CN106074357B - Ticagrelor preparation of pharmaceutically acceptable salt thereof - Google Patents

Ticagrelor preparation of pharmaceutically acceptable salt thereof Download PDF

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CN106074357B
CN106074357B CN201610278846.0A CN201610278846A CN106074357B CN 106074357 B CN106074357 B CN 106074357B CN 201610278846 A CN201610278846 A CN 201610278846A CN 106074357 B CN106074357 B CN 106074357B
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ticagrelor
release
release component
delayed
formulation
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CN106074357A (en
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陈昊
潘晓晨
卢韵
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Jiangsu Hengrui Medicine Co Ltd
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    • A61K9/2022—Organic macromolecular compounds
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The invention relates to a preparation of ticagrelor or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to an improved once daily formulation for administration of ticagrelor or a pharmaceutically acceptable salt thereof. The present invention can achieve a plasma concentration of ticagrelor greater than about 0.2 μ g/mL in a subject over a period of 2 hours; and a plasma concentration of ticagrelor greater than about 0.2 μ g/mL can still be achieved after 12 hours of dosing in the subject; and producing a maximum plasma concentration (Cmax) of ticagrelor or a pharmaceutically acceptable salt thereof in the subject of between about 0.2 μ g/mL to about 0.8 μ g/mLmax). The preparation of ticagrelor or pharmaceutically acceptable salts thereof can reduce the taking frequency, thereby improving the medication compliance of patients and reducing the risk of myocardial infarction or stroke caused by acute thrombosis due to missed taking of ticagrelor.

Description

Ticagrelor preparation of pharmaceutically acceptable salt thereof
Technical Field
The present invention relates to a formulation of ticagrelor or a pharmaceutically acceptable salt thereof, suitable for once daily oral administration.
Background
Ticagrelor is a platelet aggregation inhibitor and is a novel oral antiplatelet drug of cyclopentyl triazolopyrimidine (CPTP). The chemical name is as follows: 1S,2S,3R,5S) -3- [7- { [ (1R,2S) -2- (3, 4-difluorobenzene) cyclopropyl]Amino } -5- (propylsulfanyl) -3H- [1,2,3]-triazolo [4,5-d]Pyrimidin-3-yl]-5- (2-hydroxyethoxy) cyclopentane-1, 2-diol having the molecular formula C23H28F2N6O4S, the structural formula is as follows:
Figure BDA0000977628050000011
the product can be used for treating acute coronary syndrome (unstable angina pectoris, non-ST elevation myocardial infarction or ST elevation myocardial infarction), including patients receiving drug therapy and Percutaneous Coronary Intervention (PCI), and reducing incidence of thrombotic cardiovascular events. Compared with clopidogrel, the product can reduce the incidence of cardiovascular death, myocardial infarction or stroke composite endpoint, and the difference between the two treatment groups is derived from cardiovascular death and myocardial infarction, but has no difference in stroke.
Ticagrelor is a member of the chemical classification Cyclopentyltriazolopyrimidine (CPTP), a selective Adenosine Diphosphate (ADP) receptor antagonist that acts on the P2Y12ADP receptor to inhibit ADP-mediated platelet activation and aggregation, similar to the mechanism of action of thienopyridines such as clopidogrel. However, in contrast, the interaction between ticagrelor and the platelet P2Y12ADP receptor is reversible, with no conformational changes and signaling, and platelet function in the blood is rapidly restored following withdrawal.
In stable patients with coronary heart disease receiving aspirin therapy in the ONSET/OFFSET study, ticagrelor exhibited a rapid ONSET of pharmacological action, with a 180mg loading dose of ticagrelor giving an average platelet aggregation Inhibition (IPA) of 41% after 0.5 hour administration and a maximum IPA action of 89% after 2-4 hours administration, which could be maintained for 2-8 hours.
The pharmacokinetics of ticagrelor were linear up to 1260mg, and ticagrelor and active metabolite (AR · C124910XX) exposure was substantially proportional to dose.
The tegaserod can be absorbed quickly after being taken orally, and the median t ismaxAbout 1.5 hours. Since ticagrelor is a non-prodrug and directly acts on P2Y12 receptor, the main circulating metabolite AR-C124910XX can be rapidly generated without being activated by liver metabolism. The medicine and the metabolite thereof have activity, so the platelet aggregation mediated by ADP can be quickly and strongly inhibited, and the effectiveness is not influenced by the polymorphism of the liver CYP 2C19 gene. Ticagrelor is eliminated primarily by hepatic metabolism. By administering radiationThe mean recovery of labelled ticagrelor was determined to be about 84% radioactivity (58% in feces and 26% in urine). Average t of ticagrelor1/2About 7 hours, the active metabolite was 9 hours.
In order to reduce the number of administrations and thus improve the compliance of the patients with medication and to reduce the risk of myocardial infarction or stroke due to acute thrombosis caused by missed administration of ticagrelor, it is necessary to prepare ticagrelor as a suitable sustained-release component, e.g. as a pharmaceutical composition which can be administered only once a day.
