KR101152977B1 - Pharmaceutical preparations - Google Patents

Abstract

The present invention includes an inner core comprising an acidifying agent and bambuterol or a pharmaceutically acceptable salt thereof as an active ingredient and a coating layer coating the surface of the inner core, wherein the coating layer simultaneously contains a pH dependent polymer and a pH independent polymer. It provides a pharmaceutical formulation. The preparation of the present invention has the effect of showing the efficacy at the time of worsening of asthma symptoms by allowing the active ingredient to be released after the desired delay time even after the passage to the intestine upon oral administration.

Description

Pharmaceutical Formulation

The present invention relates to a pharmaceutical formulation comprising bambuterol, and in detail, even after passing from the stomach to the intestine upon oral administration, the active ingredient is released after the desired delay time, so as to show the efficacy at the time of worsening asthma symptoms It relates to a formulation.

Bambuterol is a persistent asthma treatment (LABAs), a prodrug of Terbutaline. The drug is slowly metabolized after being absorbed into the body and converted to the active metabolite, terbutalin, which has a pharmacological effect. The blood half-life of bambuterol is 13 hours and the blood half-life of terbutaline is 17 hours. Lasts. However, the time to peak blood concentration is very short, 1.4-1.8 hours.

Asthma symptoms vary in weight with a 24-hour cycle, depending on the biorhythm, and the symptoms usually become severe at dawn (2-4 am). However, conventional oral persistent asthma treatments have minimal improvement because they show low blood levels at the most severe time. Therefore, if the therapeutic effect of the drug varies depending on the biological rhythm, such as asthma, a situation that requires a technique for effectively controlling the disease by releasing an appropriate amount of drug in a timely manner.

U.S. Patent No. 5,788,987 discloses a sustained release formulation in which a core containing a main component such as bambuterol is coated with an expandable polymer, but it is necessary to improve the release control effect, and a coating layer coated with the expandable polymer passes through the gastrointestinal tract. If damaged while being released, there is a risk of being released faster than the target time. In this case, since the drug is released before the time of severe asthma symptoms, a problem may occur in which the optimal effect is not achieved at the severe time.

The inventors of the present invention have been conducted to develop a formulation capable of obtaining a blood concentration suitable for symptomatic improvement at 2-4 AM, when the drug is released before bedtime and after a certain delay time, which causes severe asthma symptoms. Invented.

The problem to be solved by the present invention is to provide a formulation that can ensure a blood concentration suitable for symptomatic improvement in the time zone during which the drug is released after a certain delay time is severe asthma symptoms.

The present invention includes an inner core comprising an acidifying agent and bambuterol or a pharmaceutically acceptable salt thereof as an active ingredient and a coating layer coating the surface of the inner core, wherein the coating layer simultaneously contains a pH dependent polymer and a pH independent polymer. It provides a pharmaceutical formulation.

The active ingredient may be purchased or synthesized as a precursor of terbutalin, and a preferred example of the active ingredient is bambuterol hydrochloride.

The acidifying agent means an additive that maintains the inner core in an acidic state, preferably in a pH of 2.0 to 3.0, and can maintain the release control ability of the pH-dependent polymer. That is, since the acidic agent maintains the acidic state after oral administration, the pH-dependent polymer plays a role of delaying the release in the section released by the pH increase when passing through the digestive tract. The acidifying agent is fumaric acid, succinic acid, tartaric acid, lactic acid, citric acid, alginic acid, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, acetic acid, ascorbic acid, benzoic acid, malic acid, ethetic acid, propionic acid, sorbic acid, stearic acid, aspartic acid , And / or glutamic acid and the like are preferred examples of fumaric acid. The fumaric acid is less hygroscopic and has advantages such as easy tableting.

The pH dependent polymer refers to a polymer having a property that does not dissolve or swell at an acid, preferably pH 1.0 to 5.0. The pH dependent polymers are for example polyacrylic acid, sodium alginate, hydroxyalkylcellulose phthalate, sodium cellulose acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxy Methyl ethyl cellulose, cellulose acetate phthalate, methacrylic acid-ethyl acrylate copolymer, and / or methacrylic acid-methyl methacrylate copolymer, etc., a preferable example is polyacrylic acid.

