CN114028577A - Silicon dioxide pellet core and preparation method thereof - Google Patents
Silicon dioxide pellet core and preparation method thereof Download PDFInfo
- Publication number
- CN114028577A CN114028577A CN202111223828.XA CN202111223828A CN114028577A CN 114028577 A CN114028577 A CN 114028577A CN 202111223828 A CN202111223828 A CN 202111223828A CN 114028577 A CN114028577 A CN 114028577A
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- mixing
- microcrystalline cellulose
- pellet
- pellet core
- silicon dioxide
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- 239000008188 pellet Substances 0.000 title claims abstract description 134
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 title claims abstract description 127
- 239000000377 silicon dioxide Substances 0.000 title claims abstract description 50
- 235000012239 silicon dioxide Nutrition 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 96
- 238000002156 mixing Methods 0.000 claims description 76
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 67
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 67
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 67
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 67
- 238000000227 grinding Methods 0.000 claims description 55
- 239000000203 mixture Substances 0.000 claims description 52
- 239000000463 material Substances 0.000 claims description 49
- 239000006187 pill Substances 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 30
- 229910021485 fumed silica Inorganic materials 0.000 claims description 23
- 238000005520 cutting process Methods 0.000 claims description 12
- 239000011148 porous material Substances 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 238000005243 fluidization Methods 0.000 claims description 5
- 239000008119 colloidal silica Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 3
- 238000001125 extrusion Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 29
- 238000011068 loading method Methods 0.000 abstract description 21
- 229940079593 drug Drugs 0.000 abstract description 19
- 210000002784 stomach Anatomy 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 23
- 238000010521 absorption reaction Methods 0.000 description 21
- 238000001035 drying Methods 0.000 description 21
- 230000000052 comparative effect Effects 0.000 description 16
- 239000002245 particle Substances 0.000 description 16
- 230000009286 beneficial effect Effects 0.000 description 15
- 238000007873 sieving Methods 0.000 description 13
- 238000005303 weighing Methods 0.000 description 12
- 230000006866 deterioration Effects 0.000 description 9
- 230000002349 favourable effect Effects 0.000 description 9
- 238000001514 detection method Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 239000000853 adhesive Substances 0.000 description 6
- 230000001070 adhesive effect Effects 0.000 description 6
- 239000008187 granular material Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000005096 rolling process Methods 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000003801 milling Methods 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 238000009475 tablet pressing Methods 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Glanulating (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a silicon dioxide pellet core and a preparation method thereof, the preparation method is simple to operate, and the obtained pellet core has high mechanical strength and friability, good fluidity, high drug loading capacity, good physical compatibility and small bulk density, and can be used for preparing pharmaceutical preparations, in particular to the preparation of stomach floating pellet core tablets.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a silicon dioxide pellet core and a preparation method thereof.
Background
The medical pellet has the characteristics of uniform and solid particle size, round surface, easy coating and controlled drug release speed by the thickness of a coating layer in the process; solves the incompatibility between medicines and improves the stability of the medicines; coating with different types of coating layers to prepare the preparation (quick release, positioning or slow/controlled release) required by clinical treatment. In pharmacodynamics, the medicine has the characteristics of small influence by food delivery rhythm and uniform medicine absorption speed; belongs to a multi-dose pharmaceutical preparation, has small irritation and good reproducibility of blood and medicine between preparation amounts; the medicine particles are uniformly distributed on the surface of intestinal mucosa, and the bioavailability is good. So that the medicinal pellets are more and more widely applied. In the prior art, an extrusion rounding pill making method and a melting pill making method are common.
Patent application CN200610052636.6 discloses a medicinal pellet core and a preparation method thereof, wherein the pellet core is prepared from a main material at least comprising medicinal starch or microcrystalline cellulose, and an adhesive is added to prepare the pellet core with the particle size of 0.3-2.5 mm; wherein, the main material is 60 to 95 percent, the adhesive is 3 to 25 percent, and the water is 2 to 15 percent. The preparation method comprises mixing the main material with binder, granulating in a granulator to obtain round granule, drying, and sieving to obtain pellet core, wherein the main material comprises sucrose fine powder and medicinal starch or microcrystalline cellulose.
