KR20170106126A - An oral pharmaceutical composition comprising (±)-2-[2-(3-carboxypropionyloxy)-3-dimethylaminopropoxy]-3'-methoxybibenzyl or a pharmaceutically acceptable salt thereof - Google Patents

Abstract

One embodiment of the present invention provides a pharmaceutical composition for alleviating or treating ischemic symptoms of chronic total occlusion, which comprises ()-2-[2-(3-carboxypropionyloxy)-3-dimethylaminopropoxy]-3-methoxybibenzyl hydrochloride as an effective component.

Description

An oral pharmaceutical composition comprising (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or a salt thereof, ) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or a pharmaceutically acceptable salt thereof.

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

(5- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride (sampogrillate hydrochloride) inhibits platelet and vascular serotonin receptors (5- HT2) as a platelet aggregation inhibitor with a novel mechanism of action.

Platelet aggregation prevents the formation of drugs called anti-platelet drugs, most drugs have a mechanism to inhibit the process of thrombosis and platelet activation. Aspirin, a representative drug, interferes with the action of cyclooxygenase and inhibits the action of thromboxane (anti-platelet). Another representative drug, clopidogrel, inhibits ADP 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'-methoxybibenzylhydrochloride inhibits 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. It has also been reported that it acts to inhibit the contraction of the smooth muscle of the vascular smooth muscle by serotonin and to improve the erythrocyte deformability (Non-Patent Document 1). By this action, (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride is a therapeutic agent for chronic arterial occlusive disease, chronic arterial occlusive disease It is known to be useful as an effective agent for alleviating ischemic symptoms of ulcers, pain and cold sensation, an agent for improving intermittent claudication, an agent for inhibiting thrombosis and embolization in ischemic cerebrovascular disorder, and a pain reliever for postherpetic neuralgia Document 2).

(±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride can be prepared based on the description of Example 2 of Patent Document 1 have. In addition, Patent Document 2 discloses that the compound exists as a crystalline polymorph. In the patent document 2, (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride may exist as crystal form I and crystal form II , And a method of producing the crystal form.

Such (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride has a short half-life and excellent effect, Can be a good choice.

In healthy adult men, single oral administration of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride was carried out and clinical pharmacological studies (+) - 2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride which is an effective dose of 100 mg , And the unchanged plasma concentration rapidly disappeared after reaching the maximum concentration in 1-2 hours after administration. Thus, tablets containing (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride, which is currently commercialized, The need for frequent dosing of these drugs has led to the disadvantages of poor patient adherence. Therefore, it has been found that the administration of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride Development is needed.

Japanese Patent Laid-Open Publication No. 58-32847 Korean Patent Publication 2006-0093677

1. 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 (June), (1991)

It is an object of the present invention to provide a pharmaceutical composition comprising (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or its pharmaceutically acceptable And to provide a pharmaceutically acceptable salt-containing pharmaceutical composition.

One aspect of the present invention is

A pharmaceutical composition comprising a bilayer tablet comprising a sustained-release layer and a 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 Or a pharmaceutically acceptable salt thereof.

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 the effective blood concentration of the drug can be maintained for about 24 hours while being administered once a day. Accordingly, the pharmaceutical composition according to one embodiment of the present invention is not only preferable because compliance with the medicinal drug of the patient can be significantly increased, but also can prevent an increase in the treatment period due to omission of the patient, There is an advantage that it can be used for improving or treating ischemic symptoms.

FIGS. 1A to 1D are graphs showing the dissolution rate measurement results over time for tablets of Example 1-10 of the present invention. FIG.
FIGS. 2A and 2B are graphs showing the results of measuring the dissolution rate with time for the tablets prepared in Examples 11-15 of the present invention. FIG.
FIG. 3 shows the time-blood concentration curves of three times administration of a control drug (Anplag®) for humans.
FIG. 4 shows a time-blood concentration curve at the time of single administration of two layers according to Example 15 of the present invention for a human.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

One aspect of the present invention is

A pharmaceutical composition comprising a bilayer tablet comprising a sustained-release layer and a 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 ≪ / RTI >

Pharmaceutically acceptable salts of the above (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl are those wherein the acid part of the inorganic acid salt or organic acid salt is a salt For example, 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, Gluconic acid, gluconic acid, gluconic acid, glutamic acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, 2-naphthalene disulfonic acid, But are not limited to, salts with phosphoric acid, phosphoric acid, folic 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'-methoxybibenzylhydrochloride.

