CN114302712A - Acipimox multi-unit sustained-release pellet tablet and preparation method thereof - Google Patents

Acipimox multi-unit sustained-release pellet tablet and preparation method thereof Download PDF

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CN114302712A
CN114302712A CN201980038416.3A CN201980038416A CN114302712A CN 114302712 A CN114302712 A CN 114302712A CN 201980038416 A CN201980038416 A CN 201980038416A CN 114302712 A CN114302712 A CN 114302712A
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acipimox
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sustained
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CN114302712B (en
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刘阿利
徐同强
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Lunnan Better Pharmaceutical Co ltd
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Abstract

An acipimox multi-unit sustained-release pellet tablet and a preparation method thereof. The acipimox and the auxiliary materials are uniformly mixed and then are granulated by a wet method, and the pellets are prepared by an extrusion and spheronization mode. The Eudragit L30D-55 aqueous dispersion is selected as a slow release coating material to prepare the film-controlled slow release pellet, and the coating weight is increased by 20-35%. The film-controlled sustained-release pellets and the filling auxiliary materials are mixed uniformly and tabletted to prepare the multi-unit sustained-release pellet tablet.

Description

Acipimox multi-unit sustained-release pellet tablet and preparation method thereof Technical Field
The invention belongs to the technical field of medicines, and provides an acipimox multi-unit sustained-release pellet tablet and a preparation method thereof.
Background
Acipimox capsules were developed by Farmitalia Carlo Erba, Italy and marketed in Italy in 1985 in a format of 250 mg. Acipimox is a nicotinic acid derivative which inhibits the decomposition of adipose tissue, reduces the release of free fatty acids from adipose tissue, thereby reducing the synthesis of Triglyceride (TG) in the liver, and lowers the concentration of Triglyceride (TG) and Total Cholesterol (TC) in blood by inhibiting the synthesis of Very Low Density Lipoprotein (VLDL) and Low Density Lipoprotein (LDL). The product can also inhibit activity of liver lipase, and reduce decomposition of High Density Lipoprotein (HDL).
The acipimox is quickly absorbed by oral administration, the blood concentration can reach the peak value within 2 hours after the acipimox is taken, and the half-life period is short. The medicine is not combined with plasma protein, is not metabolized, and is mainly excreted via urine in its original form. Due to the short half-life period, not only are a lot of inconvenience brought to patients, but also the requirements of increasing life and medicine application and the like cannot be met. Therefore, the acipimox is developed into a sustained-release agent. The acipimox sustained release tablet can reduce the medicine taking times, reduce the side effect and improve the compliance of patients.
Chinese patent CN03130362.5 discloses an acipimox sustained-release preparation, which aims to further ensure the effective blood concentration for a long time, improve the compliance of patients and increase the dosage of sustained-release materials, but the increase of the sustained-release materials brings certain potential safety hazard to clinical medication.
Chinese patent CN103211785A discloses an acipimox film-controlled slow-release pellet capsule, discloses a pellet core prescription and a slow-release coating film prescription, and the preparation is released slowly at the early stage, but has obvious burst release phenomenon at the later stage, so that the later-stage release is fast, the release is unstable, and the medicine release time is short.
The existing acipimox sustained-release preparation has the advantages that on one hand, the sustained-release preparation easily causes the effect of dose burst release, and on the other hand, when the sustained-release tablet is subdivided, the release characteristics of the drug are changed, so that some undesirable potential safety hazards are buried for clinical medication.
Sustained release pellet capsules are generally too large in volume, difficult to swallow by patients, and the dose cannot be divided, and sustained release pellet tablets can overcome the defects. At present, only a few varieties are on the market, such as metoprolol tartrate sustained-release multi-unit tablets (Beloc-Zok) and omeprazole multi-unit pellet systems (Antra MUDS), and the similar preparations are not on the market at home, and the main reason is that two technical problems exist, namely, a sustained-release film is protected from being damaged in the tabletting process and the stability of the controlled-release capacity is kept, and the pellets and materials are ensured not to be layered due to the difference of particle size, bulk density and the like in the tabletting process and the content uniformity is consistent in batches and between batches, so that the control of key parameters of the formula process of the acipimox sustained-release pellet tablets is quite strict, and the formula process design needs to be strictly tested and screened.
