KR20200077676A - Oral solid preparation of sildenafil free base using self-emulsifying drug delivery system - Google Patents

Abstract

The present invention provides a composition for an oral solid preparation including a sildenafil free base as an active ingredient. Particularly, the composition includes: a base composition containing caprylocaproyl polyoxyglyceride as a surfactant, diethylene glycol monoethyl ether as a co-surfactant, and coconut oil, medium-chain triglyceride or a mixture thereof as a solubilizer; a sildenafil free base; and a solidifying agent. The composition provides increased solubility and dissolution rate to the sildenafil free base to improve low bioavailability of the sildenafil free base, facilitates medicine administration through a solid formulation, and provides a rapid and high medicinal effect through high drug compliance. In addition, the composition shows high convenience in preparation and storage to provide high cost-efficiency.

Description

Oral solid preparation of sildenafil free base using self-emulsifying drug delivery system}

The present invention is an oral solid preparation composition of sildenafil free base using a self-emulsifying drug delivery system and a caryl caprolyl polyoxyglyceride as a surfactant, diethylene glycol monoethyl ether as an auxiliary surfactant, and coconut oil, a medium chain as a dissolving agent. It relates to an oral solid preparation composition comprising a sildenafil free base as an active ingredient, a base composition comprising a triglyceride or a mixture thereof, a sildenafil free base and a solidifying agent.

When using drugs as pharmaceuticals, their water solubility and the resulting bioavailability are of great interest in developing pharmaceuticals. In particular, in the use of poorly soluble drugs as pharmaceuticals, various attempts have been made to improve their solubility. There are various methods to improve the solubility, but after dissolving the drug and the water-soluble polymer in a suitable solvent, the solvent evaporation method in which the spray conditions are dissolved in a solvent and the water-soluble polymer is suspended in a solvent to spray-dry the water-soluble polymer in a solvent. It is known to dissolve and suspend the drug in a spray to spray dry the material and the water-soluble polymer to dissolve and cool and solidify the drug and the water-soluble polymer with a ball mill, etc.

The recently used self-emulsifying drug delivery system is a homogeneous mixture of the liquid phase in which the water phase is removed from the components of the microemulsion, and after taking it, when it encounters the water phase such as body fluids under the movement of the gastrointestinal tract, it rapidly disperses itself and emits and disperses quickly. Can be expected. In addition, as well as reducing the irritation caused by the contact of the drug with the mucous membrane in the stomach after dispersing, which is a disadvantage of the microemulsion, there is also an advantage of reducing the volume of the formulation because it is administered in a state where the water phase is removed among the components.

Nanoparticles formed by the self-emulsifying drug delivery system can easily pass through the mucous membrane in the gastrointestinal tract. However, since this self-emulsifying drug delivery system is liquid, it is mainly used for filling in soft capsules, which has the disadvantage of increasing the unit cost during manufacture and inconvenience in taking and storing.

On the other hand, erectile dysfunction is a condition in which the supply of blood flow to the male cavernous cavernous body is not smooth, or even if blood flow is supplied, the internal pressure of the cavernous body does not rise and the erection cannot be maintained for more than a certain period of time due to an increase in the cavernous body. In this case, 25% or more of the total sex life is the case where both men and women do not have a satisfactory sex life. The causes of erectile dysfunction can be largely divided into mental and physical causes. As an improved product of erectile dysfunction, tablets containing sildenafil citrate as an active ingredient are commercially available through Pfizer.

Sildenafil is 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl) -Phenylsulfonyl]-4-methylpiperazine, acting as a selective inhibitor of cyclic guanosine 3',5'-monophosphate phosphodiesterase type 5 (cGMP PDE-5). Sildenafil is used in the form of its water-soluble salt, citrate, to ensure rapid absorption and good bioavailability during formulation. However, due to the very bitter taste of sildenafil citrate, there may be a problem in compliance with medication, and lipid affinity of the drug is important for absorption in vivo, and the log P value of sildenafil citrate is 2.5, which may further enhance absorption in vivo.

Since sildenafil free base exhibits very low solubility in aqueous media, it does not dissolve and disperse in the gastrointestinal tract when administered orally. For this reason, sildenafil free base exhibits a low bioavailability, and therefore, improvement in the low water solubility of sildenafil free base and a low dissolution rate in the gastrointestinal tract is necessary.

Accordingly, there is a need for a new formulation that increases the dissolution rate by solving the problem of low solubility and thus bioavailability when sildenafil free base is used.

Republic of Korea Patent Publication 10-2013-0135611

One object of the present invention is a base composition comprising silyl caprol polyoxyglyceride as a surfactant, diethylene glycol monoethyl ether as a co-surfactant, and coconut oil as a solubilizer, a triglyceride as a medium, or a mixture thereof, sildenafil glass It is to provide an oral solid preparation composition comprising a base and a solidifying agent, a sildenafil free base as an active ingredient.

Another object of the present invention is to prepare a base composition comprising a carrillo caproyl polyoxyglyceride as a surfactant, diethylene glycol monoethyl ether as a co-surfactant, triglyceride as coconut oil or medium as a solubilizer, or a mixture thereof. ; Forming a self microemulsifying drug delivery system by dissolving sildenafil free base in the base composition; And forming a solid self-microemulsifying drug delivery system by uniformly suspending the self-emulsifying drug delivery system and a solidifying agent in an organic solvent and drying the solid self-emulsifying drug delivery system; an oral solid preparation comprising sildenafil free base as an active ingredient. It is to provide a method for preparing a composition.