Patent application CN107961219A discloses a medicinal pellet core and a preparation method, specifically discloses a medicinal pellet core, which comprises main materials, diluent and adhesive, wherein the main materials are glucose, the mass percent of the main materials is 55-90%, the mass percent of the diluent in the pellet core is 10-35%, the mass percent of the adhesive is 1-8%, the diluent comprises at least one of microcrystalline cellulose, starch and the like, and the adhesive comprises at least one of polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like.
However, the above patents all have the problems of poor particle size uniformity, roundness and surface smoothness, unstable quality of finished products, complicated operation, poor mechanical strength and friability, poor fluidity, low water absorption, small drug loading amount, too high density of pill cores to meet the requirements of floating tablet preparations and the like.
Therefore, a pill core which has the advantages of uniform particle size, high roundness, high surface smoothness, stable quality, mechanical strength, hardness, friability, good fluidity and high drug loading capacity and can be used for floating tablet preparations, Chinese patent medicine granules and the like and a preparation method thereof are needed.
Disclosure of Invention
In order to solve the problems, the invention provides a pill core and a preparation method thereof.
In a first aspect, the present invention provides a process for the preparation of a pellet core.
A method of making a pellet core comprising: mixing silicon dioxide and microcrystalline cellulose, grinding, extruding, rounding and fluidizing; the water content of the microcrystalline cellulose is 50 wt% -56 wt% or the total water content of the silicon dioxide and the microcrystalline cellulose before mixing is 45 wt% -55 wt%. The grinding step is adopted, so that the particle size of the microcrystalline cellulose is favorably reduced, the specific surface area of the microcrystalline cellulose is increased, more hydrogen bonds are conveniently generated among microcrystalline cellulose molecules, and the mechanical strength, the hardness and the friability of the pellet core are favorably improved; the specific surface area of the silicon dioxide pellet core is improved, the water absorption capacity of the silicon dioxide pellet core is improved, and the drug loading capacity of the drug-containing pellet core is improved.
In some embodiments, the total moisture content of the silicon dioxide and microcrystalline cellulose prior to mixing is 47 wt% to 55 wt%. In some embodiments, the total moisture content of the silicon dioxide and microcrystalline cellulose prior to mixing is 48 wt% to 55 wt%. The total water content in the range is favorable for improving the true sphericity of the pellet core, reducing the angle of repose (namely, better fluidity), improving the hardness and water absorption and reducing the 24-hour expansion rate when meeting water.
The silica may be fumed silica or colloidal silica; is favorable for improving the water absorption capacity of the silicon dioxide pellet core, thereby increasing the drug loading capacity.
The specific surface area of the fumed silica or the colloidal silica can be more than or equal to 500 square meters per gram, which is beneficial to improving the water absorption capacity of the silica pill core, thereby increasing the drug loading capacity.
The mixing may include mixing with a mixer.
The mixing time may be 10-30 minutes. In some embodiments, the time of mixing may be 15-20 minutes.
The mixer frequency of the mixing is 10Hz-60 Hz. In some embodiments, the mixer frequency of the mixing is 20Hz to 50 Hz.
The milling may include milling with a mill or an extruder.
The aperture of the screen mesh of the discharge port of the grinder can be 6mm-20 mm.
The rotation speed of the grinder can be 300-600 rpm.
The aperture of the discharge port of the extruder in the grinding step may be 6.0mm to 20.0 mm.
The rotation speed of the extruder in the grinding step is 300-1200 rpm. In some embodiments, the extruder speed of the milling step is 500-
The dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose can be 1: 4-4: 1. If the dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose is lower than 1: 4, the obtained pellet core has high density and high mechanical strength, but is not beneficial to the floating and the improvement of drug loading; if the dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose is higher than 4: 1, the obtained pellet core has low density, high drug loading capacity and low mechanical strength, and is not beneficial to storage and transportation; the dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose is 1: 4-4: 1, which is beneficial to ensuring that the density of the pill core is moderate, improving the floating and drug-loading capacity and simultaneously improving the mechanical strength, hardness and friability of the pill core.
The mixing may comprise mixing the silicon dioxide with the microcrystalline cellulose in a mixer for a time of 10 to 30 minutes, preferably 15 to 20 minutes.
The frequency of the mixer may be from 10Hz to 60Hz, preferably from 20Hz to 50 Hz.
