WO2016013795A1 - Slow release preparation - Google Patents

Slow release preparation Download PDF

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Publication number
WO2016013795A1
WO2016013795A1 PCT/KR2015/007319 KR2015007319W WO2016013795A1 WO 2016013795 A1 WO2016013795 A1 WO 2016013795A1 KR 2015007319 W KR2015007319 W KR 2015007319W WO 2016013795 A1 WO2016013795 A1 WO 2016013795A1
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Prior art keywords
ticagrelor
release
present
pharmaceutically acceptable
formulation
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PCT/KR2015/007319
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French (fr)
Korean (ko)
Inventor
김순회
손미원
장선우
원동한
김용민
이윤화
Original Assignee
동아에스티 주식회사
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Publication of WO2016013795A1 publication Critical patent/WO2016013795A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to a formulation comprising ticagrelor as an active ingredient, and more specifically, to a formulation containing ticagrelor or salts thereof as an active ingredient, by slowly releasing the ticagrelor or salts thereof for a predetermined time.
  • the present invention relates to an agent capable of improving patient convenience of medication and maximizing the therapeutic effect of ticagrelor.
  • Ticagrelor as shown in US6251910, is a breakthrough drug that can reduce the risk of patients at risk for disease through platelet aggregation inhibitory action.
  • ticagrelor is most often absorbed in the small intestine within about 2 hours after oral administration, and its half-life is short, about 6 to 13 hours, which causes many inconveniences.
  • US8425934 mixes ticagrelor with an appropriate pharmaceutical excipient to obtain a pharmaceutical composition in which the poorly soluble drug ticagrelor is released in a short time, but the release is not controlled and is released within two hours.
  • Patent Document 1 US6251910
  • Patent Document 2 US8425934
  • the present invention relates to a sustained release preparation comprising ticagrelor or salts thereof.
  • the present invention provides a sustained release oral formulation comprising Ticagrelor or a pharmaceutically acceptable salt thereof and a hydrophobic lipid excipient.
  • Ticagrelor is a compound having the above formula, it can be used in the treatment of diseases caused by thrombosis, such as stroke, acute coronary syndrome through excellent platelet aggregation inhibitory action.
  • the hydrophobic lipid excipient exhibits poorly soluble properties in water, and serves as a release controlling substance that can control the release rate of the active ingredient ticagrelor or a pharmaceutically acceptable salt thereof.
  • Formulations comprising the same may slow the dissolution of ticagrelor or a pharmaceutically acceptable salt thereof by reducing the surface area of the active ingredient ticagrelor or a pharmaceutically acceptable salt thereof in contact with water. That is, the hydrophobic lipid excipient prevents water from penetrating into the formulation, so that the surface of the formulation is gradually eroded, so that the active ingredient ticagrelor or a pharmaceutically acceptable salt thereof can be slowly contacted with the aqueous solution to be released at a constant rate. Can be.
  • the sustained-release oral preparation may include 3 to 60 parts by weight of ticagrelor or a pharmaceutically acceptable salt thereof and 3 to 30 parts by weight of hydrophobic lipid excipient with respect to 100 parts by weight of the preparation.
  • the sustained-release oral preparation contains 3 to 60 parts by weight, 5 to 55 parts by weight, 20 to 50 parts by weight or 25 to 35 parts by weight of ticagrelor or a pharmaceutically acceptable salt thereof based on 100 parts by weight of the formulation. And ticagrelor or a pharmaceutically acceptable salt thereof in an amount of about 90 to about 270 mg per unit formulation.
  • the sustained release oral preparation may include 3 to 30 parts by weight, 5 to 25 parts by weight, or 5 to 15 parts by weight of hydrophobic lipid excipient with respect to 100 parts by weight of the preparation.
  • the sustained release oral preparation may include 25 to 60 parts by weight of ticagrelor or a pharmaceutically acceptable salt thereof and 3 to 25 parts by weight of hydrophobic lipid excipient based on 100 parts by weight of the preparation.
  • the preparation comprising the ticagrelor or a pharmaceutically acceptable salt thereof and a hydrophobic lipid excipient in the above content is 12 hours or more independently of the pH of the ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient. While emitting at a constant rate. Therefore, the sustained-release oral formulation of the present invention can be taken once a day, which can significantly improve the convenience of patients' medication, and can maintain the drug concentration of ticagrelor in the body at a constant concentration in the body. It can significantly improve the efficacy of and minimize the side effects of the rapid release of the drug.
  • the hydrophobic lipid excipient may be at least one selected from glyceryl fatty acid esters, fatty acid esters, carnauba wax or castor oil.
  • Glyceryl fatty acid esters specifically include glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, glyceryl oleate, and glyceryl myristate. (glyceryl myristate) or a mixture thereof.
  • Fatty acid esters may be cetyl palmitate, cetyl caprate, stearyl palmitate, stearyl stearate or mixtures thereof.
  • hydrophobic lipid excipient is glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, cetyl palmitate, stearyl palmitate, stearyl stearate, carnauba wax, casta oil or mixtures thereof It may be, preferably be glyceryl palmitostearate, glyceryl behenate or a mixture thereof.
  • the hydrophobic lipid excipient and the ticagrelor or a pharmaceutically acceptable salt thereof are 1: 1 to 10, 1: 1 to 6, 1: 1 to 4, 1: 1.5 to 4 or 1: 2 to It can be used in a weight ratio of 3.5.
  • the sustained release formulations of the present invention can release the active ingredient ticagrelor or a pharmaceutically acceptable salt thereof at a constant rate for a long time, that is, for at least 12 hours.
  • the sustained-release preparation according to the present invention has a constant weight of 10-30% at 2 hours, 30-60% at 6 hours, and 65% at 12 hours from the administration of the formulation with respect to the total weight of the ticagrelor or salt thereof contained in the formulation. It is possible to release the active ingredient ticagrelor or a salt thereof at a rate.
  • the absorption site of the ticagrelor is the small intestine
  • the sustained-release preparation according to the present invention
  • the emission pattern remains constant at all pHs, including gastric juice (pH 1.2), artificial intestinal fluid (pH 6.8), pH 4.0 and water.
  • the pharmaceutically acceptable salt of ticagrelor may be an acid addition salt formed by a pharmaceutically acceptable free acid.
  • the free acid may be an inorganic acid and an organic acid, and the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, and the like, and the organic acid may be citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, and methanesulfur.
  • Phonic acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, and the like may be used, but is not limited thereto.
  • hydrochloric acid may be used as the inorganic acid
  • methanesulfonic acid may be used as the organic acid.
  • the ticagrelor or a pharmaceutically acceptable salt thereof is a racemate, an optical isomer, an isomer (polymorph, Polymorph), a hydrate or a solvent of the ticagrelor or a pharmaceutically acceptable salt thereof. It includes all the cargo.
  • the isomorph (polymorph) of the ticagrelor or a pharmaceutically acceptable salt thereof is a compound having the same molecular formula but different crystal structure in the solid state, and the ticagrelor or a pharmaceutically acceptable salt thereof.
  • Polymorphs of the ticagrelor or pharmaceutically acceptable salts thereof are as described in Patent No. 10-0781864.
  • the active ingredient included in the formulation may be a type II polymorph, a type I polymorph or an amorphous form of ticagrelor.
  • the hydrate of the ticagrelor or a pharmaceutically acceptable salt thereof may comprise a stoichiometric or nonstoichiometric amount of water bound by non-covalent intermolecular forces.
  • the hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water.
  • Such hydrates may be prepared by crystallizing the ticagrelor of the present invention or a pharmaceutically acceptable salt thereof from water or a solvent containing water.
  • the solvate of the ticagrelor or a pharmaceutically acceptable salt thereof may comprise a stoichiometric or nonstoichiometric amount of solvent that is bound by non-covalent intermolecular forces.
  • Preferred solvents include those which are non-volatile, non-toxic or suitable for administration to humans, for example ethanol, methanol, propanol, methylene chloride and the like.
  • Sustained release formulations of the present invention may further comprise pharmaceutically acceptable additives in addition to ticagrelor or pharmaceutically acceptable salts and hydrophobic lipid excipients thereof.
  • the pharmaceutically acceptable additives include lactose, corn starch, fillers such as microcrystalline cellulose, polyethylene glycol or dicalcium phosphate, microcrystalline cellulose highly disperse silica, mannitol, sugars such as lactose, highly disperse silica, mannitol, Binders such as lactose or polyethylene glycol, coating agents such as colloidal silicon oxide, talc, stearic acid, magnesium stearate, sodium stearyl fumarate lubricant, ethyl cellulose, hydroxypropyl methyl cellulose and methacrylic acid-alkyl acrylate copolymers;
  • dissolution aids, solubilizers, colorants, pH regulators, surfactants, stabilizers and emulsifiers may be used, but are not limited there
  • the dosage of the sustained-release preparation of the present invention may be a content suitable for the treatment or prevention of the subject and / or disease, which is the age, weight, general health, sex and diet, time of administration, type of disease, and disease of the patient. It can be adjusted according to various factors including the severity of, the type and content of other components contained in the formulation, the type of formulation, the warning of administration, the rate of composition of the composition, the duration of treatment and the drug used concurrently. For example, when the subject is an adult, the agent of the present invention may be administered in a total dose of 90 to 270 mg once a day or when converted to ticagrelor.
  • Sustained release formulations of the invention can be prepared in a variety of formulations.
  • the preparation of the present invention may be formulated into tablets, powders, pellets, mini-tablets, powders, granules or capsules, etc., preferably tablets, such as liquids, uncoated tablets, coated tablets, multi-layered tablets or core tablets. Can be.
  • the route of administration of the sustained release preparations of the invention may be suitably controlled but may be administered orally.
  • the sustained-release preparation of the present invention is administered orally, the preparation is active ingredient tikag at a constant rate of 10-30% in 2 hours, 30-60% in 6 hours, 65% or more in 12 hours. Release the salt or salts thereof.
  • the sustained-release preparation of the present invention may further include other additional active ingredients exhibiting the same pharmacological activity in addition to the ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the sustained release formulation of the present invention may further comprise aspirin as an active ingredient in addition to ticagrelor or a pharmaceutically acceptable salt thereof.
  • the ticagrelor or a pharmaceutically acceptable salt thereof and aspirin are included as an active ingredient, each of the active ingredients alone may be remarkably excellent in treating diseases caused by blood clots such as stroke and acute coronary syndrome. Can be effective.
