KR20200036143A - Pharmaceutical formulatin of poorly water soluble drug using self-microemulsifuing drug delivery system - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation of a poorly water soluble drug using a self-microemulsifying drug delivery system. The pharmaceutical formulation is made of nanoparticles solubilized by using the self-microemulsifying drug delivery system, thereby having excellent long-term stability. In addition, the pharmaceutical formulation is not affected by pH, so that a dissolution rate in other digestive organs increases in addition to an effluent of the gastrointestinal digestive fluid level, thereby improving the bioavailability of a drug. Therefore, the pharmaceutical formulation can be usefully used by substituting an existing prototype formulation in which the dissolution rate is significantly different depending on pH conditions.

Description

Pharmaceutical formulatin of poorly water soluble drug using self-microemulsifuing drug delivery system}

It relates to a pharmaceutical preparation of a poorly soluble drug using a self-emulsifying drug delivery system.

Recently, studies are being actively conducted to increase the effectiveness of drugs and reduce side effects. In particular, research on drug delivery system technology has been actively conducted in various fields, such as oral preparations with improved absorption rate of poorly soluble drugs, transdermal absorption preparations with increased permeability, and injection preparations with improved stability in body aqueous solutions.

In the case of a drug using a poorly soluble drug among currently used drugs, the absorption of the drug is not achieved as desired in vivo when administered in vivo, thereby limiting drug efficacy expression. Particularly, poorly soluble drugs have a low absorption rate in vivo, leading to a decrease in physiological activity, and when used as an intravenous injection, the insoluble portion of the drug may generate blood clots and block blood vessels due to low solubility. In case of these drugs, there are many difficulties when formulated in consideration of absorption rate, bioavailability, and side effects. In order to solve the problems of the poorly soluble drugs, solubilization studies are being conducted to improve the bioavailability of poorly soluble drugs formulated into oral, injectable, and topical dosage forms by granulating the size of the drug to a nano-sized. Methods for preparing nanoparticles for drug delivery include polymeric nanoparticles using a self-emulsifying diffusion method, nanoparticles through micelle formation using a block copolymer having a hydrophilic / lipophilic group, and liposomes in the form of hydrophilic capsules using phospholipids. have.

Microemulsion is an effective means for solubilization of poorly soluble drugs and improvement of bioavailability, and is made of nanoparticles for solubilization of drugs that are poorly soluble in polar or non-polar solvents composed of water phase, oil phase, surfactant, and auxiliary surfactant. It is applied as a means to improve the dissolution rate. In the case of microemulsion, since the average size of the oil droplets is as small as 50 nm, it is optically transparent and thermodynamically stable, so phase separation does not easily occur. have. Self Microemulsifying Drug Delivery System refers to a drug delivery system that easily forms microemulsions even by weak forces such as gastrointestinal tract movement when it encounters an aqueous phase such as body fluid. The self-emulsifying drug delivery system is more stable than general emulsifiers and can significantly increase the drug's solubility and bioavailability depending on the appropriate composition, and the drug's stability and rapid drug expression, uniformity of content, and uniform drug efficacy. It is a useful means to increase the efficient use of drugs whose use has been limited by providing expression, handling, and convenience of manufacture. In addition, when using the self-emulsifying drug delivery system, since water is excluded from the components of the microemulsion, it is possible to reduce the volume and prevent the decomposition of the drug by water, and it is possible to exclude the interaction between the capsule layer and water, so it is soft It is possible to fill capsules.

Cinacalcet hydrochloride is a calcium analog drug that increases the sensitivity of the calcium sensing receptor (CaSR) in the parathyroid gland, thereby lowering parathyroid hormone and serum calcium levels. Calcium analog drugs are a type of active molecule that reduces the secretion of parathyroid hormone by activated calcium receptors. The secretion of parathyroid hormone is usually regulated by calcium-sensing receptors. Calcium analog drug preparations inhibit the release of parathyroid hormone and lower the level of parathyroid hormone within a few hours while increasing the sensitivity of these receptors to calcium. Calcium analog drugs are used to treat hyperparathyroidism, which is characterized by hypersecretion of parathyroid hormone. Cinacalcet hydrochloride is commercially available as SENSIPARTM and is the first drug approved by the FDA among the class of compounds known as calcium analogs. However, cinacalcet hydrochloride has an absorption rate of 5.1% when consumed on an empty stomach, 20.4% when consumed with a meal, and the difference is very significant, and the bioavailability due to absorption rate of up to 20% is also low from 20 to 25%. It is also known that cinacalcet hydrochloride is absorbed only in the stomach and has a low dissolution rate.

One object of the present invention is to provide a pharmaceutical preparation of a poorly soluble drug using a self-emulsifying drug delivery system.

Another object of the present invention is to provide a method for preparing the pharmaceutical preparation.

In order to achieve the above object,

According to one aspect of the invention,

It is a pharmaceutical preparation comprising a poorly soluble drug consisting of a poorly soluble drug, oil, surfactant and auxiliary surfactant,

For 1 part by weight of poorly soluble drug,

5 to 30 parts by weight of oil; 5 to 25 parts by weight of a surfactant; And auxiliary surfactant 1 to 25 parts by weight; is provided a pharmaceutical formulation comprising a poorly soluble drug, characterized in that the mixture.

According to another aspect of the invention,

Mixing the poorly soluble drug and oil to solubilize the poorly soluble drug (step 1); And

It is a method for preparing a pharmaceutical formulation comprising a poorly soluble drug comprising the step of preparing a liquid formulation by adding a surfactant and an auxiliary surfactant to the solubilized poorly soluble drug (step 2),

With respect to 1 part by weight of the poorly soluble drug,

5 to 30 parts by weight of oil; 5 to 25 parts by weight of a surfactant; And auxiliary surfactant 1 to 25 parts by weight; is provided a method for producing a pharmaceutical preparation comprising a poorly soluble drug, characterized in that the mixed use.

