, the particle size of the prepared slurry mixture was laser diffraction particle size analyzer (Horiba, Japan, model name LA 910, Mie & Fraunhofer, Relative Refraction) Index = 1) was used to measure in aqueous conditions. At this time, the decomposition power of the ultrasonic disperser used for particle size measurement was 40W (39kHz), the stirring speed and the circulation rate was 340ml / min. The particle size was measured after performing 1 minute ultrasonic dispersion, and when the slurry mixture was redispersed in distilled water, the particle size of alpha-lipoic acid is shown in Table 3 below.

Then, the alpha-lipoic acid particle size when the nanoparticle powder formulation prepared by lyophilization of the slurry mixture was redispersed in water is shown in Table 3 below. Table 3 below shows the particle size before drying and the particle size of the final powder formulation after drying.

As a result of observing the change in particle size of alpha-lipoic acid according to the cold milling time, the longer the milling time, the larger the particle size distribution was than the slurry form, but the size of the formulation redispersed in water was still nanoparticle size. Maintained. Therefore, most preferably, the production method of the present invention was able to produce a particle size with the least aggregation between alpha-lipoic acid drug particles as a result of performing a low-temperature milling time for 10 hours at 4 ℃.

Experimental Example 3 Particle Size Changes of Nanoparticle Formulations According to Dispersant Content

Particle size changes were observed for the alpha-lipoic acid nanoparticle formulations prepared according to the dispersant content in Examples 11-13.

After low-temperature milling alpha-lipoic acid using the polymer stabilizer HPC in Examples 11 to 13, the particle size of the prepared slurry mixture was laser diffraction particle size analyzer (Horiba, Japan, model name LA 910, Mie & Fraunhofer, Relative Refraction Index = 1) was used to measure in aqueous conditions. At this time, the decomposition power of the ultrasonic disperser used for particle size measurement was 40 W (39 kHz) and the stirring speed and circulation rate was 340 ml / min. The particle size was measured after 1 minute of ultrasonic dispersion, and the particle size of alpha-lipoic acid was 0.33 μm when the slurry mixture was redispersed in distilled water.

Thereafter, when the slurry mixture was frozen in liquid nitrogen and lyophilized for at least 24 hours to redisperse the nanoparticle powder formulation in water, the alpha-lipoic acid particle sizes are shown in Table 4 and FIG. 5.

In the production method of the present invention, as a result of observing the change of the nanoparticle size of the alpha-lipoic acid drug according to the dispersant content, the higher the content of the dispersant is minimized the aggregation between drug particles.

As described above, the present invention

First, alpha-lipoic acid drug nanoparticles are functionalized using a polymer stabilizer and homogenized with a dispersant, so that the drug is maintained as nanoparticles when redispersed in water, thereby increasing the bioavailability of the drug and enhancing stability. Alpha-lipoic acid nanoparticle formulations were provided.

Second, the method for preparing the alpha-lipoic acid nanoparticle formulation may provide a nanoparticle powder formulation of the final alpha-lipoic acid by a process by low temperature wet grinding, more preferably by low temperature milling.

Although the present invention has been described in detail only with respect to the described embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made within the technical scope of the present invention, and such modifications and modifications belong to the appended claims.

1 shows particle size distribution of a suspension state of alpha-lipoic acid prepared according to the type of polymer stabilization of the present invention,

Figure 2 shows the particle size distribution when redispersing the nanoparticle powder formulation of alpha-lipoic acid prepared according to the type of polymer stabilization of the present invention in water,

3 is an electron micrograph of the drug particles when the drug particles in the suspension state of the alpha-lipoic acid prepared according to the type of the polymer stabilization of the present invention and the powder formulation of the alpha-lipoic acid are respectively redispersed in water. ,

Figure 4 shows the particle size distribution of the nano-particle powder formulation of alpha-lipoic acid prepared according to the dispersant of the present invention,

Figure 5 shows the particle size distribution of alpha-lipoic acid when redispersing the nanoparticle powder preparation of alpha-lipoic acid prepared according to the dispersant content of the present invention.

Claims (15)

The alpha-lipoic acid and the polymer stabilizer for inhibiting the coagulation of the alpha-lipoic acid are prepared as nanoparticles by low temperature wet grinding, and then the dispersant is mixed, and the stability is characterized in that the nanoparticles are maintained during redispersion in water. Enhanced Alpha-Lipoic Acid Nanoparticle Formulations. The alpha-lipoic acid nanoparticle formulation of claim 1, wherein the polymer stabilizer is any one selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, and pluronic F-127. The alpha-lipoic acid nanoparticle formulation of claim 1, wherein the dispersant is any one selected from the group consisting of sucrose, polyethylene glycol, lactose and chitosan. The alpha-lipoic acid nanoparticle formulation of claim 1, wherein the dispersant is sucrose. The alpha-lipoic acid nanoparticle formulation of claim 3, wherein the alpha-lipoic acid nanoparticle formulation is dispersed in a particle size of 0.1 to 100㎛. The alpha-lipoic acid nanoparticle formulation of claim 4, wherein the alpha-lipoic acid nanoparticle formulation is dispersed in water at a particle size of 0.1 to 0.4 µm. The alpha-lipoic acid nanoparticle formulation of claim 1, wherein the alpha-lipoic acid nanoparticle formulation is in the form of a lyophilized powder after mixing the dispersant and can be administered for oral and parenteral use. The alpha-lipoic acid nanoparticle formulation of claim 1, wherein the alpha-lipoic acid nanoparticle formulation is in the form of a lyophilized suspension after dispersant mixing and can be administered for oral and injection. After mixing alpha-lipoic acid with a solution containing a polymer stabilizer at low temperature and wet grinding, a slurry is prepared by mixing an aqueous solution containing a dispersant, Method for producing an alpha-lipoic acid nanoparticle formulation, characterized in that consisting of lyophilizing the slurry to recover in the form of a powder. The method according to claim 9, wherein 1 to 40 parts by weight of the polymer stabilizer is mixed with respect to 100 parts by weight of the alpha-lipoic acid. 10. The method as claimed in claim 9, wherein the low temperature wet grinding is performed by low temperature milling. The method according to claim 11, wherein the low temperature milling method is performed by milling for 5 to 120 hours in the range of 4 ° C. The method according to claim 9, wherein the polymer stabilizer is any one selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone and pluronic F-127. The method of claim 9, wherein the dispersant is any one selected from the group consisting of sucrose, polyethylene glycol, lactose and chitosan. 10. The method as claimed in claim 9, wherein the dispersant is contained in an amount of 30 to 80% by weight based on the weight of the dry powder.

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