KR102492147B1 - Carvedilol loaded solid oral compositions using self-nanoemulsifying drug delivery system and methods for their preparation - Google Patents

Abstract

The present invention relates to a self-nanoemulsification drug delivery system containing carvedilol with improved water solubility and dissolution, and further oral bioavailability, and a manufacturing method thereof, and more particularly, to a self-nanoemulsification containing carvedilol, a base composition and a solidifying agent. It relates to a solid oral dosage form composition for oral use using a drug delivery system, wherein the base composition includes Peseol, Labrasol, and Tween 20 or Tween 80, and a preparation method thereof. The carvedilol-containing solid self-nanoemulsified drug delivery system according to the present invention is easy to manufacture, has a solid state, so there is no inconvenience in taking and storing, and has the effect of significantly increasing the water solubility and dissolution of carvedirol, thereby improving oral bioavailability. indicates possible effects.

Description

Carvedilol loaded solid oral compositions using self-nanoemulsifying drug delivery system and methods for their preparation}

The present invention relates to a carvedilol-containing oral solid dosage form composition using a self-nanoemulsified drug delivery system and a method for preparing the same, and more specifically, contains carvedilol as an active ingredient, oil, surfactant, and auxiliary surfactant, respectively. Composition for self-nanoemulsified drug delivery system containing silicon dioxide as a solid carrier and using PESEOL (Glyceryl monooleate (Type 40)), Tween 20 or Tween 80, and Labrasol (Caprylocapryol macrogol-8/glycerides), and its composition It's about manufacturing methods.

Carvedirol is a non-selective β-blocker with α-1 receptor blocking activity, and is a drug used as a treatment for hypertension, congestive heart failure and other left ventricular dysfunction. Its IUPAC name is (±)-1(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol.

In developing new drugs, it is important to improve the water solubility of drugs. Insufficient water solubility of the drug causes inhibition of absorption and low oral bioavailability. Most of the new drug materials currently being developed are drugs belonging to BCS class II having low water solubility and high membrane permeability. Cavedirol, a model drug of the present invention, is also a drug belonging thereto.

Therefore, in order to improve the water solubility of drugs having such low water solubility, a solid dispersion (Bulletin of the Korean chemical society, 39, 778-783 (2018)), a solid self-emulsifying drug delivery system (Drug delivery, 24(1) ), 1018-1025 (2017)), clathrate compounds (Colloids and Surfaces B: Biointerfaces, 162, 420-426 (2018)), gelatin microspheres (Drug delivery, 17(5), 322-329 (2010)), etc. Several solubilization techniques have been used.

The prior art still has unsatisfactory water solubility, dissolution, and oral bioavailability of carvedilol, so there is a need to further improve the water solubility, dissolution, and bioavailability of carvedirol.

Self-nanoemulsifying drug delivery systems (SNEDDS) containing an isotropic mixture of drug, surfactant and oil are emerging as a means of increasing the oral bioavailability of hydrophobic drugs. This system spontaneously produces (nano)emulsion after contact with an aqueous medium in gastrointestinal fluid. The emulsion particles thus formed are advantageous for drug absorption due to their large surface area, thereby improving the bioavailability and reproducibility of poorly water-soluble drugs. However, liquid self-nanoemulsified drug delivery systems have several limitations, including instability during handling and storage. Therefore, in order to overcome these limitations of the liquid self-nanoemulsified drug delivery system, a solid self-nanoemulsified drug delivery system was developed by converting the liquid self-nanoemulsified drug delivery system into a powder form through spray drying. This solid dosage form offers many advantages such as high stability, ease of handling, improved water solubility and oral bioavailability.

Nonetheless, conventional solid self-nanoemulsified drug delivery systems produce relatively large and non-uniform emulsions upon contact with an aqueous medium, so there is a possibility that water solubility and water solubility may not be improved. Accordingly, as a result of research by the present inventors, a solid self-nanoemulsification drug delivery system that forms a smaller and more uniform emulsion when re-dispersed in an aqueous medium using the SPG membrane emulsification method and the high-pressure homogenization method is more improved aqueous solubility. and dissolution, and it was confirmed that the oral bioavailability was remarkably improved, thereby completing the present invention.