Currently, patent CN102657629A relates to a ticagrelor sustained release tablet system and a preparation method thereof, the patent uses hypromellose or hydroxypropyl cellulose as a sustained release material to prepare a ticagrelor sustained release component, the inventor tries to use cellulose polymer hypromellose polymer related in patent CN1102657629A to prepare a sustained release matrix tablet by a conventional tabletting preparation method, and as a result, incomplete release exists in the later period, and ticagrelor is almost insoluble in water, which is supposed to be related to solubility of ticagrelor.
The invention proves that the ticagrelor sustained-release component with good sustained-release effect can not be prepared by using the common sustained-release framework materials, such as ethyl cellulose, polymethacrylate, polyvinyl alcohol and the like by adopting the conventional granulation and tabletting or direct tabletting method through screening and investigation on a large number of sustained-release materials, but the inventor unexpectedly finds that polyoxyethylene and polyvinyl acetate polymers or alginate are suitable for being used as the sustained-release framework materials of ticagrelor and pharmaceutically acceptable salts thereof, can prepare the sustained-release component of ticagrelor or pharmaceutically acceptable salts thereof only by adopting the conventional granulation and tabletting or direct tabletting method, and has better sustained-release effect compared with the cellulose sustained-release materials adopted in the patent CN 1102657629A.
Disclosure of Invention
The invention aims to provide a slow-release component of ticagrelor or a pharmaceutically acceptable salt thereof, so as to reduce the peak-valley phenomenon of blood concentration, improve the curative effect and the medication safety of the medicament, reduce the times of taking the medicament and improve the compliance of patients.
In one aspect of the present invention, there is provided a once daily formulation comprising ticagrelor or a pharmaceutically acceptable salt thereof, wherein the formulation exhibits the following characteristics after administration to a subject in need of treatment thereof:
(a) a plasma concentration of ticagrelor of greater than about 0.2 μ g/mL, preferably greater than about 0.3 μ g/mL, can be achieved in the subject over a 2 hour period; and
(b) plasma concentrations of ticagrelor greater than about 0.2 μ g/mL were still achieved after 12 hours of dosing in the subject; and
(c) producing a maximum plasma concentration (C) of ticagrelor or a pharmaceutically acceptable salt thereof in a subject of between about 0.2 μ g/mL to about 0.8 μ g/mLmax) Preferably from 0.4. mu.g/mL to about 0.6. mu.g/mL.
In a preferred embodiment, the preparation provided by the invention contains a sustained-release component, wherein the sustained-release component contains ticagrelor or pharmaceutically acceptable salt thereof and a sustained-release framework material, and the sustained-release framework material is selected from one or more of polyoxyethylene, a mixture of polyvinyl acetate and polyvinylpyrrolidone and an alginate, wherein the alginate is preferably sodium alginate.
Because ticagrelor is almost insoluble in water, the skeleton type sustained release preparation prepared according to the conventional process cannot achieve the ideal effect, and the medicament is often dissolved too slowly or incompletely. In one embodiment of the invention, the particle size range of ticagrelor in the sustained release component is such that D (90) is less than 30 microns, more preferably D (90) is less than 15 microns.
In another embodiment of the present invention, ticagrelor or a salt thereof in the sustained release component is present in the form of a solid dispersion, wherein the solid dispersion comprises a carrier selected from one or more of povidone, copovidone, polyethylene glycol, poloxamer, and eucalyptus. Wherein the weight ratio of the carrier material to ticagrelor or salt thereof may be 1:0.1 to 1:10, preferably 1: 5 to 5: 1, more preferably 1: 2 to 3: 1, most preferably 1:1 to 2: 1. preferably, the carrier material is selected from povidone, copovidone or a mixture thereof, and when the mixture of the povidone and the copovidone is selected, the weight of the povidone and the copovidone can be arbitrarily selected, and the weight of the copovidone is 1:0.1 to 1:10, preferably 1: 5 to 5: 1, more preferably 1:1 to 1: 3, most preferably 1: 1.
when ticagrelor or salt thereof exists in the sustained-release component in the form of solid dispersion, the sustained-release framework material is selected from one or more of polyoxyethylene, a mixture of polyvinyl acetate and polyvinylpyrrolidone and sodium alginate; preferably, the ratio of polyoxyethylene or a mixture of polyvinyl acetate and polyvinylpyrrolidone (the mixture of polyvinyl acetate and polyvinylpyrrolidone is a commercially available product already mixed, for example under the trade name Kollidon SR), or a mixture of the two materials (i.e. the mixture of polyoxyethylene, polyvinyl acetate and polyvinylpyrrolidone is present at the same time), is not particularly limited, and the weight ratio between the mixture of polyoxyethylene and polyvinyl acetate and polyvinylpyrrolidone is preferably 1:0.1 to 1:10, preferably 1: 5 to 5: 1, more preferably 1: 2 to 3: 1, most preferably 2: 1. in another embodiment, the slow release matrix material is selected from polyoxyethylene, or alginate, or a mixture of the polyoxyethylene and the alginate, and the weight ratio of the polyoxyethylene to the alginate in the mixture is 1:0.1 to 1:10, preferably 1: 5 to 5: 1, more preferably 1: 2 to 2: 1, most preferably 3: 4.
the molecular weight distribution of the polyoxyethylene used in the present invention is relatively broad, from 100,000 daltons to 7,000,000 daltons, preferably 100,000 daltons to 2,000,000 daltons, more preferably 100,000 daltons to 900,000 daltons, most preferably 100,000 daltons to 600,000 daltons. These polyoxyethylenes are directly commercially available, for example PEO N80, PEO N10, PEO 1105, PEO N60K.
