KR101912224B1 - Tadalafil-containing solid dispersion, pharmaceutical composition comprising the solid dispersion, and preparation method of the solid dispersion - Google Patents

Abstract

The present invention relates to a solid dispersion comprising tadalafil, a solubilizing agent, a meglumine, and a porous carrier, and a pharmaceutical composition containing the solid dispersion, wherein the solubility and dissolution rate of tadalafil are increased to remarkably improve bioavailability .

Description

Toadarafil-containing solid dispersion, a pharmaceutical composition comprising the same, and a preparation method thereof <br> <br> <br> Patents - stay tuned to the technology Tadalafil-containing solid dispersion,

The present invention relates to a solid dispersion containing tadalafil, and a process for producing the same. The present invention also relates to a pharmaceutical composition containing the solid dispersion.

Tadalafil (TDF, Cialis ^® ) is a drug approved by the FDA in 2003 for the treatment of erectile dysfunction (ED) and benign prostatic hyperplasia (BPH). The IUPAC name is (6R, 12aR) -6- (1, 3-benzodioxol-5-yl) 2-methyl-2,3,6,7,12,12a- hexahydropyrazino [ ': 1,6] pyrido [3,4-b] indole-1,4-dione ((6R, 12aR) -6- (1,3-benzodioxol- , 6,7,12,12a-hexahydropyrazino [1 ', 2': 1,6] pyrido [3,4-b] indole-1,4-dione.

Tadalafil has low water solubility and high permeability and corresponds to BCS Class II (Wlodarski et al., 2014). The high permeability of the drug often results in low bioavailability due to the intrinsic properties that inhibit absorption.

Therefore, in order to improve the solubility and bioavailability of tadalafil, it is possible to use solid dispersions, nano-suspensions, self-nanoemulsifying drug delivery systems (SNEDDS) and nanostructured lipid carriers have been developed.

Of these methods, solid dispersion technology is the easiest approach to industrial constraints to date. (Wlodarski et al., 2015a), which is a related art technique, was prepared by freeze-drying a distilled water with a solubilizing agent (HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus). The solubility of the tadalafil / PVP-VA solid dispersion increased 16-fold over 10 minutes compared to pure tadalafil. However, the solubility was reduced from 50 ug / mL to 10 ug / mL over 24 hours. The dissolution rate of the tadalafil / PVP-VA solid dispersion was confirmed to be 2.4 ug / mL. (Park et al., 2014), and the dissolution rate of the tadalafil / PVP solid dispersion was about 80% (4.4 ug / mL) for 1 hour in distilled water Respectively. Solubilized solid dispersion formulations (Krupa et al., 2016) were prepared using ball milling and supercritical carbon dioxide impregnation (ScCO ₂ ), and the dissolution rate of this formulation was 0.1% (by weight) of sodium lauryl sulfate w / v) to 90% (9 ug / mL) than that of pure tadalafil. These techniques require expensive equipment such as freeze dryer, supercritical carbon dioxide impregnation, and ball milling and have a disadvantage in that the dissolution rate increases in the presence of a surfactant such as SLS.

As a prior art patent, Korean Patent Laid-Open Publication No. 2016-0017798 discloses a technique of preparing coadjuvant with tadalafil by selecting caffeine, urea, saccharin, or malonic acid as a coformer in order to improve the water solubility and dissolution profile of tadalafil . However, the highest solubility of tadalafil-caffeine in the comparative dissolution test conducted with final concentration of tadalafil of 100 ug / ml (50 mg / 500 mL) was 3.5 ug / mL in 60 min and the solubility of raw tadalafil was 0.6 ug / mL , Which is 5.8 times higher than that of Tadalafil, which is 3.5% lower than the initial amount of tadalafil. In addition, the prior art still has a problem that the solubility and the dissolution rate of tadalafil are unsatisfactory, and it is necessary to further improve the solubility and dissolution rate of tadalafil.

