KR20220139513A - Formulation for oral administration using self-nanoemulsifying drug delivery system - Google Patents

Abstract

The present invention relates to the development of a formulation for oral administration of AC1497, a novel anticancer drug using a self-emulsifying nanoemulsion. The formulation for oral administration of AC1497 according to the present invention improves the solubility of poorly soluble AC1497 and increases the oral bioavailability based on the self-emulsifying nanoemulsion that combines oil, surfactant, and co-surfactant.

Description

Oral administration formulation using self-emulsifying nanoemulsion {Formulation for oral administration using self-nanoemulsifying drug delivery system}

The present invention relates to a formulation for oral administration of a novel anticancer agent AC1497 using a self-emulsifying nanoemulsion.

AC1497 (methyl 3-(3-(4-(2,4,4,4-trimethylpentan-2-yl)phenoxy-propanamidol), a novel anticancer agent, has the structure of Formula 1 below, and targets cancer metabolism. is a dual inhibitor of malate dehydrogenase (MDH) 1 (MDH1) and 2 (MDH2).

AC1497 inhibits mitochondrial respiration and HIF-1α accumulation due to hypoxia and has excellent anticancer activity, but has low oral bioavailability and limited in vivo application due to low solubility.

The oral dosage form is the most preferred drug dosage form because of its high patient compliance, easy mass production and distribution, and excellent price competitiveness. One of the major factors influencing oral absorption is the solubility of a drug. Low solubility leads to low bioavailability and high inter-subject variability. Therefore, studies have been conducted to improve the bioavailability and efficacy of poorly soluble drugs by increasing the solubility of drugs using various formulation techniques. One of the widely used solubilizing formulations is a self-nanoemulsifying drug delivery system (SNEDDS) consisting of a drug, oil and surfactant, usually in combination with one or more hydrophilic co-solvents or co-emulsifiers. When exposed to an aqueous environment, SNEDDS rapidly forms ultrafine emulsification in water (o/w) nanoemulsions with slight agitation. This self-emulsifying process occurs spontaneously because the free energy required is very low. As such, the SNEDDS formulation is effective in improving the bioavailability of poorly soluble drugs by rapidly forming a nanoemulsion by self-emulsification when exposed to digestive juices in the gastrointestinal tract after oral administration. Therefore, encapsulation of the drug in the SNEDDS formulation can improve the solubility, membrane permeability, and gastrointestinal stability of the drug, and promote drug absorption through lymph, thereby improving the bioavailability of poorly soluble drugs.

Korean Patent No. 2082504 (Announcement Date: 2020. 2. 28.)

The present inventors have studied to improve the solubility and oral absorption of AC1497, a novel anticancer agent. As a result, when AC1497 is formulated as a self-emulsifying nanoemulsion containing oil, surfactant and cosurfactant, fine emulsion particles are formed and the drug It was found that solubility and dissolution rate were improved, mucosal permeability was increased, drug absorption was promoted, and bioavailability in the body was increased. Accordingly, the present invention provides a formulation for oral administration in which a self-emulsifying nanoemulsion composition containing oil, a surfactant and an auxiliary surfactant is combined with the compound of Formula 1 to improve solubility and reduce side effects such as gastrointestinal disorders and improve bioavailability; An object of the present invention is to provide a method for manufacturing the same.

In order to achieve the above object, the present invention

(i) a compound of Formula 1 or a pharmaceutically acceptable salt thereof;

(ii) self-emulsifying nanoemulsion composition containing oil, surfactant and cosurfactant

It provides a formulation for oral administration comprising:

[Formula 1]

.

.

In the formulation for oral administration according to the present invention, one of the components of the self-emulsifying nanoemulsion composition is a natural oil, polyoxyl glyceride, caprylic/caprylic acid glyceride, and propylene glycol derivatives. It may be one or more selected from, but is not limited thereto.