  • the present invention includes takagrelor or a pharmaceutically acceptable salt thereof and aspirin, the two substances may be present in co-crystal form of takagrelor or a pharmaceutically acceptable salt thereof and aspirin.
  • the sustained release preparation of the present invention further comprises an additional active ingredient
  • the additional active ingredient may be formulated to be released in a sustained release form such as ticagrelor or a pharmaceutically acceptable salt thereof.
  • the additional active ingredient may be formulated in a rapid release form differently from ticagrelor or a pharmaceutically acceptable salt thereof.
  • the sustained-release preparation of the present invention does not contain too high a content of the active ingredient ticagrelor or a pharmaceutically acceptable salt thereof per unit formulation to cause side effects, and the ticagrelor or a pharmaceutically acceptable salt thereof is uniform. It can be released for a long time at a rate to maintain a constant concentration of the active ingredient in the plasma and to adjust the frequency and dosage of the administration subjects to improve compliance, preferably in a form suitable for once-daily administration Can be provided.
  • the present invention also provides a method for producing a ticagrelor-containing sustained release preparation.
  • the method for preparing the sustained-release preparation of the present invention comprises the steps of preparing granules by mixing ticagrelor or a pharmaceutically acceptable salt thereof and a hydrophobic lipid excipient; And adding other pharmaceutically acceptable additives to the granules to prepare a mixture.
  • additional pharmaceutical additives may be further mixed in addition to the hydrophobic lipid excipient which is the release controlling substance.
  • the pharmaceutically acceptable additives are as described above.
  • the granules may be prepared by wet granulation or dry granulation, preferably by wet granulation.
  • the method of the present invention may further comprise the step of preparing the granules by sizing the granules.
  • the formulation can be prepared by drying the granules and then sizing them. Specifically, the granules are passed through a sieve having a corn size of 0.5 to 1.5 mm, and dried at a temperature of about 40 to 60 ° C., and the granules are formed by using a sieve having a corn size of 0.5 to 1.5 mm. can do.
  • the hydrophobic lipid excipient in addition to the hydrophobic lipid excipient, it may further include a pharmaceutically acceptable additive so long as it does not inhibit the sustained release of the preparation.
  • the pharmaceutically acceptable additive may be a carrier, diluent, excipient, lubricant, and the like, but is not limited thereto.
  • the pharmaceutically acceptable additive is as described above, preferably lactose or magnesium stearate.
  • the sustained release formulation of the present invention may be a tablet, in which case the preparation method may further comprise the step of tableting the mixture, and the tableted uncoated tablet may be further film coated.
  • the method for producing a sustained release formulation of the present invention can simplify the manufacturing process, improve productivity, and ensure excellent quality.
  • Sustained release formulation according to the present invention is the active ingredient ticagrelor is slowly released from the formulation at a constant rate irrespective of pH so that the ticagrelor can maintain a constant concentration in the body, the patient's medication compliance due to the reduced number of doses It can increase and maximize the therapeutic effect of the drug.
  • 1 to 3 are graphs showing the dissolution rate of tablets according to the Examples and Comparative Examples of the present invention.
  • Figure 4 is a graph showing the dissolution rate after storage of accelerated conditions of the tablet according to Example 2 of the present invention.
  • Ticagrelor, lactose monohydrate and glyceryl palmitostearate were mixed for 5 minutes in a high speed mixer, and then fermented liquor corresponding to 18.5 ⁇ l fermented liquor was added per tablet and combined for 5 minutes to form granules.
  • the granules thus prepared were passed through a sieve having a 1 mm grid size, dried at 60 ° C. for 1 hour, and struck again using a sieve having a 1 mm grid size.
  • a 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 2 of Table 1 were used.
  • a 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 3 of Table 1 were used.
  • a 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 4 of Table 1 were used.
  • a 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 5 of Table 1 were used.
  • a 400 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 6 of Table 1 were used.
  • a 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 7 of Table 1 were used.
  • a 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 8 of Table 2 were used.
  • a 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 9 of Table 2 were used.
  • a 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 10 of Table 2 were used.
  • a 400 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 11 of Table 2 were used.
  • a 300 mg sustained-release tablet containing 90 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 12 of Table 2 were used.
  • a 900 mg sustained-release tablet containing 270 mg of ticagrelor per tablet was prepared in the same manner as in Example 1, except that the ingredients and contents described in Example 13 of Table 2 were used.
  • a 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 14 of Table 2 were used.
  • Ticagrelor, lactose hydrate, and hypromellose having a viscosity of 78 to 117 mPa in a 2 w / w% aqueous solution were mixed, and then fermentation alcohol corresponding to 18.5 ⁇ l of fermentation alcohol per tablet was added to form granules. .
  • the granules thus prepared were passed through a 1 mm sieve and then dried at 60 ° C. for 1 hour, and then sieved again using a 1 mm sieve.
  • a 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1, except that the components and contents of Comparative Example 2 of Table 3 were used.
  • a 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 3 of Table 3 were used.
  • a 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 4 of Table 3 were used.
  • a 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 5 of Table 3 were used.
  • a 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 6 of Table 3 were used.
  • a 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 7 of Table 3 were used.
  • a 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 8 of Table 3 were used.
  • a 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 9 of Table 3 were used.
  • a 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 10 of Table 3 were used.
  • a 500 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 11 of Table 3 were used.
  • Example 2 The dissolution rate was evaluated for Example 2 and Comparative Example 9 tablets prepared with only binders in rapid release.
  • As a test solution 900 mL of pH 1.2 solution, pH 4.0 solution, water and pH 6.8 solution containing 1 w / v% sodium lauryl sulphate (SLS) were used.
  • a pH 1.2 solution (1st solution of the KPSI) is a 1000 mL solution prepared by dissolving 7.0 mL of hydrochloric acid and water in 2.0 g of sodium chloride. The solution is colorless and transparent, and its pH is about 1.2.
  • pH 4.0 solution (acetate buffer solution) is adjusted to pH 4.0 by making a mixture of 0.05 mol / L acetate and 0.05 mol / L sodium acetate 41: 9 (volume ratio).
  • pH6.8 (2nd solution of KEPCO disintegration test) is a 1000 mL solution prepared by adding 118 mL of 0.2 mol / L sodium hydroxide solution and water to 250 mL of 0.2 mol / L potassium dihydrogen dioxide solution. The solution is colorless and transparent. The pH is about 6.8.
  • the dissolution rate of the pH 1.2 liquid, the pH 4.2 liquid, the pH 6.8 liquid, and the water was measured for the tablet of Example 2, and the dissolution rate was measured for the pH 1.2 liquid, and the pH 6.8 liquid for Comparative Example 9.
  • the degree of dissolution of ticagrelor in the paddle method (USP Apparatus 2) at 37 ° C. ⁇ 0.5 ° C. and 50 rpm was tested and the results are shown in FIG. 1.
  • the rate of releasing ticagrelor can be effectively controlled differently from the tablets of Comparative Example 9. That is, in the case of the tablet of Example 2, it was found that the dissolution rate was maintained almost constant over time, and in particular, the release pattern was effectively controlled in all pH conditions. Therefore, the preparation according to the present invention can be expected to be constant without affecting the gastrointestinal pH environment of the subject to be administered through such a stable dissolution rate, it can also reduce the risk of side effects due to rapid dissolution.
  • the dissolution rate was evaluated for the Comparative Example 6 using the water-soluble polymer as an excipient and the Comparative Example 9 tablet prepared by containing only the binder in the immediate release.
  • As a test solution 900 mL of pH 1.2 solution containing 1 wt% SLS, pH 4.0 solution, water and pH 6.8 solution were used. The elution degree of ticagrelor in 37 ° C ⁇ 0.5 ° C and 50rpm paddle method (USP Apparatus 2) was measured. It was tested and the dissolution rate in pH 1.2 liquid and pH 6.8 liquid is shown in FIG.
  • the dissolution rate in artificial intestinal fluid is important.
  • the drug must be able to be released for at least 12 hours and at least 65% or more. Contrary to the release pattern expected under conditions of artificial intestinal fluid (pH 6.8), reaching about 100% in 6 hours cannot be expected to maintain the effectiveness of the formulation. If the drug is released 100% in 6 hours, the drug's efficacy cannot be maintained for 24 hours, which requires one or more doses per day, which significantly lowers the convenience of the patient's medication and decreases the absorption of the drug. Can be degraded.
  • the dissolution rate was evaluated for the tablets of Examples 1-5. 900 mL of pH 6.8 solution containing 1 wt% SLS was used as a test solution, and the elution degree of ticagrelor in the paddle method (USP Apparatus 2) at 37 ° C. ⁇ 0.5 ° C. and 50 rpm was tested and the results are shown in FIG. 3. .
  • the release pattern of Examples 1 to 5 is observed in a straight line, it can be seen that the drug is a zero-order release that is constantly released over time.
  • 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, dissolution over time was almost constant.
  • Dissolution rates were evaluated for Examples 2, 6, 7, 11 and Comparative Examples 10, 11 tablets.
  • 900 mL of pH 6.8 solution containing 1 wt% SLS was used as a test solution.
  • the elution degree of ticagrelor in 37 ° C ⁇ 0.5 ° C and 50rpm paddle method (USP Apparatus 2) was tested and the results are shown in Table 4. .
  • Tablets of Examples 2, 6, 7 and 11 of the present invention are about 10 to 30% at 2 hours, about 30 to 60% at 6 hours, and 70 at 12 hours in a 900 mL test solution of pH 6.8 solution containing 1% SLS.
  • the dissolution pattern was more than%.
  • CV (%) (standard deviation of dissolution rate / average of dissolution rate) X 100
  • each of the tablets produced did not exhibit a constant dissolution rate but a different dissolution rate for each tablet. It is hard to expect that the larger the deviation of the drug's release pattern in the sustained release formulation, the more consistent the drug's effect will be. Therefore, the tablets of Comparative Examples 10 and 11 are sustained release, but the dissolution of the active ingredient is delayed, but the dissolution rate is large for each tablet and a sufficient amount of the active ingredient is not released within 12 hours. Thus, Comparative Examples 10 and 11 were determined to contain glyceryl behenate in an amount that is not suitable for effective drug delivery.
  • Dissolution rates were evaluated for Example 2 tablets stored at accelerated conditions (40 ° C. and 75% relative humidity) for 2 weeks and 1 month.
  • 900 mL of pH 6.8 solution containing 1% SLS was used as a test solution, and the elution degree of ticagrelor in the paddle method (USP Apparatus 2) at 37 ° C. ⁇ 0.5 ° C. and 50 rpm was tested and the results are shown in FIG. 4.
