KR101440726B1 - Lymphatic drug delivery system composition comprising solubilizers - Google Patents

Abstract

The present invention relates to a composition for a lymphatic drug delivery system which comprises solubilizers selected from the group consisting of transcutol HP (diethylene glycol monoethyl ether), ethanol, and propylene glycol. The composition for the lymphatic drug delivery system, according to the present invention, has high solubility for lipophilic drugs by including a solubilizer, has excellent drug delivery ability of kilo microns by not forming a micelle structure, and is able to increase bioavailability of the drugs by oral administration, thereby can be practically used for various oral preparations.

Description

TECHNICAL FIELD [0001] The present invention relates to a composition for a lymphatic drug delivery system comprising a solubilizing agent,

The present invention relates to a pharmaceutical composition for delivering a lymphatic drug, and more particularly, to a pharmaceutical composition containing a solubilizing agent for increasing oral bioavailability, which comprises a solubilizing agent which is high in solubility in a lipophilic drug and does not form a micelle structure To a composition for delivering a lymphatic drug.

Drug delivery system (DDS) is used for the purpose of maximizing the therapeutic effect of the drug and minimizing the side effects of the human body. , And the term drug delivery system is widely used to refer to a simple combination of pharmaceuticals and a highly functional formulation.

In general, bioavailability of oral preparations is about 5% -70% of that of intravenous injections, and it is known that it is difficult to exceed 70% of maximal bioavailability. The causes are various factors such as dissolution rate, absorption rate, drug (drug-drug interactions) to be administered together or interaction with food, among which the main causes are first-pass metabolism in the liver (hepatic first-pass metabolism). That is, the oral preparation is transferred to the liver through the blood, and the transferred drug is decomposed in the liver and is not absorbed into the body, and is discharged again to the body. As a result, the bioavailability is very low.

For this purpose, various attempts have been made to increase the bioavailability of oral preparations. For example, a method of attaching a carrier to a drug or attempting chemical modification by attaching a suitable polymer, or a method of applying a drug to a liposome, And a method in which it is enclosed and applied.

Recently, lipophilic drugs (generally log P> 5 and long chain triglyceride solubility 50 mg / g; Charman, WN, Stella VJ, 1986. Estimating the maximum potential for intestinal lymphatic transport of lipophilic drug molecules. International Journal of Pharmaceutics 34 , 175-178) is one of the major routes of delivery to the body, increasing the interest in the intestinal lymphatic route. This lymphatic drug transport is the first step in systemic circulation, avoiding hepatic metabolism, (Porter, CJH, Charman, WN, 1997. Uptake of drugs into the intestinal lymphatics after oral administration, Advanced Drug Delivery Reviews 25, 71-89). Research is actively being done. It has been reported that the efficacy of anticancer drugs as immunomodulators can be increased when absorbed through the lymphatic route (Muranishi, S., 1980. Lymphatic delivery of drugs and its application to cancer chemotherapy, Yakugaku Zasshi 100, 687-698; Garzon Dumont, P., Atassi, G., 1983. 1,3-dipalmitoylglycerol ester of chlorambucil as a lymphotropic, orally administrable antineoplastic agent. Journal of Medical Chemistry 26, Based formulations, such as oil solutions, emulsions, solid lipid nanoparticles and self-microemulsifying drug delivery systems, can be used to formulate a lipid- There have been various attempts to deliver drugs to the lymphatic system (O'Driscoll, CM, 2002. Lipid-based formulations for intestinal lymphatic delivery. European Journal of Pharmaceutical Sciences 15, 405-415) It shows a partial improvement in relation to the lymphatic transport of (poorly water soluble drug).

On the other hand, chylomicrons (CM) are low-density lipoproteins (Porter, CJH, Trevaskis) formed in a small intestinal membrane with triglyceride, phospholipid and cholesterol , NL, Charman, WN, 2007. Lipids and lipid-based formulations: Nature Reviews Drug Discovery 6, 231-248). These kilo-microns are important for lymphatic drug delivery using lipid-based formulations (Gershkovich, P., Hoffman, A., 2005. Uptake of lipophilic drugs by plasma derived isolated chylomicrons: Linear correlation with intestinal lymphatic bioavailability. European Journal of Pharmaceutical Science 26, 394-404.).