In a preferred embodiment, the slow release matrix material of the present invention is polyoxyethylene.
In another preferred embodiment, the sustained release portion of the present invention employs alginate, preferably sodium alginate, as the sustained release matrix material.
In another preferred embodiment, the sustained release component of the present invention employs a mixture of sodium alginate and polyoxyethylene as the sustained release matrix material, i.e., both polyoxyethylene and sodium alginate. The mixing ratio of the two is not particularly limited, and it is preferably 1:0.1 to 1:10, preferably 1: 5 to 5: 1, more preferably 1: 2 to 2: 1, most preferably 1: 1.
the drug content of ticagrelor in each unit in the sustained-release component is 75-250 mg, and the preferred drug content of ticagrelor is 180 mg; the proportion range of the skeleton material in the weight of the slow-release component can be large, and the good slow-release component can be prepared when the dosage of the skeleton material in the composition exceeds 10 percent; theoretically, the higher the proportion of the matrix material, the better the sustained release effect, but other factors in the preparation process are considered, preferably 10% to 95%, more preferably 10% to 85%, most preferably 10% to 50%.
As a preferable sustained-release component, the solid dispersion and the sustained-release material in the sustained-release component have the following components and contents, wherein the carrier in the solid dispersion is selected from one or two of povidone or copovidone
Ticagrelor salt thereof 45-220 mg
22.5-440 mg of carrier
Sustained-release matrix material 30-750 mg
Further preferred is a sustained-release component, wherein the solid dispersion and the sustained-release material in the sustained-release component comprise the following components and contents, wherein the carrier in the solid dispersion is selected from one or two of povidone or copovidone
Ticagrelor salt thereof 120-220 mg
60-440 mg of carrier
75-300 mg of slow-release framework material
As a preferred embodiment of the present invention, the sustained-release component of the present invention may further comprise excipients such as diluents, binders, lubricants and the like. Wherein the diluent can be acceptable adjuvants in lactose, pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, etc.; the adhesive can be acceptable auxiliary materials on preparations such as polyvinylpyrrolidone, starch, methylcellulose and the like; the lubricant can be pharmaceutically acceptable adjuvants such as magnesium stearate, glyceryl behenate, hydrogenated vegetable oil, etc.
In one embodiment, the sustained release component of the present invention consists of ticagrelor or a pharmaceutically acceptable salt thereof, polyoxyethylene, magnesium stearate. In a further preferred embodiment, the molecular weight of the polyoxyethylene employed preferably ranges from 100,000 to 7,000,000 daltons, preferably 100,000 to 2,000,000 daltons, more preferably 100,000 to 900,000 daltons, most preferably 100,000 to 600,000 daltons.
In another embodiment, the sustained release component of the present invention consists of ticagrelor or a pharmaceutically acceptable salt thereof, a mixture of polyvinyl acetate and polyvinylpyrrolidone, magnesium stearate; or microcrystalline cellulose in addition to the above ingredients.
In another embodiment, the sustained release component of the present invention consists of ticagrelor or a pharmaceutically acceptable salt thereof, sodium alginate, magnesium stearate; or microcrystalline cellulose in addition to the above ingredients.
In another embodiment, the sustained release component of the present invention consists of ticagrelor or a pharmaceutically acceptable salt thereof, polyoxyethylene, a mixture of polyvinyl acetate and polyvinylpyrrolidone, magnesium stearate; or further comprises lactose in addition to the above ingredients.
When ticagrelor or a salt thereof according to the invention is present in the form of a solid dispersion, the solid dispersion can be prepared using conventional techniques, such as solvent methods, melt methods, solid phase deposition evaporation methods, ball mill milling, and the like. The invention preferably adopts a solvent method to prepare the solid dispersion, i.e. the drug and the carrier are dissolved in a proper solvent, and then the solid dispersion is prepared after removing the organic solvent. Wherein the solvent is selected from ethanol, acetone, ethyl acetate, dichloromethane and the like, and the solvent is further preferably ethanol; the carrier of the solid dispersion is selected from one or more of povidone, copovidone, polyethylene glycol, poloxamer and eucalyptus, and the carrier is further preferably povidone and copovidone.
The sustained-release components in the preparation can be prepared by adopting the conventional granulation and tabletting and direct tabletting processes, preferably the direct tabletting process. By using some excipients, such as microcrystalline cellulose pregelatinized starch, lactose, mannitol, calcium hydrogen phosphate, glyceryl behenate, magnesium stearate, etc., in combination, a simple direct tabletting process can be used to prepare the sustained-release component with good sustained-release effect.
The preparation method comprises the following steps:
1. pulverizing ticagrelor or a pharmaceutically acceptable salt thereof, and premixing with a sustained-release framework material;
2. mixing the mixture of the ticagrelor or the pharmaceutically acceptable salt thereof and the sustained-release framework material premixed in the step 1 with the rest of the excipients;
3. and (3) tabletting and coating the mixed granules obtained in the step (2).