1) Patent Publication No. 10-2008-0105114 (nanoparticle-type carvedilol formulation, published on December 3, 2008) 2) Patent Publication No. 10-2005-0061062 (Carvedilol formulation with improved solubility, published on June 22, 2005) 3) Patent Publication No. 10-2014-0037648 (pharmaceutical composition and controlled-release pharmaceutical formulation containing carvedilol and tartaric acid, published on March 27, 2014) 4) Patent Publication No. 10-2001-0031952 (new oral dosage form for carvedirol, published on April 16, 2001)

To provide a carvedilol-containing oral solid dosage form composition with improved water solubility, dissolution and ultimately oral bioavailability and improved intake and storage convenience through solidification using a self-nanoemulsified drug delivery system, and a manufacturing method thereof there is.

However, the problem to be solved by the present invention is not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

According to one embodiment of the present invention, the present invention is an oral solid dosage form composition using a self-nanoemulsified drug delivery system comprising carvedilol, a base composition and a solidifying agent, wherein the base composition includes Peseol, Labrasol and Tween Preparing a liquid self-nanoemulsified drug delivery system by mixing an oral solid dosage form comprising 20 or Tween 80 and (a) carvedirol, Peseol, Labrasol and Tween 20 or Tween 80 ; (b) preparing particles of the liquid self-nanoemulsification drug delivery system by SPG membrane emulsification or high-pressure homogenization; and (c) mixing a solid carrier with the liquid self-nanoemulsified drug delivery system and drying the mixture; It provides a method for producing a solid dosage form composition for oral use using a self-nano-emulsified drug delivery system comprising a.

The solid self-nanoemulsified drug delivery system containing carvedilol of the present invention spontaneously forms nano-sized emulsion particles when in contact with water in the stomach, thereby significantly increasing the solubility of carvedilol in water, and further improving dissolution and oral bioavailability. can increase

1 is a virtual three-phase phase equilibrium diagram showing the self-emulsifying regions of Peseol, Tween 80, and Labrasol.
Figure 2a is a graph showing the effect of operating time on the emulsion particle size and polydispersity (PDI) when preparing a liquid self-nanoemulsification drug delivery system by SPG membrane emulsification.
Figure 2b is a graph showing the effect of stirring speed on the emulsion particle size and polydispersity (PDI) when preparing a liquid self-nanoemulsification drug delivery system by SPG membrane emulsification.
Figure 2c is a graph showing the effect of membrane pore size on emulsion particle size and polydispersity (PDI) when preparing a liquid self-nanoemulsification drug delivery system by SPG membrane emulsification method.
Figure 3a is a graph showing the effect of repeated pressure on the emulsion particle size and polydispersity (PDI) at 900 mbar when a liquid self-nanoemulsification drug delivery system is prepared by a high-pressure emulsification method (high-pressure homogenization method).
Figure 3b is a graph showing the effect of the repetition number on the emulsion particle size and polydispersity (PDI) at 1200 mbar when the liquid self-nanoemulsification drug delivery system is prepared by high-pressure emulsification.
Figure 3c is a graph showing the effect of the repetition number on the emulsion particle size and polydispersity (PDI) at 1500 mbar when a liquid self-nanoemulsification drug delivery system is prepared by a high-pressure emulsification method.
Figure 4 is a graph showing the effect of the emulsification method on the emulsion particle size and polydispersity (PDI) of the solid self-nanoemulsified drug delivery system.
5A is a scanning electron micrograph of carvedilol.
5B is a scanning electron micrograph of silicon dioxide.
5C is a scanning electron micrograph of Example 15.
6 is a differential scanning calorimetry graph of carvedilol, a physical mixture of carvedilol and silicon dioxide, and examples.
Figure 7 is a powder X-ray diffraction measurement graph of carvedilol, a physical mixture of carvedilol and silicon dioxide, and examples.
Figure 8 is a graph showing the drug concentration in blood after administering Carvedirol, an amount corresponding to 40 mg/kg as a drug to SD-based rats of Examples.

Hereinafter, the present invention will be described in detail.

