KR20160012706A

KR20160012706A - Sustained release formulations

Info

Publication number: KR20160012706A
Application number: KR1020140094692A
Authority: KR
Inventors: 김순회; 손미원; 장선우; 원동한; 김용민; 이윤화
Original assignee: 동아에스티 주식회사
Priority date: 2014-07-25
Filing date: 2014-07-25
Publication date: 2016-02-03
Also published as: WO2016013795A1

Abstract

The present invention relates to sustained release formulations comprising a hydrophilic lipid excipient as Ticagrelor or a pharmaceutically acceptable salt thereof and a release-controlling substance. The sustained-release preparation according to the present invention can release the active ingredient ticagrella at a constant rate from the preparation at a constant rate regardless of the pH, so that the ticagrella can maintain a constant concentration in the body, And the therapeutic effect of the drug can be maximized.

Description

[0001] Sustained release formulations [

The present invention relates to a preparation containing tikageler as an active ingredient, and more particularly to a preparation containing ticagreler or a salt thereof as an active ingredient, wherein the release of the ticagreler or its salt is gradually released The present invention relates to an agent that can improve the convenience of medication and maximize the therapeutic effect of ticagrella.

Tikagarella is a breakthrough drug that can counteract the risk of potentially dangerous patients through platelet aggregation inhibition, as shown in US6251910. However, ticagrella is absorbed mostly in the small intestine within about 2 hours after oral administration, and its half-life is as short as about 6 to 13 hours, which makes it inconvenient to take many times. In particular, there is an inconvenience in that it is necessary to administer twice a day in comparison with a drug which is effective when administered once a day such as clopidogrel sulfate or prasugrel, which are the same series of drugs.

US8425934 obtained a pharmaceutical composition in which ticarguler was mixed with a suitable pharmaceutical excipient so that the insoluble drug, ticarguler, was sufficiently released in a short time, but the release was not controlled and was all released within two hours.

Therefore, it is necessary to develop a composition capable of decreasing the number of doses when taking the drug, increasing the patient's compliance with the medication, increasing the duration of the medicinal effect, exhibiting the continuous drug efficacy, and reducing the risk.

US6251910 US8425934

The present invention relates to sustained release formulations comprising ticagrella or a salt thereof.

The present invention provides a sustained release oral formulation comprising Ticagrelor or a pharmaceutically acceptable salt thereof and a hydrophobic lipid excipient.

[Chemical Formula 1]

The above-mentioned Ticagrelor is a compound having the above-mentioned formula and can be used for the treatment of thrombotic diseases such as stroke and acute coronary syndrome through an excellent platelet aggregation inhibiting action.

In the present invention, the hydrophobic lipid excipient plays a role of a release-controlling substance capable of controlling the rate of release of ticargiller or its pharmaceutically acceptable salt, which is an active ingredient contained in the preparation, exhibiting poor water-solubility . The formulation containing the same reduces the surface area of water and the active ingredient ticagrel or its pharmaceutically acceptable salt to slow the dissolution of ticagrel or its pharmaceutically acceptable salts and to prevent water from penetrating into the formulation Ticagrella or a pharmaceutically acceptable salt thereof is slowly eroded from the preparation surface so that the active ingredient ticagrella or a pharmaceutically acceptable salt thereof can be released at a constant rate such that it can be in intimate contact with the aqueous solution.

In the present invention, the sustained-release oral preparation may contain 3 to 60 parts by weight of ticagrella or a pharmaceutically acceptable salt thereof and 3 to 30 parts by weight of hydrophobic lipid excipient per 100 parts by weight of the preparation.

In the present invention, the sustained-release oral preparation may contain 3 to 60 parts by weight, 5 to 55 parts by weight, or 20 to 50 parts by weight of tikageler or a pharmaceutically acceptable salt thereof, based on 100 parts by weight of the preparation. , Ticagrella or a pharmaceutically acceptable salt thereof in an amount of about 90 to about 270 mg per unit dosage form.

In the present invention, the sustained-release oral preparation may contain 3 to 30 parts by weight, 5 to 25 parts by weight, or 5 to 15 parts by weight of hydrophobic lipid excipient per 100 parts by weight of the preparation.

