TW201831171A - Pharmaceutical composition for colon targeting, use thereof and preparation method thereof - Google Patents

Abstract

A pharmaceutical composition for colon targeting, a use thereof 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% to 95% based on a total weight of the core matrix.

Description

Medicinal composition for intestinal release, use thereof and preparation method thereof

The present invention relates to a pharmaceutical composition, a use thereof, and a preparation method thereof, and more particularly to a pharmaceutical composition for intestinal release, a use thereof, and a preparation method thereof.

For oral administration of a large bowel disorder, such as colitis or colorectal cancer, the active ingredient begins to release before reaching the large intestine. Therefore, the dose of the active ingredient in the medicament must be increased to ensure that a sufficient dose of the active ingredient reaches the large intestine. However, high doses of the active ingredient may cause side effects and cause waste of the active ingredient.

At present, drugs for treating large intestine disorders often use a layered round particle method. First, a multi-layered agent is provided, the core of which is coated with the drug layer and the enteric coating in sequence; thus, the multi-layered layered round particles can successfully reach the large intestine. Then, the layered round particles and the water-gel particles having a multi-layer structure (which can provide a protective function through the gastrointestinal tract and prepared by wet granulation) are filled in the capsule, and the obtained capsule is coated with another layer. Intestine coating to protect the water gel. The currently used drugs for treating large bowel disorders can be obtained through the aforementioned processes. However, the aforementioned process is very complicated, and it is necessary to mix the two layers of the multi-layer structure of the layered round particles and the water-gel particles. Therefore, it is quite difficult to prepare a currently used drug for treating a large bowel disorder.

Therefore, there is an urgent need to develop a novel pharmaceutical composition that can carry a drug to avoid early release of the drug, and can achieve the same purpose as the aforementioned agent formed by mixing the two particles through a single dosage form.

The main object of the present disclosure is to provide a pharmaceutical composition for intestinal release, a use thereof and a preparation method thereof, wherein the pharmaceutical composition has a high drug loading amount.

The pharmaceutical composition for intestinal release according to the present disclosure comprises: a core matrix comprising: a crosslinked water gel, and an active ingredient; wherein the active ingredient is dispersed in the crosslinked water gel, and the active ingredient is dispersed in the crosslinked water gel The active ingredient is present in an amount of from 65% to 95% by weight based on the total weight of the core matrix. In addition, the present disclosure further provides the use of the aforementioned pharmaceutical composition for the preparation of a medicament for treating colitis.

Furthermore, the present disclosure further provides a method for preparing the aforementioned pharmaceutical composition, comprising the steps of: providing an active ingredient fluid comprising: a water gel, and an active ingredient, wherein the active ingredient is dispersed in the water gel Wherein the water gel is present in an amount of from 1% to 4% by weight based on the total weight of the active ingredient fluid, and the active ingredient is present in an amount of from 10% to 25% by weight based on the total weight of the active ingredient fluid; and the active ingredient fluid is instilled a cross-linking solution to form a core matrix, wherein the core matrix comprises a cross-linked water gel, and the active ingredient, the active ingredient is dispersed in the cross-linked water gel, and the content of the active ingredient is It accounts for 65% to 95% of the total weight of the core matrix.

In the conventional pharmaceutical compositions, a fluidized bed granulation process is often used to coat an active component on a core to form a core matrix. Therefore, the structure of the conventional core matrix is a core-shell structure formed of a core and an active component. However, in the pharmaceutical composition of the present disclosure, the core matrix is formed by the active ingredient fluid, which is dropped into a crosslinking solution to cause the water gel to crosslink to form a core matrix. Therefore, the core matrix of the pharmaceutical composition of the present disclosure does not have a core-shell structure, but the active ingredient is dispersed in the crosslinked water gel. In addition, the core matrix having a core-shell structure in the past has a drug loading of at most 40%; in the pharmaceutical composition of the present disclosure, since the core matrix is formed by dispersing the active ingredient in the crosslinked water gel, The high viscosity of the water gel can be combined with the active ingredient such that the drug loading of the core matrix (i.e., the percentage of active ingredient in the total weight of the core matrix) can exceed 40% and can be as high as 65% to 95%. Therefore, when the pharmaceutical composition is prepared by the preparation method of the present disclosure, the recovery rate of the active ingredient can be improved; in particular, when the mass production is carried out, the effect of the recovery rate is more remarkable.

In an embodiment of the present disclosure, a specific example of the core matrix may be a microparticle. The size of the particles is not particularly limited and can be adjusted as needed.