The product has good stability, simple production process, good reproducibility and high industrialization degree, and can be produced in an enlarged way by using conventional production equipment.
In addition, the result of the comparison of the release rate of ticagrelor prepared by adopting the hypromellose in the conventional CN1102657629A and the release rate of the slow-release component of ticagrelor prepared by the invention proves that the slow-release component of ticagrelor medicinal salt prepared by the invention is released more completely in the later period and the release behavior is more controllable.
In a preferred embodiment of the invention, the formulation comprises any one of the sustained release components described above, as well as an immediate release component comprising ticagrelor.
The immediate release component further comprises a pharmaceutically acceptable excipient, wherein the excipient comprises one or any combination of a diluent, a binder or a lubricant. The diluent can be one or more selected from lactose, microcrystalline cellulose, calcium hydrogen phosphate, and mannitol. The adhesive can be one or more selected from polyvinylpyrrolidone, starch, carboxymethyl cellulose and hydroxypropyl methyl cellulose. The lubricant can be one or more selected from magnesium stearate, glyceryl behenate and hydrogenated vegetable oil, preferably magnesium stearate.
In a preferred embodiment of the present invention, the weight ratio of ticagrelor in the sustained release component and the immediate release component in the formulation is 1:0.1 to 1:10, preferably 1: 6 to 6: 1, more preferably 1: 2 to 6: 1, most preferably 2: 1 to 6: 1.
the preparation containing the slow release component and the quick release component can be prepared into a double-layer tablet form or a plurality of micro-tablet filling capsules.
In yet another preferred embodiment of the invention, the formulation comprises a delayed release component comprising ticagrelor or a salt thereof, wherein the delayed release component is coated with an enteric material to provide a delayed release that dissolves at a pH greater than or equal to 6.0. The enteric material may be selected from acrylic resin, HPMC-AS; preferably one or more of Ewing L100, Ewing S100, Ewing L30D-55.
Preferably, the ticagrelor in the delayed and sustained release component is in the form of a solid dispersion, which contains a carrier material, wherein the carrier is preferably selected from one or more of povidone, copovidone, polyethylene glycol, poloxamer and eucalyptus. The weight ratio of ticagrelor or salt thereof to carrier can be 1: 0.2 to 5, preferably 1: 0.5 to 2, most preferably 1: 1.
due to the poor solubility of ticagrelor itself, when the carrier is used in a relatively low amount after it is prepared as a solid dispersion, for example, the specific gravity of the drug to the carrier does not exceed 1: 5, preferably not more than 1: 2, the medicine is slowly released, the slow release effect can be achieved, and no slow release framework material is added.
In another embodiment, the delayed-release component may further comprise a sustained-release matrix material, preferably a mixture of polyethylene oxide or polyvinyl acetate and polyvinylpyrrolidone, or a mixture of the two materials. Preferably, the weight ratio of the ticagrelor or salt thereof to the sustained-release matrix material is 10: 1 to 1:1, preferably 5: 1 to 2: 1.
the delayed sustained release component may further comprise a pharmaceutically acceptable excipient, wherein the excipient comprises one or any combination of a diluent, a binder or a lubricant; preferably, the diluent of the quick release component is selected from one or more of lactose, microcrystalline cellulose, mannitol and calcium hydrophosphate; preferably, the adhesive of the quick release component is selected from one or more of polyvinylpyrrolidone, starch, carboxymethyl cellulose and hydroxypropyl methyl cellulose; preferably, the lubricant of the quick release component is one or more selected from magnesium stearate, glyceryl behenate and hydrogenated vegetable oil, and more preferably magnesium stearate.
In a more preferred embodiment, the formulation comprises, in addition to a delayed sustained release component, an immediate release component of ticagrelor or a salt thereof, the immediate release component further comprising a pharmaceutically acceptable excipient, wherein the excipient comprises one or any combination of a diluent, a binder, or a lubricant; preferably, the diluent of the quick release component is selected from one or more of lactose, microcrystalline cellulose, mannitol and calcium hydrophosphate; preferably, the adhesive of the quick release component is selected from one or more of polyvinylpyrrolidone, starch, carboxymethyl cellulose and hydroxypropyl methyl cellulose; preferably, the lubricant of the quick release component is one or more selected from magnesium stearate, glyceryl behenate and hydrogenated vegetable oil, and more preferably magnesium stearate.
The weight ratio of ticagrelor or base salt in the delayed sustained release component to the immediate release component can be 1: 0.5 to 1:10, preferably 1:1 to 1: 5, most preferably 1: 2.
in a more preferred embodiment, a delayed immediate release component comprising ticagrelor or a salt thereof in addition to a delayed sustained release component and an immediate release component, in which the immediate release component is coated with an enteric material which begins to release at a pH greater than or equal to 6.0; preferably, the enteric material is selected from acrylic resin, HPMC-AS; one or more of the aforementioned compounds, particularly, yurtzite L100 and yurtzite S100, are preferred.