Summary of The Invention
Technical problem
Solution to the problem
Technical solution
The invention aims to provide a novel acipimox multi-unit sustained-release pellet tablet, which avoids stimulation to gastric mucosa caused by overhigh local drug concentration, is beneficial to absorption of drugs, improves bioavailability and reduces individual difference. The acipimox sustained-release pellets are prepared by sustained-release coating materials and a fluidized bed coating technology, and the overall drug release behavior cannot be changed even if the coating of individual units fails, so that the clinical medication safety is ensured; in addition, the multi-unit pellet preparation is mixed with a certain filling material and pressed into tablets, so that the tablets are convenient for patients to carry and take, and the use compliance is improved. The dosage of the multi-unit sustained-release pellet tablet can be further divided, and a more flexible dosage scheme is provided for clinical medication.
The invention is realized according to the following technical scheme:
the acipimox multi-unit sustained-release pellet tablet is obtained by tabletting acipimox film-controlled sustained-release pellets and a filler, and the formula is as follows:
firstly, pill core prescription:
prescription composition The preferred amount Most preferably in an amount
Acipimox 250 portions of 250 portions of
Filler 48 to 60 portions of 50 portions of
Sodium dodecyl sulfate 0.5 to 1 portion 0.7 portion of
Purified water Proper amount of Proper amount of
Wherein, the main component of the pellet core is acipimox, the filling agent is one or more of microcrystalline cellulose, lactose and pregelatinized starch, and the sodium dodecyl sulfate is a surfactant which can promote dissolution. Wet granulating with appropriate amount of purified water.
Second, sustained release coating film prescription.
Figure PCTCN2019104272-APPB-000001
Preferably, the weight increment range of the slow-release coating film is 20-35%.
Thirdly, the weight ratio of the acipimox sustained-release pellet to the auxiliary materials when tabletting is carried out:
components Preferred proportions Most preferably in an amount
Acipimox sustained-release pellet 100 portions of 100 portions of
Filler 12 to 20 portions of 15 portions of
Disintegrating agent 0.5 to 2 portions of 1.2 parts of
Lubricant agent 0.5 to 1 portion of 0.7 portion of
Adhesive agent 1 to 3 portions of 2 portions of
The pellet tabletting filler is one or more of microcrystalline cellulose, lactose, pregelatinized starch and mannitol, the disintegrant is one of hydroxypropyl methylcellulose or sodium carboxymethyl starch, the lubricant is one or two of magnesium stearate and colloidal silicon dioxide, and the binder is hydroxypropyl cellulose or polyvidone.
The preparation method of the acipimox multi-unit sustained-release pellet tablet comprises the following steps:
1. preparation process of pill core
(1) Pulverizing and sieving acipimox raw material, controlling D90 to 90 μm
(2) Weighing the formula amount of acipimox, microcrystalline cellulose, lactose or pregelatinized starch and sodium dodecyl sulfate, adding into a wet granulator, and uniformly stirring.
(3) Adding a proper amount of purified water, and stirring to prepare a soft material.
(4) The pellet is manufactured by an extrusion spheronization machine, the aperture of a screen is set, the extrusion speed is 10-30 rpm, and the spheronization speed is 400-600 rpm.
(5) Drying in a fluidized bed, controlling the temperature of the materials at 40-60 ℃, and screening to obtain pellets containing the acipimox medicine with different grain diameters.
2. Coating film
Taking the prepared pellets containing the acipimox with proper grain size, preparing a coating solution according to a sustained-release coating film prescription, and coating in a fluidized bed. Controlling the temperature of the fluidized bed to be 25-35 ℃, the flow speed of the coating liquid to be 0.2-0.4 rpm, and controlling the weight gain of the coating film to be 20-35%.
3. Pellet tablet
Uniformly mixing the acipimox sustained-release pellets with auxiliary materials, selecting a special-shaped punch with the diameter of 9mm to be loaded in a tabletting machine, and adjusting the tabletting speed and pressure to prepare the acipimox multi-unit sustained-release pellet tablets.
