TWI661842B - Orally medicinal composition and structure thereof - Google Patents

Abstract

The invention relates to an oral pharmaceutical composition and its structure, which are composed of acid-labile physiologically active ingredients and basic amino acids in different layers, thereby improving acid-labile physiologically active ingredients that cause poor storage stability. problem.

Description

Oral pharmaceutical composition and structure

The present invention relates to an oral pharmaceutical composition, and more particularly, to an oral pharmaceutical composition containing acid-labile physiologically active ingredients with good storage stability and its structure.

Lansoprazole can inhibit the protopump, which is the inhibitory activity of (H + K) -ATPase, in gastric mucosa cells, so it can strongly and continuously inhibit gastric acid secretion. In Taiwan Patent Publication Nos. 280770 and 359614, lansoprazole is disclosed as a medicine for treating gastric ulcer, duodenal ulcer, gastroesophageal reflux disease-erosive reflux esophagitis.

According to the judgment criteria of the biopharmaceutical classification system, lansoprazole is a BCS class II drug, and its drug properties are low solubility and high permeability. Lansoprazole is extremely unstable and easily degraded into dark red degradation products under high acidity, high alkalinity, high humidity and high temperature environments. It has poor acid resistance and storage stability, which is a bottleneck that the formulation industry cannot easily overcome.

Taiwan Patent Publication No. I245642 discloses a stable oral dosage form of an acid-labile drug, which uses a compound selected from sodium alginate, methyl Copolymers of butyl acrylate: (2-dimethylaminoethyl) methacrylate: methyl methacrylate with a molar ratio of 1: 2: 1 and mixtures thereof as polymer binders, and the polymer bonds The aqueous solution of the agent has a pH value greater than 6, which can improve the stability of lansoprazole and reduce the amount of conventional stabilizers.

Taiwan Patent Bulletin No. I309168 discloses a solid pharmaceutical composition of a proton pump inhibitor, wherein the content of the proton pump inhibitor is about 2 mg to about 300 mg, and the proton pump inhibitor is selected from the group consisting of bluesoprazole ( lansoprazole) or a mirror image thereof, a base salt, an isomer thereof, or a salt thereof, and the group thereof is parenterally coated; and at least one buffering agent.

However, the lansoprazole and the polymer binder or buffer used for stabilization in the above-mentioned case are directly provided on the same layer, and their anti-acid and stabilization effects are not good. In view of this, there is an urgent need to develop new compositions and structures to improve the shortcomings such as poor storage stability caused by lansoprazole.

Therefore, one aspect of the present invention is to provide an oral pharmaceutical composition, which is composed of acid-labile physiologically active ingredients and basic amino acids in different layers, thereby improving the storage stability of the conventional oral pharmaceutical composition. Sexual problems.

According to the above aspect of the present invention, an oral pharmaceutical composition is proposed. In one embodiment, the aforementioned pharmaceutical composition includes a drug layer, an isolation layer covering the drug layer, and an enteric coating layer covering the isolating layer, wherein the drug layer may include an effective amount of an acid-labile physiologically active component, an isolating layer, and an enteric coating layer. At least one of them may include a basic amino acid. Based on acid-labile physiologically active ingredients The content is 100 weight percent, and the content of the basic amino acid may include, but is not limited to, 0.03 weight percent to 200 weight percent.

In the above embodiment, the aforementioned acid-labile physiologically active component is lansoprazole or an optically active isomer thereof.

In the above embodiments, the aforementioned isolation layer may include a basic amino acid.

In the above embodiment, the basic amino acid may include, but is not limited to, arginine, lysine, histidine, and tryptophan.

In the above embodiments, the dosage form of the aforementioned oral pharmaceutical composition may be, for example, microparticles, tablets, or capsules.

The oral pharmaceutical composition to which the present invention is applied is configured by excluding acid-labile physiologically active components and basic amino acids in the same layer, thereby improving the problem of poor storage stability caused by acid-labile physiologically active components.

In order to make the above and other objects, features, advantages, and embodiments of the present invention more comprehensible, the detailed description of the drawings is as follows: [FIG. 1A] to [FIG. 1L] show one to three embodiments according to the present invention Tablets (Figure 1G to Figure 1L), Tablets of Comparative Examples 1 to 2 (Figure 1C to Figure 1F), and commercially available products (Figure 1A to Figure 1B) after 0 days (Figure 1A, Figure 1C, Figure 1E, Figure 1G, Fig. 1I, Fig. 1K) or 7 days (Fig. 1B, Fig. 1D, Fig. 1F, Fig. 1H, Fig. 1J, Fig. 1L) of the results of the storage stability test.