As a result of intensive studies, the inventors of the present invention have found that the solid dispersion of tadalafil containing a specific additive is remarkably improved in solubility and dissolution rate compared with the solid dispersions heretofore known, thereby completing the present invention.

Korean Patent Laid-Open Publication No. 2016-0017798 (Tadalafil crystal and its preparation method, published on Feb. 26, 2016)

L., Wojnarowska, Z., Grzybowska, K., Talik, E., Paluch, M., L., Grembecka, M., Tajber, L., Wlodarski, K., Sawicki, W., Paluch, K., 2014. The influence of amorphization methods on the apparent solubility and dissolution rate of tadalafil. European Journal of Pharmaceutical Sciences 62, 132-140. Wlodarski, K., Sawicki, W., Haber, K., Knapik, J., Wojnarowska, Z., Paluch, M., Lepek, P., Hawelek, L., Tajber, L., 2015a. Physicochemical properties of tadalafil solid dispersions - Impact of polymer on the apparent solubility and dissolution rate of tadalafil. European Journal of Pharmaceutics and Biopharmaceutics 94, 106-115. Park, J., Cho, W., Kang, H., Lee, B.J., Kim, T.S., Hwang, S.J., 2014. Effect of operating parameters on PVP / tadalafil solid dispersions prepared using supercritical anti-solvent process. The Journal of Supercritical Fluids 90, 126-133. Krupa, A., Descamps, M., Willart, J. F., Jachowicz, R., Dane F., 2016. High energy ball milling and supercritical carbon dioxide impregnation as co-processing methods to improve dissolution of tadalafil. European Journal of Pharmaceutical Sciences.

It is an object of the present invention to provide a solid dispersion having improved solubility and dissolution rate of tadalafil, and a pharmaceutical composition containing the solid dispersion.

Another object of the present invention is to provide a method for producing a solid dispersion having improved solubility and dissolution rate of tadalafil.

The present invention relates to a composition comprising tadalafil; Solubilizing agents; Meglumine; And a porous carrier.

In the solid dispersion of the present invention, it is preferable that tadalafil be present in an amorphous form.

In the solid dispersion, the solubilizing agent is preferably a copolymer of vinylpyrrolidone and vinyl acetate.

In the solid dispersion, the porous carrier is preferably colloidal silicon dioxide.

The solid dispersion of the present invention may comprise at least one of tadalafil; Copolymers of vinylpyrrolidone and vinyl acetate as solubilizing agents; Meglumine; And colloidal silicon dioxide as the porous carrier.

It is also preferable that the above-mentioned tadalafil: copolymer of vinylpyrrolidone and vinyl acetate: meglumine: colloidal silicon dioxide is mixed in a weight ratio of 1: 2 to 6: 2 to 4: 2 to 4, To 5: 2.5 to 3.5: 2.5 to 3.5.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a tadalafil-containing solid dispersion, and a pharmaceutically acceptable carrier.

According to still another aspect of the present invention, there is provided a method for producing a tadalafil-containing solid dispersion comprising: a) dissolving tadalafil and a solubilizing agent in an organic solvent to prepare a tadalafil solution; b) mixing the tadalafil solution with meglumine and adding a porous excipient (porous carrier) to prepare a dispersion; c) drying the dispersion and then pulverizing the dispersion.

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

The solid dispersion of the present invention is characterized by containing tadalafil, solubilizing agent, meglumine, and a porous carrier as active ingredients.

In the solid dispersion of the present invention, when tadafil, which is an active ingredient, is changed from a crystalline form to an amorphous form, the solubility and dissolution rate of tadalafil are increased and the bioavailability is improved.

In the solid dispersion of the present invention, as the solubilizing agent, a water-soluble polymer capable of solubilizing tadalafil is used. Preferably, the use of a copolymer of vinylpyrrolidone and vinyl acetate (PVP / VA) is particularly useful for increasing the wettability to tadalafil and forming an amorphous structure. The copolymer of vinylpyrrolidone and vinyl acetate preferably has a weight average molecular weight of 30,000 to 70,000 and a weight average molecular weight of 40,000 to 60,000. Further, the ratio of vinyl pyrrolidone to vinyl acetate is preferably 7: 3 to 5: 5.

