KR20210057590A - Microsphere for controlled-release of Ticagrelor, pharmaceutical composition for the same, and preparation method thereof - Google Patents

Abstract

Provided are microspheres for controlled-release containing ticagrelor or a pharmaceutically acceptable salt thereof as an active component, a pharmaceutical composition, and a manufacturing method thereof. The microspheres or the pharmaceutical composition for controlled release achieves a dissolution rate of about 95% or more at the end point of dissolution (after 24 hours), and as a result, bioavailability can be increased.

Description

Microsphere for controlled-release of Ticagrelor, pharmaceutical composition for the same, and preparation method thereof {Microsphere for controlled-release of Ticagrelor, pharmaceutical composition for the same, and preparation method thereof}

It relates to release-controlled microspheres containing ticagrelor as an active ingredient, a pharmaceutical composition for controlling release containing ticagrelor as an active ingredient, and a method for preparing them.

Platelet adhesion and aggregation are early symptoms of arterial thrombosis. Platelet aggregation caused by platelet adhesion can promote acute thrombotic occlusion, causing symptoms with high morbidity such as myocardial infarction and unstable angina. In addition, it was found that adenosine diphosphate (ADP) acts as a major mediator of thrombosis. Platelet aggregation induced by ADP is mediated by the P2T receptor subtype uniquely located in the platelet membrane. Thus, P2T antagonists can act as antithrombotic agents.

In this regard, Patent Document 1 generally discloses a series of triazolo[4,5-d]pyrimidine compounds having activity as _{P2T (also known as P2Y 12} , P2Y _ADP or P2T _{AC) antagonists.} Further, Patent Document 2 discloses direct P2T receptor antagonists including compounds of Ticagrelor. Ticagrelor, also known as Brilinta Tablet ^TM , is a drug that can reduce the incidence of thrombotic cardiovascular events (death due to cardiovascular abnormalities, myocardial infarction, stroke) through platelet aggregation inhibitory action, and is a drug that can reduce the incidence of acute coronary syndrome or It can be used in patients with a high risk of developing thrombotic cardiovascular events with a history of myocardial infarction (occurring at least 1 year before). However, most of ticagrelor is absorbed from the small intestine within about 2 hours after oral administration, and its half-life is about 7 hours, so there is a lot of inconvenience. In particular, there is an inconvenience of having to be administered twice a day compared to drugs that are effective once a day, such as clopidogrel or prasugrel, which are the same drugs. In addition, when the formulation design for controlling the release is complicated, the manufacturing process is difficult, and unnecessary time and cost are required, which is not economical.

Therefore, in order to increase patient compliance, the number of doses is reduced and the drug is continuously effective, and the release-controlled composition and release-controlled microspheres containing ticagrelor as an active ingredient, which are simple and economical in the manufacturing process, and the There is a need to develop a manufacturing method.

International Patent Publication No. 99-05143 International Patent Publication No. 00-34283

One aspect provides a release-controlled microsphere comprising ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient for controlling the release of ticagrelor.

Another aspect provides a pharmaceutical composition for controlled release comprising ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient for controlling the release of ticagrelor.

Another aspect provides a method of manufacturing the emission control microspheres.

One aspect is

Inert core;

Ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient, and a first coating layer comprising a water-soluble polymer;

A second coating layer comprising a cellulose derivative; And

It provides a release-controlled microspheres comprising a release-controlling layer comprising a water-insoluble ethyl cellulose dispersion.

Another aspect is

Inert core material; Ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient, and a first coating layer composition comprising a water-soluble polymer; A second coating layer composition comprising a cellulose derivative; And it provides a pharmaceutical composition for controlling release containing; and a release controlling layer composition comprising a water-insoluble ethyl cellulose dispersion.

Another aspect is

Preparing an inert core;

Forming a first coating layer comprising ticagrelor or a pharmaceutically acceptable salt thereof, and a water-soluble polymer as an active ingredient on the inert core;

Forming a second coating layer comprising a cellulose derivative on the inert core on which the first coating layer is formed; And

It provides a method for producing a microsphere for controlling release comprising the step of forming a release controlling layer comprising a water-insoluble ethyl cellulose dispersion on the inert core on which the second coating layer is formed.

Controlled release microspheres and pharmaceutical compositions containing ticagrelor or a pharmaceutically acceptable salt thereof according to one aspect can be sustained release by controlling the release rate of the ticagrelor-containing formulation, and accordingly, once a day administration is possible. It is possible, and also exhibits excellent stability and dissolution rate. Ticagrelor or its pharmaceutically acceptable salt contained as an active ingredient in the release-controlled microspheres or pharmaceutical compositions is slowly released from the formulation at a constant rate regardless of external pH, thereby maintaining a constant concentration of ticagrelor in the body. It is possible to reduce the number of doses, thereby increasing patient compliance and maximizing the therapeutic effect of the drug. In addition, the release-controlled microspheres or pharmaceutical compositions not only satisfied the content test criteria under long-term preservation test and accelerated test conditions, but also satisfied the related substance test criteria, confirming the stability of the formulation containing ticagrelor, and dissolution. As a result of test evaluation, it was confirmed that administration once a day achieves a release control effect. In addition, it can be seen that the release-controlled microspheres or pharmaceutical compositions achieve a dissolution rate of about 95% or more at the dissolution end point (after 24 hours), and as a result, increase the bioavailability.

Another aspect provides a manufacturing method capable of manufacturing the emission control microspheres with a simpler process and efficiency. The above manufacturing method improves productivity and at the same time secures excellent quality of microspheres for emission control.

1 shows the pH change and the dissolution rate (%) over time for the sustained-release microsphere composition of ticagrelor prepared in Example 4.

All technical terms used in the present invention, unless otherwise defined, are used in the same meaning as those of ordinary skill in the art generally understand in the related field of the present invention. In addition, although preferred methods or samples are described in the present specification, those similar or equivalent are included in the scope of the present invention. The process described below is merely an example according to the present invention, and in the present invention, some of the steps may be omitted or may be repeatedly performed, and in some cases, the order of each step may be appropriately changed. In addition, the numerical values described herein are considered to include the meaning of "about" even if not specified. The contents of all publications referred to herein by reference are incorporated herein by reference in their entirety.

One aspect is

Inert core;

A first coating layer comprising ticagrelor or a pharmaceutically acceptable, water-soluble polymer thereof as an active ingredient;

A second coating layer comprising a cellulose derivative; And

It provides a release-controlled microspheres comprising a release-controlling layer comprising a water-insoluble ethyl cellulose dispersion.

In this specification, "Ticagrelor" is generally "(1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl) Cyclopropyl]amino}-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) -1,2-cyclopentanediol". Ticagrelor can be represented by the following formula (1).

[Formula 1]

In the present specification, ticagrelor may be referred to as a racemate of ticagrelor or a pharmaceutically acceptable salt thereof, an optical isomer, a homologue (polymorph), a hydrate or a solvate, and the like.

The pharmaceutically acceptable salt of ticagrelor refers to a salt prepared according to a conventional method in the art, and such a preparation method is known to those skilled in the art. The above 　pharmaceutical 　allowable 　 salts include, but are not limited to, pharmacologically or physiologically acceptable 　 salts derived from inorganic and organic acids and 　 bases. For example, the pharmaceutically acceptable salt of ticagrelor may be an acid addition salt formed by a pharmaceutically acceptable free acid. Inorganic acids and organic acids can be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, methanesulfuric acid can be used as organic acids. Ponic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, glutamic acid, citric acid, aspartic acid, camposulfonic acid, and the like may be used, but are not limited thereto. Suitable salts derived from bases may include, but are not limited to, alkali metals such as sodium, or potassium, alkaline earth metals such as calcium, magnesium. If necessary, ticagrelor or a pharmaceutically acceptable salt may be provided in the form of a hydrate or solvate thereof. In one embodiment, the ticagrelor or pharmaceutically acceptable salt may be hydrochloride or methanesulfonate.

