WO2023208241A1 - 一种吡非尼酮持续性释放口服固体制剂 - Google Patents

一种吡非尼酮持续性释放口服固体制剂 Download PDF

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Publication number
WO2023208241A1
WO2023208241A1 PCT/CN2023/091991 CN2023091991W WO2023208241A1 WO 2023208241 A1 WO2023208241 A1 WO 2023208241A1 CN 2023091991 W CN2023091991 W CN 2023091991W WO 2023208241 A1 WO2023208241 A1 WO 2023208241A1
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sustained
pirfenidone
release
solid preparation
preparation
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PCT/CN2023/091991
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English (en)
French (fr)
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司俊仁
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越洋医药开发(广州)有限公司
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Publication of WO2023208241A1 publication Critical patent/WO2023208241A1/zh

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • 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
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the invention belongs to pharmaceutical technology, and particularly relates to a sustained-release oral solid preparation of pirfenidone.
  • the existing pirfenidone products on the market are immediate-release tablets and capsules, and no once-a-day sustained-release preparations are currently on the market.
  • the existing dosage forms have the following shortcomings:
  • the existing products are all ordinary immediate-release preparations.
  • the clinical data and instructions clearly indicate that the products need to be taken after meals. Patient compliance is low. If the patient forgets how to take them and takes them before meals, it is easy to cause adverse reactions.
  • the existing products are all ordinary immediate-release preparations, and their clinical data and instructions clearly indicate that the products need to be taken after meals. Therefore, the daily meal and medication times are fixed at 08:00, 12:00, and 18:00. However, this series of medication times will lead to higher blood drug concentrations during the day, while the blood drug concentrations at night are too low, making it difficult to truly take medication within 24 hours. Achieve stable and effective blood drug concentration.
  • the present invention has developed an oral sustained release preparation that can be taken once a day and can be released stably and effectively for 24 hours.
  • the specific plan is as follows:
  • a sustained-release oral solid preparation of pirfenidone characterized in that: it contains a sustained-release preparation, and the sustained-release preparation contains a swelling material, a shaping material and an adhesion material;
  • the weight percentage of the swelling material in the solid preparation is 10-25%; the weight percentage of the shaping material in the solid preparation is 10-25%; the weight percentage of the adhesion material in the solid preparation is Weight percentage is 1-8%;
  • the viscosity of the swelling material is in the range of 500-300000mpa.s
  • the viscosity of the adhesive material is in the range of 50-100000mpa.s
  • the viscosity of the shaping material is in the range of 50-60000mpa.s;
  • the swelling material is selected from the group consisting of sodium carboxymethylcellulose, glyceryl behenate, sodium alginate, calcium alginate, potassium alginate, hypromellose (HPMC), carbomer, ammonium alginate, and carnauba wax. , one or more of tragacanth, acacia, and shellac;
  • the shaping material is selected from sodium carboxymethylcellulose, calcium carboxymethylcellulose, ethylcellulose, carbomer, polylactic acid, polylactic acid-glycolic acid copolymer, sodium alginate, hydrogenated vegetable oil, and ethylene-ethylene copolymer.
  • the adhesive material is selected from one or more of hydroxyethyl cellulose, gelatin, polyoxyethylene, carbomer, pectin, chitosan, glucose, alginate, fucosamine, starch, and chitin. kind;
  • the blood drug concentration parameters achieved by the sustained-release oral dosage form when administered once a day according to the daily dose are: within 24 hours after taking the drug, the maximum blood drug concentration (C max ) and the minimum blood drug concentration corresponding to the blood drug concentration curve
  • the ratio of blood drug concentration (C min ) is within 2 to 10, preferably 2 to 5, and more preferably 2 to 3.5.
  • the sustained-release oral solid preparation of pirfenidone is characterized in that the proportion of the sustained-release preparation to the total tablet weight is 50 to 100%, or any value within this range; Or the proportion of the sustained-release preparation to the total tablet weight is 50%, 60%, 65%, 70%, 73%, 78%, 85%, 73%, 80%, 85%, 90% or any of these values. Two formed ranges.
  • the pirfenidone sustained-release oral solid preparation is characterized by:
  • the API in the sustained-release preparation accounts for 50% to 100% of the total API, or any value within this range; or the proportion of the total API is 50%, 60%, 65%, 70%, 73%, 78%, 85% %, 73%, 80%, 85%, 90% or a range formed by any two of these values.
  • the pirfenidone sustained-release oral solid preparation is characterized in that the specific gravity of the swelling material and the adhesive material is 1 to 9:1, 8:1, 7:1, 6: 1, 5:1, 4:1, 3:1, 2:1 or 1:1;
  • the proportion of adhesive material and shaping material is 0.2 ⁇ 1:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1 or 0.9:1.
  • the sustained-release oral solid preparation of pirfenidone is characterized in that it is a single-layer tablet, and the sustained-release preparation accounts for 100% of the weight of the tablet.
  • the pirfenidone sustained-release oral solid preparation is characterized in that: it also contains an immediate-release preparation, and the ratio of the immediate-release preparation to the sustained-release preparation is 1 to 10; preferably 2 ⁇ 8.
  • the pirfenidone sustained-release oral solid preparation is characterized in that: the ratio of the API in the immediate-release preparation to the API in the sustained-release preparation is 0.1 to 0.6.
  • the sustained-release oral solid preparation of pirfenidone is characterized in that: the viscosity of the swelling material is selected from any of the following ranges: 500-5000mpa.s, 500-1000mpa.s, 2000-5000mpa .s, 50000 ⁇ 150000mpa.s or 150000 ⁇ 300000mpa.s;
  • the viscosity of the shaping material is selected from any of the following ranges: 55-60000mpa.s, 55-10000mpa.s, 55-1000mpa.s, or 60-200mpa.s;
  • the viscosity of the adhesive material is selected from any of the following ranges: 55 ⁇ 100000mpa.s, 60 ⁇ 200mpa.s, 65 ⁇ 10000mpa.s, 4000 ⁇ 10000mpa.s, 5000 ⁇ 10000mpa.s, 5500 ⁇ 7500mpa.s or 7000 ⁇ 10000mpa.s
  • the pirfenidone sustained release oral solid preparation is characterized by:
  • the hypromellose used as swelling material is selected from one or more of K100LV, K4M, K750, K100, K200M, and E5LV;
  • the molecular weight of the polyoxyethylene is 100,000 to 7 million.