The solid dispersion of the present invention is excellent in preventing amorphous tadalafil in the solid dispersion from being recrystallized again by using meglumine among various acids and bases.

In addition, in the solid dispersion of the present invention, the dispersibility and stability can be improved by using a porous carrier. As the porous carrier, the use of colloidal silicon dioxide is capable of forming hydrogen bonds with other components due to a large specific surface area and a large number of silanol groups, which is useful for improving dispersibility and stability. Further, by using the colloidal silicon dioxide, it is possible to prevent the difficulty in collecting on the bottom surface of the production vessel like a film when the solid dispersion is obtained, and the solid dispersion yield (10? 3.5%, 36. + -. 3.6%) compared to the control group (87.6. + -. 2.1%). The colloidal silicon dioxide preferably has a specific surface area of 100 to 300 m ² / g.

The solid dispersion of the present invention is preferably prepared by mixing tadalafil: a copolymer of vinylpyrrolidone and vinyl acetate: meglumine: colloidal silicon dioxide in a weight ratio of 1: 2 to 6: 2 to 4: 2 to 4 More preferably in a weight ratio of 1: 3 to 5: 2.5 to 3.5: 2.5 to 3.5. The solid dispersion mixed at the above weight ratio not only remarkably improves solubility and dissolution rate of tadalafil, but also has an effect of improving the stability of the solid dispersion.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a tadalafil-containing solid dispersion, and a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carriers to be contained in the composition of the present invention include well-known excipients, disintegrants, lubricants and the like. Examples of such excipients include lactose, mannitol, sorbitol, microcrystalline cellulose, starch, starch, starch, calcium phosphate, silicon dioxide, cellulose, sodium bicarbonate and mixtures thereof and examples of such disintegrants include croscarmellose sodium, Examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, and the like. Examples of the lubricant include sodium stearyl fumarate, crospovidone, sodium starch glyconate, and low-substituted hydroxypropyl cellulose. The pharmaceutically acceptable carrier may be suitably selected and used by those skilled in the art according to the finally obtained formulation.

The formulation of the pharmaceutical composition may be in various forms, but includes solid preparations such as granules, tablets, capsules, dry syrups, or powders, more preferably granules, tablets, or capsules. These formulations may be prepared according to methods commonly used in the pharmaceutical field. For example, the tablets may be prepared by mixing the solid dispersion with an excipient, a disintegrant, a lubricant or the like, or by adding an excipient or the like to the solid dispersion to prepare granules, mixing with an excipient, a disintegrant, Capsules can be prepared by filling the capsules with the above mixture. In addition, film-coating or enteric-coating may be performed for the purpose of improving stability, convenience of taking, and appearance.

A method for producing a tadalafil solid dispersion of the present invention comprises the steps of: a) dissolving tadalafil and a solubilizing agent in an organic solvent to prepare a tadalafil solution; b) mixing the tadalafil solution with meglumine and adding a porous excipient to prepare a dispersion; And c) drying and pulverizing the dispersion.

In step a), organic solvents such as acetonitrile, ethanol, and dichloromethane may be used, and acetonitrile is preferably used. In step a), a tadalafil solution is prepared while stirring for 10 to 40 minutes.

In step b), meglumine is added to the tadalafil solution obtained from step a), stirred for 10 to 40 minutes, and then the porous excipient is added and stirred again for 10 to 40 minutes to obtain a dispersion.

In the step c), the organic solvent may be removed by drying the dispersion for 12 to 36 hours, preferably 20 to 26 hours.