According to the foregoing description, the present invention provides an oral pharmaceutical composition and a structure thereof, which are configured by separating acid-labile physiologically active components and basic amino acids in different layers, which can effectively improve storage stability caused by acid-labile physiologically active components Sex.

In one embodiment, the aforementioned pharmaceutical composition includes a drug layer, an isolation layer covering the drug layer, and an enteric coating layer covering the isolation layer, which are described below.

Drug layer

The aforementioned drug layer may contain an effective amount of an acid-labile physiologically active ingredient. The aforementioned acid-labile physiologically active ingredient in the present invention refers to a physiologically active ingredient with poor stability in an acidic environment, such as lansoprazole [also known as 2-[[(3-methyl-4- (2, 2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole] or an optically active isomer thereof.

In the above embodiments, the drug layer may be coated on the microparticles. Generally, microparticles can be prepared from excipients that are not pharmaceutically active and do not react with lansoprazole. In one embodiment, the aforementioned microparticles may use conventional excipients, such as microcrystalline cellulose (MCC), sucrose, starch, any combination of the above, or the same commercially available as the above materials. product.

In an embodiment, the particle size of the core is not limited, and can be arbitrarily adjusted according to the size of the drug layer, the isolation layer, the casing layer and the capsule to be filled. However, the smaller the particle size is, the more the components of each layer tend to stick to each other in the subsequent coating process, and it is more difficult to achieve uniform coating. Generally speaking, the particle size of the core can be a screen size of 18 to 60, such as a sieve Screen numbers 18 to 30, 30 to 40, 40 to 50 or 50 to 60.

In one embodiment, the aforementioned drug layer may optionally be added with a pharmaceutically acceptable adhesive. Specific examples thereof may include, but are not limited to, hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose ( hydroxypropylmethylcellulose (HPMC), etc.

In other embodiments, the above-mentioned drug layer can further selectively add a pharmaceutically acceptable anti-adhesive agent, and specific examples thereof may include, but are not limited to, talc, stearic acid, and stearates. , Sodium stearyl fumarate and colloidal silicon dioxide.

Isolation layer

The invention is to cover the acid-labile physiologically active component with a material layer containing a basic amino acid to protect the acid-labile physiologically active component from passing through the gastric juice and reaching the small intestine for release. In one embodiment, the aforementioned material layer may be, for example, at least one of a barrier layer and a casing layer. In one example, the isolation layer may include a basic amino acid.

The aforementioned basic amino acids in the present invention may include, but are not limited to, arginine, lysine, histidine, and tryptophan. It is explained here that the acid-labile physiologically active ingredient of the oral pharmaceutical composition of the present invention is disposed on the same layer as the basic amino acid, thereby improving problems such as poor storage stability of the conventional oral pharmaceutical composition. If the acid-labile physiologically active component and the basic amino acid are provided on the same layer, the subsequent preparation of the drug is liable to have the problem of poor storage stability.

The aforementioned basic amino acids have a specific content for effective protection Acid labile physiologically active ingredients pass through gastric juices. In an embodiment, based on the content of the acid-labile physiologically active ingredient being 100% by weight, the content of the basic amino acid may include, but is not limited to, 0.03 to 200% by weight, and greater than 13.33 to 200% by weight. Preferably, 33 to 200 weight percent is more preferred.

In an example, a polymer and / or an anti-adhesive agent may be optionally added to the aforementioned isolation layer, and specific examples thereof may be the same as the polymer and / or the anti-adhesive agent used in the drug layer, and details are not described herein again.

Casing layer

In one embodiment, the casing layer can be coated on the insulation layer to give the coated particles the ability to resist the acidic environment.

In one embodiment, the aforementioned casing layer may include a polymer, such as polymethyl methacrylate (PMMA).

In one example, the aforementioned casing layer may optionally be added with a pharmaceutically acceptable plasticizer. Specific examples thereof may include, but are not limited to, triethyl citrate (TEC) or diethyl phthalate. (diethyl phthalate; DEP) and so on.

