WO2024114797A1 - 一种含氧化氯吡格雷的固体制剂及其制备方法 - Google Patents

一种含氧化氯吡格雷的固体制剂及其制备方法 Download PDF

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WO2024114797A1
WO2024114797A1 PCT/CN2023/135869 CN2023135869W WO2024114797A1 WO 2024114797 A1 WO2024114797 A1 WO 2024114797A1 CN 2023135869 W CN2023135869 W CN 2023135869W WO 2024114797 A1 WO2024114797 A1 WO 2024114797A1
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solid preparation
clopidogrel
oxo
minutes
dissolution
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PCT/CN2023/135869
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English (en)
French (fr)
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聂昱
易泽琴
张海
陆瑶
牟霞
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成都施贝康生物医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a solid preparation containing (7aS, 2'S)-2-oxo-clopidogrel and a preparation method thereof.
  • Clopidogrel is a first-line drug for the prevention and treatment of heart, brain and other arterial circulatory disorders caused by platelet hyperaggregation. Clopidogrel bisulfate tablets are its oral dosage form.
  • (7aS, 2’S)-2-Oxo-clopidogrel is an intermediate metabolite of clopidogrel in the human body. Its structure is shown in Formula I. Its chemical name is: (S)-2-(2-chlorophenyl)-2-((S)-2-oxo-2,6,7,7a-tetrahydrothiophene[3,2-c]pyridin-5(4H)yl)acetate;
  • clopidogrel resistance exists.
  • the cause is due to the difference in CYP enzyme activity in the liver of individuals.
  • clopidogrel cannot be metabolized normally in the liver of some patients, and cannot produce (7aS, 2’S)-2-oxy-clopidogrel metabolites and their optical isomers, thereby blocking the subsequent metabolism of clopidogrel into active ingredients and failing to exert an anticoagulant effect.
  • Direct administration of (7aS, 2’S)-2-oxy-clopidogrel can effectively avoid clopidogrel resistance.
  • (7aS, 2'S)-2-oxy-clopidogrel is a white or off-white crystalline powder, which dissolves in acetonitrile, is slightly soluble in methanol, and is almost insoluble in water. It is a low-solubility and high-permeability drug in the BCS biological drug classification system. It also has high temperature, acid, and alkali instability, so it is difficult to prepare a common tablet with high stability.
  • the present application provides a solid preparation containing (7aS, 2'S)-2-oxo-clopidogrel for treating blood system diseases and a preparation method thereof.
  • the solid preparation of (7aS, 2'S)-2-oxo-clopidogrel can continuously and smoothly release the active ingredient and exert the drug effect, and the solid preparation is stable and has reliable quality and safety.
  • the present invention provides a solid preparation, which comprises (7aS, 2'S)-2-oxo-clopidogrel and pharmaceutically acceptable excipients; the excipients include a filler, a disintegrant, a binder and a lubricant.
  • the mass ratio of the disintegrant to the binder is 1 to 20:1.
  • the mass ratio of disintegrant to binder in any of the above solid preparations is 2.5-15:1.
  • the mass ratio of disintegrant to binder in any of the above solid preparations is 3 to 5:1.
  • any of the above-mentioned solid preparations contains (7aS, 2'S)-2-oxo-clopidogrel in an amount of 2 mg to 9.5 mg per unit dosage form, exemplified but not limited to 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, and 9.5 mg.
  • any of the above solid preparations contains 2 mg to 8 mg of (7aS, 2'S)-2-oxo-clopidogrel per unit dosage form; preferably 4 mg, 4.5 mg, 5 mg, 5.5 mg or 6 mg.
  • any of the above solid preparations contains the following components by weight: 1.0 ⁇ 8.0wt% (7aS, 2'S)-2-oxo-clopidogrel, 65.0 ⁇ 95.0wt% filler, 3.0 ⁇ 20.0wt% disintegrant, 1.0 ⁇ 6.0wt% binder, and 0.5 ⁇ 2.5wt% lubricant.
  • any of the above solid preparations comprises the following components by weight: 1.0 ⁇ 8.0wt% (7aS, 2'S)-2-oxo-clopidogrel, 65.0 ⁇ 92.0wt% filler, 10.0 ⁇ 20.0wt% disintegrant, 1.0 ⁇ 6.0wt% binder, and 0.5 ⁇ 2.5wt% lubricant.
  • any of the above solid preparations comprises the following components by weight: 2.0 ⁇ 6.0wt% (7aS, 2'S)-2-oxo-clopidogrel, 70.0 ⁇ 90.0wt% filler, 10.0 ⁇ 20.0wt% disintegrant, 1.0 ⁇ 6.0wt% binder, and 0.5 ⁇ 2.5wt% lubricant.
  • any of the above-mentioned fillers is selected from any one or more of mannitol, lactose, pregelatinized starch, sorbitol, microcrystalline cellulose, starch, powdered sugar, dextrin, and inorganic salts; preferably, two or more of pregelatinized starch, lactose, mannitol, microcrystalline cellulose, and sorbitol;
  • any of the above disintegrants is selected from any one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, potassium polacrilin, and dry starch; preferably one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and potassium polacrilin;
  • any of the above-mentioned adhesives is selected from any one or more of gum arabic, povidone, hypromellose, hydroxypropyl cellulose, gelatin, sodium carboxymethyl cellulose, methyl cellulose, and copovidone; preferably one or more of povidone, hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and copovidone;
  • Any of the above lubricants is selected from any one or more of magnesium stearate, sodium stearyl fumarate, talcum powder, polyethylene glycol substances, and hydrogenated vegetable oil.
  • any of the above-mentioned lactose used as a filler includes but is not limited to lactose monohydrate or anhydrous lactose;
  • the above-mentioned inorganic salt used as a filler includes but is not limited to calcium sulfate, calcium hydrogen phosphate, calcium carbonate or calcium sulfate dihydrate;
  • the above-mentioned polyethylene glycol substances used as lubricants include but are not limited to PEG2000, PEG4000 or PEG6000;
  • the above-mentioned hydrogenated vegetable oil used as a lubricant includes but is not limited to hydrogenated castor oil.
  • the solid preparation comprises the following components by weight: 1.0 ⁇ 8.0wt% (7aS, 2'S)-2-oxo-clopidogrel, 10.0 ⁇ 35.0wt% pregelatinized starch, 30.0 ⁇ 65.0wt% lactose, 3.0 ⁇ 20.0wt% low-substituted hydroxypropyl cellulose, 1.0 ⁇ 6.0wt% hydroxypropyl cellulose and 0.5 ⁇ 2.5wt% sodium stearyl fumarate.
  • the solid preparation comprises the following components by weight: 3.0-6.0 wt % (7aS, 2'S)-2-oxo-clopidogrel, 10.0-35.0 wt % pregelatinized starch, 30.0-65.0 wt % lactose, 3.0-20.0 wt % low-substituted hydroxypropyl cellulose, 1.0-6.0 wt % hydroxypropyl cellulose and 0.5-2.5 wt % sodium stearyl fumarate.
  • the solid preparation comprises the following components by weight: 1.0-8.0 wt% (7aS, 2'S)-2-oxo-clopidogrel, 20.0-35.0 wt% pregelatinized starch, 40.0-60.0 wt% lactose, 6.0-18.0 wt% low-substituted hydroxypropyl cellulose, 1.0-6.0 wt% hydroxypropyl cellulose and 0.5-2.5 wt% sodium stearyl fumarate.