  • any of the above-mentioned sustained-release oral solid preparations of pirfenidone is characterized in that: it is a tablet, and its minimum size in the three dimensions of length, width and height is not less than 8.0mm;
  • the pirfenidone sustained-release oral solid preparation is characterized in that it has any of the following specifications:
  • the content of pirfenidone is 500 to 700 mg;
  • any of the above-mentioned sustained-release oral solid preparations of pirfenidone is characterized in that: according to USP standard 2 method, at 37°C, 900ml, pH 4.5 medium, when the rotation speed is 75rpm, the The above dosage form dissolves more than 15% of the active substances within 0.5 hours; more than 25% of the active substances dissolves within 2 hours; 50-70% of the active substances dissolves within 10 hours; and more than 80% of the active substances dissolve within 20 hours.
  • the pirfenidone sustained-release oral solid preparation is characterized in that: when used for individual administration, it has the following parameters: it can stay in the stomach for at least 12 hours; and it can stay in the stomach for at least 24 hours.
  • the continuous time when the blood drug concentration is higher than 300ng/ml is ⁇ 15 hours, and the maximum blood drug concentration is not higher than 3500ng/ml, and preferably the maximum blood drug concentration is not higher than 2500ng/ml.
  • the pirfenidone sustained-release oral solid preparation is characterized in that: when used for administration to an individual, the blood concentration parameter is: the maximum blood concentration (Cmax) is 800ng /ml ⁇ 3500ng/ml, preferably 1000ng/ml ⁇ 2500ng/ml, and the lowest blood concentration (Cmin) ⁇ 300ng/ml. , preferably Cmin ⁇ 400ng/ml.
  • the blood concentration parameter is: the maximum blood concentration (Cmax) is 800ng /ml ⁇ 3500ng/ml, preferably 1000ng/ml ⁇ 2500ng/ml, and the lowest blood concentration (Cmin) ⁇ 300ng/ml. , preferably Cmin ⁇ 400ng/ml.
  • the sustained-release oral solid preparation of pirfenidone is characterized in that the dosage form is tablet or capsule, wherein the tablet can be a single-layer tablet, a double-layer tablet, a three-layer tablet, or a chip-coated tablet. , ring piece.
  • the pirfenidone sustained-release oral solid preparation is characterized in that: the dosage form is a three-layer tablet, the middle layer is not less than 10% of the total tablet weight, and the third layer is not less than the total tablet weight. Tablet weight 15%.
  • the present invention has developed a continuous oral product that can be taken once a day before or after meals.
  • Sexual release oral formulation After the preparation developed by the present invention enters the human body, part of the drug is rapidly released to reach the peak value, and the other part of the drug is controlled by the expanded tablet structure to slowly release the drug, thereby ensuring that the peak blood drug concentration Cmax will not drop suddenly and within 24 hours. Smooth and effective release, the blood drug concentration is stable, and the peak-to-trough ratio can be close to 2 and lower than 3, thereby reducing adverse reactions caused by unstable blood drug concentration and high peak-to-valley ratio.
  • Maximum blood drug concentration Cmax the maximum blood concentration reached by the drug entering the blood after administration.
  • Minimum blood drug concentration Cmin the lowest blood concentration reached by the drug entering the blood after administration
  • Figure 17 Comparative curve of plasma concentration of pirfenidone bi-layer tablets for once-daily oral administration of the present invention and existing pirfenidone tablets for oral administration three times a day.
  • the preparation process of Example 1 specifically includes the following steps:
  • sustained-release layer drug-containing granules weigh 450g pirfenidone, 160g sodium alginate, 100g HPMC K100M, 200g HPMC K200M, 60gPEO, 53g microcrystalline cellulose and mix for 3 to 5 minutes, add 52g PVP K30 to make soft materials, wet granulation, and drying; then add 10g talc powder and 24g colloidal silica and mix to obtain the sustained-release layer mixed granules, which are ready for use;
  • Press double-layer tablets weigh an appropriate amount of drug-containing sustained-release layer granules and place them in the die of the tablet press, and pre-press; then weigh an appropriate amount of drug-containing immediate-release layer granules and place them in the die of the tablet press, and press them into double-layer tablets. ply.
  • Comparative Example 1 The preparation process of Comparative Example 1 was consistent with that of Example 1, and double-layer sheets with the same shape and size were produced.
  • Example 1 The difference between the prescriptions of Comparative Example 1 and Example 1 is that the unit prescription amount of HPMC K100M in the sustained-release layer in Comparative Example 1 is 200 mg, the unit prescription amount of microcrystalline cellulose PH101 is 93 mg, and the remaining prescriptions are consistent with Example 1.
  • Comparative Example 1 the ratio of swollen material to total tablet weight was 26.68%, and in Example 1, the ratio of swollen material to total tablet weight was 22.08%.
  • Comparative Example 2 The preparation process of Comparative Example 2 was consistent with that of Example 1, and double-layer sheets with the same shape and size were produced.
  • Comparative Example 2 The difference between the prescriptions of Comparative Example 2 and Example 1 is that in Comparative Example 1, the unit prescription amount of sodium alginate in the sustained-release layer is 100 mg, and the unit prescription amount of microcrystalline cellulose PH101 is 153 mg. The rest are consistent with Example 1.
  • the ratio of the molding material to the total tablet weight in Comparative Example 2 was 7.15%, while the ratio of the molding material to the total tablet weight in Example 1 was 11.77%.
  • Comparative Example 3 The preparation process of Comparative Example 3 was consistent with that of Example 1, and double-layer sheets with the same shape and size were produced.
  • the ratio of the adhesive material to the total tablet weight used in Comparative Example 3 was 10.35%, and the ratio of the adhesive material to the total tablet weight in Example 1 was 4.42%.
  • Example 2 The preparation process of Example 2 is consistent with that of Example 1, and double-layer sheets of the same shape and size are produced.
  • sustained-release layer drug-containing granules weigh 520g pirfenidone, 280g sodium alginate, 100g HPMC K750, 200g HPMC K100M, 100g PEO, 53g microcrystalline cellulose and mix for 3 to 5 minutes, add 52g PVP K30 to make soft materials, wet granulation, and drying; then add 10g talc powder and 24g colloidal silica and mix to obtain the sustained-release layer mixed granules, which are ready for use;
  • Double layer sheet Weigh an appropriate amount of drug-containing sustained-release layer granules and place them in the die of the tablet press, and pre-press; then weigh an appropriate amount of drug-containing immediate-release layer granules and place them in the die of the tablet press, and press to form Double layer sheet.
  • Comparative Example 4 The preparation process of Comparative Example 4 was consistent with that of Example 2, and double-layer sheets with the same shape and size were produced.
  • the main difference between Comparative Example 4 and Example 2 is that the viscosity of the swollen material is inconsistent.
