WO2017155350A1 - Pharmaceutical composition for oral administration comprising (±)-2-[2-(3-carboxypropionyloxy)-3-dimethylaminopropoxy]-3'-methoxybibenzyl or salts thereof - Google Patents

Abstract

One aspect of the present invention provides a pharmaceutical composition comprising (±)-2-[2-(3-carboxypropionyloxy)-3-dimethylaminopropoxy]-3'-methoxybibenzyl hydrochloride as an active ingredient.

Description

Oral pharmaceutical composition comprising (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or salts thereof

The present invention relates to an oral pharmaceutical composition comprising (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or salts thereof as an active ingredient. More specifically, (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or a salt-containing sustained release thereof that can be administered once a day It relates to an oral pharmaceutical composition.

(±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride (safoglylate hydrochloride) is a platelet and blood vessel serotonin receptor (5- It is used as a platelet aggregation inhibitor with a new mechanism of action that selectively antagonizes HT2).

Drugs that prevent the formation of platelet clumps are called antiplatelet drugs. Most drugs have mechanisms that inhibit the process of blood clots and platelet activation. Aspirin, a typical drug, exhibits antiplatelet activity by blocking the action of cyclooxygenase and interfering with the action of thromboxane. Another typical drug, clopidogrel, inhibits ADP (adenosine diphosphate) receptor activation and inhibits platelet function. However, aspirin and clopidogrel are known to have disadvantages such as gastrointestinal side effects, resistance, and cost.

(±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride may inhibit collagen-induced platelet aggregation and secondary aggregation by ADP and epinephrine In addition, it has been reported to strongly inhibit platelet aggregation enhanced by serotonin. In addition, it has been reported to inhibit the contraction of vascular smooth muscle caused by serotonin and to improve erythrocyte deformability (Yukihide Isogai, Takuo Yokose, Takashi Ikemoto, Toshihiki Maeda, Masaaki Akiyama, Hiroto Hara, Akiko Kitajima) , Osamu Izawa.Phase-I Study of Sarpogrelate Hydrochloride (MCI-9042) .Clinical Medicine No. 7, 6 (June), (1991)). By this action, (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride is used to treat chronic arterial obstruction, chronic arterial obstruction. It is known to be useful as an active ingredient for improving ischemic symptoms of ulcers, pain and cold feeling, improving intermittent claudication, inhibitors of thrombosis and embolism in ischemic cerebrovascular disorders, and relieving pain following neuralgia after shingles (Korea Patent Publication 2006-0093677).

(±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride is described in Example 2 of Japanese Patent Application Laid-Open No. 58-32847. It can manufacture based on the. In addition, Korean Patent Publication No. 2006-0093677 discloses that the compound exists as a crystal polymorph. Korean Patent Publication No. 2006-0093677 discloses that (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride as Form I and Form II. It may be present, and a method for producing the crystalline form is disclosed.

Such (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride has a short half-life, excellent effects, and low side effects, and thus antiplatelet drugs. It can be a good choice.

Clinical Pharmacological Review of Single Adult Oral Dose of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl Hydrochloride in Healthy Adult Men As a result, the effective dose of 100 mg (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride is rapidly absorbed upon single oral administration In addition, blood levels of unchanged bodies rapidly disappeared after reaching the highest concentration at 1-2 hours after administration. Thus, currently commercially available tablets containing (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride once a day 3 tablets It must be administered orally, and due to the need for such frequent taking, there is a disadvantage in that the patient's compliance with medication is poor. Therefore, it is possible to sustain the action of the effective (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride formulation once daily. Need development

One aspect of the invention is (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or a pharmaceutical thereof effective only once daily To provide an acceptable salt-containing pharmaceutical composition.

One aspect of the invention

A pharmaceutical composition comprising a bilayer tablet consisting of a sustained release layer and an immediate release layer,

The sustained release layer and the immediate release layer each contain (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or a salt thereof as an active ingredient. It provides a pharmaceutical composition.

The pharmaceutical composition according to one embodiment of the present invention is a pharmaceutical composition for improving or treating ischemic symptoms caused by chronic arterial occlusion, and may be administered once a day while maintaining an effective blood concentration of the drug for about 24 hours. Therefore, the pharmaceutical composition according to one embodiment of the present invention is not only preferable because it can significantly increase the medication compliance of the patient, it is possible to prevent the increase of the treatment period due to the omission of the patient, etc. It has the advantage that it can be used to improve or treat ischemic symptoms.

1 to 4 are graphs showing the dissolution rate measurement results over time for the tablets of Examples 1-10.

5 to 6 are graphs showing the dissolution rate measurement results over time for the tablets prepared in Examples 11-15.