  • the solid preparation comprises the following components by weight: 3.0-6.0 wt % (7aS, 2'S)-2-oxo-clopidogrel, 20.0-35.0 wt % pregelatinized starch, 40.0-60.0 wt % lactose, 6.0-18.0 wt % low-substituted hydroxypropyl cellulose, 1.0-6.0 wt % hydroxypropyl cellulose and 0.5-2.5 wt % sodium stearyl fumarate.
  • any of the above lactose comprises lactose monohydrate or anhydrous lactose, preferably anhydrous lactose.
  • the particle size distribution range of (7aS, 2'S)-2-oxo-clopidogrel in any of the above-mentioned solid preparations is: 1 ⁇ m ⁇ D90 ⁇ 40 ⁇ m; preferably 1 ⁇ m ⁇ D90 ⁇ 30 ⁇ m; more preferably 1 ⁇ m ⁇ D90 ⁇ 15 ⁇ m.
  • the particle size distribution range of (7aS, 2'S)-2-oxo-clopidogrel in any of the above-mentioned solid preparations is: 1 ⁇ m ⁇ D90 ⁇ 15 ⁇ m; preferably 2 ⁇ m ⁇ D90 ⁇ 8 ⁇ m.
  • the cumulative dissolution amount of any of the above-mentioned solid preparations within 30 minutes is 65% ⁇ 90% in the test of Method 2 of General Chapter 0931 of Part 4 of the 2020 Edition of the Chinese Pharmacopoeia at a rotation speed of 50RPM in a pH 4.5 acetate buffer dissolution medium.
  • any of the above-mentioned solid preparations, in a pH 4.5 acetate buffer dissolution medium, under the test of Method 0931, Part 4, General Chapter 0931, 2020 Edition of the Chinese Pharmacopoeia, at a rotation speed of 50 RPM, has a cumulative dissolution amount of more than 65% within 30 minutes, a cumulative dissolution amount of more than 75% within 45 minutes, and a cumulative dissolution amount of more than 85% within 90 minutes.
  • the cumulative dissolution amount of any of the above-mentioned solid preparations is more than 65% within 30 minutes, more than 80% within 45 minutes, and more than 90% within 90 minutes in the test of Method 2 of General Chapter 0931 of Part 4 of the 2020 edition of the Chinese Pharmacopoeia at a rotation speed of 50 RPM in a pH 4.5 acetate buffer dissolution medium.
  • the cumulative dissolution amount of any of the above-mentioned solid preparations is more than 85% within 15 minutes in the test of Method 0931, General Chapter 4, 2020 Edition of the Chinese Pharmacopoeia at a rotation speed of 50RPM in a pH 1.2 hydrochloric acid solution buffer dissolution medium.
  • any of the above solid preparations can achieve bioequivalence with the active metabolite H4 metabolized from clopidogrel bisulfate tablets (Plavix, 75 mg).
  • any of the above solid preparations can achieve bioequivalence with 2-oxo-clopidogrel metabolized from clopidogrel bisulfate tablets (Plavix, 75 mg).
  • any of the above-mentioned solid preparations is an oral solid preparation; preferably tablets, granules, capsules, soft capsules, pills, powders or micropills.
  • the present invention also provides a method for preparing any of the above solid preparations, comprising the following steps:
  • Step 1 Grind the raw material of (7aS, 2'S)-2-oxo-clopidogrel to obtain drug powder;
  • Step 2 Mix the drug powder with the excipients and press into tablets to obtain a solid preparation.
  • the method for preparing any of the above solid preparations comprises the following steps:
  • Step 1 Weigh (7aS, 2'S)-2-oxo-clopidogrel and grind it to a target particle size to obtain drug powder;
  • Step 2 Weigh the excipients, pre-mix the drug powder with any filler, add the remaining filler, disintegrant and binder mixture that have been mixed evenly beforehand, and mix evenly, and finally add the lubricant and mix evenly;
  • Step 3 The uniformly mixed mixture is directly compressed into tablets using a tablet press with a tablet hardness of 3.00-9.00 kg to obtain tablets of various embodiments.
  • the method of mixing the drug powder and the excipients in the above step 2 includes one-time mixing and batch mixing. It is worth noting that whether the drug powder and the excipients are mixed at one time or mixed with the excipients in batches, as long as the sufficient mixing conditions are achieved. For example, when the batch size is small, one-time mixing is sufficient, while when the batch size is large, mixing in batches is better.
  • the drug pulverization method includes but is not limited to air flow pulverization.
  • the tableting method includes but is not limited to wet granulation tableting, dry granulation tableting and powder direct tableting; preferably powder direct tableting.
  • any of the above-mentioned other dosage forms are prepared by conventional processes in the art, for example, the mixed drug powder of the present invention is directly or prepared into granules or pellets and then put into capsules, soft capsules or bags to form granules, capsules, soft capsules, pills, powders or pellets.
  • the present invention also provides use of any of the above solid preparations for treating blood system diseases.
  • the above-mentioned blood system diseases include blood diseases of the cardiovascular and cerebrovascular systems.
  • the above-mentioned blood system diseases include but are not limited to acute coronary syndrome, atherosclerotic disease, or thrombotic complications.
  • lactose in the present invention includes hydrated lactose and anhydrous lactose, especially lactose monohydrate and anhydrous lactose.
  • lactose monohydrate lactose
  • lactose in the national pharmacopoeia
  • anhydrous lactose is the same as the definition in the national pharmacopoeia
  • this patent uses the special name "lactose” to indicate the general concept.
  • filler of the present invention may also be understood as “diluent” in the art.
  • excipients used in the present invention are conventional excipients, preferably excipients included in the pharmacopoeia, and are not affected by the specific manufacturer, model, molecular weight, degree of polymerization, configuration, etc.
  • mannitol 100SD, mannitol 200SD, mannitol M200, etc. are all included in the above-mentioned "mannitol”.
  • the (7aS, 2'S)-2-oxo-clopidogrel of the present invention is an intermediate metabolite of clopidogrel, it is very difficult to achieve the bioequivalence of (7aS, 2'S)-2-oxo-clopidogrel with the marketed clopidogrel hydrogen sulfate tablets (Plavix, 75 mg), especially to meet the equivalence of the two compounds, that is, the simultaneous equivalence of the intermediate metabolite 2-oxo-clopidogrel and the active metabolite H4, which is extremely difficult. Therefore, the inventors have also conducted a lot of exploratory research, and found that different prescription compositions have a great influence on dissolution.
  • the dissolution rate of (7aS, 2'S)-2-oxy-clopidogrel will decrease slightly after tableting; for another example, adding different amounts of disintegrants has little effect on the dissolution rate of (7aS, 2'S)-2-oxy-clopidogrel; for another example, after the raw material is micronized, the dissolution of (7aS, 2'S)-2-oxy-clopidogrel will be accelerated, but if the particle size is too small, it is easy to cause a burst release problem, which in turn leads to excessive drug absorption and increased bleeding risk, or although C max is improved, AUC (0- ⁇ ) cannot be equivalent; in addition, after the raw material particle size is reduced, the contact area with the excipient is increased, the drug stability is reduced, and the risk of sticking is increased.
  • the stability of solid preparations and the process sticking phenomenon can be significantly improved, especially for prescriptions with smaller particle sizes, the improvement effect is significant;
  • two in vitro dissolution curves that are completely bioequivalent to the marketed clopidogrel hydrogen sulfate tablets (Plavix, 75 mg) are found, providing a scientific evaluation standard for the prescription screening of (7aS, 2'S)-2-oxy-clopidogrel.