As described above, there is a growing interest in compositions for lymphatic drug delivery systems that have higher bioavailability than absorption through blood, and the provision of formulation materials to further increase affinity for lipophilic drugs to the kilo-micron Although it has become an important task, detailed research on this has yet to be conducted.

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a pharmaceutical composition containing a solubilizing agent which is high in solubility for lipophilic drugs and does not form a micelle structure, And to provide a composition for a system.

It is still another object of the present invention to provide an oral preparation characterized by the above-mentioned composition being filled.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

The present invention provides a composition for a lymphatic drug delivery system comprising a solubilizer selected from the group consisting of transcutol HP (diethylene glycol monoethyl ether), ethanol and propylene glycol.

In one embodiment of the invention, the composition is characterized by enhancing the transfer of lipophilic drugs to the chylomicron.

In another embodiment of the present invention, the lipophilic drug is probacol.

In another embodiment of the present invention, the composition is characterized in that it does not form a micelle.

The present invention also provides an oral preparation characterized by the above-mentioned composition being filled.

The composition for a lymphatic drug delivery system according to the present invention includes a solubilizing agent and has a high solubility to lipophilic drugs and does not form a micellar structure and thus has excellent drug transferring capability to a kilo-micron. The bioavailability It is expected to be useful for various oral preparations.

1 is a diagram showing a drug delivery model to the intestinal lymphatic system by the kilo-micron.
2 is a graph showing the results of comparative experiments of the lipophilic drug delivery capability of the solubilizing agent and the surfactant to the kilo-micron.
FIG. 3 is a graph showing the correlation between the binding of the kilo-micron and the probucol using solubilizing agent and the solubility of propacol or the appropriate amount of solubilizing agent.
4 is a view showing the results of separation of a kilo-micron fraction by incubation of a surfactant containing a probucol and a kilo-micron and ultracentrifugation.
FIG. 5 is a graph showing the correlation between the binding of the kilo-micron and the probucol using the surfactant and the solubility of pro-bucol or the appropriate amount of the surfactant.
6 is a view showing a result of size distribution measurement of a solubilizing agent and a surfactant.
FIG. 7 is a graph showing the results of measurement of probucol-binding ability of propylene glycol with kilo-micron according to various concentrations of probucol.
FIG. 8 is a graph showing the results of measurement of probucol binding ability with a kilo-micron according to various concentrations of probucol in Transcutol HP. FIG.

Lymphatic drug transport has the advantage of being able to increase bioavailability rather than absorption through the portal vein by avoiding liver metabolism, the first pass of systemic circulation, and it has been reported that kilo micron plays an important role in this lymphatic drug delivery 1 is a diagram showing a drug delivery model to the intestinal lymph vessel by the kilo-micron.

As shown in Figure 1, Chylomicrons (CM) are low-density lipoproteins formed in small intestinal membranes with triglyceride, phospholipid and cholesterol, Lipophilic (poorly soluble or insoluble) drugs can only bind to the kilo-micron and be delivered to the lymphatic system.

On the other hand, the surfactant is a component that improves the bioabsorbability and biological efficiency of the lipophilic (weakly soluble or insoluble) drug. Such a surfactant improves the permeability by the inhibition of p-gp on the intestinal cell surface, . ≪ / RTI > However, insoluble drugs with enhanced absorption by surfactants are entrapped in micelles, and micelles containing insoluble drugs can behave like hydrophilic macromolecules, as these micelles have a hydrophilic surface. Therefore, micelles are highly likely to circulate through the blood, and the amount of drug delivered to the lymphatic vessels is very small, which is still a problem in that the bioavailability is low.

The inventors of the present invention have studied a formulation material for further increasing the affinity of the lipophilic drug to the kilo micron and found that the solubilizer has a high solubility in lipophilic drugs and does not form a micellar structure so that lipophilic drug delivery to the kilo micron And the present invention has been completed on the basis thereof.

Hereinafter, the present invention will be described in detail.

The present invention provides a composition for a lymphatic drug delivery system comprising a solubilizer selected from the group consisting of transcutol HP (diethylene glycol monoethyl ether), ethanol and propylene glycol.