FIG. 7 shows time-blood concentration curves for three doses of the reference drug (Anflag® tablets) in humans.

FIG. 8 shows time-blood concentration curves of a single dose of bilayer tablets according to Example 15 in humans. FIG.

All technical terms used in the present invention, unless defined otherwise, are used in the meaning as commonly understood by those skilled in the art in the related field of the present invention. In addition, although a preferred method or sample is described herein, similar or equivalent things are included in the scope of the present invention. In addition, numerical values described in this specification are considered to include the meaning of "about", even if not specified. The contents of all publications that are incorporated herein by reference are incorporated by reference in their entirety.

One aspect of the invention

A pharmaceutical composition comprising a bilayer tablet consisting of a sustained release layer and an immediate release layer,

The sustained release layer and the immediate release layer each contain (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or a salt thereof as an active ingredient. It provides a pharmaceutical composition.

The pharmaceutically acceptable salt of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl may be an acid addition salt of an inorganic acid salt or an organic acid salt. Examples include acetic acid, adipic acid, aspartic acid, 1,5-naphthalenedisulfonic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, ethylenediaminetetraacetic acid, fumaric acid, Glucoheptonic acid, Gluconic acid, Glutamic acid, Hydrogen iodide, Hydrobromic acid, Hydrochloric acid, Isetionic acid, Lactic acid, Maleic acid, Malic acid, Manderic acid, Methanesulfonic acid, Music acid, 2-naphthalenedisulfonic acid, Nitric acid, Oxalic acid, Parsity Salts with butyric acid, pentothenic acid, phosphoric acid, pivalic acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, or p-toluenesulfonic acid. In one embodiment, the pharmaceutically acceptable salt of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl is (±)- 2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride.

(±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or pharmaceutically acceptable salts thereof according to methods known in the art For example, (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride may be prepared in Example 2 of Patent Document 1. It can manufacture based on description of. (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride may be present in the form of any crystalline form, wherein the crystalline form is Form I , Form II, or any combination thereof.

Patent document 2 discloses a method for producing the crystalline form. In one embodiment, the pharmaceutical composition comprises about 30% of Form II of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride More preferably about 70% or more.

In one embodiment, the pharmaceutical composition comprises about 95% of Form II of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride Or more, or 98% or more.

The active ingredient may be present in the immediate release layer and the sustained release layer in an arbitrary ratio, and in order to maintain the medicinal effect in a weight ratio of 1: 1 to 5, specifically about 1: 1 to 3, in the immediate release layer and the sustained release layer. It may be present, and more specifically may be present in a weight ratio of about 1: 2 to 2.5. In one embodiment, (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride is included in the immediate release layer and 100 mg in the sustained release layer Can be. In one embodiment, 90 mg of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride is included in the immediate release layer and 210 mg in the sustained release layer Can be.

The pharmaceutical composition may be used to improve or treat chronic arterial occlusion, to improve or treat ischemic symptoms caused by chronic arterial occlusion, to improve intermittent claudication, to inhibit thrombosis and embolism in ischemic cerebrovascular disorders, or pain following neuralgia after shingles. It can be used as a reducing agent. The ischemic symptoms include ulcers, pains, or colds (Patent Document 2).

The pharmaceutical composition may be administered by any route including oral administration, intramuscular, subcutaneous, or intravenous injection administration, nasal administration, or transdermal administration. In one embodiment, the pharmaceutical composition is a pharmaceutical composition for oral administration

The pharmaceutical composition may be administered in a dosage of about 200 to 400 mg / day active ingredient. The dosage depends on these or other factors, depending on age, weight, general state of health, sex, meal, time of administration, method of administration, route of administration, rate of excretion, combination of drugs, and the extent of the condition of the patient being treated. It may vary, and it may increase or decrease according to expert judgment.

In one embodiment, the pharmaceutical composition is a pharmaceutical composition for oral administration, the pharmaceutical composition may be administered as an active ingredient about 200 ~ 400 mg / day.

In one embodiment, the pharmaceutical composition is a pharmaceutical composition for oral administration, wherein the pharmaceutical composition may be administered orally about 300 mg of an active ingredient once daily or on an empty stomach. The dosage may also vary depending on age, weight, general health, sex, meal, time of administration, method of administration, route of administration, rate of excretion, combination of drugs, and the extent of the condition of the patient being treated. It may vary depending on factors and may increase or decrease according to expert judgment.

In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition comprising a sustained release monolayer, ie, a sustained release layer. The pharmaceutical composition may include only a sustained release layer, or may be a pharmaceutical composition that is an oral multilayer tablet in the form of further comprising an immediate release layer together with the sustained release layer.