According to one embodiment, the release-controlled microspheres include an inert core; A first coating layer comprising ticagrelor or a pharmaceutically acceptable salt thereof, and a water-soluble polymer as an active ingredient, which coats the inert core; A second coating layer comprising a cellulose derivative formed on the first coating layer; And a release controlling layer comprising a water-insoluble ethyl cellulose dispersion formed on the second coating layer.

According to another embodiment, the first coating layer including ticagrelor or a pharmaceutically acceptable and water-soluble polymer thereof as an active ingredient in the release-controlled microspheres may be mixed with the inert core and exist on the same plane.

According to one embodiment, the first coating layer composition for forming a first coating layer comprising ticagrelor or a pharmaceutically acceptable and water-soluble polymer as an active ingredient in the release-controlled microspheres comprises an inert core material forming an inert core and By mixing, it is possible to prepare microspheres (cores) including the first coating layer component.

In the present specification, "microsphere" may mean particles for encapsulating a drug in a formulation, and is used interchangeably with particulates. The microparticles may be in the range of microns or µm, or smaller in size, for example, from about 1 µm to about 1000 µm, from about 10 µm to about 950 µm, from about 100 µm to about 900 µm, or from about 500 µm to about 800 µm. Includes arbitrary particles with a particle diameter of μm. For example, the particle diameter of the microspheres is about 10, 50, 100, 200, 300, 400, 500, 550, 600, 700, 800, 900, or 1000 μm, or a numerical range using these values as the lower and upper limits, respectively. It can be something to have. The microspheres may be of any shape, such as, for example, approximately spherical (eg, microspheres), spherical, elliptical, cylindrical, rod-shaped, and the like. The particle diameter of the microspheres for emission control according to an embodiment may be about 500 µm to 1000 µm, or about 550 µm to 800 µm. In one embodiment, the microspheres may be in the form of pellets.

In the present specification, “controlled release” means that the pharmaceutically active substance contained in the formulation can be continuously released for an intended period, for example, it refers to “sustained release”.

In the present specification, “inert core” refers to the core or nucleus of microspheres that do not contain a drug, which is a pharmacological component.

In one embodiment, the particle diameter of the inert core is about 1 to 1,000 μm, or about 100 to 900 μm, such as about 100 to about 800 μm, or, for example, about 500 to 600 μm or about 550 μm to 600 μm. A core having a particle diameter may be used, but is not limited thereto, and the size may be appropriately adjusted if necessary. For example, the particle diameter of the inert core is about 10, 50, 100, 200, 300, 400, 500, 550, 600, 700, 800, 900, or 1000 μm, or a numerical range using these values as the lower and upper limits, respectively. It may be to have.

In one embodiment, the inert core may include about 20 to about 70 parts by weight, for example, about 30 to 60 parts by weight, for example, about 40 parts by weight, based on 100 parts by weight of the release-controlled microspheres (total weight). In one embodiment, the weight ratio of ticagrelor to inert core may be about 1: 0.5 to 1: 2.5. For example, the weight ratio may be about 1: 1 to 1: 2.0, for example, about 1: 1.67.

In one embodiment, the inert core may be prepared from an inert coating material selected from sugar, calcium monohydrogen phosphate dihydrate, microcrystalline cellulose, starch, or a mixture thereof. For example, the inert core may be sugar spheres, microcrystalline cellulose spheres, or corn starch spheres.

In one embodiment, the inert core may include Sugar Sphere. The sugar pear generally contains about 95% or less of sucrose when calculated on a dry weight basis, and the remainder may be composed of corn starch. In one embodiment, the sugar pear may contain about 60 to 95% sucrose. Sugar pears have been widely used as excipients in the pharmaceutical industry, and commercially available ones can be used without limitation. For example, pharm-a-spheres ^TM may be used as the sugar sphere.

In the present specification, the “first coating layer” refers to a coating layer formed on the core, and includes ticagrelor or a pharmaceutically acceptable salt thereof as a drug, and is also referred to herein as a “main component coating layer”.

In one embodiment, the first coating layer is a water-soluble polymer having a viscosity of about 1.0 to 10.0 cPs, or 3.5 to 9.5 cPs or less, 4.0 to 7 cPs, 5.0 to 6.5 cPs, or, for example, about 5.0 to 7.0 cPs at 20°C. It may be to include. In one embodiment, the first coating layer may include a water-soluble polymer having a viscosity of about 3.0 to 9.0 cPs at 20°C. In one embodiment, the first coating layer may include a water-soluble polymer having a viscosity of about 5.5 to 6.5 cPs at 20°C. For example, the first coating layer may include a water-soluble polymer having a viscosity of about 5.0 to 6.0 cPs at 20°C. The viscosity may be measured by making a 2% solution at 20°C. For example, the first coating layer may include a water-soluble polymer having a viscosity of about 6.0 cPs. For example, the first coating layer may include a water-soluble polymer having a viscosity of about 3.0 to 9.0 cPs. For example, the water-soluble polymer is hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), hyaluronic acid (HA), alginic acid, and pectin. , Carrageenan, Cyclodextrin, Maltose, Lactose, Trehalose, Xanthan gum, pregelatinized starch, or a mixture thereof. In one embodiment, the water-soluble polymer may be hydroxypropylmethylcellulose (HPMC). For example, the first coating layer may include HPMC 606 (viscosity 6.0 cPs). The first coating layer is ticagrelor or a pharmaceutically acceptable salt as a drug, and a pharmaceutically acceptable additive other than a water-soluble polymer, for example, a viscosity controlling polymer (such as hydroxypropylmethylcellulose), a filler or a binder (such as Polyethylene glycol), and a lubricant (eg talc) may be further included.

In one embodiment, the first coating layer is about 5 to about 40 parts by weight, for example about 20 to 30 parts by weight, based on 100 parts by weight of the water-soluble polymer, such as hydroxypropylmethylcellulose (HPMC), based on 100 parts by weight of the microparticles (total weight) Parts, or about 8 to 20 parts by weight, such as about 10 parts by weight. In one embodiment, the water-soluble polymer (eg, weight ratio of HPMC) in the first coating layer to ticagrelor may be about 1:0.05 to 1:1. For example, the weight ratio may be about 1:0.1 to 1:0.5, for example 1:0.4.

In the emission control microspheres according to an embodiment, the core and/or the first coating layer may not contain a disintegrant. In the release-controlled microspheres according to an embodiment, as the inert core material and the microspheres prepared from the first coating layer composition do not contain a disintegrant, the effect of controlling the initial dissolution rate of the active ingredient drug and the sustained-release effect for 24 hours are increased. I can make it. In the present specification, the “second coating layer” refers to a coating layer formed on the core on which the first coating layer is formed, and exists between the first coating layer and the emission control layer, and is also referred to herein as a “protective coating layer”.

