WO2009152684A1 - 一种右佐匹克隆结晶及其组合物、其制备方法和应用 - Google Patents

一种右佐匹克隆结晶及其组合物、其制备方法和应用 Download PDF

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Publication number
WO2009152684A1
WO2009152684A1 PCT/CN2009/000414 CN2009000414W WO2009152684A1 WO 2009152684 A1 WO2009152684 A1 WO 2009152684A1 CN 2009000414 W CN2009000414 W CN 2009000414W WO 2009152684 A1 WO2009152684 A1 WO 2009152684A1
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Prior art keywords
zopiclone
preparation
crystal
hours
crystallization
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English (en)
French (fr)
Inventor
王国成
徐学宇
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Tianjin Tasly Group Co Ltd
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Tianjin Tasly Group Co Ltd
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Priority to US12/999,867 priority Critical patent/US8431577B2/en
Priority to EP20090765324 priority patent/EP2301938A4/en
Priority to AU2009260075A priority patent/AU2009260075B9/en
Priority to RU2010152782/04A priority patent/RU2492171C2/ru
Priority to JP2011513845A priority patent/JP5946274B2/ja
Priority to CA2727979A priority patent/CA2727979C/en
Publication of WO2009152684A1 publication Critical patent/WO2009152684A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention relates to the field of medicine, and in particular to a crystallization of zopiclone and a composition thereof, a preparation method thereof and a medicinal use. Background technique
  • Zopicl was developed by the French company Ronald Planck-Lean in the mid-1980s and is marketed in more than 80 countries including Europe under the trade name IMOVANE for the treatment of sleep disorders. Sales in 1999 were approximately $160 million. The drug is also used in China for nearly 10 years. At present, there are Shanghai Fahrenheit Pharmaceutical Co., Ltd., Qilu Pharmaceutical Factory and Guangdong Shunfeng Pharmaceutical Co., Ltd. The structural formula of zopiclone is as follows:
  • the zopiclone racemate dextropic dexzopiclone is a right-handed chiral monomer of zopiclone, namely (+)-(S)-(4-methylpiperazine-1-carboxylic acid) (6- (5-Chloropyridin-2-yl)-7-carbonyl-6,7-dihydro-5-hydro-pyrrolo[3,4-b]pyrazine-5-ester). It was developed by Sepracor in the United States in 1998 and was approved by the FDA in October 2004.
  • zopiclone Compared with the zopiclone racemate, zopiclone has the following significant advantages: Zopiclone has serious side effects, including: bitterness due to saliva secretion, dry mouth, drowsiness, morning fatigue, headache, dizziness , neuromotor function damage, etc., while the side effects of zopiclone are smaller than that of the zopiclone racemic; pharmacodynamic studies have shown that the short-acting hypnotic effect of zopiclone is mainly caused by the dextro isomer, so its efficacy It is better than the racemate; the acute toxicity study shows that the toxicity of zopiclone is significantly lower than that of the zopiclone racemate; compared with the zopiclone racemate, the use of zopiclone can produce anxiolytic The effect does not affect the coordination of exercise; Zopiclone is stereoselective for the benzodiazepine receptor, while the affinity of
  • Another object of the present invention is to provide a process for the preparation of the aforementioned crystalline form of zopiclone.
  • a further object of the present invention is to provide a composition comprising the aforementioned crystalline form of zopiclone.
  • a further object of the present invention is to provide a pharmaceutical use of the aforementioned crystalline form of zopiclone.
  • the peak of the differential scanning calorimetry map is: 207.7 °C.
  • the 2 ⁇ ( ⁇ grazing angle) value (average value) of the characteristic peak of the powder X-ray diffraction pattern is: about 11.08°, about 12.38°, about 15.86. , about 17.88. , about 19.98. , about 20.58. .
  • the characteristic peak of the infrared absorption spectrum is: about 30780 ⁇ 2942 ⁇ 28380 ⁇ 27900 ⁇ 1716cm" 1 1463cm" 1 1372cm" 1 757cm has a peak.
  • it is about 3078cm, about 2942 2838cm, about 2790cm, about 1716cm -1 , about 1577 ⁇ 1545 cm -1 , about 1463 cm -1 , about 1372 cm -1 , about 1007 cm -1 , about 849 cm -1 , and about 757 cm -1 have peaks.
  • the zopiclone crystals of the present invention were characterized by well-established powder X-ray diffraction, differential scanning calorimetry and infrared absorption spectroscopy.
  • the powder X-ray diffraction pattern obtained from the crystalline compound is often characterized for a given crystalline morphology, which is represented by Cu-Ka radiation at a 2 ⁇ angle.
  • DSC measures the thermal transition temperature when crystallization absorbs or releases heat due to changes in its crystal structure or crystal melting.
  • the difference between the thermal transition temperature and the melting point is typically within about 2 ° C, typically within about 1 ° C.
  • a compound has a DSC peak or melting point of a given value, it means that the difference in DSC peak or melting point is within 2 °C.
  • IR measures infrared light absorption caused by specific chemical bonds associated with groups in the molecule that correspond to light vibration.
  • DSC and IR provide information that can be used to describe the physicochemical properties of zopiclone crystallization.
  • the starting material of zopiclone required for the preparation of the zopiclone crystal of the present invention is prepared by the following method:
  • the zopiclone racemate, D-(+)-malic acid is added to a mixture of methanol and acetone, stirred and dissolved at 20 to 30 ° C, then cooled to 0 to 10 ° C, and kept for about 6 to 48 hours. Stirring was continued, filtered, washed with methanol and dried to give D-(+)-malic acid-S-zoicone.
  • the obtained D-(+)-malic acid-S-zopiclone was dissolved in water, adjusted to a pH of 6-9, extracted with ethyl acetate, dried, concentrated, filtered, washed with filter cake and dried to obtain a raw material. Pico clone.
  • the zopiclone crystallization of the present invention is prepared according to the following preparation method:
  • a stirring device is not required or can be used in the preparation process, preferably using a stirring device.
  • the present invention also encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the zopiclone crystal of the present invention together with a pharmaceutically acceptable carrier, or a combination of other drugs to form a composite preparation.
  • the pharmaceutical composition is in the form of a unit dose of a pharmaceutical preparation
  • the unit dosage form of the pharmaceutical preparation refers to a unit of the preparation, such as each tablet of the tablet, each of the capsules, each bottle of the oral solution, and the granules. Every bag, etc.
  • the zopiclone crystallization of the present invention may be 0.1 to 99.9% by weight in the preparation, and the rest is a pharmaceutically acceptable carrier; the zopiclone crystal of the present invention preferably accounts for 0.1% by weight in the preparation. 20%, most preferably 1 to 10%.
  • compositions of the present invention can be prepared by crystallization of the zopiclone of the present invention and a pharmaceutically acceptable carrier, using standard pharmaceutical techniques, including mixing, granulating, and compressing. It is well known to those skilled in the art that the form and nature of the pharmaceutically acceptable carrier will depend on the amount of active ingredient with which it is, the route of administration, and other known factors.
  • the pharmaceutically acceptable carrier used is various organic or inorganic carriers which can be administered in combination with the composition, for example: excipients, lubricants, binders, disintegrators and Coating agents; pharmaceutically acceptable additives such as coloring agents and sweeteners can also be used.
  • the pharmaceutically acceptable carrier is selected from the group consisting of: sugars such as maltose, glucose, fructose, dextran, sucrose, lactose, cyclodextrin (such as ⁇ -cyclodextrin), starch, cellulose, and derivatives thereof; Sugar alcohols such as mannitol, sorbitol and xylitol; inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; inorganic salts such as sodium chloride, potassium chloride, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, Calcium carbonate, calcium hydrogencarbonate, carbonate of monovalent alkali metal, phosphate or its aqueous solution; amino acids such as glycine, methionine and cysteine hydrochloride; organic salts such as disodium EDTA, calcium EDTA, sodium lactate , stearates (such as calcium stearate and magnesium stearate) and alg
  • the zopiclone crystal of the present invention may be in the form of a pharmaceutical preparation in any pharmaceutically acceptable dosage form. Including: tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal preparations, granules, granules, pills, powders, ointments, dan Agents, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, and patches.
  • the preparation of the present invention is preferably an oral dosage form such as a capsule, a tablet, an oral solution, a granule, a pill, a powder, a dandruff or the like; and an injection such as a powder injection, an injection, an intravenous drip, and the like.
  • the preparation of the present invention is most preferably a tablet.