  • tablets of Example 2 exhibited the same dissolution pattern as when first prepared even after 1 month and 2 months storage under accelerated conditions.
  • the sustained-release preparation of the present invention is expected from the sustained-release preparation because the release pattern of the present invention is excellent in storage stability such that the release pattern does not change during storage, and the change in the dissolution rate of the ticagrelor between the preparation immediately after the preparation and the post-storage preparation is hardly recognized. It is believed that the drug efficacy will remain the same for the storage period.
  • Sustained release formulation according to the present invention is the active ingredient ticagrelor is slowly released from the formulation at a constant rate irrespective of pH so that the ticagrelor can maintain a constant concentration in the body, the patient's medication compliance due to the reduced number of doses It can increase and maximize the therapeutic effect of the drug.

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Abstract

The present invention relates to a slow-release preparation comprising ticagrelor or a pharmaceutically acceptable salt thereof together with a hydrophobic lipid excipient acting as a release-controlling substance. In the slow-release preparation according to the present invention, the ticagrelor, which is the active ingredient, can be maintained at a constant concentration within the body because the ticagrelor is slowly released at a constant rate from the preparation regardless of pH, and thus drug-administration frequency can be reduced such that drug-taking compliance of patients can be increased and the therapeutic effects of the drug can be maximised.

Description

서방성 제제Sustained release preparations
본 발명은 티카그렐러를 유효성분으로 하는 제제에 관한 것으로, 보다 구체적으로 티카그렐러 또는 이의 염을 유효성분으로 포함하는 제제에 있어 상기 티카그렐러 또는 이의 염의 방출을 일정시간 동안 서서히 방출되게 함으로써 환자의 복약 편의성을 향상시키고 티카그렐러의 치료 효과를 최대화할 수 있는 제제에 관한 것이다.The present invention relates to a formulation comprising ticagrelor as an active ingredient, and more specifically, to a formulation containing ticagrelor or salts thereof as an active ingredient, by slowly releasing the ticagrelor or salts thereof for a predetermined time. The present invention relates to an agent capable of improving patient convenience of medication and maximizing the therapeutic effect of ticagrelor.
티카그렐러는 US6251910 에서 나타낸 것처럼 혈소판응집억제 작용을 통해 질환의 위험이 잠재된 환자의 위험률을 낯춰 줄 수 있는 획기적인 약물이다. 하지만 티카그렐러는 경구투여후 약 2시간 이내에 대부분이 소장에서 흡수되고 그 반감기가 약 6~13 시간으로 짧아서 복용 횟수가 많은 불편함이 있다. 특히, 동일 계열 약물인 클로피도그렐황산염이나 프라수그렐 등의 1일 1회 투여로 효과가 나타나는 약제와 비교시 1일 2회 투여해야하는 불편함이 있다.Ticagrelor, as shown in US6251910, is a breakthrough drug that can reduce the risk of patients at risk for disease through platelet aggregation inhibitory action. However, ticagrelor is most often absorbed in the small intestine within about 2 hours after oral administration, and its half-life is short, about 6 to 13 hours, which causes many inconveniences. In particular, it is inconvenient to administer twice a day as compared to drugs that are effective by once-daily administration of clopidogrel sulfate or prasugrel, which are drugs of the same class.
US8425934 는 티카그렐러를 적절한 약제학적 부형제와 혼합하여 난용성 약물인 티카그렐러가 단시간에 충분히 방출되는 제약조성물을 얻었으나, 그 방출은 제어되지 않고 2시간 이내에 모두 방출되었다. US8425934 mixes ticagrelor with an appropriate pharmaceutical excipient to obtain a pharmaceutical composition in which the poorly soluble drug ticagrelor is released in a short time, but the release is not controlled and is released within two hours.
따라서 복용 시 복용 횟수를 줄여 환자의 복약순응도를 높이고 또한 약효의 지속시간을 늘리고, 위험을 감소시킬 수 있는 조성물의 개발이 필요하다. Therefore, there is a need for the development of a composition that can reduce the number of doses when taken to increase patient compliance, and also increase the duration of drug efficacy and reduce risk.
[선행기술문헌][Preceding technical literature]
[특허문헌][Patent Documents]
(특허문헌 1) US6251910(Patent Document 1) US6251910
(특허문헌 2) US8425934(Patent Document 2) US8425934
본 발명은 티카그렐러 또는 이의 염을 포함하는 서방성 제제에 관한 것이다. The present invention relates to a sustained release preparation comprising ticagrelor or salts thereof.
본 발명은 티카그렐러(Ticagrelor) 또는 이의 약제학적으로 허용 가능한 염 및 소수성 지질 부형제를 포함하는 서방성 경구 제제를 제공한다. The present invention provides a sustained release oral formulation comprising Ticagrelor or a pharmaceutically acceptable salt thereof and a hydrophobic lipid excipient.
[화학식 1][Formula 1]
Figure PCTKR2015007319-appb-I000001
Figure PCTKR2015007319-appb-I000001
상기 티카그렐러(Ticagrelor)는 상기의 화학식을 갖는 화합물이며, 우수한 혈소판응집억제 작용을 통해 뇌졸중, 급성관상동맥증후군 등의 혈전으로 인한 질환 치료에 사용될 수 있다. Ticagrelor (Ticagrelor) is a compound having the above formula, it can be used in the treatment of diseases caused by thrombosis, such as stroke, acute coronary syndrome through excellent platelet aggregation inhibitory action.
본 발명에 있어 소수성 지질 부형제는 물에 대해 난용성의 성질을 나타내는 것으로 제제에 포함된 유효 성분인 티카그렐러 또는 이의 약제학적으로 허용 가능한 염의 방출 속도를 조절할 수 있는 방출 제어 물질의 역할을 수행한다. 이를 포함한 제제는 활성성분인 티카그렐러 또는 이의 약제학적으로 허용 가능한 염이 물과 접촉하는 표면적을 줄여줌으로써 티카그렐러 또는 이의 약제학적으로 허용 가능한 염의 용해를 늦출 수 있다. 즉, 상기 소수성 지질 부형제는 제제 내부에 물이 침투하는 것을 막아 제제 표면이 서서히 침식되면서 활성성분인 티카그렐러 또는 이의 약제학적으로 허용 가능한 염이 수용액과 서서히 접촉할 수 있게 하여 일정한 속도로 방출될 수 있다.In the present invention, the hydrophobic lipid excipient exhibits poorly soluble properties in water, and serves as a release controlling substance that can control the release rate of the active ingredient ticagrelor or a pharmaceutically acceptable salt thereof. . Formulations comprising the same may slow the dissolution of ticagrelor or a pharmaceutically acceptable salt thereof by reducing the surface area of the active ingredient ticagrelor or a pharmaceutically acceptable salt thereof in contact with water. That is, the hydrophobic lipid excipient prevents water from penetrating into the formulation, so that the surface of the formulation is gradually eroded, so that the active ingredient ticagrelor or a pharmaceutically acceptable salt thereof can be slowly contacted with the aqueous solution to be released at a constant rate. Can be.
본 발명에 있어 상기 서방성 경구 제제는 제제 100 중량부에 대하여 티카그렐러 또는 이의 약제학적으로 허용 가능한 염을 3 내지 60 중량부 및 소수성 지질 부형제를 3 내지 30 중량부로 포함할 수 있다. In the present invention, the sustained-release oral preparation may include 3 to 60 parts by weight of ticagrelor or a pharmaceutically acceptable salt thereof and 3 to 30 parts by weight of hydrophobic lipid excipient with respect to 100 parts by weight of the preparation.
본 발명에 있어 상기 서방성 경구 제제는 제제 100 중량부에 대하여 티카그렐러 또는 이의 약제학적으로 허용 가능한 염을 3 내지 60 중량부, 5 내지 55 중량부, 20 내지 50 중량부 또는 25 내지 35 중량부로 포함할 수 있으며, 티카그렐러 또는 이의 약제학적으로 허용 가능한 염을 단위 제제당 약 90 내지 약 270mg의 양으로 포함할 수 있다. In the present invention, the sustained-release oral preparation contains 3 to 60 parts by weight, 5 to 55 parts by weight, 20 to 50 parts by weight or 25 to 35 parts by weight of ticagrelor or a pharmaceutically acceptable salt thereof based on 100 parts by weight of the formulation. And ticagrelor or a pharmaceutically acceptable salt thereof in an amount of about 90 to about 270 mg per unit formulation.
본 발명에 있어 상기 서방성 경구 제제는 제제 100 중량부에 대하여 소수성 지질 부형제를 3 내지 30 중량부, 5 내지 25 중량부 또는 5 내지 15 중량부로 포함할 수 있다. In the present invention, the sustained release oral preparation may include 3 to 30 parts by weight, 5 to 25 parts by weight, or 5 to 15 parts by weight of hydrophobic lipid excipient with respect to 100 parts by weight of the preparation.
바람직하게는 상기 서방성 경구 제제는 제제 100 중량부에 대하여 티카그렐러 또는 이의 약제학적으로 허용 가능한 염을 25 내지 60 중량부 및 소수성 지질 부형제를 3 내지 25 중량부로 포함할 수 있다. Preferably, the sustained release oral preparation may include 25 to 60 parts by weight of ticagrelor or a pharmaceutically acceptable salt thereof and 3 to 25 parts by weight of hydrophobic lipid excipient based on 100 parts by weight of the preparation.
본 발명에 있어 상기 티카그렐러 또는 이의 약제학적으로 허용 가능한 염과 소수성 지질 부형제를 상기 함량으로 포함하는 제제는 유효성분인 티카그렐러 또는 이의 약제학적으로 허용 가능한 염을 pH와 독립적으로 12시간 이상 동안 일정한 속도로 방출한다. 따라서 본 발명의 상기 서방성 경구 제제는 1일 1회 복용이 가능하여 환자의 복약 편의성을 현저히 향상시킬 수 있으며, 체내에서의 티카그렐러의 약물 농도를 체내에서 일정한 농도로 유지할 수 있어 티카그렐러의 효능을 현저히 향상시킬 수 있고 약물의 급격한 방출에 따른 부작용을 최소화할 수 있다.In the present invention, the preparation comprising the ticagrelor or a pharmaceutically acceptable salt thereof and a hydrophobic lipid excipient in the above content is 12 hours or more independently of the pH of the ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient. While emitting at a constant rate. Therefore, the sustained-release oral formulation of the present invention can be taken once a day, which can significantly improve the convenience of patients' medication, and can maintain the drug concentration of ticagrelor in the body at a constant concentration in the body. It can significantly improve the efficacy of and minimize the side effects of the rapid release of the drug.