Preferably, the sustained release oral preparation may contain 25 to 80 parts by weight of tikageler or a pharmaceutically acceptable salt thereof and 3 to 25 parts by weight of hydrophobic lipid excipient per 100 parts by weight of the preparation.

In the present invention, the formulation containing the above-mentioned ticagrella or a pharmaceutically acceptable salt thereof and a hydrophobic lipid excipient in the above-mentioned contents is prepared by dissolving ticagrel or its pharmaceutically acceptable salt, which is an active ingredient, While at a constant rate. Accordingly, the sustained-release oral preparation of the present invention can be taken once a day, thereby remarkably improving the convenience of the patient's medication, and maintaining the concentration of the drug in the body at a constant level in the body, Lt; RTI ID = 0.0 > efficacy < / RTI > of the drug can be significantly improved and side effects due to rapid release of the drug can be minimized.

In the present invention, the hydrophobic lipid excipient may be at least one selected from glyceryl fatty acid esters, fatty acid esters, carnauba wax or castor oil. The glyceryl fatty acid esters specifically include glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, glyceryl oleate, glyceryl myristate, glyceryl myristate, or a mixture thereof. The fatty acid esters may be cetyl palmitate, cetyl caprate, stearyl palmitate, stearyl stearate or mixtures thereof. More specifically, the hydrophobic lipid excipient is selected from the group consisting of glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, cetyl palmitate, stearyl palmitate, stearyl stearate, carnauba wax, And may be preferably glyceryl palmitostearate, glyceryl behenate or a mixture thereof.

In the present invention, the hydrophobic lipid excipient and the ticagrel or its pharmaceutically acceptable salt may be used in a weight ratio of 1: 1 to 10, 1: 1 to 6, 1: 1 to 4, or 1: 2 to 3.5 have.

The sustained release formulation of the present invention can release the active ingredient ticagrel or its pharmaceutically acceptable salt at a constant rate for a long period of time, i. E. 12 hours or more, at a constant rate. The sustained-release preparation according to the present invention may be administered at a constant rate of 10-30% at 2 hours, 30-60% at 6 hours, at least 65% at 12 hours from the administration of the formulation, based on the total weight of tikagreler or salt thereof contained in the formulation / RTI > the active ingredient ticagrella or its salts. Particularly, it is important that the release pattern is kept constant between artificial gastric juice (pH 1.2) and artificial intestinal fluid (pH 6.8), considering that the absorption site of tikageler is small. The release pattern is kept constant even under water conditions including artificial gastric juice (pH 1.2), artificial intestinal fluid (pH 6.8) and pH 4.0.

In the present invention, the pharmaceutically acceptable salt of the ticagrella may be an acid addition salt formed by a pharmaceutically acceptable free acid. As the free acid, an inorganic acid and an organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. Examples of the organic acid include citric acid, acetic acid, maleic acid, fumaric acid, But are not limited to, acetic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and aspartic acid. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid.

In the present invention, the ticagreler or a pharmaceutically acceptable salt thereof may be at least one selected from the group consisting of a racemate, an optical isomer, a polymorph, a hydrate or a solvent of tikageler or a pharmaceutically acceptable salt thereof Cargo and so on.

In the present invention, the polymorph of the above-mentioned ticagrella or its pharmaceutically acceptable salt is a compound having the same molecular formula but different crystal structure in the solid state, and the ticagrella or its pharmaceutically acceptable salt Various crystalline forms of the salts possible and amorphous compounds thereof.

In the present invention, the hydrate of the ticagrella or a pharmaceutically acceptable salt thereof may contain a stoichiometric or non-stoichiometric amount of water which is bound by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water. Such a hydrate may be prepared by crystallizing the tikagaler of the present invention or a pharmaceutically acceptable salt thereof from a solvent containing water or water.

In the present invention, the solvate of tikageler or a pharmaceutically acceptable salt thereof may include a stoichiometric or non-stoichiometric amount of a solvent which is bound by noncovalent intermolecular forces. Preferred as the solvent are nonvolatile, non-toxic or solvents suitable for human administration, for example, ethanol, methanol, propanol, methylene chloride, and the like.