Specifically, it is as follows. Meanwhile, each description and embodiment disclosed in the present invention can be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention is not limited by the specific descriptions described below.

In one aspect for achieving the above object, the present invention provides caryl caprolyl polyoxyglyceride as a surfactant, diethylene glycol monoethyl ether as a co-surfactant, and triglyceride, a coconut oil, a medium, triglyceride, or a mixture thereof. Provided is an oral solid preparation composition comprising sildenafil free base as an active ingredient, including a base composition comprising, sildenafil free base and a solidifying agent.

In the present invention, in the oral solid preparation composition containing sildenafil free base as an active ingredient, the composition of the sildenafil oral solid preparation composition as a surfactant is caryl caprolyl polyoxyglyceride, diethylene glycol monoethyl ether as an auxiliary surfactant. And providing a composition comprising coconut oil, medium chain triglyceride, or a mixture thereof as a solubilizing agent, thereby improving the bioavailability by increasing the solubility and dissolution rate of sildenafil free base.

Conventionally, there is a problem in that it does not dissolve and disperse in the gastrointestinal tract when administered orally because it exhibits a very low solubility in the aqueous medium of sildenafil free base due to the very bitter taste of sildenafil citrate.

Thus, the present invention was designed to solve the problem of low solubility and the resulting decrease in bioavailability when using sildenafil free base, using a self-emulsifying drug delivery system, but an optimal combination of surfactant, auxiliary surfactant, and solvent composition By excavating the above-mentioned problems can be solved and the oral solid preparation composition having an increased dissolution rate can be provided.

The "sildenafil" is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. It shows the effect of improving erectile dysfunction and pulmonary artery pressure by smoothing blood supply by relaxing the smooth muscles distributed in the corresponding organ.

The "free base" is present in the basic state without forming a salt by binding with protons.

Since the sildenafil free base exhibits very low solubility in aqueous media, it does not dissolve and disperse in the gastrointestinal tract when administered orally. For this reason, sildenafil free base exhibits a low bioavailability, and therefore, improvement in the low water solubility of sildenafil free base and a low dissolution rate in the gastrointestinal tract is necessary.

The "Carrylocaproyl polyoxylglycerides" are mixtures of mono and di-fatty acid esters of mono-, di- and tri-glycerides and polyethylene glycols, non-ions having amphiphilic properties and dispersible in water It can be a sexual surfactant and oily liquid.

In addition, carboxy-8 glyceryl caprylate/caprate, PEG-8 caprylic/capric glyceride (PEG-8 Cprylic/Capric Glycerides) Also referred to as ), it can be used as a solubilizer, an absorption enhancer of a poorly soluble drug, and a surfactant.

In the present invention, as the caryl caproyl polyoxyglyceride serving as a surfactant, a commercially available product under the trade name Labrasol may be purchased and used, but is not limited thereto.

Surfactants are substances that not only enhance the absorption rate, but also stably disperse the active ingredient regardless of hydrogen ion concentration and temperature.

The "Diethylene Glycol Monoethyl Ether" may be used by purchasing a commercially available product under the trade name Transcutol, but is not limited thereto. In addition, it acts as a co-surfactant that facilitates absorption in the gastrointestinal tract by acting as a more stable emulsifier by adjusting the total HLB value of the surfactant in the self-emulsifying drug delivery system as a solubilizing agent for poorly soluble drugs.

The "coconut oil or medium triglyceride" is a drug solubilizer and acts as a solubilizer in a self-emulsifying drug delivery system. The solubilizer can be used as an active ingredient in the present invention, improves the absorption rate of sildenafil free base having very strong hydrophobicity and increases the solubility, thereby reducing the dosage. The medium chain triglyceride may be purchased and used as a commercial product under the trade name Captex 300, but is not limited thereto.

In a specific embodiment of the present invention, the self-emulsifying drug delivery system known in the art uses a series of materials used as surfactants, co-surfactants and/or solubilizers, and the solubility of sildenafil free base was tested. It was confirmed that a base composition comprising a carlocaproyl polyoxyglyceride as an active agent, diethylene glycol monoethyl ether as a co-surfactant, and coconut oil, a medium triglyceride as a solubilizing agent, or a mixture thereof exhibits a particularly high solubility. .

It is a surfactant selected specifically for the preparation of a suitable base for sildenafil free base contained as an active ingredient of the oral solid preparation composition of the present invention, a polyhydroxyglyceride surfactant, a co-surfactant diethylene glycol monoethyl ether, and a dissolving agent coconut. This indicates that it is necessary to use triglycerides, which are oils and mediums, or mixtures thereof.

In order to prepare an oral solid preparation using the self-emulsifying drug delivery system of the present invention, it is necessary to first prepare a liquid self-emulsifying drug delivery system without adding a solidifying agent. Therefore, first, each component of the base composition of the self-emulsifying drug delivery system will be described in more detail as follows.

Specifically, the present invention can provide an oral solid preparation composition, characterized in that 40 to 85% by weight of caryl caproyl polyoxyglyceride in the base composition.

It is more preferable to contain 60 to 80% by weight.

For example, when the amount of caryl caproyl polyoxyglyceride is less than 40% by weight, it is difficult to improve the solubility of a poorly soluble drug, i.e., sildenafil free base, to a desired level, and when used in excess of 85% by weight, emulsification is incomplete or not formed at all. Can.