본 발명에 있어 상기 소수성 지질 부형제는 글리세릴 지방산 에스테르류, 지방산 에스테르류, 카르나우바왁스 또는 캐스타 오일로부터 선택된 하나 이상이 될 수 있다. 글리세릴 지방산 에스테르류는 구체적으로 글리세릴 팔미토스 테아레이트(glyceryl palmitostearate), 글리세릴 베헤네이트(glyceryl behenate), 글리세릴 스테아레이트(glyceryl stearate), 글리세릴 올레이트(glyceryl oleate), 글리세릴 미리스테이트(glyceryl myristate) 또는 이들의 혼합물 등이 될 수 있다. 지방산 에스테르류는 세틸 팔미테이트, 세틸 카프레이트(cetyl caprate), 스테아릴 팔미테이트(stearyl palmitate), 스테아릴 스테아레이트(stearyl stearate) 또는 이들의 혼합물일 수 있다. 보다 구체적으로 상기 소수성 지질 부형제는 글리세릴 팔미토스테아레이트, 글리세릴 베헤네이트, 글리세릴 스테아레이트, 세틸팔미테이트, 스테아릴 팔미테이트, 스테아릴 스테아레이트, 카르나우바왁스, 캐스타 오일 또는 이의 혼합물일 수 있으며, 바람직하게는 글레세릴 팔미토스테아레이트, 글리세릴 베헤네이트 또는 이들의 혼합물일 수 있다. 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. Glyceryl fatty acid esters specifically include glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, glyceryl oleate, and glyceryl myristate. (glyceryl myristate) or a mixture thereof. Fatty acid esters may be cetyl palmitate, cetyl caprate, stearyl palmitate, stearyl stearate or mixtures thereof. More specifically the hydrophobic lipid excipient is glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, cetyl palmitate, stearyl palmitate, stearyl stearate, carnauba wax, casta oil or mixtures thereof It may be, preferably be glyceryl palmitostearate, glyceryl behenate or a mixture thereof.
본 발명에 있어서 상기 소수성 지질 부형제와 상기 티카그렐러 또는 이의 약제학적으로 허용 가능한 염은 1:1 내지 10, 1:1 내지 6, 1:1 내지 4, 1:1.5 내지 4 또는 1:2 내지 3.5의 중량비로 사용될 수 있다. In the present invention, the hydrophobic lipid excipient and the ticagrelor or a pharmaceutically acceptable salt thereof are 1: 1 to 10, 1: 1 to 6, 1: 1 to 4, 1: 1.5 to 4 or 1: 2 to It can be used in a weight ratio of 3.5.
본 발명의 서방성 제제는 일정한 속도로 장시간, 즉 12시간 이상 동안 활성성분인 티카그렐러 또는 이의 약제학적으로 허용 가능한 염을 일정한 속도로 방출할 수 있다. 본 발명에 따른 상기 서방성 제제는 제제에 포함된 티카그렐러 또는 이의 염의 총 중량에 대하여 제제의 투여로부터 2시간에 10~30%, 6시간에 30 ~ 60%, 12 시간에 65% 이상의 일정한 속도로 활성성분인 티카그렐러 또는 이의 염을 방출할 수 있다. 특히, 티카그렐러의 흡수부위가 소장인 점을 고려하였을 때, 인공위액 (pH1.2) 에서부터 인공장액 (pH 6.8) 사이에서 방출패턴이 일정하게 유지되는 것이 중요한데, 본 발명에 따른 서방성 제제는 인공위액 (pH 1.2), 인공장액 (pH 6.8), pH 4.0 및 물을 비롯한 모든 pH에서도 그 방출패턴이 일정하게 유지된다.The sustained release formulations of the present invention can release the active ingredient ticagrelor or a pharmaceutically acceptable salt thereof at a constant rate for a long time, that is, for at least 12 hours. The sustained-release preparation according to the present invention has a constant weight of 10-30% at 2 hours, 30-60% at 6 hours, and 65% at 12 hours from the administration of the formulation with respect to the total weight of the ticagrelor or salt thereof contained in the formulation. It is possible to release the active ingredient ticagrelor or a salt thereof at a rate. In particular, considering that the absorption site of the ticagrelor is the small intestine, it is important to maintain a constant release pattern between the gastric juice (pH1.2) and the artificial intestinal fluid (pH 6.8), the sustained-release preparation according to the present invention The emission pattern remains constant at all pHs, including gastric juice (pH 1.2), artificial intestinal fluid (pH 6.8), pH 4.0 and water.
본 발명에 있어 상기 티카그렐러의 약제학적으로 허용 가능한 염은 약제학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염일 수 있다. 상기 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탄설폰산, 아세트산, 글리콘산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파르트산 등을 사용할 수 있으나 이에 제한되지 않는다. 바람직하게는 무기산으로는 염산, 유기산으로는 메탄설폰산을 사용할 수 있다.In the present invention, the pharmaceutically acceptable salt of ticagrelor may be an acid addition salt formed by a pharmaceutically acceptable free acid. The free acid may be an inorganic acid and an organic acid, and the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, and the like, and the organic acid may be citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, and methanesulfur. Phonic acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, and the like may be used, but is not limited thereto. Preferably, hydrochloric acid may be used as the inorganic acid, and methanesulfonic acid may be used as the organic acid.
본 발명에 있어서, 상기 티카그렐러 또는 이의 약제학적으로 허용되는 염은, 티카그렐러 또는 이의 약제학적으로 허용가능한 염의 라세미체, 광학이성질체, 동질이상체(다형체, Polymorph), 수화물 또는 용매화물 등을 모두 포함하여 지칭하는 것이다. In the present invention, the ticagrelor or a pharmaceutically acceptable salt thereof is a racemate, an optical isomer, an isomer (polymorph, Polymorph), a hydrate or a solvent of the ticagrelor or a pharmaceutically acceptable salt thereof. It includes all the cargo.
본 발명에 있어 상기 티카그렐러 또는 이의 약제학적으로 허용 가능한 염의 동질이상체(다형체, Polymorph)는 동일한 분자식을 가지나 고체 상태에서의 결정 구조가 상이한 화합물로, 티카그렐러 또는 이의 약제학적으로 허용 가능한 염의 다양한 결정형 및 이들의 무정형의 화합물을 포함한다. 상기 티카그렐러 또는 이의 약제학적으로 허용 가능한 염의 동질이상체(다형체, Polymorph)는 등록 특허 10-0781864호에 기재된 바와 같다. 예를 들면, 상기 제제에 포함되는 활성성분은 티카그렐러의 II형 다형체, I형 다형체 또는 무정형일 수 있다. In the present invention, the isomorph (polymorph) of the ticagrelor or a pharmaceutically acceptable salt thereof is a compound having the same molecular formula but different crystal structure in the solid state, and the ticagrelor or a pharmaceutically acceptable salt thereof. Various crystalline forms of possible salts and amorphous compounds thereof. Polymorphs of the ticagrelor or pharmaceutically acceptable salts thereof are as described in Patent No. 10-0781864. For example, the active ingredient included in the formulation may be a type II polymorph, a type I polymorph or an amorphous form of ticagrelor.
본 발명에 있어 상기 티카그렐러 또는 이의 약제학적으로 허용 가능한 염의 수화물은 비공유적 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 양의 물을 포함할 수 있다. 상기 수화물은 1당량 이상, 바람직하게는, 1 당량 내지 5당량의 물을 함유할 수 있다. 이러한 수화물은 물 또는 물을 함유하는 용매로부터 본 발명의 상기 티카그렐러 또는 이의 약제학적으로 허용 가능한 염을 결정화시켜 제조될 수 있다.In the present invention, the hydrate of the ticagrelor or a pharmaceutically acceptable salt thereof may comprise a stoichiometric or nonstoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water. Such hydrates may be prepared by crystallizing the ticagrelor of the present invention or a pharmaceutically acceptable salt thereof from water or a solvent containing water.
본 발명에 있어 상기 티카그렐러 또는 이의 약제학적으로 허용 가능한 염의 용매화물은 비공유적 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 양의 용매를 포함할 수 있다. 상기 용매로 바람직한 것은 비휘발성, 비독성 또는 인간에게 투여되기에 적합한 용매들을 들 수 있으며, 예를 들면, 에탄올, 메탄올, 프로판올, 메틸렌클로라이드 등이 있다.In the present invention, the solvate of the ticagrelor or a pharmaceutically acceptable salt thereof may comprise a stoichiometric or nonstoichiometric amount of solvent that is bound by non-covalent intermolecular forces. Preferred solvents include those which are non-volatile, non-toxic or suitable for administration to humans, for example ethanol, methanol, propanol, methylene chloride and the like.
본 발명의 서방성 제제는 티카그렐러 또는 이의 약제학적으로 허용 가능한 염 및 소수성 지질 부형제에 더하여 약제학적으로 허용 가능한 첨가제를 더 포함할 수 있다. 상기 약제학적으로 허용 가능한 첨가제제로는 유당, 옥수수 전분, 미결정셀룰로오스, 폴리에틸렌글리콜 또는 디칼슘포스테이트등의 충전제, 미결정셀룰로오스 고분산성 실리카, 만니톨, 락토스와 같은 당 (sugar), 고분산성실리카, 만니톨, 락토스 또는 폴리에틸렌글리콜등의 결합제, 콜로이드성이산화규소, 탈크, 스테아린산, 스테아린산마그네슘, 소디움스테아릴푸마레이트 윤활제, 에틸셀룰로오스, 히드록시프로필메틸셀룰로오스 및 메타크릴산-알킬아크릴레이트 공중합체 등의 코팅제를 비롯하여, 그 밖에도 용해보조제, 가용화제, 착색제, pH 조절제, 계면활성제, 안정화제 및 유화제 등이 사용 될 수 있으나, 이에 제한되지 않고, 당업계의 공지된 기술에 따라 적절히 선택하여 사용할 수 있다. Sustained release formulations of the present invention may further comprise pharmaceutically acceptable additives in addition to ticagrelor or pharmaceutically acceptable salts and hydrophobic lipid excipients thereof. The pharmaceutically acceptable additives include lactose, corn starch, fillers such as microcrystalline cellulose, polyethylene glycol or dicalcium phosphate, microcrystalline cellulose highly disperse silica, mannitol, sugars such as lactose, highly disperse silica, mannitol, Binders such as lactose or polyethylene glycol, coating agents such as colloidal silicon oxide, talc, stearic acid, magnesium stearate, sodium stearyl fumarate lubricant, ethyl cellulose, hydroxypropyl methyl cellulose and methacrylic acid-alkyl acrylate copolymers; In addition, dissolution aids, solubilizers, colorants, pH regulators, surfactants, stabilizers and emulsifiers may be used, but are not limited thereto, and may be appropriately selected and used in accordance with known techniques in the art.
