Pharmaceutical composition for colon targeting, method for treating a colon-related disease using the same and preparation method thereof

Abstract

A pharmaceutical composition for colon targeting, a method for treating a colon-related disease using the same and a preparation method thereof are disclosed. The pharmaceutical composition of the present disclosure comprises: a core matrix comprising a cross-linked hydrogel and an active ingredient, wherein the active ingredient is dispersed in the cross-linked hydrogel, and a content of the active ingredient is 65 wt % to 95 wt % based on a total weight of the core matrix.

Claims

1. A method for treating a colon-related disease, comprising: administering a pharmaceutical composition to a subject in need, wherein the pharmaceutical composition comprises: a core matrix comprising: a cross-linked hydrogel and an active ingredient, wherein the active ingredient is mesalamine and dispersed in the cross-linked hydrogel, and a content of the active ingredient is 65 wt % to 95 wt % based on a total weight of the core matrix, wherein the core matrix is coated with a coating film comprising a pH dependent material.

2. The method of claim 1, wherein the cross-linked hydrogel comprises alginate, chitosan, pectin or a combination thereof.

3. The method of claim 2, wherein the cross-linked hydrogel comprises alginate and pectin, and a weight ratio between the alginate and the pectin is ranged from 1:1 to 1:0.5.

4. The method of claim 1, wherein the coating film comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylic acid-co-ethyl acrylate) or a combination thereof.

5. The method of claim 1, wherein the pharmaceutical composition is administered via oral administration.

6. A pharmaceutical composition for colon targeting, comprising: a core matrix comprising: a cross-linked hydrogel and an active ingredient, wherein the active ingredient is mesalamine and dispersed in the cross-linked hydrogel, and a content of the active ingredient is 65 wt % to 95 wt % based on a total weight of the core matrix, and wherein the core matrix is coated with a coating film comprising a pH dependent material.

7. A method for preparing a pharmaceutical composition for colon targeting, consisting essentially of the following steps: providing an active ingredient fluid, comprising a hydrogel and an active ingredient, wherein the active ingredient is mesalamine and dispersed in the hydrogel, a content of the hydrogel is ranged from 1 wt % to 4 wt % based on a total weight of the active ingredient fluid, and a content of the active ingredient is ranged from 10 wt % to 25 wt % based on the total weight of the active ingredient fluid; wherein the hydrogel comprises alginate and pectin, and a weight ratio between the alginate and the pectin is ranged from 1:1 to 1:0.5; adding the active ingredient fluid into a calcium containing solution dropwise to form a core matrix, wherein a concentration of Ca.sup.2+ in the calcium containing solution is ranged from 0.15 mol/L to 0.4 mol/L and the core matrix comprises: a cross-linked hydrogel and the active ingredient, the active ingredient is dispersed in the cross-linked hydrogel, and a content of the active ingredient is 65 wt % to 95 wt % based on a total weight of the core matrix; drying the core matrix; and forming a coating film, after the step of drying the core matrix, wherein the core matrix is coated with the coating film comprising a pH dependent material.

8. The method of claim 7, wherein the calcium containing solution is a CaCl2 solution.

9. The method of claim 7, wherein the coating film comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylic acid-co-ethyl acrylate) or a combination thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a graph showing dissolution profiles of pharmaceutical compositions prepared in Embodiments 3-1 and 3-2.

(2) FIG. 2 is a graph showing dissolution profiles of pharmaceutical compositions prepared in Embodiments 3-3 and 3-4.

(3) FIG. 3 is a graph showing dissolution profiles of pharmaceutical compositions prepared in Embodiments 3-5 and 3-6.

(4) FIG. 4 is a graph showing a dissolution profile of pharmaceutical composition prepared in Embodiment 4-1.

(5) FIG. 5 is a graph showing a dissolution profile of pharmaceutical composition prepared in Embodiment 4-2.

(6) FIG. 6 is a graph showing dissolution profiles of 400 mg/Tab Mesalamine, 500 mg/Tab Mesalamine and a pharmaceutical composition prepared in Embodiment 4-1.