That is, the solubilizing agent included in the composition according to the present invention does not form a micellar structure with a high solubility in a lipophilic drug, thereby improving the migration of lipophilic drugs to chylomicron as an effective vehicle , The drug is absorbed into the body through the lymphatic system rather than the blood, thereby improving the bioavailability. Examples of the lipophilic drugs that can be used in this case include, but are not limited to, pro-bacul, analgesic, anti-inflammatory, anti-asthmatic, antibacterial, antiviral, anticoagulant, antidepressant, antitumor, , vitamin A group such as beta-blocker, corticosteroid, narcotic analgesic agent, lipid concentration regulator, anxiolytic agent, sedative, hypnotic agent, neuroleptic agent, retinol and retinoic acid, carotenes, cholecalciferol, ergocalciferol Vitamin E group such as vitamin D group, tocopherol and tocotrienol, vitamin K group such as phytonadione, menaquinone and menadione, coenzyme Q such as ubiquinone, terpenes such as teprenone, eicosapentaenoic acid, Nifedipine, gefarnate, flavonol, clopribrate, nitroglycerin, flurbiprofen, ibuprofen, amiodarone, simvastatin, indomethinapharnesyl, liver oil and the like can be used. .

According to one embodiment of the present invention, the solubility of propucol, which is an oleophilic drug, in the solubilizing agent such as transcutol HP (diethylene glycol monoethyl ether) and ethanol is high (see Example 2) It was confirmed that the ability to transfer pro-beclc to kilo-micron was significantly superior (see Example 5)

When the composition according to the present invention is formulated, it may be prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like, preferably an orally administered preparation.

Accordingly, the present invention provides an oral preparation characterized in that the composition is filled.

Formulations for oral administration include tablets, pills, powders, granules, capsules, troches, emulsions, suspending agents, dispersing agents and the like. Oral solid preparations include one or more excipients such as one or more excipients For example, it is prepared by mixing starch, calcium carbonate, sucrose, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, emulsifiers, solubilizers, sweeteners, , Preservatives, and the like.

In addition, the composition according to the present invention is administered in a pharmaceutically effective amount. For purposes of the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level may vary depending on the age, sex, In general, 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight may be administered daily or every other day or one to three times per day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[Example]

Example 1. Experimental preparation

Probucol and peanut oil were purchased from Sigma-Aldrich Company (St. Louis, Mo., USA). Diethyl ether, propylene glycol, Tween 20, Tween 80 and ethanol were supplied from Daejeon Kim (Seoul, Korea). Cremophor ELP was obtained from BASF (Cleveland, Ohio, USA), and Potassium bromide and sodium chloride were supplied by Samchon Chemical (Gyeonggi Province, Korea). Transcutol HP was prepared by Gattefosse (Lyon, France) and EDTA-K ₂ -Na ₂ was obtained from Junsei Chemical (Tokyo, Japan). HPLC-grade acetonitrile from Burdick & Jackson (Muskegan, MI, USA) was used, and all other materials used were pharmaceutical grade materials.

Example 2 Comparative Evaluation of Lipophilic Drug Solubility in Solubilizing Agents and Surfactants

Experiments were carried out as follows for the comparative evaluation of the solubility of lipophilic drugs in the solubilizing agent or the surfactant.

First, transcutol HP, ethanol and propylene glycol were selected as the solubilizing agents, Cremophor ELP, Tween 20 and Tween 80 were selected as surfactants, Probucol was chosen as the oily drug.

An excess amount of probucol was added to each of the above solubilizing agents or surfactants, followed by mixing at room temperature for 24 hours using a magnetic stirrer. The prepared mixture was centrifuged at 2,000 g for 1 hour and then the level of pro-boole in the supernatant was determined by HPLC through appropriate dilution with acetonitrile and the results are shown in Table 1 .

Name of pharmaceutical ingradients Solubility of probucol (mg / g) Transcutol HP 262.42 + - 3.22 Tween 20 66.46 + - 0.54 Cremophor ELP 54.42 + 0.08 Ethanol 53.87 ± 0.23 Tween 80 47.73 ± 0.63 Propylene glycol 2.52 + - 0.12

As shown in Table 1, the solubility of procollol in transcutol HP was 262.42 ± 3.22 mg / g, which is higher than that of other additives. The solubilities of Tween 20, Cremophor IIE, ethanol and Tween 80 were 66.46 ± 0.54, 54.42 ± 0.08, 53.87 ± 0.23 and 47.73 ± 0.63 mg / g, respectively, and propylene glycol was 2.52 ± 0.12 mg / g And the lowest solubility was confirmed.