본 발명의 서방성 제제의 투여량은 투여 대상 및/또는 질환의 치료 또는 예방에 적합한 함량이 될 수 있으며 이는 환자의 연령, 체중, 일반건강상태, 성별 및 식이, 투여시간, 질환의 종류, 질환의 중증도, 제제에 함유된 다른 성분의 종류 및 함량, 제형의 종류, 투여경고, 조성물의 분비율, 치료기간 및 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절 될 수 있다. 예를 들어, 대상체가 성인인 경우 본 발명의 제제는 1일 1회 또는 복용 시 티카그렐러로 환산 시 총 90 내지 270mg 용량으로 투여될 수 있다.The dosage of the sustained-release preparation of the present invention may be a content suitable for the treatment or prevention of the subject and / or disease, which is the age, weight, general health, sex and diet, time of administration, type of disease, and disease of the patient. It can be adjusted according to various factors including the severity of, the type and content of other components contained in the formulation, the type of formulation, the warning of administration, the rate of composition of the composition, the duration of treatment and the drug used concurrently. For example, when the subject is an adult, the agent of the present invention may be administered in a total dose of 90 to 270 mg once a day or when converted to ticagrelor.
본 발명의 서방성 제제는 다양한 제형으로 제조될 수 있다. 예를 들어 본 발명의 제제는 액제, 나정, 코팅정, 다층정 또는 핵정 등의 정제, 산제, 펠렛, 미니정제, 분말제, 과립제 또는 캡슐제 등으로 제형화될 수 있으며, 바람직하게는 정제일 수 있다.Sustained release formulations of the invention can be prepared in a variety of formulations. For example, the preparation of the present invention may be formulated into tablets, powders, pellets, mini-tablets, powders, granules or capsules, etc., preferably tablets, such as liquids, uncoated tablets, coated tablets, multi-layered tablets or core tablets. Can be.
본 발명의 서방성 제제의 투여 경로는 적절하게 조절될 수 있으나 바람직하게는 경구 투여될 수 있다. 본 발명의 서방성 제제가 경구로 투여될 경우, 상기 제제는 경구 투여로부터 2시간에 10~30%, 6시간에 30 ~ 60%, 12 시간에 65% 이상 의 일정한 속도로 활성성분인 티카그렐러 또는 이의 염을 방출할 수 있다.The route of administration of the sustained release preparations of the invention may be suitably controlled but may be administered orally. When the sustained-release preparation of the present invention is administered orally, the preparation is active ingredient tikag at a constant rate of 10-30% in 2 hours, 30-60% in 6 hours, 65% or more in 12 hours. Release the salt or salts thereof.
본 발명의 서방성 제제는 유효성분으로 상기 티카그렐러 또는 이의 약제학적으로 허용 가능한 염에 더하여 동일한 약리학적 활성을 나타내는 다른 추가적인 유효성분을 더 포함할 수 있다. 예를 들면, 본 발명의 서방성 제제는 티카그렐러 또는 이의 약제학적으로 허용 가능함 염에 더하여 아스피린을 유효성분으로 더 포함할 수 있다. 상기 티카그렐러 또는 이의 약제학적으로 허용 가능함 염과 아스피린을 유효성분으로 함께 포함하는 제제는 상기 유효성분 각각을 단독으로 포함하는 경우에 뇌졸중, 급성관상동맥증후군 등의 혈전으로 인한 질환 치료에 현저히 우수한 효과를 나타낼 수 있다. 본 발명이 타카그렐러 또는 이의 약제학적으로 허용 가능한 염과 아스피린을 포함할 경우, 상기 두 물질은 타카그렐러 또는 이의 약제학적으로 허용 가능한 염과 아스피린이 공결정 형태로 존재할 수 있다. The sustained-release preparation of the present invention may further include other additional active ingredients exhibiting the same pharmacological activity in addition to the ticagrelor or a pharmaceutically acceptable salt thereof as an active ingredient. For example, the sustained release formulation of the present invention may further comprise aspirin as an active ingredient in addition to ticagrelor or a pharmaceutically acceptable salt thereof. When the ticagrelor or a pharmaceutically acceptable salt thereof and aspirin are included as an active ingredient, each of the active ingredients alone may be remarkably excellent in treating diseases caused by blood clots such as stroke and acute coronary syndrome. Can be effective. When the present invention includes takagrelor or a pharmaceutically acceptable salt thereof and aspirin, the two substances may be present in co-crystal form of takagrelor or a pharmaceutically acceptable salt thereof and aspirin.
본 발명의 서방성 제제가 추가적인 활성성분을 더 포함하는 경우 상기 추가적인 활성성분을 티카그렐러 또는 이의 약제학적으로 허용 가능한 염과 같이 서방성 형태로 방출되도록 제형화될 수 있다. 또는 상기 추가적인 활성성분은 티카그렐러 또는 이의 약제학적으로 허용 가능한 염과 상이하게 속방출 형태로 제형화될 수 있다. If the sustained release preparation of the present invention further comprises an additional active ingredient, the additional active ingredient may be formulated to be released in a sustained release form such as ticagrelor or a pharmaceutically acceptable salt thereof. Or the additional active ingredient may be formulated in a rapid release form differently from ticagrelor or a pharmaceutically acceptable salt thereof.
본 발명의 서방성 제제는 단위 제제당 활성성분인 티카그렐러 또는 이의 약제학적으로 허용 가능한 염의 함량이 부작용을 초래할 정도로 지나치게 높게 포함하지 않으며, 상기 티카그렐러 또는 이의 약제학적으로 허용 가능한 염을 일정한 속도로 장시간 동안 방출할 수 있어 혈장 내 활성성분의 농도를 일정하게 유지하고 투약횟수 및 투여량을 조절하여 투여 대상이 순응성을 높일 수 있으며, 바람직하게는 1일 1회 투여하기에 적합한 형태인 제제를 제공할 수 있다. The sustained-release preparation of the present invention does not contain too high a content of the active ingredient ticagrelor or a pharmaceutically acceptable salt thereof per unit formulation to cause side effects, and the ticagrelor or a pharmaceutically acceptable salt thereof is uniform. It can be released for a long time at a rate to maintain a constant concentration of the active ingredient in the plasma and to adjust the frequency and dosage of the administration subjects to improve compliance, preferably in a form suitable for once-daily administration Can be provided.
또한 본 발명은 티카그렐러 함유 서방성 제제의 제조방법을 제공한다. The present invention also provides a method for producing a ticagrelor-containing sustained release preparation.
본 발명의 서방성 제제의 제조방법은 티카그렐러 또는 이의 약제학적으로 허용 가능한 염 및 소수성 지질 부형제를 혼합하여 과립을 제조하는 단계; 및 상기 과립에 기타 약제학적으로 허용되는 첨가제를 첨가하여 혼합물을 제조하는 단계를 포함할 수 있다.The method for preparing the sustained-release preparation of the present invention comprises the steps of preparing granules by mixing ticagrelor or a pharmaceutically acceptable salt thereof and a hydrophobic lipid excipient; And adding other pharmaceutically acceptable additives to the granules to prepare a mixture.
본 발명에 있어 상기 과립을 제조하는 단계에 있어서, 상기 방출 제어 물질인 소수성 지질 부형제 외에 추가적인 약제학적인 첨가제를 더 혼합할 수 있다. 상기 약제학적으로 허용 가능한 첨가제는 위 기재된 바와 같다. In the step of preparing the granules in the present invention, additional pharmaceutical additives may be further mixed in addition to the hydrophobic lipid excipient which is the release controlling substance. The pharmaceutically acceptable additives are as described above.
본 발명에 있어 상기 과립물은 습식 과립법 또는 건식 과립법에 의해 제조될 수 있으며, 바람직하게는 습식 과립법에 의해 제조될 수 있다.In the present invention, the granules may be prepared by wet granulation or dry granulation, preferably by wet granulation.
본 발명의 방법은 상기 과립을 정립하여 정립물을 제조하는 단계를 더 포함할 수 있다. 상기 정립물은 과립을 건조한 후 이를 정립하여 제조될 수 있다. 구체적으로 상기 과립을 0.5 내지 1.5mm의 체눈크기를 가지는 체를 통과시키고 이를 약 40 내지 60℃의 온도에서 건조시켜 이를 다시 0.5 내지 1.5mm의 체눈크기를 가지는 체를 사용하여 정립함으로써 정립물을 제조할 수 있다. The method of the present invention may further comprise the step of preparing the granules by sizing the granules. The formulation can be prepared by drying the granules and then sizing them. Specifically, the granules are passed through a sieve having a corn size of 0.5 to 1.5 mm, and dried at a temperature of about 40 to 60 ° C., and the granules are formed by using a sieve having a corn size of 0.5 to 1.5 mm. can do.
본 발명에 있어 소수성 지질 부형제 외에 상기 제제의 서방성을 저해하지 않는 한 약제학적으로 허용 가능한 첨가제를 더 포함할 수 있다. 본 발명에 있어 상기 약제학적으로 허용 가능한 첨가제는 담체, 희석제, 부형제, 윤활제 등일 수 있으며, 이에 한정되지는 않는다. 예를 들면, 상기 약제학적으로 허용 가능한 첨가제는 위 기재된 바와 같으며, 바람직하게는 유당수화물 또는 스테아르산 마그네슘일 수 있다. In the present invention, in addition to the hydrophobic lipid excipient, it may further include a pharmaceutically acceptable additive so long as it does not inhibit the sustained release of the preparation. In the present invention, the pharmaceutically acceptable additive may be a carrier, diluent, excipient, lubricant, and the like, but is not limited thereto. For example, the pharmaceutically acceptable additive is as described above, preferably lactose or magnesium stearate.
본 발명의 서방성 제제는 정제일 수 있으며, 이 경우 상기 제조방법은 상기 혼합물을 타정하는 단계를 더 포함할 수 있으며, 또한, 상기 타정된 나정은 추가로 필름코팅될 수 있다. The sustained release formulation of the present invention may be a tablet, in which case the preparation method may further comprise the step of tableting the mixture, and the tableted uncoated tablet may be further film coated.
