KR102258372B1 - Release Controlled Oral Formulation of Bepotastine - Google Patents

Abstract

The present invention relates to a controlled-release oral formulation containing bepotastine, and more specifically, an immediate release layer containing the bepotastine; And it provides a controlled-release oral formulation comprising a sustained-release layer containing the bepotastine.

Description

Controlled Oral Formulation of Bepotastine {Release Controlled Oral Formulation of Bepotastine}

The present invention relates to a controlled release oral formulation containing bepotastine.

Bepotastine is ((S)-4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidin-1-yl]butanoic acid) having the structure of Formula 1 below. , Allergic rhinitis, chronic urticaria, and pruritus associated with skin diseases. Bepotastine is a selective antihistamine that has few side effects such as drowsiness and arrhythmia. Allergic rhinitis is a symptom in which a runny nose, sneezing, or stuffy nose occurs as an antigen-antibody reaction occurs due to an allergen-inducing substance, and is a disease that poses a great burden on public health in terms of prevalence, quality of life, or health economics. Among allergic rhinitis treatments, antihistamines are the most widely used as primary treatments. Among them, selective antihistamines such as bepotastine not only suppress the symptoms of allergic rhinitis, but also do not cross the blood brain barrier, so conventional antihistamines are used. Eggplant has the advantage of not showing side effects. In addition to these advantages, Bepotastine is an antihistamine that exhibits excellent clinical effect and rapid drug efficacy, and has little interaction with other drugs, and was first disclosed as a racemate compound in Japanese Laid-Open Patent Publication No. Hei 2-25465. Currently, Bepotastine is developed as an immediate-release formulation and is marketed by Mitsubishi Tanabe Corporation under the trade name Tarion.

[Formula 1]

However, despite these advantages, bepotastine has a problem that it is inconvenient to take bepotastine because it must be administered twice a day compared to loratadine or cetirizine, which are other antihistamines of the same family, administered once a day. Therefore, Korean Patent Application Publication No. 2012-0083276 attempted to develop a pharmaceutical formulation that can be administered once a day using bepotastine, a pharmaceutically acceptable salt, and a water-insoluble basic substance. It can be confirmed that polyethylene oxide, which is an stimulating polymer, was used for optical stability, and as a single tablet, as the initial release was delayed, it could be confirmed that it was not suitable for antihistamine preparations requiring rapid expression of the drug effect.

On the other hand, Korean Patent Application Publication No. 2015-0138104 intends to develop a bilayer tablet formulation for once-a-day administration, including glyceryl behenate, which is a hydrophobic lipid excipient. However, in the case of the tablet of the present invention, it takes 10 hours or more for dissolution of 80% or more to occur. Bepotastine is a substrate of P-gp (Permiability-glycoproteins) in the body, and if it remains in the lower part of the small intestine for a long time, it is highly likely to be degraded, resulting in a decrease in bioavailability.

Korean Patent Application Publication No. 2017-0141524 for another two-layered bepotastine formulation has the highest blood concentration of the active ingredient within 1 hour of drug administration due to the immediate release of the drug from the immediate release layer. It tends to be lost, and it can be seen that the blood concentration is not maintained for a long time. Therefore, it is important to ensure stability by preventing this.

According to the PK Experimental Example of Korean Patent Application Publication No. 2015-0138104, the total amount of bepotastine contained per tablet increases to 25 mg, and there is a problem of increasing the volume and the possibility of side effects due to the accompanying excessive dose. In addition, bepotastine is a substrate of P-gp that is present in a large amount in the lower intestine, and if the initial release is delayed when designing a sustained-release drug, the bioavailability may significantly decrease toward the lower intestine.

Accordingly, the present inventors aim to provide a controlled-release oral formulation that can be administered once a day and maintains a fast antihistamine effect at the initial stage of administration and the effect is maintained continuously in order to solve the above problems.

In order to solve the above problems, the present invention is a controlled-release oral formulation containing bepotastine or a pharmaceutically acceptable salt thereof, from about 20% to about 40% by weight, preferably based on the total weight of the bepotastine. Preferably, an immediate release layer comprising from about 25% to about 30% by weight of bepotastine; And it provides a controlled-release oral formulation comprising a sustained release layer containing about 60% to about 80% by weight, preferably about 70% to about 75% by weight of bepotastine based on the total weight of the bepotastine. do.

