KR20110136256A - Self-emulsifying drug delivery system composition containing flurbiprofen - Google Patents

Abstract

PURPOSE: An oral composition of flurbiprofen using a self-emulsifying drug delivery system is provided to enhance bioavailability and to ensure quick expression. CONSTITUTION: A self-emulsifying drug delivery composition contains 40-90 wt% of carprylo carpryloyl macrogol glyceride, 4-40 wt% of oleoyl macrogol glyceride, 2-30 wt% of diethylene glycol monoethyl ether, and 3-20 wt% of flurbiprofen. The composition contains 25-45 weight parts of dioxy silicon as a carrier. The composition also contains 40-100 weight parts of magnesium stearate, dextran, or hydroxypropyl-beta-cyclodextrin.

Description

Self-emulsifying drug delivery system composition containing flurbiprofen

The present invention relates to oral compositions of flubiprofen using a self-emulsifying drug delivery system.

Flubiprofen has a strong anti-inflammatory and analgesic effect, and it is widely used as a nonsteroidal anti-inflammatory medicine used for pain, mild and severe pain, rheumatoid arthritis, osteoarthritis, extraction and analgesia after minor surgery of dental area. .

Conventionally, these nonsteroidal anti-inflammatory drugs have been generally administered orally as solid preparations such as tablets and capsules when used clinically, but flubiprofen has very low solubility and very low bioavailability, resulting in slow drug expression. It was difficult to act as an anti-inflammatory drug.

Therefore, in order to solve this drawback by developing flubiprofen as an injection (株) Green Cross, in the flubipropene prodrug flurbiprofen axetil, 2- (2-fluoro-4- Biphenylyl) propionic acid (acetoxy) ethyl ester] was developed as an intravenous injection [Lipfen / Ropion: (:) Green Cross / (株 本)] The long-lasting efficacy and reduced side effects, however, the fluviprofen precursor used in this formulation is difficult to separate from fluviprofen and fluviprofen axetyl after the synthesis stage, is expensive, and has the advantage of rapid injection. There is a problem that can not express the expression, and because the injection is inconvenient to administer.

Therefore, there was a study on the method of applying flubiprofen as a topical preparation for transdermal administration. As a result of these studies, the topical preparation for transdermal administration that has been developed and used to date is generally a gel preparation, an ointment or a cream preparation. However, the amount of the drug from the external preparation to penetrate the skin to reach the target site is very small, there is a problem that the desired drug efficacy cannot be sufficiently obtained.

It solves the problem that the administration of the injection is inconvenient,

To solve the problem of difficult or expensive production of chemically modified flubiprofen,

It can solve the problems of discomfort and poor drug efficacy of existing external preparations.

A new concept of fluviprofen oral formulation composition is provided.

Through the following specific aspects of the present invention it was possible to achieve the above object:

(1) caprylo caproyl macrogol glyceride 40 to 90% by weight, oleyl macrogol glyceride 4 to 40% by weight, diethylene glycol monoethyl ether 2 to 30% by weight and flubiprofen 3 to 20% by weight Liquid self-emulsifying drug delivery compositions containing%;

(2) A solid self-emulsifying drug delivery composition, comprising 25 to 45 parts by weight of dioxy silicone as a carrier together with 100 parts by weight of the liquid self-emulsifying drug delivery composition together with the liquid self-emulsifying drug delivery composition of (1). ; or

(3) 40-100 weight of magnesium stearate, dextran, or hydroxyl propyl-beta-cyclodextrin as a carrier together with the liquid self-emulsifying drug delivery composition of (1), based on 100 parts by weight of the liquid self-emulsifying drug delivery composition. By weight of the solid self-emulsifying drug delivery composition.

Self-emulsifying drug delivery composition according to the present invention,

Because oral administration is possible, it is possible to solve the problem that the administration of injectables is inconvenient to achieve the convenience of taking and improve patient compliance.

By using flubiprofen itself, it solved a problem of difficulty in manufacturing or expensive manufacturing of chemically modified flubiprofen.

Increasing the solubility of flubiprofen to increase the low bioavailability of the flubiprofen and to speed up the expression time was able to solve the problems of poor drug efficacy as well as inconvenient use in conventional external preparations.