Specifically, the oral solid preparation composition of the present invention may contain 5 to 45% by weight of diethylene glycol monoethyl ether in the base composition contained therein.

More specifically, it is preferable to contain 10 to 30% by weight of diethylene glycol monoethyl ether.

For example, if the content of diethylene glycol monoethyl ether is less than 5% by weight or exceeds 45% by weight, emulsification may be incomplete or not formed at all.

Specifically, the oral solid preparation composition of the present invention may contain 8 to 20% by weight of the dissolving agent in the base composition contained therein.

The two solvents coconut oil, medium chain triglyceride can be selected and used alone or in combination, and the content of the solvent is preferably 8 to 20% by weight of the base composition according to the present invention, and more specifically contains 10 to 15% by weight It is desirable to do. When the content of the solubilizer is less than 8% by weight or exceeds 20% by weight, an incomplete emulsion may be formed even if the self-emulsifying drug delivery system is not formed or formed.

Specifically, the present invention can provide an oral solid preparation composition characterized in that the sildenafil free base is 0.1 to 5 parts by weight based on 100 parts by weight of the base composition.

More specifically, it is preferable to contain 0.7 to 3 parts by weight.

For example, when the weight part of sildenafil free base is less than 0.1 part by weight, the drug content may be lowered and a large amount of the drug may need to be taken, and if it exceeds 5 parts by weight, the self-emulsifying drug delivery system may exceed the allowable range (Table 2).

Specifically, the solidifying agent contained in the oral solid preparation composition of the present invention may contain 30 to 150 parts by weight based on 100 parts by weight of the base composition.

More specifically, it is preferable that the solidifying agent contains 40 to 75 parts by weight.

For example, when the weight part of the solidifying agent is less than 30 parts by weight based on 100 parts by weight of the base composition, the amount of the solidifying agent may be small and thus it may not be able to form a solid, and if it exceeds 150 parts by weight, the content of the drug is lowered. As a result, the dose is increased, so convenience may not be improved when taking one of the targets of the present invention (Table 3).

Specifically, the present invention provides an oral solid preparation composition, wherein the solidifying agent comprises one or more substances selected from the group consisting of colloidal silicon dioxide, magnesium silicate aluminate, magnesium metasilicate aluminate, and calcium silicate. can do.

The composition according to the present invention may be prepared in a pharmaceutical form containing other pharmaceutically acceptable excipients such as diluents, disintegrants, lubricants, etc. in addition to the above components. In addition, the method for formulating a solid dispersion containing sildenafil free base can be prepared in a pharmaceutical form such as a coated tablet containing tablets, capsules, granules, etc. by a method well known to those skilled in the art.

Carylocaproyl polyoxyglyceride (trade name Labrasol) as a surfactant with a composition according to the present invention, diethylene glycol monoethyl ether (trade name Transcutol HP) as an auxiliary surfactant, and triglyceride (medium captax) as a dissolving agent When 300) was used, it was found that the emulsion region was enlarged when the ratio of the surfactant or the co-surfactant was 70% or more by creating a phase equilibrium diagram (FIG. 3).

In addition, when using caryl caproyl polyoxyglyceride (trade name Labrasol) as a surfactant, diethylene glycol monoethyl ether (trade name Transcutol HP) as a co-surfactant, and coconut oil as a dissolving agent, phase equilibrium was prepared to create an interface. When the ratio of the active agent or the auxiliary surfactant is 60% or more, it was found that the emulsion region is enlarged (FIG. 4). Therefore, when using triglyceride (trade name Captax 300), which is a medium as a solubilizer, the solubilizer component is 30% or less by weight in each composition, and when using coconut oil as a solubilizer, the solubilizer component is 40% or less in each composition. It can be prepared as (Fig. 3 to Fig. 4, Table 1).

In yet another aspect, the present invention prepares a base composition comprising caryl caproyl polyoxyglyceride as a surfactant, diethylene glycol monoethyl ether as a co-surfactant, triglyceride as coconut oil or medium as a solubilizer, or mixtures thereof. Step of forming a self-emulsifying drug delivery system by dissolving sildenafil free base in the base composition and uniformly suspending the self-emulsifying drug delivery system and solidifying agent in an organic solvent and drying the solid self-emulsifying drug. It provides a method for preparing an oral solid preparation composition comprising sildenafil free base as an active ingredient comprising the step of forming a delivery system.

The self-emulsifying drug delivery system is a system that overcomes poor water solubility and improves permeability of the gastrointestinal mucosa at relatively weak agitation, such as gastrointestinal motility, by forming a micro-emulsion to be exposed to an aqueous phase such as body fluid.

Specifically, the present invention can provide a method for preparing an oral solid preparation composition for providing the base composition in the form of an emulsion dispersed in a solvent containing water.

The emulsion is a homogeneous mixture of the liquid phase in which the aqueous phase is removed from the components of the microemulsifying drug delivery system, and after taking it, when it meets the aqueous phase such as body fluid under the movement of the gastrointestinal tract, it self-emulsifies and disperses rapidly, thereby providing a rapid drug dissolution effect. Can. In addition, it is possible to provide an effect of reducing irritation caused by contact of the drug with the mucous membrane in the stomach.