In another example, the aforementioned casing layer may optionally be added with a pharmaceutically acceptable anti-adhesive agent, and specific examples thereof may be the same as the anti-adhesive agent used in the drug layer, and will not be repeated here.

In one embodiment, the foregoing oral pharmaceutical composition can be made into microparticles, tablets, capsules, or other dosage forms, but it depends on actual needs, and the present invention is not limited to those listed here.

In yet another embodiment, the drug layer, the isolation layer and the casing layer of the above-mentioned oral pharmaceutical composition may be spray-coated sequentially at a product temperature of 20 ° C to 50 ° C using a conventional fluidized bed granulation equipment. It is evenly coated on particles. In this embodiment, the components of the drug layer, the isolation layer and the casing layer can be separately dissolved or suspended in an aqueous solution, and then spray-coated. Since the spray coating method and the aqueous solution used are any technique well known to those having ordinary knowledge in the technical field to which the present invention pertains, they will not be described in detail.

The aforementioned storage stability in the present invention refers to that after the oral pharmaceutical composition is made into a tablet and stored in a high temperature and high humidity environment for a period of time, the tablet does not change color due to the degradation of lansoprazole (for example, by White becomes purple or black), meets the dissolution specifications (no significant impurities are detected), and has bioequivalence compared with commercially available products.

For example, in one example, after being stored at 50 ° C./80% relative humidity for 7 days, the tablets made of the above-mentioned oral pharmaceutical composition did not cause discoloration substantially. In another example, after storage of the tablets made of the above-mentioned oral pharmaceutical composition at 40 ° C / 75% relative humidity for 6 months, no impurities were clearly detected and met the dissolution specifications. In still another example, the tablets made of the above-mentioned oral pharmaceutical composition have bioequivalence with commercial products.

In other examples, the oral pharmaceutical composition of the present invention may optionally be added with a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier as referred to herein means a carrier, diluent, filler, and / or vehicle that is not itself an active ingredient, but is used to deliver the active ingredient to an individual, or is added to the above composition To improve the processing or storage properties of the composition, or to allow or facilitate the dosage unit of the composition to form excipients suitable for pharmaceutical compositions and convenient administration Agent or any ingredient. The aforementioned pharmaceutically acceptable carriers should not destroy the pharmacological activity of the active ingredient and should be non-toxic when delivering a sufficient therapeutic dose of the active ingredient.

The aforementioned suitable pharmaceutically acceptable carriers may be well known to those generally familiar with the general knowledge of manufacturing pharmaceutical compositions and include, but are not limited to, buffers, diluents, disintegrants, adhesives, adhesives, wetting agents, Polymers, lubricants, slippers, ingredients added to mask or counteract bad taste or odor, dyes, fragrances, and ingredients added to improve the appearance of the composition. Specific examples of the aforementioned pharmaceutically acceptable carrier may include, but are not limited to, citrate buffer, phosphate buffer, acetate buffer, bicarbonate buffer, stearic acid, magnesium stearate, magnesium oxide , Sodium and calcium salts of phosphoric acid and sulfuric acid, magnesium carbonate, talc, gelatin, gum arabic, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starch, gelatin, cellulose (Such as cellulose and alkyl alkyl esters of alkanoic acid), sodium chloride or other salts, liposomes, mannitol, sorbitol, glycerol or powder, polymers (such as polyvinylpyrrolidone, polyethylene Alcohols and polyethylene glycols) and other pharmaceutically acceptable ingredients.

The following uses several embodiments to illustrate the application of the present invention, but it is not intended to limit the present invention. Those with ordinary knowledge in the technical field of the present invention can make various changes and modifications without departing from the spirit and scope of the present invention. Retouch.

Example one

First, according to the microcrystalline cellulose particles listed in Table 1 (Celpere CP203) and other components of the drug layer [containing the binder (Hydroxypropyl Cellulose L (HPC-L), lansoprazole and talc) are mixed in water to form a drug layer suspension solution. The drug layer suspension solution was sprayed on the surface of microcrystalline cellulose particles in a fluidized bed granulator, and after drying, particles coated with the drug layer were obtained.

Next, the components of the isolation layer (including the binder HPC-L, spermine and talc) listed in Table 1 were mixed in water to form an isolation layer suspension solution, and the isolation layer suspension solution was sprayed to a fluidized bed granulator. On the microparticles containing the drug layer, the microparticles coated with the barrier layer can be obtained after drying the coat.