(±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or a pharmaceutically acceptable salt thereof may be prepared according to methods known in the art For example, (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride can be prepared according to Example 2 of Patent Document 1 Can be produced based on the description of " (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride may be present in any crystalline form, , Crystalline Form II, or any combination thereof.

The crystalline form described above is disclosed in Patent Document 2. In one embodiment, the pharmaceutical composition comprises about 30% crystalline Form II of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride, , More specifically about 70% or more of the total weight of the composition.

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

The active ingredient may be present in the immediate-release layer and the sustained-release layer at an arbitrary ratio, and may be present in the immediate- and extended-release layers at a weight ratio of 1: 1 to 5, specifically about 1: 1 to 3, 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'-methoxybibenzylhydrochloride is included in the immediate layer at 100 mg, . In one embodiment, (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride is included in the immediate layer at 90 mg, . The pharmaceutical composition is useful for the treatment or prevention of chronic arterial occlusive disease, for the amelioration or treatment of ischemic symptoms due to chronic arterial occlusion, for the improvement of intermittent claudication, for the inhibition of thrombosis or embolization in ischemic cerebrovascular disorder, Can be used as an abatement agent. The ischemic symptom includes ulcer, pain, or cold feeling (Patent Document 2).

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

The pharmaceutical composition may be administered at a dose of about 200 to 400 mg / day of the active ingredient. The dose may vary depending on the age, body weight, general health condition, sex, diet, administration time, administration method, administration route, excretion rate, combination of drugs, And may be increased or decreased depending on the judgment of the expert.

In one embodiment, the malignant composition is a pharmaceutical composition for oral administration, wherein the pharmaceutical composition can be administered at about 200 to 400 mg / day of the active ingredient.

In one embodiment, the composition is a pharmaceutical composition for oral administration, wherein about 300 mg of the active ingredient can be administered orally once a day on an empty stomach or after a meal. The dose may also vary depending on the age, body weight, general health condition, sex, diet, administration time, administration method, administration route, excretion rate, combination of drugs, And may be increased or decreased depending on the judgment of the expert.

In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition comprising a single layer of sustained release, i. E., A sustained release layer. The pharmaceutical composition may include only a sustained-release layer, or may be an oral multiple-layered pharmaceutical composition in which the sustained-release layer is further included together with the sustained-release layer.

In one embodiment, the pharmaceutical composition is an oral two-layer pharmaceutical composition comprising a sustained-release layer and a immediate-release layer.

As used herein, the term "extended layer" means a layer in which the active ingredient slowly dissolves slowly in the body after administration. Unlike the "immediate-release layer ", the sustained-release layer contains a substance that controls elution of the active ingredient, i.e., a sustained release agent, so that the active ingredient can be slowly eluted. The sustained release agent may be any sustained release agent known in the art.

The sustained release agent is known in the art and can be any sustained release agent. Examples of the sustained release agent include cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose or sodium carboxymethylcellulose, polyethylene oxide, polyvinylpyrrolidone ), Guar gum, locust gum gum, polyvinylacetate, polyvinylacetate phthalate, polymethacrylate (Eudragit), polyacrylic acid, carbomer (for example, carbomer 941), glycerol monostearate and poloxamer, and any combination thereof. The sustained release may be from 10 to 30% by weight, preferably from 15 to 25% by weight, based on the weight of the sustained release layer have.