The extruding can comprise adding water or not adding water to ensure that the total moisture of the silicon dioxide and the microcrystalline cellulose is 45 wt% -55 wt%, extruding by using an extruder to form a strip, wherein the moisture content of the strip is 45 wt% -55 wt%.
In some embodiments, the moisture content of the bar is 47 wt% to 55 wt%. In some embodiments, the moisture content of the bar is 47 wt% to 53 wt%. In some embodiments, the moisture content of the bar is 48 wt% to 55 wt%. In some embodiments, the moisture content of the bar is 48 wt% to 53 wt%.
The pore size of the mesh of the extruder in the extruding step may be 150 to 1100 micrometers.
The rolling can comprise rolling by a rolling machine, cutting the strips for 5-120 seconds at the rotating speed of 1000-1500 rpm, and rolling for 10-15 minutes at the rotating speed of 50-1500 rpm.
The fluidization can comprise the fluidization by adopting a fluidized bed, wherein the air inlet temperature of the fluidized bed is 55-95 ℃, the material temperature of the fluidized bed is 40-80 ℃, and the fan rotating speed of the fluidized bed is 1500-; the water content of the fluidized pill core is less than or equal to 6wt percent.
The preparation method can also comprise powder sieving after fluidization.
In some embodiments, the sifting comprises sifting with a 700 micron screen and a 500 micron screen in that order. In some embodiments, the sifting comprises sifting with a 500 micron screen and a 300 micron screen in that order. In some embodiments, the sifting comprises sifting with a 212 micron screen and a 106 micron screen in that order.
The pellet core may not comprise a binder. In some embodiments, the pellet core may not comprise any other excipients other than silicon dioxide and microcrystalline cellulose.
In some embodiments, a method of making a pellet core, comprising: mixing silicon dioxide and microcrystalline cellulose, grinding, extruding, rounding and fluidizing; the water content of the microcrystalline cellulose is 50-56 wt% or the total water content of the silicon dioxide and the microcrystalline cellulose before mixing is 10-55 wt%; the silica is fumed silica or colloidal silica. The embodiment is beneficial to reducing the grain size of the microcrystalline cellulose and increasing the specific surface area of the microcrystalline cellulose, so that more hydrogen bonds are generated among microcrystalline cellulose molecules, and the mechanical strength, hardness and friability of the pellet core are improved; is beneficial to improving the specific surface area of the silicon dioxide, improving the water absorption capacity of the silicon dioxide pellet core and further improving the drug loading capacity of the pellet core.
In some embodiments, a method of making a pellet core, comprising: mixing silicon dioxide and microcrystalline cellulose, grinding, extruding, rounding and fluidizing; the water content of the microcrystalline cellulose is 50-56 wt% or the total water content of the silicon dioxide and the microcrystalline cellulose before mixing is 10-55 wt%; the dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose can be 1: 4-4: 1. The implementation mode is favorable for reducing the grain size of the microcrystalline cellulose and increasing the specific surface area of the microcrystalline cellulose, so that more hydrogen bonds are generated among microcrystalline cellulose molecules, and the mechanical strength, hardness and friability of the pellet core are improved; the method is favorable for improving the specific surface area of the silicon dioxide, improving the water absorption capacity of the silicon dioxide pellet core and further improving the drug loading capacity of the pellet core, and simultaneously, the proper dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose is adopted, so that the pellet core is moderate in density, favorable for improving the floating and drug loading capacity, and favorable for improving the mechanical strength, hardness and friability of the pellet core.
In a second aspect, the present invention provides a pellet core obtained according to the aforementioned preparation method.
A pellet core obtained by the production method according to the first aspect.
In a third aspect, the present invention provides a pellet obtained by the preparation method of the first aspect or the use of the pellet of the second aspect.
Use of a pellet core obtained by the method of manufacture of the first aspect or a pellet core of the second aspect in the manufacture of a pharmaceutical formulation.
The pharmaceutical preparation comprises granules, tablets or capsules.
The tablet is preferably gastric floating tablet.
Advantageous effects
Compared with the prior art, the invention has at least one of the following technical effects:
(1) the true sphericity of the pellet core obtained by the grinding step is better than that of the pellet core obtained without the grinding step, the hardness is higher, the water absorption rate is higher, the expansion rate is lower after 24 hours when the pellet core meets water, the friability is better, and the angle of repose is smaller (namely, the fluidity is better)
(2) According to the invention, by limiting the water content in the process of preparing the pellet core, the obtained pellet core has better true sphericity and smaller angle of repose (namely better fluidity), the hardness and the water absorption are improved, and the 24-hour expansion rate in water is reduced.