On the other hand, the solubility of probucol in the solubilizing agent and the surfactant did not differ between the 24-hour incubation and the 72-hour incubation.

Example 3. Preparation of chylomicron dispersion

Male Wistar rats (300-330 g, 8-9 weeks) were used to prepare a kilo micron (CM) dispersion. All rats were incubated for more than a week for stabilization and fasted for at least 12 hours with free access to water for blood collection. First, 0.5 mL of peanut oil was administered by gavage 2 hours before the blood collection, and 0.3 mL of peanut oil was further administered 1 hour before the blood collection. Then, after anesthetizing with diethylether, 8-10 mL of blood was collected from a caudal vena cava using a 22 gauge needle. The collected blood was collected into a 15 mL falcon tube containing 100 μL of EDTA-K ₂ -Na ₂ 10% (w / v) and then centrifuged (2,000 g, 15 min, 15 ° C.) (plasma) was immediately obtained.

The kilo-micron (CM) was determined by density gradient ultracentrifugation (Gershkovich and Hoffman, 2005; Karpe, F., Hamsten, A., 1994. Determination of apolipoproteins B-48 and B-100 in triglyceride-rich lipoproteins by analytical SDS-PAGE. Journal of Lipid Research 13, 1311-1317). More specifically, a standard solution having a density of 1.006, 1.019 and 1.063 g / mL was prepared with an appropriate amount of sodium chloride. All standards contained EDTA-K ₂ -Na ₂ (0.01%, w / v) and were stored at 4 ° C for up to 4 weeks. To adjust the density of 1.1 g / mL, 0.57 g of Potassium bromide was added to 4 mL plasma. Density gradient was constructed using a 12 mL polyallomer tube (14 x 89 mm, Beckman Coulter), with 4 mL of plasma (1.1 g / mL) forming a layer at the bottom of the tube and 1.063 g / mL 3 mL of the solution having the density, 2 mL of the solution having the density of 1.017 g / mL and 2 mL of the solution having the density of 1.006 g / mL were formed. The sample was centrifuged (Beckman Optima XE-100 Ultracentrifuge, SW41 Ti rotor, 38 min, 38,000 rpm, 15 ° C, max acceleration and no break) and a kilo-micron fraction (Sf> 400, 1 mL (white, opaque) of the supernatant of all tubes with a density of 1.006 g / mL representing a particle flotation rate at 1.063 g / mL solution; Hodis et al., 1997) was collected and combined, and the final kilo micron emulsion - And stored at 30 ° C for up to 15 days.

Example 4. Comparison of solubilizing agent and surfactant titration against kilo-micron

In order to measure the affinity of the solubilizing agent and the surfactant with the kilo-micron by an indirect way, an appropriate test was carried out as described below.

4-1. On a kilo micron  Titration of Solubilizing Agents

Transcutol HP, ethanol and propylene glycol were titrated with a standard kilo-micron dispersion (standard CM dispersion) until the kilo-micron became clear (25 ° C), and the results are shown in Table 2. The turbidity test was determined using a spectrophotometer at room temperature, 550 nm wavelength, and the final point of titration was determined from the absorbance of the mixture estimated to be less than 0.01.

Categories Name of pharmaceutical excipients Amount of titration (mL)
Solubilizers Transcutol HP 5.2 ± 0.2 Ethanol 6.7 ± 0.1 Propylene glycol 9 Distilled water 30 <

As shown in Table 2, it was confirmed that the amounts of transcutol HP, ethanol and propylene glycol were 5.2 ± 0.2 mL, 6.7 ± 0.1 and 9 mL, respectively. From the above results, transcutol HP easily dissolves components of the kilo-micron such as triglycerides and phospholipids, and has the highest affinity for the kilo-micron, followed by ethanol and propylene glycol.

4-2. Surfactant Titration to Kilo Micron

The surfactant solution was dissolved in water to prepare a surfactant solution, and an appropriate test was carried out in the same manner as in 4-1 except that the surfactant solution was used.