In another embodiment of the present disclosure, the water gel comprises alginate (eg, sodium alginate), chitosan, pectin, or a mixture thereof. When the water gel comprises sodium alginate and pectin, the weight ratio of sodium alginate to pectin may be between 1:1 and 1:0.5.

In another embodiment of the present disclosure, the water gel is present in an amount of from 1% to 4% by weight based on the total weight of the active ingredient fluid (1% hydrophobe content ≦4%). When the content of the water gel is less than 1% or more than 4%, the viscosity of the active ingredient fluid may be too low or too high to form a core matrix.

In another embodiment of the present disclosure, if the water gel used in the active ingredient fluid comprises sodium alginate and pectin, the pectin content is from 0% to 2% of the total weight of the active ingredient fluid (0% capsule). The gel content is ≦2%). When the content of pectin exceeds 2%, the viscosity of the active ingredient fluid is too high, and it is difficult to form a spherical core matrix.

In another embodiment of the present disclosure, the active ingredient may be present in an amount from 65% to 95% by weight of the total weight of the core matrix, for example, from 70% to 90% or from 80% to 90%.

In the preparation method of the present disclosure, the crosslinking solution may include a calcium ion-containing solution. The calcium ion concentration in the cross-linking solution may be between 0.15 mol/L and 0.4 mol/L. In one embodiment of the present disclosure, the calcium ion-containing solution is a calcium chloride solution; however, the disclosure is not limited thereto.

In the pharmaceutical compositions of the present disclosure, the core matrix of the aqueous gel can be dried for subsequent film coating processes. Therefore, in the preparation method of the present disclosure, after the core matrix is formed, a step may be further included: drying the core matrix. Among them, the method of drying the core substrate is not particularly limited and may be a heat drying, freeze drying, or other drying method. If the heat drying method is used, the heating temperature is not particularly limited and may be from 30 ° C to 100 ° C, for example, from 30 ° C to 80 ° C, from 30 ° C to 60 ° C or from 40 ° C to 50 ° C.

In an embodiment of the present disclosure, after drying the core matrix, a step may be further included: forming a film coating covering the core matrix. Thereby, the formed pharmaceutical composition may further comprise a film coat in which the film coat coats the core matrix. Wherein, the material of the film coat may comprise a pH dependent material such as Eudragit FS30D, Eudragit L30D55, or a combination thereof. When the drug is administered orally, the uncoated film water gel may disintegrate in the stomach; therefore, when the film is coated on the core substrate, the active matrix formed by the water gel can be prevented from disintegrating in the gastrointestinal tract. Because the film coat used is a pH dependent material, the pharmaceutical composition of the present disclosure can successfully pass through the gastrointestinal tract. Meanwhile, when the medical composition of the present invention reaches the large intestine, since the pH of the large intestine is more than 6.0, the film coat disintegrates and the active ingredient begins to be released from the active matrix. Thereby, the active ingredient carried by the water gel can be successfully carried to the gastrointestinal tract and released in the large intestine. In addition, in the pharmaceutical composition disclosed in the present invention, in addition to being used as a carrier for the active ingredient, the water gel after disintegration can form a protective layer of the intestinal wall, thereby protecting the intestinal mucosa and even helping the intestinal wound to heal. The effect.

In one embodiment of the present disclosure, the active ingredient used may be a drug for treating colitis. For example, mesalamine. However, the present disclosure is not limited thereto, and the active ingredient may be any slightly soluble to water-insoluble active ingredient to be carried to the large intestine, for example, an animal vaccine, a probiotic, an antibody, a peptide, or other small molecule drug.

As used in this disclosure, the term "treatment" as used herein refers to the administration of a pharmaceutical composition of the present disclosure to a subject in order to inhibit, heal, ameliorate, improve, cure, ameliorate, slow, alter or affect the disease or The tendency of the illness. Furthermore, in the pharmaceutical composition of the present disclosure, at least one selected from the group consisting of an active agent, an adjuvant, a dispersing agent, a wetting agent, an excipient, and a suspending agent may be more selectively included. Furthermore, the pharmaceutical composition of the present disclosure can be administered orally.

The embodiments of the present disclosure are described below by way of specific examples, and those skilled in the art can readily appreciate the other advantages and advantages of the disclosure. The disclosure may also be implemented or applied by other different embodiments. The details of the present specification may also be applied to various aspects and applications, and various modifications and changes may be made without departing from the spirit of the present invention.

