KR101722564B1 - Solid dispersion including poorly water-soluble drugs - Google Patents

Abstract

The present invention provides a solid dispersion comprising a water-insoluble drug, a matrix and a plasticizer exhibiting significantly improved bioavailability while having low inter-individual variability.

Description

Solid dispersion including poorly water-soluble drugs < RTI ID = 0.0 >

The present invention relates to a solid dispersion comprising a water-insoluble drug, a matrix and a plasticizer.

Many attempts have been made to prepare oral formulations of water-insoluble drugs to improve oral bioavailability in the field of medicine (see Non-Patent Documents 1-3). Among them, solid dispersion (SD) in which drug molecules are dispersed in a polymeric carrier has been found to improve water solubility and oral absorption of drugs (see Non-Patent Documents 4 and 5).

SD allows this effect to be manifested by reducing drug particle size, increasing wettability, reducing agglomeration, and changing physical state in water-insoluble drugs. SD formulations can be prepared by several methods, but hot-melt extrusion (HME) has recently emerged as a useful method for making SD (see Non-Patent Documents 6 and 7).

The HME process has the advantage of being able to produce a variety of solid dosage forms (e.g., granules, pellets, or tablets) as a continuous, solvent-free, dust-free (environmentally friendly) (Refer to non-patent document 8). In the HME process, a shear force generated by the extruder screw is applied to overcome the crystal lattice energy of the crystalline drug and to soften the polymer. Mixing and dispersion of drug and polymer takes place inside the extruder, and the molten product is extruded therefrom.

SD is a mixture of eutectics, crystalline dispersions, and solid solutions, depending on the matrix and the state of the drug (crystalline, amorphous, or molecular level dispersion) (see Non-Patent Document 9). The physico-chemical properties of SD are dependent on the HME equipment used (e.g., feed, barrel, and die) and extrusion process parameters (e.g., barrel and die temperature, screw speed, melt pressure, torque, Etc.). Generally, the HME process temperature is set to be 20-30 DEG C lower than the melting point of the drug (see Non-Patent Document 8). The glass transition temperature (T _g ) or melting temperature (T _m ) of the polymer should also be considered.

Valsartan (VST) is a selective angiotensin II type 1 receptor antagonist used in the treatment of hypertension. VST has a relatively low water solubility (<0.1 mg / mL) and low oral bioavailability (<25%) due to its low solubility in acidic solutions (see non-patent document 14). This pH-dependent drug elution pattern of valsartan can lead to inter-individual and intra-individual variability in drug absorption. In order to solve this problem, several oral formulations for VST delivery have been developed (see Non-Patent Documents 14 to 16), and SD formulations containing VST have been reported (see Non-Patent Document 17) No formulations have been reported that exhibit significantly improved bioavailability even at low levels.