The preparation method is preferably carried out in a weight ratio of 1: 2 to 6: 2 to 4: 2 to 4: 1: 3 to 5: 2.5 to 3.5: 2.5 to 4: 3.5 by weight. At this time, it is preferable to use a copolymer of vinylpyrrolidone and vinyl acetate as a solubilizing agent, and colloidal silicon dioxide as a porous carrier. The solid dispersion mixed at the above weight ratio not only remarkably improves solubility and dissolution rate of tadalafil, but also has an effect of improving the stability of the solid dispersion.

The solid dispersion of the present invention not only improves the bioavailability by increasing the solubility and dissolution rate of tadalafil but also maintains the amorphous form by minimizing the recrystallization of tadalafil in the solid dispersion even when stored for a long period of time and thus has excellent stability.

Further, the production method of the present invention has an effect of improving solubility and dissolution rate of tadalafil and providing a solid dispersion having excellent stability.

1 is tadalafil-containing solid dispersion (Example 1, Comparative Example 1, 3-6), tadalafil (pure, the pure raw materials), and a graph showing the solubility of Cialis ^®.
Figure 2 is a graph showing the tadalafil-containing solid dispersions (Examples 1-2 and Comparative Examples 1-2), the elution profile of tadalafil, and Cialis ^®.
Fig. 3 is a photograph of the surface morphology of FE-SEM of (a) tadalafil, (b) physical mixture of Comparative Example 7, and (c) solid dispersion of Example 1. The magnification was 1,000x ), And the scale bar is 50 탆 (10 탆) (parenthesized is a small standard photograph).
4 shows thermal images (DSC) for the solid dispersion of Example 1, the physical mixture of Comparative Example 7, tadalafil, PVP / VA S-630, meglumine and Aerosil 200. FIG.
Figure 5 is a graphical representation of the physical X-ray diffraction spectrum of the solid dispersion (Example 1, after 1 month, 2 months after) of Example 1, the physical mixture of Comparative Example 7, the powder X-ray for tadalafil, PVP / VA S-630, meglumine and Aerosil 200 Diffraction pattern.
Figure 6 shows the FT-IR spectrum for the solid dispersion of Example 1, the physical mixture of Comparative Example 7, tadalafil, PVP / VA S-630, meglumine and Aerosil 200.
FIG. 7 shows the results of the stability test. FIG. 7 (a) shows the result of measurement of the drug content over time of the solid dispersion and Cialis ^® powder of Example 1, and FIG. 7 And Cialis ^® after 4 and 5 weeks.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein, but may be embodied in other forms. Rather, the disclosure is thorough and complete, and is provided to enable those skilled in the art to fully understand the spirit of the invention.

Example  1 and 2, and Comparative Example  1 to 6: Tadalafil  Containing solids Dispersion  Produce

The solid dispersions of Examples 1 to 2 and Comparative Examples 1 to 6 were prepared by the solvent evaporation method with the components shown in Table 1 below and their contents. Specifically, tadalafil and solubilizing agent were added to 10 mL of acetonitrile and dissolved in a magnetic stirrer at 500 rpm for 20 minutes. The resulting tadalafil solution was added with meglumine and stirred at 500 rpm for 20 minutes to obtain a dispersion. To this was added a porous excipient and stirred at 500 rpm for 20 minutes. The finally obtained dispersion was dried in a vacuum desiccator for one day. The solid mass produced as a result of drying was passed through a 40-mesh sieve.

Tadalafil  Containing solids Dispersion  Produce division ingredient
(mg) Example Comparative Example One
2
One
2
3
4
5
6
activation
ingredient Tadalafil 50 50 50 50 50 50 50 50 base Meglumine 150 150 - - - - - - Sodium hydrogencarbonate - - - - 150 - - - Potassium hydroxide - - - - - 150 - - Citric acid - - - - - - 150 - Fumaric acid - - - - - - - 150 Available
issue Copolymer of vinylpyrrolidone and vinyl acetate
(PVP / VA S-630 ^* ) 250 150 250 150 250 250 250 250 Porous
carrier Colloidal
Silicon dioxide
(Aerosil 200 ^** ) 150 150 150 150 150 150 150 150 * PVP / VA S-630: weight ratio of vinylpyrrolidone to vinyl acetate 6: 4, weight average molecular weight 51,000
^** Aerosil 200: Specific surface area of 200 ± 25 m ² / g

