KR101367775B1 - Uniformly micro-structured particles for solubilization of low-melting insoluble drugs, methods and apparatus for preparing the same - Google Patents

Abstract

The present invention comprises the steps of melting the low melting point poorly soluble compounds; It provides a solubilization method comprising the step of uniformly adsorbing in an adsorbent having a large surface area or uniformly coating a disintegrant having a large specific surface area and a swelling property to produce a microstructure having an increased dissolution rate. In addition, the present invention provides an apparatus for performing the manufacturing method. According to the method for preparing a microstructure of the low melting point poorly soluble compound of the present invention, the process for preparing the microparticles of the poorly soluble compound is very simplified, and thus the particles can be easily produced. Since the supercritical pressure is used, the resulting film is more homogeneous and stable. Since no organic solvent is used, it is highly safe and economically effective.

Description

Uniform microstructures for solubilization of low melting point poorly soluble drugs, methods and apparatus for preparing the same {Uniformly micro-structured particles for solubilization of low-melting insoluble drugs, methods and apparatus for preparing the same}

The present invention relates to a method and apparatus for solubilizing a low melting point poorly soluble compound, and more particularly, to uniformly coating or adsorbing a low melting point poorly soluble compound to a support of an adsorbent or a disintegrant using supercritical fluid technology. The present invention relates to a method for improving the solubility and bioavailability of a poorly soluble compound and an apparatus for producing the microstructure.

A US patent (US 2007/77309) describes a process for designing controlled release formulations by injecting drugs into porous particulates using liquid carriers. The above process focuses only on extended release formulations, and liquid carriers are used, and several steps are required for formulation design. Therefore, the inventors of the present invention find a method for solubilizing drugs in a simplified process without using an organic solvent and a liquid carrier, and the particles can be applied to various formulations in a single process using a supercritical fluid. To develop a process for manufacturing.

Supercritical fluids are incompressible fluids at temperatures and pressures above the critical point and exhibit unique characteristics not found in conventional organic solvents. That is, supercritical fluids have excellent physical properties such as high density close to liquid, low viscosity close to gas, high diffusion coefficient, and very low surface tension. Supercritical fluids can continuously vary in density from lean to near ideal gas to high density near liquid density, so that the fluid's equilibrium (solubility, entrainer effect) and transfer properties (viscosity, diffusion coefficient, and thermal conductivity). Fig. 2), molecular clustering (clustering) state can be adjusted. Therefore, by utilizing the ease of controlling the physical properties of the supercritical fluid, it is possible to obtain solvent characteristics comparable to various liquid solvents with one solvent. In particular, carbon dioxide has a low critical temperature of 31.1 degrees, which makes it suitable for thermally denatured substances such as drugs. It is nontoxic, nonflammable, very inexpensive, and can be recovered and reused to design several environmentally friendly processes. It is ideal for pharmaceutical applications because it has many advantages.

Using these unique properties of supercritical fluids, much research has recently been conducted in the fields of selective extraction of specific substances and analysis of substances through extraction. Also, supercritical fluids are used as solvents or anti-solvents. Research on how to obtain recrystallization or microstructures using the same method has been actively conducted, and recently, Sanganwar and Gupta (Int. J. Pharm. 360, 213-218, 2008) have been fenofibrate dissolved in supercritical fluids. ) Was adsorbed on silica to improve the dissolution of fenofibrate, a poorly soluble drug. As a result, fenofibrate adsorbed on silica showed 4 times higher dissolution rate than micronized fenofibrate, but in this method, only 25% of fenofibrate of the total weight could be adsorbed on silica due to the solubility of fenofibrate in the supercritical fluid.

In view of the fact that the melting point of the samples in the solid phase is reduced when the pressure is applied, the present inventors melt the low melting point poorly soluble drugs using a supercritical fluid, and then uniformly adsorb / coat the porous fine particles or the swellable disintegrant to dissolve the dissolution rate. And to improve bioavailability.