(4) The invention improves the true sphere rate, improves the hardness, the water absorption rate and the friability and reduces the 24-hour expansion rate when meeting water by limiting the proportion of the silicon dioxide.
(5) The pill core obtained by the invention basically does not expand after absorbing water, is beneficial to the stability and uniformity of the medicine loading amount, has high water absorption rate, can improve the medicine loading amount, and is most beneficial to Chinese patent medicine granules.
(6) The invention can greatly increase the specific surface area of the microcrystalline cellulose through the steps of grinding, extruding and the like, thereby ensuring that the product of the invention does not need to add any adhesive, but fully utilizes the hydrogen bond bonding force among microcrystalline cellulose molecules to ensure that the product has better mechanical strength and more ideal friability value.
(7) The pill core obtained by the preparation process has good fluidity, the angle of repose is 20-25 degrees, but the lowest bulk density can reach less than 0.4g/cm3Much less than the density of gastric juice (gastric juice density of about 1 g/cm)3) The method is favorable for ensuring that the physical compatibility with API and other pharmaceutical excipients is kept to be optimal when the pellet core tablet is made, is suitable for stomach floating pellet core tablet pressing due to lower bulk density, is the most preferable material for the pellet core tablet pressing process, and finally has super-strong water absorption rate favorable for improving the drug loading rate, thereby being greatly helpful for Chinese patent medicine granules.
(8) The pill core obtained by the preparation process of the invention can not contain any other auxiliary materials except silicon dioxide and microcrystalline cellulose, especially can not contain a bonding agent, is beneficial to reducing the types of the auxiliary materials, is beneficial to improving the compatibility of the auxiliary materials when the pill core is used for preparing a medicinal preparation, and reduces the risk of reducing the stability of the medicament or increasing new impurities caused by adding too many auxiliary materials.
(9) Along with the increase of the proportion of the microcrystalline cellulose, the bulk density is also increased, if the dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose is lower than 1: 4, the obtained pellet core has high density and high mechanical strength, but is not beneficial to the improvement of floating and drug loading; if the dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose is higher than 4: 1, the obtained pellet core has low density, high drug loading capacity and low mechanical strength, and is not beneficial to storage and transportation; the dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose is 1: 4-4: 1, which is beneficial to ensuring that the density of the pill core is moderate, improving the floating and drug-loading capacity and simultaneously improving the mechanical strength, hardness and friability of the pill core.
Definition of terms
Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings:
as used herein, "solids content" means the weight percent of non-volatiles based on the total weight of the components.
As used herein, "wt%" refers to the weight of an individual component of a composition divided by the total weight of the composition, multiplied by 100%.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. Based on the numbers disclosed, the numerical values of each number may vary by less than + -10% or reasonably as recognized by one of ordinary skill in the art, such as by + -1%, + -2%, + -3%, + -4%, or + -5%.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
Some of the instruments used in the specific embodiment of the present invention:
mixing machine:
Mixer Machine；
grinding machine:
Gringing Machine。
the partial detection method adopted by the specific embodiment of the invention comprises the following steps:
the water absorption detection method comprises the following steps: measuring 10ml of pellet core by using a measuring cylinder, wherein the volume is recorded as V1, weighing, the weight is recorded as W1, adding water until water completely submerges the pellet core, placing for 24 hours, observing the volume of the pellet core, wherein the volume is recorded as V2, pouring out excessive water in the measuring cylinder, then absorbing excessive water on the surface of the pellet core by using paper towels, weighing, the weight is recorded as W2, and calculating the water absorption rate and the 24-hour swelling rate when meeting water by the following formulas:
the true sphere rate detection method comprises the following steps: taking a plurality of pellet cores to be under a microscope of 40 times, randomly selecting 60 of the pellet cores, measuring the longest diameter and the shortest diameter of each pellet core by a two-point method, calculating the length-to-diameter ratio of each pellet core, and finally calculating the number average value of the length-to-diameter ratios of 60 pellet cores.
The friability detection method comprises the following steps: refer to "Chinese pharmacopoeia" 2020 edition-Sanshuitong 0923 tablet friability test method.