DETAILED DESCRIPTION OF EMBODIMENT

(7) The following embodiments when read with the accompanying drawings are made to clearly exhibit the above-mentioned and other technical contents, features and/or effects of the present disclosure. Through the exposition by means of the specific embodiments, people would further understand the technical means and effects the present disclosure adopts to achieve the above-indicated objectives. Moreover, as the contents disclosed herein should be readily understood and can be implemented by a person skilled in the art, all equivalent changes or modifications which do not depart from the concept of the present disclosure should be encompassed by the appended claims.

(8) Experimental ProcessPreparation of a Pharmaceutical Composition

(9) First, hydrogel was dissolved in water, and solid components including an active ingredient were dissolved in the hydrogel solution to obtain an active ingredient fluid. Next, the active ingredient fluid was added dropwise into the cross-linked solution (CaCl.sub.2 aqueous solution) After a predetermined cross-linking time, a drop pill (i.e. a sphere core matrix) was obtained. Then, the sphere core matrix was dried at 40 C. to 45 C., followed by a coating process to form a coating film on the sphere core matrix, After the aforesaid process, a pharmaceutical composition was obtained.

Embodiments 1-1 to 1-9 and Comparative Embodiments 1-1 to 1-2

(10) In Embodiments 1-1 to 1-9 and Comparative embodiments 1-1 to 1-2, an encapsulator machine was used to prepare the sphere core matrix. Herein, the components and the conditions used in Embodiments 1-1 to 1-9 and Comparative embodiments 1-1 to 1-2 are listed in the following Table 1.

(11) TABLE-US-00001 TABLE 1 Formulation of active ingredient fluid, cross-linking time, drug loading (LD) and entrapment efficiency (EE) Sodium Mesa- LE + alginate CaCl.sub.2 lamine Time LD EE EE (wt %) (mol/L) (wt %) (min) (%) (%) (%) Embod- 2 0.2 13 10 83.94 73.36 157.30 iment 1-1 Embod- 2 0.3 16.67 30 82.63 77.31 159.94 iment 1-2 Embod- 2 0.4 20 60 83.75 65.41 149.16 iment 1-3 Embod- 3 0.2 16.67 60 79.76 65.51 145.27 iment 1-4 Embod- 3 0.3 20 10 83.93 60.21 144.14 iment 1-5 Embod- 3 0.4 13 30 73.61 64.34 137.95 iment 1-6 Embod- 4 0.2 20 30 83.93 47.66 131.58 iment 1-7 Embod- 4 0.3 13 60 65.78 51.15 116.93 iment 1-8 Embod- 4 0.4 16.67 10 74.51 56.99 131.51 iment 1-9 Com- <1 <0.1 20 Drop pills were not parative formed. Embod- iment 1-1 Com- >4 0.2 >25 The viscosity parative of the acvie Embod- ingredient iment fluid was too 1-2 high, and the active ingredient fluid cannot be dropped out.
Drug loading=(drug content in a drug pill/total weight of the drug pill)100%
Entrapment efficiency=(drug loadingtotal weight of the drug pills/total amount of the drug used)100%

(12) According to the results shown in Table 1, the core matrix obtained in Embodiments 1-1 to 1-9 has high drug loading. However, in Comparative embodiments 1-1 to 1-2, the core matrix cannot be obtained because the used amount of sodium alginate is too high or too low, the concentration of the CaCl.sub.2 solution is too low, or the used amount of the active ingredient is too high (which means the used amount of the solid components is too high).

Embodiments 2-1 to 2-7 and Comparative Embodiments 2-1 to 2-2

(13) In Embodiments 2-1 to 2-7 and Comparative embodiments 2-1 to 2-2, an encapsulator machine was used to prepare the sphere core matrix. Herein, the components and the conditions used in Embodiments 2-1 to 2-7 and Comparative embodiments 2-1 to 2-2 are listed in the following Table 2. In addition, the concentration of the CaCl.sub.2 solution was fixed to be 0.2 mol/L, the cross-linking time was fixed to be 10 min, and the used amount of mesalamine was fixed to be 10 wt %.