According to one aspect of the present invention, in order to prepare the solid self-nanoemulsified drug delivery system of the present invention, first, a liquid self-nanoemulsified drug delivery system without the addition of a solidifying agent must be prepared. Therefore, first, each component among the base compositions of the self-nanoemulsified drug delivery system will be described in more detail as follows:

Among the base compositions of the self-nanoemulsified drug delivery system in the present invention, peseol, as an oil, corresponds to Glyceryl monooleate (Type 40) and serves as a dissolving agent in oral formulations and topical formulations of poorly soluble drugs. The oil improves the absorption rate of the poorly soluble carvedilol used in the present invention and increases the water solubility, thereby reducing the administered dose. The oil component may be contained in 10 to 35% by weight, preferably 10 to 25% by weight, particularly preferably 25% by weight in the base composition of the self-nanoemulsified drug delivery system of the present invention it could be If the amount of the dissolving agent component is less than 10% by weight, preferably less than 25% by weight, or more than 25% by weight, an incomplete emulsion may be formed even if the emulsification is incomplete or formed.

Tween 20 or Tween 80 (Polyoxyethylene (20) sorbitan monooleate) is a pharmaceutically acceptable nonionic surfactant. Surfactants, together with oil and co-surfactants, help form self-nano emulsified particles and improve absorption rates. The Tween 20 or Tween 80 may be contained in an amount of 30 to 80% by weight, more preferably 50% by weight, in the base composition of the self-nanoemulsified drug delivery system of the present invention. If the amount of Tween 20 or Tween 80 is less than 30% by weight, preferably less than 50% by weight, the water solubility of the poorly soluble drug cannot be increased, and when used in excess of 80% by weight, preferably more than 50% by weight has the disadvantage that emulsification is incomplete or not formed.

Labrasol is Caprylocapryol macrogol-8/glycerides and acts as a solubilizing agent. Specifically, it serves as a co-surfactant that facilitates absorption in the gastrointestinal tract by adjusting the total HLB value of the surfactant in the self-nanoemulsified drug delivery system to act as a more stable emulsifier. It also acts as an absorption enhancer and aids absorption. The Labrasol may be contained in 0 to 40% by weight, preferably 10 to 40% by weight, more preferably 25% by weight in the base composition of the self-nanoemulsified drug delivery system of the present invention. It can be. If the amount of Labrasol is used less than 10% by weight, preferably less than 25% by weight, or more than 40% by weight, preferably more than 25% by weight, emulsification is incomplete or not formed.

When the liquid self-nanoemulsification drug delivery system of the composition according to the present invention comes into contact with water, it spontaneously emulsifies to form nano-sized emulsion particles, which makes it easy to penetrate the fat-soluble biomembrane, so absorption in the body is very fast, resulting in high bioavailability. can be expected

The active ingredient, carvedirol, is dissolved in the self-nanoemulsified drug delivery system base composition. The content of carvedilol may be 0.1 to 2 parts by weight, more preferably 1 part by weight, based on 100 parts by weight of the base composition. When the content of the active ingredient, carvedilol, is less than 0.1 part by weight, preferably less than 1 part by weight, the drug content is too low and there is a disadvantage in that a large amount of the composition must be taken, and more than 2 parts by weight, preferably 1 part by weight. In the case of excess, a case where the maximum aqueous solubility in the self-microemulsified drug delivery system is exceeded occurs.

On the other hand, according to another aspect of the present invention, in the method for producing a solid dosage form composition for oral use using a self-nanoemulsified drug delivery system,

(a) preparing a liquid self-nanoemulsified drug delivery system by mixing Cavedirol, Peseol, Labrasol, and Tween 20 or Tween 80;

(b) preparing particles of the liquid self-nanoemulsification drug delivery system by SPG membrane emulsification or high-pressure homogenization; and

(c) mixing and drying a solid carrier with the liquid self-nanoemulsified drug delivery system;

It provides a method for producing a solid dosage form composition for oral use using a self-nano-emulsified drug delivery system comprising a.

In the method for preparing a solid dosage form composition for oral use using the self-nano-emulsified drug delivery system provided according to an embodiment of the present invention, as a method for preparing a smaller and more homogeneous emulsion in the liquid self-nano-emulsified drug delivery system, It is not particularly limited, but preferably, an SPG membrane emulsification method or a high pressure homogenization method may be used.