In one embodiment, the pharmaceutical composition is a pharmaceutical composition which is an oral bilayer tablet comprising a sustained release layer and an immediate release layer.

As used herein, the term "sustained release layer" refers to a layer in which the active ingredient is slowly dissolved and slowly eluted in the body after administration. Unlike the "fast release layer", the sustained release layer contains a substance that controls the dissolution of the active ingredient, that is, a sustained release agent, so that the active ingredient may be slowly eluted. The sustained release agent may be used any sustained release agent known in the art.

The sustained release agent may be any sustained release agent known in the art. The sustained-release agent is, for example, cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, or sodium carboxymethyl cellulose, polyethylene oxide, polyvinylpyrrolidone (Polyvinylpyrrolidone ), Guar gum, locust bean gum, polyvinylacetate, polyvinylacetate phthalate, polymethacrylate (Eudragit), polyacrylic acid, carbomer (e.g. carbomer 941), glycerol monostearate and poloxamer, and any combination thereof The sustained release agent may be 10 to 30% by weight, preferably 15 to 25% by weight relative to the weight of the sustained release layer. have.

In one embodiment, the sustained release agent comprises a combination of hydroxyl propyl methyl cellulose and carbomer.

The hydroxypropyl methyl cellulose may be hydroxypropyl methyl cellulose having any viscosity used as a sustained release agent in the art, in one embodiment 2,000 cps to 200,000 cps, preferably 4,000 cps to 100,000 cps Can be. If it is less than 2,000cps, a large amount of hydroxypropylmethylcellulose is required, and the size of the tablet becomes large, and if the viscosity exceeds 200,000cps, it may be difficult to uniformly mix with the drug. In one embodiment, the viscosity of hydroxypropylmethylcellulose may be 80,000 cps to 120,000 cps.

Sustained-release tablets containing pharmacologically active ingredients show swelling of the tablet during elution. In this case, if the matrix of the release controlling polymer is not strong, the matrix may be partially damaged (erosion) and the tablet may disintegrate, which may lead to rapid drug release.

In order to solve this problem, a mixture of hydroxypropylmethylcellulose and carbomer can be used as a release controlling polymer. When carbomer is used as a drug release controlling polymer together with hydroxypropylmethylcellulose, it has the effect of strengthening the matrix in the sustained-release tablet and maintaining the form when the tablet is expanded and maintaining the matrix of the tablet to prevent erosion of the tablet. Maintain a constant dissolution rate.

In one embodiment, the combination of the sustained release agent may be 15 to 25% by weight hydroxypropylmethylcellulose relative to the total weight of the sustained release layer, 1 to 25% by weight carbomer, more specifically, 1 to 10% by weight The hydroxypropyl methyl cellulose: carbomer may be a weight ratio of 2: 1 to 20: 1, specifically 4: 1 to 18: 1, and more specifically 8: 1 to 15: 1. have.

More specifically, when the weight ratio of the hydroxypropyl methyl cellulose and the carbomer is greater than 20: 1, the dissolution rate of the pharmacologically active ingredient may be lowered under alkaline conditions. This is because the carbomer is an anionic polymer, and when gelled in an alkaline environment, the carbomer is combined with an active ingredient having a cation. This is because drug release may be suppressed in an alkaline environment. In addition, when the weight ratio of the hydroxypropyl methyl cellulose and the carbomer is more than 20: 1, it is difficult to uniformly mix between the release control polymer, the stability may be deteriorated, and the sustained release effect is so large that sufficient elution is not achieved and effective blood There is a fear that the concentration cannot be reached. In addition, when the weight ratio is less than 2: 1, it is difficult to form a matrix in tablets, and thus, sufficient sustained release effect of the drug does not appear, and thus, once daily administration may not be possible or side effects may occur.

The combination of the sustained-release agent can keep the blood concentration almost constant by suppressing the rapid release of the active ingredient (see Experimental Example 2). Therefore, there is an advantage that the fear of possible side effects due to the rapid release of the active ingredient can be solved. In addition, the continuous release of the active ingredient can be made, so that the effective blood concentration can be maintained throughout the day by oral administration only once a day, it is also preferable in terms of the number of administration. Therefore, there is no abrupt release of the drug, so there is no fear of side effects, and since it is possible to administer once a day by continuous release, medication compliance can be increased.

In addition to the sustained release agent, the sustained release layer of the pharmaceutical composition may further include a pharmaceutical additive selected from the group consisting of excipients, binders, disintegrants, glidants, and any combination thereof.