Poorly soluble compounds, in particular U.S. Among the groups classified according to the FDA Biopharmaceutical Classification System (BCS), the compounds belonging to Class II and IV have a low dissolution rate due to low water solubility, and thus have a low bioavailability. In particular, low melting point poorly soluble compounds of these compounds have a problem in the stability and formulation design of the compound during storage because of the physicochemical properties of the compound.

Accordingly, the present inventors have designed a formulation in which the low melting point poorly soluble compound is melted to increase solubility by uniformly and finely adsorbing / coating the inside / surface of the adsorbent or disintegrant, thereby improving the bioavailability of the compound. Unlike the conventional formulation design, the supercritical fluid is used to eco-friendly organic solvents, and in consideration of economics, a small amount of compound has been invented a micro / nano structure that has the same effect as a conventional medicine. Such supercritical fluids have the advantage of having low viscosity, good diffusivity, and high density of material, such as liquid, and fast dissolving power, as gases. In addition, in the case of the particles thus prepared, there is little tendency to aggregate, and since the size of the particles is determined by the porous fine particles, crystal growth does not occur.

It is therefore an object of the present invention to provide a novel manufacturing method and apparatus having a microstructure in which a low melting point poorly soluble compound is uniformly adsorbed / coated.

In order to achieve the above object, the present invention provides a novel and efficient method for producing a micro / nano structure of poorly soluble compounds having a low melting point using a supercritical fluid.

The process proposed in the present invention adds a supercritical fluid to lower the melting point of the physiologically active compound, allows the molten compounds to evenly enter the porous adsorbent, or is coated on a disintegrant, which has a large specific surface area and swellability, and is then slowly decompressed. By solidifying and filling or coating in the porous fine particles, it is possible to produce a micro / nano structure having a very narrow and uniform particle size distribution depending on the size of the porous fine particles or disintegrant particles of the adsorbent used.

The supercritical fluid and adsorbent or disintegrant used in the micro / microstructure manufacturing method provided by the present invention may be prepared by different additives.

The method for preparing a low melting point poorly soluble compound microstructure using the supercritical fluid proposed in the present invention is as follows.

1) filling a low melting point poorly soluble compound and a porous adsorbent or disintegrant into a reactor;

2) increasing the pressure of the reactor by using a supercritical fluid to lower the melting point of the low melting point poorly soluble compound to react with the porous adsorbent or disintegrant;

3) lowering the pressure to solidify the low melting point poorly soluble compound to mix with the porous adsorbent or the disintegrant to prepare a microstructure; And

4) recovering the formed microstructure;

And a control unit.

Accordingly, an object of the present invention is to develop a microstructure having low melting point poorly soluble compounds as an active ingredient, which is uniformly adsorbed or coated on a porous adsorbent or a disintegrant.

In addition, according to another embodiment of the present invention, in the step of filling the low melting point poorly soluble compound and the porous adsorbent or disintegrant in the reaction tank, the polymer additive may be further filled.

The present invention also relates to

A reaction vessel in which a microstructure is formed by mixing and reacting a physiologically active compound and a porous adsorbent used for pharmacological use having a melting point of 30 to 80 ° C. when pressurized with a supercritical fluid;

A stirrer and agitation controller connected to the molten compound and the porous adsorbent in an efficient manner through an optimized contact area;

A heating device connected to the reaction vessel for heating in the range of 30 to 100 ° C .;

A supercritical fluid reservoir and transfer device connected to the reaction vessel for discharging a supercritical fluid; And

It provides; a recovery device for recovering the formed microstructure.

