WO2021042278A1 - 一种阿昔莫司多单元缓释微丸片及其制备方法 - Google Patents

一种阿昔莫司多单元缓释微丸片及其制备方法 Download PDF

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Publication number
WO2021042278A1
WO2021042278A1 PCT/CN2019/104272 CN2019104272W WO2021042278A1 WO 2021042278 A1 WO2021042278 A1 WO 2021042278A1 CN 2019104272 W CN2019104272 W CN 2019104272W WO 2021042278 A1 WO2021042278 A1 WO 2021042278A1
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acipimox
release
pellets
sustained
parts
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PCT/CN2019/104272
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English (en)
French (fr)
Inventor
刘阿利
徐同强
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鲁南贝特制药有限公司
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Priority to CN201980038416.3A priority Critical patent/CN114302712B/zh
Priority to PCT/CN2019/104272 priority patent/WO2021042278A1/zh
Publication of WO2021042278A1 publication Critical patent/WO2021042278A1/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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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 invention belongs to the technical field of medicine and provides a multi-unit sustained-release acipimox pellets and a preparation method thereof.
  • Acipimox capsules were developed by the Italian Farmitalia Carlo Erba company, and were launched in Italy in 1985, with a specification of 250 mg.
  • Acipimox is a derivative of niacin, which can inhibit the decomposition of adipose tissue, reduce the release of free fatty acids from adipose tissue, thereby reducing the synthesis of triglycerides (TG) in the liver, and by inhibiting very low density lipoprotein (VLDL)
  • VLDL very low density lipoprotein
  • the synthesis of) and low-density lipoprotein (LDL) reduces the concentration of triglycerides (TG) and total cholesterol (TC) in the blood.
  • This product can also inhibit the activity of liver lipase and reduce the decomposition of high-density lipoprotein (HDL).
  • Acipimox is rapidly absorbed orally, and the blood concentration can reach its peak within 2 hours after taking the drug, with a short half-life.
  • the drug does not bind to plasma proteins, is not metabolized, and is mainly excreted in the urine in its original form. Due to the short half-life, it not only brings many inconveniences to patients, but also cannot meet the increasing needs of life and drug application. Therefore, acipimox was developed as a sustained-release agent.
  • Acipimox sustained-release tablets can reduce the frequency of medication, reduce side effects, and improve patient compliance.
  • Chinese patent CN03130362.5 discloses a sustained-release acipimox preparation.
  • the dosage of sustained-release materials is increased. Increase the potential safety hazards to clinical medication.
  • Chinese patent CN103211785A discloses a kind of acipolimus film controlled sustained-release pellet capsules, which discloses a pellet core prescription and a sustained-release coating film prescription.
  • the formulation has a slow release in the early stage, but there is an obvious burst release phenomenon in the later stage, which leads to the later release. Faster, unstable release, and shorter drug release time.
  • this sustained-release preparation is prone to cause a sudden dose release effect, on the other hand, when the sustained-release tablet is divided, the drug release characteristics change, which lays some foundation for clinical medication Poor safety hazards.
  • Sustained-release pellets are generally too large for patients to swallow, and the dose cannot be divided. Sustained-release pellets can overcome these shortcomings. At present, there are only a few varieties on the market, such as metoprolol tartrate sustained-release multi-unit tablets (Beloc-Zok) and omeprazole multi-unit pellet system (Antra MUDS). There are no similar preparations on the market in China. The reason is that there are two technical problems. One is to protect the sustained and controlled release film from being damaged during the tableting process and to maintain the stability of the controlled release ability. The other is to ensure that due to the difference in particle size and bulk density during the tableting process, Pellets and materials will not be stratified, and the content uniformity is consistent within and between batches. Therefore, the key parameters of the formulation process of acipimox sustained-release pellets are controlled very strictly, and the formulation process design needs to go through rigorous testing and screening.
  • the purpose of the present invention is to provide a new type of acipimox multi-unit sustained-release pellets, which avoid the stimulation of gastric mucosa caused by excessive local drug concentration, facilitate drug absorption, improve bioavailability, and reduce The individual differences.
  • the fluidized bed coating technology is used to prepare acipolimus sustained-release pellets. Even if the individual unit coating fails, the overall release behavior will not change, ensuring the safety of clinical medication;
  • the multi-unit micropill preparation is mixed with a certain filling material to be compressed into a tablet, which is convenient for patients to take and take and increase their compliance with use.
  • the dosage of multi-unit sustained-release pellets can also be divided, which provides a more flexible dosage scheme for clinical medication.
  • the acipimox multi-unit sustained-release pellets of the present invention are obtained by compressing acipimox film-controlled sustained-release pellets and a filling agent, and the prescription is as follows:
  • Pill core prescription 1. Pill core prescription:
  • Prescription composition Preferred dosage The most preferred amount Acipimox 250 servings 250 servings Filler 48 ⁇ 60 servings 50 servings Sodium dodecyl sulfate 0.5 ⁇ 1 serving 0.7 servings purified water Right amount Right amount
  • the main ingredient in the pellet core is acipimox
  • the filler is one or more of microcrystalline cellulose, lactose, and pregelatinized starch
  • sodium lauryl sulfate is a surfactant, which can promote dissolution. . Wet granulation with proper amount of purified water.
  • the weight gain of the sustained-release coating film ranges from 20% to 35%.
  • Component Preferred ratio The most preferred amount Acipimox Sustained Release Pellets 100 servings 100 servings Filler 12 to 20 servings 15 servings Disintegrant 0.5 part ⁇ 2 part 1.2 copies Lubricant 0.5 part ⁇ 1 part 0.7 servings Adhesive 1 part to 3 parts 2 servings
  • the tableting filler of pellets is one or more of microcrystalline cellulose, lactose, pregelatinized starch, and mannitol
  • the disintegrant is one of hypromellose or sodium carboxymethyl starch
  • the lubricant is One or two of magnesium stearate and colloidal silicon dioxide
  • the binder is composed of hydroxypropyl cellulose or povidone.
  • the preparation method of acipimox multi-unit sustained-release pellets of the present invention is as follows:
  • the pellets are extruded and spheronized, the screen aperture is set, the extrusion speed is 10-30 rpm, and the spheronization speed is 400-600 rpm.