In the present invention, the oil is well mixed with a surfactant and emulsified in water to form a stable emulsion, and a pharmaceutically acceptable oil having sufficient solubility for the active ingredient AC1497 may be used. The oil is a natural oil, such as linseed oil, cottonseed oil, sunflower oil, mineral oil, oleic acid, castor oil, olive oil, krill oil; As polyoxylglycerides, oleoyl polyoxylglyceride (eg Labrafil M 1944CS), linoleoyl polyoxylglyceride (eg Labrafil M 2125CS), lauroyl polyoxylglyceride (eg Labrafil M 2130) and the like; caprylic/caprylic glycerides (eg Capmul MCM C8, Captex 355); As the propylene glycol derivative, at least one selected from propylene glycol monocaprylate (eg, Capryol 90, Capryol PGMC) may be used. Specifically, propylene glycol monocaprylate (eg, Capryol 90, Capryol PGMC) may be used as the oil, and more specifically, capryol 90 (Capryol 90) may be used.

If the content of the oil is less than 10% by weight based on the total weight of the self-emulsifying nanoemulsion composition, solubilization of AC1497 may be difficult and precipitation may occur. Problems may arise. Therefore, the oil may be used in an amount of 10 to 40 wt% based on the total weight of the self-emulsifying nanoemulsion composition, and more specifically, 10 wt% or more and less than 35 wt%.

In the formulation for oral administration according to the present invention, a surfactant as one of the components of the self-emulsifying nanoemulsion composition is polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid, polyoxyethylene alkyl ether, caprylocaproyl macro It may be at least one selected from the group consisting of bone glycerides and polyoxyethylene castor oil derivatives, but is not limited thereto.

In the present invention, the surfactant acts as a solubilizer to increase the solubility of poorly soluble AC1497, prevents recrystallization of the drug in the gastrointestinal tract, and makes the surface tension of the oil and auxiliary surfactant small in the aqueous phase regardless of pH to stabilize the formulation. By emulsifying, the particle size can be reduced and effective absorption of the drug is possible. Nonionic surfactants can be used in the present invention, for example, polyoxyethylene fatty acid esters (eg Solutol HS15); polyoxyethylene sorbitan fatty acids (eg, Tween 80); polyoxyethylene alkylethers such as Brij L4; caprylocaproyl macrogol glycerides (eg Labrasol); and at least one surfactant selected from polyoxyethylene castor oil derivatives (eg, Kolliphor ELP. Kolliphor RH40). Specifically, as a surfactant, a polyoxyethylene castor oil derivative (eg, Kolliphor RH40) may be used, and more specifically, Kolliphor RH40 (Kolliphor RH40 (formerly: Cremophor RH40)) may be used.

In the present invention, the use of less than 30% by weight of the surfactant based on the total weight of the self-emulsifying nanoemulsion composition does not sufficiently lower the surface tension of the oil and the auxiliary surfactant, so that emulsification is difficult to occur, and thus precipitation may occur. If 70% by weight or more of a surfactant is used, the amount of oil and auxiliary surfactant is small, so it is difficult to maintain a phase equilibrium state, it is not possible to sufficiently solubilize the active ingredient AC1497, and it may cause side effects in the gastrointestinal tract. Therefore, the surfactant may be used in an amount of 30 to 70 wt% based on the total weight of the self-emulsifying nanoemulsion composition, and more specifically, 30 wt% or more and less than 50 wt%.

In the pharmaceutical preparation for oral administration according to the present invention, the auxiliary surfactant, which is one of the components of the self-emulsifying nanoemulsion composition, is composed of polyethylene glycol, propylene glycol, propylene glycol fatty acid ester, alcohol, and diethylene glycol monoethyl ether. It may be one or more selected from the group, but is not limited thereto.

In the present invention, the auxiliary surfactant can increase the solubilization ability of the self-emulsifying nanoemulsion formulation, prevent precipitation of the active ingredient, and secure the stability and uniformity of the emulsion. In the present invention, as an auxiliary surfactant, polyethylene glycol (eg PEG 400), propylene glycol, propylene glycol fatty acid ester (eg Capmul PG8), alcohol (eg ethanol), diethylene glycol monoethyl ether (eg Transcutol HP) One or more selected types may be used. Specifically, diethylene glycol monoethyl ether (eg, Transcutol HP) may be used as the auxiliary surfactant, and more specifically, Transcutol HP may be used.