Wherein the delayed immediate release component further comprises a pharmaceutically acceptable excipient, wherein the excipient comprises one of a diluent, a binder or a lubricant or any combination thereof; preferably, the diluent of the quick release component is selected from one or more of lactose, microcrystalline cellulose, mannitol and calcium hydrophosphate; preferably, the adhesive of the quick release component is selected from one or more of polyvinylpyrrolidone, starch, carboxymethyl cellulose and hydroxypropyl methyl cellulose; preferably, the lubricant of the quick release component is one or more selected from magnesium stearate, glyceryl behenate and hydrogenated vegetable oil, and more preferably magnesium stearate.
When the preparation contains three components, the weight ratio of the ticagrelor or the salt thereof in the delayed sustained-release component, the immediate-release component and the delayed immediate-release component is as follows:
delayed and sustained release components: 1-10 parts;
delayed release component: 1 part;
immediate release component: 0.5-5 parts;
the preferred proportion is as follows:
delayed and sustained release components: 2-5 parts;
delayed release component: 1 part;
immediate release component: 1-3 parts;
the most preferred ratio is as follows:
delayed and sustained release components: 3 parts of a mixture;
delayed release component: 1 part;
immediate release component: 1-3 parts, for example 2 parts.
The delayed release component, the immediate release component and the delayed release component may be prepared together in the form of a multi-layer tablet or a micro-tablet containing a unit dose, and different numbers of tablets may be filled in a capsule according to need.
Drawings
FIG. 1: release profiles for different formulations in example 1;
FIG. 2: release profiles for different formulations in example 2;
FIG. 3: release profiles for different formulations in example 3;
FIG. 4: release profiles for different formulations in example 4;
FIG. 5: release profiles for the different formulations in example 5.
Detailed Description
The present invention is further described by the following specific examples, which are not intended to be limiting.
The chromatographic conditions for the release determination were: octadecylsilane chemically bonded silica is used as a chromatographic column filler, 10ml of phosphate buffer solution (1.0 mol/L sodium dihydrogen phosphate solution (pH value is adjusted to 3.0 by phosphoric acid) is taken, water is added to 480ml, and the mixture is shaken evenly to acetonitrile (48:52) to be used as a mobile phase; the column temperature was 55 ℃; the detection wavelength was 242 nm. The tailing factor of the ticagrelor peak is not more than 1.5, and the number of theoretical plates is not less than 13500 according to the ticagrelor peak.
Example 1
Polyoxyethylene, sodium alginate and Kollidon SR are respectively adopted as framework materials to prepare the sustained release tablets, hydroxypropyl methylcellulose in CN1102657629A is adopted to prepare the ticagrelor sustained release tablets for comparative study, and the release degree is evaluated.
Composition (I) Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7
Ticagrelor 180mg 180mg 180mg 180mg 180mg 180mg 180mg
PEO N80 100mg - - - - - -
PEO N10 - 50mg - - - -
Kollidon SR - - 50mg - - - -
Sodium alginate - - - 50mg - - -
HPMC K4M - - - - 100mg - -
HPMC K100LV - - - - - 100mg 150mg
Lactose 100mg 100mg 100mg 100mg 100mg 100mg 100mg
Microcrystalline cellulose 165mg 165mg 165mg 165mg 165mg 115mg 115mg
Magnesium stearate 5mg 5mg 5mg 5mg 5mg 5mg 5mg
Ticagrelor: the particle size D90 was about 8 microns.
And premixing ticagrelor, the selected sustained-release material, lactose and microcrystalline cellulose, adding magnesium stearate, uniformly mixing, and tabletting to prepare the ticagrelor framework type sustained-release tablet.
The release rate of the prepared sustained release tablet in 900ml of 0.2% Tween 80 at 50rpm was measured by HPLC method, and the results are shown in Table 1. The release profile is shown in figure 1.
Table 1 release results for different formulations in example 1
Figure BDA0000977628050000101
Ticagrelor is almost insoluble in water, and incomplete dissolution of different degrees appears in tabletting after being directly mixed with different sustained-release materials. It can be seen from table 1 that the sample preparation using hypromellose from CN1102657629A, wherein the low viscosity hypromellose (HPMCK100LV) prepared ticagrelor sustained release formulation released only about 70% in 16 hours. The ticagrelor composition prepared from the polyoxyethylene and the sodium alginate with low viscosity can be released by more than 80% within 16 hours, wherein when the sodium alginate is used as a slow release material, the release rate within 16 hours can reach nearly 90%, and the slow release within 14 to 16 hours can be basically realized.
Example 2
Considering that ticagrelor is almost insoluble in water and is directly mixed with a sustained-release material to have the phenomenon of incomplete late dissolution, in order to enable the in vitro release speed to be more controllable and meet the requirement of late release, the invention provides a design idea of' quick release and sustained release firstly, namely, the release speed of the raw material is improved by adopting a solid dispersion technology to enable the raw material to be released quickly; and then mixing the solid dispersion with a sustained-release material, and tabletting to prepare the ticagrelor sustained-release tablet.
Povidone and copovidone are respectively used as carriers, a solvent method is adopted to prepare solid dispersion, the prepared solid dispersion is uniformly mixed with polyoxyethylene, microcrystalline cellulose and magnesium stearate, and tabletting is carried out to prepare the ticagrelor sustained-release tablet.