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

The hydroxypropylmethylcellulose may be hydroxypropylmethylcellulose having any viscosity used as a sustained release in the art, and in one embodiment is from 2,000 cps to 200,000 cps, preferably from 4,000 cps to 100,000 cps . If it is less than 2,000 cps, a large amount of hydroxypropylmethylcellulose is required, which leads to a large size of the tablet. If the viscosity exceeds 200,000 cps, uniform mixing with the drug may become difficult. In one embodiment, the viscosity of the hydroxypropylmethylcellulose may be from 80,000 cps to 120,000 cps.

The sustained-release formulation containing the pharmacologically active ingredient exhibits a swelling of the tablet upon elution. In this case, if the matrix of the release-controlling polymer is not rigid, the matrix may be partially eroded and the tablet may be disintegrated, which may lead to rapid drug release.

To solve this problem, a mixture of hydroxypropylmethylcellulose and carbomer can be used as a release-controlling polymer. When used as a polymer for drug release control together with hydroxypropylmethylcellulose, carbomer has the effect of strengthening the matrix in the sustained-release tablet, maintains its shape during tablet expansion and prevents the erosion of the tablet by maintaining the tablet matrix And maintains a constant dissolution rate.

In one embodiment, the combination of sustained release agents may be 15-25% by weight hydroxypropyl methylcellulose based on the total weight of the sustained release layer, and carbomer may be present in the range of 1-25% by weight, more specifically 1-10% And the ratio of hydroxypropylmethylcellulose to carbomer may be in a weight ratio of 2: 1 to 20: 1, specifically 4: 1 to 18: 1, more specifically 8: 1 to 15: 1 have.

More specifically, when the weight ratio of hydroxypropylmethylcellulose to carbomer is more 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 it gels in an alkaline environment, it binds to a cationic active substance. This is because there is a risk that drug release is inhibited in an alkaline environment. If the weight ratio of hydroxypropylmethylcellulose to carbomer is more than 20: 1, it is difficult to uniformly mix the polymers for emission control, the stability may be deteriorated, and the release effect is too large, There is a possibility that the concentration can not be reached. If the weight ratio is less than 2: 1, it is difficult to form a matrix in tablets, so that a sufficient sustained-release effect of the drug is not exhibited, so that once-a-day administration is impossible 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 concern of the side effect that may occur due to the rapid release of the active ingredient can be solved. In addition, since the active ingredient can be continuously released, the effective blood concentration can be maintained throughout the day by oral administration once a day, which is preferable in terms of the number of administrations. Therefore, it is possible to increase the adherence of the medicament because it can be administered once a day by continuous release without the risk of occurrence of adverse effect due to no rapid release of the drug.

The sustained release layer of the pharmaceutical composition may further comprise, in addition to the sustained release agent, a pharmaceutical additive selected from the group consisting of excipients, binders, disintegrants, lubricants, and any combination thereof.

In one embodiment, the sustained layer contains a disintegrant. While it is common for the sustained release layer not to contain a disintegrant for sustained release of the active ingredient, the pharmaceutical composition according to one embodiment of the present invention is characterized in that the sustained release of the active ingredient in the latter half after oral administration of the pharmaceutical composition is 100 % ≪ / RTI > (see Experimental Example 2). Therefore, the pharmaceutical composition according to one embodiment of the present invention is advantageous in that the dissolution of the active ingredient is almost completely eliminated as compared with the case where the disintegrant is not contained, so that the bioavailability can be remarkably improved. Means that the elution can be made "close to 100%" by at least 90%, specifically at least 93%, more specifically at least 95%, even more specifically at least 97% 98% or more.

The disintegrant may be any disintegrant used in the manufacture of tablets. The disintegrant may, for example, consist of sodium starch glycolate, polyvinylpyrrolidone, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, alginic acid, sodium alginate, But not limited to, < / RTI >

In one embodiment, the disintegrant is sodium starch glycolate or polyvinylpyrrolidone.