Pharmaceutical preparations containing poorly soluble drugs according to the present invention are made of nanoparticles solubilized using a self-emulsifying drug delivery system, which has excellent long-term stability and is not affected by pH, and other digestion in addition to eluents of gastrointestinal digestive fluid levels As the dissolution rate is also improved in the institution, the bioavailability of the drug is improved. As a result, the dissolution rate is significantly different depending on the pH condition, and can be used as a substitute for an existing prototype preparation.

1 is an image taken by dispersing a pharmaceutical formulation comprising a poorly soluble drug according to the present invention in water, oil or a mixture of water and oil, and adding micronized oil to confirm the emulsification. (A: water, B: oil, C: mixture of water and oil, D: Example 13 dispersed in aqueous solution, E: Example 14 dispersed in aqueous solution, F: Example 15 dispersed in aqueous solution)
2-4 are results of cryogenic freeze scanning electron microscopy (Cryo-SEM) analysis of pharmaceutical formulations containing poorly soluble drugs according to the present invention. Figure 2: Example 13, Figure 3: Example 14, Figure 4: Example 15
Figure 5 shows the change in particle size over two months under the harsh conditions of a pharmaceutical preparation containing a poorly soluble drug according to the present invention. It was analyzed using a particle size analyzer (ELS-Z, OTSUKA, Electronic Co., Japan). ◆ represents Example 13, ■ represents Example 14, ▲ represents Example 15.
Figure 6 shows the drug content for 2 months under severe conditions. It was analyzed using HPLC, and ◆ represents Example 13, ■ represents Example 14, and ▲ represents Example 15.
7-10 is a graph showing the dissolution pattern in artificial digestive fluid. 7 is Example 13, Figure 8 is Example 14, Figure 9 is Example 15, Figure 10 is a graph showing the dissolution of the prototype REGPARA tablets in artificial digestive fluid. At this time, in the graph, ◆ indicates pH 1.2 ■ indicates pH 6.8 ▲ indicates pH 4.0.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides a pharmaceutical preparation of a poorly soluble drug using a self-emulsifying drug delivery system.

More specifically. It is a pharmaceutical preparation comprising a poorly soluble drug consisting of a poorly soluble drug, oil, surfactant and auxiliary surfactant,

For 1 part by weight of poorly soluble drug,

5 to 30 parts by weight of oil; 5 to 25 parts by weight of a surfactant; And auxiliary surfactant 1 to 25 parts by weight; provides a pharmaceutical formulation comprising a poorly soluble drug, characterized in that the mixture.

In the pharmaceutical formulation,

The oil may be any one or a combination selected from the group consisting of glyceryl oleate, polyoxyglyceride, medium chain triglyceride, diethylene glycol and polyoxyglyceride. Specifically, the oil is commercially available mycin 35-1 (Maisine 35-1, glyceryl monolinoleate), Migliol 812 (Miglyol 812, Capric Triglyceride), Labrafil M 1933 CS (Labrafil M 1933 CS, Oleoyl polyoxyl-6) glycerides), Capryol 90 (Propylene glycol monocaprylate (type II)), Triacetin (Glycerol triacetate), Labacfac CC (Capric Triglyceride) and Labrasol (Labrasol, Caprylocaproyl polyoxyl-8 glyceride) It may be any one selected from the group or a combination thereof. In addition, the oil may be any one selected from the group consisting of triacetin, Labrapac CC, Labrasol and Capryol 90 or a combination thereof. In addition, the oil may be Capryol 90.

In the pharmaceutical preparation according to the present invention, the oil may be used in 5 to 30 parts by weight, 10 to 25 parts by weight, 10 to 20 parts by weight, and 13 to 1 part by weight of the poorly soluble drug It can be used as 17 parts by weight, it can be used as 14 parts by weight. When the oil is used in an amount of less than 5 parts by weight and more than 30 parts by weight, the pharmaceutical agent may be dispersed in a solution phase to form a microemulsion, which may cause precipitation and precipitation.

In the pharmaceutical formulation according to the present invention, the surfactant is a stable microemulsion having a particle size (particle size) of 10 to 100 nm while stably emulsifying the hydrophilic component represented by the oil and the co-surfactant in the pharmaceutical formulation in water. Can be formed.

At this time, the usable surfactant is not particularly limited, and surfactants used for adding foods that are stable in vivo can be used alone or in combination, and a HLB (Hydrophilic Lipophilic Balance, HLB) coefficient value is preferably 4-18. And when using a surfactant having an HLB value in this range, the pharmaceutical preparation forms a transparent, stable and highly soluble microemulsion in an aqueous solution. Specifically, any one selected from the group consisting of castor oil, poloxamer compound, and polysorbate, or a combination thereof may be used, Pluronic L 62 (Polyoxyethylene-polyoxypropylene block copolymer), Cremophor RH 40 (Macrogolglycerol hydroxystearate), Cremophor RH 60 (Ethoxylated hydrogenated castor oil), Cremophor CO 40 (PEG-40 HYDROGENATED CASTOR OIL), Cremophor CO 60 (PEG-60 HYDROGENATED CASTOR OIL), Cremophor ELP (Polyoxyl 35 Hydrogenated Castor oil), Tween 80 (Polyethylene glycol sorbitan monooleate ), Tween 40 (Polyoxyethylenesorbitan monopalmitate 0, Tween 20 (Polyethylene glycol sorbitan monolaurate), span 60 (Sorbitan Monostearate) and span 80 (Sorbitane monooleate), any one or a combination thereof, Pluronic L 62 , Cremophor CO 40, Cremophor CO 60, Cremophor ELP, any one selected from the group consisting of Tween 20 and Tween 80 Or a combination of these may be used, any one or a combination selected from the group consisting of Cremophor CO 40, Cremophor CO 60 and Cremophor ELP may be used, and Cremophor ELP may be used.