Experimental procedure - preparation of pharmaceutical ingredients

First, the water gel is dissolved in water, and the solid matter such as the active ingredient is dispersed in the water gel solution to obtain an active ingredient fluid. Next, the active ingredient fluid is dropped into the crosslinking solution (CaCl ₂ solution), and after a predetermined crosslinking time, core particles (drop pills) can be formed. Then, the obtained active fine particles are dried at 40 ° C to 45 ° C, and then coated with a film coat. Thus, the pharmaceutical composition of the present example can be obtained.

Examples 1-1 to 1-9 and Comparative Examples 1-1 to 1-2

In Examples 1-1 to 1-9 and Comparative Examples 1-1 to 1-2, core microparticles were prepared using a microcapsule machine. The conditions of use of the respective components of Examples 1-1 to 1-9 and Comparative Examples 1-1 to 1-2 are shown in Table 1 below.

Table 1 - Active ingredient fluid formulation, crosslinking time, drug loading and coverage Drug loading = (the amount of drug contained in the pills / the total weight of the pills taken) x 100% coverage = (drug loading x total weight of recovered pills / total drug dosage) x 100%

As shown in the results of Table 1, the core substrates prepared in Examples 1-1 to 1-9 had a relatively high drug loading amount. In contrast, in Comparative Examples 1-1 to 1-2, when the sodium alginate was too much or too low, the CaCl ₂ solution was too low, or the amount of the active ingredient was too large (the amount of the solid matter was too large), the core matrix could not be successfully obtained.

Examples 2-1 to 2-7 and Comparative Examples 2-1 to 2-2

In Examples 2-1 to 2-7 and Comparative Examples 2-1 to 2-2, core microparticles were prepared using a microcapsule machine (BUCHI/B-390). The conditions of use of the respective components of Examples 2-1 to 2-7 and Comparative Examples 2-1 to 2-2 are shown in Table 2 below. In addition, the concentration of CaCl ₂ solution was fixed at 0.2 mol/L, the crosslinking time was fixed at 10 min, and the amount of mesalazine was fixed at 10 wt%.

Table 2 Comparative Example 2-2: The amount of sodium alginate was less than 1%, and the dropping pills were not easily formed regardless of the pectin ratio.

As shown in the results of Table 2, the core substrates prepared in Examples 2-1 to 2-7 had a relatively high drug loading amount. In contrast, in Comparative Examples 2-1 to 2-2, when too much or too low a sodium alginate was used, or too much pectin was used, the core matrix could not be successfully produced.

Examples 3-1 and 3-2

In Examples 3-1 and 3-2, core microparticles were prepared using a microcapsule machine. The core particles were rinsed with deionized water and dried in an oven at 50 ° C for 24 hr to prepare a semi-finished pharmaceutical composition. The semi-finished pharmaceutical composition and the coating material were coated by a fluidized bed, and after completion, 0.005 % of Talc was added and uniformly mixed to prepare a coated pharmaceutical composition. The conditions for use of the respective components of Examples 3-1 and 3-2 are shown in Table 3 below. In addition, the crosslinking time is fixed at 10 min.

table 3

The pharmaceutical compositions prepared in Examples 3-1 and 3-2 were subjected to drug dissolution analysis. At 0-2 hours, the pharmaceutical composition was placed in a 0.1 N HCl solution; at 2-6 hours, placed in an environment of pH 6.0; and at 6-14 hours, placed at pH 7.5. Environment. At the same time, the release rate of the drug is measured every hour. The results are shown in Figure 1.

As shown in Fig. 1, the pharmaceutical compositions prepared in Examples 3-1 and 3-2 did not release the drug in the environment of 0.1 N HCl and pH 6.0, and the drug was released in the environment of pH 7.5. This result indicates that the pharmaceutical compositions prepared in Examples 3-1 and 3-2 were effective in reaching the large intestine before the release of the active ingredient.

Examples 3-3 to 3-6

Examples 3-3 and 3-4 are similar to Examples 3-1 and 3-2, respectively, except that the film coat used is different, Eudragit FS30D is a film coat which dissolves above pH 7.0, and Eudragit L30D55 is at pH 5.5. The above film will dissolve. In the pharmaceutical compositions of Examples 3-1 and 3-2, the film coat was Eudragit FS30D in an amount of 10% by weight based on the weight of the core substrate, and the film was used in the pharmaceutical compositions of Examples 3-3 and 3-4. The garment was changed to Eudragit L30D55 in an amount of 20% by weight of the core matrix.

Examples 3-5 and 3-6 are similar to Examples 3-3 and 3-4, respectively, except that in the pharmaceutical compositions of Examples 3-5 and 3-6, Eudragit L30D55 used in the film coat was used. The dosage is increased by 40%.

The drug loading amounts of the finished products and semi-finished products of Examples 3-3 to 3-6 are shown in Table 4 below.