1. Cho HJ, Park JW, Yoon IS, Kim DD. 2014. Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake. Int J Nanomedicine 9: 495-504. 2. Kim JE, Yoon IS, Cho HJ, Kim DH, Choi YH, Kim DD. 2014. Emulsion-based colloidal nanosystems for oral delivery of doxorubicin: improved intestinal paracellular absorption and alleviated cardiotoxicity. Int J Pharm 464 (1-2): 117-126. 3. Yin YM, Cui FD, Mu CF, Choi MK, Kim JS, Chung SJ, Shim CK, Kim DD. 2009. Docetaxel microemulsion for enhanced oral bioavailability: preparation and in vitro and in vivo evaluation. J Control Release 140 (2): 86-94. 4. Baek HH, Kim DH, Kwon SY, Rho SJ, Kim DW, Choi HG, Kim YR, Yong CS. 2012. Development of novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose. Arch Pharm Res 35 (4): 683-689. 5. Kim SA, Kim SW, Choi HK, Han HK. 2013. Enhanced systemic exposure of saquinavir via the concomitant use of curcumin-loaded solid dispersion in rats. Int J Pharm 49 (5): 800-804. 6. Alam MA, Ali R, Al-Jenoobi FI, Al-Mohizea AM. 2012. Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates. Expert Opin Drug Deliv 9 (11): 1419-1440. 7. Lakshman JP, Cao Y, Kowalski J, Serajuddin AT. 2008. Application of melt extrusion in the development of a physically and chemically stable high-energy amorphous solid dispersion of a poorly water-soluble drug. Mol Pharm 5 (6): 994-1002. 8. Djuris J, Nikolakakis I, Ibric S, Djuric Z, Kachrimanis K. 2013. Preparation of carbamazepine-Soluplus solid dispersions by hot-melt extrusion, and prediction of drug-polymer miscibility by thermodynamic model fitting. Eur J Pharm Biopharm 84 (1): 228-237. 9. Leuner C, Dressman J. 2000. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 50 (1): 47-60. 10. 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Beg S, Swain S, Singh HP, Patra ChN, Rao ME. 2012. Development, optimization, and characterization of solid self-nanoemulsifying drug delivery systems for valsartan using porous carriers. AAPS PharmSciTech 13 (4): 1416-1427. 16. Li DX, Yan YD, Oh DH, Yang KY, Seo YG, Kim JO, Kim YI, Yong CS, Choi HG. 2010. Development of valsartan-loaded gelatin microcapsules without crystal change using hydroxypropylmethylcellulose as a stabilizer. Drug Deliv 17 (5): 322-329. 17. Yan YD, Sung JH, Kim KK, Kim DW, Kim JO, Lee BJ, Yong CS, Choi HG. 2012. Novel valsartan-loaded solid dispersion with enhanced bioavailability and no crystalline changes. Int J Pharm 422 (1-2): 202-210. 18. Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Battu SK, McGill JW, Martin C. 2007. Pharmaceutical applications of hot melt extrusion: part I. Drug Dev Ind Pharm 33 (9): 909- 926. 19. Aharoni SM. 1998. Increased glass transition temperature in motionally constrained semicrystalline polymers. Polym Adv Technol 9 (3): 169-201. 20. Nakamichi K, Nakano T, Yasuura H, Izumi S, Kawashima Y. 2002. The role of the kneading paddle and the effects of screw revolution and water content on the preparation of solid dispersions using a twin-screw extruder. Int J Pharm 241 (2): 203-211. 21. Hughey JR, Keen JM, Miller, Kolter K, Langley N, McGinity JW. 2013. The use of inorganic salts to improve dissolution characteristics of tablets containing Soluplus? based solid dispersions. Eur J Pharm Sci 48 (4-5): 758-766. 22. Mu L, Feng SS. 2003. A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS. J Control Release 86 (1): 33-48. 23. Bhugra C, Pikal MJ. 2001. Role of thermodynamic, molecular, and kinetic factors in crystallization from the amorphous state. J Pharm Sci 97 (4): 1329-1349. 24. Yu L. 2001. Amorphous pharmaceutical solids: Preparation, characterization and stabilization. Adv Drug Deliv Rev 48 (1): 27-42. 25. Flesch G, Muller P, Lloyd P. 1997. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol 52 (2): 115-120. 26. Pina MF, Zhao M, Pinto JF, Sousa JJ, Craig DQ. 2014. The effect of drug on physical state on the dissolution enhancement of solid dispersions prepared via hot-melt extrusion: a case study using olanzapine. J Pharm Sci 103 (4): 1214-1223. 27. Chen W, Miao YQ, Fan DJ, Yang SS, Lin X, Meng LK, Tang X. 2011. Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats. AAPS PharmSciTech 12 (2): 705-711. 28. Sokol RJ, Heubi JE, Butler-Simon N, McClung HJ, Lilly JR, Silverman A. 1987. Treatment of vitamin E deficiency during chronic childhood cholestasis with oral d-alpha-tocopheryl polyethylene glycol-1000 succinate. Gastroenterology 93 (5): 975-985. 29. Constantinides PP, Han J, Davis SS. 2006. Advances in the use of tocols as drug delivery vehicles. Pharm Res 23 (2): 243-255.

Disclosure of the Invention In order to solve the above-mentioned problems, the present invention provides an SD formulation in which amorphization and dispersion of a drug in a polymer matrix are achieved, and bioavailability is remarkably improved while the inter- .