In the present invention, based on the total weight of the self-emulsifying nanoemulsion composition, less than 10% by weight of the co-surfactant is difficult to sufficiently solubilize AC1497, and more than 40% by weight of the co-surfactant is not sufficiently emulsified, so dilution by water phase It is not preferable because there is a problem that precipitation occurs due to phase separation. Therefore, the auxiliary surfactant may be used in an amount of 10 to 40 wt%, and more specifically, 25 wt% or more and less than 40 wt%.

In one embodiment, the self-emulsifying nanoemulsion composition for oral administration according to the present invention contains propylene glycol monocaprylate (eg, Capryol 90, Capryol PGMC) as an oil, and a polyoxyethylene castor oil derivative ( Example: Kolliphor RH40), and diethylene glycol monoethyl ether (eg Transcutol HP) as a cosurfactant can be used.

In another embodiment, the self-emulsifying nanoemulsion composition for oral administration according to the present invention may use Capriol 90 as an oil, Colipor RH40 as a surfactant, and Transcutol HP as an auxiliary surfactant.

In another embodiment, the self-emulsifying nanoemulsion composition of the formulation for oral administration according to the present invention contains 10 to 40% by weight of oil, 30 to 70% by weight of surfactant, and 10 to 10% of auxiliary surfactant based on the total weight of the composition. 40% by weight. Specifically, the self-emulsifying nanoemulsion composition contains 10 wt% or more and less than 35 wt% of an oil, 30 wt% or more and less than 50 wt% of a surfactant, and 25 wt% or more and 40 wt% of a co-surfactant based on the total weight of the composition may contain less than More specifically, the self-emulsifying nanoemulsion composition may contain oil, a surfactant, and an auxiliary surfactant in a weight ratio of 20:45:35. For example, the self-emulsifying nanoemulsion composition may contain capriol 90, colipor RH40 and transcutol HP in a weight ratio of 20:45:35.

In the formulation for oral administration according to the present invention, the active ingredient AC1497 or a pharmaceutically acceptable salt thereof may be mixed in a ratio of 1-2% of the total weight of the self-emulsifying nanoemulsion. When the weight ratio of the active ingredient is less than 1%, the amount of AC1497 is smaller than that of the self-emulsifying nanoemulsion composition, so the total amount of nanoemulsion to be administered increases. can be formed.

In the formulation for oral administration according to the present invention, the pharmaceutically acceptable salt of AC1497 (compound of formula 1), which is the active ingredient, is an alkali metal salt (sodium salt, etc.), alkaline earth metal salt (potassium salt, etc.), or pharmaceutically It may be an acid addition salt formed with an acceptable free acid. In this case, an inorganic acid or an organic acid may be used as the free acid.

In addition, the present invention provides a method for preparing a formulation for oral administration of AC1497, a novel anticancer agent. Specifically, the present invention comprises the steps of (a) mixing an oil, a surfactant and a cosurfactant to produce a self-emulsifying nanoemulsion composition; And (b) provides a method for preparing a formulation for oral administration, comprising adding a compound of Formula 1 or a pharmaceutically acceptable salt thereof to the composition:

[Formula 1]

.

.

The formulation for oral administration according to the present invention may exhibit excellent effects as an anticancer agent.

The formulation for oral administration of the present invention may be formulated as a formulation for oral administration, for example, tablets, hard or soft capsules. For formulation into dosage forms such as tablets and capsules, pharmaceutically acceptable carriers or additives may be used, for example, binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch or sweet potato starch; A lubricant such as magnesium stearate, calcium stearate, and sodium stearyl fumarate may be contained. The oral preparation of the present invention may further include a sweetening agent, a flavoring agent, a preservative, and the like, in addition to the above ingredients.