In one embodiment, the sustained release layer contains a disintegrant. The sustained release layer generally does not contain a disintegrant for the sustained release of the active ingredient, but the pharmaceutical composition according to the embodiment of the present invention has a sustained release layer containing a disintegrant so that the effective ingredient dissolution of the active ingredient in the latter part after oral administration of the pharmaceutical composition is 100 Even closer to% (see Experimental Example 2). Therefore, the pharmaceutical composition according to the embodiment has an advantage that the dissolution of the active ingredient is almost completely compared to the case that does not contain a disintegrant, which can have a significantly improved bioavailability. The meaning that the dissolution can be “close to 100%” herein means at least 90% or more, specifically 93% or more, more specifically 95% or more, even more specifically 97% or more, and more specifically It can mean more than 98%.

The disintegrant can be any disintegrant used in the manufacture of tablets. The disintegrant may be selected from, for example, sodium starch glycolate, crospovidone, croscarmellose sodium, and any combination thereof, but is not limited thereto.

In one embodiment, the disintegrant is sodium starch glycolate.

The content of the disintegrant may be in the range of about 1 to 5% by weight based on the total weight of the sustained-release layer, if too large outside the above range, the disintegration effect is increased, which may inhibit the slow release of the active ingredient, too little In this case, there is a fear that there is no sufficient disintegration effect, so that the emission may not be nearly 100%.

The sustained-release layer may be prepared according to any method for preparing a sustained-release layer known in the art, for example, by granulating together the active ingredient, the sustained-release agent, and the pharmaceutical additive, and then using a tableting machine in tablet form. It can be prepared by tableting. The granules comprise dry granules or wet granules. In one embodiment, the granules are wet granules, which is preferred in terms of tabletting when wet granulating. Dry granules may cause problems such as tablet breakage during tableting.

As used herein, the term "immediate release layer" refers to a layer which dissolves rapidly in the body after administration and rapidly elutes the active ingredient contained in the immediate release layer. While the term "sustained release layer" requires a substance to control the release of the active ingredient, the immediate release layer does not contain a substance that controls the release of the drug. Therefore, the immediate release layer can quickly elute the active ingredient, and the immediate release layer may optionally include a fast-acting excipient.

In one embodiment, the pharmaceutical composition comprises an immediate release layer comprising a fast-acting excipient. The term "fast-acting excipient" means any excipient that serves to aid the rapid release of the active ingredient in the immediate release layer. The fast-acting excipient may use a fast-acting excipient known in the art, and may use an excipient of the same kind as lactose, sugar alcohol, microcrystalline cellulose, water-soluble polymer, or an oil-based base.

In one embodiment, the fast-acting excipient is lactose or microcrystalline cellulose.

The immediate release layer enables the rapid release of the active ingredient, thereby allowing the effective blood concentration of the active ingredient to be reached quickly upon oral administration. Therefore, the pharmaceutical composition may ensure a faster drug due to the presence of the immediate release layer.

The immediate release layer may further include a pharmaceutical additive selected from the group consisting of a binder, a stabilizer, a disintegrant, a lubricant, a pH adjuster, a stabilizer, and any combination thereof.

 Since (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl may be unstable in alkali and less stable, the immediate release layer may be stabilizer, For example citric acid. The stabilizer may be about 0.4% to 2.8% by weight, specifically 0.8% to 2.2% by weight, based on the total weight of the immediate release layer. When the weight ratio of the stabilizer is less than 0.4% by weight, the stabilizing effect in acid may be reduced. If the 2.8% by weight is exceeded, the initial dissolution rate may drop. This is because when the stabilizer is used in excess, the pH of the active ingredient may be lower than that of the fast pH condition (pH 4.0).

The immediate release layer may be prepared according to any method for preparing a rapid release layer known in the art, and for example, the active ingredient, the rapid release excipient, and the pharmaceutical additive are granulated together and then tableted using a tableting machine. It can be prepared by tableting. The granules comprise dry granules or wet granules. In one embodiment, the granules are wet granules, which is preferred in terms of tabletting when wet granulating. Dry granules may cause problems such as tablet breakage during tableting.

As a pharmaceutical additive contained in the sustained release layer and the immediate release layer,

The excipient may be any excipient known in the art, for example microcrystalline cellulose, lactose, low substituted hydroxypropyl cellulose, calcium phosphate, hard silicic anhydride, pregelatinized starch, corn starch, potato starch, white sugar , Mannitol, dextrin, precipitated calcium carbonate and any combination thereof, but is not limited thereto;

The binder may be any binder known in the art and may be selected from, for example, hydroxypropylcellulose, polyvinylpyrrolidone, povidone, copovidone, macrogol, and any combination thereof. But may not be limited to this;

The disintegrant can be any disintegrant known in the art, for example sodium starch glycolate, polyvinylpyrrolidone, crospovidone, croscarmellose sodium, pregelatinized starch (Starch 1500 or Premojel), low-substituted hydroxypropyl cellulose, starch, alginic acid, sodium alginate, and combinations thereof, but is not limited thereto;

The glidants can be any glidants known in the art, for example, metal stearates such as stearic acid, calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable Oil, high melting point waxes, glyceryl fatty acid esters, glycerol dibehenate, and any mixtures thereof, and any combination thereof, but may be selected from the group consisting of, but not limited to.