The active ingredient is not released in the stomach upon oral administration by the pH-dependent polymer, and after passing to the intestine (above pH 5.0), the pH-dependent polymer is dissolved or swelled to release the active ingredient. At this time, the pH is prevented from being radically changed by the acidifying agent, thereby preventing the active ingredient from being rapidly released even after the intestine is crossed.

The pH independent polymer refers to a polymer that is insoluble or water soluble upon oral administration regardless of pH. Such pH independent polymers include, for example, ethylcellulose, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer, carboxymethylcellulose sodium (carmellose sodium), low-substituted hydroxypropylcellulose. , Croscarmellose sodium, acacia, tragacanth, propylene glycol alginate, agar powder, gelatin, starch, partially pregelatinized starch, phospholipid (lecithin), and / or glucomannan, and the like are preferred. Cellulose. The pH independent polymer acts to delay the dissolution or swelling of the pH dependent polymer.

The acidifying agent in the formulation of the present invention may be 1 to 15% by weight of the inner core weight, there is a fear that the release control effect is insufficient at less than 1% by weight, the delayed release effect of the active ingredient further increased by more than 15% by weight There is a fear not.

The active ingredient in the formulation of the present invention may be 2 to 20% by weight of the inner core weight. If the content is less than 2% by weight, there is a concern that the desired release rate cannot be obtained because the size of the inner core is relatively increased, and if the amount of the inner core is too small when the amount exceeds 20% by weight, the release delay is difficult and the production process efficiency is low.

The pH-dependent polymer may be 50 to 150 parts by weight based on 100 parts by weight of the pH-dependent polymer in the formulation of the present invention, and if less than 50 parts by weight, there is a risk of drug release without a certain delay after moving to the intestine from above. In case of more than 150 parts by weight, release in the intestine may be delayed more than necessary.

The pH-dependent polymer is 1 to 4 parts by weight based on 100 parts by weight of the inner core of the formulation of the present invention, the pH-independent polymer may be 1 to 4 parts by weight, and may not exhibit a delayed release effect at less than 1 part by weight. There is a fear of increasing the initial delay time more than necessary in more than 4 parts by weight.

In the preparation of the present invention, the active ingredient is released after a delay time of 1 to 4 hours upon oral administration, and may be less than 10% by weight of the total active ingredient within the delay time.

The preparation of the present invention is to be released after the desired delay time even after passing the short blood bolbuterol to the intestine from the top to the highest blood concentration, and administered in the evening (9 ~ 10 o'clock) 2 ~ 4 am to increase asthma symptoms You can get blood levels that are appropriate for your symptoms. Thus, the formulations of the present invention may be for evening administration.

Inner core of the formulation of the present invention can be prepared by the addition of excipients, disintegrants, binders, lubricants, etc. in addition to the acidifying agent and the active ingredient, such as tableting, coating layer is in addition to the pH-dependent polymer and pH-independent polymer Additives, such as a plasticizer and a film auxiliary agent, can be added and formed in the inner core surface by methods, such as a fluidized bed coating method and a fan coating method.

The plasticizer is triacetin, castor oil, diethyl phthalate, dibutyl phthalate, propylene glycol, polyethylene glycol, polyoxyl stearic acid, mibaset, diacecylated monoglyceride, concentrated glycerin, glycerin fatty acid ester, triethyl citrate, dibutyl seba One or more may be selected from cate, diethylphthalate, triethyl citrate, tributyl citrate, and preferred examples are triacetin. The plasticizer is preferably contained in an amount of 0.1 to 20 parts by weight, more preferably 2 to 10 parts by weight based on 100 parts by weight of the polymer constituting the coating layer (including both pH-dependent and pH independent). Less than 2 parts by weight of the coating film may be cracked, and more than 10 parts by weight of the coating film more than necessary, there is a fear of lowering the release rate.

In addition, reference may be made to information posted in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA (Recent Edition), etc., in the preparation of the formulation.