When using the above SPG film emulsification method, it is preferable to stir at a stirring speed of 100 to 300 rpm, particularly a stirring speed of 200 rpm, and stirring for 10 to 30 minutes, particularly preferably for 10 minutes. This is desirable in terms of obtaining the smallest emulsion particle size and polydispersity (PDI).

In addition, when using the high-pressure homogenization method, it is preferable to repeat 1 to 7 times at 900 to 1500 mbar, especially 5 times at 1200 mbar. This is desirable from the standpoint of obtaining the smallest emulsion particle size and polydispersity (PDI).

In order to prepare a solid dosage form composition, which is the final dosage form of the present invention, a solid carrier may be applied to the self-nanoemulsified drug delivery system base composition and the drug to be solidified. The solidification method follows a conventional method already known to those skilled in the art, and a specific example thereof is to completely dissolve a drug in a liquid self-nanoemulsified drug delivery system base composition, and then to a solid carrier in a suspending solvent such as water or an organic solvent. After uniformly suspending with calcium silicate and silicon dioxide, it can be solidified by a method such as spray drying.

Meanwhile, as the solid carrier used herein, at least one selected from the group consisting of calcium silicate, silicon dioxide, and magnesium aluminate silicate may be used, and silicon dioxide may be preferably used. The solid carrier is preferably used in an amount greater than 25 and less than 50 parts by weight based on 100 parts by weight of the liquid self-nanoemulsified drug delivery system base composition. Below 25 parts by weight, the amount of the solid carrier is too small to form a solid, making it impossible to manufacture, and above 50 parts by weight, the content of the drug decreases, resulting in an increase in dosage. cannot promote

Further, the pharmaceutically usable drying method is not particularly limited, but for example, spray drying using a spray dryer, fluidized bed granulator, CF granulator, vacuum dryer, etc., reduced pressure drying, hot air drying, etc. may be used. .

The composition according to the present invention may be prepared in a pharmaceutical form including other pharmaceutically acceptable excipients such as diluents, disintegrants, lubricants, etc. in addition to the above components. In addition, the solid self-nanoemulsified drug delivery system containing carvedilol can be prepared in pharmaceutical forms such as coated tablets, capsules, and granules by methods well known to those skilled in the art.

Hereinafter, embodiments will be described in detail with reference to the accompanying drawings. However, since various changes can be made to the embodiments, the scope of the patent application is not limited or limited by these embodiments. It should be understood that all changes, equivalents or substitutes to the embodiments are included within the scope of rights.

Terms used in the examples are used only for descriptive purposes and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as "include" or "have" are intended to designate that there is a feature, number, step, operation, component, part, or combination thereof described in the specification, but one or more other features It should be understood that the presence or addition of numbers, steps, operations, components, parts, or combinations thereof is not precluded.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the embodiment belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and unless explicitly defined in the present application, they should not be interpreted in an ideal or excessively formal meaning. don't

In addition, in the description with reference to the accompanying drawings, the same reference numerals are given to the same components regardless of reference numerals, and overlapping descriptions thereof will be omitted. In describing the embodiment, if it is determined that a detailed description of a related known technology may unnecessarily obscure the gist of the embodiment, the detailed description will be omitted.

In addition, in describing the components of the embodiment, terms such as first, second, A, B, (a), and (b) may be used. These terms are only used to distinguish the component from other components, and the nature, order, or order of the corresponding component is not limited by the term.

Components included in one embodiment and components including common functions will be described using the same names in other embodiments. Unless stated to the contrary, descriptions described in one embodiment may be applied to other embodiments, and detailed descriptions will be omitted to the extent of overlapping.

The following is a description of a method for preparing a solid oral dosage form composition using a self-nano-emulsified drug delivery system according to an embodiment of the present invention and the effects thereof with reference to the drawings.

- Examples

<Experimental Example 1> Water solubility test of carvedilol

The water solubility test of carvedilol, which is insoluble in water, is performed using Tween 20, Tween 80, Span 20, Labrasol, Cremophor, Transcultol ), Labrafil, Solutol HS15, Plurol diisostearique, Capryol 90, Capryol PGMC, Lauro Glycol 90 (Lauroglycol 90), Lauroglycol FCC (Lauroglycol FCC), Poloxamer 188 (Poloxamer 407), Sodium Lauryl Sulfate (SLS), TPGS Interface Activators, Castor oil, Corn oil, Soybean oil, Coconut oil, Mineral oil, Peceol, Captex 355 After adding an excess of carvedilol to 1 ml of a 10% solution in the case of surfactant and an excess of carvedilol to 1 ml of oil in the case of surfactant, stirring at 25 ° C. and 100 rpm in a stirring thermostat for 1 week After that, carvedilol was quantified with a high-performance liquid chromatography (HPLC) system.