The sustained-release formulation of the present invention may further comprise a pharmaceutically acceptable excipient in addition to ticagrella or a pharmaceutically acceptable salt thereof and a hydrophobic lipid excipient. Such pharmaceutically acceptable excipients include fillers such as lactose, corn starch, microcrystalline cellulose, polyethylene glycol or dicalcium phosphate, sugars such as microcrystalline cellulose highly disperse silica, mannitol, lactose, highly disperse silica, mannitol, A binder such as lactose or polyethylene glycol, a coating agent such as colloidal silicon dioxide, talc, stearic acid, magnesium stearate, sodium stearyl fumarate lubricant, ethyl cellulose, hydroxypropylmethyl cellulose and methacrylic acid-alkyl acrylate copolymer , A solubilizing agent, a solubilizing agent, a coloring agent, a pH adjusting agent, a surfactant, a stabilizer, and an emulsifier may be used, but the present invention is not limited thereto and can be appropriately selected and used according to a known technique in the art.

The dose of the sustained-release preparation of the present invention may be an amount suitable for the treatment or prevention of the subject and / or disease to be treated, and may be appropriately determined depending on the age, weight, general health condition, sex and diet, The type and amount of the other ingredients contained in the preparation, the type of the formulation, the administration warning, the proportion of the composition, the duration of the treatment, and the drugs used simultaneously. For example, when the subject is an adult, the preparation of the present invention can be administered once a day or in a total amount of 90 to 270 mg on conversion to ticargiller.

The sustained-release preparation of the present invention can be prepared in various formulations. For example, the preparation of the present invention can be formulated into tablets, powders, pellets, mini tablets, powders, granules or capsules such as liquids, tablets, coated tablets, multilayer tablets or core tablets, .

The administration route of the sustained-release preparation of the present invention can be suitably regulated, but preferably it can be administered orally. When the sustained release formulation of the present invention is administered orally, the formulation is administered at a constant rate of 10-30% for 2 hours, 30-60% for 6 hours, and 65% or more for 12 hours from oral administration, Lt; / RTI > or a salt thereof.

The sustained-release preparation of the present invention may further comprise, as an active ingredient, other active ingredients exhibiting the same pharmacological activity in addition to the above-mentioned ticagrella or a pharmaceutically acceptable salt thereof. For example, the sustained-release preparation of the present invention may further contain aspirin as an active ingredient in addition to tikageler or a pharmaceutically acceptable salt thereof. When the above-mentioned effective ingredient is contained singly, the preparation containing the above-mentioned ticarguler or its pharmaceutically acceptable salt and aspirin as an effective ingredient is remarkably excellent in the treatment of thrombotic diseases such as stroke, acute coronary syndrome and the like Effect can be shown. When the present invention comprises tacogreler or a pharmaceutically acceptable salt thereof and aspirin, the two substances may exist in a co-crystal form with tacogreler or a pharmaceutically acceptable salt thereof and aspirin.

If the sustained-release formulation of the present invention further comprises an additional active ingredient, the additional active ingredient may be formulated to be released in sustained release form, such as tikageler or a pharmaceutically acceptable salt thereof. Or the additional active ingredient may be formulated in a fast release form different from tikageler or a pharmaceutically acceptable salt thereof.

The sustained-release preparation of the present invention does not contain an excessively high content of the active ingredient ticagrel or its pharmaceutically acceptable salt per unit of the unit, resulting in adverse effects, and the ticagrel or its pharmaceutically acceptable salt is administered in a certain amount The drug can be released for a long period of time to maintain the concentration of the active ingredient in the plasma and to control the number of times of administration and the dose to increase the compliance of the subject to be administered, Can be provided.

The present invention also provides a method for producing a sustained-release preparation containing tikageler.

The method for producing a sustained-release preparation of the present invention comprises the steps of mixing granules with tikageler or a pharmaceutically acceptable salt thereof and a hydrophobic lipid excipient; And adding the granule with other pharmaceutically acceptable additives to prepare a mixture.

In the present invention, in addition to the hydrophobic lipid excipient, which is the release-controlling material, additional pharmaceutical additive may be further added in the step of preparing the granules.

In the present invention, the granules may be produced by a wet granulation method or a dry granulation method, preferably by a wet granulation method.