1 shows the results of flubiprofen solubility test in each oil, surfactant and co-surfactant. (FIG. 1A: Oil Solubility Test, FIG. 1B: Surfactant and Cosurfactant Solubility Test)
Fig. 2 shows fluvipropene powder (●) and Example S-1 (○), S-2 (▼), S-3 (Δ) and S-4 (◇) and Comparative Example S-1 (■). ), And the results of dissolution experiments on the compositions of S-2 (□) and S-3 (◆).
3a, 3b, 3c, 3d and 3e respectively show flubiprofen powder and SEM (Scanning electron micrographs: S-4200) photographs of Examples S-1, S-2, S-3 and S-4, respectively. It is shown in photograph B compared with the SEM photograph (A) of the carrier.
4A, 4B, 4C, and 4D are differential scanning calorimeter (DSC Q200) photographs of Examples S-1, S-2, S-3, and S-4, respectively. (A, flubiprofen powder; B, carrier; C, physical mixture of fluvipropene powder and carrier; D, solid self-emulsifying composition of the present invention)
5A, 5B, 5C, and 5D are powder X-ray diffraction photographs of Examples S-1, S-2, S-3, and S-4, respectively. (A, flubiprofen powder; B, physical mixture of fluvipropene powder and carrier; C, carrier; D, solid self-emulsifying composition of the present invention)

The composition of each component contained in the flubiprofen-containing self-emulsifying drug delivery composition according to the present invention will be described in more detail as follows.

Caprylo caproyl macrogol glyceride in the composition of the present invention acts as an interfacial stabilizer for the poorly soluble drug flubiprofen and acts as an emulsifier in a self-emulsifying drug delivery system. As an example of caprylo caproyl macrogol glyceride which can be used for the composition of this invention, the brand name Labrasol can be mentioned. Caprylo caproyl macrogol glycerides are preferably used at 40-90% by weight in the liquid self-emulsifying drug delivery composition according to the present invention, but in too small amounts it does not significantly increase the solubility of poorly soluble drugs and exceeds 90% by weight. In the range of, the state is unstable even if the emulsion is not formed at all.

Oleoyl macrogol glycerides in the compositions of the present invention act as a solubilizer for the poorly soluble drug flubiprofen and act as an oil in a self-emulsifying drug delivery system. As an example of the oleoyl macrogol glyceride that can be used in the composition of the present invention, the trade name Labrafil M 1944 CS can be exemplified. Oleoyl macrogol glycerides are preferably used at 4-40% by weight in the liquid self-emulsifying drug delivery composition according to the present invention, but less than 5% or more than 40% do not form a self-emulsifying drug delivery system or have an unstable emulsion. Form.

The diethylene glycol monoethyl ether in the composition of the present invention acts as a dissolution aid for the poorly soluble drug, flubiprofen, while controlling the HLB value of the mixture of surfactants in a self-emulsifying drug delivery system to act as a more stable emulsifier. It acts as a surfactant. As an example of the diethylene glycol monoethyl ether which can be used for the composition of this invention, the brand name Transcutol HP is mentioned. Diethylene glycol monoethyl ether is preferably used at 2 to 30% by weight in the liquid self-emulsifying drug delivery composition according to the present invention to stabilize the self-emulsifying drug delivery system by adjusting the HLB value while increasing the solubility of poorly soluble drugs. Plays an important role.

Flubiprofen, an active ingredient in the composition of the present invention, is preferably used in an amount of 3 to 20% by weight in the liquid self-emulsifying drug delivery composition according to the present invention. Exceeding the weight percent range exceeds the maximum solubility so that all drugs do not form a self-emulsifying drug delivery system.

The composition ratio of the four components in the composition of the present invention is determined by finding the optimum ratio of stable emulsion state and small particle size in the liquid self-emulsifying drug delivery system made by mixing them in various ratios. When the composition of this liquid self-emulsifying drug delivery system is added to water, an emulsion is formed even by small kinetic energy, so it is absorbed very rapidly in vivo when administered in vivo, including oral administration, and thus shows an excellent bioavailability compared to conventional formulations. You can expect

Liquid self-emulsifying drug delivery compositions according to the invention can be solidified with a carrier. Thus, preferred examples of the carrier which can be used to prepare the solid self-emulsifying drug delivery composition according to the present invention include dioxy silicone, magnesium stearate, dextran, hydroxyl propyl-beta-cyclodextrin and the like. Specific examples of the dioxy silicones include trade name Aerosil 200.

The amount of the carrier used in the solid self-emulsifying drug delivery composition according to the present invention is a weight part with respect to the liquid self-emulsifying drug delivery composition, and it is preferable that the dioxy silicone is 0.25 to 0.45 part by weight, and magnesium stearate, dextran, and hydroxyl profile. In the case of -beta-cyclodextrin, the amount is preferably 0.40 to 1.00 parts by weight. If it is less than the lower limit of these preferred contents, it does not form a solid. If the upper limit is exceeded, the content of the drug in the solid self-emulsifying drug delivery composition becomes so small that the total formulation volume becomes large. Reduces the improvement.

As a method of solidifying the liquid self-emulsifying drug delivery composition according to the present invention using a carrier, spray drying (for example, a Buchi Mini-spray dryer may be used), fluidized bed drying, lyophilization and the like can be given.