In the pharmaceutical preparation according to the present invention, the surfactant may be used in 5 to 25 parts by weight, 5 to 20 parts by weight, 5 to 15 parts by weight, and 8 to 1 part by weight of the poorly soluble drug It may be used in 12 parts by weight, it may be used in 8, 10 or 12 parts by weight, it may be used in 12 parts by weight. When the surfactant is used within the range of 5 to 25 parts by weight, the pharmaceutical preparation forms a transparent and stable microemulsion in aqueous solution, but when used in less than 5 parts by weight, the amount of surfactant is too small compared to the drug and oil mixture A phenomenon in which both the drug and the oil are precipitated may occur, and when used in excess of 25 parts by weight, precipitation may occur due to excessive surfactant.

In the pharmaceutical preparation according to the present invention, the auxiliary surfactant may use any one or a combination of polyethylene glycol, polyethylene oleyl ether, propylene glycol monolaurate and polyglyceryl oleate. PEG (polyethylene glycol) 400, PEG 300, PEG 200, diethylene glycol monoethyl ether, carbitol, polyglyceryl oleate and polyethylene oleyl ether Brij 92 v (POLYETHYLENE GLYCOL MONOOLEYL ETHER) Any one selected from the group consisting of or a combination thereof may be used, and any one or combinations selected from the group consisting of PEG 400, PEG 300 and Brij 92 v may be used, and Brij 92 v may be used. .

In the pharmaceutical preparation according to the present invention, the auxiliary surfactant may be used in 1 to 25 parts by weight, 1 to 20 parts by weight, and 1 to 15 parts by weight based on 1 part by weight of the poorly soluble drug, It can be used in 1 to 10 parts by weight, can be used in 4 to 8 parts by weight, can be used in 4, 6 or 8 parts by weight, can be used in 4 parts by weight. When the auxiliary surfactant is used in the range of 1 to 25 parts by weight, the pharmaceutical preparation forms a transparent and stable microemulsion in an aqueous solution, but when used in an amount of less than 1 part by weight, the amount of the auxiliary surfactant is compared to the drug and oil mixture. Too few drugs and oils may precipitate, and when used in excess of 25 parts by weight, sediment formation due to excess auxiliary surfactant may occur.

In the pharmaceutical preparation according to the present invention, poorly soluble drugs include cinacalcet HCl, Ticagrelor, atorvastatin, Rosuvastatin, Simvastatin, Docetaxel , Ibuprofen, Dexibuprofen, and the like, or cinacalcet hydrochloride.

The pharmaceutical preparation can be dispersed in an aqueous solution and microemulsionized. The aqueous solution may be water.

The particle size (particle size) of the microemulsion may be 10 to 100 nm, and may be 10 to 50 nm.

Particularly, when the pharmaceutical preparation is an oral drug, the particle size of the microemulsion is one of the most important properties for drug absorption. Drug absorption is delayed when the particle size of the microemulsion is in the micrometer range. Therefore, the active material is better absorbed when the particle size is 100 nm or less, more preferably 50 nm or less, as in microemulsion.

The pharmaceutical formulation of the present invention can be dispersed in an aqueous solution to form a microemulsion having a particle size of 10 to 100 nm, and can form a microemulsion having a particle size of 10 to 50 nm (see Experimental Example 1). , The drug absorption is excellent.

The pharmaceutical preparation may be one type selected from the group consisting of oral preparations, injections, mucosal agents, inhalants, external preparations and transdermal absorbers, and may be oral preparations.

Pharmaceutical preparations can be prepared in one formulation selected from the group consisting of liquid formulations, tablets, pills, powders, granules, capsules, gels, creams, elixirs, alcohols, syrups and lemonades.

Another aspect of the invention,

Mixing the poorly soluble drug and oil to solubilize the poorly soluble drug (step 1); And

It is a method for preparing a pharmaceutical formulation comprising a poorly soluble drug comprising the step of preparing a liquid formulation by adding a surfactant and an auxiliary surfactant to the solubilized poorly soluble drug (step 2),

With respect to 1 part by weight of the poorly soluble drug,

5 to 30 parts by weight of oil; 5 to 25 parts by weight of a surfactant; And 5 to 25 parts by weight of an auxiliary surfactant; provides a method for producing a pharmaceutical formulation comprising a poorly soluble drug, characterized in that the mixed use.

Hereinafter, the manufacturing method will be described in detail.

In the above manufacturing method,

Step 1 is a step of solubilizing the poorly soluble drug, and specifically, solubilizing the poorly soluble drug and oil at an appropriate temperature.

The appropriate temperature may be 60 ℃ to 100 ℃.

The manufacturing method may be performed according to the following examples, but is not limited thereto.

Hereinafter, the present invention will be described in detail by examples and experimental examples.

However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.

<Derivation of optimal oil for solubilization of cinacalcet hydrochloride>

Before preparing a pharmaceutical formulation containing a poorly soluble drug, solubility was measured using Triacetin, Labrafac CC, Labrasol, and Capryol 90 as oils, respectively, to derive the optimal oil for solubilizing the poorly soluble drug. As a poorly soluble drug, cinacalcet HCl was used.