The preparation of the present invention has the effect of showing the efficacy at the time of worsening of asthma symptoms by allowing the active ingredient to be released after the desired delay time even after the passage to the intestine upon oral administration.

Examples are provided to help understand the present invention. The following examples are merely provided to more easily understand the present invention, but the contents of the present invention are not limited by the examples.

In the formulation examples and examples of the present invention, bambuterol hydrochloride (Alti Industries, Inc.), fumaric acid (Samjeon Chemical Co., Ltd.), hydroxypropylmethylcellulose (Shin-Etsu Co., Ltd., Dow Chemical Co., Ltd.), lactose (Meggle Co., Ltd.), ethyl cellulose (Hercules) Company), triacetin (Tokyo Chemical Co., Ltd.), and polyacrylic acid (Lubricazole) were used.

Preparation Example 1-5 Preparation of Inner Core

Specifically, uncoated tablets were prepared by mixing magnesium stearate as a lubricant in powder mixed with hydroxybutyrate hydrochloride, fumaric acid as acidifying agent, hydroxypropylmethylcellulose, and lactose as excipients. Each component and the content constituting the uncoated tablet are shown in Table 1 below.

[Table 1]

Preparation Examples 6 and 7 Inner Core Preparation

The inner core was prepared in the same manner as in Formulation Examples 1 to 5, with the weight of the inner core being 100 mg / tablet and 130 mg / tablet. The amount of hydroxypropylmethylcellulose was 25% of the uncoated weight, the amount of fumaric acid was 5% of the uncoated weight, and magnesium stearate was prepared to be 1% of the uncoated weight.

TABLE 2

Preparation Example 8, 9 Preparation of Inner Core

In the same manner as in Preparation Examples 1 to 5, the inner core was prepared according to the ingredients and contents shown in Table 3 below. The amount of fumaric acid in the tablet was prepared to be 10% by weight and 15% by weight.

[Table 3]

<Examples 1-3> Preparation of coated tablets

6.7 g of polyacrylic acid as a pH-dependent polymer and 1.07 g of triacetin as a plasticizer were dissolved in 675 g of ethanol, and 11.64 g of ethyl cellulose was added as a pH-independent polymer to prepare a coating solution. The ratio of polyacrylic acid and ethyl cellulose in the prepared coating solution is 1: 1.2.

The prepared coating solution was coated on a bare coating prepared in Preparation Example 1 with a pan coater. The coating temperature was set at 60 ° C., bed temperature 40 ° C., spray flow rate 6 ml / min, and fan speed 10 rpm. The coating amount was coated in an amount corresponding to 2.5 wt% (Example 1), 4.0 wt% (Example 2), and 5.5 wt% (Example 3) of the uncoated weight, respectively. The components and contents constituting each coated tablet are shown in Table 4.

[Table 4]

Coated tablets prepared in Preparation Examples 2 to 9 were coated in the same manner as in Example 2 (coating amount 4.0% by weight) to prepare coated tablets. The coated tablets corresponding to the respective uncoated tablets are shown in Table 5.

TABLE 5

Example 12 Coated Tablet Preparation

10.68 g of polyacrylic acid as a pH-dependent polymer and 1.07 g of triacetin as a plasticizer were dissolved in 675 g of ethanol, and 10.68 g of ethyl cellulose was added to a pH independent polymer to stir to prepare a coating solution. The ratio of polyacrylic acid and ethyl cellulose in the prepared coating solution is 1: 1.

The prepared coating solution was coated on the uncoated tablet prepared in Formulation Example 1 with a pan coater. Coating conditions were carried out in the same manner as in Example 1. Components and contents constituting the coated tablet are shown in Table 6 below.

TABLE 6

Example 13 Coating Tablet Preparation

Into the ethanol 675g, 8.51g of polyacrylic acid as a pH-dependent polymer and 0.47g of triacetin as a plasticizer were sufficiently dissolved, and 10.22g of ethyl cellulose was added as a pH-independent polymer to prepare a coating solution. The triacetin amount of the prepared coating solution was 2.5 parts by weight based on 100 parts by weight of the polymer.