  • the drug-containing acipolimus pellets with appropriate particle size prepared above prepare a coating solution according to the slow-release coating film prescription, and coat in a fluidized bed.
  • the temperature of the fluidized bed is controlled to be 25-35°C
  • the flow rate of the coating liquid is 0.2-0.4 rpm
  • the weight gain of the coating film is controlled to be 20-35%.
  • acipolimus sustained-release pellets Mix the acipolimus sustained-release pellets with the excipients evenly, select a 9mm diameter special-shaped punching tablet press, adjust the tableting speed and pressure, and prepare acipolimus multi-unit sustained-release pellets.
  • the content and content uniformity are determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Sibu General Principle 0512) and (Chinese Pharmacopoeia 2015 Edition Si Bu General Principle 0941 Method 1). Chromatographic conditions and system suitability tests use octadecylsilane-bonded silica gel as the filler; methanol-0.01mol/L tetrabutylammonium hydroxide (20:80) (adjust the pH to 6.0 with phosphoric acid) as the mobile phase, The detection wavelength is 264nm, the number of theoretical plates should not be less than 2000 calculated based on the acipolimus peak, and the resolution of the acipolimus peak and adjacent impurity peaks should meet the requirements.
  • Determination method Take 10 capsules of this product, pour out the contents, accurately weigh the contents, grind finely, accurately weigh an appropriate amount of fine powder (about 20mg acipimox), put it in a 100ml measuring bottle, add an appropriate amount of mobile phase, and ultrasonic Dissolve the main drug, dilute to volume, filter, accurately measure 5ml of the subsequent filtrate, place it in a 50ml measuring flask, dilute to the mark with mobile phase, as the test solution, and accurately weigh an appropriate amount of acipimox reference substance, add The mobile phase is made into 1ml solution containing about 20 ⁇ g of acipimox as the reference solution. Accurately measure 20 ⁇ l each of the test solution and the reference solution, inject into the liquid chromatograph, record the chromatogram, and measure the peak area according to the external standard method. Calculate the content and get it.
  • the dissolution rate is determined by the dissolution rate and the release rate determination method (the first method of the four general rules of the Chinese Pharmacopoeia 2015 Edition 0931).
  • the release amount of each capsule of this product in the first hour, 3 hours and 5 hours should be 15 to 35%, 60 to 85% and 80% of the labeled amount respectively, and all of them should comply with the regulations.
  • the acipimox multi-unit sustained-release pellets prepared by the present invention is a preparation composed of a multi-unit pellet system, and is a membrane-controlled sustained-release preparation that can quickly disintegrate into independent pellets in the digestive juice Small units, these pellet units can achieve 8h sustained release in the gastrointestinal tract.
  • the transit time in the gastrointestinal tract is relatively constant, avoiding the phenomenon of sudden dose release, and ensuring the safety of clinical medication.
  • the distribution area in the gastrointestinal tract is large, and the bioavailability of the drug is high.
  • the dosage of the multi-unit sustained-release pellets can also be divided, which provides a more flexible dosage plan for clinical medication, and is easy to swallow and improves patient compliance.
  • the slow and controlled release film is not damaged during the tableting process, the stability of the controlled release ability is maintained, the pellets and materials are not stratified, and the content uniformity is consistent within and between batches.
  • the preparation is convenient, which is conducive to industrialized large-scale production.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • the sieve aperture is set to 0.5 mm, the extrusion speed is 18 rpm, and the spheronization speed is 400 rpm. Dry in a fluidized bed, control the temperature of the material at 40°C, and dry for 20 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled to 25°C, the coating liquid flow rate was 0.2 rpm, Eudragit L30D-55 was 39 g, triethyl citrate was 7 g, talc was 14 g, and the weight gain of the coating film was 20%.
  • acipimox sustained-release pellets 19g microcrystalline cellulose and 5g lactose, 1g sodium carboxymethyl starch, 1g magnesium stearate and 2g hydroxypropyl cellulose in the mixer, set the mixing frequency to 30Hz, Mix for 10 minutes, select a special-shaped punch tablet press with a diameter of 9mm, adjust the tableting speed of 60,000 tablets/hour, and control the hardness to 30N to prepare acipimox multi-unit sustained-release pellets. Sampling was taken at the beginning, middle and end of tableting to test the uniformity of the tablet content; the cumulative release of acipimox multi-unit sustained-release pellets was tested according to the high-performance liquid method.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • Set the screen mesh diameter to be 0.5mm
  • the extrusion speed is 20rpm
  • the spheronization speed is 500rpm.
  • Dry in a fluidized bed control the temperature of the material at 45°C, and dry for 16 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled to 30°C, the coating liquid flow rate was 0.3 rpm, Eudragit L30D-55 was 60 g, triethyl citrate was 9 g, talc was 17 g, and the weight gain of the coating film was 29%.
  • acipimox sustained-release pellets 21g pregelatinized starch, 6g mannitol, 1.1g sodium carboxymethyl starch, 1g magnesium stearate and 2g hydroxypropyl cellulose in the mixer, set the mixing frequency 30Hz, mixing for 10 minutes, choose a special-shaped punching tablet press with a diameter of 9mm, adjust the tableting speed of 60,000 tablets/hour, and control the hardness to 35N to prepare acipolimus multi-unit sustained-release pellets. Sampling was taken at the beginning, middle and end of tableting to test the uniformity of the tablet content; the cumulative release of acipimox multi-unit sustained-release pellets was tested according to the high-performance liquid method.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • the screen aperture is set to 0.5 mm, the extrusion speed is 26 rpm, and the spheronization speed is 570 rpm. Dry in a fluidized bed, control the temperature of the material at 50°C, and dry for 14 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled to 35°C, the coating liquid flow rate was 0.4 rpm, Eudragit L30D-55 was 63 g, triethyl citrate was 10 g, talc was 30 g, and the weight gain of the coating film was 33%.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • Set the screen mesh diameter to be 0.6mm
  • the extrusion speed is 30rpm
  • the spheronization speed is 600rpm.