Specifically, the solubility was measured by using cinacalcet hydrochloride at 7 wt%, oil (5 g) was added, and the mixture was stirred at 60 ° C for 48 hours, and then mixed with an ultrasonic washer for 5 minutes. Subsequently, the mixed cinacalcet hydrochloride mixture was centrifuged at 2000 rpm using a centrifuge (Universal 320; Herrich, Germany), and then the supernatant was taken and the undissolved cinacalcet hydrochloride membrane filter (PVDF, 0.45 μm, Whatman, UK). The filtered mixture was diluted in dilution and analyzed by HPLC. The HPLC conditions are as follows, and the analysis time and conditions are summarized in Table 1, and the solubility measurement results are shown in Table 2.

Mobile phase A: After dissolving 2.72 g of potassium dihydrogen phosphate in 950 ml of distilled water, the pH was adjusted to 3.50 with phosphoric acid and a solution of 1 L with distilled water.

Mobile phase B: acetonitrile

Column: Waters xbridge C18, 4.6 × 150 mm, 5 μm

Temperature: 40 ℃

Wavelength: 225nm

Flow rate: 1.5ml / min

Time (min) Mobile phase A (%) Mobile phase B (%) 0 70 30 8 55 45 10 55 45 30 20 80 31 70 30 40 70 30

oil Solubilization performance (mg / ml) Triacetin 22.5 Labrafac CC 42.1 Labrasol 43.6 Capryol 90 65.5

As shown in Table 2 above,

It can be seen that Capryol 90 has the best performance of solubilizing cinacalcet hydrochloride. Thus, Capryol 90 was used as an oil in the preparation of a pharmaceutical formulation containing cinacalcet hydrochloride, which is performed below.

<Example> Preparation of pharmaceutical preparation containing cinacalcet hydrochloride

A pharmaceutical formulation comprising a poorly soluble drug according to the present invention was prepared. At this time, cinacalcet hydrochloride (Cinacalcet HCl) is used as a poorly soluble drug, Capryol 90 is used as an oil, and Tween 80, Tween 20, Cremophor CO 60, Cremophor CO 40, Cremophor ELP, and Pluronic L 62 are used as surfactants. Polyethylene Glycol 400, Polyethylene Glycol 300 and Brij 92 v were used as surfactants.

Step 1: Solubilization of cinacalcet hydrochloride

Cinacalcet hydrochloride (25 mg) and Capryol 90 (350 mg) were solubilized by mixing at 80 ° C. or higher until a clear liquid.

Step 2: Preparation of a pharmaceutical formulation comprising cinacalcet hydrochloride

Tween 80, Tween 20, Cremophor CO 60, Cremophor CO 40, Cremophor ELP and Pluronic L 62 were added to the solubilized cinacalcet hydrochloride at a temperature of 60 ° C. or higher, respectively, and Polyethylene Glycol 400 and Polyethylene as auxiliary surfactants. Liquid formulations were prepared by adding Glycol 300 and Brij 92 v, respectively, and mixing them until a transparent property was seen. At this time, the ratio of cinacalcet hydrochloride, surfactant, and co-surfactant was used as 1: 12: 4, 1: 8: 8 or 1: 10: 6 to prepare a liquid pharmaceutical preparation.

In Table 3, the ratio of cinacalcet hydrochloride, oil, surfactant, and co-surfactant is used as a ratio of 1: 12: 4, and the contents of each component are summarized.

In Table 4, the ratio of cinacalcet hydrochloride, oil, surfactant, and co-surfactant is used in a ratio of 1: 8: 8 to the contents of each component.

In Table 5, the ratio of cinacalcet hydrochloride, oil, surfactant, and co-surfactant is used in a ratio of 1: 10: 6, and the contents of each component are summarized.

room
city
Yes Cina knife set
Hydrochloride
content Capryol 90
content Surfactants Surfactants
content assistant
Surfactants assistant
Surfactants
content wt% mg wt% mg wt% mg wt% mg One 3.225 25 45.161 350 Tween80 38.709 300 PEG 400 12.903 100 2 “ “ “ “ “ “ “ PEG 300 “ “ 3 “ “ “ “ “ “ “ Brij 92 v “ “ 4 “ “ “ “ Tween20 “ “ PEG 400 “ “ 5 “ “ “ “ “ “ “ PEG 300 “ “ 6 “ “ “ “ “ “ “ Brij 92 v “ “ 7 “ “ “ “ Cremophor CO 60 “ “ PEG 400 “ “ 8 “ “ “ “ “ “ “ PEG 300 “ “ 9 “ “ “ “ “ “ “ Brij 92 v “ “ 10 “ “ “ “ Cremophor CO 40 “ “ PEG 400 “ “ 11 “ “ “ “ “ “ “ PEG 300 “ “ 12 “ “ “ “ “ “ “ Brij 92 v “ “ 13 “ “ “ “ Cremophor ELP “ “ PEG 400 “ “ 14 “ “ “ “ “ “ “ PEG 300 “ “ 15 “ “ “ “ “ “ “ Brij 92 v “ “ 16 “ “ “ “ Pluronic L 62 “ “ PEG 400 “ “ 17 “ “ “ “ “ “ “ PEG 300 “ “ 18 “ “ “ “ “ “ “ Brij 92 v “ “