(14) TABLE-US-00002 TABLE 2 Sodium alginate Pectin Sodium LD EE (wt %) (wt %) alginate:Pectin (%) (%) Embodiment 1 1 1:1 77.77 62.95 2-1 Embodiment 1 2 1:2 71.06 67.76 2-2 Embodiment 1.5 0.75 1:0.5 76.15 72.19 2-3 Embodiment 1.5 1.5 1:1 72.33 67.75 2-4 Embodiment 2 1 1:0.5 73.32 68.89 2-5 Embodiment 2 2 1:1 65.98 54.17 2-6 Embodiment 2.5 1.25 1:0.5 67.27 59.83 2-7 Comparative 1 >2 >1:2 The viscosity of the Embodiment acvie ingredient fluid 2-1 was too high, and the active ingredient fluid cannot be dropped out.
Comparative embodiment 2-2: The used amount of the sodium alginate was less than 1 wt %. Drop pills were not formed no matter how much the pectin was used.

(15) According to the results shown in Table 2, the core matrix obtained in Embodiments 2-1 to 2-7 has high drug loading. However, in Comparative embodiments 2-1 to 2-2, the core matrix cannot be successfully formed when the used amount of sodium alginate is too high or too low or the used amount of the pectin is too high.

Embodiments 3-1 and 3-2

(16) In Embodiments 3-1 to 3-2, an encapsulator machine was used to prepare the sphere core matrix. After washing the sphere core matrix with de-ionized water, the clean sphere core matrix was put into 50 C. oven for drying 24 hr, and a semi-finished product was obtained. The final product was obtained by using the semi-finished product and a material for forming the coating film via a fluid bed granulation process, followed by adding 0.005% Talc and mixing well. Herein, the components and the conditions used in Embodiments 3-1 to 3-2 are listed in the following Table 3. In addition, the cross-linking time was fixed to be 10 min.

(17) TABLE-US-00003 TABLE 3 Embodiment Embodiment Formualtion 3-1 3-2 Active ingredient Sodium alginate (wt %) 3 2 fluid Pectin (wt %) 1 Mesalamine (wt %) 16.67 10 Water (wt %) 80.33 87 Cross-linked CaCl.sub.2 (mol/L) 0.2 0.5 solution Coating film Core matrix (g) 400 300 Eudragit FS30D (g) 40.5 30.4 Tween 20 (g) 4 3 Water (g) 184.5 138.4 Yield 98.88% 98.67% LD of the 83.04 0.28 74.96 0.37 semi-finished product (%) LD of the final 75.98 0.24 68.77 0.26 product (%)

(18) The pharmaceutical compositions prepared in Embodiments 3-1 and 3-2 were analyzed through a dissolution analysis. At 0-2 hr, the pharmaceutical compositions were put in 0.1 N HCl solution; at 2-6 hr, the pharmaceutical compositions were put in pH 6.0 solution; and at 6-14 hr, the pharmaceutical compositions were put in pH 7.5 solution. Meanwhile, the dissolved percentages were measured every hour. The results are shown in FIG. 1.

(19) As shown in FIG. 1, the pharmaceutical compositions prepared in Embodiments 3-1 and 3-2 did not release the active ingredient in 0.1 N HCl solution and pH 6.0 solution, but started to release the active ingredient in pH 7.5 solution. These results indicate that the pharmaceutical compositions prepared in Embodiments 3-1 and 3-2 can successfully start to release the active ingredient after reaching the colon.

Embodiments 3-3 to 3-6

(20) The pharmaceutical compositions of Embodiments 3-3 and 3-4 are similar to those of Embodiments 3-1 and 3-2, except for the materials of the coating films. The coating film made of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) can be dissolved above pH 7.0, and the coating film made of poly(methacrylic acid-co-ethyl acrylate) can be dissolved above pH 5.5. In the pharmaceutical compositions of Embodiments 3-1 and 3-2, the coating films were made of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), and the used amount of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) was 10 wt % based on the weight of the sphere core matrix. In the pharmaceutical compositions of Embodiments 3-3 and 3-4, the coating films were made of poly(methacrylic acid-co-ethyl acrylate, and the used amount of poly(methacrylic acid-co-ethyl acrylate) was 20 wt % based on the weight of the sphere core matrix.