  • Dry in a fluidized bed control the temperature of the material at 55°C, and dry for 11 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled at 27°C, the coating liquid flow rate was 0.2 rpm, Eudragit L30D-55 was 64 g, triethyl citrate was 30 g, talc was 10 g, and the weight gain of the coating film was 35%.
  • acipimox sustained-release pellets 32g microcrystalline cellulose, 8g lactose, 1.8g sodium carboxymethyl starch, 1.5g magnesium stearate and 3g hydroxypropyl cellulose in the mixer and set the mixing frequency 30Hz, mixing for 10 minutes, choose a special-shaped punch tablet press with a diameter of 9mm, adjust the tableting speed of 60,000 tablets/hour, and control the hardness to 33N to prepare acipolimus multi-unit sustained-release pellets. Sampling was taken at the beginning, middle and end of tableting to test the uniformity of the tablet content; the cumulative release of acipimox multi-unit sustained-release pellets was tested according to the high-performance liquid method.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • the sieve aperture is set to 0.5mm, the extrusion speed is 30rpm, and the spheronization speed is 600rpm. Dry in a fluidized bed, control the temperature of the material at 60°C, and dry for 11 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled to 32°C, the coating liquid flow rate was 0.4 rpm, Eudragit L30D-55 was 62 g, triethyl citrate was 8 g, talc was 20 g, and the weight gain of the coating film was 30%.
  • acipimox sustained-release pellets 26g microcrystalline cellulose and 4g lactose, 2.4g sodium carboxymethyl starch, 1.4g magnesium stearate and 4g hydroxypropyl cellulose in the mixer, set the mixing frequency 30Hz, mixing for 10 minutes, choose a special-shaped punch tablet press with a diameter of 9mm, adjust the tableting speed of 60,000 tablets/hour, and control the hardness to 37N to prepare acipolimus multi-unit sustained-release pellets. Sampling was taken at the beginning, in the middle and at the end of tablet compression to test the uniformity of the tablet content; the cumulative release of acipimox multi-unit sustained-release pellets was tested according to the high-performance liquid method.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • the sieve aperture is set to 0.5 mm, the extrusion speed is 18 rpm, and the spheronization speed is 400 rpm. Dry in a fluidized bed, control the temperature of the material at 40°C, and dry for 20 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled at 25°C, the coating liquid flow rate was 0.2 rpm, Eudragit L30D-55 was 101 g, triethyl citrate was 8 g, talc was 20 g, and the weight gain of the coating film was 40%.
  • acipimox sustained-release pellets 7g microcrystalline cellulose and 3g lactose, 0.3g sodium carboxymethyl starch, 0.3g magnesium stearate and 0.8g hydroxypropyl cellulose in the mixer, set to mix Frequency of 30Hz, mixing for 10 minutes, choose a special-shaped punch tablet press with a diameter of 9mm, adjust the tableting speed of 60,000 tablets/hour, and control the hardness to 30N to prepare acipolimus multi-unit sustained-release pellets. Sampling was taken at the beginning, middle and end of tableting to test the uniformity of the tablet content; the cumulative release of acipimox multi-unit sustained-release pellets was tested according to the high-performance liquid method.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • the sieve aperture is set to 0.5 mm, the extrusion speed is 18 rpm, and the spheronization speed is 400 rpm. Dry in a fluidized bed, control the temperature of the material at 40°C, and dry for 20 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled to 27°C, the coating liquid flow rate was 0.3 rpm, Eudragit L30D-55 was 120 g, triethyl citrate was 30 g, talc was 10 g, and the weight gain of the coating film was 55%.
  • acipimox sustained-release pellets 18g microcrystalline cellulose and 6g lactose, 5.6g sodium carboxymethyl starch, 2.3g magnesium stearate and 6.5g hydroxypropyl cellulose in the mixer, set to mix Frequency of 30Hz, mixing for 10 minutes, choose a special-shaped punch tablet press with a diameter of 9mm, adjust the tableting speed of 60,000 tablets/hour, and control the hardness to 37N to prepare acipolimus multi-unit sustained-release pellets. Sampling was taken at the beginning, middle and end of tableting to test the uniformity of the tablet content; the cumulative release of acipimox multi-unit sustained-release pellets was tested according to the high-performance liquid method.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • the sieve aperture is set to 0.5 mm, the extrusion speed is 18 rpm, and the spheronization speed is 400 rpm. Dry in a fluidized bed, control the temperature of the material at 40°C, and dry for 20 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled to 30°C, the coating liquid flow rate was 0.4 rpm, Eudragit L30D-55 was 31 g, triethyl citrate was 8 g, talc was 20 g, and the weight gain of the coating film was 19%.
  • acipimox sustained-release pellets 17g microcrystalline cellulose and 3g lactose, 4.2g sodium carboxymethyl starch, 2.6g magnesium stearate and 6.7g hydroxypropyl cellulose in the mixer, set to mix Frequency of 30Hz, mixing for 10 minutes, choose a special-shaped punch tablet press with a diameter of 9mm, adjust the tableting speed of 60,000 tablets/hour, and control the hardness to 30N to prepare acipolimus multi-unit sustained-release pellets. Sampling was taken at the beginning, middle and end of tableting to test the uniformity of the tablet content; the cumulative release of acipimox multi-unit sustained-release pellets was tested according to the high-performance liquid method.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • the screen mesh diameter to be 0.6mm
  • the extrusion speed is 30rpm
  • the spheronization speed is 600rpm.
  • Dry in a fluidized bed control the temperature of the material at 60°C, and dry for 11 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled to 35°C
  • the coating liquid flow rate was 0.4 rpm
  • Eudragit L30D-55 was 72 g
  • triethyl citrate was 10 g
  • talc was 30 g
  • the weight gain of the coating film was 36%.