  • the present invention has the following beneficial effects:
  • the solid preparation of (7aS, 2'S)-2-oxo-clopidogrel of the present invention has a similar in vitro dissolution curve. Specifically, the cumulative dissolution amount under pH 4.5 conditions is more than 65% within 30 minutes, more than 75-80% within 45 minutes, and more than 85-90% within 90 minutes; the cumulative dissolution amount under pH 1.2 conditions is more than 85% within 15 minutes; the drug is released rapidly, steadily and completely.
  • the solid preparation of the present invention is completely bioequivalent to the marketed clopidogrel bisulfate tablets (Plavix, 75 mg), embodies good bioavailability and ensures the effectiveness and safety of medicine.
  • the solid preparation of the present invention is bioequivalent to the marketed clopidogrel bisulfate tablets (Plavix, 75 mg) in terms of C max , AUC (0-t) and AUC (0- ⁇ ) indicators of the intermediate metabolite 2-oxy-clopidogrel and the active metabolite H4, and C max and AUC are far below the safety window, with a low risk of bleeding.
  • the solid preparation of (7aS, 2'S)-2-oxo-clopidogrel of the present invention has conventional and easily available auxiliary materials, good preparation quality stability, safe and reliable quality, high quality and low price.
  • the solid preparation method of (7aS, 2'S)-2-oxo-clopidogrel of the present invention is simple, has low production cost, and is suitable for industrial production.
  • Figure 4 Dissolution curves of Examples 16 to 27 under pH 4.5 conditions.
  • this product the (7aS, 2'S)-2-oxo-clopidogrel (hereinafter referred to as "this product") drug raw materials involved in the following test examples and examples are all self-made products of Chengdu Shibeikang Biopharmaceutical Technology Co., Ltd., with a purity of more than 99%.
  • the related substances PZ5 and PZ2 mentioned in the following test examples and examples are hydroxy impurities and isomeric impurities, respectively, and their structures are shown below, where the PZ5 impurity is the main degradation impurity of (7aS, 2'S)-2-oxo-clopidogrel, and the PZ2 impurity is its main isomeric impurity; other known impurities of this product known as of the date of this application but not included in the representative samples of the quality test results of this application are not present or not detected.
  • Test Example 1 Tablet Prescription Screening
  • Step 1 Weigh (7aS, 2'S)-2-oxo-clopidogrel and grind it to a D90 value of less than 15 ⁇ m to obtain drug powder;
  • Step 2 Weigh the excipients, pre-mix the drug powder with any filler, add the remaining filler, disintegrant and binder mixture that have been mixed evenly beforehand, and mix evenly, and finally add the lubricant and mix evenly;
  • Step 3 The uniformly mixed mixture is directly compressed into tablets using a tablet press with a tablet hardness of 3.00-9.00 kg to obtain tablets of various embodiments.
  • Example 7 had a slight sticking phenomenon, while the other examples had no sticking or almost no sticking.
  • Dissolution determination method Take a sample and test it according to the second method of Part IV of the 2020 edition of the Chinese Pharmacopoeia, General Rule 0931, with 900ml of pH4.5 acetate buffer as the dissolution medium, the speed is 50 revolutions per minute, and the operation is carried out according to the law.
  • Test results The dissolution curves of each sample in pH 4.5 acetate buffer as the dissolution medium are shown in Figure 1.
  • the results show that the samples of Examples 1 to 8 all have similar dissolution curves under pH 4.5 conditions, and the dissolution rate is significantly better than that of the comparative example.
  • the cumulative dissolution amount of the prescriptions of Examples 1 to 8 reaches more than 65% at 30 minutes, more than 75% at 45 minutes, and more than 85% at 90 minutes.
  • the dissolution of Examples 2, 3, 5 and 6 is faster and the dissolution effect is better; it proves that the amount of disintegrant is not the more the better, and the type and amount of disintegrant have limited effect on changing the disintegration rate.
  • Dissolution determination method Take a sample and follow the dissolution and release determination method (Chinese Pharmacopoeia, 2020 edition, Part IV, General Rule 0931 Method 2), using 900ml of pH1.2 hydrochloric acid solution as the dissolution medium, the speed is 50 revolutions per minute, operate according to the law, take the solution after 5, 10, 15, 30, and 45 minutes, filter, and take an appropriate amount of the filtrate; take another (7aS, 2'S)-2-oxy-clopidogrel reference substance, accurately weigh it, put it in a 10ml volumetric flask, add acetonitrile to dissolve and fill to the scale, accurately measure 1ml, put it in a 100ml volumetric flask, add dissolution medium to fill and make a solution containing about 10 ⁇ g of (7aS, 2'S)-2-oxy-clopidogrel per 1ml. Take the above two solutions, measure the absorbance at a wavelength of 220nm according to the UV-visible spectrophotometry method (General Rule 0401), and
  • Test results The dissolution test results of the samples of each embodiment in the hydrochloric acid dissolution medium of pH 1.2 are shown in Figure 2.
  • the results show that Examples 1 to 8 all have good dissolution in the hydrochloric acid dissolution medium of pH 1.2, that is, the cumulative dissolution amount at 5 minutes is more than 50%, and at 10 minutes is close to 100%, proving that different solid preparations of (7aS, 2'S)-2-oxo-clopidogrel have the characteristics of rapid dissolution under pH 1.2 conditions. Therefore, the dissolution under pH 4.5 conditions is comprehensively compared, and the key indicator of the prescription screening of this product is the dissolution under pH 4.5 conditions.
  • Test conditions According to the relevant guidelines for stability testing, the samples of Examples 1 to 8 were subjected to accelerated stability testing (40°C ⁇ 2°C; RH: 75% ⁇ 5%).
  • Test results The accelerated results of samples of Examples 1 to 8 are shown in Table 1-2. The results show that after 6 months of accelerated stability test, compared with 0 days, the PZ5 impurity increment of Examples 1, 4 and 7 is about 1%, the PZ2 impurity increment is more than 0.2%, and the main drug content is reduced by about 2%; while the PZ5 impurity increment of Examples 2, 3, 5, 6 and 8 is less than 0.8%, the PZ2 impurity increment is about 0.1%, and the main drug content is basically unchanged, and the maximum single impurity and other total impurities are also basically unchanged. It proves that Examples 2, 3, 5, 6, and 8 have higher stability and safer and more reliable quality.
  • Example 9 The changes in different particle sizes are shown in Table 2-1 below.
  • the prescription information and preparation method of Example 9 are the same as those of Example 7, and the prescription information and preparation methods of Examples 10 to 15 are the same as those of Example 5.
  • the dissolution of the above-mentioned samples of different particle sizes in pH 4.5 acetate buffer medium was determined, and the dissolution curve was drawn.
  • the results are shown in Figure 3.
  • the results show that the cumulative dissolution amount of Examples 9 to 14 reached more than 65% at 30 minutes, more than 75% at 45 minutes, and more than 85% at 90 minutes; especially, the cumulative dissolution amount of Examples 9 to 13 reached more than about 80% at 45 minutes, and more than about 90% at 90 minutes, with faster dissolution speed and better dissolution effect.
  • the cumulative dissolution amount of Example 15 was less than 60% at 30 minutes, less than 70% at 45 minutes, and less than 85% at 90 minutes, and the dissolution speed was relatively slow, proving that the larger the particle size in the prescription, the slower the dissolution.
  • the test results in the above table show that after 6 months of accelerated stability inspection, compared with 0 days, the PZ5 impurity increase of Example 9 is about 1%, the PZ2 impurity increase is about 0.2%, and the main drug content is reduced by 1.6%; while the PZ5 impurity increase of Examples 10 to 15 is about 0.5% at most, the PZ2 impurity increase is about 0.1% at most, the main drug content decreases by no more than 0.5%, and the maximum unknown single impurity and other total impurity contents are basically stable, which proves that Examples 10 to 15 have higher stability; especially the main drug content of Examples 11 to 15 is basically unchanged, and the stability is better.