  • the viscosity range of HPMC K100LV used in Comparative Example 4 is 80-120 mpa.s; while the viscosity range of HPMC K750 used in Example 2 is 562-1050 mpa.s, and the viscosity range of HPMC K100M is 75000-140000 mpa.s.
  • Comparative Example 5 The preparation process of Comparative Example 5 was consistent with that of Example 2, and double-layer sheets of the same shape and size were produced.
  • Comparative Example 5 The main difference between Comparative Example 5 and Example 2 is that the viscosity of the molding material is inconsistent.
  • the viscosity range of the sodium alginate used in Example 2 is 60-170 mpa.s; the viscosity range of the polyvinyl alcohol used in Comparative Example 5 is 20-30 mpa.s.
  • Comparative Example 6 The preparation process of Comparative Example 6 was consistent with that of Example 2, and double-layer sheets with the same shape and size were produced.
  • Comparative Example 6 The main difference between Comparative Example 6 and Example 2 is that the viscosity of the adhesive material is inconsistent.
  • the viscosity range of chitosan used in Comparative Example 6 is 1-40 mpa.s; the viscosity range of PEO (N80) used in Example 2 is 65-90 mpa.s.
  • Example 3 The preparation process of Example 3 is consistent with that of Example 1, and double-layer sheets of the same shape and size are produced.
  • Comparative Example 7 The preparation process of Comparative Example 7 was consistent with that of Example 3, and double-layer sheets with the same shape and size were produced.
  • Comparative Example 7 The main difference between Comparative Example 7 and Example 3 is that the ratio of the sustained-release layer to the total tablet weight in Comparative Example 7 is 49.6%, and the ratio of the sustained-release layer to the total tablet weight in Example 3 is 76.8%.
  • Comparative Example 8 was consistent with that of Example 3, and a double-layer sheet of the same shape and size was produced.
  • Comparative Example 8 The main difference between Comparative Example 8 and Example 3 is that the unit prescription amount of pirfenidone in the immediate-release layer of Comparative Example 8 is 50 mg, and the unit prescription amount of pirfenidone in the sustained-release layer is 550 mg; Example 3 immediate-release The unit prescription amount of pirfenidone in the layer is 220 mg, and the unit prescription amount of pirfenidone in the sustained-release layer is 380 mg.
  • Example 4 The preparation process of Example 4 is consistent with that of Example 1, and double-layer sheets of the same shape and size are made.
  • sustained-release layer drug-containing granules weigh 500g pirfenidone, 210g sodium alginate, 250g HPMC K100M, 100g PEO, 52g microcrystalline cellulose and mix for 3 to 5 minutes, add 52g PVP K30 to prepare soft materials, and wet finish Granules and dry; then add 10g magnesium stearate and 24g colloidal silica and mix to obtain sustained-release layer mixed granules, which are ready for use;
  • Press double-layer tablets weigh an appropriate amount of drug-containing sustained-release layer granules and place them in the die of the tablet press, and pre-press; then weigh an appropriate amount of drug-containing immediate-release layer granules and place them in the die of the tablet press, and press them into double-layer tablets. ply.
  • Comparative Example 9 The preparation process of Comparative Example 9 was consistent with that of Example 4, and double-layer sheets with the same shape and size were produced.
  • the unit prescription amount of K100M is 500mg
  • the unit prescription amount of PEO(303) is 50mg
  • swelling material:adhesive material 10:1;
  • Comparative Example 10 was consistent with that of Example 4, and a double-layer sheet with the same shape and size was produced.
  • the preparation In order to ensure rapid onset of action (some can be quickly released) and continuous onset of action within 24 hours after being taken once a day, the preparation must have an expansion growth rate to ensure that it stays in the stomach for a long enough time and has a stable drug release during this period; therefore Standards need to be met in both the swelling growth rate test and the in vitro dissolution test.
  • the minimum size of the tablets made according to the formula of the present invention in the three dimensions of length, width and height is not less than 8.0mm.
  • the expansion growth rate of the dimension with the smallest size ensures that the formulation remains in the stomach through expansion for at least 12 hours to achieve slow and sustained release of the API as long as it meets the following criteria:
  • Growth rate within 1 hour ⁇ 4.5%; growth rate ⁇ 12% within 2 hours; growth rate ⁇ 25% within 4 hours; growth rate ⁇ 20% within 6 hours; growth rate ⁇ 40% within 10 hours.
  • the minimum three-dimensional dimensions of the tablets in the embodiments of the present invention are: length: 18.0 ⁇ 19.0mm, width 10 ⁇ 11mm, height 8.0 ⁇ 9.5mm; tests have found that the in vitro expansion growth rate of the smallest size tablet must comply with Table 15 The listed standards ensure slow and sustained release of the API by ensuring that the formulation remains in the stomach through expansion for at least 12 hours.
  • the swelling, shaping and adhesive materials in the tablet are all in the sustained release layer.
  • the sustained release layer must reach a certain ratio in the total tablet weight to ensure that the tablet weight contains enough swelling, shaping and adhesive materials to ensure the expansion rate and slow release.
  • the thickness of the release layer ensures that the tablet expands to a certain sufficient volume in the stomach and delays entry into the intestine to ensure sustained and smooth release.
  • the floating ratio of swelling material:adhesive material (Comparative Example 9) or the floating ratio of adhesive material:plastic material (Comparative Example 9) basically does not affect the expansion growth rate.
  • Table 24 and Figure 16 show that when the ratio of swelling material:adhesive material is higher than 9 (Comparative Example 9) or the ratio of adhesive material:shaping material is lower than 0.2 (Comparative Example 9), after the 10th hour, the dissolution The degree does not meet the standard and it cannot exert its effect stably and effectively for 24 hours.
  • Pirfenidone double-layer tablet prepared in Example 1 of the present invention each tablet is 600 mg, one tablet once every 24 hours;
  • Pirfenidone tablets 200mg, taken in the morning, noon and evening, one tablet 3 times a day;
  • the blood drug concentration test results within 24 hours are shown in Figure 17.
  • the double-layer tablet of the present invention reaches a peak value of 1500-1750ng/mL about 1 hour after taking it, and within the next 23 hours, the blood drug concentration remains at a level of 750-1500ng/mL most of the time, with a peak-to-trough ratio of 2.33.
  • control tablets were taken three times, and the three peaks were in the range of 3500-3800ng/mL, but it dropped to 1000ng/mL and below within 2-6 hours after taking the medicine, and the lowest plasma concentration at 24 hours was only about 200ng/mL. mL, the peak-to-trough ratio reached 19:1.