  • acipimox sustained-release pellets 16g microcrystalline cellulose, 8g lactose, 1g sodium carboxymethyl starch, 1g magnesium stearate and 2g hydroxypropyl cellulose in the mixer, set the mixing frequency to 30Hz, Mix for 10 minutes, select a special-shaped punch tablet press with a diameter of 9mm, adjust the tableting speed of 60,000 tablets/hour, and control the hardness to 30N to prepare acipimox multi-unit sustained-release pellets. Sampling was taken at the beginning, middle and end of tableting to test the uniformity of the tablet content; the cumulative release of acipimox multi-unit sustained-release pellets was tested according to the high-performance liquid method.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • the sieve aperture is set to 0.5mm, the extrusion speed is 30rpm, and the spheronization speed is 600rpm. Dry in a fluidized bed, control the temperature of the material at 60°C, and dry for 11 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled to 30°C, the coating liquid flow rate was 0.3 rpm, Eudragit L30D-55 was 60 g, triethyl citrate was 10 g, talc was 20 g, and the weight gain of the coating film was 30%.
  • acipimox sustained-release pellets 26g microcrystalline cellulose and 4g lactose, 2.4g sodium carboxymethyl starch, 1.4g magnesium stearate and 4g hydroxypropyl cellulose in the mixer and set the mixing frequency 30Hz, mixing for 10 minutes, choose a 9mm diameter special-shaped punch tablet press, adjust the tableting speed of 60,000 tablets/hour, and control the hardness to 30N to prepare acipimox multi-unit sustained-release pellets. Sampling was taken at the beginning, middle and end of tableting to test the uniformity of the tablet content; the cumulative release of acipimox multi-unit sustained-release pellets was tested according to the high-performance liquid method.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • the screen aperture is set to 0.5 mm, the extrusion speed is 26 rpm, and the spheronization speed is 570 rpm. Dry in a fluidized bed, control the temperature of the material at 60°C, and dry for 14 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled to 27°C, the coating liquid flow rate was 0.3 rpm, Eudragit L30D-55 was 157 g, triethyl citrate was 12 g, talc was 35 g, and the coating film weight gain was 66%.
  • acipimox sustained-release pellets 12g pregelatinized starch, 8g mannitol, 0.8g hypromellose, 2g magnesium stearate and 4g hypromellose in the mixer, set the mixing frequency 30Hz, mixing for 10 minutes, choose a 9mm diameter special-shaped punch tablet press, adjust the tableting speed of 60,000 tablets/hour, and control the hardness to 40N to prepare acipolimus multi-unit sustained-release pellets. Sampling was taken at the beginning, middle and end of tableting to test the uniformity of the tablet content; the cumulative release of acipimox multi-unit sustained-release pellets was tested according to the high-performance liquid method.
  • the soft material is placed in the pellets of the extrusion spheronization mechanism.
  • the screen aperture is set to 0.5 mm, the extrusion speed is 26 rpm, and the spheronization speed is 570 rpm. Dry in a fluidized bed, control the temperature of the material at 70°C, and dry for 14 minutes. Sieving to obtain pellets containing acipimox.
  • a high-shear homogenizer was used to prepare a coating solution according to the formulation of the slow-release coating film, and the coating was carried out in a fluidized bed.
  • the fluidized bed temperature was controlled to 20°C, the coating liquid flow rate was 0.6 rpm, Eudragit L30D-55 was 63 g, triethyl citrate was 10 g, talc was 30 g, and the weight gain of the coating film was 33%.
