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WO2016013795A1 - Preparation a liberation prolongee - Google Patents

Preparation a liberation prolongee 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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WIPO (PCT)
Prior art keywords
ticagrelor
release
present
pharmaceutically acceptable
formulation
Prior art date
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Ceased
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PCT/KR2015/007319
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English (en)
Korean (ko)
Inventor
김순회
손미원
장선우
원동한
김용민
이윤화
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Dong-A ST Co Ltd
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Dong-A ST Co Ltd
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Publication date
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Publication of WO2016013795A1 publication Critical patent/WO2016013795A1/fr
Anticipated expiration legal-status Critical
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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

La présente invention concerne une préparation à libération prolongée comprenant du ticagrélor ou un sel pharmaceutiquement acceptable de ce composé, conjointement avec un excipient lipidique hydrophobe agissant en tant que substance régulant la libération. La préparation à libération prolongée de la présente invention permet de maintenir le ticagrélor, qui constitue l'ingrédient actif, à une concentration constante à l'intérieur du corps car le ticagrélor est libéré lentement de la préparation à un débit constant, indépendamment du pH, ce qui permet de réduire la fréquence d'administration du médicament, d'accroître ainsi l'observance thérapeutique des patients et de maximiser les effets thérapeutiques du médicament.
PCT/KR2015/007319 2014-07-25 2015-07-14 Preparation a liberation prolongee Ceased WO2016013795A1 (fr)

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KR10-2014-0094692 2014-07-25
KR1020140094692A KR20160012706A (ko) 2014-07-25 2014-07-25 서방성 제제

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109700784A (zh) * 2019-03-11 2019-05-03 梁江丽 替格瑞洛缓释微球及其制备和应用
CN111991399A (zh) * 2020-09-07 2020-11-27 乐普（北京）医疗器械股份有限公司 一种含有替格瑞洛和阿司匹林的复合包装制剂

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CN111991399A (zh) * 2020-09-07 2020-11-27 乐普（北京）医疗器械股份有限公司 一种含有替格瑞洛和阿司匹林的复合包装制剂

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