In the present invention, the supercritical fluid is chlorofluorocarbons having a temperature and pressure range of 30 to 90 ° C. and 60 to 300 bar, preferably 40 to 80 ° C. and 75 to 120 bar. Fluorocarbons, including chlorofluorocarbons, hydrofluorocarbons, and fluorocarbons [eg, R-10 (tetrachloromethane), R-11 (trichlorofluoromethane), R-12 (dichlorofluoromethane), R-13 (chlorotrifluoromethane), R-14, R-20, R-21, R-22 (chlorodifluoromethane), R-23, R-30 (dichloromethane), R-40, R-41, R -111, R-112, R-113, R-114, R-115, R-116 (hexafluoroethane), R-122, R-123, R-124, R-125, R-130, R-131, R-132, R-133, R-134, R-140, R-141, R-142, R-143, R-150, R-151, R-152, R-160 (chloroethane), R-161 , R-211, R-212, R-213, R-214, R-222, R-224 (trichlorotetrafluoropropane), R-235 (chloropentfluoropropane), etc.], dimethylether, die At least one mixture selected from the group consisting of diethylether, diisopropylether, di-tert-butylether, carbon dioxide and ammonia, preferably chlorofluoro One or more mixtures selected from the group consisting of carboxylic acids, hydrochlorofluorocarbons, hydrofluorocarbons, fluorocarbons, dimethyl ether, diethyl ether, diisopropyl ether, di-tert-butyl ether, carbon dioxide and ammonia May be used, and more preferably carbon dioxide may be used.

In the present invention, the substance having a physiological activity as a solute of a solid used as a low melting point poorly soluble compound, proteins, peptides, nucleotides, functional foods (nutraceuticals), autonomic neuromodulators, corticosteroids, diuretics, analgesics, sex hormones Drugs, anesthetics, antiparasitic agents, antihistamines, antiprotozoal agents, sex hormones, anti-anemias, cardiovascular agents, anti-anxiety agents, anti-asthmatic agents, anticonvulsants, antidepressants, antidiabetics, antidiuretics, antidote, antiepileptic drugs, sex hormones, antifungal agents , Antihistamines, antihyperlipidemia, antihyperlipidemic, antihypertensive, antihypertensive, antibiotic, analgesic, antiprotozoal, antimigraine, antifungal, antiemetic, anticancer, antidepressant, antiparkinsonic, anti psoriasis, mental nerve Solvents, antiepileptics, antiplatelets, antitussive expectorants, antiulcers, bronchodilators, cardiovascular drugs, diuretics, nausea, antiulcers, hormones, antihyperlipides, immunomodulators, muscle relaxation Melting point from 30 to 100 ° C., more preferably from 30 to 100 ° C., when pressurized with a supercritical fluid from a compound having a physiological activity, including a neuro stabilizer, a vasodilator, an antiviral agent, an insecticide, another pharmaceutical agent or a pharmaceutical agent It is limited to the compound which belongs to 80 degreeC.

Bioactive compounds having a melting point in the range of 30 ° C. to 80 ° C. when pressurized with a preferred supercritical fluid include fenofibrate, coenzyme cue 10, orlistat, divaloxox sodium, phenoxybenzamine, erythritol tetranitrate, isosorbide dinitite Laterate, ibuprofen, ketoprofen, gemfibrozil, trimipramine and the like can be used, but is not limited thereto.

The adsorbent used in the present invention is SB-SL, which is a difference between the conversion specific surface area (SL) determined from the average particle diameter of the particles measured by the dynamic light scattering method and the nitrogen-absorption specific surface area (SB) of the particles by the BET method. It is a material of more than 250m ² / g, which is resistant to friction, has excellent stability against heat, has many small pores, and has a large specific surface area, which means that it has a high ability to adsorb silica gel, aluminosilicate, activated carbon, and magnesium aluminum silicate. , Cholestyramine, cholestimide, sucralate, aluminum hydroxide, calcium polystyrene sulfonate, and the like.

Swellable disintegrants with a large specific surface area used in the present invention are formalin-casein, low-substituted hydroxypropyl cellulose, chitin, chitosan, polymerized agar acrylamide, xylan, smecta, key-zo-clay, Cross-linked carboxymethyl guar and modified tapioca starch, alginic acid or alginate, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, potassium polychlorinate, croscarmellose sodium, starch, gelatinized starch, carboxymethyl starch , Gellan gum, starch sodium glycolate, crospovidone, and the like, but are not limited thereto.

Additives used in the present invention are vitamin E-TPGS, glycerly behenate, polyethylene glycol, polyethylene glycol stearate, The polymer is a polymer belonging to a melting point of 100 ° C. or lower, such as polyethylene-propylene glycol copolymer, but is not limited to the above examples.