  • the above test results further prove that although reducing the particle size can increase the dissolution rate, it will increase the risk of impurity degradation; by adjusting the prescription ratio, especially when the mass ratio of disintegrant and binder in the prescription reaches 4:1, it is beneficial to improve the stability of solid preparations, especially for prescriptions with smaller particle sizes, the stabilizing effect is significant.
  • the stability investigation results of Test Example 1 it is proved that when the mass ratio of disintegrant and binder meets 2.5 ⁇ 15:1, it is beneficial to improve the stability of solid preparations.
  • Example 23 3 mg tablet formulation
  • Example 24 5 mg tablet formulation
  • Example 25 6 mg tablet formulation
  • Example 26 4 mg tablet formulation
  • Example 27 6 mg tablet formulation
  • the dissolution of the tablets prepared in the above Examples 16 to 27 in a pH 4.5 acetate buffer medium was determined according to the method of Test Example 1, and the results are shown in Figure 4.
  • the results show that the cumulative dissolution of the samples of Examples 16 to 19 and 21 to 27 reached more than 65% at 30 minutes, more than 75% at 45 minutes, and more than 90% at 90 minutes, and the dissolution curves were similar.
  • the cumulative dissolution of Example 20 was 64% at 30 minutes, 76% at 45 minutes, and 88% at 90 minutes, and the dissolution was slightly slower. The possible reason is that the dosage is too large to affect the dissolution effect, so it is recommended to control the dosage to less than 10 mg.
  • Example 6 Example 10, Example 13, Example 21, Example 22.
  • a single-dose, single-center, single-dose, randomized, open, two-sequence, two-period, crossover design was used (washout period was ⁇ 4 days).
  • the 30 healthy volunteers were randomly divided into group A and group B, with 15 people in each group.
  • the volunteers were randomly fasted and orally administered with the example preparation (test preparation: T) or the reference preparation (Plavix: R).
  • the active metabolite H4 and 2-oxo-clopidogrel in plasma were measured.
  • Each subject had a forearm vein indwelling needle placed before medication on the morning of the test day (which could be retained until 12 hours after medication), and a blank blood sample of 3 ml was drawn 0.5 hours before medication, and 3 ml of venous blood was collected 0.25h, 0.5h, 0.75h, 1.0h, 1.5h, 2h, 2.5h, 3.0h, 4.0h, 6.0h, 8.0h, 10h, 12h, and 24h (on the second day) after medication, for a total of 15 times (including blank blood samples), and 2 tubes of whole blood were collected at each blood collection point.
  • One tube was placed in a vacuum blood collection tube with EDTA-K2 anticoagulant added with derivatization reagent in advance, mixed and placed on ice for 10 minutes and then centrifuged, and the plasma sample was placed in a cryopreservation tube with an identification label; the other tube was placed in a vacuum blood collection tube with EDTA-K2 anticoagulant added with TCEP antioxidant in advance, mixed and placed on ice for cooling, shaken and centrifuged, and the plasma sample was placed in a cryopreservation tube with an identification label.
  • the time from whole blood collection to frozen storage in a -60 ⁇ -90°C refrigerator is less than 60 min.