In one embodiment, the second coating layer may include a cellulose derivative. In one embodiment, the second coating layer may include a cellulose derivative selected from methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or a combination thereof. In one embodiment, the second coating layer may include hydroxypropylmethylcellulose. In addition to hydroxypropylmethylcellulose, the second coating layer may further include a pharmaceutically acceptable additive such as thracetin or talc. For example, the second coating layer may include Clear ^TM (Opadry ^® 03K19229 Clear). The second coating layer may be prepared from a mixture containing about 70 to 90% of hydroxypropylmethylcellulose, about 5 to 15% of triacetin, or about 5 to 15% of talc. The second coating layer may be prepared from a mixture comprising about 80 to 90% of hydroxypropylmethylcellulose, about 5 to 10% of triacetin, or about 5 to 10% of talc. In one embodiment, the second coating layer may be prepared from a mixture containing about 84.1% hydroxypropylmethylcellulose, about 8.4% triacetin, or about 7.5% talc.

In one embodiment, the second coating layer comprises about 0.1 to about 4 parts by weight, for example, about 0.5 to 3 parts by weight, such as about 1 part by weight, based on 100 parts by weight of the release-controlled microparticles (total weight). I can. In one embodiment, the Mathematica relreo for the second weight ratio is about 1 of a cellulose derivative (e. G. Opadry ^® 03K19229 cleared) in the coating layer: 0.01 to 1: 0.05 can work. For example, the weight ratio may be about 1: 0.04.

In the present specification, the "release control layer" refers to a release control layer formed on the core on which the first coating layer and the second coating layer are formed. In one embodiment, the release-controlling layer may include a water-insoluble ethylcellulose dispersion as a release-controlling material. The water-insoluble ethyl cellulose dispersion may include ethyl cellulose, medium-chain fatty acid triglyceride, oleic acid, ammonium hydroxide, and purified water. For example, the release controlling layer may include Sure Release ^™ . The release control layer may include about 1 to 20% ethyl cellulose, about 0.1 to 10% medium-chain fatty acid triglyceride, about 0.1 to 10% oleic acid, ammonium hydroxide and purified water (about 70 to 80%). The release control layer may include about 1 to 20% ethyl cellulose, about 0.1 to 5% medium-chain fatty acid triglyceride, about 0.1 to 5% oleic acid, ammonium hydroxide and purified water (about 70 to 80%). In one embodiment, the release control layer may include about 18% ethyl cellulose, about 3.19% medium-chain fatty acid triglyceride, about 2% oleic acid, ammonium hydroxide and purified water (about 76.81%). For example, the release control layer may have a ratio of medium-chain fatty acid triglyceride to ethyl cellulose of about 0.1 to 0.2, such as about 0.18, and a ratio of oleic acid to ethyl cellulose of about 0.05 to 0.2, such as about 0.11.

In one embodiment, the water-insoluble ethyl cellulose dispersion in the release control layer is about 10 to about 50 parts by weight, for example about 15 to 40 parts by weight, such as about 17 parts by weight based on 100 parts by weight of the release-controlled microparticles (total weight). It may be included in to 35 parts by weight.

In one embodiment, the water-insoluble ethylcellulose dispersion contained in the release controlling layer may be included in an amount of about 0.4 to 2 parts by weight based on 1 part by weight of ticagrelor or a pharmaceutically acceptable salt thereof. For example, the water-insoluble ethylcellulose dispersion may be included in an amount of about 0.5 to 1.5 parts by weight based on 1 part by weight of ticagrelor or a pharmaceutically acceptable salt thereof. For example, the water-insoluble ethyl cellulose dispersion may be included in an amount of about 0.6 to 1.2 parts by weight based on 1 part by weight of ticagrelor or a pharmaceutically acceptable salt thereof. For example, the water-insoluble ethylcellulose dispersion may be included in an amount of about 0.7 to 1.3 parts by weight based on 1 part by weight of ticagrelor or a pharmaceutically acceptable salt thereof.

In one embodiment, the water-insoluble ethylcellulose dispersion in the release-controlling layer (such as Sure Release ^TM ) is in an amount exceeding about 0.67 parts by weight per 1 part by weight of ticagrelor, about 0.7 or more and about 1.3 or less, for example 1 As it is included in parts by weight, it can be seen that a desirable dissolution rate is exhibited under the dissolution condition for 24 hours, a dissolution rate of about 95% or more is achieved at the dissolution end point (after 24 hours), and as a result, the bioavailability can be increased.

In one embodiment, when the water-insoluble ethylcellulose dispersion in the release control layer (eg, Sure Release ^TM ) is included in an amount outside the above range, the effect of achieving the desired controlled release and bioavailability can be controlled.

For example, when including about 0.7 parts by weight or less per 1 part by weight of ticagrelor, the dissolution rate of the drug at the dissolution end point (after 24 hours) is when the water-insoluble ethyl cellulose dispersion in the release control layer (such as Sure Release ^{TM) is included in an amount of about 0.7 parts by weight or less per 1 part by weight of ticagrelor.} It can be seen that it shows an incomplete dissolution rate of less than 80%, an excessively high initial release rate, and consequently lowers the bioavailability.

In addition, when the water-insoluble ethyl cellulose dispersion in the release control layer (such as Sure Release ^TM ) is included in an amount exceeding about 1.3 parts by weight per 1 part by weight of ticagrelor, the dissolution rate of the drug at the dissolution end point (after 24 hours) is 80%. It can be seen that the incomplete dissolution rate is less than and the initial release rate is too low, and as a result, the bioavailability will be lowered.

In one embodiment, the weight ratio of ticagrelor to the water-insoluble ethylcellulose dispersion in the release control layer may be about 1:0.4 to 1:2. For example, the weight ratio may be about 1: 0.5 to 1: 1.5, for example, about 1: 0.6 to 1: 1.2 or about 1: 0.7 to 1: 1.3.

In one embodiment, when 240 g of ticagrelor is included, Sure Release ^TM may be included in a solid content of 40 to 80 g. The solid content of the water-insoluble ethyl cellulose dispersion may be included in an amount of about 2 to about 15 parts by weight, for example, about 3 to 10 parts by weight, based on 100 parts by weight of the microparticles (total weight) for controlling release. The weight ratio of the solid content of the ticagrelor to the water-insoluble ethylcellulose dispersion may be about 1:0.05 to 1:0.5. For example, the weight ratio may be about 1: 0.1 to 1: 0.4, for example, about 1: 0.15 to 1: 0.3.

Another aspect is

Inert core material; Ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient, and a first coating layer composition comprising a water-soluble polymer; A second coating layer composition comprising a cellulose derivative; And it provides a pharmaceutical composition for controlling release containing; and a release controlling layer composition comprising a water-insoluble ethyl cellulose dispersion.

In one embodiment, the inert core material may be selected from sugar, calcium monohydrogen phosphate dihydrate, microcrystalline cellulose, starch, or a mixture thereof.

In the pharmaceutical composition according to an embodiment, the first coating layer composition, the second coating layer composition, and the release-controlling layer composition are each a water-soluble polymer contained in the first coating layer described in the release-controlled microspheres (for example, viscosity of about 1 to 10 cPs, for example, For example, a water-soluble polymer of about 5 to 7 cPs, or about 5.5 to 6.5 cPs), a cellulose derivative contained in the second coating layer (e.g., Opadry ^® 03K19229 Clear), a water-insoluble ethyl cellulose dispersion contained in the release controlling layer (e.g., Sure Release ^TM ) is the same as the description.