The content of the disintegrant may be in the range of about 1 to 5% by weight with respect to the total weight of the sustained-release layer. If the disintegrant is too large beyond the above-mentioned range, the disintegration effect becomes large and the release of the active ingredient may be inhibited. There is a fear that a sufficient disintegration effect is not obtained and thus a release close to 100% is not exhibited.

The sustained release layer may be prepared according to any sustained release process known in the art and may be prepared, for example, by granulating the active ingredient, sustained release agent, and pharmaceutical excipients together and then tableting Can be produced by tableting. The granules include dry granules or wet granules. In one embodiment, the granulate is a wet granulate, which is preferred in terms of stability in tableting with wet granules. Dry granules may cause problems such as breakage of tablets when tableted.

As used herein, the term "immediate-release layer" means a layer in which the active ingredient contained in the immediate-release layer rapidly dissolves rapidly in the body after administration. While the term "slow layer" requires a substance to control the release of the active ingredient, the immediate layer does not contain a substance that controls the release of the drug. Thus, the immediate-release layer may rapidly elute the active ingredient, and the immediate-release layer may optionally comprise a short-acting excipient.

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

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

The immediate-release layer allows for rapid release of the active ingredient, thus allowing the effective blood concentration of the active ingredient to be reached quickly upon oral administration. Therefore, the above-mentioned pharmaceutical composition can secure quicker action due to the presence of the above-mentioned immediate-release layer.

The immediate-release layer may further comprise a pharmaceutical additive selected from the group consisting of binders, stabilizers, disintegrants, lubricants, pH adjusting agents, stabilizers, and any combination thereof.

 (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl is unstable in alkali and may be inferior in stability, For example, citric acid. The stabilizer may be about 0.4 wt.% To 2.8 wt.%, More preferably 0.8 wt.% To 2.2 wt.%, Based on the total weight of the immediate layer. If the weight ratio of the stabilizer is less than 0.4 wt.%, , And if it exceeds 2.8% by weight, the initial dissolution rate may be lowered. This is because when the stabilizer is used in excess, the elution of the active ingredient may be lower in pH than in the fast pH condition (pH 4.0).

The immediate-release layer may be prepared according to any of the methods for the manufacture of any immediate-release layer known in the art, for example by granulating the active ingredient, the immediate release excipient, and the pharmaceutical additive together, . ≪ / RTI > The granules include dry granules or wet granules. In one embodiment, the granulate is a wet granulate, which is preferred in terms of stability in tableting with wet granules. Dry granules may cause problems such as breakage of tablets when tableted.

As the pharmaceutical additive contained in the slow-release layer and the immediate-release layer,

The excipient can be any excipient known in the art and includes, for example, microcrystalline cellulose, lactose, low substituted hydroxypropylcellulose, calcium phosphate, light silicic anhydride, pregelatinized starch, corn starch, potato starch, , 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 the group consisting of, for example, hydroxypropylcellulose, polyvinylpyrrolidone, povidone, copovidone, macrogol, and any combination thereof , But is not limited to;

The disintegrant may be any disintegrator known in the art and may include, for example, starch glycolic acid sodium, polyvinylpyrrolidone, crospovidone, croscarmellose sodium, pregelatinized starch, starch 1500, Starch, starch, alginic acid, sodium alginate, and combinations thereof, but are not limited to, polyvinylpyrrolidone;

The glidant may be any lubricant known in the art and may include, for example, stearic acid, calcium stearate or stearic acid metal salts such as magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, Oils, high melting point waxes, glyceryl fatty acid esters, glycerol dibehenate, and any mixture thereof, and any combination thereof, but is not limited thereto.

The oral and multilayered oral or buccal bilayer pharmaceutical compositions may contain the active ingredient, respectively, to provide release of both active and inactive ingredients of the active ingredient. It is possible to quickly reach the effective blood concentration by the rapidly released effective ingredient and thus to exhibit the fast drug efficacy, and it is possible to prevent the administration by continuous release of the active ingredient provided in the sustained release layer The number of times can be significantly reduced, for example, once a day. Therefore, the pharmaceutical composition according to the present invention can be provided as a once-a-day pharmaceutical preparation capable of rapid drug efficacy and sustained action.