Prescription:
composition (I) Prescription 8 Prescription 9 Prescription 10 Prescription 11 Prescription 12 Prescription 13
Ticagrelor 180mg 180mg 180mg 180mg 180mg 180mg
Povidone 180mg 180mg 180mg 180mg - -
Co-polyvidone - - - 180mg 180mg
PEO N60K 75mg - - - - -
PEO N80 - 150mg 225mg - 150mg -
PEO N10 - - - 225mg - 225mg
Microcrystalline cellulose 308.5mg 233.5mg 157.5mg 157.5mg 233.5mg 157.5mg
Magnesium stearate 7.5mg 7.5mg 7.5mg 7.5mg 7.5mg 7.5mg
The release rate of the prepared sustained release tablets in 900ml of 0.2% tween 80 at 50rpm was measured by HPLC, and the results are shown in table 2. The release profile is shown in figure 2.
Table 2 release results for different formulations in example 2
Figure BDA0000977628050000111
Figure BDA0000977628050000121
It can be seen from the data of the release degrees of the different formulations in example 2 that the raw materials are solubilized by the solid dispersion technique and then mixed with the excipients, and the release degree of the preparation can be well adjusted by adjusting the viscosity and the dosage of the polyoxyethylene. The preparation can be basically completely released within 16 hours, and the release speed is more controllable.
Example 3
Preparing the ticagrelor solid dispersion into a sustained-release preparation composition by respectively using sodium alginate, KollidonSR and polyoxyethylene as sustained-release framework materials, and observing the release behavior of the preparation.
Composition (I) Prescription 14 Prescription 15 Prescription 16 Prescription 17 Prescription 18 Prescription 19 Prescription 20 Prescription 21
Ticagrelor 180mg 180mg 180mg 180mg 180mg 180mg 180mg 180mg
Co-polyvidone 180mg 180mg 180mg 180mg 180mg 180mg 180mg 180mg
PEO N80 - - 75mg 75mg 150mg 112.5mg -
PEO 205 - - - - - - - 100mg
PEO N60K - - - - - - - 50mg
Kollidon SR 75mg 150mg - 75mg 112.5mg 112.5mg - 112.5mg
Sodium alginate - - 150mg - 150mg -
Lactose 75mg - - - - - - -
Microcrystalline cellulose 233.5mg 233.5mg 233.5mg 233.5mg 196.0mg 121mg 121mg 121mg
Magnesium stearate 7.5mg 7.5mg 7.5mg 7.5mg 7.5mg 7.5mg 7.5mg 7.5mg
The preparation method comprises the following steps:
firstly, preparing a solid dispersion from a carrier material and a raw material medicament, then uniformly mixing the solid dispersion and an auxiliary material, and directly tabletting to prepare the sustained-release tablet.
The release rate of the prepared sustained release tablets in 900ml of 0.2% tween aqueous solution was measured by HPLC method, and the results are shown in table 3. The release profile is shown in figure 3.
Table 3 release results for different formulations in example 3
Figure BDA0000977628050000122
Figure BDA0000977628050000131
It can be seen from table 3 and fig. 3 that sodium alginate and Kollidon SR both have a certain sustained release effect as sustained release matrix materials. Sodium alginate or Kollidon SR can be added to polyoxyethylene to better regulate the release rate. The sustained-release component with good sustained-release effect can be prepared by adopting a direct tabletting process.
Example 4
The preparation of the double-layer tablet adopts the combination of polyoxyethylene, polyvinyl acetate and polyvinylpyrrolidone (PVP) as a framework material to prepare a slow release part, and mixes ticagrelor, crospovidone, lactose, microcrystalline cellulose and magnesium stearate as a quick release part.
Prescription:
Figure BDA0000977628050000132
Figure BDA0000977628050000141
the preparation method comprises the following steps: formulas 22, 23 and 24 respectively and uniformly mixing the quick-release part and the sustained-release part according to the formula proportion, preparing a double-layer tablet by adopting a direct tabletting process, and measuring the release degree of the prepared sustained-release tablet in 900ml of 0.2% Tween aqueous solution by adopting an HPLC method, wherein the results are shown in Table 4. The release profile is shown in figure 4.
Table 4 release results for different formulations in example 4
Figure BDA0000977628050000142
As can be seen from Table 4 and FIG. 4, the rapid-release and sustained-release combination is adopted as the double-layer framework material to achieve the effects of rapid release in the early stage and slow release in the later stage.
Example 5
Preparing a composition with immediate-release ticagrelor micro tablets and delayed-release ticagrelor micro tablets according to formulas 25, 26 and 27, wherein the composition comprises a biphasic pulse consisting of a composition of quick-release micro tablets and enteric-coated slow-release micro tablets; also comprises a triphase pulse consisting of a composition of a quick-release micro-tablet, an enteric-coated quick-release micro-tablet and an enteric-coated slow-release micro-tablet. Wherein, the enteric fast-release micro-tablet is obtained by coating enteric material outside the fast-release micro-tablet. In the enteric sustained-release micro-tablet, ticagrelor is dispersed in copovidone as a carrier material to prepare a solid dispersion, and then the solid dispersion is mixed with other auxiliary materials to coat enteric coating, wherein a sustained-release framework material, such as PEO N10, can be added, but since the solubility of ticagrelor is poor, when the dosage of the carrier material is less, the effect of slow release can be achieved, and therefore, the sustained-release framework material can also not be added.