Comparative Example  7: Tadalafil  Preparation of a physical mixture containing

The physical mixture of Comparative Example 7 was prepared by preparing tadalafil, meglumine, solubilizing agent and porous excipient in the same components and contents as in Example 1, followed by mixing only the powder without solvent.

Experimental Example  1: Over time Tadalafil  Determination of apparent solubility

Samples of Example 1, Comparative Examples 1 and 3 to 5 (prepared as a solid dispersion corresponding to 10 mg of tadalafil at each composition ratio shown in Table 1) were placed in a 2 ml microtube, 1 ml of distilled water was added, vortexing was performed for 5 seconds Respectively. (N = 3) for each sampling time. Each sample was placed in a 37 ° C incubator, stirred at 200 rpm, centrifuged at 1, 2, 4, and 24 hours, and then the supernatant was filtered with a nylon filter. Then, 200 μl of the supernatant was taken into a 1.5 ml microtube, 200 [mu] l of nitrile was added, followed by vortexing for 10 seconds.

The total amount of tadalafil in all samples was analyzed by high performance liquid chromatography (HPLC, SP ^ LC model, Shiseido, Japan) and the column was subjected to Capcell Pak C18 column (150 mm × 4.6 mm ID, 5 μm particle size, Shieido) Respectively. Methanol and water (50:50 v / v) were used as mobile phases and the flow rate was set at 1 mL / min at 35 ± 0.5 ° C. The column effluent was analyzed with a UV spectrophotometer at a wavelength of 225 nm and the injected sample was 50 μl. The analytical method was based on the Tadalafil tablets (US Pharmacopeial Convention) of the US Pharmacopoeia.

The results of comparing the solubilities of tadalafil after 1 hour and 24 hours are as follows.

Tadalafil  Solubility measurement results - Experimental Example  One division ingredient Solubility of tadalafil
(ug / mL) After 1 hour After 24 hours Example Example 1 376.8 ± 9.88 30.75 ± 0.47 Comparative Example Comparative Example 1 166.8 ± 0.50 4.10 ± 0.26 Comparative Example 3 236.7 ± 3.30 6.57 ± 1.97 Comparative Example 4 117.5 ± 69.20 2.89 ± 5.43 Comparative Example 5 39.52 + 0.14 3.49 ± 0.09 Comparative Example 6 209.8 ± 0.34 6.92 + 0.18 Control group Cialis ^® 1.04 0.09 1.29 + - 0.47 Tadalafil 0.94 + - 1.62 0.05 ± 0.13

As shown in the above experimental results, the solubility after 1 hour was 376.8 ± 9.88 ug / mL in Example 1 using meglumine, which is considerably higher than that in the case of Cialis ( ^R) or pure tadalafil ( ^R ) Of course, was much higher than Comparative Example 1 in which no meglumine was used or Comparative Examples 3 to 6 in which other bases or acids were used in place of meglumine. Also, the solubility after 24 hours was 30.75. + -. 0.47 ug / mL for Example 1 and 7.5 times higher than Comparative Example 1, which is much higher than the comparative examples using other bases or acids, It has been confirmed that it is effective for prevention of fire.