  • the pirfenidone double-layer tablet developed by the present invention can quickly reach the peak blood concentration when taken once a day, and the blood concentration is stable within 24 hours, achieving its effect smoothly and effectively for 24 hours. It must be taken after meals, thereby effectively reducing side effects caused by large fluctuations in blood drug concentration and improving drug compliance.

Abstract

一种吡非尼酮持续性释放口服固体制剂，其包含缓释制剂，所述缓释制剂中含有溶胀材料、塑形材料和黏附材料；所述溶胀材料在所述固体制剂中的重量百分比为10-25％；所述塑形材料在所述固体制剂中的重量百分比为10-25％；所述黏附材料在所述固体制剂中的重量百分比为1-8％。该固体制剂一日仅需服用一次，不限制餐前或餐后，服用后快速起效其24小时能稳定有效释放，提供了一种依从性显著提高，血药浓度稳定的吡非尼酮产品。

Description

一种吡非尼酮持续性释放口服固体制剂 技术领域
本发明属于制药技术，特别涉及吡非尼酮持续性释放口服固体制剂。
背景技术
市场上现有的吡非尼酮产品为速释片及胶囊，暂无一日一次的持续性释放制剂上市，现有剂型品种存在以下缺点：
1.现有产品需要一日三次给药，患者依从性较差。
现有产品均为普通速释制剂，其临床资料及说明书中明确指出产品需要在餐后服用，患者依从性较低，若患者遗忘服用方法，导致餐前服用，容易导致不良反应发生。
2.现有产品服用方式受饮食时间影响，晚上有效血药浓度较低。
现有产品均为普通速释制剂，其临床资料及说明书中明确指出该产品均需要在餐后服用。因此，每日的用餐用药时间为固定的08:00、12:00、18:00，但该系列用药时间会导致白天血药浓度较高，而夜晚血药浓度过低，难以在24h内真正达到平稳、有效的血药浓度。
3.现有资料显示该品种出现的不良反应与最大血药浓度Cmax相关。
现有产品均为速释制剂，在被人体摄入后会经过快速崩解、释放、吸收进入血液的过程。快速吸收使得最高血药浓度时间Tmax仅约为1-2h，半衰期T1/2约为2h，导致体内会快速出现最大血药浓度Cmax，而每日三次用药意味着会出现三次最大血药浓度Cmax。有大量文献资料显示，该药品Cmax过高会引起一系列不良反应，而原研是通过建议餐后给药方式来降低Cmax过高带来的不良反应。因此，每日多次给药后较高的Cmax引起的一系列不良反应未得到真正改善。
4.现有产品峰谷比(Cmax/Cmin)较大，血药浓度不平稳。
现有产品为一日三次用药，用药次数频繁，导致峰谷血药浓度相差较多，峰谷比值较大(Cmax/Cmin)，波动次数也较多，无法形成平稳的血药浓度。根据制药领域常识可知，较大的峰谷比更容易造成一系列不良反应。
综上，有必要研发依从性好、服用次数减少、血药波动平稳的吡非尼酮新剂型产品。
发明内容
针对现有产品一日多次用药的依从性差、血药浓度波动大不平稳的问题，本发明开发了一种可以一日服用一次，24小时能稳定有效释放的口服持续性释放制剂，具体方案如下：
1.一种吡非尼酮持续性释放口服固体制剂，其特征在于：其包含缓释制剂，所述缓释制剂中含有溶胀材料、塑形材料和黏附材料；
所述溶胀材料在所述固体制剂中的重量百分比为10-25％；所述塑形材料在所述固体制剂中的重量百分比为10-25％；所述黏附材料在所述固体制剂中的重量百分比为1-8％；
所述溶胀材料的粘度在500mpa.s～300000mpa.s范围内，黏附材料的粘度在50～100000mpa.s范围内，所述塑形材料的粘度在50～60000mpa.s范围内；
所述溶胀材料选自羧甲纤维素钠、山嵛酸甘油酯、海藻酸钠、海藻酸钙、海藻酸钾、羟丙甲纤维素(HPMC)、卡波姆、海藻酸铵、巴西棕榈蜡、西黄蓍胶、阿拉伯胶、虫胶中的一种或多种；
所述塑形材料选自羧甲纤维素钠、羧甲纤维素钙、乙基纤维素、卡波姆、聚乳酸、聚乳酸-羟基乙酸共聚物、海藻酸钠、氢化植物油、乙烯-乙烯共聚物、聚甲基丙烯酸酯、蜂蜡、单硬脂酸甘油酯、聚乙烯、乙烯-醋酸乙烯共聚物中的一种或多种；
所述黏附材料选自羟乙基纤维素、明胶、聚氧乙烯、卡波姆、果胶、壳聚糖、葡萄糖、海藻酸盐、岩藻糖胺、淀粉、甲壳素中的一种或多种；
所述持续性释放口服剂型在按日剂量个体给药一日一次时达到的血药浓度参数为：在服药后的24小时内，血药浓度曲线对应的最大血药浓度(Cmax)与最低血药浓度(Cmin)的比值在2～10内,优选2～5内，更优选2～3.5。
2.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于，其中，所述缓释制剂占总片重的比例为50～100％，或该范围中的任意数值；或所述缓释制剂占总片重的比例为50％、60％、65％、70％、73％、78％、85％、73％、80％，85％、90％或这些数值中任意两个形成的范围。
3.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于，
所述缓释制剂中API占总API的50～100％，或该范围中的任意数值；或占总API的比例为50％、60％、65％、70％、73％、78％、85％、73％、80％，85％、90％或这些数值中任意两个形成的范围。
4.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于，其中所述溶胀材料与黏附材料的比重为1～9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1或1:1；
黏附材料与塑形材料的比重为0.2～1:1、0.3:1、0.4:1、0.5:1、0.6:1、0.7:1、0.8：1或0.9:1。
5.所述的吡非尼酮持续性释放口服固体制剂，其特征在于：为单层片，所述缓释制剂占片重的100％。
6.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于：含还有速释制剂，所述速释制剂与所述缓释制剂的比重为1～10；优选2～8。