  • Drug concentration determination LC-MS/MS method was used to determine the concentrations of clopidogrel thiol active metabolite H4 derivative and 2-oxo-clopidogrel in plasma.
  • Plavix After entering the human body, Plavix is first metabolized by CYP enzymes to produce 2-oxo-clopidogrel, which is then metabolized by CYP enzymes to produce active metabolite H4. After (7aS, 2’S)2-oxo-clopidogrel enters the body, it is quickly converted to 2-oxo-clopidogrel, which is then metabolized by CYP enzymes to produce active metabolite H4. Among them, 2-oxo-clopidogrel is a racemate, which contains the optical isomers of (7aS, 2’S)2-oxo-clopidogrel.

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Abstract

本发明提供了一种含有(7aS, 2'S)-2-氧-氯吡格雷的固体制剂及其制备方法，该固体制剂为含(7aS, 2'S)- 2-氧-氯吡格雷的口服片剂，包含(7aS, 2'S)- 2-氧-氯吡格雷和药学上可接受的辅料，所述辅料包括填充剂、崩解剂、粘合剂和润滑剂。

Description

一种含氧化氯吡格雷的固体制剂及其制备方法 技术领域
本申请主张2022年12月02日申请的发明名称为“一种含氧化氯吡格雷的固体制剂及其制备方法”、专利号为CN202211545401.6的中国发明专利的优先权，特此以引用的方式明确并入本文中。
本发明属于药物制剂技术领域，具体涉及一种含(7aS, 2’S)-2-氧-氯吡格雷的固体制剂及其制备方法。
 背景技术
氯吡格雷是预防和治疗因血小板高聚集引起的心、脑及其他动脉循环障碍疾病的一线用药，硫酸氢氯吡格雷片是其口服剂型。(7aS, 2’S)-2-氧-氯吡格雷为氯吡格雷在人体的中间代谢产物，结构如式I所示，化学名为：（S）-2-（2-氯苯基）-2-（（S）-2-氧代-2,6,7,7a-四氢噻吩[3,2-c]并吡啶-5（4H）基）乙酸甲酯；
。
氯吡格雷的药效特别是在亚洲人中存在显著的个体差异性，即存在氯吡格雷抵抗(CPGR)。其成因是由于个体肝脏内CYP酶活性差异化导致，具体表现为氯吡格雷在部分患者的肝脏内无法被正常代谢，无法产生(7aS, 2’S)-2-氧-氯吡格雷的代谢产物及其光学异构体，从而阻断了氯吡格雷后续进一步被代谢为活性成分，无法发挥抗凝作用。而直接服用(7aS, 2’S)-2-氧-氯吡格雷可以有效避免氯吡格雷抵抗。
(7aS, 2’S)-2-氧-氯吡格雷，为白色或类白色结晶性粉末，在乙腈中溶解，在甲醇中微溶，在水中几乎不溶，在BCS生物药剂分类系统中属于低溶解高渗透性药物，还具有高温、酸、碱不稳定性，因此制备高稳定性的普通片剂难度系数大。此外，具有与已上市的硫酸氢氯吡格雷片在人体内释放的中间代谢物2-氧-氯吡格雷和活性代谢物H4均达到生物等效的(7aS, 2’S)-2-氧-氯吡格雷的固体制剂，还未见报道。因此，研究与已上市的硫酸氢氯吡格雷片生物等效的且稳定的(7aS, 2’S)-2-氧-氯吡格雷固体制剂，保证用药的有效性与安全性，成为了本领域技术人员亟需解决的问题之一。
 发明内容
有鉴于此，本申请提供一种用于治疗血液系统疾病、含(7aS, 2’S)-2-氧-氯吡格雷的固体制剂及其制备方法，该(7aS, 2’S)-2-氧-氯吡格雷的固体制剂可持续、平稳地释放活性成分并发挥药效，且固体制剂稳定，质量安全可靠。
本发明提供一种固体制剂，所述固体制剂包含(7aS, 2’S)- 2-氧-氯吡格雷和药学上可接受的辅料；所述辅料包括填充剂、崩解剂、粘合剂和润滑剂。
进一步地，上述任一固体制剂中崩解剂与粘合剂的质量比为1~20：1。
优选地，上述任一固体制剂中崩解剂与粘合剂的质量比为2.5~15：1。
更优选地，上述任一固体制剂中崩解剂与粘合剂的质量比为3~5：1。
进一步地，上述任一固体制剂每单位剂型含有(7aS, 2’S)- 2-氧-氯吡格雷的量为2mg～9.5mg；示例性地但不局限于如2mg、2.5mg、3mg、3.5mg、4mg、4.5mg、5mg、5.5mg、6mg、6.5mg、7mg、7.5mg、8mg、8.5mg、9mg、9.5mg。
优选地，上述任一固体制剂每单位剂型含有(7aS, 2’S)- 2-氧-氯吡格雷的量为2mg～8mg；优选为4mg、4.5mg、5mg、5.5mg或6mg。
进一步地，上述任一固体制剂包含如下重量组分：1.0~8.0wt% (7aS, 2’S)- 2-氧-氯吡格雷、65.0~95.0wt %填充剂、3.0~20.0wt%崩解剂、1.0~6.0wt%粘合剂、0.5~2.5wt%润滑剂。
优选地，上述任一固体制剂包含如下重量组分：1.0~8.0wt% (7aS, 2’S)- 2-氧-氯吡格雷、65.0~92.0wt %填充剂、10.0~20.0wt%崩解剂、1.0~6.0wt%粘合剂、0.5~2.5wt%润滑剂。
更优选地，上述任一固体制剂包含如下重量组分：2.0~6.0wt% (7aS, 2’S)- 2-氧-氯吡格雷、70.0~90.0wt %填充剂、10.0~20.0wt%崩解剂、1.0~6.0wt%粘合剂、0.5~2.5wt%润滑剂。
进一步地，上述任一填充剂选自甘露醇、乳糖、预胶化淀粉、山梨醇、微晶纤维素、淀粉、糖粉、糊精、无机盐中的任意一种或几种；优选为预胶化淀粉、乳糖、甘露醇、微晶纤维素、山梨醇中的两种或多种；
上述任一崩解剂选自低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、羧甲淀粉钠、波拉克林钾、干淀粉中的任意一种或几种；优选低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、羧甲淀粉钠、波拉克林钾中的一种或几种；
上述任一粘合剂选自阿拉伯胶、聚维酮、羟丙甲纤维素、羟丙纤维素、明胶、羧甲基纤维素钠、甲基纤维素、共聚维酮中的任意一种或几种；优选聚维酮、羟丙甲纤维素、羟丙纤维素、羧甲基纤维素钠、共聚维酮中的一种或几种；
上述任一润滑剂选自硬脂酸镁、硬脂富马酸钠、滑石粉、聚乙二醇类物质、氢化植物油中的任意一种或几种。
进一步地，上述任一作为填充剂的乳糖包含但不限于一水乳糖或无水乳糖；上述作为填充剂的无机盐包含但不限于硫酸钙、磷酸氢钙、碳酸钙或二水硫酸钙；上述作为润滑剂的聚乙二醇类物质包含但不限于PEG2000、PEG4000或PEG6000；上述作为润滑剂的氢化植物油包含但不限于氢化蓖麻油。                  
进一步地，上述固体制剂包含如下重量的组分：1.0~8.0wt% (7aS, 2’S)- 2-氧-氯吡格雷、10.0~35.0wt %预胶化淀粉、30.0~65.0wt %乳糖、3.0~20.0wt%低取代羟丙基纤维素、1.0~6.0wt%羟丙纤维素和0.5~2.5wt%硬脂富马酸钠。
优选地，上述固体制剂包含如下重量的组分：3.0~6.0wt% (7aS, 2’S)- 2-氧-氯吡格雷、10.0~35.0wt %预胶化淀粉、30.0~65.0wt %乳糖、3.0~20.0wt%低取代羟丙基纤维素、1.0~6.0wt%羟丙纤维素和0.5~2.5wt%硬脂富马酸钠。