본 발명의 서방성 제제의 제조방법은 제조공정이 간단하여 생산성을 향상시킴과 동시에 우수한 품질을 확보할 수 있다.The method for producing a sustained release formulation of the present invention can simplify the manufacturing process, improve productivity, and ensure excellent quality.
본 발명에 따른 서방성 제제는 활성성분인 티카그렐러가 pH에 상관없이 제제로부터 서서히 일정한 속도로 방출되어 티카그렐러가 체내에서 일정한 농도를 유지할 수 있으며, 투약 횟수 감소로 인해 환자들의 복약 순응도를 높일 수 있고 약물의 치료 효과를 최대화할 수 있다.Sustained release formulation according to the present invention is the active ingredient ticagrelor is slowly released from the formulation at a constant rate irrespective of pH so that the ticagrelor can maintain a constant concentration in the body, the patient's medication compliance due to the reduced number of doses It can increase and maximize the therapeutic effect of the drug.
도 1 내지 도 3은 본 발명의 실시예들 및 비교예들에 따른 정제의 용출율을 보여주는 그래프이다.1 to 3 are graphs showing the dissolution rate of tablets according to the Examples and Comparative Examples of the present invention.
도 4는 본 발명의 실시예 2에 따른 정제의 가속조건 보관 후 용출율을 보여주는 그래프이다.Figure 4 is a graph showing the dissolution rate after storage of accelerated conditions of the tablet according to Example 2 of the present invention.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다. 또한 이하에서 언급된 시약 및 물질들은 특별한 언급이 없는 한 Sigma-Aldrich Korea에서 구입한 것이다. Hereinafter, examples will be described in detail to help understand the present invention. However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. In addition, the reagents and materials mentioned below were purchased from Sigma-Aldrich Korea, unless otherwise specified.
<< 실시예Example 1>  1>
티카그렐러, 유당수화물과 글리세릴 팔미토스테아레이트를 High speed mixer에서 5분간 혼합한 후, 1정당 발효주정 18.5㎕에 해당하는 발효주정을 넣고 5분간 연합하여 과립을 형성시켰다. 만들어진 과립을 1mm 체눈 크기를 가지는 체를 통과시킨 후 60℃ 에서 1시간 동안 건조시킨 후 다시 1mm 체눈 크기를 가지는 체를 사용하는 정립기로 정립하여 정립물을 제조하였다. Ticagrelor, lactose monohydrate and glyceryl palmitostearate were mixed for 5 minutes in a high speed mixer, and then fermented liquor corresponding to 18.5 μl fermented liquor was added per tablet and combined for 5 minutes to form granules. The granules thus prepared were passed through a sieve having a 1 mm grid size, dried at 60 ° C. for 1 hour, and struck again using a sieve having a 1 mm grid size.
스테아르산마그네슘을 40호체 (0.4mm 체눈 크기)를 사용하여 사과하고 이를 앞서 만든 정립물과 함께 비닐백에 넣고 100회 잘 흔들어 만들어진 혼합물을 타정기에서 압축하여 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 서방성 정제를 제조하였다. 이러한 각 성분의 배합 비율 (중량)을 표 1에 나타내었다. Apple sterilize magnesium stearate using No. 40 sieve (0.4mm eye size), put it in a plastic bag with the previous formulation, and shake well 100 times, compressing the mixture in a tableting machine, 600mg containing 180mg of ticagrelor per tablet. A sustained-release tablet was prepared. The compounding ratio (weight) of each of these components is shown in Table 1.
<< 실시예Example 2> 2>
표 1의 실시예 2에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 서방성 정제를 제조하였다.A 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 2 of Table 1 were used.
<< 실시예Example 3> 3>
표 1의 실시예 3에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 서방성 정제를 제조하였다. A 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 3 of Table 1 were used.
<< 실시예Example 4>  4>
표 1의 실시예 4에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 서방성 정제를 제조하였다. A 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 4 of Table 1 were used.
<< 실시예Example 5>  5>
표 1의 실시예 5에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 서방성 정제를 제조하였다. A 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 5 of Table 1 were used.
<< 실시예Example 6>  6>
표 1의 실시예 6에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 400mg 짜리 서방성 정제를 제조하였다. A 400 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 6 of Table 1 were used.
<< 실시예Example 7>  7>
표 1의 실시예 7에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 서방성 정제를 제조하였다. A 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 7 of Table 1 were used.
<< 실시예Example 8>  8>
표 2의 실시예 8에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 서방성 정제를 제조하였다. A 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 8 of Table 2 were used.
<< 실시예Example 9>  9>
표 2의 실시예 9에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 서방성 정제를 제조하였다. A 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 9 of Table 2 were used.
<< 실시예Example 10>  10>
표 2의 실시예 10에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 서방성 정제를 제조하였다. A 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 10 of Table 2 were used.
<< 실시예Example 11>  11>
표 2의 실시예 11에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 400mg 짜리 서방성 정제를 제조하였다. A 400 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 11 of Table 2 were used.
<< 실시예Example 12>  12>
표 2의 실시예 12에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 90mg 이 함유된 300mg 짜리 서방성 정제를 제조하였다. A 300 mg sustained-release tablet containing 90 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 12 of Table 2 were used.
<< 실시예Example 13>  13>
표 2의 실시예 13에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 270mg 이 함유된 900mg 짜리 서방성 정제를 제조하였다. A 900 mg sustained-release tablet containing 270 mg of ticagrelor per tablet was prepared in the same manner as in Example 1, except that the ingredients and contents described in Example 13 of Table 2 were used.
<< 실시예Example 14>  14>
표 2의 실시예 14에 기재된 성분 및 함량을 사용한 점을 제외하고 상기 실시예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 서방성 정제를 제조하였다. A 600 mg sustained-release tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Example 1 except that the ingredients and contents described in Example 14 of Table 2 were used.
<< 비교예Comparative example 1>  1>
티카그렐러, 유당수화물, 2 w/w% 수용액에서 78 내지 117 mPa·의 점도를 보이는 히프로멜로오스를 혼합한 후, 1정당 발효주정 18.5㎕에 해당하는 발효주정을 첨가하여 과립을 형성시켰다. 만들어진 과립을 1mm 체를 통과시킨 후 60℃ 에서 1시간 동안 건조시킨 후 다시 1mm 체를 사용하는 정립기로 정립하여 정립물을 제조하였다. Ticagrelor, lactose hydrate, and hypromellose having a viscosity of 78 to 117 mPa in a 2 w / w% aqueous solution were mixed, and then fermentation alcohol corresponding to 18.5 µl of fermentation alcohol per tablet was added to form granules. . The granules thus prepared were passed through a 1 mm sieve and then dried at 60 ° C. for 1 hour, and then sieved again using a 1 mm sieve.
스테아르산마그네슘을 40호체를 사용하여 사과하고 이를 앞서 만든 정립물과 함께 비닐백에 넣고 100회 잘 흔들어 만들어진 혼합물을 타정기에서 압축하여 1정당 티카그렐러가 180mg이 함유된 600mg 짜리 정제를 제조하였다. 이러한 각 성분의 배합 비율 (중량)을 표 3에 나타내었다.Magnesium stearate was apologized using No. 40 sieve, and it was put in a plastic bag together with the previously prepared formulation and shaken well 100 times to prepare a 600 mg tablet containing 180 mg of ticagrelor per tablet. The compounding ratio (weight) of each of these components is shown in Table 3.
<< 비교예Comparative example 2>  2>
표 3의 비교예 2의 성분 및 함량을 사용한 점을 제외하고 상기 비교예 1과 동일한 방법으로 1정당 티카그렐러가 180mg 이 함유된 600mg 짜리 정제를 제조하였다. A 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1, except that the components and contents of Comparative Example 2 of Table 3 were used.
<< 비교예Comparative example 3>  3>
표 3의 비교예 3의 성분 및 함량을 사용한 점을 제외하고 상기 비교예 1과 동일한 방법으로 1정당 티카그렐러가 180mg이 함유된 600mg 짜리 정제를 제조하였다. A 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 3 of Table 3 were used.
<< 비교예Comparative example 4>  4>
표 3의 비교예 4의 성분 및 함량을 사용한 점을 제외하고 상기 비교예 1과 동일한 방법으로 1정당 티카그렐러가 180mg이 함유된 600mg 짜리 정제를 제조하였다. A 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 4 of Table 3 were used.
<< 비교예Comparative example 5>  5>
표 3의 비교예 5의 성분 및 함량을 사용한 점을 제외하고 상기 비교예 1과 동일한 방법으로 1정당 티카그렐러가 180mg이 함유된 600mg 짜리 정제를 제조하였다. A 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 5 of Table 3 were used.
<< 비교예Comparative example 6>  6>
표 3의 비교예 6의 성분 및 함량을 사용한 점을 제외하고 상기 비교예 1과 동일한 방법으로 1정당 티카그렐러가 180mg이 함유된 600mg 짜리 정제를 제조하였다. A 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 6 of Table 3 were used.
<< 비교예Comparative example 7>  7>
표 3의 비교예 7의 성분 및 함량을 사용한 점을 제외하고 상기 비교예 1과 동일한 방법으로 1정당 티카그렐러가 180mg이 함유된 600mg 짜리 정제를 제조하였다. A 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 7 of Table 3 were used.
<< 비교예Comparative example 8>  8>
표 3의 비교예 8의 성분 및 함량을 사용한 점을 제외하고 상기 비교예 1과 동일한 방법으로 1정당 티카그렐러가 180mg이 함유된 600mg 짜리 정제를 제조하였다. A 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 8 of Table 3 were used.
<< 비교예Comparative example 9>  9>
표 3의 비교예 9의 성분 및 함량을 사용한 점을 제외하고 상기 비교예 1과 동일한 방법으로 1정당 티카그렐러가 180mg이 함유된 600mg 짜리 정제를 제조하였다. A 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 9 of Table 3 were used.
<< 비교예Comparative example 10>  10>
표 3의 비교예 10의 성분 및 함량을 사용한 점을 제외하고 상기 비교예 1과 동일한 방법으로 1정당 티카그렐러가 180mg이 함유된 600mg 짜리 정제를 제조하였다. A 600 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 10 of Table 3 were used.
<< 비교예Comparative example 11>  11>
표 3의 비교예 11의 성분 및 함량을 사용한 점을 제외하고 상기 비교예 1과 동일한 방법으로 1정당 티카그렐러가 180mg이 함유된 500mg 짜리 정제를 제조하였다. A 500 mg tablet containing 180 mg of ticagrelor per tablet was prepared in the same manner as in Comparative Example 1 except that the components and contents of Comparative Example 11 of Table 3 were used.