room
city
Yes Cina knife set
Hydrochloride
content Capryol 90
content Surfactants Surfactants
content assistant
Surfactants assistant
Surfactants
content wt% mg wt% mg wt% mg wt% mg 19 3.225 25 45.161 350 Tween80 25.806 200 PEG 400 25.806 200 20 “ “ “ “ “ “ “ PEG 300 “ “ 21 “ “ “ “ “ “ “ Brij 92 v “ “ 22 “ “ “ “ Tween20 “ “ PEG 400 “ “ 23 “ “ “ “ “ “ “ PEG 300 “ “ 24 “ “ “ “ “ “ “ Brij 92 v “ “ 25 “ “ “ “ Cremophor CO 60 “ “ PEG 400 “ “ 26 “ “ “ “ “ “ “ PEG 300 “ “ 27 “ “ “ “ “ “ “ Brij 92 v “ “ 28 “ “ “ “ Cremophor CO 40 “ “ PEG 400 “ “ 29 “ “ “ “ “ “ “ PEG 300 “ “ 30 “ “ “ “ “ “ “ Brij 92 v “ “ 31 “ “ “ “ Cremophor ELP “ “ PEG 400 “ “ 32 “ “ “ “ “ “ “ PEG 300 “ “ 33 “ “ “ “ “ “ “ Brij 92 v “ “ 34 “ “ “ “ Pluronic L 62 “ “ PEG 400 “ “ 35 “ “ “ “ “ “ “ PEG 300 “ “ 36 “ “ “ “ “ “ “ Brij 92 v “ “

room
city
Yes Cina knife set
Hydrochloride
content Capryol 90
content Surfactants Surfactants
content assistant
Surfactants assistant
Surfactants
content wt% mg wt% mg wt% mg wt% mg 37 3.225 25 45.161 350 Tween80 32.258 250 PEG 400 19.354 150 38 “ “ “ “ “ “ “ PEG 300 “ “ 39 “ “ “ “ “ “ “ Brij 92 v “ “ 40 “ “ “ “ Tween20 “ “ PEG 400 “ “ 41 “ “ “ “ “ “ “ PEG 300 “ “ 42 “ “ “ “ “ “ “ Brij 92 v “ “ 43 “ “ “ “ Cremophor CO 60 “ “ PEG 400 “ “ 44 “ “ “ “ “ “ “ PEG 300 “ “ 45 “ “ “ “ “ “ “ Brij 92 v “ “ 46 “ “ “ “ Cremophor CO 40 “ “ PEG 400 “ “ 47 “ “ “ “ “ “ “ PEG 300 “ “ 48 “ “ “ “ “ “ “ Brij 92 v “ “ 49 “ “ “ “ Cremophor ELP “ “ PEG 400 “ “ 50 “ “ “ “ “ “ “ PEG 300 “ “ 51 “ “ “ “ “ “ “ Brij 92 v “ “ 52 “ “ “ “ Pluronic L 62 “ “ PEG 400 “ “ 53 “ “ “ “ “ “ “ PEG 300 “ “ 54 “ “ “ “ “ “ “ Brij 92 v “ “

<Experimental Example 1> Microemulsion particle size and property analysis of a pharmaceutical formulation dispersed in an aqueous phase

When the pharmaceutical preparation is oral, the particle size of the microemulsion is one of the most important properties for drug absorption. Drug absorption is delayed when the particle size of the microemulsion is in the micrometer range. Therefore, the active material is better absorbed when the particle size is 100 nm or less, more preferably 50 nm or less, as in microemulsion. Accordingly, the particle sizes of the pharmaceutical formulations of the microemulsions formed when the pharmaceutical formulations prepared in Examples 1 to 54 were dispersed in an aqueous solution phase were analyzed.

Specifically, the particle size distribution for the microemulsion formed by dispersing the pharmaceutical preparations prepared in each of the above embodiments in an aqueous phase (water) using a particle size analyzer (ELS-Z, OTSUKA, Electronic Co., Japan) It was measured and observed. Since the particle size distribution measurement is impossible when the phase separation or sedimentation is settled, the particle size distribution measurement was not performed.

The properties of the pharmaceutical preparations containing cinacalcet hydrochloride prepared in Examples 1 to 54 and the particle size distribution in the microemulsion state in aqueous solution are shown in Table 6 below.

Example Surfactants Auxiliary surfactant Particle size (nm) Microemulsion properties One Tween 80 PEG 400 - Phase separation 2 “ PEG 300 - Phase separation 3 “ Brij 92 v - Phase separation 4 Tween 20 PEG 400 - Phase separation 5 “ PEG 300 - Phase separation 6 “ Brij 92 v - Phase separation 7 Cremophor CO 60 PEG 400 123 Stable 8 “ PEG 300 108.8 Stable 9 “ Brij 92 v 110 Stable 10 Cremophor CO 40 PEG 400 91.2 Stable 11 “ PEG 300 81.9 Stable 12 “ Brij 92 v 63 Stable 13 Cremophor ELP PEG 400 25.5 Stable 14 “ PEG 300 30.6 Stable 15 “ Brij 92 v 20.8 Stable 16 Pluronic L 62 PEG 400 - Precipitation 17 “ PEG 300 - Precipitation 18 “ Brij 92 v - Precipitation 19 Tween 80 PEG 400 - Phase separation 20 “ PEG 300 - Phase separation 21 “ Brij 92 v - Phase separation 22 Tween 20 PEG 400 - Phase separation 23 “ PEG 300 - Phase separation 24 “ Brij 92 v - Phase separation 25 Cremophor CO 60 PEG 400 151 Stable 26 “ PEG 300 - Phase separation 27 “ Brij 92 v - Phase separation 28 Cremophor CO 40 PEG 400 165 Stable 29 “ PEG 300 108 Stable 30 “ Brij 92 v - Phase separation 31 Cremophor ELP PEG 400 77 Stable 32 “ PEG 300 80 Stable 33 “ Brij 92 v - Phase separation 34 Pluronic L 62 PEG 400 - Precipitation 35 “ PEG 300 - Precipitation 36 “ Brij 92 v - Precipitation 37 Tween 80 PEG 400 - Phase separation 38 “ PEG 300 - Phase separation 39 “ Brij 92 v - Phase separation 40 Tween 20 PEG 400 - Phase separation 41 “ PEG 300 - Phase separation 42 “ Brij 92 v - Phase separation 43 Cremophor CO 60 PEG 400 - Phase separation 44 “ PEG 300 - Phase separation 45 “ Brij 92 v - Phase separation 46 Cremophor CO 40 PEG 400 - Phase separation 47 “ PEG 300 79 Stable 48 “ Brij 92 v 70.4 Stable 49 Cremophor ELP PEG 400 65 Stable 50 “ PEG 300 65.3 Stable 51 “ Brij 92 v 80.2 Stable 52 Pluronic L 62 PEG 400 - Precipitation 53 “ PEG 300 - Precipitation 54 “ Brij 92 v - Precipitation

