KR20090037715A - Pharmaceutical composition with improved bioavailability - Google Patents

Abstract

A pharmaceutical composition having improved bioavailability is provided to improve the solubility of a 2-hydroxy-5-(4-(trifluoromethyl) phenethylamino)benzoic acid by using polyethylene-polypropylene glycol as an auxiliary dissolving agent. A pharmaceutical composition having improved bioavailability comprises 2-hydroxy-5-(4-(trifluoromethyl) phenethylamino)benzoic acid of the chemical formula 1 or pharmaceutically acceptable salts and polyethylene-polypropylene glycol. The polyethylene-polypropylene glycol is mixed in the amount of 0.1-30 parts by weight based on the weight of the 2-hydroxy-5-(4-(trifluoromethyl) phenethylamino)benzoic acid.

Description

Pharmaceutical composition having improved bioavailability

The present invention relates to a composition having improved bioavailability of 2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid or a pharmaceutically acceptable salt thereof.

2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid and its pharmaceutically acceptable salts include ischemia, ischemia, hypoxia, hypoglycemia, brain Traumatic brain injury, traumatic spinal cord injury, epilepsy, Huntington's disease, Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis It is known to be very useful for damage to the central nervous system (CNS) such as amyotrophic lateral sclerosis (see US Patent No. 6,964,982).

However, the 2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid or a pharmaceutically acceptable salt thereof has a low solubility, which causes a problem of low bioavailability. In particular, low solubility in the gastrointestinal tract not only decreases the oral absorption rate, but also increases the absorption deviation between and in the individual, and at high doses, dose-responsiveness cannot be obtained due to absorption saturation. Big.

Accordingly, the present invention provides a pharmaceutical composition having improved bioavailability of 2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid or a pharmaceutically acceptable salt thereof. will be.

The present invention to achieve the above technical problem is 2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition comprising a polyethylene-polypropylene glycol.

Hereinafter, the composition of the present invention will be described in more detail.

The present invention relates to 2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid or a pharmaceutically acceptable salt thereof (hereinafter referred to as the 'compound or salt thereof') of polyethylene It is based on the surprising finding that the bioavailability of the compounds of the invention or salts thereof can be significantly improved when mixed with polypropylene glycol.

In the present invention, "pharmaceutically acceptable salts" refer to salts that are nontoxic or made with less base. Base addition salts of the compounds of this invention can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base and a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, salts consisting of lithium, sodium, potassium, calcium, ammonium, magnesium or organic amino.

Compositions of the present invention may also include hydrated forms of the compounds of the present invention and may include solvated as well as unsolvated forms. In addition, the compounds of the present invention or salts thereof may exist in crystalline or amorphous form, and all such physical forms are included in the scope of the present invention.

The composition of the present invention comprises polyethylene-polypropylene glycol for the purpose of enhancing the bioavailability of the compound of the present invention or salts thereof. The polyethylene-polypropylene glycol is poloxamer (Poloxamer) is named, also known as 407, preferably, but may be a commercially Lutrol ^® F127 is available by using the present invention is not limited thereto.

The present inventors have evaluated using various methods for increasing the bioavailability of the compound of the present invention and various dissolution aids, so that the solubilization method using polyethylene-polypropylene glycol is superior to other methods and other dissolution aids. It showed a bioavailability enhancing effect. More specifically, the absorption rate of oral administration of 100 mg / kg of the free base compound of the present invention in distilled water is very low at about 4.1%, but the absorption rate is orally administered at 10% polyethylene-polypropylene glycol suspension. Silver 33.9-42.7% not only improves bioavailability very much, but can also reduce in- and inter-dose deviations.

Such polyethylene-polypropylene glycol is preferably mixed in an amount of 0.1 to 30 parts by weight based on the weight of 2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid used as an active ingredient.

The composition of the present invention may include a pharmaceutically acceptable excipient or additive in addition to the compound of the present invention or a salt thereof and polyethylene-polypropylene glycol. The compositions of the present invention may be administered alone or in admixture with any convenient carrier, excipient, etc., and such dosage forms may be single or repeated dose formulations.

The composition of the present invention may be a solid formulation or a liquid formulation. Solid preparations include, but are not limited to, powders, granules, tablets, capsules, suppositories, and the like. Solid form preparations may include, but are not limited to, excipients, flavors, binders, preservatives, disintegrants, lubricants, fillers and the like. Liquid formulations include, but are not limited to, solutions such as water, propylene glycol solutions, suspensions, emulsions, and the like, and may be prepared by adding suitable colorants, flavors, stabilizers, viscosity agents, and the like.