In order to accomplish the above-mentioned technical object, the present invention provides a solid dispersion comprising a water-insoluble drug, a matrix and a plasticizer.

Also, the present invention provides a method for preparing a pharmaceutical composition, which comprises (a) preparing a mixture by mixing a water-insoluble drug, a matrix and a plasticizer; And (b) supplying the mixture prepared in the step (a) to a hot-melt extruder to prepare a solid dispersion by a heat-melt extrusion method.

The solid dispersion comprising the water-insoluble drug, matrix and plasticizer according to the present invention is characterized in that the water-insoluble drug is amorphous in the polymer matrix and is dispersed at the molecular level, Is a stable formulation which does not cause recrystallization even after storage for a certain period of time and can be usefully used for improving oral bioavailability of a water-insoluble drug.

FIG. 1A is a schematic view showing a process of developing a formulation with a heat-melt extruder, and FIG . 1B is an image showing the shape of the extrudates F1 and F2.
Figure 2 shows the FT-IR spectra of VST, SP, TPGS, F1 and F2.
3 shows XRD patterns of VST, SP, TPGS, F1 and F2.
4 shows DSC results of VST, SP, TPGS, F1 and F2.
Figure 5 shows the DSC results for F1 (6 months post-production) and F2 (6 months post-production).
6 is a graph showing the in vitro dissolution profile of VST at pH 1.2 and pH 6.8 (each point is expressed as mean + standard deviation, n = 3).
Figure 7 is a graph showing in vivo pharmacokinetic study results in rats (oral dose: 4 mg / kg, each point expressed as mean ± standard deviation: n ≥ 3 VST: valsartan powder: F1, F2: solid Dispersion).

The present invention provides a solid dispersion comprising a water-insoluble drug, a matrix and a plasticizer.

In one aspect of the invention, the water-insoluble drug is preferably selected from the group consisting of ketoprofen, ibuprofen, indomethacin, piroxicam, fenoprofen, , Acetaminophen, diclofenac, chloropheniramine, theophylline, phenylpropanolamine, nifedipine, nicardipine, lidocaine, hydrocortisone (see, for example, hydrocortisone, carbamazepine, valsartan, and mixtures thereof, and more preferably valsartan.

In one aspect of the present invention, the matrix is preferably a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), a polyvinylpyrrolidone (polyvinylpyrrolidone) PVP, polyethylene-co-vinylacetate (EVA), polyethylene glycol (PEG), polyethylene oxide (PEO), cellulose ether, acrylate, poly (Meth) acrylates, Eudragit, poly (lactic-co-glycolic acid), PLGA, microcrystalline cellulose, hydroxypropyl cellulose (hydroxypropyl cellulose, Klucel), hydroxypropyl methylcellulose and derivatives thereof, ethyl cellulose (Ethocel) , Cellulose acetate butylate (CAB), cellulose acetate phathalate, polyvinyl alcohol (PVA), chitosan, polycarbophil, polycaprolactone, Selected from the group consisting of corn starch, potato starch, maltodextrin, pectin, xanthan gum, carnauba wax, and mixtures thereof. And polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) is more preferable. The term &quot; polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer &quot;

In one aspect of the invention, the plasticizer is preferably selected from the group consisting of triethyl citrate, tributyl citrate, acetyl triethyl citrate, or acetyl tributyl citrate. citrate esters such as tributyl citrate; Fatty acid esters such as butyl stearate, glycerol monostearate, and stearyl alcohol; Sebacate esters such as dibutyl sebacate; Phthalate esters such as diethyl phthalate, dibutyl phthalate and dioctyl phosphate; Glycol derivatives such as polyethylene glycol and propylene glycol; Triacetin; Castor oil; Mineral oil; d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS); And mixtures thereof. More preferably, the d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) is one selected from the group consisting of d-alpha-tocopherol polyethylene glycol 1000 succinate.

In one aspect of the present invention, the water-insoluble drug is preferably contained in an amount of 1 to 90% by weight, more preferably 10 to 50% by weight.