The oral multi-layered tablet or oral dual-layer tablet may be prepared by firstly granulating the granules prepared for the production of the immediate-release layer using a tableting machine, as a first layer, applying a lubricant and a later- Filling and secondary tableting to produce a two-layer tablet, and the order of the immediate layer and the extended layer can be changed. Optionally, a film coating process may be further performed with the coating. The specific conditions for the manufacture of the immediate-release layer granules, the manufacture of the sustained-release layer granules, the primary tableting and the secondary tableting, and the film coating can be suitably carried out using techniques known in the art.

In one embodiment, the pharmaceutical composition is a bi-layer or multi-layer tablet comprising a immediate layer and a sustained layer, and both the immediate layer and the sustained release can be obtained due to the inclusion of the immediate layer and the sustained layer. In one embodiment, the pharmaceutical composition, which is a bi-layer or multilayer tablet comprising a immediate layer and a sustained-release layer, is prepared by dissolving (900 mL of water, stirring speed: 50 rpm, test solution temperature: 37 ± 0.5), a dissolution rate of 25-45% at 60 minutes, 45-70% at 5 hours and 80% at 24 hours (see Experimental Example 2). The pharmaceutical composition may be administered orally once a day by such an elution pattern.

In one embodiment, the multi-layered pharmaceutical composition or bi-layered pharmaceutical composition may have a blood systemic drug exposure (AUCt, t = 24) value of 1766.2 to 2058.4 h 占 퐂 / L after oral administration. In addition, the geometric mean ratio (postprandial / fasting) of the postprandial administration to the fasting administration of the blood total system drug exposure (AUCt, t = 24) value of the subject after oral administration may be 0.77 to 0.96. In addition, the maximum blood concentration (C _max ) value of the tissue after the oral administration may be 467.3 to 721.4 占 퐂 / L. In addition, the geometric mean ratio (postprandial / fasting) of the postprandial administration to the fasting administration of the maximum blood concentration (C _max ) value of the subject after oral administration may be 0.57 to 0.73. In addition, the time (T _max ) at which the blood concentration of the tissue after the oral administration reaches the maximum value may be 0.5 to 3.97 hours. In addition, the half-life ( _{t 1/2} ) of the effective half-life 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 was lowered and the highest blood concentration was also lowered after the meal administration compared with the fasting administration. Therefore, the amount of the active ingredient contained in the pharmaceutical composition may vary depending on the method of administration.

The pharmaceutical composition is prepared by dissolving (dimethylamino) -3- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] -2-propanol hydrochloride (BP- It was found to contain not more than 0.5% by weight in the general test method according to the liquid chromatography method (see Experimental Example 3). Thus, it has been confirmed that the above-described pharmaceutical composition can be produced as a stable preparation in which the release of the active ingredient is possible, while the production of the drug substance is below the reference value.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  1-10: (±) -2- [2- (3- Carboxypropionyloxy ) -3- Dimethylaminopropoxy ] -3'-methoxybenzyl Hydrochloride  Manufacture of sustained-release tablets

According to the composition and 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'-methoxybibenzylhydrochloride, lactose hydrate, Hypromellose Carbomer 941, and sodium starch glycolate were mixed, and the mixture was subjected to coalescence, granulation, and drying with the above-mentioned binding liquid, followed by 20 Followed by sieving to form a sustained-release granule. Then, the prepared sustained-bed granules were post-mixed with magnesium stearate. The granules were tableted at a hardness of about 14 kgf to prepare sustained release tablets. Then, the opaque white film of Table 2 was coated.