Experimental Example  2: Tadalafil  Simulated dissolution test

According to the following method, a simulated dissolution test of tadalafil was performed on the solid dispersion using meglumine. The test was carried out in distilled water using a hot plate magnetic stirrer (MS-33MH, J-Otec, Korea). To estimate the in vitro dissolution rate, the concentration of tadalafil was adjusted to the concentration of the elution medium (0.022 mg / mL). A sample (equivalent to 2 mg of tadalafil) was added to 90 mL of distilled water and stirred under conditions of 500 rpm and 37 ± 0.1 ° C. After one hour, the samples were collected by centrifugation (MICRO-12, Hanil centrifuge, Hanil Science Ind. Co., Korea). The tadalafil content of all the samples was measured by the HPLC measurement method as described in Experimental Example 1. Solubility measurement results are shown as mean ± standard deviation of the three results and are shown in Table 3 and Figure 1 below.

Tadalafil  Simulated dissolution test results - Experimental Example  2 division ingredient Solubility of tadalafil
(ug / mL) Example Example 1 17.0 ± 1.09 (76.7 ± 4.92%) Example 2 17.6 ± 0.47 (79.4 ± 1.65%) Comparative Example Comparative Example 1 19.0 ± 1.57 (85.3 ± 7.05%) Comparative Example 2 14.6 ± 0.63 (65.9 ± 4.58%) Comparative Example 7 4.0 ± 1.0 (18.0 ± 4.6%) Control group Tadalafil (pure) 0.73 ± 0.08

As shown in Table 3 above, the solid dispersions of Examples 1 and 2 were found to have a much higher solubility of tadalafil than the physical mixture of Comparative Example 7 or pure tadalafil. The solubility of tadalafil in the solid dispersions of Comparative Examples 1 and 2 also increased, but there was a problem in that the recrystallization rate was high over time as confirmed in Experimental Example 1.

Experimental Example  3: Tadalafil  Dissolution test

The in vitro dissolution test from the prepared solid dispersion was carried out using a dissolution tester (DST-610, Labfine, Korea). The solid dispersions of Examples 1 and 2 and Comparative Examples 1 and 2 are weighed to the weight corresponding to 20 mg of tadalafil. Three solutions (900 mL) including artificial gastric juice (pH 1.2), intestinal juice (pH 6.8), and distilled water were used as the eluate and according to the USP Apprartus II Paddle Method according to the US Pharmacopoeia The elution test was carried out at a stirring speed of 37 ± 0.5 ° C and 100 rpm. At time intervals of 5, 15, 30, 45, and 60 minutes, samples (1 ml each) were taken and then the insoluble tadalafil was isolated by centrifugation. The supernatant was collected and the concentration of tadalafil was measured by the same HPLC method as in Experimental Example 1.

As shown in FIG. 2 (a), as a result of dissolution test in distilled water, the dissolution rate at the elapse of 60 minutes was 83.9 ± 0.68% in the solid dispersion of Example 2, while the solid dispersion of Comparative Example 2 was 63.4 ± 0.48 %. 1 (b), the dissolution rate at the elapse of 60 minutes was 89.1 ± 3.93% in the solid dispersion of Example 1, while the solid dispersion of Comparative Example 1 was 83.6 ± 2.16%. The dissolution rates of tadalafil and Cialis ( ^R) powders used as control groups were respectively 6.2 ± 2.5% and 16.0 ± 1.9%, respectively, and it was confirmed that the solid dispersions of Examples 1 and 2 showed excellent dissolution rates.

As a result of the dissolution test on distilled water, artificial gastric juice (pH 1.2) and artificial intestinal fluid (pH 6.8) for the solid dispersion of Example 1 showing a high dissolution rate, as shown in Fig. 1 (c) Min, respectively, 89.0 ± 3.9%, 84.4 ± 2.2% and 96.5 ± 0.3% release, respectively.

Unlike the case where the dissolution rate was conventionally increased by using a surfactant such as sodium laurylsulfate (SLS), it was confirmed that the solid dispersion of the present invention significantly increased the dissolution rate without using SLS.

Experimental Example  4: Solid Dispersion  Surface morphology confirmation test

Tadalafil, the solid dispersion of Example 1, and the physical mixture formulation of Comparative Example 7 were measured using an FE-SEM (LYRA3 XMU, TESCAN, Czech Republic) at an accelerating voltage of 5 kV. Each powder sample of tadadafil, solid dispersion, and physical mixture was placed on a carbon tape in advance and then coated with platinum in vacuum for 70 seconds.