In one embodiment of the present invention, the matrix is preferably contained in an amount of 10 to 90% by weight, more preferably 40 to 80% by weight.

In one embodiment of the present invention, the plasticizer is preferably contained in an amount of 0.1 to 50% by weight, more preferably 0.1 to 30% by weight.

In one aspect of the present invention, the solid dispersion may be manufactured by HME, but is not limited thereto.

Of the polymers suitable for the HME process used in one embodiment of the present invention, SP and TPGS were selected as an embodiment in the present invention. SP (T _g About 70 캜) is an amphipathic copolymer consisting of polyethylene glycol 6000 (PEG 6000), vinylcaprolactam, and vinyl acetate and has improved permeation of drug solubilizer and biofilm (See Non-Patent Documents 10 and 11). TPGS is a d-alpha vitamin E ester derived from vitamin E, and T _m is about 40 ° C (see Non-Patent Document 12). TPGS can be used as a non-ionic surfactant due to its amphiphilic nature and can improve the solubility and permeability of water-insoluble drugs and stabilize amorphous drugs in SD (non-patent 13). As a result of the solid state study of the present invention, it was confirmed that the T _g and T _m values of SP and TPGS are suitable for the HME process used in one embodiment of the present invention.

Also, the present invention provides a method for preparing a pharmaceutical composition, comprising: (a) preparing a mixture by mixing a water-insoluble drug, a matrix and a plasticizer; And (b) supplying the mixture prepared in the step (a) to a hot-melt extruder to prepare a solid dispersion by a heat-melt extrusion method.

In one embodiment of the present invention, the temperature of the heat-melt extruder of step (b) may be preferably in the range of 60 to 120 캜, more preferably in the range of 80 to 100 캜.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are illustrative of the present invention, and the present invention is not limited thereto.

< Example >

(1) Raw materials and materials

Valsartan (VST) was purchased from Tecoland Corp. (Irvine, Calif., USA). SP and TPGS were purchased from BASF SE (Ludwigshafen, Germany), and phosphoric acid and hydrochloric acid were purchased from Sigma-Aldrich Co. (St. Louis, Mo., USA). All other samples used analytical grade.

(2) VST -include SD Manufacturing

In order to improve the solubilization and absorption of VST (active pharmaceutical ingredient, API), SP and TPGS were respectively used as main matrix and plasticizer (see Non-Patent Documents 10 and 12), and solid dispersions were prepared as follows. VST and polymer (total amount of about 250 g) were constituted in the proportions listed in Table 1 below and mixed for 3 minutes before extrusion.

ingredient F1 F2 SP 70% 60% TPGS - 10% VST 30% 30%

This mixture was fed into a twin-screw thermo-melt extruder (STS-25HS, Hankook E.M. Ltd., Pyoung-Taek, Korea) equipped with a circular die (diameter 1 mm) The temperature of the heating portion was maintained as shown in Table 2 below.

Formulation Heating section temperature One 2 3 4 5 6 adapter die F1 80 80 90 90 100 100 100 100 F2 80 80 90 90 100 100 100 100

The extrusion speed was 28 - 30 g / min and the extrusion pressure was about 100 bar. The screw speed was set at 150 rpm. The obtained extrudate was cooled to room temperature and pulverized. After grinding, powder was prepared using a sieve of 0.21-mm sagittal width (70 mesh) to prepare Form F1 and Form F2.

(3) VST -include SD Characterization of

Solid-state studies were conducted to investigate whether the drug molecules were dispersed at the molecular level into the polymer matrix and between the crystalline / amorphous state.

(a) Fourier transform infrared spectral measurement

The Fourier transform infrared spectrum (FT-IR) of VST, SP, TPGS, F1, and F2 was measured using a KBr method using a measuring instrument (Jasco FT / IR-4200 type A, Jasco Co., Tokyo, Japan) ) Were measured. All samples were scanned in the range of 600 - 4,000 cm ^-1 .