Specifically, the present invention can provide a method for preparing a solid preparation composition by forming the mixture in distilled water of 58 to 62 times and stirring at a temperature of 20 to 45°C, but is not limited thereto.

Specifically, the present invention may provide a method for preparing an oral solid preparation composition comprising the colloidal silicon dioxide, magnesium aluminate metasilicate, or calcium silicate, although the solidifying agent is not limited thereto.

Specifically, the present invention may provide a method for preparing an oral solid preparation composition comprising the purified water, although the organic solvent is not limited thereto.

Specifically, in the present invention, the step of forming the self-emulsifying drug delivery system includes using a high pressure homogenizer (HPH) or SPG membrane emulsification, an oral solid preparation composition for oral use. It can provide a manufacturing method.

The SPG film emulsification is a method suitable for making functional particles because it has the advantage of easily producing multiple emulsions, monodispersions, and various forms.

The high pressure homogenizer may be a method of degrading a coarse oily liquid or suspended solids into fine particles to improve the quality of a stable emulsion state.

When using the high pressure homogenizer and SPG membrane emulsification, it can be confirmed that the dissolution rate increased by 0.1 to 1.3 times than in the case of untreated treatment (Table 6).

In the case of using the SPG membrane emulsification, the present invention is not limited thereto, but the operation time, 10 minutes by comparing the emulsion size and polydispersity (PDI) according to the operation time, the number of agitation, and the pore size of the membrane when manufacturing the liquid self-emulsifying drug delivery system, Microemulsions may be provided when the conditions of the stirring frequency are 100 to 200 rpm, and the size of the pores is 1.1 to 2.5 μm (FIGS. 5 to 10 ).

In the case of using the high pressure homogenizer, but not limited thereto, when providing a self-emulsifying drug delivery system for liquids, when providing conditions of 3 to 7 times of repeated operation at a pressure of 900 bar to 1500 bar, providing a microemulsion and deviation of polydispersity Also, it can be confirmed that it is small (FIGS. 11 to 16 ).

Specifically, the present invention is not limited to the step of forming the solid self-emulsifying drug delivery system by drying, but the oral solid preparation characterized by performing a drying method including spray drying, reduced pressure drying or hot air drying It may provide a method for preparing the composition.

In addition, when the liquid self-emulsifying drug delivery system of the composition according to the present invention is put in water, emulsification is formed with only a small amount of kinetic energy, so absorption in vivo is very fast and high bioavailability can be expected (Table 8).

The present invention provides an oral solid preparation composition of sildenafil free base to increase the solubility and dissolution rate of sildenafil free base to improve the low bioavailability of sildenafil free base, and provides a solid preparation to provide an effect without any inconvenience to taking and The medication compliance is high, providing a quick and excellent effect.

In addition, by providing the manufacturing method of the present invention, it is also easy to manufacture and has no inconvenience in storage, thereby providing excellent effects in economical aspects.

1 is a SEM shape photograph of Examples 3-1 and 3-4 below.
2 is a SEM image of sildenafil free base and colloidal silicon dioxide.
Figure 3 is an emulsion shown in the phase equilibrium diagram consisting of a triglyceride (trade name Captax 300) medium as a dissolving agent, diethyl glycol monoethyl ether (trade name Transcutol HP), caryl caproyl polyoxyglyceride (trade name Labrasol) It is a graph of the formation area.
Figure 4 is a graph of the emulsion formation region shown in the phase equilibrium diagram consisting of caryl caproyl polyoxyglyceride (trade name Labrasol), diethylene glycol monoethyl ether (trade name Transcutol HP), and coconut oil.
5 is a graph showing the comparison of emulsion size and polydispersity (PDI) according to the operating time when preparing the liquid self-emulsifying drug delivery system with the composition of Examples 2-3 below using SPG membrane emulsification.
FIG. 6 is a graph showing the comparison of emulsion size and polydispersity (PDI) according to the stirring time when preparing the liquid self-emulsifying drug delivery system using the SPG membrane emulsification method of Example 2-3 below.
7 is a graph showing a comparison of emulsion size and polydispersity (PDI) according to the pore size of the membrane when preparing the liquid self-emulsifying drug delivery system using the SPG membrane emulsification method of Example 2-3 below.
8 is a graph showing the comparison of emulsion size and polydispersity (PDI) according to the operating time when preparing the liquid self-emulsifying drug delivery system with the following Example 2-8 SPG membrane emulsification method.
FIG. 9 is a graph showing the comparison of emulsion size and polydispersity (PDI) according to the number of agitations when preparing the liquid self-emulsifying drug delivery system with the composition of Example 2-8 using the SPG membrane emulsification method.
FIG. 10 compares the emulsion size and polydispersity (PDI) according to the pore size of the membrane when preparing the liquid self-emulsifying drug delivery system with the following Example 2-8 SPG membrane emulsification method.
11 is a graph illustrating the comparison of emulsion size and polydispersity (PDI) according to the number of repetitive operations at a pressure of 900 bar when preparing a liquid self-emulsifying drug delivery system using the high-pressure emulsification method of Example 2-3 below.
FIG. 12 is a graph showing the comparison of emulsion size and polydispersity (PDI) according to the number of repetitive operations at 1200 bar pressure when preparing the liquid self-emulsifying drug delivery system using the high-pressure emulsification method of Example 2-3 below.
13 is a comparison graph of emulsion size and polydispersity (PDI) according to the number of repetitive operations at a pressure of 1500 bar when preparing a liquid self-emulsifying drug delivery system using the high-pressure emulsification method of Example 2-3 below.
FIG. 14 is a graph of comparison of emulsion size and polydispersity (PDI) according to the pressure of 900 bar and the number of repetitive operations when preparing the self-emulsifying drug delivery system of the following Example 2-8 by high pressure emulsification.
15 is a graph comparing the emulsion size and polydispersity (PDI) according to the pressure of 1200 bar and the number of repetitive operations when preparing the self-emulsifying drug delivery system of the following Example 2-8 by high pressure emulsification.
FIG. 16 is a graph showing the comparison of emulsion size and polydispersity (PDI) according to the pressure of 1500 bar and the number of repetitive operations when preparing the liquid self-emulsifying drug delivery system of the following Example 2-8 by high pressure emulsification.
Figure 17 is sildenafil free base, medium chain triglyceride (trade name Captax 300), carlocaproyl polyoxyglyceride (trade name Labrasol), diethylene glycol monoethyl ether (trade name Transcutol HP), coconut oil, colloidal Differential scanning calorimetry graphs of silicon dioxide, Examples 3-1 and 3-4, and physical mixtures thereof.
FIG. 18 is a graph of powder X-ray diffraction measurement of sildenafil free base, colloidal silicon dioxide, Examples 3-1 and 3-4 below, and physical mixtures thereof.
FIG. 19 shows the non-treated, SPG membrane, and high pressure homogenizer of the liquid self-emulsifying drug delivery system and the solid self-emulsifying drug delivery system in Example 3-1. ) Is a comparison graph of emulsion size and polydispersity (PDI).
20 is a non-treated, SPG membrane emulsification method (SPG membrane), high pressure emulsification method (High pressure homogenizer) of the liquid self-emulsifying drug delivery system and the solid self-emulsifying drug delivery system in Example 3-4 below. ) Is a comparison graph of emulsion size and polydispersity (PDI).