In Table 6 above,

Stable indicates that the phase is stable, phase separation indicates that the phase is separated, and precipitation indicates the state in which the precipitate has settled in the aqueous solution.

As shown in Table 6,

In Examples 1 to 18 in which the ratio of cinacalcet hydrochloride, surfactant, and auxiliary surfactant is 1: 12: 4, a pharmaceutical is maintained in a stable state while having a particle size of 100 nm or less by forming a microemulsion in an aqueous solution. Red formulations are Examples 10-15, and it can be seen that pharmaceutical formulations that maintain a stable state while having a particle size of 50 nm or less, which is a more preferable particle size, are Examples 13 to 15.

Specifically, when a surfactant of Cremophor is used as the surfactant, the property is maintained in a stable state regardless of the type of the auxiliary surfactant. Among them, when using Cremophor CO 40 or Cremophor ELP, the particle size is 100 nm. When the Cremophor ELP was used, it was found that the particle size was 50 nm, indicating a more preferable particle size.

In addition, in Examples 19 to 36 in which the ratio of cinacalcet hydrochloride, surfactant, and auxiliary surfactant is 1: 8: 8, a microemulsion is formed in an aqueous solution, having a particle size of 100 nm or less, and maintaining a stable state. It can be seen that the pharmaceutical formulations are Examples 13 and 14, and there are no pharmaceutical formulations having a particle size of 50 nm or less, which is a more preferable particle size.

Furthermore, in Examples 37 to 54 in which the ratio of cinacalcet hydrochloride, surfactant, and auxiliary surfactant is 1: 10: 6, a microemulsion is formed in an aqueous solution, having a particle size of 100 nm or less, and maintaining a stable state It can be seen that the pharmaceutical formulation to be described is Example 11-15, and there is no pharmaceutical formulation having a particle size of 50 nm or less, which is a more preferable particle size.

That is, it can be seen that the pharmaceutical formulation containing cinacalcet hydrochloride according to the present invention changes the size and size of the aqueous phase in the aqueous solution according to the use ratio and type of the surfactant and co-surfactant.

Therefore, in order to maintain a stable state while having a particle size of 100 nm or less,

When the ratio of cinacalcet hydrochloride, surfactant, and auxiliary surfactant is 1: 12: 4, Cremophor CO 40 or Cremophor ELP is used as the surfactant, and PEG 400, PEG 300, or Brij 92 v is used as the auxiliary surfactant. It is preferred to use,

When the ratio of cinacalcet hydrochloride, surfactant and auxiliary surfactant is 1: 8: 8, Cremophor ELP is used as the surfactant, and PEG 400 or PEG 300 is preferably used as the auxiliary surfactant.

When the ratio of cinacalcet hydrochloride, surfactant and co-surfactant is 1: 10: 6, use Cremophor CO 40 as surfactant, PEG 300 or Brij 92 v as co-surfactant, or Cremophor as surfactant It is preferred to use ELP and to use PEG 400, PEG 300 or Brij 92 v as auxiliary surfactant.

Cinacalcet hydrochloride, surfactants and auxiliary surfactants are used in a ratio of 1: 12: 4 to prepare a pharmaceutical preparation that forms a microemulsion having a particle size of 50 nm, which is a more preferable particle size, and as a surfactant It is preferable to use Cremophor ELP and PEG 400, PEG 300 or Brij 92 v as the auxiliary surfactant.

<Experimental Example 2> Measurement of particle size distribution in artificial digestive fluid

Cinacalcet hydrochloride is used as a treatment for hyperparathyroidism, and exhibits poorly soluble properties, absorbing 5.1% when ingested on an empty stomach, 20.4% when ingesting, and the difference is very severe. Bioavailability due to is also shown to be low from 20 to 25%. In addition, cinacalcet hydrochloride is absorbed only in the stomach, and the dissolution rate is also low.

Thus, in order to confirm that the pharmaceutical formulation containing cinacalcet hydrochloride according to the present invention has improved the above problems, the particle size distribution of microemulsions formed in artificial digestive fluids at pH 1.2, 4.0 and 6.8 was confirmed. The particle size distribution was measured using the same method as in Experimental Example 1.

The experiment was carried out using Examples 13-15 showing excellent particle size and properties in Experimental Example 1. The results are shown in Table 7 below.

Example Particle size in artificial digestive fluid (nm) pH 1.2 pH 6.8 pH 4.0 13 24 27.5 26.3 14 35.1 35.3 32 15 18 21 19.8

As shown in Table 7 above,

All of Examples 13-15 maintained similar particle size at all pH conditions. Specifically, microemulsified particles having an average of 25.7 nm at pH 1.2, 26.033 nm at pH 4.0, and 27.9 nm at pH 6.8 were formed, and even three artificial digestive fluids exhibited a transparent liquid microemulsion form.