That is, the surfactant was titrated with 20% (w / v) surfactant solution due to its high viscosity and slow mixing with the kilo-micron dispersion. More specifically, 2 g of the surfactant was added to 6 mL of distilled water using a 10 mL volumetric flask and then mixed using a magnetic stirrer at 150 rpm for 2 hours. Thereafter, the rest of the solution was filled with water and stirred for 1 hour to prepare a surfactant solution, and this surfactant solution was immediately mixed with the kilo-micron, so that correct titration was possible. Therefore, titration tests were carried out using the prepared surfactant solution, and the results are shown in Table 3.

Categories Name of pharmaceutical excipients Amount of titration (mL)
Surfactants 20% (w / v) Tween 80 solution 4.45 ± 0.05 20% (w / v) Tween 20 solution 4.75 ± 0.05 20% (w / v) Cremophor ELP solution 5.7

As shown in Table 3, Tween 80 required the least amount (4.45 +/- 0.05 mL) of clarity to make the kilo-micron (CM) clear, followed by Tween 20 (4.75 +/- 0.05 mL) and Cremophor II 5.7 mL). From the above results it can be deduced that Twin 80 has the highest affinity to the kilo-micron, followed by Tween 20 and Cremophor ELP.

On the other hand, CMC (critical micelle concentration) of TW 80, TW 20 and Cremophor ELP were 0.02, 0.08 and 0.12-0.18 mM, respectively (Apte, SP, 2010) . Selective surfactants for the maximum inhibition of the activity of the multidrug resistance efflux pump transporter, P-glycoprotein: conceptual development. Journal of Excipients and Food Chemistry 3, 51-59.). From the above results, surfactant molecules with lower CMCs form more strongly micelles because the tail portion of the surfactant is more hydrophobic, which allows the lipophilic components of the kilo-microns, such as triglycerides, phospholipids and cholesterol, to readily dissolve into the micelles It can be seen.

Example 5. Comparison of lipophilic drug delivery capability of solubilizing agent and surfactant to kilo-micron

5-1. sample preparation

Transcutol HP, ethanol, propylene glycol, Tween 80, Tween 20, and Cremophor ELP were added to ProBacol (lipophilic drug), respectively, and mixed using a magnetic stirrer for 24 hours , The kilo-micron emulsion (0.5 mL) prepared in Example 3 above was added to a 5 mL glass vial. Thirteen samples were prepared by incubating the prepared mixture using gentle shaking at 37 DEG C for 3 hours, and the respective contents for the samples are shown in Table 4. Sample 1 (P1) was prepared by dissolving 1 mg of procollol in 10 mL of acetonitrile without using any solubilizing agent and surfactant, placing 2 μL of the prepared mixture in a 5 mL glass vial, adding acetonitrile (acetonitrile) was evaporated by nitrogen gas and added by adding 0.5 mL of kilo-micron.

No. CM emulsion
(mL) Probucol
(μg) Pharmaceutical excipient selected for vehicle Amount of vehicle (mg) P1 0.5 2.5 - - P2 0.5 2.5 Transcutol HP 25.0 P3 0.5 2.5 Ethanol 25.0 P4 0.5 2.5 Propylene glycol 25.0 P5 0.5 2.5 Tween 20 25.0 P6 0.5 2.5 Cremophor ELP 25.0 P7 0.5 2.5 Tween 80 25.0 P8 0.5 1.25 Propylene glycol 25.0 P9 0.5 7.5 Propylene glycol 25.0 P10 0.5 12.5 Propylene glycol 25.0 P11 0.5 25 Transcutol HP 25.0 P12 0.5 50 Transcutol HP 25.0 P13 0.5 100 Transcutol HP 25.0 P14 0.5 250 Transcutol HP 25.0

5-2. Kilo-micron Pro Boole  Validation of Solubilization Effects on Delivery

Density gradient ultracentrifugation was performed again to separate the probucol-bound kilo-micron particles. The density gradient was constructed using a 12 mL polyallomer tube, with 0.5 mL of incubated kilo-micron adjusted to a density of 0.1 g / mL using Potassium bromide, located at the bottom of the tube, 4 mL of a solution having a density of 1.063 g / mL, 3 mL of a solution having a density of 1.019 g / mL, and 3 mL of a solution having a density of 1.006 g / mL were formed. The samples were centrifuged (Beckman Optima XE-100 Ultracentrifuge, SW41 Ti rotor, 38 min, 38,000 rpm, 15 ° C, max acceleration and no break) and then 1.006 g / mL representing a kilo-micron fraction 0.5 mL of the supernatant having the density was obtained and stored at -30 ° C.