As a result of the experiment, the surface morphology of each substance and preparation by FE-SEM is shown in Fig. Tadalafil exhibited a needle-like crystal structure having a particle size of about 10 to 50 mu m (Fig. 3 (a)). The physical mixture of Comparative Example 7 was found to exist in a clearly separated form of tadalafil and the additive (Fig. 3 (b)). However, the solid dispersion of Example 1 was a composite of tadalafil and additive as a lump (Fig. 3 (c)). According to Fig. 3 (c), it is confirmed that the solid dispersion has been successfully produced because its form has clearly changed.

Experimental Example  5: Differential scanning calorimetry, DSC )

DSC measurements were performed to evaluate the thermal change between the tadalafil and the tadalafil-containing solid dispersion. A solid dispersion of Example 1, a physical mixture of Comparative Example 7, tadalafil, PVP / VA S-630, meglumine, and Aerosil 200 were prepared as samples. The sample (2 to 3 mg) was placed on an aluminum pan and heated to 10 to 350 ° C at a scanning rate of 10 ° C / min under nitrogen injection of 40 mL / min.

As a result of DSC measurement, tadalafil has a melting point at 301.8 캜, but the physical mixture of Comparative Example 7 and the solid dispersion of Example 1 do not show this peak in Fig. The physical mixture and the solid dispersion showed a single endothermic peak at 128.5 캜 and 128.0 캜, which corresponds to the intrinsic melting point (128.6 캜) of meglumine. The reason for the absence of the melting point of tadalafil in the physical mixture may be due to the low proportion of tadalafil.

Experimental Example  6: Powder X-ray diffraction ( PXRD ) analysis

The PXRD patterns of the solid dispersion of Example 1, the physical mixture of Comparative Example 7, tadalafil, meglumine, PVP / VA S-630 and Aerosil 200 were analyzed using a high resolution X-ray diffractometer (D8 DISCOVER, Bruker AXS, Germany) . The samples were collected at an angle (diffraction angle 2θ) of between 5 ° and 70 ° with a step size of 0.02 ° at 40 kV.

PXRD analysis was performed to identify the drug itself or the state of the polymer mixture (amorphous or crystalline). The solid dispersion of Example 1, the physical mixture of Comparative Example 7, and the PXRD pattern of tadalafil are shown in Fig.

The PXRD peak of tadalafil appeared at 7.2, 9.1, 10.5, 12.5, 13.5, 15.5, 16.9, 18.4, 21.6, and 24.2 2? (Degrees). Also, the PXRD peaks of meglumine were 9.0, 9.7, 12.5, 16.0, 17.3, 17.4 and 19.5 2? (Degrees). It has been found that tadalafil has a peak at 2 &amp;thetas; similar to the meglumine peak. On the other hand, the physical mixture has peaks of both tadalafil and meglumine (in Fig. 5, the red arrow indicates the meglumine peak and the blue arrow indicates the tadafil peak), while the solid dispersion has a peak corresponding to meglumine But no peak corresponding to tadalafil was shown. These results show that in the solid dispersion, tadalafil changed from crystalline to amorphous, but tadalafil exhibited its crystalline nature in the physical mixture. In addition, it was confirmed that the tadalafil in the solid dispersion of Example 1 was kept in the amorphous state for 2 months or more and had excellent stability.

Experimental Example  7: Fourier-transform infrared spectroscopy (FT-IR)

FT-IR was measured using an ATR-FT-IR spectrophotometer (Alpha-P, Bruker Optik, Ettlingen, Germany) to identify potential interactions between tadalafil and the additive in the solid dispersion of Example 1. In the wavelength range of 500 ~ 4000cm ^-1 it was measured with a resolution of 2cm ^-1. The FT-IR analysis results are shown in Fig.