In the present invention, a compound and an adsorbent or a disintegrant and / or an additive are added to a reaction tank, a supercritical gas is added to melt the compound by increasing the pressure of the reaction tank, and the pressure is lowered after mixing the compound so that the compound is in the adsorbent or on the surface of the disintegrant. It is to form a microstructure by allowing to precipitate in. The microstructures thus formed can be adjusted to have a more fine and uniformly adsorbed or coated distribution depending on the conditions of the adsorbent or disintegrant.

The present invention is characterized in that it contains a supercritical fluid, an adsorbent, a compound and other additives to produce a microstructure having a uniform particle size distribution, and does not use an organic solvent, and a reactor is used to perform such an operation. Can be.

In the present invention, the reaction tank refers to a pressure vessel equipped with a paddle or a stirring device to efficiently perform mixing between two substances by allowing the adsorbent or disintegrant and the molten compound to have a maximum contact area.

The recovery of the microstructures prepared in the present invention may be performed by any of the equipment typically used for dust collection, including a metal or polymer filter and a net, or a cyclone collected by using a stream of air.

As described above, the uniformly adsorbed or coated microstructures and microstructure compositions of various compounds are prepared by melting the low melting point poorly soluble compounds using pressure to adsorb or coat the adsorbent or disintegrant. can do.

In addition, the particle production method provided by the present invention can reduce environmental pollution by not using an organic solvent, and because the process is simplified and economical, and the particle size is determined by the size of the adsorbent, uniform particle size distribution can be achieved through the adjustment thereof. Eggplants are capable of producing microstructures.

1 is a schematic diagram of a method and apparatus for producing a microstructure according to an embodiment of the present invention.
2 shows the results of observing the melting point of FNB with temperature and pressure.
3 is a result of scanning the X-ray wavelength of a certain range to the sample and measuring the energy from the constant wavelength value for each element using the electron scanning microscope and the energy dispersive x-ray spectrometer, (a) is the FNB raw material It is the energy peak for the atoms it has, (b) is the energy peak for the MAS feedstock, and (c) is the energy peak for the processed FNB and MAS mixture microstructures. (c) The peak means that the particles of the drug are distributed inside the adsorbent by the mixed peaks of (a) and (b).
Figure 4 is a SEM photograph of (a) crospovidone raw material, (b) particles produced by the Solvent evaporation method, (c) the particles produced by the present invention taken using an electron scanning microscope.
5 is a dissolution test result of Comparative Example 1, Examples 5, 8, 11, 16 and 17.
6 shows the results of animal experiments using the SD-Rat models of Comparative Examples 1, 8 and 16. FIG.
7 is a schematic diagram of melting point change according to temperature and pressure of coenzyme Q10.

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

However, these embodiments are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto in any sense.

Example 1-17 Preparation of fenofibrate (FNB) microstructures

      1) Preparation of fenofibrate microstructure, and dissolution test results

FNB microstructures were prepared by the particle preparation process devised in the present invention. Melting point of the FNB was confirmed that the melting point is changed as shown in Figure 2 as the pressure is applied to 80 ℃ at normal pressure. First, the FNB and magnesium aluminum silicate (MAS) and / or additives are placed in a paddle reactor and sealed, and then the pressure and temperature are adjusted. At this time, the temperature below the original melting point of the drug to 30 ~ 100 ℃ and pressure of about 60 ~ 300bar is appropriate. Preferably it is 40-80 degreeC and 75-120 bar. After applying a predetermined temperature and pressure, after stirring for 2 hours through the paddle, the pressure was gradually lowered to prepare a FNB microstructure.

Example 1-3 was performed at 50 ° C. and 90 bar, no additives were used, and microstructures were prepared by adjusting only the ratio of FNB and MAS.

In Example 4-12, the microstructure was manufactured by fixing the ratio of FNB and MAS and using no additives, and having a difference in temperature and pressure.