Bulk density detection method: the stainless steel cup was placed under a chute and the powder was added by volumeter slowly from a height of 5.1cm above the funnel (flowing down at a suitable speed to prevent clogging, if clogging is severe on the screen, the screen was removed) into the stainless steel cup until the powder overflowed, scraping the excess powder to make the powder level with the cup mouth. The weight was weighed and the bulk density was calculated.
The repose angle detection method comprises the following steps: slowly adding the powder from the upper part of the funnel, and calculating the inclination angle of the material leaked from the bottom of the funnel to form a conical accumulation body on the horizontal plane, namely the angle of repose.
Example 1: preparation of pellet cores
Table 1: prescription of pill core
| Name (R) | Microcrystalline cellulose | Fumed silica |
| Weight ratio (in dry matter) | 20 | 80 |
The preparation method comprises the following steps:
(1) mixing: weighing 200 g of microcrystalline cellulose dry product and 800 g of fumed silica dry product according to the formula shown in the table 1, adding 1000 g of water, and mixing in a mixer for 20 minutes at the mixing frequency of 10 Hz; controlling the water content in the mixing process to be 48-51 wt% (about 49 wt%) to obtain a mixture;
(2) grinding: transferring the mixture to a grinding machine for treatment, wherein the diameter of a discharge hole of the grinding machine is 12mm, and the rotating speed is 500 r/min;
(3) extruding: adding water or not to make the total water content of the mixture after grinding 45-55 wt% (about 50 wt%); mixing the ground mixture by a mixer for 10 minutes, then putting the mixture into an extruder, wherein the pore plate of the extruder is 500 microns, and extruding the material into strips to obtain strips, wherein the moisture of the strips is 45-55 wt% (about 50 wt%);
(4) rounding: transferring the strips into a rounding machine, processing for 20 seconds at the rotating speed of 1350 revolutions per minute, cutting the strips into small particles, and rounding for 8 minutes at the rotating speed of 120 revolutions per minute; obtaining a wet pill core;
(5) and (3) drying: transferring the wet pellet cores into a fluidized bed for drying, wherein the inlet air temperature of the fluidized bed is 75 ℃, the material temperature is 65 ℃, the rotating speed of a fan is 2200 rpm, and the material moisture is controlled within 6 percent to obtain crude pellet cores;
(6) sieving: the crude pellet cores are respectively screened by a 500-micron screen and a 300-micron screen, and the pellet cores screened by a 500-micron screen and a 300-micron screen are the target pellet cores in the embodiment.
Example 2: preparation of pellet cores
Table 2: prescription of pill core
The preparation method comprises the following steps:
(1) mixing: weighing 800 g of microcrystalline cellulose dry product and 200 g of fumed silica dry product according to the formula shown in the table 2, adding 1000 g of water, and mixing in a mixer for 20 minutes at the mixing frequency of 10 Hz; controlling the water content in the mixing process to be 51-53 wt% (about 52 wt%) to obtain a mixture;
(2) grinding: transferring the mixture to a grinding machine for treatment, wherein the diameter of a discharge hole of the grinding machine is 12mm, and the rotating speed is 500 r/min;
(3) extruding: adding water or not to make the total water content of the mixture after grinding 45-55 wt% (about 50 wt%); mixing the ground mixture by a mixer for 10 minutes, then putting the mixture into an extruder, wherein the pore plate of the extruder is 200 microns, and extruding the material into strips to obtain strips, wherein the moisture of the strips is 45-55 wt% (about 50 wt%);
(4) rounding: transferring the strips into a rounding machine, processing for 60 seconds at the rotating speed of 1450 revolutions per minute, cutting the strips into small particles, and rounding for 9 minutes at the rotating speed of 1350 revolutions per minute; obtaining a wet pill core;
(5) and (3) drying: transferring the wet pellet cores into a fluidized bed for drying, wherein the inlet air temperature of the fluidized bed is 75 ℃, the material temperature is 65 ℃, the rotating speed of a fan is 2200 rpm, and the material moisture is controlled within 6 percent to obtain crude pellet cores;
(6) sieving: the crude product of the pellet core is respectively screened by a 212-micron screen and a 106-micron screen, and the pellet core screened by the 212-micron screen but not the 106-micron screen is the target pellet core in the embodiment.