优选地，上述固体制剂包含如下重量的组分：1.0~8.0wt% (7aS, 2’S)- 2-氧-氯吡格雷、20.0~35.0wt %预胶化淀粉、40.0~60.0wt %乳糖、6.0~18.0wt%低取代羟丙基纤维素、1.0~6.0wt%羟丙纤维素和0.5~2.5wt%硬脂富马酸钠。
优选地，上述固体制剂包含如下重量的组分：3.0~6.0wt% (7aS, 2’S)- 2-氧-氯吡格雷、20.0~35.0wt %预胶化淀粉、40.0~60.0wt %乳糖、6.0~18.0wt%低取代羟丙基纤维素、1.0~6.0wt%羟丙纤维素和0.5~2.5wt%硬脂富马酸钠。
进一步地，上述任一乳糖包含一水乳糖或无水乳糖，优选无水乳糖。
进一步地，上述任一固体制剂中 (7aS, 2’S)- 2-氧-氯吡格雷的粒径分布范围为：1μm≤D90≤40μm；优选为1μm≤D90≤30μm；更优选为1μm≤D90≤15μm。
优选地，上述任一固体制剂中 (7aS, 2’S)- 2-氧-氯吡格雷的粒径分布范围为：1μm≤D90≤15μm；优选为2μm≤D90≤8μm。
进一步地，上述任一固体制剂在pH4.5醋酸盐缓冲液溶出介质中，50RPM旋转速度的2020年版中国药典第四部通则0931第二法测试下，30min 以内累积溶出量为65%~90%。
进一步地，上述任一固体制剂在pH4.5醋酸盐缓冲液溶出介质中，50RPM旋转速度的2020年版中国药典第四部通则0931第二法测试下，30min以内累积溶出量达到65%以上，45min以内累积溶出量达到75~80%以上，90min以内累积溶出量达到85~90%以上。
优选地，上述任一固体制剂在pH4.5醋酸盐缓冲液溶出介质中，50RPM旋转速度的2020年版中国药典第四部通则0931第二法测试下，30min 以内累积溶出量为65%以上，45min以内累积溶出量为75%以上，90min以内累积溶出量为85%以上。
更优选地，上述任一固体制剂在pH4.5醋酸盐缓冲液溶出介质中，50RPM旋转速度的2020年版中国药典第四部通则0931第二法测试下，30min 以内累积溶出量为65%以上，45min以内累积溶出量为80%以上，90min以内累积溶出量为90%以上。
进一步地，上述任一固体制剂在pH1.2盐酸溶液缓冲液溶出介质中，50RPM旋转速度的2020年版中国药典第四部通则0931第二法测试下，15min 以内累积溶出量为85%以上。
进一步地，上述任一固体制剂能与硫酸氢氯吡格雷片（波立维，75mg）所代谢生成的活性代谢物H4达到生物等效。
进一步地，上述任一固体制剂能与硫酸氢氯吡格雷片（波立维，75mg）所代谢生成的2-氧-氯吡格雷达到生物等效。
进一步地，上述任一所述的固体制剂为口服固体制剂；优选片剂、颗粒剂、胶囊剂、软胶囊剂、丸剂、散剂或微丸剂。
本发明还提供上述任一项固体制剂的制备方法，包括以下步骤：
步骤1. 将(7aS, 2’S)-2-氧-氯吡格雷的原料粉碎，得到药物粉末；
步骤2. 将所述药物粉末与辅料混合后压片，得到固体制剂。
进一步地，上述任一项固体制剂的制备方法，包括以下步骤：
步骤1：称取(7aS, 2’S)-2-氧-氯吡格雷，粉碎至目标粒径，得到药物粉末；
步骤2：称取辅料，将药物粉末与任一种填充剂预混合后，加入事先已混合均匀的剩余填充剂、崩解剂和粘合剂混合物，并混合均匀，最后加入润滑剂并混合均匀；
步骤3：将上述混合均匀的混合物料用压片机直接压片，压片硬度3.00～9.00kg，得到各实施例片剂。
进一步地，上述步骤2的药物粉末与辅料混合的方式包括一次性混合、分批次混合。值得注意的是，无论是将药物粉末与辅料一次性混合，还是与辅料分批次混合，只要达到充分混合条件均可。比如当批量小时一次性混合即可，而当批量较大时，采用分批次混合时混合效果更好。
进一步地，上述任一制备方法中，药物的粉碎方式包括但不限于气流粉碎。
进一步地，上述任一制备方法中，制片方法包括但不限于湿法制粒压片法、干法制粒压片法和粉末直接压片法；优选粉末直接压片法。
进一步地，上述其它任一剂型采用本领域常规工艺制备。示例性如将本发明的混合药物粉末直接或制备颗粒或微丸后装入胶囊、软胶囊或袋中形成颗粒剂、胶囊剂、软胶囊剂、丸剂、散剂或微丸剂等。
本发明还提供上述任一项固体制剂用于治疗血液系统疾病的应用。
进一步地，上述血液系统疾病包括心脑血管系统的血液疾病。
进一步地，上述血液系统疾病包括但不限于急性冠状动脉综合征、动脉粥样硬化疾病、或血栓性并发症。
术语特别说明：
本发明术语“乳糖”包括含水乳糖和无水乳糖，尤其包含一水乳糖和无水乳糖。其中“一水乳糖”为国家药典中的“乳糖”；“无水乳糖”同国家药典定义；本专利为了统一含水乳糖和无水乳糖，特用名称“乳糖”指示上位概念。
本发明术语“填充剂”在本领域还可以理解为“稀释剂”。
本发明使用的辅料为常规辅料，优选药典收录辅料，不受辅料具体厂家、型号、分子量、聚合度、构型等细分区别影响。示例性如甘露醇100SD、甘露醇200SD、甘露醇M200等都包含在上述“甘露醇”中。
由于本发明的(7aS, 2’S)-2-氧-氯吡格雷为氯吡格雷的中间代谢物，因此要达到(7aS, 2’S)-2-氧-氯吡格雷与已上市的硫酸氢氯吡格雷片（波立维，75mg）的生物等效，难度系数大，尤其满足两个化合物的等效，即中间代谢物2-氧-氯吡格雷和活性代谢物H4的同时等效，难度系数巨大。本发明人也因此做了非常多的探索研究，其中发现，不同的处方组成对溶出影响较大，如加入微晶纤维素作为填充剂，虽然微晶纤维素改善了颗粒的流动性，但压片后，(7aS, 2’S)-2-氧-氯吡格雷的溶出速度会略有下降；又如，加入不同用量崩解剂后对(7aS, 2’S)-2-氧-氯吡格雷的溶出速度影响不大；再如，将原料药微粉化处理后，(7aS, 2’S)-2-氧-氯吡格雷溶出会加快，但粒度太小，又容易产生突释问题，继而导致药物吸收过快，增加出血风险，或者C max虽得到提高，但AUC （0-∞）无法等效；此外，原料粒度降低后，与辅料接触面增大，药物稳定性降低，且会增加粘冲风险。因此，常规的解决难溶性药物溶出问题的方法均难以很好地使(7aS, 2’S)-2-氧-氯吡格雷固体制剂达到持续、平稳且完全释放的要求，且很难平衡固体制剂的稳定性要求。
在本发明人无数次结合规格、粒度与不同处方之间的无数次研究后，终于发现了本发明范围的合适的(7aS, 2’S)-2-氧-氯吡格雷规格、粒度、处方组成之间的三维动态平衡。首先，本申请人意料之外地发现加入粘合剂并控制崩解剂与粘合剂的比例可以一定程度上改善较小粒径下C max过高的突释现象，从而降低出血风险；其次，通过限定崩解剂与粘合剂用量配比后，能显著提高固体制剂的稳定性和工艺粘冲现象，尤其对于较小粒径处方，改善作用显著；最后，通过大量溶出行为评估，找到两条与已上市品种硫酸氢氯吡格雷片（波立维，75mg）完全生物等效的体外溶出曲线，为(7aS, 2’S)-2-氧-氯吡格雷的处方筛选工作提供了科学的评估标准。
与现有技术相比，本发明具有以下有益效果：
1、本发明的 (7aS,2’S)-2-氧-氯吡格雷的固体制剂具有相似的体外溶出曲线，具体地，在pH4.5条件下的30min以内累积溶出量达到65%以上，45min以内达到75~80%以上，90min以内达到85~90%以上；在pH1.2条件下的15min以内累积溶出量达到85%以上；药物快速平稳释放且释放完全。
2、本发明的固体制剂与已上市的硫酸氢氯吡格雷片（波立维，75mg）完全生物等效，体现较好的生物利用度且保证了药用的有效性和安全性。具体地，本发明的固体制剂与已上市的硫酸氢氯吡格雷片（波立维，75mg）具有中间代谢物2-氧-氯吡格雷和活性代谢物H4的C max、AUC （0-t）和AUC （0-∞）指标一致的生物等效，且C max、AUC远低于安全窗，出血风险小。
3、本发明的 (7aS,2’S)-2-氧-氯吡格雷的固体制剂，辅料常规易得，制剂质量稳定性好，质量安全可靠，质优价廉。
4、本发明的(7aS,2’S)-2-氧-氯吡格雷的固体制剂制备方法简单，生产成本低，适于工业生产。
 附图说明