The method of formulating the self-emulsifying drug delivery composition according to the present invention is by methods well known to those skilled in the art, and may be prepared in a pharmaceutical form including conventional excipients, lubricants, diluents and the like. The pharmaceutical forms include oral preparations such as tablets, capsules, and powders.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by Examples.

Experimental Example  1. Solubility Experiment

As oils sunflower oil, castor oil, corn oil, cotonside oil, sesam oil, peanut oil, Labrapak CC, Labrafil M 1944 CS, Labrafil M 2125 CS, with mineral oils,

The solubility test of flubiprofen was conducted on Tween 20, Tween 80, Labrasol, Transcutol HP, Span 20, Span 80, Capriol 90, Lauroglycol FCC, and Cramophor ER as surfactants and cosurfactants. It was.

An excess of fluviprofen (500 mg) was added to 1 ml of each of the oil, surfactant, and co-surfactant components, followed by shaking for 3 days at 25 ° C. and 100 RPM in a stirred thermostat, followed by quantification by HPLC / UV system.

HPLC conditions are as follows.

HPLC System: Hitachi L-2130

HPLC column: Inertsil ODS-3 reverse-phase C18 column (GL science, 250 mm x 4.6 mm 0.5 μm, I.D.)

Mobile phase: Acetonitrile, water and phosphoric acid (600/400/5, volume ratio)

Detector: Hitachi L-2400

Injection volume: 20 μl

Flow rate: 1.5 ml / min

Wavelength: 254 nm

Solubility test results (FIGS. 1A and 1B), the surfactant is Labrasol (caprylo caproyl macrogol glyceride), the oil is Labrafil M 1944 CS (oleoyl macrogol glyceride), co-surfactant is trans Curtol HP (diethylene glycol monoethyl ether) showed the highest solubility of flubiprofen.

Experimental Example  2. Preparation of Liquid Self-Emulsifying Drug Delivery Composition

Caprilo caproyl macrogol glyceride (Labrasol), oleoyl macrogol glyceride (Labrafil M 1944 CS), diethylene glycol monoethyl ether (Transcutol HP) selected from the above solubility test results Each composition was mixed according to the compositions of Tables 1 to 3 below and then rotated at a rate of 2000 times per minute.

0.1 ml of the prepared composition was added to 100 ml of water, and a magnetic rod was added thereto to rotate for 1 minute at a speed of 150 times per minute to confirm the formation of an emulsion, and the rotation was stopped for 48 hours. The compositions of the comparative examples did not all maintain a stable self-emulsification phase and were phase separated within 24 hours, in particular, within 12 hours for Comparative Examples 1 and 2, but the examples according to the present invention all maintained stable self emulsification conditions for 48 hours or more. .

Experimental Example  3. Shaped Emulsion  Particle size

Dynamic light scattering was performed using Zetasizer Nano ZS (Malvern Instruments, UK). The particle size of the emulsion formed by adding 0.1 ml of the composition prepared in Experiment 2 to 100 ml of water and then rotating the magnetic rod for 1 minute at a speed of 150 times per minute was used. Measured by technique.

The results of the measured particle size are shown in Table 4. In the case of the compositions (examples) according to the present invention, it was confirmed that the emulsion formed was stable and the particle size of the emulsion was all 130 nm or less, thus being suitable as a poorly soluble drug delivery system. Especially in the case of Example 37, an emulsion having a very good particle size of 92 nm was formed. The smaller the particles, the better the dissolution rate as well as the absorption of the drug in the body has already been demonstrated in the paper (Jun-ichi. J., Naoki. K., Masateru. M., at. All., Effect of particle size reduction on dissolution and oral absorption of poorly water-soluble drug, cilostazol, in beagle dogs 2006. J Controll Release. 111. 56-64). In contrast, in Comparative Examples 7, 8, 9, and 10, the emulsion particle size exceeded 130 nm, and thus, it was judged to be inadequate as a poorly soluble drug delivery system. In Comparative Examples 1, 2, and 3, although the particle size was small, Experimental Example As shown in Fig. 1, the emulsion was decomposed within 24 hours and thus could not be applied as a drug delivery system. Comparative Examples 4 and 6 did not contain a cosurfactant component and Comparative Example 5 did not contain an oil component to form a liquid self-emulsifying drug delivery system.