That is, since the pharmaceutical preparation containing the poorly soluble drug according to the present invention is not affected by pH, it can be inferred that it is stable in all organs having various pHs and the absorption rate is high.

<Experimental Example 3> Confirmation of microemulsion using methylene blue

In order to confirm the microemulsification (microemulsion) of the pharmaceutical preparation according to the present invention, a microemulsification confirmation experiment using methylene blue was performed using Examples 13-15 showing excellent particle size and properties in Experimental Example 1 above. . The results are shown in FIG. 1.

When the pharmaceutical preparation prepared in Example 13-15 is dispersed in an aqueous solution, a microemulsion in a transparent liquid state is formed.

To confirm the fine emulsification, an appropriate amount of water-soluble dye methylene blue was added thereto to confirm the oil-in-water type. Specifically, methylene blue was added to water, oil, or a mixture of water and oil, and an appropriate amount of methylene blue dye was added to Examples 13, 14, and 15 dispersed in water, and the results are shown in FIG. 1.

1 is an image taken by dispersing a pharmaceutical formulation comprising a poorly soluble drug according to the present invention in water, oil or a mixture of water and oil, and adding micronized oil to confirm the emulsification. (A: water, B: oil, C: mixture of water and oil, D: Example 13 dispersed in aqueous solution, E: Example 14 dispersed in aqueous solution, F: Example 15 dispersed in aqueous solution)

As shown in Fig. 1, methylene blue was well-dissolved in the aqueous solution and uniformly distributed (A), and the reagent did not dissolve in oil, so it was not distributed (B), and only mixed with water in the mixing of water and oil It was confirmed that it was dissolved. In view of this, the pharmaceutical formulation of Examples 13-15 of the present invention was confirmed to be oil-in-water because methylene blue is well distributed and exhibits a color displayed in an aqueous solution.

<Experimental Example 4> Cryogenic Freeze Scanning Electron Microscopy Analysis

Cryo-Scanning Electronic Microscopy using Example 13-15 showing excellent particle size and properties in Experimental Example 1 to confirm the oil droplets of the pharmaceutical preparations according to the present invention ; Cryo-SEM) to analyze Examples 13-15. The results are shown in Figs. 2-4.

2-4 are results of cryogenic freeze scanning electron microscopy (Cryo-SEM) analysis of pharmaceutical formulations containing poorly soluble drugs according to the present invention. Figure 2: Example 13, Figure 3: Example 14, Figure 4: Example 15

As shown in Figure 2-4, it can be confirmed that the pharmaceutical formulation according to the present invention has a relatively uniform spherical remains.

<Experimental Example 5> Stability test (severe temperature stability)

In order to evaluate the stability of the pharmaceutical preparation according to the present invention, stability was evaluated using Examples 13-15 showing excellent particle size and properties in Experimental Example 1, and the results are shown in FIGS. 5 and 6.

Specifically, after long-term storage of the pharmaceutical formulations of Examples 13-15 under harsh conditions (37 ° C., 75% relative humidity), the sample stability over time was confirmed. The stability was visually confirmed whether or not there was an unstable property such as re-precipitation of the drug, and a certain amount of samples were taken at a certain point in time to verify the particle size distribution using ELS-Z and the content confirmation analysis using HPLC.

Figure 5 shows the change in particle size over two months under the harsh conditions of a pharmaceutical preparation containing a poorly soluble drug according to the present invention. It was analyzed using a particle size analyzer (ELS-Z, OTSUKA, Electronic Co., Japan). ◆ represents Example 13, ■ represents Example 14, ▲ represents Example 15.

Figure 6 shows the drug content for 2 months under severe conditions. It was analyzed using HPLC, and ◆ represents Example 13, ■ represents Example 14, and ▲ represents Example 15.

As shown in FIG. 5, it can be seen that the size of the particle size is maintained even when time passes.

As shown in FIG. 6, the area ratio obtained by analyzing the content of each example by HPLC was compared with the content standard solution, and it was confirmed that the drug content was maintained at 80% or more for two months.

That is, it can be seen that the pharmaceutical formulation according to the present invention is a stable formulation because the particle size and the content of the drug are maintained even after a lapse of time under harsh conditions.

<Experimental Example 6> Confirmation of drug dissolution pattern

The pharmaceutical preparation of the embodiment of the present invention was prepared by using cinacalcet hydrochloride as a poorly soluble drug, and cinacalcet hydrochloride absorbed 5.1% when taken on an empty stomach, 20.4% when consumed when eating, and the difference was very severe. It is known that the bioavailability due to the absorption rate of up to 20% is also low from 20 to 25%, and the dissolution rate is also poor because it is absorbed only in the stomach. Thus, the pharmaceutical formulation comprising the cinacalcet hydrochloride of the embodiment of the present invention prepared using the self-emulsifying drug delivery system, upon contact with the eluate, requires rapid drug release from the formulation.

Thus, in order to evaluate the extent of dissolution of the pharmaceutical preparations according to the present invention in organ organs in vivo, the pattern of drug dissolution in artificial digestive fluid was confirmed. The dissolution pattern was confirmed using Example 13-15 showing excellent particle size and properties in Experimental Example 1, and the results are shown in Table 8 and FIGS. 7-10. As a comparative example, a prototype Regpara tablet was used.

For rapid distribution, the pharmaceutical formulations of Examples 13-15 were filled in capsules capable of rapidly releasing the formulations, and then dissolution experiments were performed.