The method of the present invention may further comprise the step of granulating the granules to produce a sized product. The sized product can be prepared by drying the granules and then drying them. Specifically, the granules are passed through a sieve having a sieve size of 0.5 to 1.5 mm, dried at a temperature of about 40 to 60 ° C, and then dried using a sieve having a sieve size of 0.5 to 1.5 mm to prepare a sieved product can do.

In the present invention, the pharmaceutically acceptable excipient may further include, in addition to the hydrophobic lipid excipient, a pharmaceutically acceptable additive as long as it does not inhibit the sustained release of the tablet. In the present invention, the pharmaceutically acceptable additives may be carriers, diluents, excipients, lubricants, and the like, but are not limited thereto. For example, the pharmaceutically acceptable excipient may be lactose hydrate or magnesium stearate.

The sustained-release preparation of the present invention may be a tablet. In this case, the preparation method may further include a step of tableting the mixture, and the tableted tablet may further be film-coated.

The production method of the sustained-release preparation of the present invention can simplify the production process, thereby improving productivity and ensuring excellent quality.

The sustained-release preparation according to the present invention can release the active ingredient ticagrella at a constant rate from the preparation at a constant rate irrespective of the pH so that the ticagrella can maintain a constant concentration in the body and the patient's compliance with the medication And the therapeutic effect of the drug can be maximized.

1 to 3 are graphs showing dissolution rates of tablets according to Examples and Comparative Examples of the present invention.
4 is a graph showing the dissolution rate after storage of the tablet according to Example 2 of the present invention after storage under accelerated conditions.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art. Also, the reagents and materials mentioned below are purchased from Sigma-Aldrich Korea unless otherwise noted.

< Example 1>

Tikagarella, lactose hydrate and glyceryl palmitostearate were mixed in a high speed mixer for 5 minutes, and a fermented alcohol equivalent to 18.5 μl per fermented liquor was added to the mixture for 5 minutes to form granules. The resulting granules were passed through a sieve having a size of 1 mm, dried at 60 ° C for 1 hour, and further granulated using a sieving machine using a sieve having a sieve size of 1 mm.

The magnesium stearate was applied to a 40-tongue (0.4 mm sieve size) apple and placed in a plastic bag together with the above-prepared sizing material. The mixture was shaken 100 times and compressed in a tablet machine to give 600 mg of Tikagarella 180 mg Gt; tablets < / RTI > The mixing ratios (weight) of each of these components are shown in Table 1.

< Example 2>

A sustained release tablet of 600 mg containing 180 mg of ticagrella per tablet was prepared in the same manner as in Example 1, except that the ingredients and the contents described in Example 2 of Table 1 were used.

< Example 3>

A sustained release tablet of 600 mg containing 180 mg of ticagrella per tablet was prepared in the same manner as in Example 1, except that the ingredients and the contents described in Example 3 of Table 1 were used.

< Example 4>

A sustained-release tablet of 600 mg containing 180 mg of ticagrella per one tablet was prepared in the same manner as in Example 1, except that the ingredients and the contents described in Example 4 of Table 1 were used.

< Example 5>

A sustained-release tablet of 600 mg containing 180 mg of ticagrella per tablet was prepared in the same manner as in Example 1, except that the ingredients and the content described in Example 5 of Table 1 were used.

< Example 6>

A sustained release tablet of 400 mg containing 180 mg of Ticagrella per tablet was prepared in the same manner as in Example 1 except that the ingredients and the contents described in Example 6 of Table 1 were used.

< Example 7>

A sustained release tablet of 600 mg containing 180 mg of Ticagrella per tablet was prepared in the same manner as in Example 1 except that the ingredients and the contents described in Example 7 of Table 1 were used.

< Example 8>

A sustained release tablet of 600 mg containing 180 mg of ticagrella per tablet was prepared in the same manner as in Example 1, except that the ingredients and the content described in Example 8 of Table 2 were used.

< Example 9>

A sustained-release tablet of 600 mg containing 180 mg of ticagrella per tablet was prepared in the same manner as in Example 1 except that the components and the contents described in Example 9 of Table 2 were used.

< Example 10>

A sustained release tablet of 600 mg containing 180 mg of ticagrella per tablet was prepared in the same manner as in Example 1 except that the ingredients and the contents described in Example 10 of Table 2 were used.

< Example 11>

A sustained-release tablet of 400 mg containing 180 mg of Ticagelera per tablet was prepared in the same manner as in Example 1, except that the components and the contents described in Example 11 of Table 2 were used.