 [Table 1]

Experimental Example  1: (±) -2- [2- (3- Carboxypropionyloxy ) -3- Dimethylaminopropoxy ] -3'-methoxybenzyl Hydrochloride  Dissolution test of the sustained-release tablet containing (1)

(1) Preparing the test solution

≪ Dissolution condition >

Test apparatus: According to the second method (paddle method) of the Korean Pharmacopoeia general test method,

Eluent: 900 mL of water

Stirring speed: 50 rpm

Test liquid temperature: 37 ± 0.5 ° C

Six tablets of sustained-release tablets prepared in each of Examples 1-10 were subjected to a dissolution test according to the dissolution test method 2 (paddle method) in the General Practice of the Korean Pharmacopoeia according to the above conditions, and syringe filters of 0.45 탆 or less filter, and 5 mL of the first filtrate was discarded. The next filtrate was used as the sample solution.

(2) Standard solution preparation

The active ingredient, (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride standard was dried at 105 ° C for 2 hours to obtain about 33.3 mg Weigh accurately, add 80 mL of water and dissolve. Add water to make exactly 100 mL.

(3) Operation and calculation

40 μL of the sample solution and standard solution after 60 minutes, 5 hours and 24 hours after the start of the elution were tested according to the liquid chromatographic method in the general test method of the Korean Pharmacopoeia under the following machine operating conditions to measure the peak areas A _T and A _S of the active ingredient And the dissolution rate was calculated by the following equation.

<Device operation condition>

Detector: Ultraviolet absorptiometer (measuring wavelength: 272 nm)

Column: C18, 4.0 mm x 150 mm, 5 m

Column temperature: room temperature

Mobile phase: methanol 0.05 mol / L potassium dihydrogen phosphate solution (7: 3)

Flow rate: Adjust so that the holding time of the effective component is about 7 minutes.

System suitability test: When the test is repeated 6 times with 40 μL of the standard solution under the above conditions, the relative standard deviation of the active ingredient peak area is 2.0% or less.

Area measurement range: Approximately twice the effective component holding time

<Formula>

[Table 2]

The initial dissolution profiles of Examples 5 and 6, including carbomers, were lower than the initial dissolution profiles of Examples 7 and 8 which did not contain carbomer (FIG. 1).

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 of the drug dropped to the late half of the drug at a final dissolution rate of about 92%. However, in Examples 5 and 6 including povidone, the final dissolution rate in the late portion was improved by about 95%. As a disintegrant Starch glycolate sodium In the case of Examples 9 and 10, the dissolution rate in 24 hours was about 97%, and the dissolution rate in the latter half of the active ingredient was further improved.

Example  11-15: (+ -) - 2- [2- (3- Carboxypropionyloxy ) -3- Dimethylaminopropoxy ] -3'-methoxybenzyl Hydrochloride  Manufacture of two-layer containing definition

First, a granule of granules containing (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride was prepared.

According to the ingredients and the content of the immediate 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- Hydroxy-3'-methoxybibenzylhydrochloride, lactose hydrate, sodium starch glycolate, and citric acid, followed by association, granulation, and drying with the binding solution, followed by sieving with a No. 20 sieve, Layer granules were prepared. Then, the prepared inner layer granules were post-mixed with magnesium stearate.

According to the composition and 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) Hydroxy-3'-methoxybibenzylhydrochloride, lactose hydrate, microcrystalline cellulose 101, hypromellose, carbomer 941, and sodium starch glycolate were mixed and then combined, granulated and dried And then sieved through a No. 20 sieve to form a western layer granule. Then, the prepared sustained-bed granules were post-mixed with magnesium stearate.

The inner layer granules were firstly pressed with a hardness of about 3 kgf, and then the later-mixed granules were filled with the inner layer granules, followed by secondary tableting at a hardness of about 15 kgf. Then the film was coated with the coating material of Table 3 below to complete the two-layer tablet.

[Table 3]

Experimental Example  2: (~) -2- [2- (3- Carboxypropionyloxy ) -3- Dimethylaminopropoxy ] -3'-methoxybenzyl Hydrochloride  Containing sustained release double layer elution test (2)

With respect to the tablets prepared in Examples 11 to 15, the dissolution rate was measured in the same manner as in Experimental Example 1 above. The results of the dissolution test are shown in Table 4 and FIG. In the case of Examples 11-15 including the disintegrant, the elution of the active ingredient in the latter half after oral administration was found to be close to 100%.