Prescription:
Figure BDA0000977628050000143
Figure BDA0000977628050000151
the preparation method comprises the following steps: the quick-release and sustained-release mini-tablets were prepared by tabletting process, coated with enteric coating film at the corresponding ratio and filled into capsules, and the release degree of the prepared sustained-release capsules in 900ml of 0.2% tween solution of hydrochloric acid ph1.0 and 0.2% tween solution of phosphate ph6.8 was measured by HPLC method, and the results are shown in table 5.
Table 5 results of the release rates of the capsules in different media in example 5
Figure BDA0000977628050000152
Figure BDA0000977628050000161
Example 6
The formulations in the above examples were selectively subjected to human pharmacokinetic (blood concentration) and pharmacodynamic (platelet inhibition rate) tests, and the in vitro and in vivo correlations of ticagrelor were investigated by comprehensively analyzing the relationship between in vitro release and Pharmacokinetics (PK) and Pharmacodynamics (PD).
According to the invention, different prescriptions are subjected to random, cross, single-center and contrast test studies by adopting healthy volunteer subjects, and the study evaluates the pharmacokinetics and pharmacodynamics of ticagrelor in the healthy subjects. In this study, the formulation of the present invention was administered once a day at a dose of 180mg, and the commercial immediate release formulation was administered twice a day at a dose of 90 mg. Plasma samples were collected for determining plasma levels and platelet inhibition of ticagrelor. Samples were analyzed by HPLC/MS/MS.
Table 6: ticagrelor pharmacokinetic parameters with multiple in vitro release profiles
Figure BDA0000977628050000162
Platelet aggregation inhibition rates of healthy volunteer subjects were measured before and 2, 4, 8, 12 and 24 hours after administration of the platelet aggregation inhibitor, and the ratio of the platelet inhibition rate to the platelet inhibition rate of a commercially available immediate release preparation is shown in the attached table 2.
Table 2: ticagrelor pharmacodynamic parameters with multiple release profiles
Preparation 2h 4h 8h 12h 24h
Prescription 19 0.97 0.95 1.23 1.01 0.97
Prescription 21 0.91 0.89 0.96 1.15 0.74
Prescription 22 1.08 1.08 1.25 1.01 0.94
Prescription 24 1.05 0.99 1.17 1.09 1.04
Prescription 25 1.14 0.99 1.16 1.24 0.66
Prescription 27 1.09 1.04 1.11 1.10 1.06
Commercial formulation 1 _ _ _ _ _
Combining the in vivo pharmacokinetics of the drug and the in vitro release data analysis, the preparation is dissolved out in vitro in a certain period to have certain drug release, which is helpful for having certain blood concentration (C)2h) Further ensuring the drug effect of the drug within 2 and 4 hours, thereby ensuring the rapid effect of the drug; the blood concentration of the drug after 12 hours is ensured to be at a certain level, for example, at least more than 0.2 mu g/mL, and the drug effect can be maintained for 24 hours; maximum blood concentration (C) of the drug of the present inventionmax) Is equivalent to or slightly higher than the commercial quick-release preparation, so as to avoid causing side effects due to overhigh drug effect for 8h and 12 h.
In particular, a plasma concentration of ticagrelor greater than about 0.2 μ g/mL can be achieved in the subject over a 2 hour period; and a plasma concentration of ticagrelor greater than about 0.2 μ g/mL can still be achieved after 12 hours of dosing in the subject; and producing a maximum plasma concentration (Cmax) of ticagrelor or a pharmaceutically acceptable salt thereof in the subject of between about 0.2 μ g/mL to about 0.8 μ g/mLmax)。
Since the invention has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (24)

1. A once daily formulation comprising ticagrelor or a pharmaceutically acceptable salt thereof, wherein the formulation exhibits the following characteristics after administration to a subject in need of treatment thereof:
a) a plasma concentration of ticagrelor greater than 0.2 μ g/mL can be achieved in the subject over a 2 hour period; and
b) plasma concentrations of ticagrelor greater than 0.2 μ g/mL were still achieved after 12 hours of dosing in the subject; and
c) producing a maximum plasma concentration (C) of ticagrelor or a pharmaceutically acceptable salt thereof in a subject of between 0.2 μ g/mL to 0.8 μ g/mLmax)；
The preparation comprises a delayed sustained release component containing ticagrelor or a salt thereof, wherein the delayed release component is coated with an enteric material selected from acrylic resin or HPMC-AS to provide delayed release dissolving at a pH greater than or equal to 6.0;
the ticagrelor in the delayed slow release component is in the form of a solid dispersion, and comprises a carrier material;
the carrier material is selected from povidone, copovidone, polyethylene glycol, poloxamer, eucalyptus, or mixture thereof; the weight ratio of ticagrelor or salt thereof to carrier is 1: 0.2 to 5;
the preparation also contains an immediate-release component of the ticagrelor or the salt thereof, and the immediate-release component also contains a pharmaceutically acceptable excipient, wherein the excipient comprises one or any combination of a diluent, a binder or a lubricant, and the weight ratio of the ticagrelor or the salt thereof in the delayed-release component to the immediate-release component is 1: 0.5 to 1: 10.