Hereinafter, the present invention will be described in more detail through examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited by these examples.

Example 1: Preparation of base composition of self-emulsifying drug delivery system

As a base composition of self-emulsifying drug delivery system, surfactant is carilocaproyl polyoxyglyceride (trade name Labrasol), auxiliary surfactant is diethylene glycol monoethyl ether (trade name Transcutol HP), and medium chain as dissolving agent. Triglyceride (trade name Captax 300) or coconut oil was mixed in various ratios as shown in Table 1 below to prepare a base composition.

To 300 mg of the base composition, 300 mL of distilled water at 37° C. was added and stirred at 300 rpm to form a base composition emulsion.

Furtherance Composition of base composition (% by weight) Particle size (nm) Labrasol Transcutol
HP Captax 300 Coconut oil Example 1-1 90 - 10 - 192.5 ± 8.2 Example 1-2 85 - 15 - 199.4 ± 11.7 Example 1-3 80 - 20 - 246.9 ± 14.4 Example 1-4 75 - 25 - 367.4 ± 42.9 Example 1-5 70 - 30 - 325.1 ± 38.5 Example 1-6 75 10 15 - 177.8 ± 20.5 Example 1-7 70 15 15 - 150.3 ± 2.7 Example 1-8 65 20 15 - 173.8 ± 38.5 Example 1-9 60 25 15 - 255.6 ± 56.3 Example 1-10 90 - - 10 227.2 ± 18.4 Example 1-11 80 - - 20 343.3 ± 94.2 Example 1-12 70 - - 30 259.8 ± 69.3 Example 1-13 60 - - 40 375.7 ± 43.3 Example 1-14 81 9 - 10 286.9 ± 77.3 Example 1-15 72 18 - 10 180.2 ± 15.1 Example 1-16 63 27 - 10 431.8 ± 7.1 Example 1-17 54 36 - 10 434.4 ± 73.2 Example 1-18 45 45 - 10 498.2 ± 134.9 Comparative Example 1 95 - 5 - 252.4 ± 109.6 Comparative Example 2 75 - 35 - 488.2 ± 128.7 Comparative Example 3 95 - - 5 322.5 ± 118.4 Comparative Example 4 65 - - 45 495.3 ± 147.1

As shown in Table 1, when Captax 300 is used as a solubilizer, the solubilizer component is 30% or less by weight in each composition, and when coconut oil is used as a solubilizer, the solubilizer component is 40% or less by weight in each protocol. As shown in Table 1, a base for a self-emulsifying drug delivery system was prepared. In addition, the particle size was measured after the emulsion was formed. In addition, referring to FIG. 3 in which a component-based phase equilibrium diagram was prepared in order to know the composition for forming an emulsion well, when using Latexol transcutol HP as a surfactant and a co-surfactant and a dissolving agent as Captax 300, surfactant or auxiliary When the proportion of the surfactant is 70% or more, it can be seen that the emulsion region is enlarged. In addition, referring to FIG. 4, when coconut oil was used as a solubilizing agent for Labrasol and Transcutol HP surfactants and cosurfactants, it was confirmed that the emulsion region was enlarged when the ratio of surfactant to auxiliary surfactant was 60% or more. .

As a result, it was confirmed that Example 1-7 and Example 1-15 of the base composition of the self-emulsifying drug delivery system according to the present invention had the smallest and ideal particle size.