The prepared coating solution was coated on the uncoated tablet prepared in Formulation Example 1 with a pan coater. Coating conditions were carried out in the same manner as in Example 1. Components and contents constituting the coated tablet are shown in Table 7 below.

TABLE 7

Experimental Example Dissolution Test

A. Unspecified Dissolution Test

For the uncoated tablet prepared in Preparation Example 1-9, a dissolution test was performed by a basket method of the USP dissolution test method. Eluent (pH6.8) was used for 900ml, the basket stirring speed was 100rpm.

After starting the elution, 5 ml samples were taken at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, and 8 hours, and filtered with a 0.45 μm filter as a sample solution. The dissolution rate of the active ingredient was analyzed from this sample solution. Dissolution rate analysis was performed using the liquid chromatograph method.

B. Coating Tablet Dissolution Test Method

The dissolution test was performed by the basket method of the USP dissolution test method for the coated tablets prepared in Examples 1-13. During elution, the mixture was eluted for 2 hours in a pH1.2 solution by virtual GI (gastrointestinal method), and then changed to pH6.8 for 6 hours. The eluate volume was 900 ml and the basket stirring speed was 100 rpm.

After starting the elution, take a sample in pH1.2 solution for 1 or 2 hours, change the eluent to pH6.8, and take 5ml samples at 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours at pH6.8. What filtered on a 0.45 micrometer filter was used as the test liquid. The dissolution rate of the active ingredient was analyzed from this sample solution. Dissolution rate analysis was performed using the liquid chromatograph method.

C. Uncoated Tablets of Formulation Examples 1-5

Table 8 shows the dissolution test results for the uncoated tablet prepared in Formulation Examples 1-5.

[Table 8]

As a result of the dissolution test for the uncoated tablet prepared in Formulation Examples 1 to 5, it can be seen that the dissolution pattern is different depending on the type of hydroxypropyl methyl cellulose as an excipient.

D. Coating Tablets of Examples 1-3

The dissolution test results of the coated tablets prepared in Examples 1 to 3 are shown in Table 9 and FIG. 1. 1 is a graph showing the dissolution test results, wherein the x-axis shows time (hr) and the y-axis shows dissolution rate (%).

TABLE 9

The coated tablet prepared in Example 1 exhibited a delayed release effect up to 2 hours, exhibited a dissolution rate of more than 10% by weight at 3 hours, and rapidly releases the active ingredient from 3 hours. Examples 2 and 3 showed a delayed release effect up to 3 hours and confirmed that the active ingredient was released from 4 hours. These results indicate that the release delay effect can be controlled by the coating amount.

E. Coating Tablets of Examples 4-7

Table 10 shows the results of the dissolution test of the coated tablets of Examples 4 to 7 prepared by coating the uncoated tablets of Formulation Examples 2 to 5.

TABLE 10

Unlike the dissolution test results for the uncoated tablets of Formulation Examples 2 to 5, the coating tablets of Examples 4 to 7 showed similar dissolution rates. It can be seen that the formulation of the present invention is not significantly affected by excipients such as hydroxypropylmethylcellulose contained in the inner core, and can be controlled by the coating layer in the formulation of the present invention including a pH-dependent polymer and a pH-independent polymer. have.

F. Coated Tablets of Examples 8-9

The dissolution test results for the coated tablets of Examples 8 to 9 are shown in Table 11 and FIG. Figure 2 is a graph showing the dissolution test results, x-axis shows the time (hr), y-axis shows the dissolution rate (%).

TABLE 11

From the above results, it can be seen that the release delay time is similar even if the uncoated weight is changed. That is, it can be seen that the formulation of the present invention can be formulated to have a desired release delay time even when the uncoated weight is changed.

G. Coating Tablets of Examples 10-11

The dissolution test results of the coated tablets of Examples 10 to 11 are shown in Table 12.

[Table 12]

The coated tablets of Example 10 (containing 10% by weight of fumaric acid) and Example 11 (containing 15% by weight of fumaric acid) and the coated tablets of Example 8 (containing 5% by weight of fumaric acid) exhibit similar release delay times, and the elution graph of Example 8 It can be seen that the slope is larger than that of Examples 10 and 11. From the above results it can be seen that by controlling the amount of the acidulant in the formulation of the present invention, it is possible to control the dissolution of the active ingredient. In addition, when the amount of fumaric acid is more than a certain amount, it can be seen that the increase in usage does not significantly affect the dissolution pattern.