[표 1] (단위: mg)TABLE 1 (unit: mg)
Figure PCTKR2015007319-appb-I000002
Figure PCTKR2015007319-appb-I000002
[표 2] (단위: mg)TABLE 2 (unit: mg)
Figure PCTKR2015007319-appb-I000003
Figure PCTKR2015007319-appb-I000003
[표 3] (단위: mg)TABLE 3 (unit: mg)
Figure PCTKR2015007319-appb-I000004
Figure PCTKR2015007319-appb-I000004
<< 시험예Test Example 1> pH 조건별  1> pH Condition 용충률Melt Rate 평가  evaluation
실시예 2와 속방정으로 결합제만 포함하여 제조된 비교예 9 정제에 대해 용출률을 평가하였다. 시험액으로는 1 w/v% SLS(sodium lauryl sulphate) 를 포함하는 pH 1.2액, pH 4.0액, 물 그리고 pH 6.8액 900mL 를 사용하였다. The dissolution rate was evaluated for Example 2 and Comparative Example 9 tablets prepared with only binders in rapid release. As a test solution, 900 mL of pH 1.2 solution, pH 4.0 solution, water and pH 6.8 solution containing 1 w / v% sodium lauryl sulphate (SLS) were used.
pH1.2액 (대한약전 붕해시험법의 제1액)은 염화나트륨 2.0g에 염산 7.0mL 및 물을 넣어 녹여 제조된 1000mL의 액으로 이 액은 무색 투명하고 그 pH 는 약 1.2이다.A pH 1.2 solution (1st solution of the KPSI) is a 1000 mL solution prepared by dissolving 7.0 mL of hydrochloric acid and water in 2.0 g of sodium chloride. The solution is colorless and transparent, and its pH is about 1.2.
pH4.0액 (초산염완충액)은 0.05mol/L 초산액과 0.05mol/L 초산나트륨혼합액을 41 : 9 (부피비)를 만들어 pH 4.0 으로 조절한다.pH 4.0 solution (acetate buffer solution) is adjusted to pH 4.0 by making a mixture of 0.05 mol / L acetate and 0.05 mol / L sodium acetate 41: 9 (volume ratio).
pH6.8 (대한약전 붕해시험법 제2액)은 0.2mol/L 이산이수소칼륨시액 250mL에 0.2mol/L 수산화나트륨시액 118mL 및 물을 넣어 제조된 1000mL의 액으로 이 액은 무색투명하고 그 pH 는 약 6.8 이다.pH6.8 (2nd solution of KEPCO disintegration test) is a 1000 mL solution prepared by adding 118 mL of 0.2 mol / L sodium hydroxide solution and water to 250 mL of 0.2 mol / L potassium dihydrogen dioxide solution. The solution is colorless and transparent. The pH is about 6.8.
구체적으로 실시예 2의 정제에 대해서는 상기 pH 1.2액, pH 4.2액, pH 6.8 액 및 물에 대해서 용출율을 측정하였으며, 비교예 9에 대해서는 pH 1.2액, 및 pH 6.8 액에 대해서 용출율을 측정하였으며, 37℃ ±0.5℃ 및 50rpm 의 패들법 (USP Apparatus 2)에서 티카그렐러의 용출 정도를 시험하고 그 결과를 도 1에 나타내었다.Specifically, the dissolution rate of the pH 1.2 liquid, the pH 4.2 liquid, the pH 6.8 liquid, and the water was measured for the tablet of Example 2, and the dissolution rate was measured for the pH 1.2 liquid, and the pH 6.8 liquid for Comparative Example 9. The degree of dissolution of ticagrelor in the paddle method (USP Apparatus 2) at 37 ° C. ± 0.5 ° C. and 50 rpm was tested and the results are shown in FIG. 1.
본 발명의 실시예 2에 의해 제조된 정제의 경우, 비교예 9 정제와는 매우 다르게 티카그렐러를 방출하는 속도를 효과적으로 제어할 수 있음을 확인 할 수 있었다. 즉, 실시예 2의 정제의 경우 시간에 따른 용출속도가 거의 일정하게 유지되고 있음을 알 수 있었으며, 특히 모든 pH 조건에서 동일하게 방출패턴이 효과적으로 제어되었다. 따라서 본 발명에 따른 제제는 이와 같은 안정된 용출률을 통해 투여 대상의 위장관내 pH 환경에 영향을 받지 않고 일정하게 약효를 기대할 수 있으며 급격한 용출에 따른 부작용의 위험도 줄일 수 있다. In the case of the tablets prepared by Example 2 of the present invention, it was confirmed that the rate of releasing ticagrelor can be effectively controlled differently from the tablets of Comparative Example 9. That is, in the case of the tablet of Example 2, it was found that the dissolution rate was maintained almost constant over time, and in particular, the release pattern was effectively controlled in all pH conditions. Therefore, the preparation according to the present invention can be expected to be constant without affecting the gastrointestinal pH environment of the subject to be administered through such a stable dissolution rate, it can also reduce the risk of side effects due to rapid dissolution.
<< 시험예Test Example 2>  2> 비교예Comparative example 6 및 9 정제에 대한 용출률 평가  Dissolution Rate Assessment for 6 and 9 Tablets
부형제로 수용성 고분자를 사용한 비교예 6과 속방정으로 결합제만 포함하여 제조된 비교예 9 정제에 대해 용출률을 평가하였다. 시험액으로는 1 중량% SLS 를 포함하는 pH 1.2액, pH 4.0액, 물 그리고 pH 6.8액 900mL 를 사용하였으며 37℃ ±0.5℃ 및 50rpm 의 패들법 (USP Apparatus 2) 에서 티카그렐러의 용출 정도를 시험하고 pH 1.2액 및 pH 6.8액에서의 용출율을 도 2에 나타내었다.The dissolution rate was evaluated for the Comparative Example 6 using the water-soluble polymer as an excipient and the Comparative Example 9 tablet prepared by containing only the binder in the immediate release. As a test solution, 900 mL of pH 1.2 solution containing 1 wt% SLS, pH 4.0 solution, water and pH 6.8 solution were used. The elution degree of ticagrelor in 37 ° C ± 0.5 ° C and 50rpm paddle method (USP Apparatus 2) was measured. It was tested and the dissolution rate in pH 1.2 liquid and pH 6.8 liquid is shown in FIG.
본 발명의 비교예 6에 의해 제조된 정제의 경우, 비교예 9의 정제와 비교시 pH 1.2, pH4.0 및 물 조건에서는 티카그렐러의 방출속도가 조절되었다. 하지만, 인공장액 (pH 6.8) 에서는 그 방출패턴이 심각하게 변화하였다. 이는 시험예 1의 실시예 2와 비교 시에 더욱 뚜렷해진다.In the case of the tablet prepared by Comparative Example 6 of the present invention, the release rate of ticagrelor was controlled at pH 1.2, pH 4.0 and water conditions when compared to the tablet of Comparative Example 9. However, in the intestinal fluid (pH 6.8), the emission pattern changed significantly. This is more pronounced in comparison with Example 2 of Test Example 1.
티카그렐러는 주로 소장에 흡수창이 있기 때문에 인공장액에서의 용출률이 중요하다. 그리고 인체 내에서 인공장액 (pH 6.8)조건인 소장에 도달하는 시간을 고려하였을 때, 적어도 12시간 동안 약물이 방출될 수 있어야 하며 적어도 65% 이상 방출될 필요가 있다. 인공장액 (pH 6.8) 조건에서 기대했던 방출패턴과 다르게 6시간 만에 약 100%에 도달하는 것은 제제의 효과가 충분히 유지될 것이라고 기대할 수 없다. 약물이 6시간 만에 100% 방출되는 경우 약효가 24시간 동안 유지될 수 없어 1일 1회 이상의 복용이 필요하여 환자의 복약 편의성을 현저히 저하시키며 약물의 흡수가 저하되어 동일 투여량 복용 시 약효가 저하될 수 있다. Since ticagrelor mainly has an absorption window in the small intestine, the dissolution rate in artificial intestinal fluid is important. Considering the time to reach the small intestine, which is a condition of artificial intestinal fluid (pH 6.8) in the human body, the drug must be able to be released for at least 12 hours and at least 65% or more. Contrary to the release pattern expected under conditions of artificial intestinal fluid (pH 6.8), reaching about 100% in 6 hours cannot be expected to maintain the effectiveness of the formulation. If the drug is released 100% in 6 hours, the drug's efficacy cannot be maintained for 24 hours, which requires one or more doses per day, which significantly lowers the convenience of the patient's medication and decreases the absorption of the drug. Can be degraded.
<< 시험예Test Example 3> 인공 장액에서의 용출률 평가  3> Evaluation of Dissolution Rate in Artificial Serous
실시예 1 내지 실시예 5의 정제에 대해 용출률을 평가하였다. 시험액으로는 1 중량% SLS를 포함하는 pH 6.8액 900mL를 사용하였으며 37℃ ±0.5℃ 및 50rpm의 패들법 (USP Apparatus 2)에서 티카그렐러의 용출 정도를 시험하고 그 결과를 도 3에 나타내었다.The dissolution rate was evaluated for the tablets of Examples 1-5. 900 mL of pH 6.8 solution containing 1 wt% SLS was used as a test solution, and the elution degree of ticagrelor in the paddle method (USP Apparatus 2) at 37 ° C. ± 0.5 ° C. and 50 rpm was tested and the results are shown in FIG. 3. .
실시예 1 내지 5의 방출패턴은 직선적으로 관찰되며, 약물이 시간에 따라 일정하게 방출되는 0차 방출임을 알 수 있다. 특히 실시예 2의 경우 용출률의 회귀직선의 R2 값은 0.9975로 0차 방출패턴, 즉, 시간에 따른 용출이 거의 일정함을 확인할 수 있었다.The release pattern of Examples 1 to 5 is observed in a straight line, it can be seen that the drug is a zero-order release that 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, dissolution over time was almost constant.
본 발명의 실시예의 부형제를 특정한 비율로 사용하였을 때, 그 조성 및 비율에 따라 티카그렐러의 방출패턴이 일정하게 조절됨을 확인할 수 있었다. When the excipient of the embodiment of the present invention was used at a specific ratio, it was confirmed that the release pattern of ticagrelor was constantly adjusted according to its composition and ratio.