图1：实施例1~8和对比例的pH4.5条件溶出曲线；
图2：实施例1~8的pH1.2条件溶出曲线；
图3：实施例9~15的pH4.5条件溶出曲线；
图4：实施例16~27的pH4.5条件溶出曲线。
 具体实施方式
以下将结合实施例和试验例对本发明作进一步的详细描述，本发明的实施例和试验例仅用于说明本发明的技术方案，并非对本发明的限制，本领域技术人员凡依照本发明公开的内容所作的任何本领域的等同置换或在没有做出创造性劳动前提下所获得的所有其他实施例，均属于本发明的保护范围。实施例中未注明的具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用辅料、试剂或仪器未注明生产厂商或型号者，均为通过市购获得的常规产品。
以下试验例和实施例中所涉及的(7aS, 2’S)-2-氧-氯吡格雷（以下简称“本品”）药物原料在没有特别说明的情况下均为成都施贝康生物医药科技有限公司自制品，纯度99%以上。以下试验例和实施例所提及的有关物质PZ5和PZ2分别是羟基杂质和异构体杂质，结构如下所示，其中PZ5杂质为(7aS, 2’S)-2-氧-氯吡格雷的主要降解杂质，而PZ2杂质为其主要异构体杂质；至本申请日起已知的本品的其它已知杂质但未例入本申请的质量检测结果的代表样品中没有或未检出。
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试验例1：片剂处方筛选
(7aS, 2’S)-2-氧-氯吡格雷极易发生氧化降解产生PZ5杂质，因此单纯的体外溶出很难筛选出高稳定性制剂。鉴于此，本试验例将通过不同处方的体外溶出和稳定性评估筛选可靠处方。
1、筛选处方及其制备
在前期大量摸索试验基础下，为了证明不同物料及其比例对溶出的影响，筛选出如下表所示的具有代表性的处方。
制备方法：
步骤1：称取(7aS, 2’S)-2-氧-氯吡格雷，粉碎至D90为15μm以下，得到药物粉末；
步骤2：称取辅料，将药物粉末与任一种填充剂预混合后，加入事先已混合均匀的剩余填充剂、崩解剂和粘合剂混合物，并混合均匀，最后加入润滑剂并混合均匀；
步骤3：将上述混合均匀的混合物料用压片机直接压片，压片硬度3.00～9.00kg，得到各实施例片剂。
对比例：仅将药物活性成分噻吩并吡啶组合物换为本发明的(7aS, 2’S)-2-氧-氯吡格雷，其它同专利CN111249241A实施例4的编号B1处方及其制备方法。
在制备实施例1~8处方制剂中，各片剂流动性、可压性、成型性均好，但实施例7出现轻微粘冲现象，其它实施例无粘冲或几乎无粘冲。
2、pH4.5条件溶出测定
溶出度测定方法：取样品，照2020年版中国药典第四部通则0931第二法测试下，以pH4.5醋酸盐缓冲液900ml为溶出介质，转速为每分钟50转，依法操作，经5、10、15、30、45、60、90、120分钟时，取溶液，滤过，量取续滤液适量；另取(7aS, 2’S)-2-氧-氯吡格雷对照品，精密称定，至10ml容量瓶中，加乙腈溶解并填充至刻度，精密量取1ml，置100ml容量瓶中，加溶出介质填充并制成每1ml约含(7aS, 2’S)-2-氧-氯吡格雷 10μg的溶液。取上述两种溶液，按照紫外-可见分光光度法（通则0401），在220nm的波长处分别测定吸光度，计算每片的溶出量。
试验结果：各例样品在pH4.5醋酸盐缓冲液为溶出介质中的溶出曲线结果见附图1。结果显示，实施例1~8样品在pH4.5条件下均具有相似的溶出曲线，且溶出速度明显优于对比例。具体地，实施例1~8的处方在30min时累积溶出量达到65%以上，45min时达到75%以上，90min时达到85%以上，尤其实施例2、实施例3、实施例5和实施例6的溶出更快，溶出效果更佳；证明崩解剂的用量并非越多越好，且崩解剂的种类和用量对改变崩解速度的影响效果有限。
3、pH1.2条件溶出测定
溶出度测定方法：取样品，照溶出度与释放度测定法（中国药典，2020年版，四部，通则0931第二法），以pH1.2盐酸溶液900ml为溶出介质，转速为每分钟50转，依法操作，经5、10、15、30、45分钟时，取溶液，滤过，量取续滤液适量；另取(7aS, 2’S)-2-氧-氯吡格雷对照品，精密称定，至10ml容量瓶中，加乙腈溶解并填充至刻度，精密量取1ml，置100ml容量瓶中，加溶出介质填充并制成每1ml约含(7aS, 2’S)-2-氧-氯吡格雷 10μg的溶液。取上述两种溶液，按照紫外-可见分光光度法（通则0401），在220nm的波长处分别测定吸光度，计算每片的溶出量。
试验结果：各实施例样品在pH1.2的盐酸溶出介质中的溶出度测试结果见附图2。结果显示，实施例1~8在pH1.2盐酸溶出介质中均具有较好的溶出，即在5min时累积溶出量均达到50%以上，10min时接近100%，证明(7aS, 2’S)-2-氧-氯吡格雷的不同固体制剂在pH1.2条件下具有快速溶出特点。因此综合对比pH4.5条件的溶出情况，本品处方筛选的指标重点在于pH4.5条件的溶出。
4、稳定性考察
考察条件：根据稳定性试验相关指导原则要求，对实施例1～8样品进行加速稳定性（40℃±2℃；RH：75%±5%）考察。
试验结果：实施例1~8的样品加速结果见表1-2。结果显示，各例样品经6月加速稳定性考察后，与0天相比，实施例1、实施例4和实施例7的PZ5杂质增量约1%，PZ2杂质增量超过0.2%，主药含量降低约2%左右；而实施例2、实施例3、实施例5、实施例6和实施例8的PZ5杂质增量均小于0.8%，PZ2杂质增量约0.1%，而主药含量基本不变，最大单杂和其他总杂也基本不变。证明实施例2、3、5、6、8的稳定性更高，质量更安全可靠。
试验例2：粒径筛选
不同粒径变化见下表2-1。其中，实施例9的处方信息和制备方法同实施例7，实施例10~15的处方信息和制备方法同实施例5。
1、pH4.5溶出条件测定
按照试验例1方法测定上述不同粒度样品在pH4.5醋酸盐缓冲液介质中的溶出度，并绘制溶出曲线，结果见附图3。结果显示，实施例9~14在30min时累积溶出量达到65%以上，45min时达到75%以上，90min时达到85%以上；尤其实施例9~13在45min时累积溶出量达到约80%以上，90min时达到约90%以上，溶出速度更快，溶出效果更佳。而实施例15在30min时累积溶出量不足60%，45min时不足70%，90min时不足85%，溶出速度相对较慢，证明处方中粒径越大，溶出越慢。
2、稳定性考察
按照试验例1项下的“稳定性考察”进行，考察实施例9~15样品的稳定性，试验结果统计见下表。
上表试验结果显示，各例样品经6月加速稳定性考察后，与0天相比，实施例9的PZ5杂质增量约1%，PZ2杂质增量约0.2%，主药含量减低1.6%；而实施例10~15的PZ5杂质增量最高约0.5%左右，PZ2杂质增量最高约0.1%左右，主药含量降幅最高不超0.5%，最大未知单杂和其它总杂含量基本稳定，证明实施例10~15的稳定性更高；尤其实施例11~15的主药含量基本不变，稳定性更佳。
综上，上述试验结果进一步证明，虽然降低粒径可以提高溶出速度，但会增加杂质降解风险；而通过调整处方配比，尤其当处方中崩解剂和粘合剂的质量比达到4：1时，有利提高固体制剂稳定性，尤其对使用了较小粒径的处方，稳定作用显著。而结合试验例1的稳定性考察结果，证明崩解剂和粘合剂的质量比满足2.5~15：1时，均有利于提高固体制剂的稳定性。
试验例3：处方剂量筛选
为了验证各处方对剂量的包容性，以筛选生物等效的合适剂量，现对剂量进行筛选研究，不同剂量变化处方见如下实施例16~27，各实施例制备方法同试验例1。
实施例23：3mg片剂处方
实施例24：5mg片剂处方
实施例25：6mg片剂处方
实施例26：4mg片剂处方
实施例27：6mg片剂处方
1、pH4.5条件溶出测定