Then, the components of the casing layer (containing the polymer Eudragit L30D, plasticizer TEC, and talc) were mixed into the casing suspension layer solution as shown in Table 1. Then, the casing was sprayed in a fluidized bed granulator by spraying. The layer suspension solution is coated on the particles containing the insulation layer, and the coat is dried to obtain the particles coated with the enteric coating layer. The above process is a spraying step of each layer using a product temperature of 20 ° C to 50 ° C and an amount of air entering to avoid each The particles at the process stage are sticking to each other, and the above-mentioned air intake can be made by conventional methods, which is well known to those with ordinary knowledge in the technical field to which the present invention pertains, and will not be repeated here. After the casing coating is completed, it can be used The conventional drying method and drying temperature dry the particles.

Subsequently, the microparticles coated with the enteric coating layer are uniformly mixed with the ingredients of the tablets listed in Table 1, and then tabletted by a high-speed rotary tableting machine. Subsequent evaluation of the microparticles and lozenges obtained above.

Examples 2 to 3 and Comparative Examples 1 to 2

Examples 2 to 3 and Comparative Examples 1 to 2 were performed in the same manner as in Example 1 according to the usage amounts listed in Table 1, except that the components and / or ratios were different.

Evaluation method of storage stability

1. Appearance color change

The particles of Example 1 to Example 3 and Comparative Example 1 to Comparative Example 2 were partially translucent polyvinylidene chloride (Polyvinylidene chloride; PVDC) as the packaging material for storing the finished product and placed at 50 ° C. / 80% relative humidity or 40 ° C / 75% relative humidity to evaluate the storage stability of the microparticles of Examples 1 to 3, Comparative Examples 1 to 2, and compare with the commercially available product Takepron® OD (as Aclar ( (Poly-chloro-tri-fluoro-ethylene (PCTFE) film as a packaging material for finished products). Compare the appearance and color over time. The results are shown in Figures 1A to 1L and Table 1. Show.

Please refer to FIG. 1A to FIG. 1L, which show microparticles (FIG. 1G to FIG. 1L), comparative examples 1 to 2 (FIG. 1C to FIG. 1F), and commercial products (FIG. (Figure 1B) After 0 days (Figure 1A, Figure 1C, Figure 1E, Figure 1G, Figure 1I, Figure 1K) or 7 days (Figure 1B, Figure 1D, Figure 1F, Figure 1H, Figure 1J, Figure 1L), storage stability Photos of results of sex tests. FIGS. 1A to 1B are photos of particles of commercially available products, FIGS. 1C to 1D are photos of particles of Comparative Example 1, FIGS. 1E to 1F are photos of particles of Comparative Example 2, and FIGS. 1G to 1H are particles of Example 1. 1I to FIG. 1J are photos of the particles of the second embodiment, and FIGS. 1K to 1L are photos of the particles of the third embodiment.

In Table 1, the drawing number "◎" indicates that the particle color has not changed significantly (for example, white), the drawing number "○" indicates that the particle color has changed slightly (for example, white to pink), and the drawing number "×" indicates that the particle color has changed from white It turns purple or black.

From the above results, it can be seen that although the particles of Examples 1 to 3 used the packaging material PVDC with poor storage capacity, but did not produce discoloration, as shown in Table 1 and Figures 1G to 1L, it represents better storage stability and can effectively avoid Lanso Degradation of prazole. In contrast, the particles of Comparative Examples 1 to 2 are obviously discolored, as shown in Table 1 and FIG. 1C to FIG. 1F, which indicates that the storage stability is not good and Lansora cannot be avoided Azole degradation. In addition, although the commercial product Takepron® OD uses Aclar, which is better than PVDC, as the packaging material for the finished product, it will still discolor. .

2. Impurity analysis

Next, the tablets of Example 3 and the commercial product Takepron® OD were subjected to the above-mentioned storage stability test, and the impurities were analyzed by HPLC. The results are shown in Table 2 (commercial product Takepron® OD) and Table 3 (Example 3 of Example 3). Lozenges).