Example 2: Preparation of self-emulsifying drug delivery system

The self-emulsifying drug delivery system was prepared by dissolving active ingredients (sildenafil free base) in various ratios as shown in Table 2 below in a liquid base composition prepared according to Example 1.

Furtherance Composition of base composition (% by weight) Active ingredient (ratio of sildenafil free base to 100 parts by weight of the base composition) Labrasol Transcutol HP Captax 300 Coconut oil Example
2-1 70 15 15 - 0.1 Example 2-2 70 15 15 - 0.5 Example
2-3 70 15 15 - One Example
2-4 70 15 15 - 2.5 Example 2-5 70 15 15 - 5 Example 2-6 72 18 - 10 0.1 Example 2-7 72 18 - 10 0.5 Example 2-8 72 18 - 10 One Example 2-9 72 18 - 10 2.5 Example 2-10 72 18 - 10 5 Comparative example
5 70 15 15 - 5.5 Comparative Example 6 72 18 - 10 5.5

As shown in Table 2, in Examples 2-1 to 2-10, all of the active ingredients were completely dissolved in the base composition of the self-emulsifying drug delivery system, but in Comparative Examples 5 to 6, the active ingredient compositions were It was not completely dissolved because it was more than 5.5 ratio compared to 100 parts by weight of the base composition.

Example 3: Preparation of sildenafil free base oral solid preparation composition using self microemulsifying drug delivery system

After the self-emulsifying drug delivery system prepared according to Example 2 was prepared, purified water was used as a solvent to add a solidifying agent, a porous silicate, in the ratio shown in Table 3, and then suspended uniformly, and solidified in the same manner as spray drying. Thus, an oral solid preparation composition was prepared.

Furtherance Components of base composition
(weight%) Ratio of solidifying agent to 100 parts by weight of the base composition Solubility (μg/mL) Labrasol Transcutol HP Captax 300 Coconut oil Active ingredients
Colloidal silicon dioxide Magnesium aluminate metasilicate Calcium silicate Example 3-1 70 15 15 - One 50 - - 493.3 ± 92.1 Example 3-2 70 15 15 - One 100 - - 112.1 ± 35.3 Example 3-3 70 15 15 - One 150 - - 21.3 ± 2.4 Example 3-4 72 18 - 10 One 50 - - 612.6 ± 107.4 Example 3-5 72 18 - 10 One 100 - - 214.2 ± 23.9 Example 3-6 72 18 - 10 One 150 - - 127.6 ± 10.7 Comparative Example 7 70 15 15 - One 25 - - - Comparative Example 8 70 15 15 - One - 50 - 376.2 ± 73.3 Comparative Example 9 70 15 15 - One - - 50 415.5 ± 27.9 Comparative Example 10 72 18 - 10 One 25 - - - Comparative Example 11 72 18 - 10 One - 50 - 493.3 ± 92.1 Comparative Example 12 72 18 - 10 One - - 50 587.6 ± 120.6

As shown in Table 3, in the solubility test results, Comparative Example 7 and Comparative Example 10 had too little amount of solidifying agent to make solid powder preparation after spray drying, and both Examples 3-1 to 3-6 were sildenafil free bases. The solubility increased more, and in particular, Examples 3-1 and 3-4, in which the amount of the solid carrier was 50% by weight relative to the base, showed higher solubility than the other examples.

In addition, Comparative Example 8, Comparative Example 9, Comparative Example 11 and Comparative Example 12 were all compared with different solidifying agents and showed lower solubility than the examples using colloidal silicon dioxide as the solidifying agent.

Accordingly, it was confirmed that the solubility was highest when preparing the solid preparation composition according to the embodiment of the present invention.

Preparation Example 1: Preparation of liquid self-emulsifying drug delivery system using SPG membrane emulsification

The SPG membrane emulsification method was used to reduce the size and polydispersity (PDI) of the emulsion formed from the liquid self-emulsifying drug delivery system using Examples 2-3 and 2-8, and the operating time (0 Minutes to 30 minutes), stirring speed (100 rpm to 200 rpm), pore size (1.1 μm and 2.5 μm) of the membrane were evaluated for emulsion size and polydispersity.

Preparation Example 2: Preparation of a liquid self-emulsifying drug delivery system using a high pressure homogenizer (HPH)

A high pressure homogenizer was used to reduce the size and polydispersity (PDI) of the emulsion formed from the liquid self-emulsifying drug delivery system using Examples 2-3 and 2-8, and pressure (900-1500 bar). And emulsion size and polydispersity with respect to the number of repetitive operations (0-7 cycles).

Experimental Example 1: Solubility test of sildenafil base

Sildenafil base solubility test, a poorly soluble drug, was added to an excess of sildenafil base in 1 mL of the solubilizer and stirred at 25°C and 100 rpm in a stirred thermostat for 72 hours, followed by quantification of sildenafil free base by a high performance liquid chromatography (HPLC) system. .

The conditions of the liquid chromatography were as follows.