The FT-IR spectra of the measured VST, SP, TPGS, F1, and F2 are shown in FIG. VST showed two carbonyl absorption bands at 1730 cm ^-1 (C = O group) and 1603 cm ^-1 (C = N band) (see Non-Patent Document 14). The spectrum of SP showed a peak at 2924 cm ^-1 (aliphatic CH stretching) with 1730 and 1629 cm ^-1 (C = O stretching) (see non-patent document 8). The TPGS spectrum showed peaks at 2885 cm ^-1 (aliphatic CH stretching) and 1737 cm ^-1 (C = O stretching). The spectra of the F1 and F2 formulations showed that typical peaks of VST were modified to have strong intermolecular interactions between drug and polymer (SP and TPGS).

(b) X-ray diffraction  Analytical measurement

X-ray diffraction (XRD) was performed at room temperature with a D5005 model diffractometer (D5005 model diffractometer, Brucker, Germany). Monochromatic CuK-radiation at 40 mA and 40 kV at a scan rate of 1 [deg.] / Min with angular increment of 0.02 [deg.] / S in the 2 _[ theta] _? -radiation,? = 1.5406?).

The XRD patterns of the measured VST, SP, TPGS, F1, and F2 are shown in FIG. The crystallinity was confirmed in the profile of VST (see Non-Patent Document 17). The SP before being used for the preparation of the solid dispersion showed an amorphous phase (halo) with no crystallinity as reported (see Non-Patent Document 21). On the other hand, it was found from the XRD pattern of TPGS that TPGS is a crystalline material (see Non-Patent Document 12). There was no crystalline peak in the profiles of F1 and F2, indicating the amorphous form of the drug in the polymer matrix.

(c) Differential scanning calorimetry

The thermal behavior of VST, SP, TPGS, F1, and F2 was evaluated by differential scanning calorimetry (DSC). The DSC pyrolysis curve was measured using a DSC-Q100 instrument (TA Instruments, UK). DSC analysis of SD formulations (F1 and F2) after 6 months storage at room temperature was also performed. The pyrolysis curve was scanned in the range of 30 to 190 ° C at a rate of 10 ° C / min temperature under nitrogen gas feed (50 mL / min).

The T _m of VST was measured at 104.6 캜 (Fig. 4), and this value was similar to the value reported in the literature (see Non-Patent Document 17). Taking into account the T _m and T _g values of the drug and the polymer, the temperature of the melt extrusion process was set at 80-100 ° C as shown in Table 2. In general, the temperature of parts of the heating is semi- it is possible to increase 60 ℃ (see Non-Patent Document 18), the set temperature (80 - - 100 ℃) crystallinity of the polymer T _m or amorphous polymer 15 than the T _g is successful in the polymer Lt; RTI ID = 0.0 &gt; extrusion &lt; / RTI &gt; Also, the drug-polymer mixing and co-dispersing process can be achieved due to thixotropic behavior in which the viscosity of the polymer decreases with increasing shear force.

The addition of a plasticizer such as a TPGS formulation F2 contained in the effect of reducing the T _g and melt viscosity of the polymer in the extrusion process process (see Non-Patent Document 19). The use of high shear twin screws and 1-mm diameter dies also contributed to creating a uniform extrudate. It should be noted that the twin-screw extruder can change the crystallinity of the drug and the dissolution characteristics of the drug from the solid dispersion formulation (see Non-Patent Document 20). Furthermore, a more efficient melting process can be performed according to the high shear rate determined by the screw arrangement, and a low viscosity extrudate can be obtained.

As mentioned above, in the DSC curve of VST, a pronounced endothermic peak was measured at 104.6 ° C, which indicates the crystallinity and melting point of the drug (see Non-Patent Document 17). The DSC pyrolysis curve of SP showed a gentle peak near 70 ° C, which indicates the transition of the amorphous polymer from the glassy state to the gummy state accompanied by the enthalpy relaxation phenomenon (see Non-Patent Document 8). The pyrolysis curve of TPGS contains an endothermic peak at 39.7 ° C, which is indicative of the crystallinity and T _m of TPGS, which is consistent with reported values (see non-patent reference 22). The disappearance of the pronounced endothermic peak of VST on the pyrolysis curve of F1 and F2 indicates that the drug has changed from crystalline to amorphous during the HME process.