  • the zopiclone of the present invention is stably crystallized, and the preparation for oral administration may contain a usual excipient, a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, and a seasoning. And humectants, if necessary, the tablets can be coated.
  • Preferred exemplary excipients include: lactose, D-mannitol, D-sorbitol, starch (eg alpha-starch, amylopectin, dextrin), cellulose and its derivatives (eg crystalline cellulose, low substituted Hydroxypropyl cellulose, sodium carboxymethyl cellulose), gum arabic, light anhydrous silicic acid, synthetic aluminum silicate, aluminum magnesium silicate, and the like.
  • Preferred exemplary lubricants include: magnesium stearate, calcium stearate, talc, silica gel, and the like.
  • Preferred exemplary binders include: starch (eg, alpha-starch, dextrin, amylopectin), sucrose, trehalose, gelatin, gum arabic, cellulose, and derivatives thereof (methylcellulose, carboxymethylcellulose) , sodium carboxymethyl cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose), D-mannitol and pyrrolidone.
  • starch eg, alpha-starch, dextrin, amylopectin
  • sucrose trehalose
  • gelatin gum arabic
  • cellulose and derivatives thereof (methylcellulose, carboxymethylcellulose) , sodium carboxymethyl cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose), D-mannitol and pyrrolidone.
  • Preferred exemplary disintegrants include: lactose, starch, sodium carboxymethyl starch, cellulose and its derivatives (carboxymethylcellulose, calcium carboxymethylcellulose, low substituted hydroxypropylcellulose), lightweight Anhydrous silicic acid, etc.
  • Preferred exemplary coating agents include: hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, polyvinyl alcohol, and the like.
  • Preferred exemplary colorants include: water soluble edible eucalyptus dyes (food dyes such as Edible Red No. 2 and No. 3, Edible Yellow No. 4 and No. 5, Edible Blue No. 1 and No. 2); An insoluble coloring dye (for example, an aluminum salt of the above water-soluble edible yellow dye); a natural dye (for example, ⁇ -carotene, chlorophyll, and iron oxide).
  • water soluble edible eucalyptus dyes food dyes such as Edible Red No. 2 and No. 3, Edible Yellow No. 4 and No. 5, Edible Blue No. 1 and No. 2
  • An insoluble coloring dye for example, an aluminum salt of the above water-soluble edible yellow dye
  • a natural dye for example, ⁇ -carotene, chlorophyll, and iron oxide
  • Preferred exemplary sweeteners include: sodium saccharin, dipotassium glycyrrhetinate, aspartame, and stevia.
  • composition of the present invention can be conveniently administered by any route suitable for administration, for example, orally, topically, parenterally or by inhalation, preferably orally.
  • the pharmaceutical composition of the present invention has a dose of from 1 to 15 mg per dosage unit, preferably from 3 to 12 mg per dosage unit, in the treatment of sleep disorders.
  • the pharmaceutical composition of the invention determines the dosage according to the condition of the patient during use, and can be administered once a day, 1 ⁇ 10 doses each time, such as: taking 1 ⁇ 10 bags, or 1 ⁇ 10 tablets, or 1 ⁇ 10 before going to bed. sheet.
  • Figure 1 is an X-ray diffraction spectrum of zopiclone crystals of the present invention.
  • Figure 2 is a differential scanning thermogram of the zopiclone crystal of the present invention.
  • Figure 3 is an infrared absorption spectrum of the zopiclone crystal of the present invention.
  • Fig. 4 is an X-ray diffraction pattern of the zopiclone of the present invention placed at a high temperature (60 ° C) for 10 days.
  • Fig. 5 is an X-ray diffraction pattern of the zopiclone crystal of the present invention placed in a high humidity (25 ° C, relative humidity 92.5%) for 10 days.
  • Fig. 6 is an X-ray diffraction spectrum of zozopiclone crystal light (4500 ⁇ 500 Lx) irradiated for 10 days in the present invention.
  • Fig. 7 is an X-ray diffraction pattern of the zopiclone crystal of the present invention placed in an environment of a temperature of 40 ⁇ 2 ° C and a relative humidity of 75 ⁇ 5% for 6 months.
  • Figure 8 is an X-ray diffraction pattern of zopiclone crystallization of the present invention placed at room temperature for 36 months.
  • the invention also provides the use of zopiclone crystallization in the preparation of a medicament for treating a sleep disorder.
  • the following are the results of its pharmacodynamic studies.
  • zopiclone differs from that of benzodiazepines and is currently believed to act on different binding sites for benzodiazepine receptors in the GAB AA receptor/C1 channel complex.
  • test drug zopiclone crystallization was prepared in accordance with Example 1 of the present invention.
  • IC 5Q value of zopiclone binding to the benzodiazepine receptor (IC 5Q value is the half inhibitory concentration, which is inversely proportional to the receptor binding capacity) is 21 ⁇ 3 (nmol / L), indicating that zopiclone and The receptor has a strong affinity.
  • IC 5Q value is the half inhibitory concentration, which is inversely proportional to the receptor binding capacity
  • Animals were selected from male Long-Evans rats (body weight 250-275 g) divided into three groups, 12-hour light and dark cycle feeding. The experiment was carried out one week after feeding.
  • Total autonomous activity was determined by observing the horizontal activity of the rats in an open environment.
  • the animals were placed in 8 black opaque chambers, and the autonomous activities were monitored by an infrared light meter placed equidistantly on the wall, recorded every 10 minutes for 120 minutes.
  • the zopiclone crystallization was administered at a dose of 10 mg/Kg, and the inhibition of activity was peaked 30 to 60 minutes after administration, and the effect disappeared after 2 hours.
  • This product is white or off-white crystal or crystalline powder.
  • test drug zopiclone crystals were prepared in accordance with Example 1 of the present invention.
  • Test method Accurately weigh the appropriate amount of fine powder, add a certain amount of solvent (accuracy ⁇ 2%), shake vigorously for 30 seconds every 5 minutes at 25 ⁇ 2 ° C, observe the dissolution within 30 minutes happening.
  • the test results are shown in Table 1.
  • the zopiclone crystals are easily soluble in chloroform, dissolved in 0.1 mol/L hydrochloric acid, slightly soluble in acetone, ethyl acetate or methanol, slightly soluble in ethanol and diethyl ether, and hardly soluble in water.
  • test drug zopiclone crystals were prepared in accordance with Example 1 of the present invention.
  • the zopiclone crystals were placed in batches in an open, colorless, transparent weighing bottle and placed in an incubator at 60 ° C for 10 days. Samples were taken on the 5th and 10th days respectively, and the test was carried out according to the stability key investigation items. The test results are shown in Table 3. The test results show that: The product is placed at a high temperature of 60 ° C for 10 days, its properties, melting point, related substances including Zuo Zuo The results of the determination of the cloned content were basically consistent with the results of 0 days, and the sample was stable.
  • the X-ray diffraction pattern of the zopiclone crystal of the present invention placed under high temperature for 10 days is shown in Fig. 4.
  • the zopiclone crystals were placed in an open, colorless and transparent weighing bottle, and placed in a closed container with a relative humidity of 92.5% (KN0 3 saturated solution) for 10 days, and samples were taken on the 5th and 10th days, respectively. According to the stability key inspection project, the weight of the test sample before and after the test is accurately weighed. The test results are shown in Table 2 and Table 3.
  • test results show that: The product is placed under high humidity conditions for 10 days, and the sample is slightly weighted.
  • the test results are shown in Table 2. It is basically consistent with the 0-day result.
  • the X-ray diffraction pattern of the zopiclone crystal of the present invention placed under high humidity conditions for 10 days is shown in Fig. 5.
  • the crystal samples of zopiclone were placed in an open, colorless and transparent weighing bottle, and directly irradiated for 10 days under 4500 ⁇ 500 Lx light, and samples were taken on the 5th and 10th days respectively.
  • the test results are shown in Table 3.
  • the test results show that:
  • the product is light (4500 ⁇ 500Lx) for 10 days.
  • Its traits, melting point and related substances, including the content of zozopiclone, are basically consistent with the results of 0 days, and the sample is stable.
  • the X-ray diffraction pattern of the zopiclone crystal of the present invention placed under strong light irradiation for 10 days is shown in Fig. 6.
  • the zopiclone crystallization sample was simulated and packaged in a listed drug, and placed in an incubator at a temperature of 40 ⁇ 2 ° C and a relative humidity of 75 ⁇ 5% for 6 months, sampling at 1 2 3 and 6 months, respectively.