<< 시험예Test Example 4>  4> 글리세릴베헤네이트Glyceryl Behenate 함량 변화에 따른 용출률 평가  Dissolution Rate Evaluation According to Content Change
실시예 2, 6, 7, 11 및 비교예 10, 11 정제에 대해 용출률을 평가하였다. 시험액으로는 1 중량% SLS 를 포함하는 pH 6.8액 900mL 를 사용하였으며 37℃ ±0.5℃ 및 50rpm 의 패들법 (USP Apparatus 2)에서 티카그렐러의 용출 정도를 시험하고 그 결과를 표 4 에 나타내었다.Dissolution rates were evaluated for Examples 2, 6, 7, 11 and Comparative Examples 10, 11 tablets. 900 mL of pH 6.8 solution containing 1 wt% SLS was used as a test solution. The elution degree of ticagrelor in 37 ° C ± 0.5 ° C and 50rpm paddle method (USP Apparatus 2) was tested and the results are shown in Table 4. .
본 발명의 실시예 2, 6, 7 그리고 11의 정제는 1% SLS를 포함하는 pH 6.8액 900mL 시험액에서 2시간에 약 10 내지 30%, 6시간에 약 30 내지 60%, 그리고 12시간에 70% 이상의 용출패턴을 보였다. Tablets of Examples 2, 6, 7 and 11 of the present invention are about 10 to 30% at 2 hours, about 30 to 60% at 6 hours, and 70 at 12 hours in a 900 mL test solution of pH 6.8 solution containing 1% SLS. The dissolution pattern was more than%.
반면, 비교예 10 내지 11은 방출이 매우 서서히 진행되어 최종시점에서도 낮은 용출률을 보였다. On the other hand, in Comparative Examples 10 to 11, the release proceeded very slowly, showing a low dissolution rate even at the final point.
또한, 비교예 10의 경우 12시간 용출률의 CV(편차)값은 27%, 비교예 11의 경우 12시간 용출률의 CV값은 39.4% 로 그 편차가 매우 크게 나타났다. In Comparative Example 10, the CV (deviation) value of the 12-hour dissolution rate was 27%, and in Comparative Example 11, the CV value of the 12-hour dissolution rate was 39.4%, and the variation was very large.
CV(%) = (용출율의 표준편차/용출율의 평균) X 100CV (%) = (standard deviation of dissolution rate / average of dissolution rate) X 100
(총 6개의 정제에 대해 측정)(Measured for a total of six tablets)
즉, 제조된 정제 각각이 일정한 용출율을 나타내지 못하고 각 정제마다 상이한 용출율을 나타내었다. 서방성 제제에서 약물의 방출패턴 편차가 클수록 그 약물의 효과가 일정할 것이라고 기대하기는 힘들다. 따라서 비교예 10과 11의 정제는 서방성으로 활성성분의 용출이 지연되기는 하지만 각 정제마다 용출율의 차이가 크고 12시간 안에 충분한 양의 활성성분이 방출되지 않았다. 따라서 상기 비교예 10 및 11은 효과적으로 약물을 전달하기에 적합하지 않은 함량의 글리세릴베헤네이트가 포함된 것으로 판단되었다. That is, each of the tablets produced did not exhibit a constant dissolution rate but a different dissolution rate for each tablet. It is hard to expect that the larger the deviation of the drug's release pattern in the sustained release formulation, the more consistent the drug's effect will be. Therefore, the tablets of Comparative Examples 10 and 11 are sustained release, but the dissolution of the active ingredient is delayed, but the dissolution rate is large for each tablet and a sufficient amount of the active ingredient is not released within 12 hours. Thus, Comparative Examples 10 and 11 were determined to contain glyceryl behenate in an amount that is not suitable for effective drug delivery.
그에 반해 본 발명의 실시예들에 따른 정제들은 모두 CV 값이 대부분 10% 이하로 나타났다. 따라서 본 발명의 정제들은 12시간 동안 약물이 충분히 방출될 뿐만 아니라 각 정제의 용출율이 거의 일정하게 유지됨을 알 수 있었다. In contrast, all of the tablets according to the embodiments of the present invention showed a CV value of mostly 10% or less. Therefore, the tablets of the present invention was found to not only release the drug sufficiently for 12 hours, but also maintain the constant dissolution rate of each tablet.
[표 4]TABLE 4
Figure PCTKR2015007319-appb-I000005
Figure PCTKR2015007319-appb-I000005
<< 시험예Test Example 5> 안정성 평가  5> Stability Evaluation
가속조건 (40℃ 및 75%의 상대습도)에서 2주와 1개월간 보관 한 실시예 2 정제에 대해 용출률을 평가하였다. 시험액으로는 1% SLS 를 포함하는 pH 6.8액 900mL 를 사용하였으며 37℃ ±0.5℃ 및 50rpm 의 패들법 (USP Apparatus 2) 에서 티카그렐러의 용출 정도를 시험하고 그 결과를 도 4 에 나타내었다.Dissolution rates were evaluated for Example 2 tablets stored at accelerated conditions (40 ° C. and 75% relative humidity) for 2 weeks and 1 month. 900 mL of pH 6.8 solution containing 1% SLS was used as a test solution, and the elution degree of ticagrelor in the paddle method (USP Apparatus 2) at 37 ° C. ± 0.5 ° C. and 50 rpm was tested and the results are shown in FIG. 4.
도 4 에서 알 수 있는 바와 같이 실시예 2의 정제는 가속조건에서 1개월 및 2개월 보관 후에도 처음 제조되었을 때와 마찬가지의 용출패턴을 나타내었다. As can be seen in Figure 4 tablets of Example 2 exhibited the same dissolution pattern as when first prepared even after 1 month and 2 months storage under accelerated conditions.
이로부터 본 발명의 서방성 제제는 보관 중 그 방출패턴이 변화하지 않는 등 보관 안정성이 뛰어나고 제조 직후와 보관 후 제제 사이에 티카그렐러의 용출 속도의 변화는 거의 인지되지 않았기 때문에 서방성 제제로부터 기대되는 약효도 보관 기간 동안 동일하게 유지될 것이라고 생각된다.From this, the sustained-release preparation of the present invention is expected from the sustained-release preparation because the release pattern of the present invention is excellent in storage stability such that the release pattern does not change during storage, and the change in the dissolution rate of the ticagrelor between the preparation immediately after the preparation and the post-storage preparation is hardly recognized. It is believed that the drug efficacy will remain the same for the storage period.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시예일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.Having described the specific parts of the present invention in detail, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. will be. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
본 발명에 따른 서방성 제제는 활성성분인 티카그렐러가 pH에 상관없이 제제로부터 서서히 일정한 속도로 방출되어 티카그렐러가 체내에서 일정한 농도를 유지할 수 있으며, 투약 횟수 감소로 인해 환자들의 복약 순응도를 높일 수 있고 약물의 치료 효과를 최대화할 수 있다.Sustained release formulation according to the present invention is the active ingredient ticagrelor is slowly released from the formulation at a constant rate irrespective of pH so that the ticagrelor can maintain a constant concentration in the body, the patient's medication compliance due to the reduced number of doses It can increase and maximize the therapeutic effect of the drug.

Claims (8)

  1. 제제 100 중량부에 대하여 티카그렐러(Ticagrelor) 또는 이의 약제학적으로 허용가능한 염 3 내지 60 중량부; 및 소수성 지질 부형제 3 내지 30 중량부를 포함하는 서방성 경구 제제.3 to 60 parts by weight of Ticagrelor or a pharmaceutically acceptable salt thereof based on 100 parts by weight of the formulation; And 3 to 30 parts by weight of a hydrophobic lipid excipient.
  2. 제1항에 있어서, 상기 소수성 지질 부형제는 글리세릴 팔미토스테아레이트, 글리세릴 베헤네이트, 글리세릴 스테아레이트, 글리세릴 올레이트, 글리세릴 미리스테이트, 세틸 카프레이트, 세틸팔미테이트, 스테아릴 팔미테이트, 스테아릴 스테아레이트, 카르나우바왁스 및 캐스타 오일로 이루어진 군에서 선택되는 하나 이상인 것인 서방성 제제.The method of claim 1, wherein the hydrophobic lipid excipient is glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, glyceryl oleate, glyceryl myristate, cetyl caprate, cetyl palmitate, stearyl palmitate A sustained release formulation of at least one selected from the group consisting of stearyl stearate, carnauba wax and castor oil.
  3. 제2항에 있어서, 상기 소수성 지질 부형제는 글리세릴 팔미토스테아레이트, 글리세릴 베헤네이트, 또는 이들의 혼합인 것인 서방성 제제.The sustained release formulation of claim 2, wherein the hydrophobic lipid excipient is glyceryl palmitostearate, glyceryl behenate, or a mixture thereof.
  4. 제1항에 있어서, 상기 제제는 제제 100 중량부에 대하여 티카그렐러(Ticagrelor) 또는 이의 약제학적으로 허용가능한 염 25 내지 60 중량부; 및 소수성 지질 부형제 3 내지 25 중량부를 포함하는 서방성 제제.According to claim 1, wherein the formulation is based on 100 parts by weight of Ticagrelor (Ticagrelor) or a pharmaceutically acceptable salt thereof 25 to 60 parts by weight; And 3 to 25 parts by weight of hydrophobic lipid excipient.
  5. 제1항에 있어서, 상기 제제는 경구 복용 시 적어도 12시간 동안 티카그렐러(Ticagrelor) 또는 이의 약제학적으로 허용 가능한 염이 방출되는 것인 서방성 제제. The sustained release formulation of claim 1, wherein the formulation releases Ticagrelor or a pharmaceutically acceptable salt thereof for at least 12 hours when taken orally.
  6. 제1항 내지 제5항 중 어느 한 항에 있어서, 상기 제제는 아스피린을 더 포함하는 것인 서방성 제제.The sustained-release preparation according to any one of claims 1 to 5, wherein the preparation further comprises aspirin.
  7. 제1항 내지 제5항 중 어느 한 항에 있어서, 상기 제제는 경구 제제인 것인 서방성 제제.The sustained release preparation according to any one of claims 1 to 5, wherein the preparation is an oral preparation.
  8. 제7항에 있어서, 상기 제제는 산제, 과립제, 펠렛, 미니정제, 캡슐제 또는 정제인 것인 서방성 제제.8. The sustained release formulation of claim 7, wherein the formulation is a powder, granule, pellet, minitablet, capsule or tablet.
PCT/KR2015/007319 2014-07-25 2015-07-14 Slow release preparation WO2016013795A1 (en)

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