As a result of this solid-state study, it was confirmed that the drug was amorphous and dispersed in the polymer matrix.

(d) VST Whether or not it is recrystallized

The material tends to be transformed into a crystalline state with a low energy free energy at high energy level over time (see non-patent documents 23 and 24). Several factors, including atmospheric moisture and residual crystalline drugs (acting as seed crystals), can accelerate the transformation of amorphous to crystalline states during storage of the material (see Non-Patent Document 7). One of the common methods for inhibiting the recrystallization of such drugs is to prepare solid dispersions.

The DSC pyrolysis curve was measured after 6 months at room temperature to confirm whether the F1 and F2 formulations prepared in this Example were to be recrystallized during storage, which is shown in FIG. The endothermic peak of VST was not observed in the pyrolysis curve of FIG. 5, indicating that recrystallization of the drug did not occur after storage of the F1 and F2 formulations for six months.

Based on the fact that recrystallization did not occur after the F1 and F2 formulations were stored for 6 months, the SD prepared in this invention may be a solid glassy solution. The molecular level distribution of the drug can be fixed through the interaction of the drug with the SP (e.g., hydrogen bonding). It is presumed that the HME process reported in this study contributed to maintaining the dynamical stability of the amorphous drug.

As described above, solid-state studies were conducted to confirm that the drug molecules were dispersed at the molecular level in the polymer matrix. In the prepared examples, the drug was transformed from crystalline to amorphous state and recrystallization occurred after storage for a certain period of time Respectively.

< Experimental Example >

(One) In vitro ( in vitro )  Drug elution

In vitro drug elution was measured using a dissolution tester (TDT-08L; Electrolab, Maharashtra, India). Each VST powder corresponding to 20 mg of VST and example formulations (F1 and F2) were filled in gelatin capsules and the resulting capsules were dissolved in 900 mL of eluate (fit to pH 1.2 with hydrochloric acid, pH 6.8 with phosphoric acid) And the paddle speed was 100 rpm at 37 캜. An aliquot (7 mL) of the eluate was taken at a fixed time (15, 30, 45, 60, 90, and 120 minutes) and a new eluate of the same volume was replenished at each sampling time. (Waters 1525), an automatic injector (Waters 717 plus), and UV / Vis &lt; (R) &gt; The eluted VST was quantitatively analyzed using a high performance liquid chromatography (HPLC) instrument (Waters Co., Milford, MA, USA) equipped with a detector (Waters 2487). The mobile phase was prepared with acetonitrile and DDW (60:40, v / v) and adjusted to pH 3.0 with phosphoric acid. The detection wavelength and the flow rate were 247 nm and 1.0 mL / min, respectively. The injection volume was 20 μl, and the analytical and analytical daily deviations of the HPLC analysis used were within acceptable limits.

The results of in vitro drug elution tests performed at pH 1.2 (artificial gastric juice) and pH 6.8 (artificial intestinal fluid) as described above are shown in FIG. Comparing the drug elution profile from SD (F1 and F2) to the elution of VST powder, the VST elution from the F1 and F2 formulations was significantly higher than the elution from the drug powders at both pH conditions.

Improved drug elution in SD formulations of the Examples of the invention appears to be related to the low solubility of VST in water. VST shows a low water solubility at low pH due to the weak acidity of the drug itself (see Non-Patent Document 25). Due to the pH-dependent solubility of VST, the amount of drug eluted at pH 6.8 was higher than the elution at pH 1.2 (FIG. 6). In the pH 1.2 environment, the elution of drug from F1 and F2 for 120 min was 68.0% and 69.6% higher than the elution from VST powder, respectively. In the pH 6.8 environment, drug elution from F1 and F2 reached almost 100% in 15 minutes. Thus, at pH 6.8, rapid and complete drug elution was observed from the SD formulations of the Examples as compared to the VST powder.