The formulation for oral administration of AC1497 according to the present invention improves drug solubility, membrane permeability and gastrointestinal stability by encapsulating AC1497 in a self-emulsifying nanoemulsion containing oil, surfactant and auxiliary surfactant, and promotes absorption in lymph By doing so, the bioavailability of AC1497 can be improved and it can be developed into various formulations for oral administration.

1 shows the results of evaluating the solubility of AC1497 in various (A) oils, (B) surfactants and (C) cosurfactants.
Figure 2 shows the particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE) and emulsification time of a SNEDDS formulation encapsulated with AC1497.
3 shows the drug release properties of SNEDDS-F4. Figure 3A is a comparison of the drug release pattern of SNEDDS-F4 and drug powder in water, Figure 3B shows the drug release pattern of SNEDDS-F4 at different pH.
4 shows the dissolution pattern of the drug in various eluates of the SNEDDS formulation encapsulated in AC1497, that is, (A) water, (B) a buffer of pH 1.2, (C) a buffer of pH 4.5, and (D) a buffer of pH 6.8. it has been shown
FIG. 5 shows changes in blood concentration of AC1497 with time after oral administration of SNEDDS-F4 to experimental animals (rat) compared with AC1497 powder formulation.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.

Example 1. SNEDDS component screening

The solubility of AC1497 in various oils, surfactants, and cosurfactants was determined using the shake-flask method. As the oil, oleic acid, Captex 355, Labrafil M 2125CS, Labrafil M 1944 CS, Capmul MCM C8, Capriol 90, and krill oil were used. As surfactants, Solutol HS15, Tween 80, Brij L4, Labrasol, Colifor ELP, and Colifor RH40 were used, and as auxiliary surfactants, polyethylene glycol 400 (PEG400), propylene Glycol, Capmule PG8, ethanol and Transcutol HP were used. An excess of AC1497 (250 mg) was added to each oil, surfactant or cosurfactant, followed by shaking for 2 minutes, and the mixture was stirred in a water bath at 37° C. for 72 hours. The mixture was then centrifuged at 17,000 x g for 10 min and the supernatant was filtered through a membrane filter (0.45 μm). The drug concentration of the filtrate was determined by HPLC analysis.

HPLC analysis

Drug concentrations were determined using a high performance liquid chromatography (HPLC) system (Perkin Elmer series 200) and a reversed-phase C18 column (Gemini C18, 4.6×250 mm, 5 μm, Phenomenex, Torrance, CA). The mobile phase was composed of acetonitrile and 0.1% trifluoroacetic acid (80:20, v/v), and the flow rate was 1 mL/min at 30°C. The UV wavelength was set to 254 nm. Simvastatin was used as an internal standard.

In the present invention, in order to develop an effective self-emulsifying nanoemulsion formulation with optimal physicochemical properties, three components of the ternary system, oil, surfactant, and auxiliary surfactant, were selected based on solubilization ability and emulsification efficiency. Considering that these three components of the self-emulsifying nanoemulsion formulation should have high solubilizing ability for drugs to prevent drug precipitation when diluted by digestive juices in the gastrointestinal tract, solubilization of various oils, surfactants and auxiliary surfactants The results of evaluating the effect are shown in FIG. 1 . The solubilizing ability of the oil phase is a decisive factor in improving drug bioavailability because it affects drug encapsulation efficiency, drug solubility upon in vivo dilution, and drug transport through the intestinal lymphatic system. Among the oils tested, capriol 90, a medium-chain fatty acid, maximized the solubility of AC1497 (46.04±1.46 mg/mL). Therefore, Capriol 90 was chosen as a suitable oil for the preparation of SNEDDS of AC1497.

In addition, the solubilization effect and emulsification efficiency of various surfactants were investigated. In general, nonionic surfactants are less toxic and have a lower critical micelle concentration than ionic surfactants. Furthermore, surfactants with a high hydrophilic-lipophilic balance (HLB) exhibit excellent emulsification efficiency because they are hydrophilic and can form a fine and uniform emulsion with gentle stirring. Therefore, in the present invention, nonionic surfactants with HLB >10 were screened to form o/w nanoemulsions. Colipor RH 40 (HLB: 14-16) effectively improved drug solubility (85.02±1.14 mg/mL) and showed the highest permeability upon dilution. In addition, Transcutol HP, a co-surfactant, exhibited the highest dissolution effect and maximum transmittance upon dilution, and formed a transparent, fine, and uniform emulsion. These results suggest that adding Transcutol HP as a co-surfactant can help improve drug encapsulation rate and promote rapid nanoemulsion formation. Therefore, Capriol 90, Kollipor RH 40 and Transcutol HP were used as oils, surfactants and cosurfactants, respectively.