In one embodiment, when measured by a paddle method (USP Apparatus 2) of 37°C±0.5°C and 50 rpm using a pH 1.2 test solution, more than 20% of Bepotastine is eluted after 1 hour with respect to the total weight of Bepotastine. It can be.

In one embodiment, when measured by a paddle method (USP Apparatus 2) of 37°C±0.5°C and 50 rpm using a pH 6.8 test solution, 80% or more of Bepotastine is eluted after 12 hours with respect to the total weight of Bepotastine. And, after administration of the formulation, the drug may be released at a zero-order release rate.

In one embodiment, the controlled-release oral formulation may be administered once a day.

In one embodiment, the sustained-release layer included in the controlled-release oral formulation may not contain microcrystalline cellulose.

In one embodiment, the sustained-release layer included in the controlled-release oral formulation may include a lactose hydrate.

In one embodiment, the sustained-release layer included in the controlled-release oral formulation may include about 30% to about 35% lactose hydrate based on the total weight of the sustained-release layer.

In one embodiment, the sustained-release layer included in the controlled-release oral formulation may include one or more binders selected from the group consisting of polyethylene glycol, hydroxypropylcellulose, and hydroxypropylmethylcellulose. In this case, the binder may be HPMC 4.5 CPS, HPMC K15M, and/or HPMC K4M.

In one embodiment, the immediate-release layer included in the controlled-release oral formulation may include mannitol.

In one embodiment, the immediate-release layer included in the controlled-release oral formulation may include microcrystalline cellulose.

In one embodiment, the controlled-release oral formulation is based on 100 parts by weight of the total weight, cellulose propionate, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate. It may be one comprising 1 to 5 parts by weight of one or more coating agents selected from the group consisting of succinate.

In one embodiment, the bepotastine or a pharmaceutically acceptable salt thereof included in the controlled-release oral formulation may be present in an amount of 20 mg.

The controlled-release oral formulation of the present invention can be administered once a day, but can exhibit a rapid antihistamine effect at the beginning of administration and a release-controlled effect in which the effect is continuously maintained.

1 shows the results of dissolution analysis for the (1) pH 1.2 test solution and (2) the pH 6.8 test solution of Examples 1 to 3.
Figure 2 shows the dissolution analysis results for the (1) pH 1.2 test solution and (2) pH 6.8 test solution of Comparative Examples 1 and 2.
3 shows dissolution analysis results for (1) a pH 1.2 test solution and (2) a pH 6.8 test solution of Comparative Examples 3 and 4;
4 shows the dissolution analysis results of (1) a pH 1.2 test solution and (2) a pH 6.8 test solution of Comparative Examples 5 and 6.
5 shows the pharmacokinetic analysis results of Examples 1 to 3.
6 shows the pharmacokinetic analysis results of Comparative Example 2.
7 shows the pharmacokinetic analysis results of Comparative Examples 5 and 6.

The present invention provides a controlled-release oral formulation comprising bepotastine or a pharmaceutically acceptable salt thereof.

In the controlled-release oral formulation of the present invention, bepotastine or a pharmaceutically acceptable salt thereof (hereinafter, collectively referred to as "bepotastine" for convenience, and the description of "bepotastine" below is a pharmaceutically acceptable salt thereof. Includes) is pharmacologically effective, or includes a drug that is pharmacologically effective by a chemical or enzymatic method in the body, specifically bepotastine drug itself, its precursor, such as a pharmaceutically acceptable salt or ester thereof Can be used. Bepotastine is included in one controlled-release oral formulation, and thus it is possible to solve a problem in the process.

The "bepotastine" of the present invention is a free base, a pharmaceutically acceptable salt, a pharmacologically active metabolite of bepotastine and a pharmaceutically acceptable salt thereof, a hydrate, an enantiomer thereof, or a racemic compound thereof. Includes.

The term "pharmaceutically acceptable salt" as used in the present invention means a salt prepared by a conventional method, and specifically includes salts derived from the following inorganic acids and organic acids and bases that are pharmacologically or physiologically acceptable. It is not limited to this. For example, hydrochloric acid, bromic acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid , Formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. The salt of bepotastine according to the present invention may be bepotastine besylate.