 [Table 4]

Experimental Example  3: (~) -2- [2- (3- Carboxypropionyloxy ) -3- Dimethylaminopropoxy ] -3'-methoxybenzyl Hydrochloride  Definition of containing two layers Flexible material  exam

(±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride prepared in Example 15 according to the following conditions: A material test was conducted.

(One) Preparation of test liquid

Precisely weigh 75 mg of the active compound-containing double layer preparation of Example 15, dissolve in 0.01 mol / L hydrochloric acid, and dilute to 100 mL with 0.01 mol / L hydrochloric acid. Use this solution as the sample solution.

(2) Prepare standard solution

Dry the sample at 105 ° C for 2 hours, accurately weigh 37.5 mg, dissolve in 0.01 mol / L hydrochloric acid, and make exactly 100 mL with 0.01 mol / L hydrochloric acid to prepare a standard stock solution. Take exactly 1 mL of the standard stock solution and make exactly 100 mL with 0.01 mol / L hydrochloric acid. Use this solution as the standard solution.

(3) Manipulation and calculation

20 μL of the sample solution and the standard solution are subjected to the liquid chromatographic method in the general test method of the KPG under the following machine operating conditions, and the peak areas A _T and A _S of BP-984 are measured.

<Device operation condition>

Detector: Ultraviolet absorptiometer (measuring wavelength: 272 nm)

Column: C18, 4.0 mm x 150 mm, 5 m

Column temperature: room temperature

Mobile phase: methanol 0.05 mol / L potassium dihydrogen phosphate solution (7: 3)

Flow rate: Adjusted so that the retention time of the (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzylhydrochloride as an effective ingredient is about 7 minutes .

Selection of column: 75 mg of the active ingredient standard is precisely weighed into a 100-mL volumetric flask and dissolved in 80 mL of 0.01 mol / L hydrochloric acid. Add 1 mL of the standard stock solution prepared above and dilute to 100 mL with 0.01 mol / L hydrochloric acid. When 20 μL of this solution is tested under the above conditions, it is to be eluted in the order of BP-984 and active ingredient, and the degree of separation is 1.5 or more.

Reproducibility of the system: When the test is repeated 6 times under the above conditions with 20 μL of the standard solution, the relative standard deviation of the active ingredient peak area is 2.0% or less.

Area measurement range: Approximately twice the effective component holding time

<Formula>

(4) Results

As a result of the measurement of the flexible substance, it was confirmed that BP-984 represented by the following formula was 0.5% or less.

Experimental Example  4: Pharmacokinetics  exam

In this clinical trial, pharmacokinetic properties (pharmacokinetic properties) were confirmed by single administration of the two-layer tablet of Example 15 to healthy volunteers and compared with that of the commercially available Anplag® oral tablet. In addition, the effect of food was investigated by comparing the pharmacokinetic properties of the double-layered formulation of Example 15 and the fasting administration.

(One) Overall clinical trial method

To evaluate the pharmacokinetic properties of the two formulations and the effects of food, open, randomized, and group 3 and 3 Williams clinical trials were conducted.

Each subject was randomly assigned to receive either Group A (RT-TF) or Group B (T-TF-R) or Group C (TF-RT) or Group D (TF- (R-TF-T). (R: Reference substance (Fasting), T: Test substance (fasting), TF: Test substance (Postprandial) We took the test drug in the fasting state and took the test drug in the postnatal period in the third period.

(2) Blood collection for pharmacokinetic analysis

Blood was collected at the time immediately before and at the time of the administration of each period. Control drug: before each administration (0h) (first administration after blood sampling), 0.25, 0.5, 1, 1.5, 2, 3, 12, 12.5, 13, 13.5, 14, 15, 16, 24h (total 23 times), 6.25, 6.5, 7, 7.5,

Tests were given before each dose (0h), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16,

Blood was collected by centrifugation at 3,000 rpm at 4 ° C for 10 minutes. The blood was dispensed into 3 labeled eppendorf tubes (1.5 mL each) and stored frozen at -70 ° C.