Example 2. Preparation of drug-encapsulated SNEDDS

The maximum drug encapsulation capacity of SNEDDS was measured while varying the concentration of AC1497 from 0.1% w/w to 20% w/w. AC1497 in a concentration range of 0.1-20% (w/w) was mixed with SNEDDS preconcentrate by shaking for 1 minute, and then gently stirred for 24 hours while maintaining at 37°C in a water bath. Drug concentrations were analyzed by HPLC. HPLC analysis was performed under the same conditions as in Example 1.

SNEDDS in which drugs were encapsulated in various weight ratios of selected oils (20-40%), surfactants (30-70%) and auxiliary surfactants (10-40%) were prepared. The drug content (2% w/w) in all formulations was kept constant. The oil, surfactant and cosurfactant were mixed with agitation in a stoppered glass vial. AC1497 was added to the resulting mixture and shaken until a clear solution was obtained for uniform mixing. The prepared formulations were stored in sealed transparent vials at room temperature until use.

The mixing ratio of oil and surfactant and cosurfactant plays an important role in the formation of SNEDDS because surfactant and cosurfactant reduce the interfacial energy and provide a mechanical barrier against coalescence of emulsion particles to improve the thermodynamic stability of SNEDDS. do. The self-emulsifying properties of the prepared SNEDDS formulations were visually observed. In addition, in order to identify the self-nano-emulsification region and optimize the concentration of phase components in the SNEDDS, a phase equilibrium diagram containing oil (Capriol 90), surfactant (Colifor RH40) and auxiliary surfactant (Transcutol HP) was constructed. . Spontaneous emulsion formation was observed when the surfactant content was 30~70%, and the emulsification efficiency was good when the total concentration of surfactant and auxiliary surfactant accounted for more than 60% of SNEDDS.

Example 3. SNEDDS in vitro characteristic

To predict the stability of nanoemulsions upon dilution with aqueous phase in vivo, each formulation was diluted 10-fold, 100-fold and 1000-fold with distilled water, 0.1N HCl, or phosphate buffer (pH 6.8) with stirring at 37°C at 100 rpm. . Each diluted sample was kept at room temperature for 24 hours to monitor phase separation or drug precipitation.

To evaluate the self-emulsification time, 1 mL of each formulation was added to 500 mL of distilled water and gently mixed at 37° C. while stirring at 100 rpm. Emulsification time was visually evaluated as the time required to form a fine transparent emulsion upon dilution.

Each formulation (0.2 mL) was diluted with 20 mL of distilled water. The average particle size and zeta potential of the obtained nanoemulsion were measured by dynamic light scattering (DLS) using a Zetasizer Nano-ZS90 (Malvern Instruments, Malvern, UK). The polydispersity index (PDI) representing the size distribution was also measured.

The particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE) and emulsification time of the AC1497-encapsulated SNEDDS formulation are shown in FIG. 2 . The SNEDDS formulation showed a uniform distribution of nano-sized negatively charged particles.