The pharmaceutical composition according to an embodiment may be used to prepare microspheres for controlled release comprising ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition or microspheres for controlled release prepared therefrom according to an embodiment may further include a pharmaceutically acceptable excipient. Examples of the pharmaceutically acceptable excipients include fillers such as lactose, corn starch, microcrystalline cellulose, polyethylene glycol or dicalcium potassium; Microcrystalline cellulose highly dispersible silica, sugar such as mannitol and lactose, highly dispersible silica, binders such as mannitol, lactose or polyethylene glycol; Lubricants such as colloidal silicon dioxide, talc, stearic acid, magnesium stearate, and sodium stearyl fumarate; Coatings such as ethyl cellulose, hydroxypropylmethylcellulose, and methacrylic acid-alkyl acrylate copolymer; In addition, solubilizers, solubilizers, colorants, pH adjusters, surfactants, stabilizers, and emulsifiers can be used. However, the present invention is not limited thereto, and may be appropriately selected and used according to known techniques in the art.

The pharmaceutical composition or microparticles for controlled release according to an embodiment do not contain too high an active ingredient, ticagrelor or a pharmaceutically acceptable salt thereof, to cause side effects per unit formulation, and the ticagrelor or pharmaceutical thereof The acceptable salt can be released at a constant rate for a long time, so that the concentration of the active ingredient in the plasma is kept constant, and the adherence of the administration target can be increased by controlling the number of doses and dosage, preferably administered once a day. It is possible to provide a formulation in a form suitable for the following.

The pharmaceutical composition or microspheres for controlled release according to an embodiment may be provided as an oral formulation containing the same. The formulation may be a tablet such as a liquid, powder, granule, pellet, mini tablet, capsule or uncoated tablet, coated tablet, multi-layered tablet, or core tablet. In one embodiment, the oral formulation may be a tablet.

The pharmaceutical composition or the controlled release microspheres according to an embodiment may be for oral administration. The composition may be a controlled release composition that can be administered once a day. The composition or microspheres may be capable of sustained release of ticagrelor or a pharmaceutically acceptable salt thereof. The composition or microspheres may exhibit improved stability and dissolution rate.

The pharmaceutical composition according to an embodiment, or microspheres for controlled release prepared therefrom, or a formulation containing the same, is about 10 to 30%, 5 to 2 hours from administration of ticagrelor or a pharmaceutically acceptable salt thereof. It can be released at a constant rate of about 40-60% per hour, about 80% in 12 hours, and about 90% in 24 hours. In particular, considering the fact that the absorption site of ticagrelor is the small intestine, it is important to maintain a constant release pattern between disintegration 1 solution (artificial gastric solution, pH 1.2) and disintegration 2 solution (artificial plant solution, pH 6.8). , The release control microspheres, pharmaceutical compositions, or formulations comprising the same according to one embodiment are artificial gastric juice (pH 1.2), artificial intestinal fluid (pH 6.8), or a pH range between pH 1.2 and pH 6.8, such as pH 4.0, or water Even under the conditions, the emission pattern remains constant.

The dosage of the pharmaceutical composition may be an amount suitable for treatment or prevention of a subject and/or a disease to be administered, which is the patient's age, weight, general health condition, sex and diet, administration time, type of disease, and severity of disease. , The type and content of other ingredients contained in the formulation, the type of the formulation, the route of administration, the distribution rate of the drug or composition in the body, the treatment period, and can be adjusted according to various factors including drugs used simultaneously. For example, when the subject is an adult, the formulation of the present invention may be administered once a day or in a total dose of about 90 to 270 mg in terms of ticagrelor when taken.

Another aspect is

Preparing an inert core;

Forming a first coating layer comprising ticagrelor or a pharmaceutically acceptable salt thereof, and a water-soluble polymer as an active ingredient on the inert core;

Forming a second coating layer comprising a cellulose derivative on the inert core on which the first coating layer is formed; And

It provides a method for producing a microsphere for controlling release comprising the step of forming a release controlling layer comprising a water-insoluble ethyl cellulose dispersion on the inert core on which the second coating layer is formed.

The order of the manufacturing method may be appropriately changed or omitted as necessary. For example, a commercially available product may be used as the inert core, and for example, Sugar Pear ^TM may be used.

According to one embodiment, the first coating layer composition for forming a first coating layer comprising ticagrelor or a pharmaceutically acceptable and water-soluble polymer as an active ingredient in the release-controlled microspheres comprises an inert core material forming an inert core and By mixing, it is possible to prepare microspheres (cores) including the first coating layer component.

The forms of the term "comprising" and "including" the term "comprising" as used herein do not limit the present invention to exclude any modification or addition. Additionally, while the present invention has been described in terms of “comprising”, the methods, materials and compositions described herein may also be described as “consisting of essentially” or “consisting of”.

The term “to” as used herein includes the end points of the range and all intermediate points therebetween. In the present specification, the term “about” or approximately (approximately)” means that the stated value can vary to some extent, for example, the value is 10%, 5%, 2%, etc. , Or may vary by 1%. For example, “about 5” includes any value between 4.5 and 5.5, between 4.75 and 5.25, or between 4.9 and 5.1, or between 4.95 and 5.05. Those skilled in the art will understand that deviations in numerical quantities are possible, therefore, whenever a number is referred to in the specification or in the claims, such value, or approximately additional values relating to such value, may also be present. It is understood to be within the scope of the invention.

[Example]

Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

Examples 1 to 3: Preparation of ticagrelor sustained-release microsphere composition comprising a protective coating layer and a release-controlling layer

According to the ingredient and weight of the drug substance shown in Table 1, a sustained-release microsphere composition containing ticagrelor was prepared.

(1) Preparation of main component coating solution

For each example, a coating solution containing a drug was prepared as follows.

Example 1: After mixing 240 g of ticagrelor in 80% ethanol, 100 g of hydroxypropylmethylcellulose 606, 8 g of polyethylene glycol, and 4 g of talc were mixed to prepare a coating solution containing ticagrelor drug.

Example 2: After mixing 240 g of ticagrelor in 80% ethanol, 100 g of hydroxypropylmethylcellulose 603, 8 g of polyethylene glycol, and 4 g of talc were mixed to prepare a coating solution containing ticagrelor drug.

Example 3: After mixing 240 g of ticagrelor in 80% ethanol, 100 g of hydroxypropylmethylcellulose 645, 8 g of polyethylene glycol, and 4 g of talc were mixed to prepare a coating solution containing ticagrelor drug.

In Examples 1 to 3, hydroxypropylmethylcellulose 606 grade (viscosity: 6 cPs), 603 grade (viscosity: 3 cPs), and 645 grade (viscosity: 4.5 cPs), respectively, were used as a viscosity controlling polymer when preparing the main component coating solution. .

(2) Preparation of a core and manufacture of the inner core with the main component coating layer (first coating layer) formed

As a core (Pharm-a-spheres ^TM ) of a predetermined weight for each example was put into a fluidized bed granulator, and then the main component coating solution prepared in (1) was spray-coated on the core to form a main component coating layer on the core. Formed. This was used as the inner core on which the main component coating layer was formed.

(3) Preparation of protective coating layer and manufacture of inner core with protective coating layer (second coating layer) formed

For each example, a protective coating layer was prepared as follows. In Examples 1 to 3, ^{10 g of Clear TM} as a protective coating base was diluted with 120 g of purified water to prepare a protective coating solution, which was spray-coated on the inner core including the coating layer formed in (2). This was used as the inner core on which the protective coating layer was formed. Clear ^TM (Opadry ^® 03K19229 Clear) Hypromellose 84.1%, triacetin 8.4%, and talc 7.5%.