  • the project is tested and the test results are shown in Table 4.
  • the test results show that: The product has been accelerated for 6 months, and its traits, melting point and related substances, including the content of zozopiclone, are basically consistent with the results of 0 days, and the sample is stable.
  • the X-ray diffraction pattern of the zopiclone crystal of the present invention placed in a temperature of 40 ⁇ 2 ° C and a relative humidity of 75 ⁇ 5% for 6 months is shown in Fig. 7
  • the zopiclone crystallization sample was simulated and packaged at room temperature, respectively, at 3 6 9 12 18
  • test results show that: The product has been tested for a long time, and its traits, melting point and related substances, including the content of zozopiclone, are basically consistent with the results of 0 days, and the sample is stable.
  • the X-ray diffraction pattern of the zopiclone crystal of the present invention placed at room temperature for 36 months is shown in Fig. 8.
  • the zopiclone crystals were placed in an open, colorless and transparent weighing bottle, and exposed to a high temperature of 60 ° C, a relative humidity of 92.5%, and an illuminance of 4500 ⁇ 500 Lx for 10 days;
  • This product simulates the commercial packaging at 40 ⁇ 2°C and the relative humidity of 75 ⁇ 5%.
  • This product simulates the commercial packaging for a long period of time at room temperature for 36 months.
  • the traits, melting points and related substances of zopiclone crystals, including the results of zozopiclone determination, have no significant changes compared with the results of 0 days.
  • the high dose that all subjects in the Tolerance Test can tolerate is 1 1.25 mg/kg body weight. , set low, medium and high doses of 3, 6 and 12 mg / kg body weight respectively. All three subjects were randomly divided into three groups. Each group received different doses of test drugs at each test. After each test, each subject was Latin. The order of the square design was accepted in three doses of high, medium and low, and the interval between the two trials was 2 weeks.
  • the subjects took the veins immediately before the medication and at the 15th, 30th, 45th, 60th and 1.5th, 2nd, 3rd, 4th, 6th, 8th, 12th, 16th and 24th hours after the medication. Heparin was anticoagulated 6 mL, and the concentration of zopiclone was determined. The plasma drug concentration of each subject at different time points was determined by HPLC method and the drug time curve was plotted. The main pharmacokinetic parameters AUC, C max , T max , AUC 0 ⁇ AUC Q- ⁇ P t of each subject were calculated. 1/2 and so on.
  • Inclusion and exclusion criteria 19 45 years old, body mass index 19 ⁇ 29kg/m 2 .
  • the subject's medical history, physical examination, electrocardiogram, and laboratory tests were used to indicate the health of the subject. A written informed consent was signed prior to the trial.
  • Pharmacokinetic indicators Determination of plasma drug concentration immediately before administration and at different time points after administration, plot the drug time and calculate the main pharmacokinetic parameters, including C max T max AUC 0- ⁇ AUC ⁇ P t 1/2
  • Pharmacokinetics The main pharmacokinetic parameters were calculated using 3P97 statistical analysis software.
  • Safety A list of meaningful clinical safety indicators by type and frequency of occurrence.
  • the main adverse reaction is bitterness, accounting for 25% to 40%; followed by dizziness and headache.
  • the frequency and type of adverse reactions in the 12 mg dose group were higher than those in the low dose group and the middle dose group.
  • Two subjects who received 12 mg had a sputum state with more words, more activity, and a higher consciousness. These adverse reactions were mild, no special treatment, and short duration, all disappeared within 12 hours after taking the drug. in conclusion:
  • the zopiclone crystalline tablets were rapidly absorbed orally, and the dose was linearly related to the plasma concentration of the drug in the range of 3-12 mg. Common adverse reactions are bitterness and dizziness, to a lesser extent, suggesting a better safety for clinical use.
  • a crystal is a solid substance in which atoms (or ions, molecules) are periodically arranged in space, and the crystal of an organic drug is basically a molecular lattice. Different crystal forms are produced depending on the process conditions. Different crystal forms of the same drug often cause significant differences in physical and chemical properties such as appearance, solubility, melting point, density, and drug dissolution and bioavailability, thereby affecting drug stability and bioavailability.
  • the study of drug polymorphism has become an indispensable part of the development and approval of new drugs, the production and quality control of drugs, and the design of new drug types.
  • Oral absorption is fast. Within the effective dose range, the dose has a linear relationship with the plasma concentration of the drug, which is safe for clinical use.
  • the peak value of the differential scanning calorimetry map is about 207.7 ° C;
  • the infrared absorption spectrum has peaks at about 3078 cm -1 , 2942 - 2838 cm “ 1 2790 cm “ 1 1715 cm , 1463 cm “ 1 1372 cm “ 1 757 cm .
  • the peak value of the differential scanning calorimetry map is about 208.4 ° C;
  • lO.Og eszopiclone was placed in a 1000 mL flask, 500 mL of ethyl acetate was added, stirred, heated, the solid gradually dissolved, refluxed for 10 minutes, cooled to about 35 ° C by natural cooling, stirred for 7 hours, then cooled to 3 About °C, stir for 5 hours, suction filtration, and vacuum drying to obtain 8.7 g of sample.
  • the peak value of the differential scanning calorimetry map is about 207.3 °C;
  • lO.Og eszopiclone was placed in a 250 mL flask, 100 mL of ethyl acetate was added, stirred, heated, the solid gradually dissolved, refluxed for 10 minutes, cooled to 50 ° C by natural cooling, stirred for 4 hours, then cooled to 8 After stirring at about °C, the mixture was stirred for 7 hours, suction filtered, and dried under vacuum to obtain 9.2 g of a sample.
  • the characteristic peaks of the X-ray powder diffraction spectrum at 2 ⁇ angle are about 11.08° and 12.38. , 15.86°, 17.85°, 19.90°, 20.58°;
  • the peak value of the differential scanning calorimetry map is about 207.2 ° C;
  • the infrared absorption spectrum has peaks at about 3077 cm, 2941 to 2837 cm, 2792 cm" 1 1715 cm, 1463 cm" 1 1372 cm" 1 758 cm.
  • lO.Og eszopiclone was placed in a 1000 mL flask, 800 mL of ethyl acetate was added, stirred, heated, the solid gradually dissolved, refluxed for 10 minutes, cooled to about 30 ° C by natural cooling, stirred for 10 hours, then cooled to - At about 5 °C, stir for 50 minutes, suction filtration, and vacuum drying to obtain 8.4 g of sample.
  • the characteristic peaks of the X-ray powder diffraction spectrum at 2 ⁇ angle are about 11.07° and 12.35. , 15.86°, 17.88°, 19.94°, 20.58°;
  • the peak value of the differential scanning thermogram is approximately: 208.rC;
  • the infrared absorption spectrum is about 3077cm -1 , 2943 ⁇ 2839cm _1 2791 cm" 1 1715cm , 1463cm" 1 1371cm -1 ,
  • eszopiclone 10.0 g was placed in a 1000 mL flask, 750 mL of ethyl acetate was added, stirred, heated, and the solid gradually dissolved, refluxed for 10 minutes, cooled to 45 ° C by natural cooling, stirred for 10 minutes, and then cooled to 0 °. Around C, the mixture was stirred for 2 hours, suction filtered, and vacuum dried to obtain 8.8 g of a sample.
  • the peak value of the differential scanning calorimetry map is about 207.5 °C;
  • the infrared absorption spectrum has peaks at about 3078 cm -1 , 2942 - 2838 cm “ 1 2790 cm “ 1 1717 cm “ 1 1463 cm “ 1 1371 cm -1 , and 759 cm -1 .
  • eszopiclone 10.0 g was placed in a 500 mL flask, 400 mL of ethyl acetate was added, stirred, heated, and the solid was gradually dissolved, refluxed for 10 minutes, cooled to about 35 ° C by natural cooling, stirred for 12 hours, and then cooled to -10. About °C, stir for 10 minutes, suction filtration, and vacuum drying to obtain 8.3 g of sample.
  • the peak value of the differential scanning calorimetry map is about 207.7 ° C;
  • the infrared absorption spectrum has peaks at about 3078 cm -1 , 2941 to 2837 cm , 2790 cm “ 1 1715 cm , 1464 cm “ 1 1372 cm “ 1 757 cm .