Since the self-emulsifying nanoemulsion formulation should be quickly and completely dispersed under gentle stirring when diluted with water, the self-emulsification efficiency was estimated based on the emulsification rate and particle size distribution. Among the formulations tested, SNEDDS-F4 composed of 20% by weight of Capriol 90, 45% by weight of Kolipor RH40 and 35% by weight of Transcutol HP quickly formed a clear emulsion upon dilution with water (emulsion time: -18 seconds). SNEDDS-F4 also had an average particle size of 17.8±0.36 nm, a narrow particle size distribution, and a high drug encapsulation rate of over 90%. Due to the presence of free fatty acids, SNEDDS-F4 is negatively charged, which can help maintain the stability of the dispersion system through electrostatic repulsion. In addition, when diluted (10, 100, and 1000 times) with distilled water, 0.1N HCl and phosphate buffer of pH 6.8, SNEDDS-F4 maintains a transparent and stable emulsion for 24 hours without phase separation or drug precipitation, so It is expected to be able to stably maintain the nanoemulsion state upon dilution. Combining the above characteristics, SNEDDS-F4 was selected as the optimal formulation for further characterization.

Example 4. in vitro dissolution analysis in

An in vitro dissolution test of pure drug (AC1497 powder) and drug-encapsulated SNEDDS was performed in a dissolution machine DT1420 (ERWEKA, Heusenstamm, Germany) using the paddle method at 37±0.5° C. and 50 rpm. Each SNEDDS (corresponding to 5 mg of AC1497) and pure AC1497 (5 mg) were filled into hard gelatin capsules and then exposed to a buffer of pH 1.2-6.8 or distilled water. Samples (1 mL) were taken at defined time points (10 min, 15 min, 20 min, 30 min, 45 min and 60 min) and then filtered through a membrane filter (0.45 μm). To keep the volume of the eluate constant, an equal volume of the new eluate was added to the vessel. The amount of drug released was determined by HPLC analysis. HPLC analysis was performed under the same conditions as in Example 1.

The drug dissolution rate analysis of the selected SNEDDS formulation (SNEDDS-F4) was evaluated compared to the drug powder. As can be seen in FIG. 3A, SNEDDS-F4 greatly improved the dissolution rate and dissolution rate of the drug in water, so that about 80% of the drug was dissolved within 10 minutes, whereas the drug in powder form had a very insignificant dissolution rate (<2%) ) was shown. The rapid and greatly improved drug dissolution rate by SNEDDS-F4 can be explained by the spontaneous formation of nanoemulsions and the promotion of dissolution by increasing the specific surface area of the nano-sized emulsion particles. In addition, SNEDDS-F4 showed similarly high and rapid drug dissolution under acidic to neutral pH conditions, suggesting that drug release can be effectively achieved at the pH of the gastrointestinal tract ( FIG. 3B ).

The drug dissolution rates of SNEDDS-F4, SNEDDS-F6, and SNEDDS-F9 and SNEDDS-F9 and drug powder were compared in water, sodium chloride/hydrochloric acid buffer of pH 1.2, acetate buffer of pH 4.5, and phosphate buffer of pH 6.8, and the results are shown in FIG. shown. According to FIG. 4, AC1497 drug powder hardly eluted until 60 minutes in both water and pH 1.2, pH 4.5 and pH 6.5 buffers, whereas SNEDDS-F4, SNEDDS-F6, and SNEDDS-F9 were approximately soluble within 10 minutes. It can be confirmed that 60-80% of the drug is eluted, and the drug release occurs rapidly in acidic to neutral conditions.

Example 5. Pharmacokinetic analysis

The pharmacokinetic analysis of the pure drug powder and the optimized SNEDDS (SNEDDS-F4) formulation was investigated in laboratory animals (rat). The experimental protocol was approved by the Review Committee of Dongguk University (IACUC-2017-016-2). Male rats (Sprague-Dawley, 245-280 g) were purchased from Orient Bio. All rats were allowed to freely ingest water and standard feed (Superfeed Company, Wonju, Korea). The experimental animals were divided into two groups (n = 3 per group) and fasted for 12 hours prior to the experiment. Pure AC1497 powder was dispersed in 0.5% aqueous methylcellulose containing 5% polyethylene glycol (PEG). Each formulation (pure drug suspension or SNEDDS-F4) was orally administered at a dose corresponding to 20 mg/kg AC1497. Blood samples were taken from the femoral artery at defined time points (0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h). After centrifuging the blood sample at 17,000 x g for 5 minutes, the obtained plasma sample was stored frozen at -20°C until analysis by mass spectrometry (LC-MS/MS).