  • the acipimox multi-unit sustained-release pellets prepared by the present invention are completely released within 8 hours without sudden release, and samples are taken at the beginning, middle and end of the tableting to detect the tablet content Uniformity, it is found that the value of mixing uniformity A+2.2s of the products produced according to the present invention are all less than 15 and the mixing uniformity is in a qualified state, while the value of mixing uniformity A+2.2s of the products produced according to the comparative example are all greater than 15 The uneven mixing is in an unqualified state.

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Abstract

一种阿昔莫司多单元缓释微丸片及其制备方法。阿昔莫司与辅料混合均匀后湿法制粒，通过挤出滚圆方式制备微丸。选用Eudragit L30D-55水分散体作为缓释包衣材料制备膜控型缓释微丸，其包衣增重为20％～35％。将膜控型缓释微丸与充填辅料混合均匀压片制备多单元缓控微丸片。

Description

一种阿昔莫司多单元缓释微丸片及其制备方法 技术领域
本发明属于医药技术领域，提供了一种阿昔莫司多单元缓释微丸片及其制备方法。
背景技术
阿昔莫司胶囊由意大利Farmitalia Carlo Erba公司研制开发，于1985年在意大利上市，规格为250mg。阿昔莫司为烟酸的衍生物，能抑制脂肪组织的分解，减少游离脂肪酸自脂肪组织释放，从而降低甘油三酯(TG)在肝中的合成，并通过抑制极低密度脂蛋白(VLDL)和低密度脂蛋白(LDL)的合成，使血液中甘油三酯(TG)和总胆固醇(TC)的浓度下降。本品还可抑制肝脏脂肪酶的活性，减少高密度脂蛋白(HDL)的分解。
阿昔莫司口服吸收迅速，服药后2小时内血药浓度可达峰值，半衰期较短。该药不与血浆蛋白结合，不被代谢，主要以原形经尿排出。由于半衰期短，不仅给患者带来诸多不便，也不能满足日益增长的生活及药物应用等需要。故将阿昔莫司开发成缓释剂。阿昔莫司缓释片可以减少服药次数，降低副作用，提高患者的依从性。
中国专利CN03130362.5公开了一种阿昔莫司缓释制剂，发明中为了进一步保证长时间的有效血药浓度，提高病人的顺应性，加大了缓释材料的用量，但缓释材料的增加给临床用药带来一定的安全隐患。
中国专利CN103211785A公开了一种阿昔莫司膜控缓释微丸胶囊，公开了丸芯处方和缓释衣膜处方，该制剂前期释放较慢，但后期有明显的突释现象，导致后期释放较快，释放不稳定，且药物释放时间较短。
现有的阿昔莫司缓释制剂，一方面这种缓释制剂容易引起剂量突释效应，另一方面当这种缓释片再分时，药物释放特性发生变化，给临床用药埋下一些不良的安全隐患。
缓释微丸胶囊一般体积过大，患者难以吞咽，而且剂量无法分割，而缓释微丸 片可以克服这些缺点。目前，市场上仅有少量品种上市，如酒石酸美托洛尔缓释多单元片剂(Beloc-Zok)和奥美拉唑多单元微丸系统(Antra MUDS)，国内未见同类制剂上市，主要原因是存在两个技术难题，一是保护缓控释膜在压片过程中不被破坏，保持控释能力的稳定性，二是在压片过程中，由于粒径和堆密度等差异，保证微丸和物料不会分层，含量均匀度在批内和批间一致性，因此，阿昔莫司缓释微丸片处方工艺的关键参数控制相当严谨，处方工艺设计需要经过了严格试验筛选。
发明概述
技术问题
问题的解决方案
技术解决方案
本发明的目的是提供一种新型的阿昔莫司多单元缓释微丸片，其避免了局部药物浓度过高引起的对胃粘膜的刺激，有利于药物的吸收，提高生物利用度，减少了个体差异性。通过缓释包衣材料，运用流化床包衣技术制得阿昔莫司缓释微丸，即使个别单元包衣的失败也不会导致整体释药行为的改变，保证了临床用药安全性；另外，将多单元微丸制剂与一定的填充材料混合压制成片剂，便于患者携带服用，增加其使用的顺应性。多单元缓释微丸片的剂量还可以分割，为临床用药提供了更加灵活的剂量方案。
本发明按照以下技术方案实现：
本发明所述的阿昔莫司多单元缓释微丸片由阿昔莫司膜控缓释微丸和充填剂压片得到，其处方如下：
一、丸芯处方：
处方组成 优选用量 最优选用量
阿昔莫司 250份 250份
填充剂 48～60份 50份
十二烷基硫酸钠 0.5～1份 0.7份
纯化水 适量 适量
其中，丸芯中的主要成分为阿昔莫司，填充剂为微晶纤维素、乳糖、预胶化淀粉中的一种或者几种，十二烷基硫酸钠为表面活性剂，可促进溶出。以适量的纯化水湿法制粒。
二、缓释包衣膜处方。
Figure PCTCN2019104272-appb-000001
优选缓释包衣膜的增重范围为20％～35％。
三、阿昔莫司缓释微丸压片时与辅料重量比例：
组分 优选比例 最优选用量
阿昔莫司缓释微丸 100份 100份
填充剂 12份～20份 15份
崩解剂 0.5份～2份 1.2份
润滑剂 0.5份～1份 0.7份
粘合剂 1份～3份 2份
微丸压片填充剂为微晶纤维素、乳糖、预胶化淀粉、甘露醇的一种或几种，崩解剂为羟丙甲纤维素或者羧甲基淀粉钠的一种，润滑剂为硬脂酸镁、胶体二氧化硅的一种或两种，粘合剂为羟丙纤维素或聚维酮组成。
本发明阿昔莫司多单元缓释微丸片的制备方法如下：
1、丸芯制备工艺
(1)阿昔莫司原料粉碎过筛，控制D90＝90μm
(2)称取处方量阿昔莫司，微晶纤维素、乳糖或者预胶化淀粉，十二烷基硫酸钠加入湿法制粒机中，搅拌均匀。
(3)加入适量的纯化水，搅拌制软材。
(4)用挤出滚圆机制微丸，设置筛网孔径，挤出速度10～30rpm，滚圆速度400～600rpm。
(5)置流化床中干燥，物料温度控制在40℃～60℃，筛分得到不同粒径的含阿昔莫司药物的微丸。
2、包衣
取上述制备的适宜粒径含药阿昔莫司微丸，按缓释包衣膜处方配制包衣液，在流化床中进行包衣。控制流化床温度25～35℃，包衣液流速0.2～0.4rpm，控制包衣膜增重20～35％。
3、微丸压片
将阿昔莫司缓释微丸与辅料混合均匀，选择直径9mm的异形冲头装压片机，调节压片速度和压力，制得阿昔莫司多单元缓释微丸片。
含量及含量均匀度测定照高效液相色谱法(中国药典2015年版四部通则0512)和(中国药典2015年版四部通则0941第一法)测定。色谱条件与系统适用性试验用十八烷基硅烷键合硅胶为填充剂；甲醇-0.01mol/L氢氧化四丁基铵(20∶80)(用磷酸调节pH值至6.0)为流动相，检测波长为264nm，理论塔板数按阿昔莫司峰计算应不低于2000，阿昔莫司峰和相邻杂质峰的分离度应符合规定。测定法取本品10粒，倾出内容物，精密称定内容物，研细，精密称取细粉适量(约含阿昔莫司20mg)，置100ml量瓶中，加流动相适量，超声使主药溶解，定容，滤过，精密量取续滤液5ml，置50ml量瓶中，用流动相稀释至刻度，作为供试品溶液，另精密称取阿昔莫司对照品适量，加流动相配成1ml约含阿昔莫司20μg的溶液，作为对照品溶液，精密量取供试品溶液和对照品溶液各20μl，注入液相色谱仪，记录色谱图，按外标法以峰面积计算含量，即得。
释放度照溶出度与释放度测定法(中国药典2015年版四部通则0931第一法)测定。以0.1mol/L的盐酸溶液1000ml为溶剂，转速每分钟100转，依法操作，经1小时、3小时、5小时分别取样10ml，滤过，并及时在操作容器中补充相同温度的溶出介质10ml，精密量取续滤液5ml，置100ml量瓶中，用0.1mol/L的盐酸溶液稀释至刻度，作为供试品溶液；另精密称取经105℃干燥至恒重的阿昔莫司对照品适量，加0.1mol/L的盐酸溶液制成每1ml中含7.5μg的溶液，作为对照品溶液。分别取供试品溶液和对照品溶液，照紫外-可见分光光度法(中国药典2015 年版四部通则0401)，在269nm的波长处分别测定吸收度，计算每粒在不同时间的释放量。本品每粒在第1小时、3小时和5小时的释放量应分别为标示量的15～35％、60～85％和80％以上，均应符合规定。
发明的有益效果
有益效果