"Zero-order release rate" means a substantially constant release rate, that the drug is dissolved in a solution in the environment of use at a substantially constant rate. More specifically, it means that the rate of release of the drug varies as a function of time by about 30% or less, preferably about 20% or less, more preferably about 10% or less, more preferably about 5% or less, wherein Measurements are measured over a period in which the cumulative release is between about 25 and about 75%, preferably between about 25% and about 90% of the total weight of the drug in the formulation.

The term “about” is defined as close as understood by one of ordinary skill in the art, and in one non-limiting embodiment, the term is within 10%, preferably within 5%, more preferably 1%. Within, and most preferably within 0.5%.

The amount of bepotastine or its pharmaceutically acceptable salt of the present invention is about 5 to about 40 mg. In a preferred embodiment, the amount of bepotastine or a pharmaceutically acceptable salt thereof to be used is about 5 to about 25 mg. In another embodiment, the amount of bepotastine or a pharmaceutically acceptable salt thereof to be used is about 5 to about 20 mg.

In one embodiment, the controlled-release oral formulation according to the present invention may include an immediate-release layer and a sustained-release layer to control release. As immediate-release excipients and sustained-release excipients with different molecular weight and viscosity gradually disintegrate in the eluate with a time difference, and the release rate of the active ingredient bepotastine can be controlled by using coatings with different elution rates for pH. . In this case, the immediate-release layer and the sustained-release layer excipient may be understood as a binder by one of ordinary skill in the art. In the present invention, high viscosity refers to a case where the viscosity is 10,000 cP or more at 20°C, and low viscosity refers to a case where the viscosity is 4,000 cP or less at 20°C. In a preferred embodiment, the high viscosity hydrophilic excipient is a hydrophilic excipient having a viscosity of at least 15,000 cP at 20°C. In the case of using a hydrophilic excipient having a high viscosity, a release pattern of a drug that exhibits both initial immediate release and mid- to long-term sustained release can be implemented by adjusting the ratio with the hydrophobic excipient.

Binders that can be included in the sustained-release layer of the controlled-release oral formulation of the present invention are polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyethylene oxide, polyethylene glycol, xanthan gum, guar gum, locust It may be selected from bean gum, sodium alginate, carrageenan, chitosan, carbopol, and sodium alginate, but is not limited thereto. In a preferred embodiment, the high viscosity hydrophilic excipient is polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyethylene oxide, and/or polyethylene glycol.

Hydrophobic excipients that may be included in the controlled-release oral formulation of the present invention include ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate, cellulose triacetate, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate and hydroxy. Fatty acids and fatty acid esters such as glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, cetyl palmitate, glyceryl monooleate and stearic acid; Fatty acid alcohols such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol; You can choose from waxes such as carnauba wax, beeswax, and microcrystalline wax. In a preferred embodiment, the hydrophobic excipient is ethylcellulose, polyvinyl acetate, polyvinyl chloride, cellulose acetate, cellulose propionate, cellulose acetate, cellulose triacetate, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate. And/or hydroxypropylmethylcellulose acetate succinate. However, the above-mentioned additives for controlling the release are not limited to those described above as examples of listing hydrophilic polymers, hydrophobic polymers and fatty acids, fatty acid esters, fatty alcohols, waxes, and the like.

The controlled-release oral formulation of the present invention comprises an immediate release layer comprising about 20% to about 40% by weight, preferably about 25% to about 30% by weight of bepotastine based on the total weight of the bepotastine; And a sustained-release layer including about 60% to about 80% by weight, preferably about 70% to about 75% by weight of bepotastine based on the total weight of the bepotastine. When less than about 20% by weight of bepotastine is included in the immediate-release layer or more than about 80% by weight of bepotastine is included in the sustained-release layer based on the total weight of bepotastine, the initial release of bepotastine is small, so rapid-acting There is a problem that it is not secured. When more than about 40% by weight of bepotastine is included in the immediate release layer or less than about 60% by weight of bepotastine is included in the sustained release layer, the loss of bepotastine is rapid, so sustained release There is a problem that does not indicate.