< Example 12>

A sustained-release tablet of 300 mg containing 90 mg of Ticagrella per tablet was prepared in the same manner as in Example 1, except that the components and the contents described in Example 12 of Table 2 were used.

< Example 13>

A sustained-release tablet of 900 mg containing 270 mg of ticagrella per tablet was prepared in the same manner as in Example 1 except that the ingredients and the content described in Example 13 of Table 2 were used.

< Example 14>

A sustained release tablet of 600 mg containing 180 mg of ticagrella per tablet was prepared in the same manner as in Example 1 except that the ingredients and the content described in Example 14 of Table 2 were used.

< Comparative Example 1>

After mixing the tikageler, lactose hydrate and hypromellose having a viscosity of 78 to 117 mPa · s in an aqueous solution of 2 w / w%, a fermented alcohol equivalent to 18.5 μl per fermented liquor was added to form granules . The resulting granules were passed through a 1 mm sieve, dried at 60 ° C for 1 hour, and further granulated using a sizing machine using a 1 mm sieve to prepare a sized product.

Magnesium stearate was applied to a 40-tuple, which was then poured into a plastic bag together with the above-prepared sizing product. The mixture was shaken 100 times and compressed in a tablet machine to prepare a 600 mg tablets containing 180 mg of ticagrella per tablet. The blending ratios (weight) of each of these components are shown in Table 3.

< Comparative Example 2>

A 600-mg tablets containing 180 mg of ticagrella per tablet were prepared in the same manner as in Comparative Example 1, except that the ingredients and content of Comparative Example 2 in Table 3 were used.

< Comparative Example 3>

A 600 mg tablets containing 180 mg of ticagrella per tablet were prepared in the same manner as in Comparative Example 1, except that the ingredients and the content of Comparative Example 3 in Table 3 were used.

< Comparative Example 4>

600 mg tablets containing 180 mg of ticagrella per tablet were prepared in the same manner as in Comparative Example 1, except that the ingredients and the content of Comparative Example 4 in Table 3 were used.

< Comparative Example 5>

A 600 mg tablets containing 180 mg of ticagrella per tablet were prepared in the same manner as in Comparative Example 1, except that the ingredients and the content of Comparative Example 5 in Table 3 were used.

< Comparative Example 6>

A 600 mg tablets containing 180 mg of ticagrella per tablet were prepared in the same manner as in Comparative Example 1, except that the ingredients and the content of Comparative Example 6 in Table 3 were used.

< Comparative Example 7>

A 600 mg tablets containing 180 mg of ticagrella per tablet were prepared in the same manner as in Comparative Example 1, except that the ingredients and the content of Comparative Example 7 in Table 3 were used.

< Comparative Example 8>

A 600 mg tablets containing 180 mg of ticagrella per tablet were prepared in the same manner as in Comparative Example 1, except that the ingredients and the content of Comparative Example 8 in Table 3 were used.

< Comparative Example 9>

600 mg tablets containing 180 mg of ticagrella per tablet were prepared in the same manner as in Comparative Example 1, except that the ingredients and the content of Comparative Example 9 in Table 3 were used.

< Comparative Example 10>

A 600 mg tablets containing 180 mg of ticagrella per tablet were prepared in the same manner as in Comparative Example 1, except that the ingredients and the content of Comparative Example 10 in Table 3 were used.

< Comparative Example 11>

500 mg tablets containing 180 mg of ticagrella per tablet were prepared in the same manner as in Comparative Example 1, except that the ingredients and content of Comparative Example 11 in Table 3 were used.

[Table 1] (Unit: mg)

[Table 2] (Unit: mg)

[Table 3] (unit: mg)

< Test Example 1> pH By condition Tranquility evaluation

The dissolution rate of the tablets prepared in Example 2 and Comparative Example 9, which was prepared with only the binder at the internal fixation, was evaluated. The test solutions used were pH 1.2, pH 4.0, water and 900 mL of pH 6.8 solution containing 1 w / v% sodium lauryl sulphate (SLS).

The pH 1.2 solution (the first solution of the Pharmacopoeia disintegration test method) was prepared by dissolving 7.0 mL of hydrochloric acid and 2.0 g of sodium chloride into 1000 mL of a solution prepared by dissolving in water. The solution was colorless transparent and had a pH of about 1.2.