* HPLC conditions for quantification of carvedirol

Column: Hypersil ODS-2 ^® C18 (4.6 Х 150 mm, 5 μm)

Flow rate: 1.0 mL/min

Injection volume: 10 μL

Detection wavelength: 242 nm

Mobile phase: mobile phase A- 0.2% aqueous phosphoric acid solution, mobile phase B- methyl alcohol (50:50 v/v)

The water solubility test results are shown in Table 1 and Table 2 below. As a substance that significantly increases the water solubility of carvedirol, Tween 80 among Tween 20 and Tween 80 was selected as the surfactant, Labrasol was selected as the co-surfactant, and Peseol was selected as the oil for self-nano-emulsified drug delivery. system was made.

Surfactant water solubility test ingredient name Water solubility (μg/ml) Tween20 3034.7 ± 92.8 Tween80 2737.7 ± 15.6 Span20 332.9 ± 18.9 Labrasol 1134.6 ± 8.1 CremophorEL 496.7 ± 8.5 Cremophor ELP 258.4 ± 10.8 Cremophor RH40 250.5 ± 5.2 Cremophor RH60 214.8 ± 6.5 Transcutol P 11.4 ± 1.3 Transcutol HP 12.3 ± 1.2 Labrafil M1944CS 21.2 ± 1.9 Labrafil M2125CS 47.5 ± 19.8 Solutol HS15 11.5 ± 0.2 Plurol diisostearique 11.4 ± 0.4 Capryol 90 11.2 ± 0.6 Capryol PGMC 9.3 ± 0.5 Lauroglycol90 12.8 ± 0.6 Lauroglycol FCC 12.8±1.0 Poloxamer 188 14.9 ± 0.9 Poloxamer 407 30.7 ± 1.1 SLS 1036.0 ± 10.7 TPGS 9.5 ± 0.3

Oil water solubility test ingredient name Water solubility (μg/ml) Castor oil 9.6 ± 0.7 Corn oil 0.4 ± 0.0 Soybean oil 1158.5 ± 382.2 Coconut oil 746.6 ± 78.1 Mineral oil 0.4 ± 0.0 Peceol 5455.9 ± 1311.0 Captex 355 1379.9 ± 46.3

<Experimental Example 2> Preparation of liquid self-nanoemulsified drug delivery system (SNEDDS)

In order to create the optimal composition of the liquid self-nano-emulsified drug delivery system, the areas where Peseol, Tween 80, and Labrasol selected in the above water solubility experiment were mixed in various weight ratios to form self-nano-emulsified particles of 300 nm or less were marked. A virtual three-phase phase equilibrium diagram as shown in FIG. 1 was completed. Within this self-emulsification area, as shown in Table 3 below, first, experiment while adjusting the weight ratio of Peseol/Tween 80 to select the ratio of Example 3 having the smallest emulsion particle size as 25/75, and then select the ratio of oil After fixing Phosphorus 25, experiments were conducted while changing the ratio of Tween 80 and Labrasol, and 25/50/25 of Example 6 having the smallest emulsion particle size was determined as the optimal base composition for a liquid self-nanoemulsified drug delivery system. .

Liquid self-nanoemulsified drug delivery system base composition and emulsion particle size Furtherance Components (% by weight) Particle size (nm) peseol twin 80 Labrasol Example 1 35 65 - 419.0 ± 29.8 Example 2 30 70 - 508.9 ± 106.6 Example 3 25 75 - 364.0 ± 47.2 Example 4 20 80 - 501.3 ± 73.8 Example 5 25 35 40 267.4 ± 37.9 Example 6 25 50 25 264.5 ± 30.0 Example 7 25 60 15 334.2 ± 70.1 Example 8 35 30 35 415.8 ± 43.0 Example 9 35 45 20 340.7 ± 26.0 Example 10 35 55 10 394.3 ± 109.0 Comparative Example 1 10 - 90 753.2 ± 84.6 Comparative Example 2 90 - 10 797.6 ± 148.5