(4) Preparation of release control layer and manufacture of inner core with release control layer

For each example, a release control layer was prepared as follows. In Examples 1 to 3, ^{160g of SureRelease TM} was diluted with 320g of purified water to prepare a release-controlled coating solution as a release-controlling agent, which was spray-coated on the inner core including the protective coating layer formed in (3). ^SURELEASE™ (SURELEASE E-7-19040) contains 18% ethylcellulose, 3.19% medium chain fatty acid triglycerides, 2.1% oleic acid, 0% glycerin, and 76.71% others. This was made into a sustained-release microsphere containing ticagrelor including a final protective coating layer and a release-controlling layer.

Raw material Weight(g) Example 1 Example 2 Example 3 Inert core Sugar Spear 400.0 400.0 400.0 chief ingredient
Coating layer
(First coating layer) Ticagrelor 240.0 240.0 240.0 Hydroxypropylmethylcellulose 606 100.0 - - Hydroxypropylmethylcellulose 603 - 100.0 - Hydroxypropylmethylcellulose 645 - - 100.0 Polyethylene glycol 6000 8.0 8.0 8.0 Talc 4.0 4.0 4.0 Protective coating layer
(2nd coating layer) Clear ^TM 10.0 10.0 10.0 Emission control layer Sure Release ^TM (solid content) 160.0 (40.0) 160.0 (40.0) 160.0 (40.0)

Examples 4 to 5: Preparation of ticagrelor sustained-release microsphere composition comprising a protective coating layer and a release-controlling layer

According to the ingredients and weight of the drug substance shown in Table 2, a sustained-release microsphere composition containing ticagrelor was prepared.

(1) Preparation of main component coating solution and production of inner core with main component coating layer and protective coating layer formed

In the same manner as in Example 1, the main component coating liquids of Examples 4 to 5 were prepared according to the composition of Table 2, and after putting sugar pears of a predetermined weight for each example as a core into a fluidized bed granulator, the main component coating solution was added to the core. Spray-coated on the core to form a main component coating layer on the core. This was used as the inner core in which the main component coating layer was formed. Subsequently, in the same manner as in Example 1, a protective coating layer was prepared according to the composition of Table 2, and spray-coated on the inner core including the coating layer of the main component. This was used as the inner core on which the protective coating layer was formed.

In Examples 4 to 5, hydroxypropylmethylcellulose 606 grade (viscosity: 6 cPs) was used as a viscosity controlling polymer when preparing the main component coating solution.

(2) Preparation of release control layer and manufacture of inner core with release control layer

In the same manner as in Example 1, a release controlling layer was prepared according to the composition in Table 2.

In Example 4, ^{240 g of Sure Release TM} was diluted with 480 g of purified water to prepare a release-controlled coating solution as a release-controlling agent, and spray-coated on the inner core with the protective coating layer formed in (1). Compared with Example 1, in Examples 4 to 5, the content of ^{Sure Release TM in the release control layer was gradually increased.}

In Example 5, ^{320 g of Sure Release TM} was diluted with 640 g of purified water to prepare a release-controlled coating solution as a release-controlling agent, and spray-coated on the inner core including the protective coating layer formed in (1). This was made into a sustained-release microsphere containing ticagrelor including a final protective coating layer and a release-controlling layer.

Raw material Weight(g) Example 1 Example 4 Example 5 Inert core Sugar Spear 400.0 400.0 400.0 chief ingredient
Coating layer
(First coating layer) Ticagrelor 240.0 240.0 240.0 Hydroxypropylmethylcellulose 606 100.0 100.0 100.0 Polyethylene glycol 6000 8.0 8.0 8.0 Talc 4.0 4.0 4.0 Protective coating layer
(2nd coating layer) Clear ^TM 10.0 10.0 10.0 Emission control layer Sure Release ^TM (solid content) 160.0 (40.0) 240.0 (60.0) 320.0 (80.0)

Example 6: Preparation of Ticagrelor Sustained-Release Microsphere Composition Containing a Release Control Layer

According to the ingredients and weight of the drug substance shown in Table 3 below, a sustained-release microsphere composition containing ticagrelor was prepared.

(1) Preparation of the main component coating solution and the production of the inner core with the main component coating layer formed

In the same manner as in Example 1, the main component coating solution of Example 6 was prepared according to the composition of Table 3, and a sugar pear of a predetermined weight for each example was put into a fluidized bed granulator as a core, and then the main component coating solution was sprayed on the core. By coating, the main component coating layer was formed on the core. This was used as the inner core on which the main component coating layer was formed.

In Example 6, hydroxypropylmethylcellulose 606 grade (viscosity: 6 cPs) was used as a viscosity controlling polymer when preparing the main component coating solution.

(2) Preparation of release control layer and manufacture of inner core with release control layer

In the same manner as in Example 1, a release control layer was prepared according to the composition in Table 3.

In Example 6, ^{160g of SureRelease TM} was diluted with 320g of purified water to prepare a release-controlled coating solution as a release-controlling agent, and spray-coated it on the inner core including the coating layer formed in (1). This was made into a sustained-release microsphere containing ticagrelor with a final release control layer formed thereon.

Raw material Weight(g) Example 1 Example 6 Inert
core Sugar Spear 400.0 400.0 chief ingredient
Coating layer
(First coating layer) Ticagrelor 240.0 240.0 Hydroxypropylmethylcellulose 606 100.0 100.0 Polyethylene glycol 6000 8.0 8.0 Talc 4.0 4.0 Protective coating layer
(2nd coating layer) Clear ^TM 10.0 - Emission control layer Sure Release ^TM (solid content) 160.0 (40.0) 160.0 (40.0)

Examples 7 to 10: Preparation of ticagrelor sustained-release microsphere composition comprising a protective coating layer and a release-controlling layer

According to the ingredient and weight of the drug substance shown in Table 4, a sustained-release microsphere composition containing ticagrelor was prepared.

(1) Preparation of a mixture of the main component coating component (first coating layer composition) and the core microsphere component (inert core material) (the microparticle production layer)

For each example, a mixture of the main component coating component and the core microsphere (pellet) component containing the drug was prepared as follows.

Example 7: 240 g of ticagrelor, 16 g of hydroxypropyl cellulose, 140 g of mannitol, and 300 g of microcrystalline cellulose were mixed.

Example 8: 240 g of ticagrelor, 16 g of hydroxypropyl cellulose, 140 g of mannitol, 300 g of microcrystalline cellulose, and 5 g of sodium carboxymethylcellulose were mixed.

Example 9: 240 g of ticagrelor, 16 g of hydroxypropyl cellulose, 140 g of mannitol, 300 g of microcrystalline cellulose, and 5 g of crospovidone were mixed.

Example 10: 240 g of ticagrelor, 16 g of hydroxypropyl cellulose, 140 g of mannitol, 300 g of microcrystalline cellulose, and 5 g of sodium starch glycolate were mixed.

In Examples 7 to 10, hydroxypropylcellulose 606 grade (viscosity: 6 cPs) was used as a viscosity controlling polymer when preparing the main component coating solution. Compared with Example 7, in Examples 8 to 10, sodium carboxymethylcellulose, crospovidone, and sodium starch glycolate were used as disintegrants, respectively.

(2) Preparation of microspheres containing a coating component (first coating layer composition)

The mixture of (1) was put in a high-speed mixer and mixed, and then 260 g of 45% ethanol was added to perform a wet coalescence process for 5 to 10 minutes. After putting the pulverized material into an extruder having a size of 0.8 mm inserted into an extruder and pulling out at a speed of 70 rpm, core fine spheres (core pellets) were prepared at 1200 rpm for 2 minutes using a spheronizer.