本发明所制备的阿昔莫司多单元缓释微丸片是由多单元微丸系统构成的制剂，是一种膜控型缓释制剂，可以在消化液中迅速崩解成独立的微丸小单元，这些微丸单元可以在胃肠道内达到8h缓释的效果。在胃肠道转运时间相对恒定，避免剂量突释现象，保证临床用药安全性。同时在胃肠道分布面积大，药物的生物利用度高。多单元缓释微丸片的剂量还可以分割，为临床用药提供了更加灵活的剂量方案，并且易吞咽，提高患者顺应性。并且利用该技术生产过程中缓控释膜在压片过程中不被破坏，保持控释能力的稳定性，保证微丸和物料不会分层，含量均匀度在批内和批间一致性。制备方便，利于工业化的大规模生产。
发明实施例
本发明的实施方式
通过以下实施例对本发明进行进一步的描述，这些实施例仅用于说明性目的，而并不用于限制本发明的范围。
实施例1：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，36g微晶纤维素、12g乳糖，0.5g十二烷基硫酸钠加入湿法制粒机中，设置搅拌转速330rpm，剪切速度300rpm，混合10分钟。先加入50g纯化水，设置搅拌转速400rpm，剪切速度600rpm，再加入32g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.5mm，挤出速度18rpm，滚圆速度400rpm。置流化床中干燥，物料温度控制在40℃，干燥20分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度25℃，包衣液流速0.2rpm，Eudragit L30D-55为39g，柠檬酸三乙酯7g，滑石粉14g，包衣膜增重为20％。将200g阿 昔莫司缓释微丸、19g微晶纤维素和5g乳糖、1g羧甲基淀粉钠、1g硬脂酸镁和2g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为30N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表1 实施例1体外累积释放度
Figure PCTCN2019104272-appb-000002
实施例2：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，32g预胶化淀粉和18g预胶化淀粉，0.7g十二烷基硫酸钠加入湿法制粒机中，设置搅拌转速280rpm，剪切速度300rpm，混合10分钟。先加入50g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开40秒，再加入32g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.5mm，挤出速度20rpm，滚圆速度500rpm。置流化床中干燥，物料温度控制在45℃，干燥16分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度30℃，包衣液流速0.3rpm，Eudragit L30D-55为60g，柠檬酸三乙酯9g，滑石粉17g，包衣膜增重为29％。将200g阿昔莫司缓释微丸、21g预胶化淀粉和6g甘露醇、1.1g羧甲基淀粉钠、1g硬脂酸镁和2g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为35N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表2 实施例2体外累积释放度
Figure PCTCN2019104272-appb-000003
实施例3：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，48g预胶化淀粉和12g乳糖，1g十二烷基硫酸钠加入湿法制粒机中，设置搅拌转速300rpm，剪切速度280rpm，混合10分钟。先加入50g纯化水，设置搅拌转速400rpm，剪切速度800rpm同时开40秒，再加入32g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.5mm，挤出速度26rpm，滚圆速度570rpm。置流化床中干燥，物料温度控制在50℃，干燥14分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度35℃，包衣液流速0.4rpm，Eudragit L30D-55为63g，柠檬酸三乙酯10g，滑石粉30g，包衣膜增重为33％。将200g阿昔莫司缓释微丸、32g预胶化淀粉和8g甘露醇、2g羟丙甲纤维素、2g硬脂酸镁和4g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为40N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表3 实施例3体外累积释放度
Figure PCTCN2019104272-appb-000004
实施例4：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，42g微晶纤维素和6g乳糖，0.5g十二烷基硫酸钠加入湿法制粒机中，设置搅拌转速330rpm，剪切速度300rpm，混合10分钟。先加入50g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开40秒，再加入32g纯化水，设置搅拌转速400rpm，剪切速度800rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.6mm，挤出速度30rpm，滚圆速度600rpm。置流化床中干燥，物料温度控制在55℃，干燥11分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度27℃，包衣液流速0.2rpm，Eudragit L30D-55为64g，柠檬酸三乙酯30g，滑石粉10g，包衣膜增重为35％ 。将200g阿昔莫司缓释微丸、32g微晶纤维素和8g乳糖、1.8g羧甲基淀粉钠、1.5g硬脂酸镁和3g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为33N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表4 实施例4体外累积释放度
时间(h) 1 2 3 4 5 6 7 8
累积释放度(％) 28 40 54 65 75 84 92 99
实施例5：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，30g微晶纤维素和20g乳糖，0.7g十二烷基硫酸钠加入湿法制粒机中，设置搅拌转速330rpm，剪切速度300rpm，混合10分钟。先加入50g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开40秒，再加入32g纯化水，设置搅拌转速400rpm，剪切速度800rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.5mm，挤出速度30rpm，滚圆速度600rpm。置流化床中干燥，物料温度控制在60℃，干燥11分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度32℃，包衣液流速0.4rpm，Eudragit L30D-55为62g，柠檬酸三乙酯8g，滑石粉20g，包衣膜增重为30％。将200g阿昔莫司缓释微丸、26g微晶纤维素和4g乳糖、2.4g羧甲基淀粉钠、1.4g硬脂酸镁和4g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为37N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表5实施例5体外累积释放度
时间(h) 1 2 3 4 5 6 7 8
累积释放度(％) 32 45 57 69 78 86 92 99
对比实施例1：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，56g微晶纤维素、12g乳糖，0.3g十二烷基硫酸钠加入湿法制粒机中，搅拌均匀。先加入50g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开40秒，再加入32g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.5mm，挤出速度18rpm，滚圆速度400rpm。置流化床中干燥，物料温度控制在40℃，干燥20分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度25℃，包衣液流速0.2rpm，Eudragit L30D-55为101g，柠檬酸三乙酯8g，滑石粉20g，包衣膜增重为40％。将200g阿昔莫司缓释微丸、7g微晶纤维素和3g乳糖、0.3g羧甲基淀粉钠、0.3g硬脂酸镁和0.8g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为30N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表6对比实施例1体外累积释放度