The sustained release layer and immediate release layer of the oral multilayer tablet or oral bilayer tablet pharmaceutical composition may contain the active ingredient, respectively, to provide release of both sustained release and immediate release of the active ingredient. As it provides release of both sustained and immediate release, it is possible to reach the effective blood concentration quickly by the effective release of active ingredient, so that it can be shown fast effect and can be administered by the release of continuous active ingredient provided by the sustained release layer. Frequency can be significantly reduced, for example, once daily. Therefore, the pharmaceutical composition according to the present invention may be provided as a once-a-day administrable preparation capable of rapid medicinal effect and continuous action.

The oral multilayer tablet or oral bilayer tablet is a granule prepared for the preparation of the immediate release layer as a first tableting tablet with a tableting machine as a first layer, the sustained-layer granules mixed with a lubricant and a post-mixing agent on the first layer Secondary tablets may be prepared by filling and secondary tableting, and the order of the immediate release layer and the sustained release layer may be changed. Optionally, a film coating process may be further performed with the coating agent. The preparation of the immediate release layer granules, the preparation of the sustained release layer granules, the first tableting and the second tableting, and the specific conditions of the film coating may be appropriately performed using techniques known in the art.

In one embodiment, the pharmaceutical composition is a bilayer or multilayer tablet comprising an immediate release layer and a sustained release layer, and due to the inclusion of such immediate release layer and the sustained release layer, both rapid release and sustained release can be obtained. In one embodiment, the pharmaceutical composition, which is a two-layer or multilayer tablet comprising an immediate release layer and a sustained release layer, is prepared under the dissolution test conditions according to the second method of the Korean Pharmacopoeia (paddle method) (eluate: 900 mL of water, stirring rate: 50 rpm, test solution temperature: 37 ± 0.5), elution rate of 25 to 45% in 60 minutes, 45 to 70% in 5 hours and 80% or more in 24 hours (see Experimental Example 2). The pharmaceutical composition can be administered orally once a day by such an dissolution aspect.

In one embodiment, the multi-layered pharmaceutical composition or two-layered pharmaceutical composition may have a blood systemic drug exposure (AUCt, t = 24) of 1766.2 to 2058.4 h˙µg / L after oral administration. In addition, the geometric mean ratio (postprandial / fasting) of postprandial administration to fasting administration of blood systemic drug exposure (AUCt, t = 24)) value of the donor after oral administration may be 0.77 to 0.96. In addition, the maximum blood concentration (C _max ) value of the blood donor after oral administration may be 467.3 to 721.4 ㎍ / L. In addition, the geometric mean ratio (postprandial / fasting) of postprandial administration to fasting administration of the highest blood concentration (C _max ) value of the blood donor after oral administration may be 0.57 to 0.73. In addition, the time (T _max ) to reach the highest blood concentration of the recipient after oral administration may be 0.5 to 3.97 hours. In addition, the half-life ( _{t 1/2} ) of the drug after oral administration may be 1.45 to 3.23 hours. According to the pharmacokinetic parameters, it was confirmed that the absorption of the drug during the postprandial administration and the peak blood concentration are also lower than the fasting administration. Therefore, the pharmaceutical composition may vary in the amount of the active ingredient contained depending on the dosage regimen.

The pharmaceutical composition comprises (dimethylamino) -3- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] -2-propanol hydrochloride (BP-984), which is a representative flexible substance of the active ingredient. It was found to contain less than 0.5% by weight according to the general test liquid chromatography method (see Experimental Example 3). Therefore, it was confirmed that the pharmaceutical composition can be prepared as a stable formulation that allows the continuous release of the active ingredient, while forming a flexible substance below the baseline.

EXAMPLE

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example  1-10: (±) -2- [2- (3- Carboxypropionyloxy ) -3- Dimethylaminopropoxy ] -3'-methoxybibenzyl Hydrochloride  Preparation of Sustained Release Tablets

According to the components and the content of the sustained-release layer shown in Table 1 below, a binding solution in which povidone was dissolved in anhydrous ethanol was separately prepared, and (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminoprop Foxy] -3'-methoxybibenzyl hydrochloride, lactose hydrate, hypromellose carbomer 941, and sodium starch glycolate, followed by association, granulation, and drying with the binding solution. It was sieved through a sieve and sieved to prepare a sustained-release layer granules. Then, the prepared sustained layer granules were postmixed with magnesium stearate. The granules were compressed to a hardness of about 14 kgf to prepare a sustained release tablet. Then, Opadry white film coating of Table 2 below.