In Tables 2 and 3, the impurity A refers to 2-[(RS)-[[3-methyl-1-oxo-4- (2,2,2-trifluoro) represented by formula (I). Ethoxy) pyridin-2-yl] methyl] sulfinyl] -1H-benzimidazole)]] and its optically active isomer [2-[(RS)-[[3-methyl-1- oxido-4- (2,2,2-trifluoro ethoxy) pyridin-2-yl] methyl] sulfinyl] -1 H -benximida zole)]] and its optically active isomers; impure B refers to formula (II) 2-[[[[3-Methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methyl] thiofluorenyl] -1 H -benzimidazole)] shown [2-[[[[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methyl] sulfonyl] -1 H -benximidazole)]] and its optically active isomers, where the formula ( X of II) represents SO ₂ ; and impure E refers to 2-mercaptobenzimidazole represented by formula (III) and its optically active isomer.

The results in Tables 2 and 3 show that the oral pharmaceutical composition and the tablets thereof of Examples 1 to 3 have no significant impurities detected, and meet the dissolution specifications.

3. Bioequivalence test

Combining the tablet of Example 3 with the commercial product Takepron® OD A bioequivalence test was conducted. The experimental test method was to allow 8 subjects to fast for at least ten hours before taking lansoprazole orally dissolving tablets, and for four hours after taking the drug, randomized, single-dose and two-way crossing the way. At the following time points (0, 0.25, 0.5, 1, 1.33, 1.67, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours) after each administration, plasma samples were taken to measure blood The results of concentration and pharmacokinetic analysis are shown in Table 4 and Table 5.

The results in Tables 4 and 5 show that the data obtained from the pharmacokinetic parameters of the tablet of Example 3 and the commercial product Takepron® OD are not statistically significant, so it is judged that the two are biologically equivalent. Sex.

In summary, although the present invention uses specific ingredients of oral pharmaceutical compositions, specific dosage forms, or specific evaluation methods as examples to illustrate the oral pharmaceutical composition and its structure of the present invention, any one in the technical field to which the present invention belongs has the usual The knowledgeable person knows that the present invention is not limited to this, and the oral pharmaceutical composition and its structure of the present invention can also be performed using other ingredients, other dosage forms, or other evaluation methods without departing from the spirit and scope of the present invention.

As can be seen from the above examples, the oral pharmaceutical composition and its structure of the present invention have the advantage that the acid-labile physiologically active ingredient and the basic amino acid are excluded from the same layer, which effectively improves the storage stability of the conventional oral pharmaceutical composition. Sexual problems.

Although the present invention has been disclosed as above with several embodiments, it is not intended to limit the present invention. Any person with ordinary knowledge in the technical field to which the present invention pertains can make various modifications without departing from the spirit and scope of the present invention. more Motion and retouching, so the scope of protection of the present invention shall be determined by the scope of the attached patent application.

Claims (7)

An oral pharmaceutical composition includes: a drug layer covering a microparticle, wherein the drug layer contains an effective dose of an acid-labile physiologically active ingredient; an isolation layer covering the drug layer; and an enteric coating layer, the coating Covering the isolation layer, wherein at least one of the isolation layer and the casing layer comprises a basic amino acid, and wherein the content of one of the physiologically active components based on the acid instability is 100% by weight, and the basic amino acid One content is from 0.03 weight percent to 200 weight percent, and the acid-labile physiologically active ingredient and the basic amino acid are excluded from the same layer. The oral pharmaceutical composition according to item 1 of the scope of the patent application, wherein the acid-labile physiologically active ingredient is Lansoprazole or an optically active isomer thereof. The oral pharmaceutical composition according to item 1 of the patent application scope, wherein the barrier layer comprises the basic amino acid. The oral pharmaceutical composition according to item 1 of the application, wherein the basic amino acid is selected from the group consisting of arginine, lysine, histidine, and tryptophan. The oral pharmaceutical composition according to item 1 of the scope of the patent application, wherein a dosage form of the oral pharmaceutical composition is a microparticle, a lozenge, or a capsule. The oral pharmaceutical composition according to item 1 of the scope of patent application, wherein the content based on the acid-labile physiologically active ingredient is 100% by weight, and the content of the basic amino acid is greater than 13.33% by weight to 200% by weight . The oral pharmaceutical composition according to item 1 of the scope of the patent application, wherein the content based on the acid-labile physiologically active ingredient is 100% by weight, and the content of the basic amino acid is from 33% to 200% by weight.