Considering that the major sites of drug absorption are generally small intestine, it can be said that the drug elution from the formulation of Example is increased at pH 6.8 rather than pH 1.2, which is advantageous for drug absorption. TPGS contained only in F2 did not significantly affect the drug release pattern at pH 1.2 or pH 6.8.

Improvements in drug elution from Example SD can be explained by several factors. Drug amorphosylation may be associated with increased elution of the water-insoluble drug in the HME-processed product. In addition, SP appears to contribute to drug elution from SD in the aqueous phase. Without the problem of permeability of the drug in the gastrointestinal tract, promotion of drug elution can lead to increased drug uptake in the gastrointestinal tract.

(2) In vivo ( in vivo ) Pharmacokinetics  Research

In vivo pharmacokinetic studies were performed in male SD rats (Sprague-Dawley rats, weight 250 ± 5 g, Orient Bio, Sungnam, Korea). A polyethylene tube (PE-50, Becton Dickinson Diagnostics, MD, USA) was inserted into the left femoral artery under anesthesia for blood sampling. VST powder or SD formulations were orally administered at 4 mg / kg in gelatin microcapsules (Torpac Inc., Fairfield, NJ, USA). 200 μl of blood samples were collected from the femoral artery at 5, 15, 30, 45, 60, 90, 120, 240, 480 and 1440 minutes after the administration of VST. Blood samples were centrifuged at 16,000 rpm for 3 minutes at 4 ° C, and a certain amount (70 μl) of plasma samples were stored at -70 ° C until quantitative analysis.

The concentration of VST in rat plasma was measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS). 5 μl of LST (internal standard) solution (15 μg / mL) and 145 μl of acetonitrile were added to 50 μl of the plasma sample, followed by vortex-mixing for 5 minutes. The supernatant (2 μl) was then transferred to an HPLC system (Agilent Technologies 1260 Infinity HPLC system, Agilent Technologies, Wilmington, DE, USA) and an LC / MS system (Agilent Technologies 6430 Triple Quad LC / MS system). Chromatographic separation was carried out using a column (Synergi ^™ 4 μ Hydro-RP 80 Å column, 75 × 2.0 mm, Phenomenex, CA, USA). The mobile phase was prepared with acetonitrile and 5 mM ammonium formate buffer (85:15, v / v) and the flow rate was 0.4 mL / min. The ESI source was manually optimized. The gas temperature, gas flow rate, nebulizer pressure and capillary voltage were 300 ° C, 11 L / min, 15 psi and 4000 V, respectively. The fragmentation transition was m / z 436.2 - 291.2 for VST and m / z 423.4 - 207.3 for LST. The fragmentor voltage and impinging energy were 98 V and 14 eV for VST and 115 V and 20 eV for LST, respectively. The retention times of VST and LST were 0.46 min and 0.47 min, respectively. Data collection and processing was performed with quantitative analysis software (MassHunter Workstation Software Quantitative Analysis, Version B.05.00; Agilent Technologies, Wilmington, DE, USA).

The VST concentration in the plasma from the starting point to the infinite-time curve was calculated from the total area under the VST concentration in the platinum-time curve from time to zero to infinity (AUC) , t _1/2), the time-average of the total clearance (time-averaged total body clearance, CL), the apparent volume of distribution at steady state (apparent volume of distribution at a steady state, V ss), and the average residence time (mean residence time, MRT) were calculated using the Winnonlin program (WinNonlin, Version 3.1, Pharsight, Mountain View, CA, USA).

The oral absorption results of the VST powder, F1, and F2 thus tested in rats are shown in Table 3 and FIG.

parameter VST powder F1 F2 AUC (占 퐂 / min / mL) 168.10 ± 28.88 ^* 482.99 + - 184.77 ^* 922.89 + 163.06 ^* C _max ([mu] g / mL) 0.72 + 0.28 0.84 + 0.07 4.72 ± 1.72 ^{#, +} T _max (min) 60 (45-60) 30 (15-60) 45 (30-45) Relative bioavailability (%) 100 287 549

Data are expressed as mean ± standard deviation (n ≥ 3).

*: p <0.05, statistically different from other groups.

#: p <0.05, compared with VST group.

+: p < 0.05, compared with F1 group.