 TABLE 1

Experimental Example  1: (±) -2- [2- (3- Carboxypropionyloxy ) -3- Dimethylaminopropoxy ] -3'-methoxybibenzyl Hydrochloride  Dissolution Test of Contained Sustained Release Tablets (1)

(1) Test Preparation

<Elution condition>

Tester: Method 2 of the Pharmacopoeia General Test Method (paddle method)

Eluent: 900 mL of water

Stirring Speed: 50 rpm

Test solution temperature: 37 ± 0.5 ℃

Six tablets of each sustained-release tablet prepared in Example 1-10 were eluted and tested by dissolution test method 2 (paddle method) of the Korean Pharmacopoeia General Test Method according to the above conditions. filter) and the first filtrate 5 mL was discarded and the next filtrate was used as the sample solution.

(2) Standard liquid preparation

The active ingredient (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride standard was dried at 105 DEG C for 2 hours and about 33.3 mg Weigh accurately and add 80 mL of water to dissolve it, and add water to make exactly 100 mL (as measured immediately after preparation).

(3) operation and calculation

The peak areas A _T and A _S of the active ingredient were measured by the liquid chromatograph method of the Korean Pharmacopoeia General Test Method with 40 μL of the test solution and the standard solution after 60 minutes, 5 hours, and 24 hours after the start of dissolution. The dissolution rate was calculated by the following formula.

<Operation Conditions>

Detector: ultraviolet absorption photometer (wavelength: 272 nm)

Column: C18, 4.0 mm × 150 mm, 5 μm

Column Temperature: Room Temperature

Mobile phase: Methanol˙0.05 mol / L Potassium dihydrogen phosphate solution (7: 3)

Oil amount: Adjust to keep the active ingredient about 7 minutes.

System Suitability Test: When the test is repeated 6 times with 40 μL of standard solution under the above conditions, the relative standard deviation of the peak area of the active ingredient is not more than 2.0%.

Area measurement range: twice the range of active ingredient holding time

<Calculation Formula>

A _S : Peak area of active ingredient in standard solution

A _T : Peak area of the active ingredient in the sample solution

W _S : Active ingredient standard dose (mg)

P: Standard Purity (%)

Dissolution test results are shown in Table 2 and FIGS. 1-4.

TABLE 2

The initial dissolution profiles of Examples 5 and 6 with carbomer were lower than those of Examples 7 and 8 without carbomer.

Examples 3 and 4 showed a sustained release pattern in which the drug was released at a constant rate for 24 hours, but the dissolution rate decreased in the latter part of the drug at a final dissolution rate of about 92%. In Examples 5 and 6 including the binder povidone, the final dissolution rate of the latter part was improved to about 95%. In Examples 9 and 10 including the disintegrant sodium starch glycolate, the dissolution rate of 24 hours was about 97%, which showed a further improvement in the latter dissolution rate of the active ingredient.

Example  11-15: (±) -2- [2- (3- Carboxypropionyloxy ) -3- Dimethylaminopropoxy ] -3'-methoxybibenzyl Hydrochloride  Preparation of Containing Two-Layered Tablets

First, immediate release layer granules containing (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride were prepared.

According to the components and contents of the immediate release layer shown in Table 3 below, a binding solution in which povidone was dissolved in anhydrous ethanol was separately prepared, and (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminoprop Foxy] -3'-methoxybibenzyl hydrochloride, lactose hydrate, sodium starch glycolate, and citric acid are mixed, and then combined with the binder solution, sieved, dried and sieved through a No. 20 sieve for immediate release. Layer granules were prepared. Then, the prepared immediate-layer granules were postmixed with magnesium stearate.

According to the components and the content of the sustained-release layer shown in Table 3 below, a binding solution in which povidone was dissolved in anhydrous ethanol was separately prepared, and (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminoprop Foxy] -3'-methoxybibenzyl hydrochloride, lactose hydrate, microcrystalline cellulose 101, hypromellose, carbomer 941, and sodium starch glycolate, followed by association, granulation, and drying After the process, the mixture was sieved through a No. 20 sieve to prepare a sustained-release layer granules. Then, the prepared sustained layer granules were postmixed with magnesium stearate.