Example 13-16 was carried out with different additives at 50 ℃, 90bar. Example 14 is vitamin E-TPGS, 15 is Gelucire ^® 44/14 (Lauroyl Macrogolglycerides), 16 is Mryj53 (2-hydroxyethyl octadecanoate, 2-hydroxyethyl octadecanoate), 17 the Pluronic ^® F77 (2- methyl oxirane, 2-methyloxirane) was used.

Example 17 prepared microstructures using crospovidone as a disintegrant instead of MAS.

Table 1 shows the process conditions of Example 1-17 and the dissolution rate of the prepared microstructures, and the dissolution test was performed in 900 ml of 0.025M sodium lauryl sulfate. As a result of the dissolution test, the FNB microstructures prepared by the present invention showed a faster dissolution rate than the FNB raw materials.

In order to identify the microstructures prepared according to the present invention, the specific surface area and pore size of the MAS material were measured through a specific surface area analyzer, and the specific surface area of the processed microstructures was measured. As a result, the specific surface area of MAS raw material was 403.93 ± 2.89 m ² / g, and the pore size was 14.83 ± 0.43 nm. In contrast, the specific surface area of the processed microstructure (Example 9) was found to be 72.11 ± 1.08 m ² / g, thereby adsorbing / coating the empty pores of the porous MAS as microparticles with fenofibrate particles having a particle size of ㎚. It can be seen that.

In FIG. 3, the X-ray wavelength of a certain range is scanned in a sample, and the energy from a certain wavelength value of each element is measured using an electron scanning microscope and an energy dispersive x-ray spectrometer. After the process (c) The peak confirmed that the particle | grains of a drug were distributed in the inside of an adsorbent by the mixed peak of (a) FNB raw material and (b) MAS raw material. In addition, SEM images of the processed microstructures were the same as SEM images of the MAS raw material, indicating that the fenofibrate raw material was uniformly adsorbed / coated in the empty pores of the MAS.

Table 2 is a table comparing the particle size distribution and content of the particles prepared according to the process 10g by adsorbing / coating the low melting point poorly soluble drug in the adsorbent (Example 8) or disintegrant (Example 17) by the present invention The case and the case where the low melting point poorly soluble drug is adsorbed / coated to the adsorbent or disintegrant by solvent evaporation (SE) method in the same composition as in Example 8 or 17 are compared. That is, Comparative Examples 2 and 3 were prepared by adding MAS (Comparative Example 2) or crospovidone (Comparative Example 3) to a methanol solution in which FNB was dissolved, and then evaporating the methanol using a rotary evaporator. The particle size distribution was evaluated by classifying 10 g of the prepared particles through 20 (eye size: 850 μm), 45 (eye size: 355 μm), and No. 120 body (eye size: 125 μm), and uniform adsorption / coating. In order to evaluate the sex, the drug content of each particle size was calculated through HPLC.

In the case of particles prepared by the SE method using an adsorbent as a support (Comparative Example 2), the fraction having a particle size of 850 μm or more was found to be 3.56 g (35.63%) among the particles of 10 g. The particles became larger and the drug content was higher. In addition, the fraction having a particle size of 125 μm or less appeared to be 1.04 g (10.42%). In this case, the drug content was low because the drug was not evenly adsorbed / coated on the adsorbent. In contrast, in Example 8, aggregated particles having a particle size of 850 μm or more did not appear, and the content of the drug was nearly 100% in all fractions.

Particles prepared using disintegrants as supports also showed similar results with adsorbents. In the case of particles prepared by the SE method (Comparative Example 3), the fraction having a particle size of 850 μm or more was found to be 2.01 g (20.1%) among 10 g of particles. This can be seen from Fig. 4- (b) as a result of the aggregation of the drug adsorbed / coated to the disintegrant and the neighboring disintegrant or drug, which is large. Also, the content of the drug was also high due to the aggregation phenomenon between the drug and the drug. In addition, the fraction having a particle size of 355 μm or less was 5.2g (52%) in 10g. In this fraction, the drug content was low because the drug was not evenly adsorbed / coated to the disintegrant. On the contrary, in Example 17 prepared by the present invention, the aggregated particles having a particle size of 850 μm or more did not appear, and the content of the drug was nearly 100% in all fractions, indicating uniform adsorption / coating. there was. In addition, as shown in FIGS. 4- (a) and (c), the drug was uniformly and finely adsorbed / coated to the disintegrant, and thus, the microstructure manufactured by the present invention was the same as the SEM photograph of the crospovidone raw material.