The pharmacokinetic parameters of AC1497 and changes in blood concentration with time are summarized in Table 1 and FIG. 5 . Compared with drug powder, SNEDDS-F4 significantly improved the oral absorption of AC1497 in rats. As shown in Table 1, SNEDDS-F4 increased the Cmax and AUC of AC1497 by 6.82-fold and 3.14-fold, respectively, compared to the drug powder. In addition, SNEDDS-F4 showed a much faster drug absorption with a shorter Tmax than the drug powder formulation. These results include (a) improved drug solubility and dissolution rate through spontaneous formation of fine nanoemulsion particles, (b) effective diffusion of nanoemulsion particles and increased mucosal permeability, and (c) increased drug absorption through lymphatics. It may be explained by several factors. Overall, SNEDDS-F4 was effective in improving oral absorption of AC1497 in rats.

Pharmacokinetic parameters of AC1497 after oral administration of SNEDDS-F4 or drug powder to rats (mean±s.d., n=3). The dose corresponded to AC1497 20 mg/kg. parameter pure drug SNEDDS-F4 C _max (ng/mL) 2.30 ± 0.44 15.7 ± 6.40 T _max (h) 4.0 ± 3.5 0.8 ± 0.3 AUC (ng*h/mL) 25.0 ± 6.26 78.5 ± 38.9

In light of the above experimental results, SNEDDS-F4 containing Capriol 90, Colifor RH40 and Transcutol HP (20:45:35 w/w) was very effective in improving the dissolution rate and bioavailability of AC1497, a poorly soluble drug. It was effective.

The foregoing description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the test examples described above are illustrative in all respects and not restrictive.

Claims (10)

(i) a compound of Formula 1 or a pharmaceutically acceptable salt thereof;
(ii) self-emulsifying nanoemulsion composition containing oil, surfactant and cosurfactant
A formulation for oral administration comprising:
[Formula 1]

.
According to claim 1,
The oil is at least one selected from the group consisting of natural oils, polyoxyl glycerides, caprylic/caprylic acid glycerides, and propylene glycol derivatives, formulations for oral administration
According to claim 1,
The surfactant is at least one selected from the group consisting of polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid, polyoxyethylene alkyl ether, caprylocaproyl macrogol glyceride, and polyoxyethylene castor oil derivative, for oral administration formulation
According to claim 1,
The auxiliary surfactant is at least one selected from the group consisting of polyethylene glycol, propylene glycol, propylene glycol fatty acid ester, alcohol, and diethylene glycol monoethyl ether, formulation for oral administration
5. The method according to any one of claims 1 to 4,
The oil is propylene glycol monocaprylate, the surfactant is a polyoxyethylene castor oil derivative, and the auxiliary surfactant is diethylene glycol monoethyl ether, a formulation for oral administration.
6. The method of claim 5,
The oil is Capryol 90, the surfactant is Kolliphor RH40, and the cosurfactant is Transcutol HP, a formulation for oral administration
5. The method according to any one of claims 1 to 4,
The self-emulsifying nanoemulsion composition contains 10-40% by weight of oil, 30-70% by weight of surfactant, and 10-40% by weight of co-surfactant, based on the total weight of the composition, for oral administration.
8. The method of claim 7,
The self-emulsifying nanoemulsion composition contains 10% by weight or more and less than 35% by weight of oil, 30% by weight or more and less than 50% by weight of surfactant, and 25% by weight or more and less than 40% by weight of co-surfactant, based on the total weight of the composition. , formulations for oral administration
9. The method of claim 8,
The self-emulsifying nanoemulsion composition is a formulation for oral administration containing oil, a surfactant and an auxiliary surfactant in a weight ratio of 20:45:35
(a) mixing an oil, a surfactant and a co-surfactant to produce a self-emulsifying nanoemulsion composition; and
(b) adding a compound of Formula 1 or a pharmaceutically acceptable salt thereof to the composition
A method for preparing a formulation for oral administration according to any one of claims 1 to 4, comprising:
[Formula 1]

.

Images