时间(h) 1 2 3 4 5 6 7 8
累积释放度(％) 30 47 60 72 76 83 92 94
对比实施例2：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，20g微晶纤维素、15g乳糖，1.2g十二烷基硫酸钠加入湿法制粒机中，搅拌均匀。先加入50g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开40秒，再加入32g纯化水，设置搅拌转速500rpm，剪切速度600rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.5mm，挤出速度18rpm，滚圆速度400rpm。置流化床中干燥，物料温度控制在40℃，干燥20分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度27℃，包衣液流速0.3rpm，Eudragit L30D-55为120g，柠檬酸三乙酯30g，滑石粉10g，包衣膜增重为55％。将200g阿昔莫司缓释微丸、18g微 晶纤维素和6g乳糖、5.6g羧甲基淀粉钠、2.3g硬脂酸镁和6.5g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为37N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表7 对比实施例2体外累积释放度
时间(h) 1 2 3 4 5 6 7 8
累积释放度(％) 20 45 60 76 79 85 92 96
对比实施例3：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，36g微晶纤维素、22g乳糖，1.3g十二烷基硫酸钠加入湿法制粒机中，搅拌均匀。先加入50g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开40秒，再加入32g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.5mm，挤出速度18rpm，滚圆速度400rpm。置流化床中干燥，物料温度控制在40℃，干燥20分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度30℃，包衣液流速0.4rpm，Eudragit L30D-55为31g，柠檬酸三乙酯8g，滑石粉20g，包衣膜增重为19％。将200g阿昔莫司缓释微丸、17g微晶纤维素和3g乳糖、4.2g羧甲基淀粉钠、2.6g硬脂酸镁和6.7g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为30N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表8 对比实施例3体外累积释放度
时间(h) 1 2 3 4 5 6 7 8
累积释放度(％) 33 50 62 75 79 86 90 95
对比实施例4：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，40g微晶纤维素和18g乳糖，1g十二烷基硫酸钠加入湿法制粒机中，搅拌均匀。先加入50g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开40秒，再加入32g纯化水，设置搅拌转速400rpm，剪切速度800rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.6mm，挤出速度30rpm，滚圆速度600rpm。置流化床中干燥，物料温度控制在60℃，干燥11分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度35℃，包衣液流速0.4rpm，Eudragit L30D-55为72g，柠檬酸三乙酯10g，滑石粉30g，包衣膜增重为36％。将200g阿昔莫司缓释微丸、16g微晶纤维素和8g乳糖、1g羧甲基淀粉钠、1g硬脂酸镁和2g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为30N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表9 对比实施例4体外累积释放度
时间(h) 1 2 3 4 5 6 7 8
累积释放度(％) 35 47 53 65 73 85 91 93
对比实施例5：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，30g微晶纤维素和20g乳糖，0.7g十二烷基硫酸钠加入湿法制粒机中，搅拌均匀。先加入50g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开40秒，再加入32g纯化水，设置搅拌转速400rpm，剪切速度800rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.5mm，挤出速度30rpm，滚圆速度600rpm。置流化床中干燥，物料温度控制在60℃，干燥11分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度30℃，包衣液流速0.3rpm，Eudragit L30D-55为60g，柠檬酸三乙酯10g，滑石粉20g，包衣膜增重为30％。将200g阿昔莫司缓释微丸、26g微晶 纤维素和4g乳糖、2.4g羧甲基淀粉钠、1.4g硬脂酸镁和4g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为30N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表10 对比实施例5体外累积释放度
时间(h) 1 2 3 4 5 6 7 8
累积释放度(％) 31 45 51 62 71 79 87 92
对比实施例6：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，48g预胶化淀粉和12g乳糖，0.8g十二烷基硫酸钠加入湿法制粒机中，搅拌均匀。先加入50g纯化水，设置搅拌转速400rpm，剪切速度800rpm同时开40秒，再加入32g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.5mm，挤出速度26rpm，滚圆速度570rpm。置流化床中干燥，物料温度控制在60℃，干燥14分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度27℃，包衣液流速0.3rpm，Eudragit L30D-55为157g，柠檬酸三乙酯12g，滑石粉35g，包衣膜增重为66％。将200g阿昔莫司缓释微丸、12g预胶化淀粉和8g甘露醇、0.8g羟丙甲纤维素、2g硬脂酸镁和4g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为40N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表11 对比实施例6体外累积释放度
时间(h) 1 2 3 4 5 6 7 8
累积释放度(％) 33 42 53 74 79 83 85 94
对比实施例7：
阿昔莫司原料粉碎过筛，控制D90＝90μm，称取250g阿昔莫司，48g预胶化淀粉和12g乳糖，1g十二烷基硫酸钠加入湿法制粒机中，设置搅拌转速300rpm，剪切速度280rpm，混合10分钟。先加入50g纯化水，设置搅拌转速400rpm，剪切速度800rpm同时开40秒，再加入32g纯化水，设置搅拌转速400rpm，剪切速度600rpm同时开30秒制软材。将软材置于挤出滚圆机制微丸。设置筛网孔径0.5mm，挤出速度26rpm，滚圆速度570rpm。置流化床中干燥，物料温度控制在70℃，干燥14分钟。筛分得到含阿昔莫司药物的微丸。使用高剪切匀化机按缓释包衣膜处方配置包衣液，在流化床中进行包衣。控制流化床温度20℃，包衣液流速0.6rpm，Eudragit L30D-55为63g，柠檬酸三乙酯10g，滑石粉30g，包衣膜增重为33％。将200g阿昔莫司缓释微丸、32g预胶化淀粉和8g甘露醇、2g羟丙甲纤维素、2g硬脂酸镁和4g羟丙纤维素置于混合机中，设定混合频率30Hz，混合10分钟，选择直径9mm的异形冲头装压片机，调节压片速度6万片/小时，控制硬度为40N，制得阿昔莫司多单元缓释微丸片。在压片开始、中间及结束时取样检测片剂含量均匀度；照高效液相法检测阿昔莫司多单元缓释微丸片累积释放度。