The pH 4.0 solution (acetate buffer solution) is adjusted to pH 4.0 by making a 0.05 mol / L acetic acid solution and a 0.05 mol / L sodium acetate mixed solution at a ratio of 41: 9 (volume ratio).

pH 6.8 (the second solution of the Pharmacopoeia disintegration test method) was prepared by adding 250 mL of 0.2 mol / L disodium hydrogen citrate solution to 118 mL of 0.2 mol / L sodium hydroxide solution and 1000 mL of water, The pH is about 6.8.

Specifically, the dissolution rate of the tablets of Example 2 was measured with respect to the pH 1.2 solution, the pH 4.2 solution, the pH 6.8 solution, and water. For the Comparative Example 9, the dissolution rate was measured with respect to the pH 1.2 solution and the pH 6.8 solution, The degree of dissolution of tikageler was tested in a paddle method (USP Apparatus 2) at 37 ° C ± 0.5 ° C and 50 rpm, and the results are shown in FIG.

In the case of the tablets prepared in Example 2 of the present invention, it was confirmed that the rate of releasing tikageler can be effectively controlled, which is very different from that in the tablets of Comparative Example 9. That is, it was found that the elution rate with time was kept almost constant in the case of the tablet of Example 2, and the release pattern was effectively controlled in all pH conditions. Therefore, the formulation according to the present invention can be expected to have a uniform efficacy without being affected by the pH environment in the gastrointestinal tract of the subject through the stable dissolution rate, and the risk of side effects due to rapid dissolution can be reduced.

< Test Example 2> Comparative Example Evaluation of dissolution rate for 6 and 9 tablets

The dissolution rate was evaluated in Comparative Example 6 using a water-soluble polymer as an excipient and in Comparative Example 9 tablets prepared by incorporating only a binder in a solid phase. The test solution used was a solution of pH 1.2, pH 4.0, water and pH 6.8 containing 1% by weight SLS, and the dissolution degree of tikageler in a paddle method (USP Apparatus 2) at 37 ° C ± 0.5 ° C and 50 rpm And the dissolution rate in pH 1.2 solution and pH 6.8 solution is shown in FIG.

Compared with the tablets of Comparative Example 9, the release rate of ticagrella was controlled at pH 1.2, pH 4.0 and water conditions in the case of tablets prepared in Comparative Example 6 of the present invention. However, the release pattern changed significantly in artificial intestinal fluid (pH 6.8). This becomes more apparent in comparison with Example 2 of Test Example 1.

The dissolution rate in the artificial intestinal fluid is important because the tikagelera mainly has an absorption window in the small intestine. Considering the time to reach the small intestine (pH 6.8) condition in the human body, the drug should be released for at least 12 hours and at least 65% should be released. Unlike the expected release pattern under artificial intestinal fluid (pH 6.8) conditions, reaching about 100% in 6 hours can not be expected to ensure that the effect of the formulation is maintained sufficiently. If the drug is released at 100% in 6 hours, the efficacy can not be maintained for 24 hours. Therefore, it is necessary to take one or more times per day, which significantly reduces the convenience of the patient's medication and decreases the absorption of the drug. Can be degraded.

< Test Example 3> Estimation of dissolution rate in artificial intestinal fluid

The dissolution rates of the tablets of Examples 1 to 5 were evaluated. 900 mL of pH 6.8 solution containing 1 wt% SLS was used as the test solution, and the degree of dissolution of tikageler was measured in a paddle method (USP Apparatus 2) at 37 ° C ± 0.5 ° C and 50 rpm, and the results are shown in FIG. 3 .

The emission patterns of Examples 1 to 5 are observed linearly and it can be seen that the drug is a zero-order release which is constantly released over time. In particular, in the case of Example 2, the R ² value of the regression line of the dissolution rate was 0.9975, and it was confirmed that the 0th-order emission pattern, that is, the elution with time was almost constant.

When the excipients of the examples of the present invention were used in a specific ratio, it was confirmed that the emission pattern of tikageler was controlled to be constant according to the composition and ratio.