7.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于：所述速释制剂中API与所述缓释制剂中API之比为0.1～0.6。
8.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于：所述溶胀材料的粘度选自以下任意范围：500～5000mpa.s，500～1000mpa.s，2000～5000mpa.s，50000～150000mpa.s或150000～300000mpa.s；
所述塑形材料的黏度选自以下任意范围：55～60000mpa.s，55～10000mpa.s,55～1000mpa.s,或60～200mpa.s范围；
所述黏附材料的黏度选自以下任意范围：55～100000mpa.s,60～200mpa.s,65～10000mpa.s,4000～10000mpa.s,5000～10000mpa.s,5500～7500mpa.s或7000～10000mpa.s
9.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于：
溶胀材料采用的羟丙甲纤维素，其型号选自K100LV、K4M、K750、K100、K200M、E5LV中的一种或多种；
所述聚氧乙烯的分子量为10～700万。
10.优选地，上述任一吡非尼酮持续性释放口服固体制剂，其特征在于：其为片剂，其在长、宽、高三个维度上的最小尺寸不低于8.0mm；
其具有最小尺寸的维度在膨胀增长率上须满足以下条件：
在37℃,900ml，pH4.5的介质中，转速75rpm时；
在1h内增长率≥4.5％；2h增长率≥12％；4h内增长率≥25％；6h增长率≥20％；10h增长率≥40％。
11.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于：其具有以下任一规格：
(1)其中吡非尼酮的含量为500～700mg；
(2)其中吡非尼酮的含量为600mg；
(3)其中吡非尼酮的含量为700～1000mg；
(4)其中吡非尼酮的含量为801mg。
12.优选地，上述任一所述的吡非尼酮持续性释放口服固体制剂，其特征在于：以USP标准2法，在37℃,900ml，pH4.5的介质中，转速75rpm时，所述剂型在0.5h内溶出大于15％的活性物质；2h内溶出超过25％的活性物质，10h内溶出50～70％的活性物质，20h内溶出大于80％的活性物质。
13.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于：其在被用于个体给药时，具有以下参数特性：可在胃部停留至少12h；且在24h单次给药间隔内，血药浓度高于300ng/ml的连续时间≥15h，且最高血药浓度不高于3500ng/ml，优选最高血药浓度不高于2500ng/ml。
14.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于：在被用于对个体给药时，表现的血药浓度参数为：最大血药浓度(Cmax)为800ng/ml～3500ng/ml，优选1000ng/ml～2500ng/ml，而最低血药浓度(Cmin)≥300ng/ml。，优选Cmin≥400ng/ml。
15.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于：剂型为片剂、胶囊剂，其中片剂可以是单层片、双层片、三层片、包芯片、环形片。
16.优选地，所述的吡非尼酮持续性释放口服固体制剂，其特征在于：所述剂型为三层片，中间层不少于总片重10％，且第三层不少于总片重15％。
鉴于现有吡非尼酮口服产品一日多次用药的依从性差、只能餐后服用以及血药浓度波动大的问题，本发明开发了一种一日一次可以餐前或餐后服用的持续性释放口服制剂。本发明研制的制剂在进入人体后，一部分药物快速释放达到峰值，另一部分药物通过膨胀的片型结构实现对药物缓慢释放的控制，从而保证峰值血药浓度Cmax不会骤降、在24小时内平稳有效地释放，血药浓度平稳、峰谷比值能够接近2，低于3，从而减少了因血药浓度不平稳峰谷比高引起的不良反应。
名词定义
最大血药浓度Cmax:用药后药物进入血液所达到的最大血液浓度。
最低血药浓度Cmin：用药后药物进入血液所达到的最低血液浓度
附图说明
图1.本发明实施例1与对比例1、2、3的吡非尼酮双层片在长度上的膨胀增长率曲线；
图2.本发明实施例1与对比例1、2、3的吡非尼酮双层片在宽度上的膨胀增长率曲线；
图3.本发明实施例1与对比例1、2、3的吡非尼酮双层片在高度上的膨胀增长率曲线；
图4.本发明实施例2与对比例4、5、6的吡非尼酮双层片在长度上的膨胀增长率曲线；
图5.本发明实施例2与对比例4、5、6的吡非尼酮双层片在宽度上的膨胀增长率曲线；
图6.本发明实施例2与对比例4、5、6的吡非尼酮双层片在高度上的膨胀增长率曲线；
图7.本发明实施例3与对比例7、8的吡非尼酮双层片在长度上的膨胀增长率曲线；
图8.本发明实施例3与对比例7、8的吡非尼酮双层片在宽度上的膨胀增长率曲线；
图9.本发明实施例3与对比例7、8的吡非尼酮双层片在高度上的膨胀增长率曲线；
图10.本发明实施例4与对比例9、10的吡非尼酮双层片在长度上的膨胀增长率曲线；
图11.本发明实施例5与对比例9、10的吡非尼酮双层片在宽度上的膨胀增长率曲线；
图12.本发明实施例6与对比例9、10的吡非尼酮双层片在高度上的膨胀增长率曲线；
图13.实施例1与对比例1、2、3的累积溶出度曲线；
图14.实施例2与对比例4、5、6的累积溶出度曲线
图15.实施例3与对比例7、8的累积溶出度曲线；
图16.实施例4与对比例9、10的累积溶出度曲线；
图17.本发明一日一次口服吡非尼酮双层片与现有一日三次吡非尼酮片血药浓度比较曲线。
具体实施方式
一、实施例处方及对照例
实施例1.制备1000片吡非尼酮双层片
表1.按照下表各组分制备1000片吡非尼酮双层片：
实施例1的制备工艺具体包括以下步骤：
A、制备速释层含药颗粒：称取150g吡非尼酮、30g预胶化淀粉、60g微晶纤维素、8g交联聚维酮混合均匀，进行制粒、湿整粒、干燥；再加入将2g硬脂富马酸钠，进行混合，得速释层总混颗粒，备用；