The content and content uniformity were measured by high performance liquid chromatography (0512 in the four-part general regulation of 2015 edition of Chinese pharmacopoeia) and by the first method of 0941 in the four-part general regulation of 2015 edition of Chinese pharmacopoeia. Octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability tests; methanol-0.01 mol/L tetrabutylammonium hydroxide (20: 80) (pH value is adjusted to 6.0 by phosphoric acid) is used as a mobile phase, the detection wavelength is 264nm, the theoretical plate number is not less than 2000 calculated according to an acipimox peak, and the separation degree of the acipimox peak and an adjacent impurity peak is in accordance with the specification. Taking 10 granules of the product by a measuring method, pouring out the content, precisely weighing the content, grinding, precisely weighing a proper amount of fine powder (about 20mg of acipimox), putting the fine powder into a 100ml measuring flask, adding a proper amount of a mobile phase, dissolving a main drug by ultrasound, fixing the volume, filtering, precisely weighing 5ml of subsequent filtrate, putting the subsequent filtrate into a 50ml measuring flask, diluting the subsequent filtrate to a scale by using the mobile phase to be used as a test sample solution, precisely weighing a proper amount of acipimox reference, adding the mobile phase to prepare 1ml of solution containing 20 mu g of acipimox, using the solution as a reference sample solution, precisely weighing 20 mu l of each of the test sample solution and the reference sample solution, injecting the solution into a liquid chromatograph, recording a chromatogram, and calculating the content according to an external standard method.
The release rate is determined by a dissolution and release rate measuring method (first method of 0931 in the four general rules of the chinese pharmacopoeia 2015 edition). Taking 1000ml of 0.1mol/L hydrochloric acid solution as a solvent, operating at a rotating speed of 100 revolutions per minute by a method, sampling 10ml of the hydrochloric acid solution respectively after 1 hour, 3 hours and 5 hours, filtering, timely supplementing 10ml of dissolution medium with the same temperature into an operating container, precisely measuring 5ml of subsequent filtrate, placing the subsequent filtrate into a 100ml measuring flask, and diluting the subsequent filtrate to a scale with 0.1mol/L hydrochloric acid solution to be used as a test solution; an appropriate amount of acipimox control dried at 105 ℃ to constant weight was precisely weighed and added with 0.1mol/L hydrochloric acid solution to make a solution containing 7.5. mu.g per 1ml as a control solution. Respectively taking the test solution and the reference solution, respectively measuring absorbance at 269nm wavelength by ultraviolet-visible spectrophotometry (0401 in the fourth pharmacopoeia 2015 of China), and calculating the release amount of each granule at different time. The release amount of each granule in 1 hour, 3 hours and 5 hours is respectively 15-35%, 60-85% and more than 80% of the marked amount, and the release amounts are in accordance with the regulations.
Advantageous effects of the invention
Advantageous effects
The acipimox multi-unit sustained-release pellet tablet prepared by the invention is a preparation formed by a multi-unit pellet system, is a film-controlled sustained-release preparation, can be rapidly disintegrated into independent pellet small units in digestive juice, and the pellet units can achieve the effect of sustained release for 8 hours in the gastrointestinal tract. The transport time in the gastrointestinal tract is relatively constant, the phenomenon of dose burst release is avoided, and the safety of clinical medication is ensured. Meanwhile, the distribution area in the gastrointestinal tract is large, and the bioavailability of the medicine is high. The dosage of the multi-unit sustained-release pellet tablet can be further divided, a more flexible dosage scheme is provided for clinical medication, swallowing is easy, and the compliance of patients is improved. And the sustained-release film is not damaged in the tabletting process in the production process by utilizing the technology, the stability of the controlled-release capability is kept, the pellets and the materials are not layered, and the content uniformity is consistent in batches and between batches. The preparation is convenient and is beneficial to industrial large-scale production.
Examples of the invention
Modes for carrying out the invention
The invention is further described by the following examples, which are intended for illustrative purposes only and are not intended to limit the scope of the invention.