(21) The pharmaceutical compositions of Embodiments 3-5 and 3-6 are similar to those of Embodiments 3-3 and 3-4, except that the used amount of poly(methacrylic acid-co-ethyl acrylate) was increased to 40 wt % in the pharmaceutical compositions of Embodiments 3-5 and 3-6.

(22) The drug loadings of the semi-finished products and the final products of Embodiments 3-3 to 3-6 are listed in the following Table 4.

(23) TABLE-US-00004 TABLE 4 Embodiment 3-3 Embodiment 3-4 LD of the semi-finished 83.78 0.75 74.94 0.09 product (%) LD of the final product (%) 64.85 0.36 56.73 0.62 Embodiment 3-5 Embodiment 3-6 LD of the semi-finished 83.78 0.75 74.94 0.09 product (%) LD of the final product (%) 55.86 0.44 40.05 0.05

(24) The pharmaceutical compositions prepared in Embodiments 3-3 to 3-6 were analyzed through a dissolution analysis. At 0-4 hr, the pharmaceutical compositions were put in 0.1 N HCl solution; and at 4-12 hr, the pharmaceutical compositions were put in pH 6.0 solution. Meanwhile, the dissolved percentages were measured every hour. The results are shown in FIG. 2 and FIG. 3.

(25) As shown in FIG. 2 and FIG. 3, the pharmaceutical compositions prepared in Embodiments 3-3 to 3-9 did not release the active ingredient in 0.1 N HCl solution, but started to release the active ingredient in pH 6.0 solution. These results indicate that the pharmaceutical compositions prepared in Embodiments 3-3 to 3-6 can successfully start to release the active ingredient after reaching the targeting environment (for example, colon

(26) Experimental ProcessAnimal Test

(27) Male Wistar mice were starved for 24 hr, and distal colitis was induced via intracolonic injection of DNBS (2,4-dinitrobenzene sulfonic acid, 30 mg in 0.5 mL ethanol (30%)). Then, 2 mL air was injected after instillation of the enema to ensure the solution was remained in the colon. The test substance (the pharmaceutical composition of Embodiment 3-1) and mesalamine were oral administered 24 hr and 2 hr prior to the DNBS injection, followed by administering one dose a day, and 5 days. The total doses of the test substance and mesalamine were 7 doses. The body weight, fecal occult blood and fecal consistency were recorded every day during the experiment. The animals were sacrificed at Day 8. The adhesions of colon and other organs were observed after abdominal opening, the colitis still can be observed, and the colon was carried out and weighted.

(28) After dissection, the exist of the pharmaceutical composition sphere can be observed in the gastrointestinal tract before colon, but no pharmaceutical composition sphere is found in the colon. This result indicates that pharmaceutical composition of the present disclosure can pass the first half part of the gastrointestinal tract and is degraded in colon.

(29) In addition, the evaluation indicators for inflammation and colon width as well as the total score are listed in the following Table 5.

(30) TABLE-US-00005 TABLE 5 Ulcers/ Inflam- Colon Total Dose Adhesion Strictures mation width score Sham N/A 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 control (without DNBS) Vehicle 2.5 mL/ 0.0 0.0 2.8 0.2 3.8 0.6 1.0 0.0 7.6 0.7 control animal qd 7, PO Embod- 2 CAP/ 0.0 0.0 2.0 0.0 3.2 0.62 1.0 0.0 6.2 0.2 iment animal 3-1 qd 7, PO Mesa- 2 CAP/ 0.0 0.0 2.6 0.2 3.2 0.54 1.0 0.0 6.8 lamine qd 7, 0.76 PO

(31) As shown in FIG. 5, the pharmaceutical compositions of the present disclosure show better effect on inflammation and colon width as well as the total score, and these results indicates that the pharmaceutical composition of the present disclosure has colon targeting effect.

Embodiment 4-1Large Scale Process

(32) In Embodiment 4-1, an encapsulator machine was used to prepare the sphere core matrix in large scale. The components and the conditions used herein are listed in the following Table 6. In addition, the cross-linking time was fixed to be 10 min.