The sustained-release layer included in the controlled-release oral formulation of the present invention may not contain microcrystalline cellulose. When microcrystalline cellulose is included, the bulk density of the granules is lowered, resulting in a disadvantage in that the filling property is reduced.

The controlled-release oral formulation of the present invention may contain 10 parts by weight or less, preferably 1 part by weight to 5 parts by weight, of a pH-dependent release-controlled coating agent based on 100 parts by weight based on the total weight. When the coating agent is less than 1 part by weight, control of initial dissolution does not occur, and since bepotastine is rapidly released, there is a problem in that the sustained-release property is lost. On the other hand, when the coating agent is more than 10 parts by weight, there is a problem that elution does not occur at pH 1.2.

The controlled-release oral formulation of the present invention uses purified water as a test solution. Preferably, it is measured by a paddle method (USP Apparatus 2) of 37° C.±0.5° C. and 50 rpm under the condition of a test solution containing purified water. When administered in a pH 1.2 test solution, the controlled-release oral formulation of the present invention can release 20% or more of the active ingredient bepotastine after 1 hour based on the total weight. In addition, the controlled-release oral formulation of the present invention can release more than 80% of the active ingredient bepotastine after 12 hours based on the total weight of the drug when administered in a pH 6.8 test solution, and at a zero-order release rate after administration of the formulation. Drugs can be released. Due to this release behavior, the present invention increases the amount of release within 1 hour after administration to 20% or more, while maintaining the characteristics of antihistamine, which is important for a rapid effect at the beginning of administration, and sustained release at a constant rate for up to 12 hours after the initial release. It makes it possible to avoid the problem that the bioavailability decreases markedly as it goes down the small intestine.

The controlled-release oral formulation of the present invention may contain an alkalinizing agent. The alkalizing agent serves to maintain the optical stability of Bepotastine, which is unstable in an acidic environment in the formulation. Examples include calcium silicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, L-arginine, meglumine, calcium carbonate, sodium carbonate, disodium hydrogen phosphate, sodium hydrogen carbonate, magnesium carbonate, magnesium hydroxide, light nitrate magnesium oxide, magnesium oxide, and among them It is a mixture of two or more. In a preferred embodiment, the alkalinizing agent is calcium silicate and/or calcium hydrogen phosphate.

The immediate release layer is formulated with additives found to be suitable for combination by the present invention to provide rapid release of bepotastine. A therapeutically effective amount of 20 to 40% bepostatin or a pharmaceutically acceptable salt thereof and excipients selected from at least one selected from D-mannitol, microcrystalline cellulose and lactose, polyethylene glycol 6000, hypromellose, hydroxypropyl cellulose And a lubricant selected from one or more binders selected from, stearic acid or a magnesium salt thereof, stearyl fumaric acid or sodium salt thereof, and colloidal silicon dioxide.

The sustained release layer is formulated with additives found to be suitable for combination by the present invention to provide sustained release of bepotastine. A therapeutically effective amount of 60-80% bepostatin or a pharmaceutically acceptable salt thereof and one or more from polyethylene glycol 6000, hypromellose, hydroxypropyl cellulose as a release-controlled matrix polymer, ethyl cellulose, D- One or more excipients selected from mannitol, microcrystalline cellulose, hypromellose, sodium alginate, calcium hydrogen phosphate, calcium silicate, methacrylic acid copolymer and lactose, stearic acid or its magnesium salt, stearyl fumaric acid or its sodium salt, and colloids It includes a lubricant selected from one or more types of silicon dioxide.

The formulation described in the present invention is a coating formulation of the sustained-release part and the immediate-release part, as a pH-dependent polymer and a hydrophobic polymer for coating, as a cellulose propionate, a cellulose acetate phthalate, a methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, and It contains at least one type of hydroxypropylmethylcellulose acetate succinate.

In addition to the above-mentioned components, the controlled-release oral formulation of the present invention may contain a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include, for example, excipients, fillers, bulking agents, binders, wetting agents, disintegrants, diluents such as surfactants, and/or lubricants that are commonly used in controlled release formulations. Examples of such carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, lactose, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, and mineral oil.