For example, powders may be prepared by simply mixing a compound of the present invention or a salt thereof with a suitable pharmaceutically acceptable excipient such as lactose, starch and microcrystalline cellulose. Granules are compounds of the present invention; Pharmaceutically acceptable excipients; And a suitable pharmaceutically acceptable binder such as polyvinylpyrrolidone, hydroxypropyl cellulose, and the like, followed by a wet granulation method using a solvent such as water, ethanol or isopropanol, or a dry granulation method using compression force. Can be. Tablets may also be prepared by mixing the granules with a suitable pharmaceutically acceptable glidant such as magnesium stearate and then tableting using a tableting machine.

The present invention therefore also provides a method for improving the bioavailability of a compound of the invention or a salt thereof, comprising mixing polyethylene-polypropylene glycol with a compound of the invention or a salt thereof.

The present invention provides compositions having improved bioavailability of 2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid or a pharmaceutically acceptable salt thereof.

Hereinafter, the following examples and the like will be described in order to describe the present invention in more detail. However, embodiments according to the present invention may be modified in many different forms and the scope of the present invention should not be construed as being limited to the embodiments described below. Embodiments of the present invention are provided by way of example in order to facilitate a specific understanding of the present invention.

Example 1 Preparation and Evaluation of Microparticles

Although the free base powder of the present invention was dissolved in an organic solvent having a high solubility and a low boiling point, it was intended to prepare amorphous microparticles by spray drying. It was. Therefore, the compound free base of the present invention was suspended in distilled water, homogenized (homogenization) for 10 minutes to reduce the particle size and orally administered to evaluate the absorption rate. The dosage was 100 mg / kg, and the dosage composition was prepared by adding 250 mg of the free base of the present invention to 5 ml of distilled water and homogenizing for 10 minutes.

Rats (Sprague-Dawley, male, 7-8 weeks old, n = 4) were used as experimental animals, and blood collection was performed for 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, and 2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid concentration in plasma was used by LC-MS / MS. Waters Alliance 2695 (Waters Corporation, Milford, Mass.) Was used as HPLC and Micromass Quattro micro API (Waters Corporation) was used as Mass Spectrometer. HPLC conditions and MS / MS conditions were as follows.

[HPLC Condition]

Column: Inertsil ODS-II ( ₅ C ₁₈ , 2.1 mm ID × 50 mm L)

Guard column: Inertsil ODS-II ( ₃ C ₁₈ , 1.5 mm ID × 10 mm L)

Mobile phase: 0.1% TFA-50% acetonitrile

Flow rate: 0.2 ml / min

Injection volume: 0.01 ml

[MS / MS Condition]

Ionization mode: positive electrospray ionization mode (+ ESI)

Mass spec. mode: Multiple reaction monitoring (MRM mode)

Mass spec. temp. : ion source 120 ℃ / desolvation 350 ℃

Corn voltage: 29 V

Collision energy: 19 eV

Ions transition: M / Z 325.8 → 173.0

From the measured plasma concentrations, the area under the plasma concentration-time curve (AUC) up to 8 hours was determined by the Trapezoidal rule, and the oral absorption rate was calculated from the ratio of AUC at the same dose of intravenous administration. AUC was calculated using the linear trapezoidal rule in the rising plasma-level phase and the logarithmic trapezoidal rule in the declining phase.

When the compound of the present invention free base / distilled water suspension was administered orally, the plasma concentration of the compound of the present invention was very low and showed delayed absorption. In addition, the variation in the plasma concentration profile was so large that Tmax was 113 ± 165 minutes, Cmax was 2.24 ± 1.11 ug / ml, and AUC up to 8 hours was 569 ± 414 ug min / kg. The oral absorption rate divided by intravenous AUC was very low at 4.1%.