Tadalafil is a secondary amine group of the NH stretching vibration (stretching vibration), in the CH stretching vibration, 1,678 cm ^-1 of the aliphatic group on -CH ₃ 2,906cm ^-1 C = O stretching, and at 1,649 3,327cm ^-1 as the major peak cm &lt; ^{-1 &} gt ;, indicating the C = C stretching vibration of the aromatic rings. PVP / VA S-630 showed a C = O stretching vibration in the CH stretching vibration, and 1,739 / 1,674cm ^-1 of aliphatic CH ₃ OH groups in the new, 2,962cm ^-1 in 3,492cm ^-1.

Both the physical mixture of Comparative Example 7 and the solid dispersion of Example 1 exhibited different peaks at 1,749 cm ^-1 , which is related to C = O stretching at PVP / VA S-630 compared to tadalafil (pure). In particular, the peak at 1,678 / 1,649 cm- ¹ of the tadalafil and the physical mixture was clearly shifted to the peak at 1,672 cm- ¹ in the solid dispersion. These results indicate that tadalafil and PVP / VA S-630 form strong hydrogen bonds, changing the formulation from crystalline to amorphous.

Experimental Example  8: Stability test

The stability of the solid dispersion of Example 1 and Cialis ( ^R) powder was evaluated by confirming the drug content over time. The sample powder was placed in a capillary vial and stored in an enclosed state. The stability was evaluated under accelerated conditions (40 ° C, 75% RH) for 4 weeks in a thermostat (Environmental Chamber 6020-2; Caron, Marietta, Ohio). At each predetermined time point (1, 2, 3, 4 weeks), the drug content and the ex vivo dissolution rate were evaluated (n = 3). The content of tadalafil was measured by HPLC in the same manner as described in Experimental Example 1.

As a result of the stability test of the solid dispersion of Example 1 and Cialis ( ^R) powder, both showed excellent stability. The drug content was early (99.9 ± 4.5% and 101.2 ± 4.1%) and four weeks (99.3 ± 2.3% and 100.7 ± 2.6%), respectively, of the solid dispersion and Cialis ^® powder of Example 1 )). The dissolution rates were 89.1 ± 3.9% and 13.9 ± 0.6% respectively in the distilled water and after 4 weeks (89.7 ± 2.8% and 16.0 ± 1.9%) of the solid dispersion and Cialis ^® powder, respectively (FIG. 7 (b) ). The stability of the amorphous solid dispersion (Example 1) at accelerated conditions (40 캜, 75% RH) was excellent as confirmed by the powder X-ray diffraction (PXRD) pattern in Experimental Example 4.

Claims (8)

Tadalafil;
Copolymers of vinylpyrrolidone and vinyl acetate as solubilizing agents;
Meglumine; And
A solid dispersion containing tadalafil comprising colloidal silicon dioxide as a porous carrier. The method according to claim 1,
A toadafil-containing solid dispersion characterized in that tadalafil in the solid dispersion is amorphous. delete delete delete The method according to claim 1,
Wherein the solid dispersion is characterized in that the copolymer of tadalafil: vinylpyrrolidone and vinyl acetate: meglumine: colloidal silicon dioxide is mixed at a weight ratio of 1: 2 to 6: 2 to 4: 2 to 4 Tadalafil-containing solid dispersion. A pharmaceutical composition comprising a solid dispersion according to any one of claims 1, 2, and 6 and a pharmaceutically acceptable carrier. A method of producing a tadalafil-containing solid dispersion according to any one of claims 1, 2, and 6,
a) preparing a tadalafil solution by dissolving tadalafil and a copolymer of vinylpyrrolidone and vinyl acetate as a solubilizing agent in an organic solvent;
b) mixing meglumine in the tadalafil solution and adding colloidal silicon dioxide as a porous carrier to prepare a dispersion;
c) drying and pulverizing the dispersion;
Containing solid dispersion. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;

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