2. the formulation of claim 1, which achieves a plasma concentration of ticagrelor greater than 0.3 μ g/mL in a subject over a period of 2 hours, anProducing a maximum plasma concentration (C) of ticagrelor or a pharmaceutically acceptable salt thereof in a subject of between 0.4 μ g/mL to 0.6 μ g/mLmax)。
3. The formulation of claim 2, wherein the enteric material is selected from one or more of Ewing L100, Ewing S100, Ewing L30D-55.
4. The formulation of claim 1, wherein the weight ratio of ticagrelor or salt thereof to carrier material is 1: 1.
5. the formulation of claim 1, wherein the delayed sustained release component further comprises a sustained release matrix material.
6. The preparation of claim 5, wherein the sustained release matrix material is selected from polyoxyethylene or a mixture of polyvinyl acetate and polyvinylpyrrolidone, or a mixture of the foregoing two materials.
7. The formulation of claim 6, wherein the weight ratio of ticagrelor or salt thereof to sustained release matrix material is 10: 1 to 1: 1.
8. the formulation of claim 7, wherein the weight ratio of ticagrelor or salt thereof to sustained release matrix material is 5: 1 to 2: 1.
9. the formulation of claim 1, wherein the delayed release component further comprises a pharmaceutically acceptable excipient, wherein the excipient comprises one or any combination of a diluent, a binder, or a lubricant.
10. The preparation of claim 9, wherein the diluent of the delayed slow release component is selected from one or more of lactose, microcrystalline cellulose, mannitol, and calcium hydrogen phosphate; the adhesive in the delayed slow release component is selected from one or more of polyvinylpyrrolidone, starch, carboxymethyl cellulose and hydroxypropyl methyl cellulose; the lubricant in the delayed slow release component is one or more selected from magnesium stearate, glyceryl behenate and hydrogenated vegetable oil.
11. The formulation of claim 10, wherein the lubricant is magnesium stearate.
12. The formulation of claim 1, wherein the diluent of the immediate release component is selected from one or more of lactose, microcrystalline cellulose, mannitol, calcium hydrogen phosphate; the adhesive of the immediate release component is selected from one or more of polyvinylpyrrolidone, starch, carboxymethyl cellulose and hydroxypropyl methyl cellulose; the lubricant of the immediate release component is one or more selected from magnesium stearate, glyceryl behenate and hydrogenated vegetable oil.
13. The formulation of claim 12, wherein the immediate release component lubricant is magnesium stearate.
14. The formulation according to claim 1, wherein the weight ratio of ticagrelor or salt thereof in the delayed release component to the immediate release component is 1:1 to 1: 5.
15. the formulation according to claim 14, wherein the weight ratio of ticagrelor or salt thereof in the delayed release component to the immediate release component is 1: 2.
16. the formulation of claim 1, further comprising an immediate release delayed component of ticagrelor or a salt thereof, wherein the immediate release component of the immediate release delayed component is coated with an enteric material that begins to release at a pH greater than or equal to 6.0.
17. The formulation according to claim 16, said enteric material being selected from acrylic resins, HPMC-AS.
18. The formulation of claim 17, the enteric material being selected from one or more of ewing L100, ewing S100, ewing L30D-55.
19. The formulation of claim 18, wherein the immediate release delayed component further comprises a pharmaceutically acceptable excipient, wherein the excipient comprises one or any combination of a diluent, a binder, or a lubricant.
20. The formulation of claim 19, wherein the diluent of the immediate release component is selected from one or more of lactose, microcrystalline cellulose, mannitol, calcium hydrogen phosphate; the adhesive of the quick-release component is one or more selected from polyvinylpyrrolidone, starch, carboxymethyl cellulose and hydroxypropyl methyl cellulose; the lubricant of the quick release component is one or more selected from magnesium stearate, glyceryl behenate and hydrogenated vegetable oil.
21. The formulation of claim 20, wherein the lubricant of the immediate release component is magnesium stearate.
22. The formulation according to claim 16, wherein the weight ratios of ticagrelor or salt thereof in the delayed release, immediate release and immediate release components are as follows:
delayed and sustained release components: 1-10 parts;
delayed release component: 1 part;
immediate release component: 0.5-5 parts.
23. The formulation according to claim 22, wherein the weight ratios of ticagrelor or salt thereof in the delayed release, immediate release and immediate release components are as follows:
delayed and sustained release components: 2-5 parts;
delayed release component: 1 part;
immediate release component: 1-3 parts.
24. The formulation according to claim 23, wherein the weight ratios of ticagrelor or salt thereof in the delayed release, immediate release and immediate release components are as follows:
delayed and sustained release components: 3 parts of a mixture;
delayed release component: 1 part;
immediate release component: 1-3 parts.
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CN103690502A (en) * 2013-12-31 2014-04-02 程刚 Ticagrelor sustained release preparation

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