(3) Preparation of microspheres with protective coating layer formed

For each example, a protective coating layer was prepared as follows. In Examples 7 to 10, 10 ^{g of Clear TM} as a protective coating base was diluted with 120 g of purified water to prepare a protective coating solution, which was spray-coated on the core microspheres (core pellets) formed in (2). This was made into a core pellet having a protective coating layer formed thereon. Clear ^TM silver Hypromellose 84.1%, triacetin 8.4%, and talc 7.5%.

(4) Preparation of release control layer and preparation of microspheres with release control layer formed

For each example, a release control layer was prepared as follows. In Examples 7 to 10, ^{160g of SureRelease TM} was diluted with 320g of purified water to prepare a release-controlled coating solution as a release-controlling agent, and it was spray-coated on the core microspheres (core pellets) including the protective coating layer formed in (3). ^SURELEASE™ (SURELEASE E-7-19040) contains 18% ethylcellulose, 3.19% medium chain fatty acid triglycerides, 2.1% oleic acid, 0% glycerin, and 76.71% others. This was made into a sustained-release microsphere containing ticagrelor in which the final protective coating layer and the release control layer were formed.

Raw material Weight(g) Example 7 Example 8 Example 9 Example 10 Microspheres
Manufacturing layer
(Including the inert core material and the first coating layer composition) Ticagrelor 240.0 240.0 240.0 240.0 Hydroxypropyl cellulose 16.0 16.0 16.0 16.0 Mannitol 140.0 140.0 140.0 140.0 Microcrystalline cellulose 300.0 300.0 300.0 300.0 Sodium carboxymethylcellulose - 5.0 - - Crospovidone - - 5.0 - Sodium starch glycolate - - - 5.0 Protective coating layer
(2nd coating layer) Clear ^TM 10.0 10.0 10.0 10.0 Emission control layer Sure Release ^TM (solid content) 160.0 (40.0) 160.0 (40.0) 160.0 (40.0) 160.0 (40.0)

Examples 11 to 13: Preparation of ticagrelor sustained-release microsphere composition comprising a protective coating layer and a release-controlling layer

According to the ingredients and weight of the drug substance shown in Table 5 below, a sustained-release microsphere composition containing ticagrelor was prepared.

(1) Preparation of a mixture of the main component coating component (first coating layer composition) and the core microsphere component (inert core material) (microsphere production layer)

According to the composition of Table 5 in the same manner as in Examples 7 to 10, a mixture of the main component coating component and the core microsphere component of Examples 11 to 13 were prepared. Subsequently, core microspheres were prepared using a high-speed mixer, and ^{10 g of Clear TM} as a protective coating base was diluted with 120 g of purified water to prepare a protective coating solution, which was spray-coated on the core microspheres. This was made into a core microsphere (core pellet) with a protective coating layer formed thereon. Clear ^TM silver Hypromellose 84.1%, triacetin 8.4%, and talc 7.5%.

In Examples 11 to 13, hydroxypropylmethylcellulose 606 grade (viscosity: 6 cPs) was used as a viscosity controlling polymer when preparing the main component coating solution.

(2) Preparation of release control layer and preparation of microspheres with release control layer

In the same manner as in Examples 7 to 10, a release controlling layer was prepared according to the composition in Table 5. In Examples 11 to 13, ^{320g of SureRelease TM} was diluted with 640g of purified water to prepare a release-controlled coating solution as a release-controlling agent, and this was spray-coated on core microspheres (core pellets) with a protective coating layer formed thereon. ^SURELEASE™ (SURELEASE E-7-19040) contains 18% ethylcellulose, 3.19% medium chain fatty acid triglycerides, 2.1% oleic acid, 0% glycerin, and 76.71% others. Compared with Examples 7 to 10, in Examples 11 to 13, the content of ^{Sure Release TM in the release control layer was increased.}

This was made into a sustained-release microsphere containing ticagrelor in which the final protective coating layer and the release controlling layer were formed.

Raw material Weight(g) Example 11 Example 12 Example 13 Microspheres
Manufacturing layer
(Including the inert core material and the first coating layer composition) Ticagrelor 240.0 240.0 240.0 Hydroxypropyl cellulose 16.0 16.0 16.0 Mannitol 140.0 140.0 140.0 Microcrystalline cellulose 300.0 300.0 300.0 Sodium carboxymethylcellulose 5.0 - - Crospovidone - 5.0 - Sodium starch glycolate - - 5.0 Protective coating layer
(2nd coating layer) Clear ^TM 10.0 10.0 10.0 Emission control layer Sure Release ^TM (solid content) 320.0 (80.0) 320.0 (80.0) 320.0 (80.0)

Comparative Example 1: Preparation of ticagrelor formulation

Table 6 below with reference to the method described in Korean Patent Publication No. 10-2009-0055561 (composition suitable for oral administration containing triazolo[4,5-D] pyrimidine derivatives) for the ticagrelor formulation. Ticagrelor-containing tablets were prepared with the indicated ingredients and weight of the drug substance.

(1) A binding solution was prepared by dissolving 9 mg of hydroxypropyl cellulose in 50 mg of purified water.

(2) After sufficiently mixing 90 mg of ticagrelor, 126 mg of mannitol, 63 mg of calcium hydrogen phosphate, and 9 mg of sodium starch glycolate, the binder solution prepared in (1) was added to proceed with the coalescence process, and then dried at 60° C. 3 mg of magnesium acid was then mixed and tableted.

(3) A coating solution was prepared by mixing 5.6 mg of hypromellose 2910, 1.7 mg of titanium oxide, 1.0 mg of talc, 0.6 mg of macrogol 400, and 0.1 mg of iron oxide in 80% ethanol.

(4) The tablets prepared in (2) were coated with the coating solution prepared in (3).

Raw material Weight(mg) Comparative Example 1 Ticagrelor 90.0 Mannitol 126.0 Calcium hydrogen phosphate 63.0 Sodium starch glycolate 9.0 Hydroxypropyl cellulose 9.0 Magnesium stearate 3.0 Hypromellose 2910 5.6 Titanium oxide 1.7 Talc 1.0 Macrogol 400 0.6 Iron oxide 0.1

Experimental Example 1: Stability check-content test evaluation

In order to confirm the drug interaction between the drug contained in the formulation, Ticagrelor and the release-controlling agent, Sure Release, Example 1 prepared using both a protective coating base and a release-controlling agent, and Example 6 prepared using only a release-controlling agent. The content test was evaluated as a stability test item. The following Tables 7 and 8 are results obtained by comparing and measuring the content test for the sustained-release microparticle composition of Ticagrelor prepared in Example 1 and Example 6. The content test standard is 95.0~105.0%.

content (%) Long-term storage test conditions (25±2℃, RH60±5%) Early 1 month 2 months 3 months 6 months 12 months 24 months Example 1 97.0 97.0 97.2 97.8 97.1 97.0 100.5 Example 6 100.8 102.6 - 101.9 99.7 100.6 105.3

content (%) Accelerated test conditions (40±2℃, RH75±5%) Early 1 month 2 months 3 months 6 months Example 1 97.0 97.4 97.0 97.7 96.3 Example 6 100.8 99.9 - 93.0 90.1

Compared to Example 1, in the case of Example 6 in which the protective coating base was not used, the content was decreased under accelerated conditions. It has been shown that the content stability of ticagrelor, a drug contained in the formulation, can be improved by including a protective coating base.