  • Example 8 Preparation of zopiclone crystallization lO.Og eszopiclone was placed in a 1000 mL flask, 700 mL of ethyl acetate was added, stirred, heated, the solid gradually dissolved, refluxed for 10 minutes, cooled to about 38 ° C by natural cooling, stirred for 12 hours, then cooled to 10 The mixture was stirred at a temperature of about °C for 12 hours, filtered by suction, and dried under vacuum to obtain a sample of 8.9 g.
  • the peak value of the differential scanning calorimetry map is about 207.6 ° C;
  • the infrared absorption spectrum has peaks at about 3081 cm, 2943 ⁇ 2838 cm _1 2790 cm" 1 1715 cm, 1466 cm" 1 1372 cm" 1 757 cm.
  • a tablet of 10,000 tablets each containing 3 mg of eszopiclone crystals was prepared.
  • the specific operation process is as follows: zopiclone crystallization, lactose, corn starch, pregelatinized starch, povidone K30, sodium carboxymethyl starch, and microsilica gel are respectively passed through a 100 mesh sieve for use.
  • the zopiclone crystals were weighed according to the prescription, mixed with other excipients according to the same amount, and passed through a 100 mesh sieve for 3 times.
  • the above powder was added with an appropriate amount of 8% povidone 30 aqueous solution to make a soft material.
  • Granulation wet granules are dried at 50 ⁇ 60 °C; granules are sieved through 20 mesh sieves, added with micro-silica gel, mixed; added with magnesium stearate; measured by angle of repose, less than 30 °; Tablet weight; using a 6mm shallow concave punch for tableting; to be coated.
  • the tablets were coated with an Opardry II coating agent in an Opardry ll coating (stomach-soluble) conventionally formulated as a coating solution.
  • the water is selected as the solvent, and the solid content of the coating liquid is 18%.
  • the inlet air temperature is 80 ° C
  • the bed temperature is 38 to 40 ° C
  • the atomization pressure is 3.5 bar
  • the coating pan speed is 23 rpm
  • the feed flow rate is 2 to 3 g/min.
  • the film has good strength and adhesion, complete coverage and uniform coloration. The patient took about 1 hour before going to bed and took 1 to 4 tablets a day.
  • a capsule of 10,000 capsules containing 3 mg of eszopiclone crystals per capsule was prepared.
  • the specific operation process is as follows: zopiclone crystallization, lactose, corn starch, pregelatinized starch, povidone K30, sodium carboxymethyl starch, and microsilica gel are respectively passed through a 100 mesh sieve for use.
  • the zopiclone crystals were weighed according to the prescription, mixed with other excipients according to the same amount, and passed through a 100 mesh sieve for 3 times.
  • the above powder was added with an appropriate amount of 8% povidone 30 aqueous solution to make a soft material.
  • Granulation wet granules are dried at 50 ⁇ 60 °C; sieve through 20 mesh sieves, add micro-silica gel, mix; add magnesium stearate to mix; measure the angle of repose, less than 30 °; determine the content, determine the loading Involvement.

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Description

一种右佐匹克隆结晶及其组合物、 其制备方法和应用 技术领域
本发明涉及医药领域， 具体涉及一种右佐匹克隆的结晶及其组合物， 其制备方法和医药 用途。 背景技术
佐匹克隆由法国罗纳普朗克 -乐安公司于 80年代中期研制，以商品名忆梦返（IMOVANE) 等在欧洲等 80多个国家上市， 用于治疗睡眠紊乱。 1999年的销售额约为 1亿 6千万美元。 该药在国内也有接近 10年的应用。 目前有上海华氏制药有限公司、齐鲁制药厂、广东顺峰药 业 生产。 佐匹克隆的结构式如下：
Figure imgf000003_0001