Example 1:
the raw material of the acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of the acipimox, 36g of microcrystalline cellulose, 12g of lactose and 0.5g of sodium dodecyl sulfate are weighed and added into a wet granulator, the stirring speed is set to be 330rpm, the shearing speed is set to be 300rpm, and the mixture is mixed for 10 minutes. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 600rpm, 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 600rpm, and simultaneously the stirring is started for 30 seconds to prepare a soft material. Placing the soft material into an extrusion spheronization machine-made pellet. The aperture of the screen mesh is set to be 0.5mm, the extrusion speed is 18rpm, and the rounding speed is 400 rpm. Drying in fluidized bed at 40 deg.C for 20 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of a fluidized bed to be 25 ℃, the flow speed of a coating solution to be 0.2rpm, 39g of Eudragit L30D-55, 7g of triethyl citrate, 14g of talcum powder and 20% of weight gain of a coating film. 200g of the sustained-release pellet of the acipimox, 19g of microcrystalline cellulose, 5g of lactose, 1g of sodium carboxymethyl starch, 1g of magnesium stearate and 2g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the mixture is mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, the hardness is controlled to be 30N, and the sustained-release pellet tablet of the acipimox multi-unit is prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
Table 1 example 1 in vitro cumulative release
Figure PCTCN2019104272-APPB-000002
Example 2:
the raw material of the acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of the acipimox, 32g of pregelatinized starch, 18g of pregelatinized starch and 0.7g of sodium dodecyl sulfate are weighed and added into a wet granulator, the stirring speed is set to be 280rpm, the shearing speed is set to be 300rpm, and the mixture is mixed for 10 minutes. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 600rpm, the opening time is simultaneously 40 seconds, 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 600rpm, the opening time is simultaneously 30 seconds, and soft materials are prepared. Placing the soft material into an extrusion spheronization machine-made pellet. The aperture of the screen mesh is set to be 0.5mm, the extrusion speed is 20rpm, and the rounding speed is 500 rpm. Drying in a fluidized bed at 45 deg.C for 16 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of the fluidized bed to be 30 ℃, the flow rate of the coating liquid to be 0.3rpm, 60g of Eudragit L30D-55, 9g of triethyl citrate, 17g of talcum powder and 29% of weight gain of the coating film. 200g of acipimox sustained-release pellets, 21g of pregelatinized starch, 6g of mannitol, 1.1g of sodium carboxymethyl starch, 1g of magnesium stearate and 2g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the mixture is mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, the hardness is controlled to be 35N, and the acipimox multi-unit sustained-release pellet tablets are prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
Table 2 example 2 in vitro cumulative release
Figure PCTCN2019104272-APPB-000003
Example 3:
the raw material acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of acipimox, 48g of pregelatinized starch, 12g of lactose and 1g of sodium dodecyl sulfate are weighed and added into a wet granulator, the stirring speed is set to be 300rpm, the shearing speed is set to be 280rpm, and the mixture is mixed for 10 minutes. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 800rpm and the opening is carried out simultaneously for 40 seconds, and 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 600rpm and the opening is carried out simultaneously for 30 seconds to prepare a soft material. Placing the soft material into an extrusion spheronization machine-made pellet. The mesh opening size of the screen mesh is set to be 0.5mm, the extrusion speed is 26rpm, and the rounding speed is 570 rpm. Drying in fluidized bed at 50 deg.C for 14 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of the fluidized bed to be 35 ℃, the flow speed of the coating liquid to be 0.4rpm, 63g of Eudragit L30D-55, 10g of triethyl citrate, 30g of talcum powder and 33% of weight gain of the coating film. 200g of acipimox sustained-release pellets, 32g of pregelatinized starch, 8g of mannitol, 2g of hydroxypropyl methylcellulose, 2g of magnesium stearate and 4g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the mixture is mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, and the hardness is controlled to be 40N, so that the acipimox multi-unit sustained-release pellet tablet is prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
Table 3 example 3 in vitro cumulative release
Figure PCTCN2019104272-APPB-000004
Example 4:
the raw material of the acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of the acipimox, 42g of microcrystalline cellulose and 6g of lactose are weighed, 0.5g of sodium dodecyl sulfate are added into a wet granulator, the stirring speed is set to be 330rpm, the shearing speed is set to be 300rpm, and the mixture is mixed for 10 minutes. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 600rpm and the opening is carried out for 40 seconds at the same time, 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 800rpm and the opening is carried out for 30 seconds at the same time to prepare a soft material. Placing the soft material into an extrusion spheronization machine-made pellet. The aperture of the screen mesh is set to be 0.6mm, the extrusion speed is 30rpm, and the rounding speed is 600 rpm. Drying in fluidized bed at 55 deg.C for 11 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of the fluidized bed to be 27 ℃, controlling the flow rate of the coating liquid to be 0.2rpm, controlling the Eudragit L30D-55 to be 64g, controlling the weight of the coating film to be 35 percent, controlling the weight of the triethyl citrate to be 30g, controlling the talcum powder to be 10g and controlling the weight of the coating film to be 35 percent. 200g of acipimox sustained-release pellets, 32g of microcrystalline cellulose, 8g of lactose, 1.8g of sodium carboxymethyl starch, 1.5g of magnesium stearate and 3g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the mixture is mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, the hardness is controlled to be 33N, and the acipimox multi-unit sustained-release pellet tablets are prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
Table 4 example 4 in vitro cumulative release
Time (h) 1 2 3 4 5 6 7 8
Cumulative Release (%) 28 40 54 65 75 84 92 99
Example 5:
the raw material of the acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of the acipimox, 30g of microcrystalline cellulose and 20g of lactose are weighed, 0.7g of sodium dodecyl sulfate are added into a wet granulator, the stirring speed is set to be 330rpm, the shearing speed is set to be 300rpm, and the mixture is mixed for 10 minutes. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 600rpm and the opening is carried out for 40 seconds at the same time, 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 800rpm and the opening is carried out for 30 seconds at the same time to prepare a soft material. Placing the soft material into an extrusion spheronization machine-made pellet. The aperture of the screen mesh is set to be 0.5mm, the extrusion speed is 30rpm, and the rounding speed is 600 rpm. Drying in fluidized bed at 60 deg.C for 11 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of the fluidized bed to be 32 ℃, the flow speed of the coating liquid to be 0.4rpm, 62g of Eudragit L30D-55, 8g of triethyl citrate, 20g of talcum powder and 30% of weight gain of the coating film. 200g of acipimox sustained-release pellets, 26g of microcrystalline cellulose, 4g of lactose, 2.4g of sodium carboxymethyl starch, 1.4g of magnesium stearate and 4g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the mixture is mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, the hardness is controlled to be 37N, and the acipimox multi-unit sustained-release pellet tablets are prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
Table 5 example 5 cumulative in vitro release
Time (h) 1 2 3 4 5 6 7 8
Cumulative Release (%) 32 45 57 69 78 86 92 99
Comparative example 1:
the raw material of the acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of the acipimox, 56g of microcrystalline cellulose, 12g of lactose and 0.3g of sodium dodecyl sulfate are weighed and added into a wet granulator, and the mixture is stirred uniformly. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 600rpm, the opening time is simultaneously 40 seconds, 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 600rpm, the opening time is simultaneously 30 seconds, and soft materials are prepared. Placing the soft material into an extrusion spheronization machine-made pellet. The aperture of the screen mesh is set to be 0.5mm, the extrusion speed is 18rpm, and the rounding speed is 400 rpm. Drying in fluidized bed at 40 deg.C for 20 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of a fluidized bed to be 25 ℃, the flow speed of a coating solution to be 0.2rpm, 101g of Eudragit L30D-55, 8g of triethyl citrate, 20g of talcum powder and 40% of weight gain of a coating film. 200g of acipimox sustained-release pellets, 7g of microcrystalline cellulose, 3g of lactose, 0.3g of sodium carboxymethyl starch, 0.3g of magnesium stearate and 0.8g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the materials are mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, the hardness is controlled to be 30N, and the acipimox multi-unit sustained-release pellet tablet is prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
Table 6 comparative example 1 in vitro cumulative release
Time (h) 1 2 3 4 5 6 7 8
Cumulative Release (%) 30 47 60 72 76 83 92 94
Comparative example 2:
the raw material of the acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of the acipimox, 20g of microcrystalline cellulose, 15g of lactose and 1.2g of sodium dodecyl sulfate are weighed and added into a wet granulator, and the mixture is stirred uniformly. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 600rpm, the opening time is simultaneously 40 seconds, 32g of purified water is added, the stirring speed is set to be 500rpm, and the shearing speed is set to be 600rpm, the opening time is simultaneously 30 seconds, and soft materials are prepared. Placing the soft material into an extrusion spheronization machine-made pellet. The aperture of the screen mesh is set to be 0.5mm, the extrusion speed is 18rpm, and the rounding speed is 400 rpm. Drying in fluidized bed at 40 deg.C for 20 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of the fluidized bed to be 27 ℃, controlling the flow rate of the coating liquid to be 0.3rpm, controlling the Eudragit L30D-55 to be 120g, controlling the weight of the coating film to be 55 percent, controlling the weight of the triethyl citrate to be 30g, controlling the talcum powder to be 10 g. 200g of acipimox sustained-release pellets, 18g of microcrystalline cellulose, 6g of lactose, 5.6g of sodium carboxymethyl starch, 2.3g of magnesium stearate and 6.5g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the mixture is mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, the hardness is controlled to be 37N, and the acipimox multi-unit sustained-release pellet tablet is prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
Table 7 comparative example 2 in vitro cumulative release
Time (h) 1 2 3 4 5 6 7 8
Cumulative Release (%) 20 45 60 76 79 85 92 96
Comparative example 3:
the raw material of the acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of the acipimox, 36g of microcrystalline cellulose, 22g of lactose and 1.3g of sodium dodecyl sulfate are weighed and added into a wet granulator, and the mixture is stirred uniformly. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 600rpm, the opening time is simultaneously 40 seconds, 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 600rpm, the opening time is simultaneously 30 seconds, and soft materials are prepared. Placing the soft material into an extrusion spheronization machine-made pellet. The aperture of the screen mesh is set to be 0.5mm, the extrusion speed is 18rpm, and the rounding speed is 400 rpm. Drying in fluidized bed at 40 deg.C for 20 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of a fluidized bed to be 30 ℃, controlling the flow rate of the coating liquid to be 0.4rpm, controlling Eudragit L30D-55 to be 31g, controlling the weight of the coating film to be 19 percent, controlling the weight of triethyl citrate to be 8g, controlling the talcum powder to be 20g and controlling the weight of the coating film to be 19 percent. 200g of acipimox sustained-release pellets, 17g of microcrystalline cellulose, 3g of lactose, 4.2g of sodium carboxymethyl starch, 2.6g of magnesium stearate and 6.7g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the materials are mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, the hardness is controlled to be 30N, and the acipimox multi-unit sustained-release pellet tablet is prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
TABLE 8 COMPARATIVE EXAMPLE 3 in vitro cumulative Release
Time (h) 1 2 3 4 5 6 7 8
Cumulative Release (%) 33 50 62 75 79 86 90 95
Comparative example 4:
the raw material of the acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of the acipimox, 40g of microcrystalline cellulose and 18g of lactose are weighed, 1g of sodium dodecyl sulfate are added into a wet granulator, and the mixture is stirred uniformly. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 600rpm and the opening is carried out for 40 seconds at the same time, 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 800rpm and the opening is carried out for 30 seconds at the same time to prepare a soft material. Placing the soft material into an extrusion spheronization machine-made pellet. The aperture of the screen mesh is set to be 0.6mm, the extrusion speed is 30rpm, and the rounding speed is 600 rpm. Drying in fluidized bed at 60 deg.C for 11 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of the fluidized bed to be 35 ℃, controlling the flow speed of the coating liquid to be 0.4rpm, controlling the Eudragit L30D-55 to be 72g, controlling the weight of the coating film to be 36 percent, controlling the weight of the triethyl citrate to be 10g, controlling the talcum powder to be 30g and controlling the weight of the coating film to be 36 percent. 200g of acipimox sustained-release pellets, 16g of microcrystalline cellulose, 8g of lactose, 1g of sodium carboxymethyl starch, 1g of magnesium stearate and 2g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the materials are mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, the hardness is controlled to be 30N, and the acipimox multi-unit sustained-release pellet tablet is prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
TABLE 9 COMPARATIVE EXAMPLE 4 in vitro cumulative Release
Time (h) 1 2 3 4 5 6 7 8
Cumulative Release (%) 35 47 53 65 73 85 91 93
Comparative example 5:
the raw material of the acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of the acipimox, 30g of microcrystalline cellulose and 20g of lactose are weighed, 0.7g of sodium dodecyl sulfate are added into a wet granulator, and the mixture is stirred uniformly. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 600rpm and the opening is carried out for 40 seconds at the same time, 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 800rpm and the opening is carried out for 30 seconds at the same time to prepare a soft material. Placing the soft material into an extrusion spheronization machine-made pellet. The aperture of the screen mesh is set to be 0.5mm, the extrusion speed is 30rpm, and the rounding speed is 600 rpm. Drying in fluidized bed at 60 deg.C for 11 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of the fluidized bed to be 30 ℃, controlling the flow rate of the coating liquid to be 0.3rpm, controlling the Eudragit L30D-55 to be 60g, controlling the weight of the coating film to be 30 percent, controlling the weight of the coating film to be 10g, controlling the flow rate of the coating liquid to be 20g, and controlling the weight of the coating film to be 30 percent. 200g of acipimox sustained-release pellets, 26g of microcrystalline cellulose, 4g of lactose, 2.4g of sodium carboxymethyl starch, 1.4g of magnesium stearate and 4g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the materials are mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, the hardness is controlled to be 30N, and the acipimox multi-unit sustained-release pellet tablets are prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
TABLE 10 COMPARATIVE EXAMPLE 5 in vitro cumulative Release
Time (h) 1 2 3 4 5 6 7 8
Cumulative Release (%) 31 45 51 62 71 79 87 92
Comparative example 6:
the raw material of the acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of the acipimox, 48g of pregelatinized starch, 12g of lactose and 0.8g of sodium dodecyl sulfate are weighed and added into a wet granulator, and the mixture is stirred uniformly. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 800rpm and the opening is carried out simultaneously for 40 seconds, and 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 600rpm and the opening is carried out simultaneously for 30 seconds to prepare a soft material. Placing the soft material into an extrusion spheronization machine-made pellet. The mesh opening size of the screen mesh is set to be 0.5mm, the extrusion speed is 26rpm, and the rounding speed is 570 rpm. Drying in fluidized bed at 60 deg.C for 14 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of the fluidized bed to be 27 ℃, controlling the flow rate of the coating liquid to be 0.3rpm, controlling the flow rate of Eudragit L30D-55 to be 157g, controlling the flow rate of Eudragit L30-55 to be 12g, controlling the flow rate of the coating liquid to be 35g, and controlling the weight of the coating film to be 66 percent. 200g of acipimox sustained-release pellets, 12g of pregelatinized starch, 8g of mannitol, 0.8g of hydroxypropyl methylcellulose, 2g of magnesium stearate and 4g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the mixture is mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, the hardness is controlled to be 40N, and the acipimox multi-unit sustained-release pellet tablets are prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
TABLE 11 COMPARATIVE EXAMPLE 6 in vitro cumulative Release
Time (h) 1 2 3 4 5 6 7 8
Cumulative Release (%) 33 42 53 74 79 83 85 94
Comparative example 7:
the raw material acipimox is crushed and sieved, the D90 is controlled to be 90 mu m, 250g of acipimox, 48g of pregelatinized starch, 12g of lactose and 1g of sodium dodecyl sulfate are weighed and added into a wet granulator, the stirring speed is set to be 300rpm, the shearing speed is set to be 280rpm, and the mixture is mixed for 10 minutes. 50g of purified water is added, the stirring speed is set to be 400rpm, the shearing speed is set to be 800rpm and the opening is carried out simultaneously for 40 seconds, and 32g of purified water is added, the stirring speed is set to be 400rpm, and the shearing speed is set to be 600rpm and the opening is carried out simultaneously for 30 seconds to prepare a soft material. Placing the soft material into an extrusion spheronization machine-made pellet. The mesh opening size of the screen mesh is set to be 0.5mm, the extrusion speed is 26rpm, and the rounding speed is 570 rpm. Drying in fluidized bed at 70 deg.C for 14 min. Screening to obtain pellets containing the acipimox drug. Coating liquid is prepared according to the formula of the slow-release coating film by using a high-shear homogenizer, and coating is carried out in a fluidized bed. Controlling the temperature of the fluidized bed to be 20 ℃, controlling the flow rate of the coating liquid to be 0.6rpm, controlling the Eudragit L30D-55 to be 63g, controlling the weight of the coating film to be 33 percent, controlling the weight of the triethyl citrate to be 10g, controlling the talcum powder to be 30g and controlling the weight of the coating film to be 33 percent. 200g of acipimox sustained-release pellets, 32g of pregelatinized starch, 8g of mannitol, 2g of hydroxypropyl methylcellulose, 2g of magnesium stearate and 4g of hydroxypropyl cellulose are placed in a mixer, the mixing frequency is set to be 30Hz, the mixture is mixed for 10 minutes, a special-shaped punch with the diameter of 9mm is selected to be arranged in a tablet press, the tablet pressing speed is adjusted to be 6 ten thousand tablets/hour, and the hardness is controlled to be 40N, so that the acipimox multi-unit sustained-release pellet tablet is prepared. Sampling at the beginning, middle and end of tabletting to detect the content uniformity of the tablets; and detecting the accumulated release degree of the acipimox multi-unit sustained-release pellet tablets by a high performance liquid chromatography method.