B、制备缓释层含药颗粒：称取450g吡非尼酮、160g海藻酸钠、100g HPMC K100M、200g HPMC K200M、60gPEO、53g微晶纤维素混合3～5min，加入52g PVP K30进行制软材、湿整粒、干燥；再加入10g滑石粉、24g胶态二氧化硅进行混合，得到缓释层总混颗粒，备用；
C、压制双层片：称取适量含药缓释层颗粒置于压片机的冲模内，预压；再称取适量含药速释层颗粒置于压片机的冲模内，压制成双层片。
对比例1.制备1000片吡非尼酮双层片
表2.按照下表各组分制备1000片吡非尼酮双层片：
对比例1的制备工艺与实施例1一致，制成相同形状尺寸的双层片。
对比例1与实施例1处方的不同在于，对比例1中缓释层的HPMC K100M的单位处方量为200mg，微晶纤维素PH101单位处方量为93mg，其余处方与实施例1一致。
对比例1中溶胀材料与总片重的比值为26.68％，实施例1中溶胀材料与总片重的比值为22.08％。
对比例2.制备1000片吡非尼酮双层片
表3.按照下表各组分制备1000片吡非尼酮双层片：
对比例2的制备工艺与实施例1一致，制成相同形状尺寸的双层片。
对比例2与实施例1处方的不同在于，对比例1中缓释层的海藻酸钠的单位处方量为100mg，微晶纤维素PH101单位处方量为153mg，其余与实施例1一致。
对比例2塑形材料与总片重的比值为7.15％，而实施例1塑形材料与总片重的比值为11.77％。
对比例3.制备1000片吡非尼酮双层片
表4.按照下表各组分制备1000片吡非尼酮双层片：

对比例3的制备工艺与实施例1一致，制成相同形状尺寸的双层片。
对比例3与实施例1处方的不同在于，对比例1中缓释层的PEO(N80)单位处方量为150mg，其余与实施例1一致。
对比例3所用的黏附材料与总片重的比值为10.35％，实施例1黏附材料与总片重的比值为4.42％。
实施例2.制备1000片吡非尼酮双层片
表5.按照下表各组分制备1000片吡非尼酮双层片：
实施例2的制备工艺与实施例1一致，制成相同形状尺寸的双层片。
具体制备工艺：
A、制备速释层含药颗粒：称取80g吡非尼酮、50g预胶化淀粉、50g微晶纤维素、8g交联羧甲基纤维素钠混合均匀，进行制粒、湿整粒、干燥；再加入将2g硬脂酸镁，进行混合，得速释层总混颗粒，备用；
B、制备缓释层含药颗粒：称取520g吡非尼酮、280g海藻酸钠、100g HPMC K750、200g HPMC K100M、100gPEO、53g微晶纤维素混合3～5min，加入52g PVP K30进行制软材、湿整粒、干燥；再加入10g滑石粉、24g胶态二氧化硅进行混合，得到缓释层总混颗粒，备用；
C、压制双层片：：称取适量含药缓释层颗粒置于压片机的冲模内，预压；再称取适量含药速释层颗粒置于压片机的冲模内，压制成双层片。
对比例4.制备1000片吡非尼酮双层片
表6.按照下表各组分制备1000片吡非尼酮双层片：
对比例4的制备工艺与实施例2一致，制成相同形状尺寸的双层片。
对比例4与实施例2的主要区别在于，溶胀材料的粘度不一致。对比例4所用的HPMC K100LV粘度范围在80～120mpa.s；而实施例2所用的HPMC K750粘度范围在562～1050 mpa.s，HPMC K100M粘度范围在75000-140000mpa.s。
对比例5.制备1000片吡非尼酮双层片
表7.按照下表各组分制备1000片吡非尼酮双层片：

对比例5的制备工艺与实施例2一致，制成相同形状尺寸的双层片。
对比例5与实施例2的主要区别在于，塑形材料的粘度不一致，
实施例2所用的海藻酸钠粘度范围在60～170mpa.s；对比例5所用的聚乙烯醇粘度范围在20～30mpa.s。
对比例6制备1000片吡非尼酮双层片
表8.按照下表各组分制备1000片吡非尼酮双层片：
对比例6的制备工艺与实施例2一致，制成相同形状尺寸的双层片。
对比例6与实施例2的主要区别在于，黏附材料的粘度不一致。对比例6所用的壳聚糖粘度范围在1～40mpa.s；实施例2所用的PEO(N80)粘度范围在65～90mpa.s。
实施例3.制备1000片吡非尼酮双层片
表9.按照下表各组分制备1000片吡非尼酮双层片：

实施例3的制备工艺与实施例1一致，制成相同形状尺寸的双层片。
对比例7.制备1000片吡非尼酮双层片
表10.按照下表各组分制备1000片吡非尼酮双层片：
对比例7的制备工艺与实施例3一致，制成相同形状尺寸的双层片。
对比例7与实施例3的主要区别在于，对比例7缓释层与总片重的比值为49.6％，实施例3缓释层与总片重的比值为76.8％.
对比例8.制备1000片吡非尼酮双层片
表11.按照下表各组分制备1000片吡非尼酮双层片：

对比例8的制备工艺与实施例3一致，制成相同形状尺寸的双层片。
对比例8与实施例3的主要区别在于，对比例8速释层中吡非尼酮的单位处方量为50mg，缓释层中吡非尼酮的单位处方量为550mg；实施例3速释层中吡非尼酮的单位处方量为220mg，缓释层中吡非尼酮的单位处方量为380mg。
实施例4.制备1000片吡非尼酮双层片
表12.按照下表各组分制备1000片吡非尼酮双层片：
实施例4的制备工艺与实施例1一致，制成相同形状尺寸的双层片
具体制备工艺：
A、制备速释层含药颗粒：称取100g吡非尼酮、30g预胶化淀粉、60g微晶纤维素、8g交联羧甲基纤维素钠混合均匀，进行制粒、湿整粒、干燥；再加入将2g硬脂酸镁，进行混合，得速释层总混颗粒，备用；
B、制备缓释层含药颗粒：称取500g吡非尼酮、210g海藻酸钠、250g HPMC K100M、100gPEO、52g微晶纤维素混合3～5min，加入52g PVP K30进行制软材、湿整粒、干燥；再加入10g硬脂酸镁和24g胶态二氧化硅进行混合，得到缓释层总混颗粒，备用；
C、压制双层片：称取适量含药缓释层颗粒置于压片机的冲模内，预压；再称取适量含药速释层颗粒置于压片机的冲模内，压制成双层片。
对比例9.制备1000片吡非尼酮双层片
表13.按照下表各组分制备1000片吡非尼酮双层片：
对比例9的制备工艺与实施例4一致，制成相同形状尺寸的双层片。
对比例9与实施例4的主要区别在于，对比例9缓释层中HPMC
K100M的单位处方量为500mg，PEO(303)的单位处方量为50mg，溶胀材料:黏附材料＝10:1；
实施例4缓释层中HPMC/K100M的单位处方量为250mg，PEO(303)的单位处方量为100mg，溶胀材料：黏附材料＝5:2。
对比例10.制备1000片吡非尼酮双层片
表14.按照下表各组分制备1000片吡非尼酮双层片：