Example 2 Preparation and Evaluation of Solid Dispersion

In order to prepare a solid dispersion in a molecular dispersion state, a method of dissolving or melting a drug and a dispersion medium and then solidifying is preferable. However, as described above, the solubility of the compound of the present invention in the organic solvent was too low to prepare a solution, and decomposed with discoloration when heated with a dispersion medium. Therefore, in this example, the effect of improving the water absorption in the particle dispersed state was evaluated. As a polymer which is expected to have a dissolution assisting effect on the compound of the present invention, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and polyethylene-polypropylene glycol To evaluate the oral absorption effect in the aqueous solution such as (Lutrol) and to administer the test formulation in which the compound of the present invention dispersed in the selected aqueous polymer solution as in Example 1 to evaluate the oral absorption rate.

Dispersion medium  Melting aid effect

Lutrol F127, PEG 8K, HPL-LF, HPMC 615 and PVP 30K were used as test materials, the test concentration was 1.0%, and only Lutrol F127 was 1, 3 and 10%. 10 ml of 0.1 N-HCl solution in which each polymer was dissolved at 1% concentration was added to a double tube at 37 ° C., and 10 mg of free base of the compound of the present invention was added thereto, followed by stirring for 1 hour. 0.3 M Na ₃ PO ₄ solution was added to the sample solution, the pH was adjusted to 6.8, and the solution was continuously stirred at 37 ° C., and 1 ml of each sample was taken immediately before pH adjustment and 0.5, 1, 2, and 4 hours after pH adjustment. Was filtered. The filtrate was diluted with methanol and quantified by HPLC. The polymer having the highest dissolution assisting effect was selected as the dispersion medium. The test temperature was 37 ° C. Lutrol F-127, which had the best dissolution aid effect among the tested polymers, was tested in the same manner as the dissolution aid effect at 1, 3 and 10% concentration. The solubility of the compounds of the present invention in the first liquid-second liquid (final pH 6.8) system containing 1% of Lutrol F-127, PEG 8K, HPL-LF, HPMC 615 and PVP 30K are shown in Table 1 below. It was.

Polymer Conc (mg / ml) pH at 37 ℃ Concentration (ug / ml) Before Titrated After 0 hr 0.5 hr 1 hr 2 hr 4 hr Lutrol F127 10 1.01 6.78 6.82 37 165 174 179 184 Lutrol F127 30 0.99 6.77 6.79 44 381 509 394 380 Lutrol F127 100 1.03 6.78 6.77 71 655 1046 965 980 HPMC615 10 1.01 6.78 6.79 15 39 42 46 52 HPC-LF 10 1.01 6.78 6.78 21 46 49 54 63 PEG8000 10 1.01 6.84 6.84 28 68 73 74 80 PVP30K 10 1.01 6.84 6.86 25 73 78 84 89

As shown in Table 1 above, the solubilization effect of Lutrol F127, the polyethylene-polypropylene glycol, was the largest among the tested polymers. And concentration-dependently increased to 980 ug / ml.

Particle dispersion Test formulation  Oral Absorption Rate Evaluation

25, 75 and 250 mg of the compound free base of the present invention was prepared by adding 5 ml of 10% Lutrol F127 aqueous solution, homogenizing for 10 minutes, and removing bubbles (5, 15 and 50 mg / ml). Dosages were 10, 30 and 100 mg / kg, and the oral absorption rate was evaluated in the same manner as in Example 1. Oral absorption rate compared to the same dose of intravenous AUC is shown in Table 2 below.

Dose (mg / kg) Cmax (ug / ml) Tmax (min) AUClast (ug min / ml) IV AUClast (ug min / ml) F (%) 10 Mean 1.76 60 268 792.4 33.9 SD 1.02 0 65 95.9 30 Mean 8.57 64 1473 3451.9 42.7 SD 4.43 43 660 1049.3 100 Mean 34.14 60 5412 14043.7 38.5 SD 23.77 0 3300 1394.0

As shown in Table 2, Tmax was generally constant at 60 ± 0, 64 ± 43, and 60 ± 0 minutes, but Cmax was 1.76 ± 1.02, 8.57 ± 4.43, and 34.14 ± 23.77 ug / ml, increasing at a higher rate than the dose rate. It was. Dose-normalized AUC was 26.8 ± 6.5, 49.1 ± 22.0, and 54.1 ± 33.0 ug min / kg, which was significantly lower at 10 ug / kg dose. Relatively constant at% and 38.5%. This fact indicates that the compositions according to the invention can increase the bioavailability of 2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid and reduce the variation in absorption between and within individuals. Shows.