Secondary tablets were prepared by first tableting the immediate release layer granules at a hardness of about 3 kgf, and then filling the post-mixed sustained release layer granules thereon with secondary tableting at a hardness of about 15 kgf. Then, the film was coated with the coating material of Table 3 to complete the two-layered tablet.

TABLE 3

Experimental Example  2: (±) -2- [2- (3- Carboxypropionyloxy ) -3- Dimethylaminopropoxy ] -3'-methoxybibenzyl Hydrochloride  Dissolution Test of Sustained-Release Double-Layered Tablets (Part 2)

For tablets prepared in Examples 11 to 15, the dissolution rate was measured in the same manner as in Experimental Example 1. The dissolution test results are shown in Table 4 and FIGS. 5-6. In Examples 11-15 containing a disintegrant, it was found that the effective ingredient dissolution of the latter part was nearly 100% after oral administration.

 TABLE 4

Experimental Example  3: (±) -2- [2- (3- Carboxypropionyloxy ) -3- Dimethylaminopropoxy ] -3'-methoxybibenzyl Hydrochloride  2-layer definition Leading substance  exam

Flexible against bilayer tablets containing (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride prepared in Example 15 under the following conditions Material testing was performed.

(1) Test Preparation

75 mg of the bilayer tablet containing the active ingredient of Example 15 was precisely weighed, dissolved in 0.01 mol / L hydrochloric acid, and the solution was diluted to 100 mL with 0.01 mol / L hydrochloric acid as a sample solution.

(2) Standard liquid preparation

BP-984 standard is dried at 105 ° C for 2 hours, precisely weighed 37.5 mg is dissolved in 0.01 mol / L hydrochloric acid, and accurately prepared to be 100 mL with 0.01 mol / L hydrochloric acid. Take exactly 1 mL of the standard stock solution and make exactly 100 mL with 0.01 mol / L hydrochloric acid.

(3) operation and calculation

Using 20 μL of the sample solution and the standard solution, test according to the liquid chromatograph method of the Korean Pharmacopoeia General Test Method under the following instrument operating conditions, and measure the peak areas A _T and A _S of BP-984 and calculate the flexible substance by the following formula.

<Operation Conditions>

Detector: ultraviolet absorption photometer (wavelength: 272 nm)

Column: C18, 4.0 mm × 150 mm, 5 μm

Column Temperature: Room Temperature

Mobile phase: Methanol˙0.05 mol / L Potassium dihydrogen phosphate solution (7: 3)

Oil amount: Adjust so that the holding time of the active ingredient (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride is about 7 minutes. .

Selection of column: Accurately weigh 75 mg of the active ingredient standard into a 100 mL volumetric flask, dissolve 80 mL of 0.01 mol / L hydrochloric acid, and add 1 mL of the standard stock solution prepared above to make 100 mL with 0.01 mol / L hydrochloric acid. When tested under the conditions above with 20 µL of this solution, elute in the order of BP-984 and the active ingredient, and use a separation of 1.5 or more.

Reproducibility of the system: Relative standard deviation of the peak area of the active ingredient is not more than 2.0% when the test is repeated 6 times with 20 μL of standard solution under the above conditions.

Area measurement range: twice the range of active ingredient holding time

<Calculation Formula>

A _S : Peak area of BP-984 in standard solution

A _T : Peak area of BP-984 in the sample solution

P: Standard Purity (%)

(4) results

As a result of the measurement of the analog, BP-984 was found to be 0.5% or less.

Experimental Example  4: Pharmacokinetics  exam

This trial was to pharmacokinetic properties in healthy volunteers in a single dose and two layers defined in Example 15 confirmed (pharmacokinetic properties) and comparing it to a plaque ^® not defined when orally available in bangjeong. In addition, the effect of food was examined by comparing the pharmacokinetic characteristics of the double-layered tablets of Example 15 after the meal and fasting.

(1) Overall clinical trial method

Public, randomized, group 3, phase 3 Williams design trials were conducted to assess the pharmacokinetic properties and dietary effects of the two formulations.

Each subject was randomized to either Group A (RT-TF) or Group B (T-TF-R) or Group C (TF-RT) or Group D (TF-TR), Group E (TR-TF) or Group F. (R: control drug (fasting), T: test drug (fasting), TF: test drug (postprandial)). Subjects in group A took the control drug on an empty stomach in the first phase, the test drug on the fasting phase in the second phase, and the test drug in the post-prandial phase in the third phase. The drug was administered at the time of dosing, and then the drug was administered to the next time.

(2) Blood collection for pharmacokinetic analysis

Blood was drawn just before and after each time period.