佐匹克隆消旋体 右佐匹克 右佐匹克隆是佐匹克隆的右旋手性单体， 即 (+)-(S)-(4-甲基哌嗪 -1-羧酸) (6-(5-氯吡啶 -2- 基) -7-羰基 -6,7-二氢 -5-氢-吡咯并 [3,4-b]吡嗪 -5-酯)。 由美国 Sepracor公司从 1998年起开始研 制， 并于 2004年 10月获得 FDA批准上市。右佐匹克隆与佐匹克隆消旋体相比， 具有以下显 著优点： 佐匹克隆存在严重的副作用， 包括： 由于唾液分泌药物引起的口苦、 口干、 倦睡、 早晨疲劳、 头痛、 眩暈、 神经运动功能损伤等， 而右佐匹克隆的副作用较佐匹克隆消旋体小; 药效学研究表明， 佐匹克隆的短效催眠作用主要由右旋异构体引起， 因此其药效比消旋体要 好； 急毒比较研究显示， 右佐匹克隆的毒性显著低于佐匹克隆消旋体的毒性； 与佐匹克隆消 旋体相比， 服用右佐匹克隆可在产生抗焦虑作用的同时不影响运动协调能力； 佐匹克隆对于 苯二氮罩受体具有立体选择性， 而右佐匹克隆对苯二氮罩受体的亲和力为左旋对映体的 50 倍。
众所周知， 化合物包括药物常常有一种以上的结晶形态， 称作多晶型现象。 通常同一药 物的不同晶型会表现出不同的物理性质和化学稳定性， 所以使用确定结晶形态的药物活性成 分用于制剂生产， 对于保证药物的疗效、 降低毒副作用发生率有着重要作用。 目前为止， 所 公开的有关右佐匹克隆的制备方法及其组合物的应用均未涉及确定的结晶形态描述。 发明内容
本发明的目的是提供一种具有稳定结晶形态的右佐匹克隆。
本发明的另一目的是提供前述结晶形态右佐匹克隆的制备方法。
本发明再一目的是提供含有前述结晶形态右佐匹克隆的组合物。
本发明又一目的是提供前述结晶形态右佐匹克隆的医药用途。
本发明的右佐匹克隆结晶形态， 其粉末 X-射线衍射图谱、 差示扫描热分析 （DSC) 图谱 和红外吸收 （IR) 图谱分别清楚地示于附图。 其相关数据如下。
差示扫描热分析图谱的峰值为： 207.7°C。
粉末 X-射线衍射图谱特征峰的 2Θ ( Θ为掠射角）值（平均值） 为: 约 11.08°、 约 12.38°、 约 15.86。、 约 17.88。、 约 19.98。、 约 20.58。。
红外吸收图谱的特征峰为：约在 30780^ 2942~28380^ 27900^ 1716cm"1 1463cm"1 1372cm"1 757cm 有峰。 优选在约 3078cm 、 约 2942 2838cm 、 约 2790cm 、 约 1716cm-1、 约 1577~1545cm-1、 约 1463cm-1、 约 1372cm-1、 约 1007cm-1、 约 849cm-1、 约 757cm-1有峰。
以公认的粉末 X-射线衍射、差示热扫描法和红外吸收光谱对本发明中的右佐匹克隆结晶 进行了表征。
由结晶化合物得到的粉末 X-射线衍射图谱对于给定的结晶形态往往是特征的， 其使用 Cu-Ka辐射， 以 2Θ角度表示。
DSC测定当结晶由于其晶体结构发生变化或晶体熔融而吸收或释放热时的热转变温度。 在连续的分析中， 热转变温度和熔点的差异典型地是在约 2°C之内， 通常在约 1 °C之内。 当一 个化合物具有一给定值的 DSC峰或熔点时，是指 DSC峰或熔点的差异在 2°C之内。这是一种 辨别不同右佐匹克隆结晶形态的替代方法。 不同的结晶形态可 （至少是部分地） 根据其不同 的转变温度特性而加以初步识别。
IR测定由与分子中对应于光振动的基团相关的特定化学键引起的红外光吸收。
DSC和 IR可提供能用来描述右佐匹克隆结晶的理化性质的信息。
制备本发明右佐匹克隆结晶所需的原料右佐匹克隆通过以下方法制得：
将佐匹克隆消旋体、 D-(+)-苹果酸加入甲醇和丙酮的混合液中， 20~30°C下搅拌溶解， 然 后降温到 0~10°C， 保温约 6~48小时， 继续搅拌， 过滤， 用甲醇洗涤， 干燥得 D-(+)-苹果酸 -S- 佐匹克隆。 将得到的 D-(+)-苹果酸 -S-佐匹克隆溶解在水中， 调 pH值为 6~9， 乙酸乙酯萃取， 干燥， 浓缩， 过滤， 滤饼洗涤、 干燥， 得到原料右佐匹克隆。
由于化合物晶体的生成不可预期， 与其制备条件关系非常密切。 在右佐匹克隆精制过程 中， 乙酸乙酯作为结晶溶剂不仅毒性低、 操作简便、 成本低， 而且收率高。 申请人充分考察 了以乙酸乙酯为溶剂进行结晶的不同条件。
本发明的右佐匹克隆结晶按照下述制备方法制得：
( 1 ) 将右佐匹克隆溶解在 60°C至回流温度的乙酸乙酯中， 对于每克右佐匹克隆， 乙酸 乙酯用量为 10~80mL， 优选为对于每克右佐匹克隆， 乙酸乙酯用量为 25~50mL;
(2) 自然冷却至 30~50°C， 优选 35~45 °C ; 保温 10分钟〜 12小时， 优选 1~6小时；
( 3 ) 继续降温至 10~-10°C， 优选为 5 5 °C ; 保温 10分钟〜 12小时， 优选 1~6小时； 以 及
(4) 分离出结晶。
制备过程中无需或可以使用搅拌装置， 优选使用搅拌装置。
本发明还包括一种药物组合物， 所述药物组合物含有治疗有效量的本发明的右佐匹克隆 结晶以及药学上可接受的载体， 也可以加入其他药物一起配伍制成复合制剂。
所述的药物组合物， 是单位剂量的药物制剂形式， 所述单位剂量的药物制剂形式是指制 剂的单位， 如片剂的每片、 胶囊的每粒、 口服液的每瓶、 颗粒剂的每袋等。
本发明的右佐匹克隆结晶在制剂中所占重量百分比可以是 0.1~99.9%，其余为药学上可接 受的载体； 本发明的右佐匹克隆结晶在制剂中所占重量百分比优选为 0.1~20%， 最优选为 1~10%。
通常可使用标准的制药技术， 即可将本发明的右佐匹克隆结晶和药学上可接受的载体制 得本发明的药物组合物， 这些方法包括混合、 制粒和压制。 本领域技术人员熟知， 药学上可 接受的载体的形式和特性取决于与其混合的活性成分的量、 给药途径和其他已知因素。 本文 中， 所用的药学上可接受的载体是可与组合物联用给药的各种有机或无机载体， 例如： 用于 固体制剂的赋形剂、 润滑剂、 粘合剂、 崩解剂和包衣剂； 也可使用药学上可接受的添加剂如 着色剂和甜味剂。 所述药学上可接受的载体选自： 糖类， 例如麦芽糖、 葡萄糖、 果糖、 右旋 糖苷、 蔗糖、 乳糖、 环糊精 （如 β-环糊精）、 淀粉、 纤维素及其衍生物； 糖醇， 例如甘露醇、 山梨醇和木糖醇； 无机酸类， 例如盐酸、 硫酸和磷酸； 无机盐类， 例如氯化钠、 氯化钾、 焦 亚硫酸钠、 亚硫酸氢钠、 硫代硫酸钠、 碳酸钙、 碳酸氢钙、 一价碱金属的碳酸盐、 磷酸盐或 其水溶液； 氨基酸类， 例如甘氨酸、 蛋氨酸和盐酸半胱氨酸； 有机盐类， 例如 EDTA二钠、 EDTA钙钠、 乳酸钠、 硬脂酸盐 （如硬脂酸钙和硬脂酸镁） 和藻酸盐； 以及其他常用的药学 上可接受的载体巯基乙酸、 醋酸、 维生素 C、 硅衍生物、 明胶、 聚乙烯吡咯烷酮、 甘油、 吐 温 80、 琼脂、 表面活性剂、 聚乙二醇、 磷脂类材料、 高岭土和滑石粉等。
本发明的右佐匹克隆结晶， 其药物制剂形式可以是任何药学上可接受的剂型， 这些剂型 包括： 片剂、 糖衣片剂、 薄膜衣片剂、 肠溶衣片剂、 胶囊剂、 硬胶囊剂、 软胶囊剂、 口服液、 口含剂、 颗粒剂、 冲剂、 丸剂、 散剂、 膏剂、 丹剂、 混悬剂、 粉剂、 溶液剂、 注射剂、 栓剂、 软膏剂、 硬膏剂、 霜剂、 喷雾剂、 滴剂和贴剂。 本发明的制剂， 优选的是口服剂型， 例如胶 囊剂、 片剂、 口服液、 颗粒剂、 丸剂、 散剂和丹剂等； 以及注射剂， 例如粉针剂、 注射液和 静脉滴注剂等。 本发明的制剂， 最优选为片剂。
本发明的右佐匹克隆稳定结晶， 其口服给药的制剂可含有常用的赋形剂、 粘合剂、 填充 齐 U、 稀释剂、 压片剂、 润滑剂、 崩解剂、 着色剂、 调味剂和湿润剂， 必要时可对片剂进行包 衣。
优选的示例赋形剂包括： 乳糖、 D-甘露醇、 D-山梨醇、 淀粉 （例如 α-淀粉、 支链淀粉、 糊精）、 纤维素及其衍生物 （例如结晶纤维素、 低取代的羟丙基纤维素、 羧甲基纤维素钠）、 阿拉伯胶、 轻质无水硅酸、 合成硅酸铝、 硅酸铝镁等。
优选的示例润滑剂包括： 硬脂酸镁、 硬脂酸钙、 滑石粉和硅胶等。
优选的示例粘合剂包括： 淀粉 （例如 α-淀粉、 糊精、 支链淀粉）、 蔗糖、 海藻糖、 明胶、 阿拉伯胶、 纤维素及其衍生物 （甲基纤维素、 羧甲基纤维素、 羧甲基纤维素钠、 结晶纤维素、 羟丙基纤维素、 羟丙基甲基纤维素）、 D-甘露醇和吡咯烷酮等。
优选的示例崩解剂包括： 乳糖、 淀粉、 羧甲基淀粉钠、 纤维素及其衍生物 （羧甲基纤维 素、 羧甲基纤维素钙、 低取代的羟丙基纤维素）、 轻质无水硅酸等。
优选的示例包衣剂包括： 羟丙基甲基纤维素、 羟丙基纤维素、 乙基纤维素、 羧甲基纤维 素和聚乙烯醇等。