对比例10的制备工艺与实施例4一致，制成相同形状尺寸的双层片。
对比例10与实施例4的主要区别在于，对比例10缓释层中海藻酸钠的单位处方量为400mg，PEO(303)的单位处方量为70mg，黏附材料：塑形材料＝7:40；实施例4缓释层中HPMCK100M的单位处方量为210mg，PEO(303)的单位处方量为100mg；其中黏附材料:塑形材料＝10:21。
二、制剂的体外测试
为了保证一日一次服用后，快速起效(部分能快速释放)、24小时内持续起效，制剂须具有膨胀增长率从而保证停留在胃中足够长的时间，期间有平稳的药物释放；因此需在膨胀增长率测试和体外溶出测试中同时达到标准。
2.1体外膨胀研究
体外溶出实验条件：介质：pH4.5，桨法+沉降篮，37℃，转速：75rpm，介质体积：900ml。
根据本发明的多次小试实验发现，对于600-800mg的片剂，其按照本发明配方制成的片剂，其在长、宽、高三个维度上的最小尺寸不低于8.0mm，其具有最小尺寸的维度的膨胀增长率只要达到以下标准即可确保制剂在胃中通过膨胀停留至少12小时从而实现API缓慢持久释放：
1h内增长率≥4.5％；2h增长率≥12％；4h内增长率≥25％；6h增长率≥20％；10h增长率≥40％。
本发明实施例中的片剂的最小三维尺寸为：长：18.0～19.0mm,宽10～11mm,高8.0～9.5mm；经试验发现最小尺寸的片剂其体外膨胀增长率须符合表15所列的标准才能过确保制剂在胃中通过膨胀停留至少12小时从而实现API缓慢持久释放。
表15.体外膨胀增长率标准
表16.实施例1与对比例1、2、3体外膨胀增长率
备注：加粗斜体部分为不符合标准的数据
实施例1与对比例1、2、3的吡非尼酮双层片在长宽高上的膨胀增长率曲线见图1～图3所示。
从表16和图1～3可以看出，当溶胀材料比重高于25％(对比例1)、塑形材料比重低于10％(对比例2)、和黏附材料(对比例3)的比重高于8％时，从第2小时开始，药片的长宽高三个维度中至少出现一个纬度的膨胀增长率不合格，这会导致依赖药片膨胀来控制API缓慢持久释放失败。
表17.实施例2与对比例4、5、6体外膨胀增长率
备注：加粗斜体部分为不符合标准的数据
实施例2与对比例4、5、6的吡非尼酮双层片在长宽高上的膨胀增长率曲线见图4～图6所示。
从表17和图4～6可以看出，即便溶胀材料，塑形材料，黏附材料的比重在适当的范围内，但是当处方中溶胀材料的黏度低于500mpa.s(对比例4)、塑形材料的黏度低于50mpa.s(对比例5)、和黏附材料的黏度低于50mpa.s(对比例6)时，从一开始，药片的长宽高三个维度中就会至少出现一个纬度，尤其是具有最小尺寸的高维度上的膨胀增长率显著不合格，这会导致依赖药片膨胀来控制API缓慢持久释放失败。
表18.实施例3与对比例7、8体外膨胀增长率

备注：加粗斜体部分为不符合标准的数据
实施例3与对比例7、8的吡非尼酮双层片在长宽高上的膨胀增长率曲线见图7～图9所示。
从表18和图7、8、9可以看出，缓释层与总片重的比值低于50％(对比例7)，会影响药片的膨胀增长率。
片剂中溶胀，塑形和粘附材料都在缓释层中，缓释层在总片重中达到一定比值才能确保片剂重含有足够溶胀，塑形和粘附材料以保障膨胀率和缓释层的厚度，从而确保片剂在胃中膨胀达到一定的足够体积，延缓进入肠道从而保证缓释平稳释放。
表19.实施例4与对比例9、10体外膨胀增长率
备注：加粗斜体部分为不符合标准的数据
实施例4与对比例9、10体外膨胀增长率的吡非尼酮双层片在长宽高上的膨胀增长率曲线见图10～图12所示。
从表19和图10-12，溶胀材料：黏附材料的比值浮动(对比例9)或黏附材料：塑形材料的比值浮动(对比例9)基本不影响膨胀增长率。
2.2体外溶出度研究
体外溶出实验条件：介质：pH4.5，桨法+沉降篮，37℃，转速：75rpm，介质体积：900ml。
经多次小试试验确定，体外溶出度须满足表20的标准时才能保证用于体内时血药浓度快速达到峰值并在24小时内完全释放并保证血药浓度保持有效浓度范围，峰谷比不高于3。
表20.体外溶出度标准
表21实施例1、对比例1、对比例2、对比例3累积溶出度见下表及图13
从表21和图13可以看出，当溶胀材料比重高于25％(对比例1)、塑形材料比重低于10％(对比例2)、和黏附材料(对比例3)的比重高于8％时,溶胀材料的比重对溶出特性有轻微影响，溶出特性对塑形材料和黏附材料的比重变化不敏感；总的来说，溶胀材料、塑形材料和黏附材料主要影响膨胀特性。
表22.实施例2、对比例4、对比例5、对比例6累积溶出度见下表及图14.
从表22和图14可以看出，溶胀材料的黏度(对比例4)、塑形材料的黏(对比例5)、和黏附材料的黏度(对比例6)对药片的溶出影响不显著。主要是影响膨胀特性。
表23实施例3、对比例7、对比例8累积溶出度见下表及图15
从表23和图15可以看出，缓释层与总片重的比值波动(对比例7)对溶出特性没有明显影响，但是速释层和缓释层中API比例过低时(对比例8)，前期溶出度达不到标准，可以推测血药浓度无法快速达到峰值，影响药效发挥。
表24实施例4、对比例9、对比例10累积溶出度见下表及图16
表24和图16显示，当溶胀材料：黏附材料的比值高于9时(对比例9)或黏附材料：塑形材料的比值低于0.2时(对比例9)，在第10小时之后，溶出度达不到标准，达不到24小时稳定有效地发挥药效的作用。
三、体内血药浓度对比
实验：本发明实施例1制备的吡非尼酮双层片，每片600mg，24小时1次1片；
对比：吡非尼酮片，200mg，早中晚服药，每日3次每次一片；
实验对象：19～45岁健康受试者；
24小时内血药浓度检测结果见图17。本发明的双层片在服用后1小时左右达到峰值1500～1750ng/mL，并在随后的23小时内，血药浓度大多数时候保持在750～1500ng/mL的水平，峰谷比为2.33。
而对照药片，进行了三次服用，产生三次峰值在3500～3800ng/mL范围，但是在服药后的2-6小时内将至1000ng/mL及以下，24小时时最低血药浓度仅为约200ng/mL，峰谷比在达到了19:1。
进一步佐证，本发明研制的吡非尼酮双层片在一日一次服用的情况下，可以快速达到血药浓度峰值，24小时内血药浓度平稳，实现了24小时平稳有效地其作用，不需要必须安排在餐后服用，从而有效减少因血药浓度波动大带来的副作用，提高了药物依从性。

Claims (16)

  1. 一种吡非尼酮持续性释放口服固体制剂，其特征在于：其包含缓释制剂，所述缓释制剂中含有溶胀材料、塑形材料和黏附材料；