5 shows a dissolution graph of the microstructures prepared in Examples 5, 8, 11, 16 and 17 and FNB raw materials (Comparative Example 1).

Example

Experimental condition
Composition ratio (weight ratio)
Dissolution rate (%) Temperature
(℃) pressure
(bar) Active drugs
(FNB) absorbent
(MAS)
Disintegrant
additive
D _{30 ( min )}
D _{120 ( min )} One 50 90 2 2 - - 84.9 94.3 2 50 90 2 3 - - 99.4 98.9 3 50 90 2 4 - - 100.8 101.5 4 40 70 2 3 - - 90.2 93.6 5 40 90 2 3 - - 97.8 99.3 6 40 110 2 3 - - 86.5 94.7 7 50 70 2 3 - - 91.0 97.7 8 50 90 2 3 - - 99.4 98.9 9 50 110 2 3 - - 84.7 95.9 10 60 70 2 3 - - 85.4 98.7 11 60 90 2 3 - - 80.0 89.6 12 60 110 2 3 - - 91.7 96.0 13 50 90 2 3 - 1 ^a 82.9 84.3 14 50 90 2 3 - 1 ^b 89.3 97.9 15 50 90 2 3 - 1 ^c 89.6 101.1 16 50 90 2 3 - 1 ^d 92.3 102.5 17 50 90 2 - 3 ^e 95.5 103.1 Comparative Example 1 Raw FNB 53.7 83.5 a: vitamin E-TPGS, b: Gelucire ^® 44/14, c: Myrj53, d: Pluronic ^® F77
e: Crospovidone

division Particle size distribution Fraction weight
(g) Fraction weight
(%) theory
Drug amount (g) Actual drug amount (g) content
(%)

Example 8 > 850 μm 0 0 0 0 - 850 ~ 355 ㎛ 0.65 6.50 0.26 0.26 100 355 ~ 125 ㎛ 5.90 58.96 2.36 2.46 104.3 <125 μm 3.45 34.54 1.38 1.36 98.3 Sum 10 100 4 4.08 102.0

Example 17 > 850 μm 0 0 0 0 - 850 ~ 355 ㎛ 1.54 15.40 0.62 0.64 103.2 355 ~ 125 ㎛ 7.50 75.00 3 3.09 103.0 <125 μm 0.96 9.60 0.38 0.37 97.4 Sum 10 100 4 4.1 102.5

Comparative Example-2 > 850 μm 3.56 35.63 1.42 1.68 118.3 850 ~ 355 ㎛ 2.26 22.63 0.91 0.96 105.9 355 ~ 125 ㎛ 3.13 31.32 1.25 1.31 104.2 <125 μm 1.04 10.42 0.42 0.39 92.5 Sum 10 100 4 4.33 108.4

Comparative Example-3 > 850 μm 2.01 20.14 0.80 1.01 126.3 850 ~ 355 ㎛ 2.79 27.96 1.12 1.09 97.3 355 ~ 125 ㎛ 4.30 43.00 1.72 1.21 70.3 <125 μm 0.90 9.00 0.36 0.20 52.8 Sum 10 100 4 3.51 87.8

2) Confirmation of Bioavailability of Fenofibrate Microstructures

In order to confirm the bioavailability of the fenofibrate microstructures prepared according to the present invention, the microstructures and FNB raw materials prepared in Examples 8 and 16 were orally administered to SD-Rat, and then in the tail vein of SD-Rat every certain time. After taking the blood, the concentration of FNB in serum was calculated. As a result of the test, as shown in FIG. 6, the bioavailability of the microstructures prepared according to the present invention was significantly improved compared to the FNB raw materials.