表12对比实施例7体外累积释放度
时间(h) 1 2 3 4 5 6 7 8
累积释放度(％) 28 35 52 63 75 87 91 96
含量均匀度测定结果
表12压片开始、中间及结束取样检测混合均匀度结果
Figure PCTCN2019104272-appb-000005
综上所述，本发明所制备的阿昔莫司多单元缓释微丸片，在8小时内释放完全，没有出现突释现象，并且在压片开始、中间及结束时取样检测片剂含量均匀度，发现按照本发明制作得到的产品混合均匀度A+2.2s的值均小于15混合均匀处于合格状态，而按照对比实施例生产得到的产品混合均匀度A+2.2s的值均大 于15混合不均匀处于不合格状态。

Claims (9)

  1. 一种阿昔莫司多单元缓释微丸片，其特征在于，其由含缓释包衣膜的阿昔莫司微丸和填充辅料通过如下工艺压片而成，阿昔莫司微丸的用量如下：
    一、丸芯处方：
    阿昔莫司250份
    填充剂 48～60份
    十二烷基硫酸钠0.5～1份
    纯化水 适量；
    二、缓释包衣膜处方：
    Eudragit L30D-55 41～65份
    柠檬酸三乙酯 7～10份
    滑石粉 14～30份
    纯化水余量；
    三、阿昔莫司缓释微丸压片时与辅料用量：
    阿昔莫司缓释微丸 100份
    填充剂 12份～20份
    崩解剂 0.5份～2份
    润滑剂 0.5份～1份
    粘合剂 1份～3份。
  2. 如权利要求1所述的阿昔莫司多单元缓释微丸片，其特征在于，
    一、丸芯处方：
    阿昔莫司250份
    填充剂 50份
    十二烷基硫酸钠0.7份
    纯化水 适量；
    二、缓释包衣膜处方
    Eudragit L30D-5560份
    柠檬酸三乙酯9份
    滑石粉17份
    纯化水余量；
    三、阿昔莫司缓释微丸压片时与辅料用量：
    Figure PCTCN2019104272-appb-100001
  3. 如权利要求1所述的阿昔莫司多单元缓释微丸片，其特征在于所述丸芯处方中的填充剂为微晶纤维素、乳糖、预胶化淀粉中的一种或者几种。
  4. 如权利要求1所述的阿昔莫司多单元缓释微丸片，其特征在于所述缓释包衣膜处方中的缓释包衣膜的增重范围为20％～35％。
  5. 如权利要求1所述的阿昔莫司多单元缓释微丸片，其特征在于所述微丸压片中的填充剂为微晶纤维素、乳糖、预胶化淀粉、甘露醇的一种或几种。
  6. 如权利要求1所述的阿昔莫司多单元缓释微丸片，其特征在于所述微丸压片中的崩解剂为羟丙甲纤维素或者羧甲基淀粉钠的一种。
  7. 如权利要求1所述的阿昔莫司多单元缓释微丸片，其特征在于所述微丸压片中的润滑剂为硬脂酸镁、胶体二氧化硅的一种或两种。
  8. 如权利要求1所述的阿昔莫司多单元缓释微丸片，其特征在于所述微丸压片中的粘合剂为羟丙纤维素或聚维酮组成。
  9. 如权利要求1所述的阿昔莫司多单元缓释微丸片，其特征在于制备方法包含如下步骤：
    1)丸芯制备工艺：阿昔莫司原料粉碎过筛，控制D90＝90μm，称取处方量阿昔莫司，微晶纤维素、乳糖或者预胶化淀粉，十二烷基硫酸钠加入湿法制粒机中，搅拌均匀，加入适量的纯化水，搅 拌制软材；用挤出滚圆机制微丸，置流化床中干燥，物料温度控制在40℃～60℃，干燥筛分得到不同粒径的含阿昔莫司药物的微丸；
    2)包衣：取上述制备的适宜粒径含药阿昔莫司微丸，按缓释包衣膜处方配制包衣液，在流化床中进行包衣，控制流化床温度25～35℃，包衣液流速0.2～0.4rpm，控制包衣膜增重20～35％；
    3)微丸压片：将阿昔莫司缓释微丸与辅料混合均匀，通过调节压片机的压片速度和压力，制得阿昔莫司多单元缓释微丸片。
PCT/CN2019/104272 2019-09-04 2019-09-04 一种阿昔莫司多单元缓释微丸片及其制备方法 WO2021042278A1 (zh)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115039888A (zh) * 2022-07-25 2022-09-13 安徽九春堂药业有限公司 一种维生素c片及其制备方法
CN117323305A (zh) * 2023-11-07 2024-01-02 杭州沐源生物医药科技有限公司 溴隐亭片剂及其制备方法
CN117462516A (zh) * 2023-08-04 2024-01-30 青岛海洋生物医药研究院 一种新型缓释微丸及其制备方法和其微丸片剂

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103211785A (zh) * 2012-01-18 2013-07-24 北京天衡药物研究院 阿昔莫司膜控缓释微丸胶囊
EP2542228B1 (en) * 2010-03-05 2017-11-29 University of Strathclyde Pulsatile drug release

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR9908911A (pt) * 1998-03-19 2001-10-02 Bristol Myers Squibb Co Sistema bifásico e processo de distribuição por liberação controlada de substâncias farmacêuticas de alta solubilidade
GB2460915B (en) * 2008-06-16 2011-05-25 Biovascular Inc Controlled release compositions of agents that reduce circulating levels of platelets and methods therefor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2542228B1 (en) * 2010-03-05 2017-11-29 University of Strathclyde Pulsatile drug release
CN103211785A (zh) * 2012-01-18 2013-07-24 北京天衡药物研究院 阿昔莫司膜控缓释微丸胶囊

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG, MEIYAN, FAN YUN-ZHOU，GAO CHUN-SHENG: "Advance on the Biphasic Drug Release System Based on Controlled Release Technology", vol. 48, no. 13, 1 July 2013 (2013-07-01), pages 1044 - 1047, XP055788789 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115039888A (zh) * 2022-07-25 2022-09-13 安徽九春堂药业有限公司 一种维生素c片及其制备方法
CN115039888B (zh) * 2022-07-25 2023-11-21 安徽九春堂药业有限公司 一种维生素c片及其制备方法
CN117462516A (zh) * 2023-08-04 2024-01-30 青岛海洋生物医药研究院 一种新型缓释微丸及其制备方法和其微丸片剂
CN117323305A (zh) * 2023-11-07 2024-01-02 杭州沐源生物医药科技有限公司 溴隐亭片剂及其制备方法
CN117323305B (zh) * 2023-11-07 2024-06-07 杭州沐源生物医药科技有限公司 溴隐亭片剂及其制备方法

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