Table 4

The pharmaceutical compositions prepared in Examples 3-3 to 3-6 were subjected to drug dissolution analysis. At 0-4 hours, the pharmaceutical composition was placed in a 0.1 N HCl solution; at 4-12 hours, it was placed in a pH 6.0 environment. At the same time, the release rate of the drug is measured every hour. The results are shown in Figures 2 and 3.

As shown in Fig. 2 and Fig. 3, the pharmaceutical compositions prepared in Examples 3-3 and 3-6 did not release the drug in the environment of 0.1 N HCl, but began to release the drug in an environment of pH 6.0. This result indicates that the pharmaceutical compositions prepared in Examples 3-3 and 3-6 can effectively reach the target environment (e.g., the large intestine) before the rapid release of the active ingredient begins.

Experimental Procedure - Rat Animal Experiment

Male Wistar rats were fasted for 24 hours, then induced by distal DNBS (2,4-dinitrobenzenesulfonic acid, 30 mg 30% in 0.5 mL ethanol), and then gently injected with 2 mL of air. The rectal cannula is used to ensure that the solution remains in the colon. Test substances (Examples 3-1) and mesalazine were administered by oral gavage 24 and 2 hours prior to DNBS instillation, followed by daily administration for 5 consecutive days for a total of 7 doses. Body weight, fecal occult blood and stool consistency were recorded daily during the study. Animals were sacrificed on day 8, and adhesions between the colon and other organs were observed when the abdominal cavity was opened, the presence of colon ulcers, and then the colon tissue was removed and weighed.

After dissecting the rat, it was found that in the digestive tract before the large intestine, the presence of round granules of the pharmaceutical composition was found, and no medicinal composition round particles were found in the large intestine, confirming that the pharmaceutical composition provided by the present disclosure can pass through the first half of the gastrointestinal tract. While disintegrating in the large intestine.

In addition, the inflammatory response, the evaluation index of the large intestine width, and the comprehensive evaluation results are shown in Table 5 below.

table 5

As shown in the results of Table 5, the pharmaceutical composition provided by the present disclosure has a better reaction in the inflammatory reaction, the evaluation index of the large intestine width, and the comprehensive evaluation, and shows that the pharmaceutical composition provided by the present disclosure has the function of a large intestinal marker. .

Example 4-1 - Amplification process

In Example 4-1, a microcapsule machine was used, and the core particles were prepared by amplifying the process. The conditions for use of the respective components of Example 4 are shown in Tables 6 and 7 below. In addition, the crosslinking time is fixed at 10 min.

Table 6 – Core Matrix Formulations and Process Parameters

Table 7 - Membrane Formulation and Process Parameters

Example 4-2

Example 4-2 was similar to Example 4-1 except that in Example 4-2, pectin was not used in the active ingredient fluid, and the concentration of sodium alginate was raised to 2 wt%. Further, in Example 4-2, Eudragit FS30D used in Example 4-1 was replaced by Eudragit L30D55, but in both Example 4-1 and Example 4-2, Eudragit FS30D was used in Eudragit L30D55. 10% by weight of the core matrix.

The drug loading amounts of the finished products and semi-finished products of Examples 4-1 and 4-2 are shown in Table 8 below.

Table 8

The pharmaceutical compositions prepared in Examples 4-1 and 4-2 were subjected to drug dissolution analysis. The results are shown in Figures 4 and 5, respectively.

As shown in Fig. 4 and Fig. 5, the pharmaceutical compositions prepared in Examples 4-1 and 4-2 did not release the drug in the environment of 0.1 N HCl. The pharmaceutical composition of Example 4-1 started to release the drug in an environment of pH 7.5, and the pharmaceutical composition of Example 4-2 began to release the drug in an environment of pH 6.0. This result indicates that the pharmaceutical compositions prepared in Examples 4-1 and 4-2 can effectively reach the large intestine or the target environment before the release of the active ingredient begins.

Further, the pharmaceutical composition prepared in Example 4-1 was subjected to drug dissolution analysis with commercially available ASACOL and PENTASA. Wherein, the pharmaceutical composition prepared in Example 4-1 is placed in a 0.1 N HCl solution at 0-2 hours; in the 2-3 hours, placed in an environment of pH 6.0; In the 3rd to 11th hour, it was placed in an environment of pH 7.5. ASACOL is placed in 0.1 N HCl solution at 0-2 hours; placed in pH 6.0 at 2-3 hours; and placed at pH 3-9 hours. In the environment of 7.5. PENTASA is placed in 0.1 N HCl solution at 0-2 hours; placed in pH 6.0 at 2-3 hours; and placed at pH 3-9 hours. In the environment of 7.2.