H. Coated Tablets of Example 12

The dissolution test results for the coated tablets of Example 12 are shown in Table 13. In addition, the results of the coated tablets of Example 12 together with the experimental results for the coated tablets of Example 2 are shown in FIG. Figure 3 is a graph showing the dissolution test results, x-axis shows the time (hr), y-axis shows the dissolution rate (%).

TABLE 13

It can be seen from the above results that the coated tablet of Example 12 was released after 2 hours of delay time.

Elution test results of the coated tablet of Example 12 (EC: PAA = 1: 1) As shown in FIG. 3, the slope of the dissolution graph was reduced as compared to Example 2 (EC: PAA = 1.2: 1) while the emission delay time was short. You can see something similar to These results indicate that the formulation of the present invention can be controlled by controlling the ratio of the pH-dependent polymer and the pH-independent polymer in the coating layer.

Figure 1 is a graph of dissolution test results for the formulation of Examples 1-3.

Figure 2 is a graph of dissolution test results for the formulations of Examples 8 and 9.

Figure 3 is a graph of dissolution test results for the formulations of Examples 2 and 12.

Claims (13)

An inner core including an acidifying agent and bambuterol or a pharmaceutically acceptable salt thereof and a coating layer for coating the surface of the inner core, wherein the coating layer comprises a pharmaceutical agent comprising a pH dependent polymer and a pH independent polymer simultaneously. As an agent, The pH dependent polymer is polyacrylic acid, sodium alginate, hydroxyalkylcellulose phthalate, sodium cellulose acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose At least one selected from the group consisting of cellulose acetate phthalate, methacrylic acid-ethyl acrylate copolymer and methacrylic acid-methyl methacrylate copolymer, The pH independent polymers are ethylcellulose, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer, carboxymethylcellulose sodium (carmellose sodium), low substituted hydroxypropylcellulose, croscarmellose At least one member selected from the group consisting of sodium, acacia, tragacanth, propylene glycol alginate, agar powder, gelatin, starch, partially pregelatinized starch, phospholipid (lecithin) and glucomannan, The preparation is a pharmaceutical formulation that is released after a delay of 1 to 4 hours when the active ingredient is administered orally, wherein less than 10% by weight of the total active ingredient is released within the delay time. The pharmaceutical formulation of claim 1, wherein the active ingredient is bambuterol hydrochloride. According to claim 1, wherein the acidifying agent is fumaric acid, succinic acid, tartaric acid, lactic acid, citric acid, alginic acid, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, acetic acid, ascorbic acid, benzoic acid, malic acid, etetic acid, propionic acid, A pharmaceutical formulation that is one or more selected from sorbic acid, stearic acid, aspartic acid, and glutamic acid. delete delete The pharmaceutical formulation of claim 1, wherein the acidifying agent is fumaric acid, the active ingredient is bambuterol hydrochloride, the pH dependent polymer is polyacrylic acid, and the pH independent polymer is ethylcellulose. The pharmaceutical formulation of claim 1, wherein the acidifying agent in the formulation is 1-15 wt% of the inner core weight. The pharmaceutical formulation of claim 1, wherein the active ingredient is 2-20% by weight of the inner core weight. The pharmaceutical formulation of claim 1, wherein the pH independent polymer is 50 to 150 parts by weight based on 100 parts by weight of the pH dependent polymer. The pharmaceutical preparation according to claim 1, wherein the pH dependent polymer is 1-4 parts by weight and the pH independent polymer is 1-4 parts by weight based on 100 parts by weight of the inner core. The pharmaceutical formulation of claim 1, wherein the coating layer further comprises a plasticizer. The pharmaceutical formulation of claim 11, wherein the plasticizer is 0.1 to 20 parts by weight based on 100 parts by weight of the pH dependent polymer and the pH independent polymer in the coating layer. delete

Images