A liquid self-nanoemulsified drug delivery system was prepared while adding carvedilol in various ratios to the composition selected above. Among the compositions of Table 4 below, the active ingredients of the compositions of Examples were completely dissolved in the base composition of the self-nanoemulsified drug delivery system, but the compositions of Comparative Examples were not completely dissolved. In addition, it was confirmed in FIG. 2 that there was no significant difference in emulsion particle size and polydispersity (PDI) before and after drug addition.

Liquid self-nanoemulsified drug delivery system Furtherance Components (% by weight) active ingredient
(Ratio with respect to 100 parts by weight of base) peseol twin 80 Labrasol Example 11 25 50 25 0.1 Example 12 25 50 25 0.25 Example 13 25 50 25 0.5 Example 14 25 50 25 One Comparative Example 3 30 20 50 2

<Experimental Example 2-1> Optimization of SPG Membrane emulsification method and High Pressure Homogenizer (HPH) method

The SPG membrane emulsification method was used to reduce the emulsion particle size and polydispersity (PDI) formed in the composition of the liquid self-nanoemulsification drug delivery system selected in Experimental Example 2, and to optimize this method, the stirring speed ( 100-300 rpm) and operating time (10-30 min) were changed, and conditions with the smallest emulsion particle size and polydispersity (PDI) were selected.

First, the membrane pore size was fixed at 2.5 μm and the operating time was constantly fixed at 10 minutes, and then the stirring speed was changed to 100-300 rpm. When measuring the emulsion particle size and polydispersity (PDI), the emulsion particle size according to the stirring speed and polydispersity (PDI) was low at 200 rpm. Therefore, 200 rpm was selected as an appropriate stirring speed.

Next, the membrane pore size is 1.1 μm and 2.5 μm, the stirring speed is constantly fixed at 200 rpm, and the operating time is constantly fixed at 10 minutes, and then the emulsion particle size and polydispersity (PDI) are measured. Both emulsion particle size and polydispersity (PDI) were significantly lower at 1.1 μm. Therefore, a membrane pore size of 1.1 μm was selected.

A high-pressure homogenizer was used to reduce the emulsion particle size and polydispersity (PDI) formed in the composition of the liquid self-nanoemulsified drug delivery system selected in Experimental Example 2, and to optimize this method, the pressure (900 to 1500 mbar ), and the number of iterations (0 to 7 times) were changed, and conditions with the smallest emulsion particle size and polydispersity (PDI) were selected.

First, HPH was treated by changing the pressure from 900 to 1200 mbar and changing the number of repetitions from 0 to 7. As a result, when measuring the emulsion particle size and polydispersity (PDI), 5 times at 1200 mbar, where the emulsion particle size decreases according to the pressure, was selected as the appropriate number of repetitions.

As a result of manufacturing a liquid self-nanoemulsification drug delivery system under optimized conditions, the group using the SPG membrane emulsification method (particle size: 264.50 ± 39.98, polydispersity (PDI): 0.31 ± 0.018) compared to the unsag group (particle size: 264.50 ± 39.98) Size: 246.02 ± 143.43), polydispersity (PDI): 0.23 ± 0.15) and high-pressure homogenization group (particle size: 87.7 ± 8.4, polydispersity (PDI): 0.20 ± 0.01) all significantly decreased. It was confirmed that the emulsion particle size and polydispersity (PDI) were significantly reduced, especially in the case of the high-pressure homogenization method, compared to the untreated group.

<Experimental Example 3> Preparation of solid self-nanoemulsified drug delivery system and evaluation of water solubility and dissolution

The liquid self-nanoemulsification drug delivery system (L-SNEDDS) containing 1 part by weight of the drug with respect to 100 parts by weight of the base composition confirmed through the above experiment was used as a solvent in 300 ml of distilled water as follows, without treatment, SPG film emulsification , After emulsification through a high-pressure homogenization method, silicon dioxide or calcium silicate was added as a solid carrier and spray-dried to completely evaporate the solvent to prepare a solid self-nanoemulsified drug delivery system. In the case of Comparative Example 10, the amount of the solid carrier was small, and solidification was not performed.