TABLE 12 COMPARATIVE EXAMPLE 7 in vitro cumulative Release
Time (h) 1 2 3 4 5 6 7 8
Cumulative Release (%) 28 35 52 63 75 87 91 96
Measurement of content uniformity
TABLE 12 mixing uniformity results for the beginning, middle and end of tablet sampling
Figure PCTCN2019104272-APPB-000005
In conclusion, the acipimox multi-unit sustained-release pellet tablet prepared by the invention can be completely released within 8 hours, no burst release phenomenon occurs, and the sampling detection of the content uniformity of the tablet at the beginning, the middle and the end of the tabletting process finds that the value of the mixing uniformity A +2.2s of the product prepared according to the invention is smaller than 15, the mixing uniformity is in a qualified state, and the value of the mixing uniformity A +2.2s of the product prepared according to the comparative example is larger than 15, the mixing uniformity is in a unqualified state.

Claims (9)

  1. The acipimox multi-unit sustained-release pellet tablet is characterized by being formed by tabletting acipimox pellets containing a sustained-release coating film and filling auxiliary materials through the following process, wherein the dosage of the acipimox pellets is as follows:
    firstly, pill core prescription:
    250 portions of acipimox
    48 to 60 parts of a filler
    0.5-1 part of sodium dodecyl sulfate
    A proper amount of purified water;
    II, a slow-release coating film formula:
    eudragit L30D-5541-65 parts
    7-10 parts of triethyl citrate
    14-30 parts of talcum powder
    The balance of purified water;
    thirdly, when the acipimox sustained-release pellets are tableted, the dosage of the auxiliary materials is as follows:
    100 parts of acipimox sustained-release pellets
    12 to 20 portions of filling agent
    0.5 to 2 portions of disintegrating agent
    0.5 to 1 portion of lubricant
    1-3 parts of adhesive.
  2. The Acipimox multiunit sustained-release pellet of claim 1, wherein,
    firstly, pill core prescription:
    250 portions of acipimox
    50 portions of filler
    Sodium dodecyl sulfate 0.7 part
    A proper amount of purified water;
    second, sustained-release coating film prescription
    Eudragit L30D-5560 parts
    Triethyl citrate 9 parts
    17 portions of talcum powder
    The balance of purified water;
    thirdly, when the acipimox sustained-release pellets are tableted, the dosage of the auxiliary materials is as follows:
    Figure PCTCN2019104272-APPB-100001
  3. the acipimox multi-unit sustained-release pellet of claim 1, wherein the filler in the pellet core prescription is one or more of microcrystalline cellulose, lactose and pregelatinized starch.
  4. The acipimox multi-unit sustained-release pellet of claim 1, wherein the weight gain of the sustained-release coating film in the sustained-release coating film prescription is in the range of 20-35%.
  5. The acipimox multi-unit sustained-release pellet tablet of claim 1, wherein the filler in the pellet tablet is one or more of microcrystalline cellulose, lactose, pregelatinized starch and mannitol.
  6. The acipimox multi-unit sustained-release pellet tablet of claim 1, wherein the disintegrant in the pellet tablet is one of hypromellose or sodium carboxymethyl starch.
  7. The acipimox multi-unit sustained-release pellet of claim 1, wherein the lubricant in the pellet tablet is one or two of magnesium stearate and colloidal silicon dioxide.
  8. The acipimox multi-unit sustained-release pellet tablet of claim 1, wherein the binder in the pellet tablet is composed of hydroxypropyl cellulose or povidone.
  9. The acipimox multi-unit sustained-release pellet of claim 1, wherein the preparation method comprises the steps of:
    1) the preparation process of the pill core comprises the following steps: pulverizing and sieving the raw material acipimox, controlling D90 to be 90 mu m, weighing the formula amount of acipimox, microcrystalline cellulose, lactose or pregelatinized starch and sodium dodecyl sulfate, adding the obtained mixture into a wet granulator, uniformly stirring, adding a proper amount of purified water, and stirring to prepare a soft material; extruding and rounding the pellets by a mechanism, drying the pellets in a fluidized bed, controlling the temperature of the material at 40-60 ℃, and drying and screening to obtain pellets containing the acipimox medicine with different grain sizes;
    2) coating: taking the prepared drug-containing acipimox pellets with proper particle size, preparing a coating solution according to a slow-release coating film prescription, coating in a fluidized bed, controlling the temperature of the fluidized bed to be 25-35 ℃, controlling the flow speed of the coating solution to be 0.2-0.4 rpm, and controlling the weight of the coating film to be increased by 20-35%;
    3) and (3) pellet tabletting: uniformly mixing the acipimox sustained-release pellets with auxiliary materials, and preparing the acipimox multi-unit sustained-release pellet tablets by adjusting the tabletting speed and pressure of a tabletting machine.
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