Example 3 Preparation and Evaluation of Inclusion Complex

Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) is a derivative substituted with a hydroxypropyl group to improve the water solubility of beta-CD. Since HP-beta-CD has a hydrophobic cavity, it forms a clathrate with a hydrophobic material to increase its solubility. In this example, the solubility of the free base compound of the present invention according to the concentration of HP-beta-CD was measured, and the oral absorption rate was evaluated by administering this sample to mice as in Example 1.

HP - beta - CD Melting aid effect

Test concentrations were 1, 3, 10 and 30%, and were evaluated in the same manner as in the solid dispersion of Example 2. The dissolution aid effect by inclusion of HP-beta-CD is shown in Table 3 below.

Polymer Conc (ug / ml)) pH Concentration (ug / ml) Before Titrated After 0 hr 0.5 hr 1 hr 2 hr 4 hr HP-beta-CD 10 1.01 6.76 6.78 69 243 262 279 296 HP-beta-CD 30 0.99 6.80 6.81 134 588 798 619 616 HP-beta-CD 100 1.00 6.82 6.77 383 863 2323 1851 1783 HP-beta-CD 300 1.06 6.78 6.69 1453 5337 5388 5570 5461

As shown in Table 3, the solubility of the compound of the present invention in the first liquid-second liquid (final pH 6.8) system containing HP-beta-CD 1, 3, 10, 30% The concentration increased to 296, 616, 1783, 5461 ug / ml and the solubilizing effect of HP-beta-CD on the compound of the present invention was about 2 times greater than that of Lutrol F127.

Clathrate Test formulation  Oral Absorption Rate Evaluation

25, 75, 250 mg of the compound base of the present invention was prepared by adding 5 ml of 30% HP-beta-CD aqueous solution, homogenizing for 10 minutes, and removing bubbles (5, 15, 50 mg / ml). Dosage was 10, 30, 100 mg / kg, experimental animals, pretreatment, administration method and blood collection time was evaluated in the same manner as in Example 1. When the compound of the present invention / 30% HP-beta-CD suspension was orally administered at a dose of 10, 30, 100 mg / kg, the oral absorption rate compared to the same dose of intravenous AUC is shown in Table 4 below.

Dose (mg / kg) Cmax (ug / ml) Tmax (min) AUClast (ug min / ml) IV AUClast (ug min / ml) F (%) 10 Mean 0.65 90 89 792.4 11.2 SD 0.26 35 20 95.9 30 Mean 1.90 34 336 3451.9 9.7 SD 0.53 19 83 1049.3 100 Mean 2.94 68 483 14043.7 3.4 SD 2.70 38 444 1394.0

As shown in Table 4, Tmax was irregularly expressed between dose groups at 90 ± 35, 34 ± 19, and 68 ± 38 minutes, and Cmax was 0.65 ± 0.26, 1.90 ± 0.53, 2.94 ± 2.70 ug / ml. It was low, similar to the compound / distilled water suspension. Dose-normalized AUC was very low at 8.9 ± 2.0, 11.2 ± 2.8, 4.8 ± 4.4 ug min / kg and was lower at the 100 ug / kg dose than in other dosing trials. The oral absorption rates, divided by intravenous AUC, were the lowest among the 11.2%, 9.7%, and 3.4% tested vehicles.

HP-beta-CD is in In vitro , two-times higher solubility-assisting effect than Lutrol F127, but no contribution to the improvement of oral absorption, is believed to be due to the mechanism of increasing the solubility of the compound of the present invention. That is, Lutrol F127 can increase the solubility of the compound of the present invention and at the same time increase the dissolution rate, whereas HP-beta-CD is the equilibrium between the concentration of glass in the solution and the concentration present in the clathrate after the compound of the present invention is dissolved. Since the solubility of the compound of the present invention is low and the upper part of the duodenum is interpreted to show little dissolution aid action. Therefore, in order for HP-beta-CD to have an absorption improvement effect, it is preferable to prepare and administer the clathrate in advance, but HP-beta-CD is insoluble in high concentrations except water and alcohol, whereas the compound of the present invention is Solubility in the very low and when using a base there is a problem that can not guarantee the stability in the process.

Claims (2)

2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid or a pharmaceutically acceptable salt; And polyethylene-polypropylene glycol. The composition of claim 1, wherein the polyethylene-polypropylene glycol is mixed in an amount of 0.1 to 30 parts by weight based on the weight of 2-hydroxy-5- (4- (trifluoromethyl) phenethylamino) benzoic acid. .