Experimental Example 2: Stability confirmation-Related substance test evaluation

In order to confirm the drug interaction between the drug contained in the formulation, Ticagrelor and the release-controlling agent, Sure Release, Example 1 prepared using both a protective coating base and a release-controlling agent, and Example 6 prepared using only a release-controlling agent. The related substance test was evaluated as a stability test item. The following Tables 9 and 10 are the results of comparing and measuring the related substance test for the sustained-release microparticle composition of the present invention prepared in Example 1 and Example 6. Related substances test standards are unknown impurity of 0.2% or less and total impurity of 0.5% or less.

Related substances (%) Long-term storage test conditions (25±2℃, RH60±5%) Early 1 month 2 months 3 months 6 months 12 months 24 months Example 1 Unknown IMP N/D N/D N/D 0.03 0.06 - 0.02 Total IMP N/D N/D N/D 0.06 0.06 - 0.05 Example 6 Unknown IMP N/D - - - 0.07 0.06 0.04 Total IMP N/D - - - 0.13 0.14 0.09

* IMP, impurities; N/D; Not detected

Related substances (%) Accelerated test conditions (40±2℃, RH75±5%) Early 1 month 2 months 3 months 6 months Example 1 Unknown IMP N/D 0.06 0.04 0.03 0.10 Total IMP N/D 0.06 0.04 0.05 0.12 Example 6 Unknown IMP N/D - - - 0.07 Total IMP N/D - - - 0.14

* IMP, impurities; N/D; Not detected

In the storage conditions of the long-term preservation test and the accelerated test, it was confirmed that the production of related substances was formed below the reference value in both Examples 1 and 6, so that the formulation was stable.

Experimental Example 3: Confirmation of dissolution rate-Evaluation of dissolution test (1)

Table 11 below shows the dissolution rates of the ticagrelor sustained-release microsphere compositions prepared in Examples 1 to 5 and 7 to 13 and the ticagrelor tablets prepared in Comparative Example 1 (eg, immediate release tablet: IR tablet). It is the result of comparison measurement.

In the in vitro dissolution test, microspheres corresponding to 120 mg of ticagrelor were filled into capsules No. 1, and then tested according to the dissolution test method 2 (paddle method) among general test methods of the Korean Pharmacopoeia. However, the rotational speed was set to 50 rpm and the eluate was 900 mL of water to which 0.1% of tween 80 was added. After 2 hours, 5 hours, 8 hours, 12 hours, and 24 hours after the initiation of the dissolution test, 5 mL of the eluate was collected, filtered, and the absorbance was tested according to the measurement method using the filtrate as a sample solution.

Item Dissolution rate (%) 2 hours(%) 5 hours (%) 8 hours (%) 12 hours (%) 24 hours(%) Example One 22.3 47.1 73.1 89.0 96.8 2 21.7 63.1 85.8 96.5 103.5 3 17.2 57.5 84.1 97.8 103.7 4 30.0 50.5 67.6 81.7 96.3 5 13.6 23.3 38.8 53.4 70.6 7 31.8 49.4 62.3 70.4 78.7 8 40.0 66.4 83.1 93.2 103.2 9 55.5 75.2 86.2 92.9 99.9 10 31.4 48.4 60.2 69.2 81.9 11 20.9 32.9 42.2 49.1 58.3 12 25.1 36.7 45.9 52.3 59.3 13 13.6 23.8 32.8 39.5 49.8 Comparative example One 77.3 93.3 96.1 96.1 96.1

As shown in Table 11, by varying the viscosity of the hydroxypropylmethylcellulose used in the main component coating layer, hydroxypropylmethylcellulose 606 grade (viscosity 6 cPs), 603 grade (viscosity 3 cPs), and 645 grade (viscosity As a result of comparing the dissolution rates of Examples 1 to 3 using 4.5 cPs), hydroxypropylmethylcellulose 606 grade (viscosity 6 cPs) showed the most even dissolution rate over time.

In the case of Example 2 or Example 3 using 603 grade (viscosity 3 cPs) or 645 grade (viscosity 4.5 cPs) hydroxypropylmethylcellulose in the main component coating layer, the dissolution rate exceeded about 96% before 12 hours, It was shown that the controlled release effect for 24 hours was weak.

On the other hand, Example 3 using hydroxypropylmethylcellulose 645 grade (viscosity 4.5 cPs) as the main component coating layer showed a slightly lower initial dissolution rate than Example 2 using hydroxypropylmethylcellulose 603 grade (viscosity 3 cPs). The difference was not large, and the dissolution rates of the second half between Examples 2 and 3 were similar. It can be seen that the initial dissolution rate may decrease slightly as the viscosity of the viscosity controlling polymer increases among the main component coating layers, but the effect is not large.

When using a viscosity-controlling polymer having a higher viscosity than hydroxypropylmethylcellulose 606 grade (viscosity 6 cPs) used in Example 1, there is a possibility that the initial dissolution rate or the dissolution rate at 5 hours or 12 hours may be excessively controlled.

In addition, as in Table 11, as in Example 1, Example 4 using hydroxypropylmethylcellulose 606 grade (viscosity 6 cPs) as the main component coating layer showed the best dissolution rate among the Examples and Comparative Examples in Table 11 Showed.

Examples 4 to 5, and 7 to 13 all contain 240.0 g of ticagrelor in the particulate composition, and all contain hydroxypropylmethylcellulose 606 grade (viscosity 6 cPs) as the main component coating layer, and only the number in the release controlling layer Only the content condition of the insoluble ethyl cellulose dispersion (Sure Release ^TM ) or whether the disintegrant is included in the main component coating layer (first coating layer) is different. The content of Sure Release ^TM in Example 4 is 240.0 g (60.0 g in solid content), and is an amount containing 1 part by weight per 1 part by weight of ticagrelor, and as converted per capsule containing 120 mg of ticagrelor, Sure Release ^{It is} an amount containing 30 mg of TM based on solid content (30 mg/C).

The content of Sure Release ^TM in Example 5 is 320.0 g (80.0 g in solid content), and is an amount containing about 1.33 parts by weight per 1 part by weight of ticagrelor, and when converted per capsule containing 120 mg of ticagrelor, Sure It is ^{an amount containing 40 mg of Release TM} on a solid basis (40 mg/C).

The content of Sure Release ^TM in Example 7 is 160.0 g (40.0 g in solid content), and is an amount containing about 0.67 parts by weight per 1 part by weight of ticagrelor, and when converted per capsule containing 120 mg of ticagrelor, Sure Release ^TM is an amount (20 mg/C) containing 20 mg based on solids.

As shown in Table 11, Example 4 had the best controlled release effect for 24 hours, and showed a desirable dissolution rate that allows the drug to be administered once a day. In comparison, Examples 5 and 7 showed an incomplete dissolution rate of less than 80% of the drug at the dissolution end point (after 24 hours). In addition, Example 5 showed an excessively low initial release rate, and Example 7 showed an excessively high initial release rate.

In Examples 11 to 13 containing the same amount of Sure Release ^TM as in Example 5, the dissolution rate of the drug at the dissolution end point (after 24 hours) was less than 80%, showing an incomplete dissolution rate, and an excessively low initial release rate.

From the above results, the water-insoluble ethyl cellulose dispersion (Sure Release ^TM ) in the release control layer is in an amount exceeding about 0.67 parts by weight per 1 part by weight of ticagrelor, about 0.7 or more and about 1.3 or less by weight, for example, 1 part by weight. When included, it can be seen that a desirable dissolution rate is exhibited under the dissolution condition for 24 hours, a dissolution rate of about 95% or more is achieved at the dissolution end point (after 24 hours), and as a result, the bioavailability can be increased.