(33) TABLE-US-00006 TABLE 6 Formulation of the core matrix and the process conditions Formulation Weight (g) Concentration Active ingredient Sodium alginate 30 1.5 wt % fluid Pectin 15 0.75 wt % Mesalamine 440 22 wt % Water 1515 75.75 wt % Cross-linked CaCl.sub.2 111.1 0.2 mol/L solution Water 4888.9 Core speed 8 rpm Vibrating motor speed 100 rpm Blowing control 0.1 bar

(34) TABLE-US-00007 TABLE 7 Formulation of the coating filim and the process conditions Formulation Weight (g) Solid (g) Coating film Core matrix 430 Eudragit FS30D 145.12 43.54 Tween 20 21.50 4.3 Water 79.55 Coating time 2 hr Yield (%) 98.67 Inlet temperature 34-36 C. Outlet temperature 28-30 C. (Set) Product temperature 30-31 C. Spry rate (g/min) 3.5-4.8 (On process) Spray pressure (act) 1.5 Vilocity of air 35%

Embodiment 4-2

(35) The pharmaceutical compositions of Embodiment 4-2 is similar to that of Embodiment 4-1, except that the active ingredient fluid does not contain pectin, and the concentration of the sodium alginate was increased to 2 wt %. In addition, in Embodiment 4-2, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) used in Embodiment 4-1 was substituted with poly(methacrylic acid-co-ethyl acrylate). In both Embodiments 4-1 and 4-2, the used amounts of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) and poly(methacrylic acid-co-ethyl acrylate) were respectively 10 wt % based on the weight of the core matrix.

(36) The drug loadings of the semi-finished products and the final products of Embodiments 4-1 and 4-2 are listed in the following Table 8.

(37) TABLE-US-00008 TABLE 8 Embodiment 4-1 Embodiment 4-2 LD of the semi-finished 88.77 0.23 91.23 0.40 product (%) LD of the final product (%) 80.74 0.17 81.42 0.50

(38) The pharmaceutical compositions prepared in Embodiments 4-1 and 4-2 were analyzed through a dissolution analysis. The results are shown in FIG. 4 and FIG. 5.

(39) As shown in FIG. 4 and FIG. 5, the pharmaceutical compositions prepared in Embodiments 4-1 and 4-2 did not release the active ingredient in 0.1 N HCl solution. The pharmaceutical composition prepared in.

(40) Embodiment 4-1 started to release in pH 7.5 solution, and the pharmaceutical composition prepared in Embodiment 4-2 started to release in pH 6.0 solution. These results indicate that the pharmaceutical compositions prepared in Embodiments 4-1 and 4-2 can successfully start to release the active ingredient after reaching the targeting environment (for example, colon).

(41) In addition, 400 mg/Tab Mesalamine, 500 mg/Tab Mesalamine and the pharmaceutical composition prepared in Embodiment 4-1 were analyzed through a dissolution analysis. At 0-2 hr, the pharmaceutical composition of Embodiment 4-1 was put in 0.1 N HCl solution; at 2-3 hr, the pharmaceutical composition was put in pH 6.0 solution; and at 3-11 hr, the pharmaceutical composition was put in pH 7.5 solution. At 0-2 hr, 400 mg/Tab Mesalamine was put in 0.1 N HCl solution; at 2-3 hr, 400 mg/Tab Mesalamine was put in pH 6.0 solution; and at 3-9 hr, 400 mg/Tab Mesalamine was put in pH 7.5 solution. At 0-2 hr, 500 mg/Tab Mesalamine was put in 0.1 N HCl solution; at 2-3 hr, 500 mg/Tab Mesalamine was put in pH 6.0 solution; and at 3-9 hr, 500 mg/Tab Mesalamine was put in pH 7.2 solution.

(42) As shown in FIG. 6, the pharmaceutical composition of Embodiment 4-1 and 400 mg/Tab Mesalamine started to release the active ingredient in pH 7.5 solution, which indicates the pharmaceutical composition of Embodiment 4-1 can successfully start to release the active ingredient after reaching the targeting environment (for example, colon).

(43) The results shown in the aforesaid embodiments indicate that the pharmaceutical composition prepared by the method of the present disclosure can successfully start to release the active ingredient after reaching the targeting environment (for example, colon) and the purpose of colon targeting can be achieved.

(44) Although the present disclosure has been explained in relation to its embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the disclosure as hereinafter claimed.