The binder, povidone, copovidone, powder, crystalline or microcrystalline cellulose, silicon-added microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, starch, pregelatinized starch, polymethacrylate, and 2 of these It includes a mixture of more than one species, but is not limited thereto.

The diluent includes lactose, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, calcium hydrogen phosphate, polyvinylpyrrolidone, starch, pregelatinized starch, methylcellulose, copolyvidone, and mixtures of two or more of them, and is limited thereto. It doesn't work. The diluent makes it possible to make a formulation large enough to take the active ingredient, and provides sufficient bonding strength when tableting.

The lubricant includes magnesium stearate, calcium stearate, glyceryl behenate, stearic acid, talc, aerosil, castor oil, sodium stearyl fumarate, and mixtures of two or more of them, but is not limited thereto. The lubricant provides sufficient fluidity during tableting and prevents bonding between the punch and the die.

Bepotastine of the present invention is a substrate of P-gp (Permiability-glycoproteins) present in a large amount in the lower part of the small intestine. If the drug is released into the lower part of the small intestine due to delayed release of the drug, the bioavailability may significantly decrease. In the present invention, the release control time of the sustained-release layer was adjusted in consideration of the properties of bepotastine. Through this, a controlled release formulation was prepared that increases the bioavailability of bepotastine and its pharmaceutically acceptable salts and does not affect the expression of the effect.

Bepostatin or a pharmaceutically acceptable salt thereof of the present invention, a sustained-release layer and an immediate-release layer containing a release-controlling base based on a hydrophilic polymer are prepared as a two-layer tablet to exhibit independent release characteristics, and the surface thereof is acrylic, a pH-dependent release control agent. It is capable of fast-acting tablets and sustained release of bepotastine or a pharmaceutically acceptable salt thereof by coating with a rate (methacrylate copolymer polymer), and can be prepared through a relatively simple process.

The controlled-release oral formulation containing bepotastine of the present invention can be formulated in the form of an oral formulation. For example, the controlled-release oral formulation containing bepotastine of the present invention may be in the form of a tablet or capsule, and the tablet or capsule may be a direct-press method, a wet granulation method, a dry granulation method, a compressed granulation method, a spray drying method, a fluid bed granulation method, etc. In general, it can be manufactured using any one of the manufacturing methods that can be used in a pharmaceutical process.

In addition, as a pharmaceutical composition of the sustained-release layer of the present invention, in order to solve the problem that the absorption rate decreases toward the lower part of the small intestine by adjusting the release pattern in the test solution of pH 6.8, the zero-order release pattern was displayed, and the time point at which the elution was 80%. It can be prepared through a relatively simple process by adjusting the release pattern by using a hydrophilic excipient, a hydrophobic excipient, and a pH-dependent excipient in order to be within 12 hours.

As a specific example, the hydrophilic polymer described above is polyvinylpyrrolidone, povidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, polyethylene oxide, polyethylene glycol, xanthan gum, guar gum, locust bean gum, sodium alginate , Dextran, carrageenan, chitosan, carbopol, and may be selected from the group consisting of sodium alginate.

The pH-dependent excipient and coating agent is not limited thereto, but is selected from the group consisting of acrylate, methacrylate, methacrylate copolymer polymer, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate. Can be.

In addition, the hydrophilic excipients used to show the zero-order release pattern showing linearity at pH 6.8 include polyvinylpyrrolidone, povidone, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyethylene oxide, It may be selected from the group consisting of polyethylene glycol, xanthan gum, guar gum, locust bean gum, sodium alginate, dextran, carrageenan, chitosan, carbopol, and sodium alginate, and the hydrophobic excipients include ethylcellulose, cellulose propionate, It may be selected from the group consisting of cellulose acetate, cellulose triacetate, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate. In addition, as a pH-dependent excipient, it may be one selected from the group consisting of acrylate, methacrylate, methacrylate copolymer polymer, and hydroxypropylmethylcellulose phthalate.

In order for the sustained-release layer and the immediate-release layer to exhibit independent release characteristics, each of which is not limited thereto, but preferably, a hydrophobic polymer may be used as an additive for the sustained-release layer.