    所述溶胀材料在所述固体制剂中的重量百分比为10-25％；所述塑形材料在所述固体制剂中的重量百分比为10-25％；所述黏附材料在所述固体制剂中的重量百分比为1-8％；
    所述溶胀材料的粘度在500mpa.s～300000mpa.s范围内，黏附材料的粘度在50～100000mpa.s范围内，所述塑形材料的粘度在50～60000mpa.s范围内；
    所述溶胀材料选自羧甲纤维素钠、山嵛酸甘油酯、海藻酸钠、海藻酸钙、海藻酸钾、羟丙甲纤维素(HPMC)、卡波姆、海藻酸铵、巴西棕榈蜡、西黄蓍胶、阿拉伯胶、虫胶中的一种或多种；
    所述塑形材料选自羧甲纤维素钠、羧甲纤维素钙、乙基纤维素、卡波姆、聚乳酸、聚乳酸-羟基乙酸共聚物、海藻酸钠、氢化植物油、聚甲基丙烯酸酯、蜂蜡、单硬脂酸甘油酯、聚乙烯、乙烯-醋酸乙烯共聚物中的一种或多种；
    所述黏附材料选自羟乙基纤维素、明胶、聚氧乙烯、卡波姆、果胶、壳聚糖、葡萄糖、海藻酸盐、岩藻糖胺、淀粉、甲壳素中的一种或多种；
    所述持续性释放口服剂型在按日剂量个体给药一日一次时达到的血药浓度参数为：在服药后的24小时内，血药浓度曲线对应的最大血药浓度(Cmax)与最低血药浓度(Cmin)的比值在2～10内,优选2～5内，更优选2～3.5。
  2. 如权利要求1所述的吡非尼酮持续性释放口服固体制剂，其特征在于，其中，所述缓释制剂占总片重的比例为50～100％，或该范围中的任意数值；或所述缓释制剂占总片重的比例为50％、60％、65％、70％、73％、78％、85％、73％、80％，85％、90％或这些数值中任意两个形成的范围。
  3. 如权利要求2所述的吡非尼酮持续性释放口服固体制剂，其特征在于，
    所述缓释制剂中API占总API的50～100％，或该范围中的任意数值；或占总API的比例为50％、60％、65％、70％、73％、78％、85％、73％、80％，85％、90％或这些数值中任意两个形成的范围。
  4. 如权利要求1所述的吡非尼酮持续性释放口服固体制剂，其特征在于，其中所述溶胀材料与黏附材料的比重为1～9:1或该范围中的任意数值,或8:1、7:1、6:1、5:1、4:1、3:1、2:1或1:1；
    黏附材料与塑形材料的比重为0.2～1:1或该范围中的任意数值，或0.3:1、0.4:1、0.5:1、 0.6:1、0.7:1、0.8：1或0.9:1。
  5. 根据权利要求2所述的吡非尼酮持续性释放口服固体制剂，其特征在于：
    为单层片，所述缓释制剂占片重的100％。
  6. 根据权利要求2所述的吡非尼酮持续性释放口服固体制剂，其特征在于：
    含还有速释制剂，所述速释制剂与所述缓释制剂的比重为1～10，优选2～8。
  7. 根据权利要求6所述的吡非尼酮持续性释放口服固体制剂，其特征在于：所述速释制剂中API与所述缓释制剂中API之比为0.1～0.6。
  8. 根据权利要求1所述的吡非尼酮持续性释放口服固体制剂，其特征在于：
    所述溶胀材料的粘度选自以下任意范围：500～5000mpa.s，500～1000mpa.s，2000～5000mpa.s，50000～150000mpa.s或150000～300000mpa.s；
    所述塑形材料的黏度选自以下任意范围：55～60000mpa.s，55～10000mpa.s,55～1000mpa.s,或60～200mpa.s范围；
    所述黏附材料的黏度选自以下任意范围：55～100000mpa.s,60～200mpa.s,65～10000mpa.s,4000～10000mpa.s,5000～10000mpa.s,5500～7500mpa.s或7000～10000mpa.s
  9. 根据权利要求1的吡非尼酮持续性释放口服固体制剂，其特征在于：
    溶胀材料采用的羟丙甲纤维素，其型号选自K100LV、K4M、K750、K100、K200M、E5LV中的一种或多种；
    所述聚氧乙烯的分子量为10～700万。
  10. 根据权利要求1-9任一所述的吡非尼酮持续性释放口服固体制剂，其特征在于：其为片剂，其在长、宽、高三个维度上的最小尺寸不低于8.0mm；
    其具有最小尺寸的维度在膨胀增长率上须满足以下条件：
    在37℃,900ml，pH4.5的介质中，转速75rpm时；
    在1h内增长率≥4.5％；2h增长率≥12％；4h内增长率≥25％；6h增长率≥20％；10h增长率≥40％。
  11. 权利要求10所述的吡非尼酮持续性释放口服固体制剂，其特征在于：其具有以下任一规格：
    (1)其中吡非尼酮的含量为500～700mg；
    (2)其中吡非尼酮的含量为600mg；
    (3)其中吡非尼酮的含量为700～1000mg；
    (4)其中吡非尼酮的含量为801mg。
  12. 根据权利要求1～9任一所述的吡非尼酮持续性释放口服固体制剂，其特征在于：以 USP标准2法，在37℃,900ml，pH4.5的介质中，转速75rpm时，所述剂型在0.5h内溶出大于15％的活性物质；2h内溶出超过25％的活性物质，10h内溶出50～70％的活性物质，20h内溶出大于80％的活性物质。
  13. 根据权利要求11所述的吡非尼酮持续性释放口服固体制剂，其特征在于：其在被用于个体给药时，具有以下参数特性：可在胃部停留至少12h；且在24h单次给药间隔内，血药浓度高于300ng/ml的连续时间≥15h，且最高血药浓度不高于3500ng/ml，优选最高血药浓度不高于2500ng/ml。
  14. 根据权利要求11所述的吡非尼酮持续性释放口服固体制剂，其特征在于：在被用于对个体给药时，表现的血药浓度参数为：最大血药浓度(Cmax)为800ng/ml～3500ng/ml，优选1000ng/ml～2500ng/ml，而最低血药浓度(Cmin)≥300ng/ml。，优选Cmin≥400ng/ml。
  15. 根据权利要求1所述的吡非尼酮持续性释放口服固体制剂，其特征在于：剂型为片剂、胶囊剂，其中片剂可以是单层片、双层片、三层片、包芯片、环形片。
  16. 根据权利要求1所述的吡非尼酮持续性释放口服固体制剂，其特征在于：所述剂型为三层片，中间层不少于总片重10％，且第三层不少于总片重15％。
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