Solid self-nanoemulsified drug delivery system Furtherance Components (% by weight) Oil painting method L-SNEDDS silicon dioxide calcium silicate Magnesium Silicate Aluminate Example 15 100 50 untreated Example 16 100 50 SPG film emulsification Example 17 100 50 high pressure homogenizer Comparative Example 4 100 50 untreated Comparative Example 5 100 50 SPG film emulsification Comparative Example 6 100 50 high pressure homogenizer Comparative Example 7 100 50 untreated Comparative Example 8 100 50 SPG film emulsification Comparative Example 9 100 50 high pressure homogenizer Comparative Example 10 100 25 untreated

Each Example and Comparative Example was tested according to the water solubility test method of Experimental Example 1. In addition, dissolution experiments were conducted according to the following dissolution conditions.

- Elution conditions

Eluent: 900 ml of water

Elution temperature: 37 ℃

Dissolution method: 2nd method (paddle method)

Paddle rotation speed: 50 rpm

25 mg of carvedilol was tested according to the above elution conditions, and carvedilol was quantified with a high-performance liquid chromatography (HPLC) system of water solubility test method with each eluate.

Water solubility and dissolution evaluation results Water solubility (μg/ml) Dissolution rate at 30 minutes (%) Example 15 838.1 ± 41.7 49.1 ± 2.4 Example 16 841.3 ± 19.2 45.3 ± 6.1 Example 17 815.3 ± 9.7 43.6 ± 5.6 Comparative Example 4 713.9 ± 28.7 25.1±6.0 Comparative Example 7 741.0 ± 19.1 32.1 ± 1.4 Comparative Example 10 - - carvedilol powder 1.6 ± 0.1 3.8 ± 0.1

As a result of the water solubility test in Table 6, all of the Examples and Comparative Examples showed a large increase in water solubility and dissolution compared to the carvedilol powder, especially in the examples (Examples 15 to 17) in which silicon dioxide was used as a solid carrier. In each case, both water solubility and dissolution were significantly increased compared to the corresponding silicon dioxide formulations. Looking at the difference in water solubility and dissolution rate according to the emulsification method in each Example and Comparative Example, untreated, SPG film emulsified and There is no significant difference between high pressure homogenizers.

<Experimental Example 4> Physical and chemical property test

Figure 4 is a graph measuring the emulsion particle size and polydispersity (PDI) after redispersing the solidified self-nanoemulsified drug delivery system in water. The emulsion particle size and polydispersity (PDI) decreased in the order of no treatment > SPG film emulsification > high pressure homogenization, which was related to the increase in average value of water solubility and increase in dissolution rate.

5 is a SEM (Scanning electron micrographs) photograph of carvedilol, silicon dioxide, and Example 15. In the case of carvedilol, it shows an irregular shape, but in the case of Example 15, it can be observed that the self-nanoemulsified drug delivery system is encapsulated in porous calcium silicate.

Figure 6 is a differential scanning calorimetry (DSC) graph of carvedilol, a physical mixture of carvedilol and silicon dioxide, Example 15. It was carried out from 50 to 200 ℃ under the conditions of temperature rise of 10 ℃ per minute. Unlike the melting point peak of the drug at 120 ° C. of carvedilol and the physical mixture, the disappearance of the drug melting point peak in Example 15 confirmed that the drug was converted to an amorphous form.

Figure 7 is a graph of powder X-ray diffraction (PXRD) of carvedilol, a physical mixture of carvedirol and silicon dioxide, Example 15. The crystalline form of the drug was confirmed by the appearance of specific peaks in the carvedilol and physical mixtures, and the disappearance of these specific peaks in Example 15 confirmed that the drug was converted to an amorphous form.

<Experimental Example 5> In vivo kinetics of carvedilol-containing solid self-nanoemulsified drug delivery system (pharmacokinetic study)

To evaluate the oral bioavailability, Example 15 and carvedilol were orally administered to SD rats at 40 mg/kg, and blood was collected from the femoral artery using a heparinized disposable syringe. The collected blood was extracted through liquid-liquid extraction after plasma separation, and the pretreated plasma using sildenafil citrate as an internal standard was analyzed in the same manner as in the aqueous solubility evaluation. The following [Table 7] shows the pharmacokinetic parameters, and FIG. 8 shows the drug concentration in the body according to time.