Typically, bepotastine is administered twice a day, 10 mg at a time. However, the controlled-release oral formulation of the present invention slowly releases bepotastine and can maintain its effect for a long time even once a day is administered. In addition, it can be expected to increase the convenience of taking the patient, thereby increasing medication compliance. For example, the present invention may contain a total of 20 mg of bepotastine in the formulation. As a result, the number of administration can be reduced once a day without an unnecessary increase in the volume of the preparation. In addition, compared to the conventional 25mg once-a-day dosage form, while significantly improving the patient's medication convenience, it is possible to reduce the concern of side effects that occur when the 25mg preparation is used.

Hereinafter, the present invention will be described in more detail by examples. However, the following examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples. The embodiments of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.

Examples 1 to 3

In order to prepare a double-layer tablet, a mixture of a sustained-release layer and an immediate-release layer was prepared, respectively. In the case of the sustained release layer, 70% or 75% of the allowable amount of bepotastine or a pharmaceutically acceptable salt and excipient thereof, as a methacrylic acid copolymer, lactose hydrate, ethyl cellulose, sodium alginate, calcium hydrogen phosphate, calcium silicate, as a binder In the case of Examples 1 and 2, hypromellose having a viscosity of 4.5 cps (Lotte Fine Chemical, Hypromellose (2910) 4.5 cps), in the case of Example 3, Hypromellose K15M having a viscosity of 15,000 cps, and all In the example, hypromellose K4M was mixed with a release-controlled hydrophilic polymer having a viscosity of 4,500 cps. The mixture was granulated on a high-speed kneader based on the ethanol binding solution. The mixture was dried at 60° C. for 1 hour and then sieved to a size of 1016 microns using Comil, and then magnesium stearate was mixed as a lubricant to prepare a mixture 1). In the case of an immediate release layer, 25% or 30% of the allowable amount of bepotastine or a pharmaceutically acceptable salt thereof and D-mannitol as an excipient, and polyethylene glycol 6000 as a binder are mixed, and ethanol is used as a binding solution in the sustained release layer. Granules were produced in the same manner as in the process of making granules in the phase. After drying and sizing the granules, microcrystalline cellulose was mixed, and magnesium stearate was mixed as a lubricant to prepare a mixture 2). After tableting the mixtures 1) and 2) into two-layer tablets using a tablet press, coating with a methacrylic acid copolymer (Acryliz White) in purified water, and spraying a hypromellose-based coating solution (Opadry) to make a second coating. I did it. Table 1 shows the mixing ratio (unit: weight) of each of the components used.

Comparative Examples 1 to 4

For the manufacture of a single-layer release control agent, bepotastine, lactose hydrate, methacrylic acid copolymer, hypromellose K15M and K4M, ethyl cellulose, sodium alginate, calcium hydrogen phosphate, calcium silicate 200 were added to a No. 20 sieve ( Size 0.85 mm) and mixed evenly. This mixture was made into wet granules using ethanol on a high-speed kneader. After drying of the granules, the mixture was sieved using Comil and then sieved through a sieve No. 40 (size 0.425 mm) to complete the mixture. The mixture was prepared in a tablet uncoated tablet using a tablet press. In the case of Comparative Example 1, coating was performed by spraying a hypromellose-based coating solution. In the case of Comparative Example 2, after coating with a methacrylic acid copolymer in purified water, a second coating was performed by spraying a hypromellose-based coating solution. In Comparative Examples 3 and 4, tablets were prepared through coating using a methacrylic acid copolymer after tableting was completed using the same conditions as in Comparative Examples 1 and 2.

Comparative Example 5

In Comparative Example 5, unlike the above example, a floating system was introduced to increase the residence time in the stomach by excluding lactose and forming granules based on microcrystalline cellulose. For this, bepotastine, microcrystalline cellulose, Tween 80, hypromellose K15M and K4M, ethyl cellulose, sodium alginate, calcium hydrogen phosphate, and calcium silicate 200 were passed through a No. 20 sieve (screen size 0.85 mm) and then evenly mixed. This mixture was made into wet granules using ethanol on a high-speed kneader. After drying of the granules, the mixture was sieved using Comil and then sieved through a sieve No. 40 (size 0.425 mm) to complete the mixture. The mixture was coated by spraying a hypromellose-based coating solution after preparing uncoated tablets using a tablet press.