The dissolution test was conducted according to the second method (paddle method) of the Korean Pharmacopoeia Dissolution Test Method. The eluate was 900 ml of the first pharmacopoeia solution (pH 1.2), the second solution (pH 6.8), and the pH 4.0 eluate. The temperature of the eluate was 37 ° C and the rotational speed of the paddle was 100 rpm. The sample solution was taken at 5, 10, 15, 30, and 45 minutes and supplemented with fresh eluate prepared in advance at the same temperature. The collected sample was filtered with a certain amount of 0.45 μm membrane filter and analyzed by HPLC to dissolve. Was confirmed. Table 13 and Figures 7-10 show the dissolution patterns in Example 13-15 and the first liquid, the second liquid, and the artificial digestive juice at pH 4.0 of the prototype Regpara tablets.

Example Time (min) pH 1.2 pH 6.8 pH 4.0 13 5 2.33 2.60 14.35 10 26.92 20.49 49.79 15 39.73 32.39 73.41 30 42.52 38.24 76.99 45 43.08 40.49 82.42 14 5 12.75 12.64 0.85 10 51.31 60.47 6.33 15 69.98 71.53 8.50 30 75.06 75.48 8.20 45 75.49 75.72 9.05 15 5 4.00 17.47 28.18 10 16.47 44.80 43.13 15 56.63 60.51 48.78 30 66.44 64.45 49.19 45 80.90 70.22 66.63 REGPARA TAB 5 0.22 0.30 1.91 10 0.56 0.35 37.66 15 25.94 0.33 47.98 30 38.23 0.42 55.64 45 54.57 0.51 55.95

7-10 is a graph showing the dissolution pattern in artificial digestive fluid. 7 is Example 13, Figure 8 is Example 14, Figure 9 is Example 15, Figure 10 is a graph showing the dissolution of the prototype REGPARA tablets in artificial digestive fluid. At this time, in the graph, ◆ indicates pH 1.2 ■ indicates pH 6.8 ▲ indicates pH 4.0.

As shown in Table 8 and Figures 7-10,

The prototype REGPARA tablet was found to have a dissolution rate of about 50% in the eluate at pH 1.2 and pH 4.0 after 45 minutes, but it was confirmed that the elution was very low in the pH 6.8 eluate.

On the other hand, Example 13 according to the present invention, after 45 minutes, exhibited a dissolution rate of 40% or more at all pH, in particular, at pH 4.0, a dissolution rate of 80% or more was significantly higher than that of the prototype.

Example 14 showed a high dissolution rate of 45% or more at pH 1.2 and pH 6.8 after 45 minutes.

Example 15, after 45 minutes, not only showed a high dissolution rate in all pH conditions from 80% or more at pH 1.2, 70% or more at pH 6.8, and 60% or more at pH 4.0, and also exhibited a higher dissolution rate compared to the prototype Looked.

In other words, the pharmaceutical formulation according to the present invention shows a high dissolution rate regardless of the pH, and can be usefully used as a formulation that can replace the existing prototype whose elution rate is affected by pH.

Claims (11)

It is a pharmaceutical preparation comprising a poorly soluble drug consisting of a poorly soluble drug, oil, surfactant and auxiliary surfactant,
For 1 part by weight of poorly soluble drug,
5 to 30 parts by weight of oil; 5 to 25 parts by weight of a surfactant; And 1 to 25 parts by weight of auxiliary surfactant; Pharmaceutical formulation comprising a poorly soluble drug, characterized in that the mixture.
According to claim 1,
The poorly soluble drugs include cinacalcet HCl, Ticagrelor, atorvastatin, Rosuvastatin, Simvastatin, Docetaxel, Ibuprofen and Deck. Pharmaceutical preparation characterized in that it is any one selected from the group consisting of Shibuprofen (Dexibuprofen).
According to claim 1,
The oil is a pharmaceutical preparation, characterized in that any one or a combination thereof selected from the group consisting of glyceryl oleate, polyoxyglyceride, medium chain triglyceride, diethylene glycol and polyoxyglyceride.
According to claim 1,
The surfactant is a pharmaceutical agent, characterized in that any one or a combination thereof selected from the group consisting of castor oil, poloxamer compound and polysorbate.
According to claim 1,
The auxiliary surfactant is a pharmaceutical preparation, characterized in that any one or a combination of polyethylene glycol, polyethylene oleyl ether, propylene glycol monolaurate and polyglyceryl oleate.
According to claim 1,
The pharmaceutical formulation is dispersed in an aqueous solution, characterized in that the microemulsion (microemulsion) pharmaceutical formulation.
The method of claim 6,
The pharmaceutical formulation characterized in that the particle size of the microemulsion is 10-100 nm.
According to claim 1,
The surfactant is a pharmaceutical formulation characterized in that the HLB coefficient is 4 to 18.
According to claim 1,
The pharmaceutical preparation is a pharmaceutical preparation characterized in that it is a form selected from the group consisting of oral, injection, mucosal, inhalation, external preparations and transdermal absorption.
According to claim 1,
The pharmaceutical formulation is a pharmaceutical preparation, characterized in that it can be prepared in one formulation selected from the group consisting of liquid formulations, tablets, pills, powders, granules, capsules, gels, creams, elixirs, alcohols, syrups and lemonades Formulation.
Mixing the poorly soluble drug and oil to solubilize the poorly soluble drug (step 1); And
It is a method for preparing a pharmaceutical formulation comprising a poorly soluble drug comprising the step of preparing a liquid formulation by adding a surfactant and an auxiliary surfactant to the solubilized poorly soluble drug (step 2),
With respect to 1 part by weight of the poorly soluble drug,
5 to 30 parts by weight of oil; 5 to 25 parts by weight of a surfactant; And 1 to 25 parts by weight of an auxiliary surfactant; a method for preparing a pharmaceutical preparation comprising a poorly soluble drug, characterized in that it is mixed.

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