Pharmacokinetic parameters carved roll Example 15 ¹⁾ T _max (hr) 2.00 ± 0.00 2.00 ± 0.00 ²⁾ _Cmax (μg/ml) 0.75 ± 0.12 1.45 ± 0.30 ³⁾ AUC (hr×μg/ml) 9.06 ± 2.80 16.90 ± 3.78 ⁴⁾ K _el (hr ^-1 ) 0.02 ± 0.02 0.03 ± 0.01 ⁵ )t _1/2 (hr) 29.94 ± 29.44 20.10 ± 6.03

Each figure means "mean ± S.D." (n=6)

*P < 0.05 compared to carvedilol

1) indicates the time to reach the maximum blood concentration.

2) shows the maximum blood concentration.

3) shows the area under the blood concentration-time curve.

4) represents the elimination rate constant of the drug.

5) represents the half-life of the drug.

Example 15, a composition according to the present invention, showed a significant increase in the area under the plasma concentration-time curve, which is an indicator of oral bioavailability, compared to carvedirol. A significant increase was also observed in the highest plasma concentration. Therefore, it was confirmed that the composition of the present invention exhibited excellent oral bioavailability.

As described above, although the embodiments have been described with limited drawings, those skilled in the art can apply various technical modifications and variations based on the above. For example, the described techniques may be performed in an order different from the method described, and/or components of the described system, structure, device, circuit, etc. may be combined or combined in a different form than the method described, or other components may be used. Or even if it is replaced or substituted by equivalents, appropriate results can be achieved.

Therefore, other implementations, other embodiments, and equivalents of the claims are within the scope of the following claims.

Claims (12)

An oral solid dosage form composition using a self-nanoemulsified drug delivery system containing carvedilol, a base composition and a solidifying agent,
The base composition comprises 25% by weight of glyceryl monooleate, 25% by weight of caprylocaproyl macrogol-8/glyceride and 50% by weight of Tween 20 or Tween 80,
1 part by weight of carvedilol based on 100 parts by weight of the base composition, and 50 parts by weight of a solidifying agent,
The solidifying agent is characterized in that at least one selected from the group consisting of calcium silicate, silicon dioxide and magnesium silicate aluminate, oral solid dosage form composition.
delete delete delete According to claim 1,
Characterized in that it further comprises at least one additive selected from the group consisting of pharmaceutically acceptable excipients, diluents, disintegrants, coloring agents and lubricants, oral solid dosage form composition.
delete In the method for preparing a solid dosage form composition for oral use using a self-nanoemulsified drug delivery system,
(a) preparing a liquid self-nanoemulsified drug delivery system by mixing a base composition with carvedilol;
(b) preparing particles of the liquid self-nanoemulsification drug delivery system by SPG membrane emulsification or high-pressure homogenization; and
(c) mixing and drying a solid carrier with the liquid self-nanoemulsified drug delivery system;
including,
The base composition comprises 25% by weight of glyceryl monooleate, 25% by weight of caprylocaproyl macrogol-8/glyceride and 50% by weight of Tween 20 or Tween 80,
Mixing 1 part by weight of carvedilol with respect to 100 parts by weight of the base composition and mixing 50 parts by weight of a solidifying agent,
Characterized in that the solidifying agent is at least one selected from the group consisting of calcium silicate, silicon dioxide and magnesium silicate aluminate,
Manufacturing method of solid dosage form composition for oral use using self-nanoemulsified drug delivery system.
According to claim 7,
The SPG film emulsification method in step (b) is a method for producing an oral solid dosage form composition using a self-nano emulsified drug delivery system, comprising stirring for 10 minutes at a stirring speed of 200 rpm.
According to claim 7,
The high-pressure homogenization method in step (b) is a method for producing an oral solid dosage form composition using a self-nano emulsion drug delivery system, comprising repeating 5 times at 1200 mbar.
According to claim 7,
Drying in the step (c) is characterized in that at least one selected from the group consisting of spray drying, reduced pressure drying and hot air drying, a method for producing an oral solid dosage form composition using a self-nano emulsion drug delivery system.
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