0.2 mL of the fraction of the kilo-micron was thawed, and 2 mL of acetonitrile was added thereto. The mixture was vortexed for 5 minutes and centrifuged at 2,000 g for 5 minutes at room temperature to dissolve probucol and precipitate proteins containing kilo micron. The level of probucol in the supernatant was then determined by HPLC analysis using UV detection at 241 nm and the results are shown in FIG. Isolation of ProBoCol was achieved at room temperature by a mobile phase consisting of YL9100 HPLC on Zorbax ODS column (4.6 mm x 150 mm, 5 m) and acetonitrile: water (94: 6, v / v). The retention time of ProBocol was 10.6 minutes at a flow rate of 1.0 mL / min. The limit of quantification was 0.375 μg / mL, and the linearity of the calibration curve was confirmed at 0.375-200 μg / mL.

On the other hand, in order to confirm that it is only binding to the kilo-micron, the experiment was carried out in the same manner as described above except that there is no kilo-micron. That is, probucol and transporter were incubated with 0.5 mL sodium chloride solution having a density of 1.006 g / mL instead of kilo-micron, and incubation and ultracentrification conditions were the same as described above. 0.5 mL of the supernatant was collected and stored at -30 [deg.] C until HPLC analysis was performed.

As shown in Fig. 2, transcutol HP (P2) exhibited the highest pro- bucole transport capacity (2.30 μg) in the kilo-micron, followed by ethanol (1.85 μg) (P3) and propylene glycol 0.51 μg) (P4).

On the other hand, probucol was not detected in the kilo-micron dispersion in Sample 1 (P1), because of its very low solubility in water (<0.005 μg / ml, Christensen et al., 2004) , Which appears to be able to significantly reduce the possibility of physical contact with the kilo-micron particles which can interfere with the natural scattering of the probucol blend powder and thereby solubilize the drug.

3 is a graph showing the correlation between the binding of the kilo-micron and the probucol using the solubilizing agent and the solubility of propacol or the appropriate amount of the solubilizer. More specifically, Fig. 3 (A) (Lipophilic drug) solubility measured by the method of Example 2. FIG. 2 (B) is a graph showing the relationship between the binding of kilo-micron and propucol using a solubilizing agent and the solubility of pro- 4-1. &Lt; tb &gt; &lt; TABLE &gt;

As shown in Fig. 3 (A), it was confirmed that the solubilizing agent having a high solubility of pro-bucol tends to deliver a larger amount of pro-bokol. In addition, as shown in FIG. 3 (B), through the appropriate results, which are indirect methods for evaluating the affinity between the kilo-micron and the solubilizer, the solubilizer having a high kilo-micron affinity has a higher amount of pro- The results of this study are as follows.

From the above results, it was found that the solubility of the good pro-baclo and the affinity with the kilo-micron is an important factor in becoming an efficient carrier for delivering pro-beclol by the kilo-micron.

5-3. Kilo-micron Pro Boole  Surfactant effect on transfer

The effect of the surfactant on propagation of probucol to the kilo-micron was verified in the same manner as in Example 5-2 (see Fig. 4). The results are shown in Fig.

As shown in Figure 1, Propucoyl transfer to kilo-micron by Tween 20, Cremophor ELP and Tween 80 resulted in 0.42 μg (P5), 0.38 μg (P6) and 0.19 μg (P7) . That is, even after 3 hours of incubation, the micelles coexisted with the kilo-micron and did not merge or interact with the kilo-micron, which limited the delivery of probucol in the micelle to the kilo-micron, It was confirmed that the amount of pro-bucole found in the post-kilo micron was small (see Fig. 4)

5 is a graph showing the correlation between the binding of the kilo-micron and the probucol using the surfactant and the solubility of the probucol or the appropriate amount of the surfactant. More specifically, Fig. 5 (A) (Lipophilic drug) solubility measured in Example 2, and FIG. 5 (B) is a graph showing the relationship between the binding of the kilo-micron and the probucol using the surfactant, 4-2. &Lt; tb &gt; &lt; TABLE &gt;

As shown in Fig. 5 (A), it was confirmed that, in the case of a surfactant having a high solubility in proBocol, it tends to deliver a larger amount of pro-bokol. On the other hand, the titration of the surfactant solution seems to be independent of the pro-beclol transfer to the kilo-micron by the surfactant (Fig. 5 (B)) and the results show that the solubility of probucol in the surfactant is higher than that of the surfactant And it was found to be a dominant factor in affinity.