In comparison, when the water-insoluble ethyl cellulose dispersion (Sure Release ^TM ) in the release control layer is included in an amount of about 0.7 parts by weight or less per 1 part by weight of ticagrelor, the dissolution rate of the drug is 80 at the dissolution end point (after 24 hours). It can be seen that it shows an incomplete dissolution rate of less than %, an excessively high initial release rate, and consequently lowers the bioavailability.

In addition, when the water-insoluble ethyl cellulose dispersion (Sure Release ^TM ) in the release control layer is included in an amount exceeding about 1.3 parts by weight per 1 part by weight of ticagrelor, the dissolution rate of the drug at the dissolution end point (after 24 hours) is less than 80%. As a result, it can be seen that the incomplete dissolution rate was shown, the initial release rate was too low, and as a result, the bioavailability would be lowered.

On the other hand, the microsphere production layer (including the inert core material and the first coating layer composition) contained a disintegrant, and in Examples 8 to 13, it was not easy to control the initial dissolution rate. For example, in the case of Example 9 containing crospovidone as a disintegrant, a dissolution rate of 50% or more was shown after 2 hours of the measurement test as shown in Table 11. In comparison, Example 7 containing no disintegrant showed better initial dissolution rate control than Example 9.

In addition, in ^{the case of Examples 11 to 13, in which the content of Sure Release TM in} the formulation was increased by two times, the dissolution rate was reduced by about 50% compared to Examples 7 to 10, and the dissolution rate of the drug at the dissolution end point was less than 80%. The dissolution rate was shown, and accordingly, the bioavailability of the drug may be lowered.

From the above results, as the main component coating layer, a viscosity controlling polymer having a viscosity of about 5.5 to 6.5, such as 6 cPs (for example, hydroxypropylmethylcellulose 606 grade) is included, and a water-insoluble ethyl cellulose dispersion in the release controlling layer (SureRelease ^TM ) In an amount exceeding about 0.67 parts by weight per 1 part by weight of ticagrelor, about 0.7 to 1.3 parts by weight, for example, about 1 part by weight (e.g., 30 mg/C based on the solid content of ^{Surrelease™), and a disintegrant.} It can be seen that the dissolution rate of the sustained-release microsphere composition prepared not to contain ticagrelor is the best.

Experimental Example 4: Confirmation of dissolution rate-Evaluation of dissolution test (2)

Table 12 below shows the dissolution rate of the ticagrelor sustained-release microsphere composition prepared in Example 4 and the ticagrelor tablet prepared in Comparative Example 1 (e.g., immediate release tablet: IR tablet) according to pH change and time. It is the result of comparison measurement.

1 shows the pH change and the dissolution rate (%) over time for the sustained-release microsphere composition of ticagrelor prepared in Example 4.

In the in vitro dissolution test, microspheres corresponding to 120 mg of ticagrelor were filled into capsules No. 1, and then tested according to the dissolution test method 2 (paddle method) among general test methods of the Korean Pharmacopoeia. However, the rotational speed was set to 50 rpm and the first solution of the disintegration test method, the second solution of the disintegration test method, a pH 4.0 solution as an acetate buffer, and 900 mL of water were each used as the eluate (test solution). Tween 80 corresponding to 0.1% was added to each eluate. After 2 hours, 5 hours, 8 hours, 12 hours, and 24 hours after the initiation of the dissolution test, 5 mL of the eluate was collected, filtered, and the absorbance was tested according to the measurement method using the filtrate as a sample solution.

Item Dissolution rate (%) 2 hours(%) 5 hours (%) 8 hours (%) 12 hours
(%) 24 hours
(%) Example 4 water 30.0 50.5 67.6 81.7 96.3 1 solution of disintegration
(pH 1.2) 29.3 - - - - pH 4.0 27.9 47.1 68.9 84.7 97.3 Disintegration 2 solution (pH 6.8) 29.0 47.7 65.0 80.1 94.3 Comparative Example 1 water 77.3 93.3 96.1 96.1 96.1 1 solution of disintegration
(pH 1.2) 75.3 - - - - pH 4.0 87.3 98.5 99.5 99.5 99.5 Disintegration 2 solution (pH 6.8) 82.8 97.8 97.8 97.8 97.8

As shown in Table 12 and FIG. 1, in the case of the ticagrelor sustained-release microsphere composition of Example 4, all of the conditions of water, pH 1.2, pH 4.0, and pH 6.8 showed a good dissolution rate, despite the pH change. And showed a constant drug dissolution rate for 24 hours, it was confirmed that the drug dissolution rate can be administered once a day. In addition, as a result of synthesizing the results of Experimental Examples 1 to 4, Example 4 showed the best dissolution rate and stability.

In comparison, it was found that the tablet of Comparative Example 1 had an initial dissolution rate of 70% or more in each eluate, which was not easy to control, and could not achieve the purpose of sustained release and once daily administration.

So far, the present invention has been looked at around its preferred embodiments. Those of ordinary skill in the art to which the present invention pertains will be able to understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative point of view rather than a limiting point of view. The scope of the present invention is shown in the claims rather than the above description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (11)

Inert core;
Ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient, and a first coating layer comprising a water-soluble polymer;
A second coating layer comprising a cellulose derivative; And
A release control layer comprising a water-insoluble ethyl cellulose dispersion; release control microspheres containing. The method according to claim 1, wherein the inert core has a particle diameter of 100 to 900 ㎛ for emission control fine particles. The method of claim 1, wherein the first coating layer contains a water-soluble polymer having a viscosity of 3.0 to 9.0 cPs at 20 °C, controlled release microspheres. The method according to claim 1, wherein the second coating layer comprises a cellulose derivative selected from methyl cellulose, hydroxyethyl cellulose, 　 hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, or a combination thereof. The method of claim 1, wherein the second coating layer comprises hydroxypropylmethylcellulose, the microspheres for emission control. The method according to claim 1, wherein the core or the first coating layer does not contain a disintegrant, the microspheres for emission control. The method according to claim 1, wherein the water-insoluble ethylcellulose dispersion contained in the release control layer is contained in an amount of 0.4 to 2 parts by weight based on 1 part by weight of ticagrelor or a pharmaceutically acceptable salt thereof. The method according to claim 1, wherein the water-insoluble ethyl cellulose dispersion contained in the release control layer is contained in an amount of 0.7 to 1.3 parts by weight based on 1 part by weight of ticagrelor or a pharmaceutically acceptable salt thereof, microspheres for controlled release. Inert core material; Ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient, and a first coating layer composition comprising a water-soluble polymer; A second coating layer composition comprising a cellulose derivative; And a release controlling layer composition comprising a water-insoluble ethyl cellulose dispersion; containing, a pharmaceutical composition for controlled release. The pharmaceutical composition of claim 9, wherein the inert core material is selected from sugar, calcium monohydrogen phosphate dihydrate, microcrystalline cellulose, starch, or mixtures thereof. Preparing an inert core;
Forming a first coating layer comprising ticagrelor or a pharmaceutically acceptable salt thereof, and a water-soluble polymer as an active ingredient on the inert core;
Forming a second coating layer comprising a cellulose derivative on the inert core on which the first coating layer is formed; And
The method for producing a microsphere for controlling the release of claim 1, comprising the step of forming a release controlling layer comprising a water-insoluble ethyl cellulose dispersion on the inert core on which the second coating layer is formed.

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