Comparative Example 6

Bepotastine, hypromellose K15M and K4M, ethyl cellulose, sodium alginate, calcium hydrogen phosphate, and calcium silicate 200 were passed through a No. 20 sieve (body size of 0.85 mm) for the manufacture of sustained-release tablets excluding pH-dependent release formulations. And then evenly mixed. This mixture was made into wet granules using ethanol on a high speed kneader. After drying of the granules, the mixture was sieved using Comil and then sieved through a sieve No. 40 (size 0.425 mm) to complete the mixture. The mixture was tableted to prepare uncoated tablets, and then coated by spraying a hypromellose-based coating solution.

Table 2 shows the blending ratio (unit: weight) of each of the components used in each of the components used in Comparative Examples 1 to 6.

Experimental Example 1

In order to check the blending suitability and stability of various additives of bepotastine besylate, each additive is mixed in a ratio of 1:1, and the initial conditions (ie, when mixing), acceleration conditions (40°C/75% relative humidity, After storage at 4 weeks), the content of related substances was measured. The results are shown in Table 3. Through this, it was confirmed that the related substances did not increase when the additives of the Comparative Examples and Examples were mixed with bepotastine and stored, and stability was ensured.

Experimental Example 2

A dissolution test was performed on the prepared Examples 1 to 3 above. Using pH 1.2 and pH 6.8 solutions as test solutions, the dissolution rate of bepotastine was analyzed for 12 hours using a 50 rpm paddle method (USP Apparatus 2) at 37°C±0.5. (Fig. 1)

It was confirmed that the initial dissolution rate of the two-layer tablets of Examples 1 to 3 was significantly increased compared to the single-layer tablet. The pH 6.8 test solution showed a dissolution rate of 80% or more within 6 hours, and the pH 1.2 test solution showed a dissolution rate of 80% or more within 8 hours. It was confirmed that at a low pH of 1.2, a polymer coating having low solubility showed a slower dissolution rate in the pH 1.2 test solution compared to pH 6.8.

Experimental Example 3

Dissolution experiments were conducted for the prepared Comparative Examples 1 to 4. In the same manner as in Experimental Example 2, the dissolution rate of bepotastine was analyzed for 12 hours using a paddle method on the pH 1.2 and pH 6.8 test solutions. (Figures 2 and 3)

It was confirmed that Comparative Examples 1 to 3 showed similar dissolution rates, and on the pH 6.8 test solution, all three examples showed a dissolution pattern of zero-order release up to 12 hours, and showed a dissolution rate of 80% or more within 12 hours. In the pH 1.2 test solution, Comparative Example 2 showed a lower dissolution rate of up to 6 hours compared to Comparative Example 1 by the presence or absence of a coating using a pH-dependent coating agent with a pH-dependent release. In both the pH 1.2 and pH 6.8 test solutions, Comparative Example 2 showed a higher final dissolution rate compared to Comparative Example 1. In the case of Comparative Example 4, the dissolution rate of pH 6.8 exhibited a dissolution rate similar to that of the Comparative Example. However, due to the increase of the pH-dependent coating agent, at pH 1.2, the dissolution rate was less than 10% up to 2 hours, and it was confirmed that the final dissolution rate up to 24 hours was also as low as 75%.

Experimental Example 4

Dissolution experiments were performed on the prepared Comparative Examples 5 and 6. In the same manner as in Experimental Example 2, the dissolution rate of bepotastine was analyzed for 12 hours using a paddle method on the pH 1.2 and pH 6.8 test solutions. (Fig. 4)

In Comparative Examples 5 and 6, the dissolution results of pH 1.2 showed similar dissolution as in other examples, but the initial dissolution rate was high, so it is thought that the drug was released early, resulting in poor persistence. In addition, the dissolution result of pH 6.8 indicates more than 80% dissolution within 12 hours, and it was confirmed that the final dissolution rate was lower than that of other examples.

The dissolution rates per hour according to the pH of Examples 1 to 3 and Comparative Examples 1 to 6 are shown in Tables 4 and 5, respectively.