优选的示例着色剂包括： 水溶性食用枸橼黄染料 （食用染料例如食用红 No. 2和 No. 3， 食用黄 No. 4和 No. 5， 食用蓝 No. 1和 No. 2)； 水不溶性色沉染料 （例如上述水溶性食用枸 橼黄染料的铝盐）； 天然染料 （例如 β-胡萝卜素、 叶绿素、 铁丹） 等。
优选的示例甜味剂包括： 糖精钠、 甘草次酸二钾、 阿斯帕坦和甜菊等。
本发明的药物组合物可以经任何适于给药的途径方便地施用， 例如可经口服、 局部、 非 肠道或吸入， 优选经口服施用。
本发明的药物组合物在治疗睡眠紊乱时的剂量为 l~15mg/剂量单位， 优选为 3~12mg/剂 量单位。
本发明的药物组合物在使用时根据病人的情况确定用法用量， 可每日用药一次， 每次 1~10剂， 如： 睡前服用 1~10袋、 或 1~10粒、 或 1~10片。
附图说明
图 1 是本发明右佐匹克隆结晶的 X-射线衍射图谱。 图 2 是本发明右佐匹克隆结晶的差示扫描热分析图谱。
图 3 是本发明右佐匹克隆结晶的红外吸收图谱。
图 4 是本发明右佐匹克隆结晶高温 （60°C ) 放置 10天的 X-射线衍射图谱。
图 5 是本发明右佐匹克隆结晶高湿 （25 °C、 相对湿度 92.5% ) 放置 10天的 X-射线衍射 图谱。
图 6 是本发明右佐匹克隆结晶强光 （4500±500Lx) 照射 10天的 X-射线衍射图谱。
图 7 是本发明右佐匹克隆结晶在温度 40±2°C、 相对湿度 75±5%环境中放置 6个月的 X- 射线衍射图谱。
图 8 是本发明右佐匹克隆结晶在室温条件下放置 36个月的 X-射线衍射图谱。
本发明还提供了右佐匹克隆结晶在制备治疗睡眠紊乱的药物中的应用。 下面是其药效学 研究结果。
试验例 1本发明的右佐匹克隆结晶的药效学研究结果
右佐匹克隆的化学结构与苯二氮罩类药物不同，目前认为其作用于 GAB AA受体 /C1通道 复合体中苯二氮罩受体的不同结合位点。
试验药物右佐匹克隆结晶依照本发明实施例 1制得。
1. 右佐匹克隆结晶药效学体外试验
右佐匹克隆与苯二氮罩受体结合 IC5Q值 （IC5Q值是半数抑制浓度， 该值与受体结合能力 成反比） 为 21±3(nmol/L)， 说明右佐匹克隆与受体的亲和力很强。 尽管佐匹克隆的化学结构 与苯二氮罩类药物不同， 但二者的作用机制类似， 均与苯二氮罩受体结合， 只是结合位点不 同。
2. 右佐匹克隆结晶药效学体内试验
动物选用雄性 Long-Evans大鼠 （体重 250~275g) 分为三组， 12小时光照与黑暗循环饲 养。 饲养一周后进行实验。
2.1 自主活动试验
通过在开放环境下观察大鼠的水平活动来测定总的自主活动。动物分别置于 8个黑色不 透光室中， 由按等距离放置在墙上的红外光感仪监测自主活动， 每隔 10分钟记录一次， 记录 120分钟。
以 10 mg/Kg的剂量给予右佐匹克隆结晶，服药后 30〜60分钟对于活动能力的抑制作用 达到峰值， 并且在 2个小时后作用消失。
2.2迷宫试验 给予 lOmg/Kg 右佐匹克隆结晶对进入总数、 开放臂及闭合臂进入数均有显著性作用； 5mg/Kg及 10mg/Kg右佐匹克隆结晶均可显著增加大鼠在开放臂中的停留时间。
以上试验结果显示， 右佐匹克隆结晶可以有效地治疗睡眠紊乱， 在产生抗焦虑作用的同 时对运动协调能力的影响很小。
试验例 2右佐匹克隆结晶的性质和稳定性研究
本品为白色或类白色结晶或结晶性粉末。
1. 溶解性
根据中国药典 2000年版凡例中的方法， 做常用溶剂的溶解度试验。
试验药物右佐匹克隆结晶， 依照本发明实施例 1制得。
试验法： 准确称取本品细粉适量， 加入一定量的溶剂 （准确度 ±2% )， 在 25±2°C下， 每 隔 5分钟强力振摇 30秒钟， 观察 30分钟内的溶解情况。 试验结果列于表 1。
表 1 本发明的右佐匹克隆结晶的
Figure imgf000008_0001
结论:
右佐匹克隆结晶在氯仿中易溶， 在 O. lmol/L盐酸中溶解， 在丙酮、 乙酸乙酯或甲醇中微 溶， 在乙醇和乙醚中极微溶解， 在水中几乎不溶解。
2. 稳定性
试验药物右佐匹克隆结晶， 依照本发明实施例 1制得。
2.1 高温 （60°C ) 试验
将右佐匹克隆结晶批量放置在敞口无色透明的称量瓶中，在 60°C的恒温箱中放置 10天， 分别于第 5天和第 10天取样， 按稳定性重点考察项目进行测定， 试验结果见表 3 试验结果表明： 本品在高温 60°C放置 10天， 其性状、 熔点、 有关物质包括左佐匹克隆 含量的测定结果， 与 0天的结果比较基本一致， 样品稳定。 本发明的右佐匹克隆结晶在高温 条件下放置 10天的 X-射线衍射图谱见图 4
2.2 高湿 （25 °C， 相对湿度 92.5%) 试验
将右佐匹克隆结晶批量放置在敞口无色透明的称量瓶中， 在相对湿度 92.5% (KN03饱 和溶液） 的密闭容器中放置 10天， 分别于第 5天和第 10天取样， 按稳定性重点考察项目进 行测定， 同时准确称量试验前后供试品的重量。 试验结果见表 2和表 3
试验结果表明： 本品在高湿条件下放置 10天， 样品略有增重， 试验结果见表 2。 与 0 天结果比较基本一致。 本发明的右佐匹克隆结晶在高湿条件下放置 10天的 X-射线衍射图谱 见图 5
表 2 右佐匹克隆结晶高湿试验增重情况
Figure imgf000009_0001
2.3 强光照射试验
将右佐匹克隆结晶样品置于敞口无色透明的称量瓶中， 在 4500±500Lx灯光下直接照射 10天， 分别于第 5天和第 10天取样， 按稳定性重点考察项目进行测定， 试验结果见表 3 试验结果表明： 本品经光照 （4500±500Lx) 10 天， 其性状、 熔点、 有关物质包括左佐 匹克隆含量的测定结果， 与 0天结果比较基本一致， 样品稳定。 本发明的右佐匹克隆结晶在 强光照射条件下放置 10天的 X-射线衍射图谱见图 6
表 3右佐匹克隆结晶影响因素试验结果
Figure imgf000009_0002
2.4 加速试验
将右佐匹克隆结晶样品模拟上市药品包装， 在温度 40±2°C、 相对湿度 75±5%的恒温箱 中放置 6个月， 分别于 1 2 3和 6个月取样， 按稳定性重点考察项目进行测定， 试验结果 见表 4
试验结果表明： 本品经加速试验 6个月， 其性状、 熔点、 有关物质包括左佐匹克隆含量 的测定结果， 与 0天结果比较基本一致，样品稳定。本发明的右佐匹克隆结晶在温度 40±2°C 相对湿度 75±5%环境中放置 6个月的 X-射线衍射图谱见图 7
表 4 右佐匹克隆结晶加速试验结果
Figure imgf000010_0001
2.5 长期留样试验
将右佐匹克隆结晶样品模拟上市药品包装在室温条件下放置， 分别于 3 6 9 12 18
24和 36个月取样， 按稳定性重点考察项目进行测定， 与 0天的数据比较， 试验结果分别见 表 5
试验结果表明： 本品经长期留样考察， 其性状、 熔点、 有关物质包括左佐匹克隆含量的 测定结果， 与 0天结果比较基本一致， 样品稳定。 本发明的右佐匹克隆结晶在室温条件下放 置 36个月的 X-射线衍射图谱见图 8
表 5 右佐匹克隆结晶长期留样试验结果
Figure imgf000010_0002
结论：
综合上述试验结果，右佐匹克隆结晶置于敞口无色透明的称量瓶中，分别置于高温 60°C、 相对湿度 92.5%和照度为 4500±500 Lx强光下照射 10天；同时本品模拟市售包装置于 40±2°C、 相对湿度 75±5%条件下， 进行加速试验 6个月后， 其性状、 熔点、 有关物质包括左佐匹克隆 含量的测定结果， 与 0天结果比较均无明显变化。 影响因素结果说明本品应在密封、 干燥处 保存。
本品模拟市售包装在室温条件下长期试验 36个月， 右佐匹克隆结晶的性状、 熔点、 有 关物质包括左佐匹克隆含量测定结果， 与 0天结果比较均无明显变化。
在所述各种试验条件下，没有发现晶型的转变，表明本发明的右佐匹克隆结晶形态稳定。 试验例 3右佐匹克隆结晶单次给药健康人体药代动力学研究
1 . 试验目的
评价在正常健康人体多剂量单次给药的药代动力学， 以及药物在体内的分布、 代谢和排 泄的规律， 由于该药为口服制剂， 同时评价进食对药物吸收、 分布、 代谢和排泄过程的影响。
2. 研究方法