As shown in Table 3, the AUC values were VST < F1 < F2 in the order from low value to high value. ( P <0.05). The AUC values of the F1 and F2 groups were 2.87 times and 5.49 times higher than those of the VST powder group, respectively ( p <0.05). The C _max values of the F2 group were 6.56 and 5.62 times higher than those of the VST powder group and the F1 group, respectively ( p <0.05). There was no significant difference in T _max values between groups.

The measured AUC value in this experiment shows that SP can increase drug absorption. Due to the solubilizing ability of SP, SP enhanced the absorption of orally administered drug (see non-patent reference 11).

As described above, the increase in the oral bioavailability of the drug is based on the in vivo interaction of drug, SP, and intestinal fluid (including bile and phospholipid, which may serve as a raw material of micelle) (See Non-Patent Document 11).

TPGS in the F2 formulation was found to significantly improve relative oral bioavailability over SP. TPGS did not change the drug release pattern (Figure 6), but resulted in an unexpectedly significant increase in oral drug absorption. As a plasticizer, TPGS can reduce the process temperature and melt viscosity during the HME process.

The absorption fraction of the VST dose in humans is from 23% (capsule) to 39% (solution), and significant individual differences in AUC and C _max values have been reported (see non-patent reference 25). The development of SD formulations through the HME process can be an effective way to achieve high VST oral bioavailability while exhibiting low variability among individuals compared to drug powders.

(3) Statistical analysis

All experiments were performed at least 3 times and data were expressed as mean ± SD. Statistical analysis was performed by analysis of variance (ANOVA).

(4) Conclusion

VST-containing oral SDs based on SP and TPGS were prepared using the HME process. The SD was prepared using a twin-screw HME process to induce a high shear rate. The amorphization of the VST into the polymer matrix and the dispersion at the molecular level of the SD thus prepared were confirmed. The amorphisation and associated thermodynamic properties of the drugs in the formulations produced were investigated by FT-IR, XRD, and DSC. Drug elution from the prepared formulation was improved compared to drug powder and an increase in drug elution at pH 6.8 (artificial intestinal fluid) was observed compared to pH 1.2 (artificial gastric juice). Oral bioavailability of VST in the rats of the developed formulation was significantly improved as compared to the administration of the drug powder. The SD using the HME process based on SP and TPGS of the present invention can be effectively used to improve the oral bioavailability of a poorly soluble drug.

Claims (9)

But are not limited to, ketoprofen, ibuprofen, indomethacin, piroxicam, fenoprofen, acetaminophen, diclofenac, chloropheniramine, Theophylline, phenylpropanolamine, nifedipine, nicardipine, lidocaine, hydrocortisone, carbamazepine, valsartan, and the derivatives thereof. A solid dispersion comprising a water-insoluble drug selected from the group consisting of water-insoluble drugs, polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer and d-alpha-tocopherol polyethylene glycol 1000 succinic acid. delete delete delete delete The method of claim 1, wherein the water-insoluble drug is 10-50 wt%, the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 40-80 wt%, the d-alpha-tocopherol polyethylene glycol 1000 And the content of succinic acid is in the range of 0.1 to 30% by weight. The solid dispersion according to claim 1, wherein the solid dispersion is prepared by hot-melting extrusion (HME). (a) a compound selected from the group consisting of ketoprofen, ibuprofen, indomethacin, piroxicam, fenoprofen, acetaminophen, diclofenac, such as chloropheniramine, theophylline, phenylpropanolamine, nifedipine, nicardipine, lidocaine, hydrocortisone, carbamazepine, valsartan, Preparing a mixture by mixing a water-insoluble drug, a polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer and d-alpha-tocopherol polyethylene glycol 1000 succinic acid selected from the group consisting of polyvinylpyrrolidone and a mixture thereof; And
(b) supplying the mixture prepared in the step (a) to a heat-melt extruder to prepare a solid dispersion by heat-melt extrusion;
&Lt; / RTI &gt; The method according to claim 8, wherein the temperature of the heat-melt extruder in step (b) is in the range of 60 to 120 ° C.

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