On the other hand, when comparing the results of Examples 5-2 and 5-3, it was confirmed that the pro-betole delivery to the kilo-micron was not consistent with the solubility of probucol. That is, although the propocole solubility at tween 80 is higher than propocole solubility in propylene glycol, propylene glycol is more effective than propylene glycol in propylene glycol solubility, It is more effective. Moreover, considering that the amount of pro-bucol delivered to the kilo-micron by the three solubilizers is greater than that of the surfactant, it can be assumed that there is another factor apart from the solubility or affinity with pro- there was. From the above results, the reason for the low probucol transport by the surfactant is that since the concentration of the surfactant is higher than the CMC at P5, P6 and P7, the added surfactant forms a micelle during the incubation with the kilo-micron. And it was found.

Example  6. Size distribution of solubilizing agent and surfactant ( you distribution ) Measurement comparison

0.5 mL of the kilo-micron was added to the formulation (containing 2.5 μg of probucol in 25 mg of pharmaceutical additive as in P2-P7 of Table 1) and the untreated kilo-micron dispersion was incubated for 3 hours using gentle shaking . 0.1 mL of the mixture was diluted in 1 mL of distilled water and the size distribution was measured. In addition, 25 mg of Cremophor ELP, Tween 20 and Tween 80, each containing 2.5 μg of procollol, was dissolved in 5 mL of distilled water and the size distribution was evaluated. The size distribution was measured at room temperature using a Zetasizer Nano ZS (Malvern Instruments, UK). The results are shown in FIG.

As shown in Figure 6, the size distribution of kilo-micron doses administered with transcutol HP, ethanol, or propylene glycol, including the blank kilo micron and probucol, exhibited monodispersion, The average size was 220.8 nm, 219.6 nm, 209.0 nm and 254.4 nm, respectively. On the other hand, twin 20, twenty 80 and Cremophor ELP showed two peaks.

On the other hand, in Fig. 6, the peak of B was regarded as a kilo-micron because the peak of B showed a size distribution similar to that of untreated kilo-micron. 6, the peak of A was regarded as the micelle peak formed by the surfactant. In order to confirm the micelle of each surfactant, the size distribution of the micelle containing probucol was measured. As a result, tween 20, tween 80 and It was confirmed that the mean micelle sizes of Cremophor ELP were 8.1 nm, 9.6 nm and 14.2 nm, respectively, which was consistent with the A peak in FIG. 6.

Example  7. Lipophilic  Depending on drug concentration Kilo-micron  Verification of coupling effect

Experiments with binding to the kilo-micron according to the lipophilic drug Propobol concentration have shown that low concentrations of propylene glycol (P4 and P8-P10 in Table 1) and high concentrations of Transcutol HP (P2 and P11- P14), and the results are shown in Figs. 7 and 8, respectively.

As shown in FIG. 7, it was confirmed that, if the concentration of probucol given in the formulation is high, the amount of probucol bound to the kilo-micron increases. In addition, as shown in Fig. 8, it was confirmed that the delivered procollol was also increased by the pro-covalent enriched in transcutol HP.

On the other hand, given 2.5 μg of probucol, approximately 92.4% of the initial dose was delivered in kilo-microns. However, as the concentration of procobokol administered increased, the percentage of probucol binding to the kilo-micron decreased. For example, given 25, 50, 100 and 250 μg of probucol (P14-P17), 35.2%, 26.3%, 21.4% and 16.8% of probucol bound to the kilo-micron respectively. From the above results, it was found that the probucol delivered in kilo-microns was increased to a high concentration to be administered without saturating the kilo-micron capacity for probucol.

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (5)

A composition for a lymphatic drug delivery system, said composition comprising: a solubilizer selected from the group consisting of transcutol HP (diethylene glycol monoethyl ether), ethanol and propylene glycol; And probucol, wherein the solubilizer does not form micelles.
2. The composition of claim 1, wherein the composition enhances the delivery of probucol to the chylomicron.
delete delete An oral preparation, characterized in that the composition of claim 1 is filled.

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