Column: Iner tsil ODS-3

Flow rate: 1.0 mL/min

Injection volume: 10 μl

Detection wavelength: 285 nm

Mobile phase: Mobile phase A-0.1% TFA in distilled water, Mobile phase B-0.1% TFA in Acetonitrile

Ingredient name Solubility (μg/mL) Tween20 394.3 ± 3.0 Tween80 162.8 ± 23.8 Span20 20.3 ± 1.7 Span80 92.4 ± 26.0 Labrasol 18892.1 ± 439.2 CremophorEL 518.0 ± 2.3 Cremophor ELP 107.8 ± 13.3 Cremophor RH40 687.8 ± 4.2 Cremophor RH60 1130.3 ± 442.1 Cremophor A25 1161.3 ± 13.5 Transcutol P 1833.1 ± 23.1 Transcutol HP 11872.5 ± 250.8 Labrafil M1944CS 1524.7±38.5 Labrafil M2125CS 188.5 ± 3.4 Solutol HS15 555.3 ± 10.4 Plurol diisostearique 108.1 ± 13.4 Capryol 90 46.9 ± 2.7 Capryol PGMC 51.2 ± 4.8 Lauroglycol90 18.2 ± 0.4 Lauroglycol FCC 17.9 ± 1.0 Poloxamer 188 32.2 ± 3.3 Poloxamer 407 151.5 ± 6.1 Acconon MC8-2 9780.8 ± 732.3 PEG 4000 23.5 ± 1.0 PEG 6000 1426.0 ± 15.2 TPGS 1213.2 ± 15.4

Ingredient name Solubility (μg/mL) Cotton seed oil 460.0 ± 7.6 Corn oil 223.5 ± 2.1 Peanut oil 389.9 ± 32.0 Sesame oil 436.7 ± 14.5 Soybean oil 171.8 ± 87.6 Coconut oil 516.8 ± 11.2 Olive oil 250.8 ± 11.0 Linseed oil 461.2 ± 10.3 Mineral oil 6.5 ± 0.7 Peceol 697.9 ± 401.1 Captex 300 1121.4 ± 4.1

As shown in Tables 4 to 5, when the solubility test results of the surfactants and co-surfactants of Table 4 and the solubility solubility tests of Table 5 were tested, as a material that greatly increases the solubility of sildenafil free base, in the present invention Carylocaproyl polyoxyglyceride (trade name Labrasol) as a surfactant, diethylene glycol monoethyl ether (trade name Transcutol HP) as a co-surfactant, and triglyceride (trade name Captax 300) as a medium or coconut When selecting a milk to prepare a liquid self-emulsifying drug delivery system, it can be seen that it shows the highest solubility.

Experimental Example 2: Dissolution evaluation

Liquid self-microemulsion drug delivery system without any treatment (no treatment) of the composition of Examples 3-1 and 3-2, and SPG membrane emulsification method, a liquid self-emulsification drug delivery system prepared by high pressure emulsification method. After preparing the composition of each prepared Example 3-1 and Example 3-4 and sildenafil free base drug, the corresponding amount of sildenafil free base 10 mg was tested according to the following dissolution conditions, and each with an eluate. Sildenafil free base was quantified by a high performance liquid chromatography (HPLC) system of the solubility test method.

The eluate was evaluated for 500 mL of water, the elution temperature was 37°C, the elution method was the second method (paddle method), and the paddle rotation speed was 50 rpm.

Dissolution rate at 15 minutes (%) Dissolution rate at 45 minutes (%) Example 3-1 (no treatment) 71.3 ± 3.2 76.9 ± 0.5 Example 3-1 (SPG membrane emulsification method) 82.4 ± 0.9 86.4 ± 1.4 Example 3-1 (High pressure emulsification method) 91.6 ± 1.3 91.9 ± 1.6 Example 3-4 (no treatment) 66.7 ± 7.3 74.3 ± 0.8 Example 3-4 (SPG membrane emulsification method) 79.5 ± 1.7 82.9 ± 1.7 Example 3-4 (High pressure emulsification method) 86.0 ± 4.2 86.7 ± 3.4 Sildenafil free base 10.6 ± 1.6 11.1 ± 1.5

As shown in Table 6, it was confirmed that in all experimental examples, the dissolution rate was improved over sildenafil free base alone, and the dissolution rate was improved when the SPG membrane emulsification method and the high pressure emulsification method were used than the untreated example.

Experimental Example 3: Physical and chemical properties test

Sildenafil free base, colloidal silicon dioxide, untreated in Example 3-1, SPG membrane emulsification method, high pressure emulsification method, SPG membrane emulsification method in Example 3-4, and high pressure emulsification method were prepared for each type and their particles The size was measured.

Dx 10 (um) Dx 50 (um) Dx 90 (um) Sildenafil free base 6.4 ± 0.2 29.5 ± 0.5 104.2 ± 6.3 Colloidal silicon dioxide 10.5 ± 0.9 31.3 ± 5.2 102.6 ± 24.5 Example 3-1 (no treatment) 3.8 ± 0.1 10.0 ± 0.1 21.8 ± 0.3 Example 3-1 (SPG membrane emulsification method) 5.2 ± 0.2 12.9 ± 0.4 26.7 ± 0.7 Example 3-1 (High pressure emulsification method) 5.4 ± 0.1 13.8 ± 0.3 32.5 ± 3.3 Example 3-4 (no treatment) 3.8 ± 0.1 10.4 ± 0.3 27.2 ± 4.7 Example 3-4 (SPG membrane emulsification method) 3.6 ± 0.0 10.0 ± 0.1 23.6 ± 0.6 Example 3-4 (High pressure emulsification method) 3.8 ± 0.0 10.4 ± 0.1 24.1 ± 0.8

As shown in Table 7 above, as a result of measuring the particle size of the self-emulsifying drug delivery system, it can be confirmed that the particle size was reduced through a partial drying process.