药代动力学评价： 根据 I期临床耐受性试验的结果以及 II期临床试验预计采用的治疗剂 量， 耐受性试验中所有受试者均能耐受的高剂量为 1 1.25mg/kg体重， 设定低、 中和高剂量分 别为 3、 6和 12mg/kg体重。 采用三向交叉拉丁方设计， 全部受试者随机分为 3个试验组， 每 组受试者每次试验时分别接受不同剂量的试验药， 3 次试验后， 每位受试者均按拉丁方设计 的顺序接受过高、 中和低三个剂量， 两次试验间隔为 2周。
其次评价进食对药物体内代谢过程的影响， 8例受试者随机分为 2个试验组， 每组受试 者分别在两次试验中空腹或标准饮食餐后 5分钟服药， 2次试验时接受同一剂量（6mg)的试 验药， 两次试验间隔为 2周。
受试者单次口服研究药物后， 分别在服药前即刻及服药后第 15、 30、 45、 60 分钟及第 1.5、 2、 3、 4、 6、 8、 12、 16和 24小时各取静脉肝素抗凝血 6mL， 测定右佐匹克隆的浓度。 采用 HPLC方法测定各受试者不同时间点的血浆药物浓度并绘制药时曲线， 计算各受试者的 主要药代动力学参数 AUC、 Cmax、 Tmax、 AUC0^ AUCQ-^P t1/2等。
3. 受试者选择
数量： （计划的和分析的） 每组 10人
入选及排除标准： 19 45岁， 体重指数 19~29kg/m2。 在筛查时根据受试者病史、 体格检 查、 心电图及实验室检查提示受试者身体健康， 试验前签署书面知情同意书。
4. 受试药物的规格、 用法用量： 右佐匹克隆结晶， 依照本发明实施例 1和实施例 9制成包衣片剂， 3mg/片， 单次口服。
5. 治疗时间
单次口服药物后共观察 24小时。
6. 评价标准
药代动力学指标： 给药前即刻及给药后不同时间点测定血浆药物浓度， 绘制药时曲线并 计算主要药代动力学参数， 包括 Cmax Tmax AUC0-∞ AUC<^^P t1/2
安全性指标： 在筛查及给药后 24小时测量生命体征、 体格检查、 心电图、 实验室检查， 在试验期间记录不良事件。
7. 统计方法
药代动力学： 采用 3P97统计分析软件计算主要药代动力学参数。
安全性： 对有意义的临床安全性指标按类型和发生频率列表。
8. 结果和结论
受试者严格遵守研究方案， 未发生任何方案偏离或违背， 无合并用药。 一名受试者服用 12mg药物 8小时后， 因非医疗原因未能完成后面三次取血。
药代动力学结果
受试者单次口服右佐匹克隆结晶后的药代动力学参数如表 6所示：
表 6 受试者单次口服右佐匹克隆结晶后的药代动力学参数
单次口服药代动力学研究 进食前后药代动力学研究 药代动力学参数 3mg 6mg 12mg 6mg (空腹） 6mg (进食）
C ( g L) 33.96±8.63 60.94±11.44 182.72±67.44 60.69±11.43 62.60±18.95
T (hr) 1.50±0.66 1.28±0.43 1.58±0.40 1.31±0.44 1.75±0.89
AUC0— ^g/hr L) 259.66±92.58 404.21±73.32 1291.26±426.68 335.73±145.57 284.00±88.36 ti/2(hr) 6.98±0.99 8.20±6.14 8.06±2.82 7.17±2.69 6.75±1.49 血浆清除率 (L/hr) 14.10±4.5 15.80±3.0 10.90±5.00 16.00±3.3 21.4±7.4 安全性结果：
主要的不良反应是口苦， 占 25%~40%； 其次是头暈头痛。 12mg剂量组不良反应频次和 种类多于低剂量组和中剂量组。 2例服 12mg的受试者出现了话多、 活动多、 意识朦胧的谵妄 状态。 这些不良反应轻微， 未进行特殊处理， 持续时间短暂， 均在服药后 12小时内消失。 结论：
右佐匹克隆结晶片剂口服吸收快速， 3~12mg剂量范围内，剂量与药物血浆浓度有线性关 系。 常见的不良反应是口苦和头暈， 程度轻微， 提示临床使用有较好的安全性。
晶体是由原子 （或离子、 分子） 在空间周期地排列构成的固体物质， 有机药物的结晶基 本上属于分子晶格。 随着工艺条件的不同而产生不同的晶型。 同一药物的不同晶型常引起药 物在外观、 溶解度、 熔点、 密度等理化性质以及药物溶出度、 生物有效性等的显著差异， 从 而影响药物稳定性、 生物利用度等的发挥。 药物多晶型的研究已经成为新药开发和审批、 药 物的生产和质量控制以及新药剂型确定前设计所不可缺少的重要组成部分。
本发明的右佐匹克隆结晶的有益效果在于：
1. 可以有效地治疗睡眠紊乱， 在产生抗焦虑作用的同时对运动协调能力的影响很小。
2. 口服吸收快速。在有效剂量范围内， 剂量与药物血浆浓度有线性关系， 临床使用有较 好的安全性。
3. 在所述各种试验条件下， 没有发现晶型的转变， 表明本发明的右佐匹克隆的结晶形态 稳定。
4. 具有良好的流动性、 可压性 （压片容易成型）。 在药效学和药代动力学完全能满足临 床需要的前提下， 为实际的制剂生产带来了极大的便利。
具体实施方式
下面通过具体的实施方式对本发明作进一步的说明， 但不作为对本发明的限制。
制备例 原料右佐匹克隆的制备
在 3L反应瓶中加入 100g佐匹克隆消旋体、 34g D-C+ 苹果酸、 lOOOmL甲醇和 1500mL 丙酮， 室温下搅拌溶解 2小时， 然后降温到 6°C， 保温存储大约 24小时， 继续搅拌 1小时， 过滤， 用 lOOmL甲醇分两次洗涤， 干燥得 D-(+)-苹果酸 -S-佐匹克隆 52.5g。
将得到的 D-(+)-苹果酸 -S-佐匹克隆 52.5g溶解在 lOOOmL水中， 用 8%的碳酸氢钾将 pH 值调为 8， 有固体析出， 用 lOOOmL乙酸乙酯分四次萃取， 将乙酸乙酯层用无水硫酸钠干燥 5 小时， 过滤除去干燥剂后蒸熘浓缩， 过滤， 用 lOOmL乙酸乙酯分 3次洗涤， 干燥得到 33.2g 原料右佐匹克隆。
实施例 1 右佐匹克隆结晶的制备
将 lO.Og右佐匹克隆置于 500mL烧瓶中， 加入 350mL乙酸乙酯， 搅拌， 加热， 固体逐渐 溶解， 回流 10分钟， 自然冷却降温至 40°C左右， 保温搅拌 2小时， 然后冷却至 0°C左右， 保 温搅拌 1小时， 抽滤， 真空干燥， 得样品 8.9g。 鉴定： X-射线粉末衍射光谱以 2Θ角度表示的特征峰约在 11.08°、 12.38。、 15.86°、 17.88°、 19.98°、 20.58°；
差示扫描热分析图谱的峰值约为： 207.7°C ;
红外吸收图谱约在 3078cm-1、 2942-2838cm"1 2790cm"1 1715cm 、 1463cm"1 1372cm"1 757cm 有峰。
实施例 2 右佐匹克隆结晶的制备
将 lO.Og右佐匹克隆置于 500mL烧瓶中， 加入 250mL乙酸乙酯， 搅拌， 加热， 固体逐渐 溶解， 回流 10分钟， 自然冷却降温至 45 °C左右， 保温搅拌 10分钟， 然后冷却至 1 °C左右， 保温搅拌 2小时， 抽滤， 真空干燥， 得样品 9.0g。
鉴定： X-射线粉末衍射光谱以 2Θ角度表示的特征峰约在 11.15°、 12.38°、 15.92°、 17.79°、
19.93。、 20.52°；
差示扫描热分析图谱的峰值约为： 208.4°C ;
红外吸收图谱约在 3081cm-1、 2941~2838cm 、 2791 cm"1 1716cm"1 1463cm"1 1372cm"1 758cm 有峰。
实施例 3 右佐匹克隆结晶的制备
将 lO.Og右佐匹克隆置于 lOOOmL烧瓶中， 加入 500mL乙酸乙酯， 搅拌， 加热， 固体 逐渐溶解， 回流 10分钟， 自然冷却降温至 35 °C左右，保温搅拌 7小时，然后冷却至 3 °C左右， 保温搅拌 5小时， 抽滤， 真空干燥， 得样品 8.7g。
鉴定： X-射线粉末衍射光谱以 2Θ角度表示的特征峰约在 11.08°、 12.42°、 15.87°、 17.81°、 19.90°、 20.55°；
差示扫描热分析图谱的峰值约为： 207.3 °C ;
红外吸收图谱约在 3077cm-1、 2942~2839cm_1 2791 cm"1 1714cm 、 1463cm"1 1372cm"1 757cm 有峰。
实施例 4 右佐匹克隆结晶的制备