Control: Before (0h) (1st time after blood collection), 0.25, 0.5, 1, 1.5, 2, 3, 6 (2nd time after blood collection), 6.25, 6.5, 7, 7.5, 8, 9, 12 (third dose after blood collection), 12.25, 12.5, 13, 13.5, 14, 15, 16, 24h (23 total)

Test drug: before each administration (0h), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24h (15 times in total)

The collected blood was separated from the plasma at about 4 ° C. and 3,000 rpm in a centrifuge for 10 minutes, and then divided into three labeled eppendorf tubes by 1.5 mL and stored at -70 ° C. for freezing.

(3) Pharmacokinetic Analysis Results

Average blood concentration-time curves of the administration groups are shown in FIGS. 7 and 8.

7 is a time at three times the reference product (not plaque ^® tablets) in humans administered - shows the plasma concentration curve.

Figure 8 shows the time-blood concentration curve of a single dose of a bilayer tablet according to Example 15 of the present invention in humans.

7 and 8, the bars represent standard deviations (top: linear, bottom: linear).

Concentration of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl as an active ingredient when the reference drug was administered on an empty stomach was peaked at 0.48 hours. After reaching the concentration, it decreased to a half-life of 0.70 hours. When fasting the test drug on an empty stomach, the peak blood concentration was reached at 0.5 hours and then decreased to a half-life of 3.23 hours. When the test drug was administered after ingestion of food, the peak blood concentration reaching time and half-life were 3.97 hours and 1.45 hours, respectively.

There was a statistically significant difference in half-life and tmax between the reference drug and the test drug (fasting). (In order; p-value <0.0001, p-value = 0.0259)

Descriptive statistics and estimation results for pharmacokinetic parameters are presented in Tables 5 and 6 below.

TABLE 5

TABLE 6

There was a statistically significant difference in half-life and tmax between postprandial and fasting doses (in order; p-value <0.0001, p-value <0.0001).

Estimates of food effects are presented in Tables 7 and 8.

TABLE 7

TABLE 8

So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.

Claims (13)

1. A pharmaceutical composition comprising a bilayer tablet consisting of a sustained release layer and an immediate release layer,

   The sustained release layer and the immediate release layer each contain (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or a salt thereof as an active ingredient. Phosphorus pharmaceutical composition.
2. The method of claim 1,

   Wherein the sustained release layer further comprises a pharmaceutical additive selected from the group consisting of excipients, sustained release agents, binders, disintegrants, glidants, and any combination thereof.
3. The method of claim 1,

   Wherein the immediate release layer further comprises a pharmaceutical additive selected from the group consisting of excipients, binders, stabilizers, disintegrants, lubricants, pH adjusting agents, stabilizers and any combination thereof.
4. The method of claim 2,

   The sustained-release agent may be hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, or cellulose derivatives such as sodium carboxymethyl cellulose, polyethylene oxide, polyvinylpyrrolidone, guar gum. , Locust bean gum, polyvinylacetate, polyvinylacetate phthalate, polymethacrylate (Eudragit), polyacrylic acid, carbomer (e.g. carbomer 941), glycerol A pharmaceutical composition selected from the group consisting of monostearate and poloxamer, and any combination thereof.
5. The method of claim 2,

   The sustained release agent is 10 to 30% by weight based on the total weight of the sustained release layer.
6. The method of claim 4, wherein

   Pharmaceutical composition comprising 15 to 25% by weight of hydroxypropylmethylcellulose relative to the total weight of the sustained release layer.
7. The method of claim 4, wherein

   Pharmaceutical composition comprising 1 to 25% by weight carbomer relative to the total weight of the sustained release layer.
8. The method of claim 2,

   The disintegrant is selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, and any combination thereof.
9. The method of claim 8,

   The content of the disintegrant is 1 to 5% by weight based on the total weight of the sustained release layer.
10. The method of claim 1,

    Pharmaceutical composition of the weight ratio of the active ingredient contained in the immediate release layer and the sustained release layer is 200: 100 to 210: 90.
11. The method of claim 1,

    300 mg of the (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or a pharmaceutically acceptable salt thereof once daily on an empty stomach or after a meal The pharmaceutical composition to be orally administered to.
12. The method of claim 1,

    1.5% by weight of 1- (dimethylamino) -3- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] -2-propanol hydrochloride as measured according to the Pharmacopoeia General Test Method Liquid Chromatography. Pharmaceutical composition comprising below.
13. The method of claim 1,

    Under elution test conditions according to the KEPCO General Test Method No. 2 (paddle method) (eluate: 900 mL of water, stirring speed: 50 rpm, test solution temperature: 37 ± 0.5), 25 to 45% in 60 minutes, 5 hours A pharmaceutical composition exhibiting a dissolution rate of 45% to 70% and at least 80% at 24 hours.

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