Experimental Example 3: In vivo dynamics experiment

To measure bioavailability and body dynamics, Example 3-1, Example 3-4, sildenafil free base as a raw material as a control agent, and sildenafil citrate, a major component of commercially available viagra, as a drug in SD rats at 10 mg/kg Blood was administered orally and with a disposable syringe treated with heparin in the femoral artery. After separating plasma from the blood, the pre-treated plasma was analyzed in the same manner as the solubility evaluation using levaprazan as an internal standard.

Pharmacokinetic parameters Sildenafil
Free base Example 3-1
(Untreated) Example 3-4
(Untreated) ¹⁾ T _max (hr) 0.56 ± 0.63 2.32 ± 1.23* 2.25 ± 1.19* ²⁾ C _max (μg/mL) 0.011 ± 0.004 0.079 ± 0.026 0.084 ± 0.026 ³⁾ AUC (hr×μg/mL) 0.024 ± 0.007 0.317 ± 0.228* 0.352 ± 0.236*

The above values mean "mean ± S.D." (n=6)

As shown in Table 8 above, pharmacokinetic parameters were indicated.

1) shows the time to reach the highest blood concentration.

2) shows the highest blood concentration.

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

The compositions according to the present invention, Examples 3-1 and 3-4, both had a peak blood concentration of at least 7-fold and an AUC of at least 13-fold higher than sildenafil free base. Therefore, it was confirmed that the composition of the present invention exhibits excellent bioavailability.

Accordingly, it can be seen that when the composition for oral solid preparation of the present invention is provided, the solubility and dissolution rate of sildenafil free base is increased to improve the low bioavailability of sildenafil free base.

From the above description, those skilled in the art to which the present invention pertains will appreciate that the present invention may be implemented in other specific forms without changing its technical spirit or essential features. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as including all changes or modifications derived from the meaning and scope of the following claims rather than the detailed description and equivalent concepts thereof.

Claims (18)

A base composition comprising carlylocaproyl polyoxyglyceride as a surfactant, diethylene glycol monoethyl ether as a co-surfactant, and coconut oil, triglyceride as a medium, or mixtures thereof as a solubilizer;
Sildenafil free base; And
Solidifying agent; containing,
An oral solid preparation composition containing sildenafil free base as an active ingredient.
According to claim 1,
Caryl caprolyl polyoxyglyceride in the base composition is an oral solid preparation composition, characterized in that 40 to 85% by weight.
According to claim 1,
Diethylene glycol monoethyl ether in the base composition is an oral solid preparation composition, characterized in that 5 to 45% by weight.
According to claim 1,
The solid composition for oral administration, characterized in that the solubilizer in the base composition is 8 to 20% by weight.
According to claim 1,
The sildenafil free base is an oral solid preparation composition, characterized in that 0.1 to 5 parts by weight based on 100 parts by weight of the base composition.
According to claim 1,
The solidifying agent is 30 to 150 parts by weight based on 100 parts by weight of the base composition Oral solid preparation composition for oral use.
According to claim 1,
The solidifying agent is an oral solid preparation composition comprising at least one material selected from the group consisting of colloidal silicon dioxide, magnesium silicate aluminate, magnesium aluminate metasilicate and calcium silicate.
Preparing a base composition comprising caryl caproyl polyoxyglyceride as a surfactant, diethylene glycol monoethyl ether as a co-surfactant, triglyceride as coconut oil or medium as a solubilizer, or mixtures thereof;
Forming a self microemulsifying drug delivery system by dissolving sildenafil free base in the base composition; And
The self-emulsifying drug delivery system and the solidifying agent are uniformly suspended in an organic solvent and then dried to form a solid self-emulsifying drug delivery system; an oral solid preparation composition comprising sildenafil free base as an active ingredient Manufacturing method.
The method of claim 8,
The base composition is a method for preparing an oral solid preparation composition provided in the form of an emulsion dispersed in a solvent containing water.
The method of claim 8,
The method of preparing an oral solid preparation composition, characterized in that 40 to 85% by weight of caryl caproyl polyoxyglyceride as the surfactant.
The method of claim 8,
Diethylene glycol monoethyl ether as the auxiliary surfactant is 10 to 25% by weight of the oral solid preparation composition method.
The method of claim 8,
The solubilizer is a method for preparing an oral solid preparation composition, characterized in that 8 to 20% by weight.
The method of claim 8,
The sildenafil free base is a method for preparing an oral solid preparation composition, characterized in that 0.1 to 5 parts by weight based on 100 parts by weight of the base composition.
The method of claim 8,
The solidifying agent is 40 to 150 parts by weight based on 100 parts by weight of the base composition oral oral preparation composition method.
The method of claim 8,
The solidifying agent is a method for preparing an oral solid preparation composition comprising colloidal silicon dioxide, metasilicate silicate magnesium aluminate or calcium silicate.
The method of claim 8,
The organic solvent is a method for preparing an oral solid preparation composition comprising purified water.
The method of claim 8,
The step of forming the self microemulsifying drug delivery system comprises using a high pressure homogenizer (HPH) or SPG membrane emulsification, a method for preparing an oral solid preparation composition.
The method of claim 8,
The step of drying to form a solid self-emulsifying drug delivery system is a method for preparing an oral solid preparation composition comprising performing a drying method including spray drying, reduced pressure drying, or hot air drying.

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