将 lO.Og右佐匹克隆置于 250mL烧瓶中， 加入 lOOmL乙酸乙酯， 搅拌， 加热， 固体逐渐 溶解， 回流 10分钟， 自然冷却降温至 50°C左右， 保温搅拌 4小时， 然后冷却至 8°C左右， 保 温搅拌 7小时， 抽滤， 真空干燥， 得样品 9.2g。
鉴定： X-射线粉末衍射光谱以 2Θ角度表示的特征峰约在 11.08°、 12.38。、 15.86°、 17.85°、 19.90°、 20.58°；
差示扫描热分析图谱的峰值约为： 207.2°C ; 红外吸收图谱约在 3077cm 、 2941~2837cm 、 2792cm"1 1715cm 、 1463cm"1 1372cm"1 758cm 有峰。
实施例 5 右佐匹克隆结晶的制备
将 lO.Og右佐匹克隆置于 lOOOmL烧瓶中， 加入 800mL乙酸乙酯， 搅拌， 加热， 固体逐 渐溶解， 回流 10分钟， 自然冷却降温至 30°C左右， 保温搅拌 10小时， 然后冷却至 -5 °C左右， 保温搅拌 50分钟， 抽滤， 真空干燥， 得样品 8.4g。
鉴定： X-射线粉末衍射光谱以 2Θ角度表示的特征峰约在 11.07°、 12.35。、 15.86°、 17.88°、 19.94°、 20.58°；
差示扫描热分析图谱的峰值约为： 208.rC;
红外吸收图谱约在 3077cm-1、 2943~2839cm_1 2791 cm"1 1715cm 、 1463cm"1 1371cm-1、
757cm 有峰。
实施例 6 右佐匹克隆结晶的制备
将 10.0g右佐匹克隆置于 lOOOmL烧瓶中， 加入 750mL乙酸乙酯， 搅拌， 加热， 固体逐 渐溶解， 回流 10分钟， 自然冷却降温至 45 °C左右， 保温搅拌 10分钟， 然后冷却至 0°C左右， 保温搅拌 2小时， 抽滤， 真空干燥， 得样品 8.8g。
鉴定： X-射线粉末衍射光谱以 2Θ角度表示的特征峰约在 11.08°、 12.38。、 15.86°、 17.86°、 19.98°、 20.58°；
差示扫描热分析图谱的峰值约为： 207.5 °C ;
红外吸收图谱约在 3078cm-1、 2942-2838cm"1 2790cm"1 1717cm"1 1463cm"1 1371cm-1、 759cm-1有峰。
实施例 7 右佐匹克隆结晶的制备
将 10.0g右佐匹克隆置于 500mL烧瓶中， 加入 400mL乙酸乙酯， 搅拌， 加热， 固体逐渐 溶解， 回流 10分钟， 自然冷却降温至 35 °C左右， 保温搅拌 12小时， 然后冷却至 -10°C左右， 保温搅拌 10分钟， 抽滤， 真空干燥， 得样品 8.3g。
鉴定： X-射线粉末衍射光谱以 2Θ角度表示的特征峰约在 11.08°、 12.34°、 15.92°、 17.88°、
19.98°、 20.58°；
差示扫描热分析图谱的峰值约为： 207.7°C ;
红外吸收图谱约在 3078cm-1、 2941~2837cm 、 2790cm"1 1715cm 、 1464cm"1 1372cm"1 757cm 有峰。
实施例 8 右佐匹克隆结晶的制备 将 lO.Og右佐匹克隆置于 lOOOmL烧瓶中， 加入 700mL乙酸乙酯， 搅拌， 加热， 固体逐 渐溶解， 回流 10分钟， 自然冷却降温至 38°C左右，保温搅拌 12小时，然后冷却至 10°C左右， 保温搅拌 12小时， 抽滤， 真空干燥， 得样品 8.9g。
鉴定： X-射线粉末衍射光谱以 2Θ角度表示的特征峰约在 11.08°、 12.41°、 15.86°、 17.81°、 19.98°、 20.58°；
差示扫描热分析图谱的峰值约为： 207.6°C ;
红外吸收图谱约在 3081cm 、 2943~2838cm_1 2790cm"1 1715cm 、 1466cm"1 1372cm"1 757cm 有峰。
实施例 9 右佐匹克隆结晶片剂的制备
处方：
Figure imgf000016_0001
制成每片含 3mg右佐匹克隆结晶的片剂 10,000片。
具体操作过程为： 将右佐匹克隆结晶、 乳糖、 玉米淀粉、 预胶化淀粉、 聚维酮 K30、 羧 甲基淀粉钠、 微粉硅胶分别过 100 目筛备用。 按处方量称量右佐匹克隆结晶， 按等量递加法 与其他辅料混合均匀， 过 100目筛 3次； 上述粉状物加入适量 8 %聚维酮 Κ30水溶液制软材， 过 20目筛制粒， 湿粒于 50〜60°C下烘干； 颗粒过 20目筛整粒， 加入微粉硅胶， 混匀； 加入 硬脂酸镁混匀； 测休止角， 小于 30°; 测含量， 定片重； 使用 6mm浅凹冲头进行压片； 待包 衣。
素片采用 Opardry II包衣剂， 按 Opardry ll包衣剂 （胃溶型） 常规配制包衣液进行包衣。 选水为溶剂， 包衣液的固体含量 18%。 进风温度为 80°C， 片床温度为 38~40°C， 雾化压力为 3.5bar, 包衣锅转速为 23转 /分钟， 进料流速 2~3g/分钟。 衣膜强度、 附着力较好， 遮盖完全， 着色均匀。 患者睡前 1小时左右， 单次口服 1〜4片。
实施例 10 右佐匹克隆结晶胶囊剂的制备
处方：
Figure imgf000017_0001
制成每粒胶囊含 3mg右佐匹克隆结晶的胶囊剂 10,000粒。
具体操作过程为： 将右佐匹克隆结晶、 乳糖、 玉米淀粉、 预胶化淀粉、 聚维酮 K30、 羧 甲基淀粉钠、 微粉硅胶分别过 100 目筛备用。 按处方量称量右佐匹克隆结晶， 按等量递加法 与其他辅料混合均匀， 过 100目筛 3次； 上述粉状物加入适量 8 %聚维酮 Κ30水溶液制软材， 过 20目筛制粒， 湿粒于 50〜60°C下烘干； 过 20目筛整粒， 加入微粉硅胶， 混匀； 加入硬脂 酸镁混匀； 测休止角， 小于 30°; 测定含量， 确定装入量。
装入 3号胶囊。
患者睡前 1小时左右， 单次口服 1~4粒。

Claims

权利要求
1 . 一种右佐匹克隆结晶， 其特征在于： 其使用 Cu-Ka辐射， 以 2Θ角度表示的 X-射线粉 末衍射光谱约在 11.08。、 12.38°、 15.86°、 17.88°、 19.98°、 20.58°有峰； 其差示扫描热分析图 谱的峰值约为： 207.7°C ; 红外吸收图谱约在 3078cm 、 2942-2838cm"1 2790cm"1 1716cm"1 1463cm"1 1372cm"1 757cm 有峰。
2.权利要求 1所述的右佐匹克隆结晶的制备方法，其特征在于：所述方法包括以下步骤:
( 1 )将右佐匹克隆溶解在 60°C至回流温度的乙酸乙酯中， 对于每克右佐匹克隆， 乙酸乙 酯用量为 10~80mL;
(2) 自然冷却至 30~50°C， 保温 10分钟〜 12小时；
( 3 ) 降温至 10~-10°C， 保温 10分钟〜 12小时； 以及
(4) 分离出结晶。
3. 权利要求 2所述的制备方法， 其特征在于： 所述步骤（1 ) 中， 对于每克右佐匹克隆， 乙酸乙酯用量为 25~50mL; 所述步骤（2) 中自然冷却至 35~45 °C， 保温 1~6小时； 所述步骤
( 3 ) 中降温至 5~-5 °C， 保温 1~6小时。
4. 一种药物组合物， 其特征在于： 所述组合物含有权利要求 1所述的右佐匹克隆结晶和 药学上可接受的载体。
5. 权利要求 4所述的药物组合物， 其特征在于， 所述右佐匹克隆结晶的含量为 l~15mg/ 剂量单位。
6. 权利要求 5所述的药物组合物， 其特征在于， 所述右佐匹克隆结晶的含量为 3~12mg/ 剂量单位。
7. 权利要求 1所述的右佐匹克隆结晶在制备治疗睡眠紊乱的药物中的应用。
8. 权利要求 4~6任意一项所述的药物组合物在制备治疗睡眠紊乱的药物中的应用。
PCT/CN2009/000414 2008-06-18 2009-04-17 一种右佐匹克隆结晶及其组合物、其制备方法和应用 Ceased WO2009152684A1 (zh)

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RU2010152782/04A RU2492171C2 (ru) 2008-06-18 2009-04-17 Кристаллическая форма эсзопиклона, ее состав, приготовление и применение
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