(3) Pharmacokinetic analysis results

The mean blood concentration-time curve for each administration group is shown in FIGS. 3 and 4. FIG.

FIG. 3 shows the time-blood concentration curves of three times administration of a control drug (Anplag®) for humans.

FIG. 4 shows a time-blood concentration curve at the time of single administration of two layers according to Example 15 of the present invention for a human.

In FIGS. 3 and 4, bar represents a standard deviation (top: linear, bottom: linear).

The concentration of (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybenzyl in the blood, which is the active ingredient in fasting treatment, Concentration, and then decreased to a half-life of 0.70 hours. On the fasting, when the test drug was administered, the peak blood concentration was reached at 0.5 hour and then decreased to a half-life of 3.23 hours. At the time of administration of the test drug after the ingestion of food, the maximum blood concentration reaching time and half life were 3.97 hours and 1.45 hours, respectively.

The half-life and tmax between the control and test drug (fasting) were statistically significant. (In order: p-value < 0.0001, p-value = 0.0259)

The descriptive statistics and the estimation results for the pharmacokinetic parameters are presented in Tables 5 and 6 below.

[Table 5]

[Table 6]

(P-value <0.0001, p-value <0.0001) were statistically significant differences between the postprandial and fasting doses of the test drug and tmax.

Estimation results for food effects are presented in Tables 7 and 8.

[Table 7]

[Table 8]

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (13)

A pharmaceutical composition comprising a bilayer tablet comprising a sustained-release layer and a 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 &Lt; / RTI &gt; The method according to claim 1,
Wherein the sustained release layer further comprises a pharmaceutical additive selected from the group consisting of excipients, sustained release agents, binders, disintegrants, lubricants, and any combination thereof. The method according to 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. 3. The method of claim 2,
The sustained release agent may be a cellulose derivative such as hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose or sodium carboxymethylcellulose, polyethylene oxide, polyvinylpyrrolidone, Polyvinyl acetate, polyvinylacetate phthalate, polymethacrylate (Eudragit), polyacrylic acid, carbomer (for example, carbomer 941), glycerol &Lt; / RTI &gt; monostearate and poloxamer, and any combination thereof. 3. The method of claim 2,
Wherein the sustained release agent is 10-30 wt% based on the total weight of the sustained release layer. 5. The method of claim 4,
And 15-25% by weight of hydroxypropylmethylcellulose based on the total weight of the sustained release layer. 5. The method of claim 4,
And 1 to 25% by weight of the carbomer based on the total weight of the sustained release layer. 3. The method of claim 2,
The disintegrant is selected from the group consisting of sodium starch glycolate, polyvinylpyrrolidone, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, alginic acid, sodium alginate, and any combination thereof &Lt; / RTI &gt; 9. The method of claim 8,
Wherein the content of the disintegrant is 1 to 5% by weight based on the total weight of the sustained release layer. The method according to claim 1,
Wherein the weight ratio of the effective ingredient contained in the immediate-release layer to the sustained-release layer is from 200: 100 to 210: 90. The method according to claim 1,
300 mg of said (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybibenzyl or a pharmaceutically acceptable salt thereof is administered orally &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. The method according to claim 1,
1.5% by weight of 1- (dimethylamino) -3- [2- [2- (3-methoxyphenyl) ethyl] phenoxy] -2-propanol hydrochloride as measured by liquid chromatography, &Lt; / RTI &gt; The method according to claim 1,
(Elution solution: 900 mL of water, stirring rate: 50 rpm, test solution temperature: 37 ± 0.5) at 25 to 45% for 60 minutes at 5 hours in accordance with the general method of Korean Pharmacopoeia 45-70% and a dissolution rate of 80% or more at 24 hours.

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