< Test Example 4> Glyceryl behenate Estimation of dissolution rate according to content

The dissolution rates of the tablets of Examples 2, 6, 7, 11 and Comparative Examples 10, 11 were evaluated. 900 mL of pH 6.8 solution containing 1 wt% SLS was used as the test solution, and the degree of dissolution of tikageler was measured in a paddle method (USP Apparatus 2) at 37 ° C ± 0.5 ° C and 50 rpm, and the results are shown in Table 4 .

The tablets of Examples 2, 6, 7 and 11 of the present invention contained about 10 to 30% at 2 hours, about 30 to 60% at 6 hours, and 70% at 12 hours in a 6.8-liter, 900 mL test solution containing 1% Or more.

On the other hand, in Comparative Examples 10 to 11, the release proceeded very slowly and showed a low dissolution rate even at the final time point.

In Comparative Example 10, the CV (deviation) value of the 12-hour dissolution rate was 27%. In Comparative Example 11, the 12-hour dissolution rate CV value was 39.4%.

CV (%) = (standard deviation of dissolution rate / average of dissolution rate) X 100

(Measured for a total of 6 tablets)

That is, each of the prepared tablets did not exhibit a constant dissolution rate and showed a different dissolution rate for each tablet. It is difficult to expect that the effect of the drug will be constant as the deviation pattern of release of the drug from the sustained-release preparation increases. Therefore, the tablets of Comparative Examples 10 and 11 exhibited slow dissolution of the active ingredient, but there was a large difference in the dissolution rate between each tablet and no sufficient amount of the active ingredient was released within 12 hours. Therefore, it was judged that Comparative Examples 10 and 11 contained a content of glyceryl behenate which was not suitable for effectively delivering the drug.

On the other hand, all the tablets according to the embodiments of the present invention showed a CV value of 10% or less. Therefore, it was found that the tablets of the present invention not only sufficiently released the drug for 12 hours but also maintained the dissolution rate of each tablet to be almost constant.

[Table 4]

< Test Example 5> Evaluation of stability

The dissolution rate was evaluated for the tablets of Example 2 stored under accelerated conditions (40 < 0 > C and 75% relative humidity) for 2 weeks and 1 month. As test solution, 900 mL of pH 6.8 solution containing 1% SLS was used and the degree of elution of tikageler was measured in a paddle method (USP Apparatus 2) at 37 ° C ± 0.5 ° C and 50 rpm, and the results are shown in FIG.

As can be seen from FIG. 4, the tablets of Example 2 exhibited the same elution pattern as those when they were first prepared even after 1 month and 2 months storage under accelerated conditions.

From this, it can be seen that the sustained-release preparation of the present invention has excellent storage stability such that its release pattern does not change during storage, and almost no change in dissolution rate of tikageler is observed between the preparation immediately after preparation and the preparation after storage. Will remain the same throughout the storage period.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that such detail is solved by the person skilled in the art without departing from the scope of the invention. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

3 to 60 parts by weight of Ticagrelor or a pharmaceutically acceptable salt thereof per 100 parts by weight of the preparation; And 3 to 30 parts by weight of a hydrophobic lipid excipient.

The method according to claim 1,
Wherein the hydrophobic lipid excipient is selected from the group consisting of glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, glyceryl oleate, glyceryl myristate, cetyl caprate, cetyl palmitate, stearyl palmitate, stearyl stearate, Carnauba wax and castor oil. &Lt; RTI ID = 0.0 > 8. < / RTI >

3. The method of claim 2,
Wherein the hydrophobic lipid excipient is glyceryl palmitostearate, glyceryl behenate, or a mixture thereof.

The composition according to claim 1,
25 to 60 parts by weight of Ticagrelor or a pharmaceutically acceptable salt thereof per 100 parts by weight of the preparation; And 3 to 25 parts by weight of a hydrophobic lipid excipient.

The sustained release formulation of claim 1, wherein the formulation releases Ticagrelor or a pharmaceutically acceptable salt thereof for at least 12 hours upon oral administration.

6. The method according to any one of claims 1 to 5,
Wherein the formulation further comprises aspirin.

6. The sustained-release preparation according to any one of claims 1 to 5, wherein the preparation is an oral preparation.

8. The method of claim 7,
Wherein the formulation is a powder, granule, pellet, mini tablet, capsule or tablet.