As shown in the results of FIG. 6, the pharmaceutical composition of Example 4-1 and ASACOL both began to release the drug under the environment of pH 7.5, indicating that the pharmaceutical composition prepared in Example 4-1 can effectively reach the large intestine and then begin to release. Active ingredient.

The above examples demonstrate that, in the method provided by the present disclosure, the prepared pharmaceutical composition can effectively reach the large intestine and then begin to release the active ingredient to achieve the purpose of releasing the intestinal marker.

The above-mentioned embodiments are merely examples for convenience of description, and the scope of the claims is intended to be limited to the above embodiments.

no.

Fig. 1 is a graph showing the results of drug dissolution analysis of the pharmaceutical compositions of Examples 3-1 and 3-2. 2 is a graph showing experimental results of drug dissolution analysis of the pharmaceutical compositions of Examples 3-3 and 3-4. 3 is a graph showing experimental results of drug dissolution analysis of pharmaceutical compositions of Examples 3-5 and 3-6. Fig. 4 is a graph showing the results of a drug dissolution analysis experiment of the pharmaceutical composition of Example 4-1. Fig. 5 is a graph showing experimental results of drug dissolution analysis of the pharmaceutical composition of Example 4-2. Fig. 6 is a graph showing experimental results of drug dissolution analysis of the pharmaceutical composition of Example 4-1 and ASACOL and PENTASA.

Claims (19)

A pharmaceutical composition for intestinal release, comprising: a core matrix comprising: a cross-linked water gel, and an active ingredient; wherein the active ingredient is dispersed in the cross-linked water gel, and the active ingredient The content is from 65% to 95% of the total weight of the core matrix. The pharmaceutical composition according to claim 1, wherein the water gel comprises alginate, chitosan, pectin or a mixture thereof. The pharmaceutical composition according to claim 2, wherein the water gel comprises sodium alginate and pectin, and the weight ratio of sodium alginate to pectin is between 1:1 and 1:0.5. The pharmaceutical composition according to claim 1, further comprising a film coat, wherein the film coat coats the core substrate. The pharmaceutical composition of claim 4, wherein the film coat comprises a pH dependent material. The pharmaceutical composition according to claim 5, wherein the film coat comprises: Eudragit FS30D, Eudragit L30D55, or a combination thereof. The pharmaceutical composition according to claim 1, wherein the active ingredient is a drug for treating colitis. A pharmaceutical composition for the preparation of a medicament for treating colitis, wherein the pharmaceutical composition comprises: a core matrix comprising: a crosslinked water gel, and an active ingredient; wherein the active ingredient is dispersed in the cross In the water gel, the active ingredient is present in an amount of from 65% to 95% by weight based on the total weight of the core matrix. A method for preparing a pharmaceutical composition for intestinal release, comprising the steps of: providing an active ingredient fluid comprising: a water gel, and an active ingredient, wherein the active ingredient is dispersed in the water gel, and The water gel is present in an amount of from 1% to 4% by weight based on the total weight of the active ingredient fluid, and the active ingredient is present in an amount of from 10% to 25% by weight based on the total weight of the active ingredient fluid; and the active ingredient fluid is instilled into a crosslink. Forming a core matrix in the solution, wherein the core matrix comprises: a cross-linked water gel, and the active ingredient, the active ingredient is dispersed in the cross-linked water gel, and the content of the active ingredient accounts for The total weight of the core matrix ranges from 65% to 95%. The preparation method of claim 9, wherein the water gel comprises alginate, chitosan, pectin or a mixture thereof. The preparation method according to claim 10, wherein the water gel comprises sodium alginate and pectin, and the weight ratio of sodium alginate to pectin is between 1:1 and 1:0.5. The preparation method of claim 9, wherein the crosslinking solution comprises a calcium ion-containing solution. The preparation method according to claim 12, wherein the calcium ion concentration in the crosslinking solution is between 0.15 mol/L and 0.4 mol/L. The preparation method according to claim 12, wherein the calcium ion-containing solution is a calcium chloride solution. The preparation method of claim 9, wherein after the core substrate is formed, the method further comprises the step of drying the core substrate. The preparation method according to claim 15, wherein after drying the core substrate, the method further comprises the step of: forming a film coating covering the core substrate. The preparation method of claim 16, wherein the film coat comprises a pH dependent material. The preparation method of claim 17, wherein the film coat comprises: Eudragit FS30D, Eudragit L30D55, or a combination thereof. The preparation method according to claim 9, wherein the active ingredient is a drug for treating colitis.