Example 18-19 Preparation of Microstructure of Coenzyme Q10 (CoQ10)

The microstructure of CoQ10 was prepared by the particle manufacturing process devised in the present invention. The melting point of CoQ10 was confirmed that the melting point changes as shown in FIG. First, CoQ10 and magnesium aluminum silicate (MAS) or disintegrant are placed in a paddle reactor and sealed, and then pressure and temperature are adjusted. At this time, the temperature below the original melting point of the drug to 30 ~ 50 ℃ and the pressure of about 20 ~ 400 bar is appropriate. Preferably it is 40-50 degreeC and 40-120 bar. The solubility of coenzyme Q10 in supercritical carbon dioxide is summarized in Table 3 under conditions where the drug is hardly dissolved in the supercritical CO2 under the above temperature and pressure conditions.

T (K)
P (MPa)
ρCO ₂ (gl ^-1 )
y _CoQ10 (10 ^-5 ) Solubility in
CO ₂ (gl ^-1 )


305

11.6 784.8 1.57 0.24 14.1 822.8 2.99 0.48 17.8 862.9 5.21 0.88 22.2 896.8 6.51 1.15 22.9 901.5 6.97 1.23 25.9 919.4 9.91 1.79

313

12.1 720.6 0.99 0.14 15.8 791.2 2.78 0.43 18.4 823.8 4.24 0.69 21.1 849.7 6.62 1.10 26.2 887.8 11.29 1.97

323


9.2 297.5 0 0 12.1 598.6 0 0 14.2 678.9 0.74 0.10 15.8 719.9 1.30 0.18 18.1 759.2 2.51 0.37 21.7 804.3 4.68 0.74 25.3 833.8 9.56 1.56 <Reference> Ana A. Matias, Ana V.M. Nunes, Teresa Casimiro, Catarina M.M. Duarte, Solubility of coenzyme Q10 in supercritidcal carbon dioxide. Journal of Supercritical Fluids 28 (2004) 201-206

Example

Experimental condition
Composition ratio (weight ratio)
Dissolution rate (%) Temperature (℃) Pressure (bar) CoQ10 MAS Disintegration D ₂ (hr) D ₂₄ (hr) 18 30 90 2 3 - 17.9 54.7 19 30 90 2 - 3 ^a 13.6 45.4 Comparative Example-4 Raw CoQ10 1.1 21.0 ^a Microcrystalline cellulose

Table 4 shows the dissolution rate of the prepared microstructures and the process conditions of Example 18-19, the dissolution test was carried out in 900mL 5% Tween 80. As a result of the dissolution test, the CoQ10 microstructure prepared by the present invention showed a faster dissolution rate than the CoQ10 raw material.

Example 20-21 Preparation of Microstructures of Orlistat

Example

Experimental condition
Composition ratio (weight ratio)
Dissolution rate (%) Temperature (℃) Pressure (bar) Orlistat MAS Disintegration D ₃₀ (%) D ₆₀ (%) 20 30 90 2 3 - 94.7 96.4 21 30 90 2 - 3 ^a 76.5 89.3 Comparative Example-5 Raw orlistat 16.4 27.8 ^a Croscarmellose Sodium

Orlistat microstructures were prepared in the same process as producing FNB fine particles. The melting point of Orlistat was found to decrease as the melting point was applied from normal pressure to 47 ° C. First, orlistat and MAS or disintegrant are placed in a paddle reactor and sealed, and then pressure and temperature are adjusted. At this time, the temperature below the original melting point of the drug to 30 ~ 47 ℃ and the pressure of about 70 ~ 200bar is appropriate. Preferably it is 30-45 degreeC and 90-150 bar.

Table 5 shows the process conditions of Example 20-21 and the dissolution rate of the prepared microstructure, and the dissolution test was performed at 900 mL (pH 1.2) of 0.1N HCl. As a result of the dissolution test, the orlistat microstructure produced by the present invention showed a faster dissolution rate than the orlistat raw material.