Experimental Example 5

Among the tablets prepared above, pharmacokinetic analysis was performed using a beagle dog for Examples 1 to 3 and Comparative Examples 2, 5, and 6. In the case of Comparative Example 1, the lowering of the final dissolution rate compared to Comparative Example 2 was observed, so the experiment was performed except for this. Pharmacokinetic analysis of the drug was performed by analyzing the drug concentration in the blood over time for 24 hours after oral administration of an acceptable amount of Bepotastine tablets. For the experiment, analysis was conducted with the number of study samples of 5 per experimental group. (Figures 5 to 7)

According to FIG. 5, in the case of Example 1, when compared to the control _{drug, T max} and t _1/2 (Half life time) were shown, but the AUC (Area under curve) and C _max values were lower than that of the control drug, so that the low drug body Showed utilization rate. It was confirmed that Examples 1 and 2 showed similar pharmacokinetic parameters to each other, showing a late T _max , t _1/2 compared to the control drug, and a high AUC and a low C _max value compared to the control drug. When the pharmacokinetic parameters of Comparative Example 2 were analyzed, it was confirmed that the drug was not sufficiently absorbed by showing a _{late T max} and t _1/2 compared to the control drug, which was an immediate-release tablet, but showed low AUC and C _{max values.} In the case of Comparative Example 5, T _max was late compared to the control drug, but t _1/2 was faster than the control drug, indicating that it was not suitable for use as a sustained-release tablet, and it was _{confirmed that AUC and C max} were also low. In the case of Comparative Example 6, when compared to the control _{drug, which is an immediate-release tablet, a late T max} was displayed, and a low AUC and C _max value were shown, indicating that the sustained-release tablet did not maintain the persistence of the drug. Specific pharmacokinetic parameters are shown in Table 6. Through this, it was confirmed that the tablets of Examples 1 and 2 can be used as sustained-release tablets that can be administered once a day.

As described above, specific parts of the present invention have been described in detail, and for those of ordinary skill in the art, it is obvious that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Accordingly, it will be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (14)

A controlled-release oral formulation comprising bepotastine or a pharmaceutically acceptable salt thereof, comprising: an immediate release layer comprising 20% to 40% by weight of bepotastine based on the total weight of the bepotastine; And a sustained-release layer comprising 60% to 80% by weight of bepotastine based on the total weight of the bepotastine,
The formulation comprises at least one selected from the group consisting of cellulose propionate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate, and a coating agent comprising a methacrylic acid copolymer. , Controlled release oral formulation. The method of claim 1,
When measured by a paddle method (USP Apparatus 2) of 37° C.±0.5° C. and 50 rpm using a pH 1.2 test solution, bepotastine is more than 20% eluted after 1 hour with respect to the total weight of the bepotastine, a formulation. The method of claim 1,
When measured by a paddle method (USP Apparatus 2) of 37°C±0.5°C and 50 rpm using a pH 6.8 test solution, 80% or more of Bepotastine is eluted after 12 hours with respect to the total weight of Bepotastine. A formulation in which the drug is released at a zero-order release rate after administration. The method of claim 1,
The controlled-release oral formulation is administered in a once-a-day regimen, a formulation. The method of claim 1,
The sustained-release layer does not contain microcrystalline cellulose, the formulation. The method of claim 1,
The sustained-release layer comprises a lactose hydrate, the formulation. The method of claim 6,
The sustained-release layer contains 30% to 35% lactose hydrate based on the total weight of the sustained-release layer. The method of claim 1,
The sustained-release layer includes one or more binders selected from the group consisting of polyethylene glycol, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. The method of claim 8,
The formulation, wherein the binder is HPMC 4.5 CPS and HPMC K4M. The method of claim 1,
The immediate-release layer contains mannitol, the formulation. The method of claim 1,
The immediate-release layer comprises microcrystalline cellulose, the formulation. The method of claim 1,
An immediate release layer comprising 25% to 30% by weight of bepotastine based on the total weight of the bepotastine; And a sustained-release layer comprising 70% to 75% by weight of bepotastine based on the total weight of the bepotastine. The method of claim 1,
The controlled-release oral formulation comprises 1 part by weight to 10 parts by weight of the coating agent based on 100 parts by weight based on the total weight. The method of claim 1,
The bepotastine or a pharmaceutically acceptable salt thereof is present in an amount of 20 mg, the formulation.

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