按照试验例1方法测定上述实施例16~27所制备的片剂在pH4.5醋酸盐缓冲液介质中的溶出度，结果见附图4。结果显示，实施例16~19、21~27样品在30min时累积溶出量达到65%以上，45min时达到75%以上，90min时达到90%以上，溶出曲线相似。而实施例20在30min时累积溶出量为64%，45min时达到76%，90min时达到88%，溶出稍慢，可能原因是剂量太大影响溶出效果，因此建议控制剂量至10mg以下。
2、稳定性考察
按照试验例1项下的“稳定性考察”进行，统计结果见下表。
结果显示，经6月加速稳定性考察后，与0天相比，各实施例样品的有关物质中PZ5增量约0.5%（不超1.0%），PZ2的增量不超0.2%，最大未知单杂和其它总杂基本不变，含量变化不超1.0%，尤其实施例16~19、21~27的含量变化不超0.5%，证明本发明范围的处方质量稳定性佳。
试验例4：健康成人生物等效性研究
1、受试药物
实施例6、实施例10、实施例13、实施例21、实施例22。
2、空腹给药
每个受试药物纳入30例健康成人志愿者（女性至少占1/3），随机分成2组，每组15人；试验分为2个阶段，给药分组情况如下：随机空腹口服受试制剂或参比制剂(波立维，75mg)，参见表4-1。
单次给药，采用单中心、单剂量、随机、开放、两序列、两周期、交叉设计方法（清洗期为≥4天），将入选的30名健康志愿者随机分为A、B组，每组15人。随机空腹口服实施例制剂（受试制剂：T）或参比制剂(波立维：R)。测定血浆中氯吡格雷硫醇活性代谢产物H4及2-氧-氯吡格雷。
3、血样采集
每名受试者于试验当日晨给药前在前臂静脉安置留置针（可保留至给药后12小时），于服药前0.5小时抽取空白血样3ml，服药0.25h、0.5h、0.75h、1.0h、1.5h、2h、2.5h、3.0 h、4.0 h、6.0 h、8.0 h、10 h、12 h、24 h（第2天）各采静脉血3 ml，共15次（含空白血样），每个采血点各采2管全血。其中一管置于事先加入衍生化试剂的EDTA-K2抗凝剂的真空采血管中，混匀后在冰上放置10分钟后离心，将血浆样品装于贴好识别标签的冻存管中；另一管置于事先加入TCEP抗氧剂的EDTA-K2抗凝剂的真空采血管中，混匀后置冰上冷却，摇匀后离心，将血浆样品装于贴好识别标签的冻存管中。从全血采集至放入-60 ~ -90℃冰箱中冷冻保存，时间小于60 min 。
4、药物浓度测定和数据分析
药物浓度测定：采用LC-MS/MS法测定血浆中氯吡格雷硫醇活性代谢产物H4衍生物及2-氧-氯吡格雷的浓度。
药代动力学参数统计和分析：计算各例受试者单剂量给药后各时间点的血药浓度数据，并绘制药--时曲线。分别计算受试者口服试验制剂和参比制剂后各时间点的血药浓度均值，并绘制均值药-时曲线。采用WinNonlin 7.5软件处理单剂量给药后血药浓度经时变化数据，求出AUC（统计矩计算）、C max（实测值）、T max（实测值）等药代动力学参数，计算生物利用度（F值），同时进行生物等效性分析。统计学分析采用方差分析及双单侧t检验，以1－α置信区间作出生物等效性判断。
药效学参数统计和分析：统计分析将采用SAS9.1统计软件进行。非劣效性试验的主要疗效指标采用单侧t检验，P<0.025认为有统计学意义；其余指标采用双侧检验，P<0.05认为有统计学意义。定量指标列出均数、标准差、中位数、最大值与最小值。
5、试验结果
波立维进入人体后，先经CYP酶代谢生成2-氧-氯吡格雷，之后再经CYP酶代谢后产生活性代谢物H4。而(7aS, 2’S)2-氧-氯吡格雷进入体内后，会快速转换为2-氧-氯吡格雷，之后经CYP酶代谢后产生活性代谢物H4。其中，2-氧-氯吡格雷为消旋体，即包含了(7aS, 2’S)2-氧-氯吡格雷的光学异构体。
空腹下各受试制剂与参比制剂（波立维®）的生物等效结果见如下表4-2。
上述统计结果显示，本发明实施例6、10、13、21、22样品在2-氧-氯吡格雷和H4两检测指标的C max、AUC (0-t)和AUC (0-∞)的90%置信区间均位于参比制剂（波立维®）的80%~125%之间，证明本发明实施例与参比制剂达到生物等效。据此可以合理预期与实施例6、10、13、21、22具有相似体外溶出曲线的处方能够达到与波立维®生物等效。
以上所述仅是本发明的优选实施方式，应当指出，对于使本技术领域的专业技术人员，在不脱离本发明技术原理的前提下，是能够实现对这些实施例的多种修改的，而这些修改也应视为本发明应该保护的范围。

Claims (10)

  1. 一种固体制剂，其特征在于，所述固体制剂包含(7aS, 2’S)- 2-氧-氯吡格雷和药学上可接受的辅料，所述辅料包括填充剂、崩解剂、粘合剂和润滑剂。
  2.  根据权利要求1所述的固体制剂，其特征在于，所述崩解剂与粘合剂的质量比为2.5~15：1。
  3.  根据权利要求1或2所述的固体制剂，其特征在于，所述固体制剂每单位剂型含有 (7aS, 2’S)- 2-氧-氯吡格雷的量在10mg以下，如为2～9.5mg；优选为4mg、4.5mg、5mg、5.5mg或6mg。
  4.  根据权利要求1或2所述的固体制剂，其特征在于，所述固体制剂包含1.0~8.0wt% (7aS,2’S)- 2-氧-氯吡格雷、65.0~95.0wt %填充剂、3.0~20.0wt%崩解剂、1.0~6.0wt%粘合剂、0.5~2.5wt%润滑剂。
  5.  根据权利要求1或2所述的固体制剂，其特征在于，所述填充剂选自甘露醇、乳糖、预胶化淀粉、山梨醇、微晶纤维素、淀粉、糖粉、糊精、无机盐中的任意一种或几种；优选为预胶化淀粉、乳糖、甘露醇、微晶纤维素、山梨醇中的两种或多种；
    所述崩解剂选自低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、羧甲淀粉钠、波拉克林钾、干淀粉中的任意一种或几种；优选低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、羧甲淀粉钠、波拉克林钾中的一种或几种；
    所述粘合剂选自阿拉伯胶、聚维酮、羟丙甲纤维素、羟丙纤维素、明胶、羧甲基纤维素钠、甲基纤维素、共聚维酮中的任意一种或几种；优选聚维酮、羟丙甲纤维素、羟丙纤维素、羧甲基纤维素钠、共聚维酮中的一种或几种；
    所述润滑剂选自硬脂酸镁、硬脂富马酸钠、滑石粉、聚乙二醇类物质、氢化植物油中的任意一种或几种。
  6.  根据权利要求1或2所述的固体制剂，其特征在于，所述固体制剂包含1.0~8.0wt% (7aS,2’S)- 2-氧-氯吡格雷、10.0~35.0wt %预胶化淀粉、30.0~65.0wt %乳糖、3.0~20.0wt%低取代羟丙基纤维素、1.0~6.0wt%羟丙纤维素及0.5~2.5wt%硬脂富马酸钠。
  7.  根据权利要求1~6任一项所述的固体制剂，其特征在于，所述 (7aS, 2’S)- 2-氧-氯吡格雷的粒径分布范围为：1μm≤D90≤40μm；优选为1μm≤D90≤30μm；更优选为1μm≤D90≤15μm。
  8.  根据权利要求1~7任一项所述的固体制剂，其特征在于，所述固体制剂在pH4.5醋酸盐缓冲液溶出介质中，50RPM旋转速度的2020年版中国药典第四部通则0931第二法测试下，30min 以内累积溶出量为65%以上，45min以内累积溶出量为75~80%以上，90min以内累积溶出量为85~90%以上；或所述固体制剂在pH1.2盐酸溶液缓冲液溶出介质中，50RPM旋转速度的2020年版中国药典第四部通则0931第二法测试下，15min以内累积溶出量为85%以上。
  9.  根据权利要求1~7任一项所述的固体制剂，其特征在于，所述固体制剂为口服固体制剂，优选片剂、颗粒剂、胶囊剂、软胶囊剂、丸剂、散剂或微丸剂。
  10.  权利要求1~7任一项所述固体制剂的制备方法，其特征在于，所述方法包括以下步骤：
    步骤1. 将(7aS, 2’S)-2-氧-氯吡格雷的原料粉碎，得到药物粉末；
    步骤2. 将所述药物粉末与辅料混合后压片，得到固体制剂。
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