Example 22-23 Preparation of microstructure of ibuprofen

Example

Experimental condition
Composition ratio (weight ratio)
Dissolution rate (%) Temperature (℃) Pressure (bar) Ibuprofen MAS Disintegration D ₃₀ (%) D ₂₄₀ (%) 22 50 90 2 3 - 96.1 101.3 23 50 90 2 - 3 ^a 21.7 62.7 Comparative Example-6 Raw ibuprofen 1.3 30.5 ^a Crospovidone

Ibuprofen microstructures were prepared in the same process as the FNB microparticles were prepared. Melting point of ibuprofen was confirmed that the melting point decreases as the pressure is applied from normal pressure to 76 ℃. First, ibuprofen and MAS or disintegrant are placed in a paddle reactor and sealed, and then pressure and temperature are adjusted. At this time, the temperature below the original melting point of the drug to 30 ~ 47 ℃ and the pressure of about 70 ~ 200bar is appropriate. Preferably it is 30-45 degreeC and 90-150 bar.

Table 6 shows the process conditions of Example 22-23 and the dissolution rate of the prepared microstructure, and the dissolution test was performed at 900 mL (pH 1.2) of 0.1N HCl. As a result of the dissolution test, the ibuprofen microstructure prepared by the present invention showed a faster dissolution rate than the ibuprofen raw material.

Claims (12)

In the microstructure manufacturing method using a supercritical fluid,
Filling a reactor with a low melting point poorly soluble compound selected from the group consisting of fenofibrate, coenzyme cue 10, orlistat, and ibuprofen and a porous adsorbent or a disintegrant having a large specific surface area and swelling property (first step);
1 type selected from the group consisting of chlorofluorocarbon, hydrochlorofluorocarbon, hydrofluorocarbon, fluorocarbon, dimethyl ether, diethyl ether, diisopropyl ether, di-tert-butyl ether, carbon dioxide and ammonia Injecting the above supercritical fluid into the reactor to increase the pressure of the reactor to lower the melting point of the low melting point poorly soluble compound, thereby melting the low melting point poorly soluble compound to react with the porous adsorbent or the disintegrant (second step);
Discharging the supercritical fluid from the reactor to lower the pressure of the reactor, thereby coagulating the low melting point poorly soluble compound and mixing with the porous adsorbent or the disintegrant to prepare a microstructure of the solid phase dispersion (third step); And
Recovering the formed microstructures (step 4); and
In the second step, the temperature and pressure conditions when the supercritical fluid is introduced into the reaction tank as the low melting point poorly soluble compound,
When fenofibrate is used at 40-80 ° C. and 75-120 bar;
40-50 ° C. and 40-120 bar when coenzyme cue 10 was used;
When orlistat is used, it is 30-45 ° C. and 90-150 bar;
Ibuprofen, if used, 30-45 ° C. and 90-150 bar;
Method for producing a microstructure with increased dissolution rate characterized in that. delete delete The method of claim 1,
The porous adsorbent is at least one member selected from the group consisting of silica gel, aluminosilicate, activated carbon, magnesium aluminum silicate, cholestyramine, cholestimide, sucralate, aluminum hydroxide and calcium polystyrene sulfonate. Increased microstructure manufacturing method. The method of claim 1,
The disintegrants include formalin-casein, low-substituted hydroxypropylcellulose, chitin, chitosan, polymerized agar acrylamide, xylan, smecta, key-co-clay, crosslinked carboxymethyl guar, modified tapioca starch, alginic acid, alginate At least one member selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, potassium polyacrylic acid, croscarmellose sodium, starch, gelatinized starch, carboxymethyl starch, gellan gum, sodium starch glycolate and crospovidone. Microstructure manufacturing method characterized in that the dissolution rate is increased. The method of claim 1,
In the first step, the method for producing a microstructure with increased dissolution rate characterized in that the filling step in the reactor by adding a polymer additive having a melting point of 30 ~ 80 ℃ range in the second step. The method according to claim 6,
The polymer additive is an increase in dissolution rate, characterized in that the vitamin is at least one selected from the group consisting of TPG, glyceryl behenate, polyethylene glycol, polyethylene glycol styrate and polyethylene-propylene glycol copolymer Microstructure manufacturing method. delete delete delete delete delete

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