Composition Particle Size (nm) Comparative Example 1 86 Comparative Example 2 91 Comparative Example 3 90 Comparative Example 7 135 Comparative Example 8 139 Comparative Example 9 167 Comparative Example 10 185 Example 36 121 Example 6 101 Example 37 92 Example 5 98 Example 38 110 Example 4 106 Example 39 121 Example 10 116 Example 40 110 Example 9 106 Example 41 98 Example 8 103 Example 42 105 Example 7 103

Experimental Example  4. Preparation of Solid Self-Emulsifying Drug Delivery Composition

Example 37 was selected from the particle size test results of Experimental Example 3 as an optimum composition and solidified by spray drying (Buchi Mini-spray dryer, Buchi, German) with seven carriers in the composition shown in Table 5 below. Solid self-emulsifying drug delivery compositions were prepared.

Constituent Example S-1 Example S-2 Example S-3 Comparative Example S-1 Comparative Example S-2 Comparative Example S-3 Example S-4
basic
Composition of Example 37
(800 μl Labrasol, 125 μl Labrafil M 1944 CS, 75 μl of Transcutol HP and 200 mg of flubiprofen)
Solvent (ml) Ethanol: 100 Ethanol: 100 Water: 100 Water: 100 Water: 100 Water: 100 Water: 100 Carrier (mg) Dioxy Silicone: 500 Magnesium Stearate: 1000 Dextran: 1000 Polyvinyl Alcohol: 1000 Carboxy Methyl Cellulose Sodium: 1000 Gelatin: 1000 Hydroxyl propyl-beta-cyclodextrin: 1000 Inlet temperature (℃) 60 60 120 120 120 120 120 Outlet temperature (℃) 38 42 83 75 82 78 75 Aspiration (%) 80 80 80 80 80 80 80 Flow rate (ml / min) 5 5 5 5 5 5 5

Experimental Example  5. Drug Dissolution Experiment from Solid Self-Emulsifying Drug Delivery Composition

Examples S-1, S-2, S-3 and S-4 and Comparative Examples S-1, S-2 and S-3 were fixed in 50 mg of flubiprofen, and filled into gelatin hard capsules to elute them. The test result using the test method 2 (paddle method) by rotating speed: 100 RPM, eluent: water, eluent amount: 900 ml is shown in FIG.

Experimental results show that dispersing or dissolving very well in water (Examples S-1, S-2, S-3, and S-4) is fast and high in dissolution rate depending on the characteristics of the carrier. It was found that the dissolution rate (Comparative Examples S-1, S-2 and S-3) was low.

 Drug Analysis Method for Dissolution Test

 HPLC System: Hitachi L-2130

 HPLC column: Inertsil ODS-3 reverse-phase C18 column (GL science, 250 mm x 4.6 mm 0.5 μm, I.D.)

 Mobile phase: Acetonitrile, water and phosphoric acid (600/400/5, volume ratio)

 Detector: Hitachi L-2400

 Injection volume: 20 μl

 Flow rate: 1.5 ml / min

Wavelength: 254 nm

Experimental Example  6. Confirmation of the Preparation Status of the Solid Self-Emulsifying Drug Delivery Composition

3A, 3B, 3C, 3D, and 3E are flubiprofen powders and SEM (Scanning electron micrographs: S-4200) photographs of Examples S-1, S-2, S-3, and S-4, respectively. Compared to flubiprofen powder. SEM images showed that the solid carrier surrounded the drug in all formulations.

4A, 4B, 4C, and 4D show differential scanning calorimeters (DSC Q200) photographs (D) of fluvipropene powder (Examples S-1, S-2, S-3, and S-4, respectively). A), the carrier (B) and the fluvipropene powder were compared with the physical mixture (C) of the carrier, respectively. As a result of experiments with a temperature rise of 10 ° C. per minute, the drug melting point peak of fluviprofen at 110 ° C. disappeared in all formulations, indicating that the physicochemical change of the drug occurred.

5A, 5B, 5C and 5D show powder X-ray diffraction photographs (D) of Examples S-1, S-2, S-3 and S-4, respectively, for fluviprofen powder (A), the carrier (C) and the fluvipropene powder and the physical mixture of the carrier (B), respectively. As a result of the experiments, it was confirmed that flubiprofen crystalline form was changed from an amorphous form to an amorphous form.

Claims (3)

Caprylocaproyl macrogol glyceride 40 to 90% by weight, oleoyl macrogol glyceride 4 to 40% by weight, diethylene glycol monoethyl ether 2 to 30% by weight and flubiprofen 3 to 20% by weight Liquid self-emulsifying drug delivery composition. A solid self-emulsifying drug delivery composition comprising dioxy silicone as a carrier in an amount of 25 to 45 parts by weight based on 100 parts by weight of the liquid self-emulsifying drug delivery composition according to claim 1. 10 to 40 parts by weight of magnesium stearate, dextran or hydroxyl propyl-beta-cyclodextrin, based on 100 parts by weight of the liquid self-emulsifying drug delivery composition, together with the liquid self-emulsifying drug delivery composition of claim 1 Solid self-emulsifying drug delivery composition.

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