Example 3: preparation of pellet cores
Table 3: prescription of pill core
| Name (R) | Microcrystalline cellulose | Fumed silica |
| Weight ratio (in dry matter) | 50 | 50 |
The preparation method comprises the following steps:
(1) mixing: weighing 500 g of microcrystalline cellulose dry product and 500 g of fumed silica dry product according to the formula shown in the table 3, adding 1000 g of water, and mixing in a mixer for 20 minutes at the mixing frequency of 10 Hz; controlling the water content to be 50-52 wt% (about 51 wt%) during the mixing process to obtain a mixture;
(2) grinding: transferring the mixture to a grinding machine for treatment, wherein the diameter of a discharge hole of the grinding machine is 20mm, and the rotating speed is 500 r/min;
(3) extruding: adding water or not to make the total water content of the mixture after grinding 45-55 wt% (about 50 wt%); mixing the ground mixture by a mixer for 10 minutes, then putting the mixture into an extruder, wherein the pore plate of the extruder is 700 microns, and extruding the material into strips to obtain strips, wherein the moisture of the strips is 45-55 wt% (about 50 wt%);
(4) rounding: transferring the strips into a rounding machine, processing for 40 seconds at the rotating speed of 1150 revolutions per minute, cutting the strips into small particles, and rounding for 9 minutes at the rotating speed of 650 revolutions per minute; obtaining a wet pill core;
(5) and (3) drying: transferring the wet pellet cores into a fluidized bed for drying, wherein the inlet air temperature of the fluidized bed is 75 ℃, the material temperature is 65 ℃, the rotating speed of a fan is 2200 rpm, and the material moisture is controlled within 6 percent to obtain crude pellet cores;
(6) sieving: taking the crude product of the pellet core, respectively sieving with a 700 micron sieve and a 500 micron sieve, and obtaining the pellet core passing through a sieve with a size of 700 microns but not 500 microns as the target pellet core in the embodiment.
Comparative example 1: pellet core without grinding treatment
Table 4: prescription of pill core
| Name (R) | Microcrystalline cellulose | Fumed silica |
| Weight ratio (in dry matter) | 20 | 80 |
The preparation method comprises the following steps:
(1) mixing: weighing 200 g of microcrystalline cellulose dry product and 800 g of fumed silica dry product according to the formula shown in Table 4, adding 1000 g of water, and mixing in a mixer for 20 minutes at the mixing frequency of 10 Hz; controlling the water content in the mixing process to be 48-51 wt% (about 49 wt%) to obtain a mixture;
(2) extruding: adding water or no water to make the total moisture of the unmilled mixture 45 wt% to 55 wt% (about 50 wt%); mixing the mixture for 10 minutes by using a mixer, then putting the mixture into an extruder, wherein the pore plate of the extruder is 500 micrometers, extruding the material into strips to obtain strips, and the moisture of the strips is 45-55 wt% (about 50 wt%);
(3) rounding: transferring the strips into a rounding machine, processing for 20 seconds at the rotating speed of 1350 revolutions per minute, cutting the strips into small particles, and rounding for 8 minutes at the rotating speed of 120 revolutions per minute; obtaining a wet pill core;
(4) and (3) drying: transferring the wet pellet cores into a fluidized bed for drying, wherein the inlet air temperature of the fluidized bed is 75 ℃, the material temperature is 65 ℃, the rotating speed of a fan is 2200 rpm, and the material moisture is controlled within 6 percent to obtain crude pellet cores;
(5) sieving: the crude pellet cores are respectively screened by a 500-micron screen and a 300-micron screen, and the pellet cores screened by a 500-micron screen and a 300-micron screen are the target pellet cores of the comparative example.
Comparative example 2: investigating the influence of the over-low water content of the material on the quality of the pellet core
Table 5: prescription of pill core
| Name (R) | Microcrystalline cellulose | Fumed silica |
| Weight ratio (in dry matter) | 20 | 80 |
The preparation method comprises the following steps:
(1) mixing: weighing 200 g of microcrystalline cellulose dry product and 800 g of fumed silica dry product according to the formula shown in Table 5, adding 800 g of water, and mixing in a mixer for 20 minutes at the mixing frequency of 10 Hz; controlling the water content to be 43-44 wt% in the mixing process to obtain a mixture;
(2) grinding: transferring the mixture to a grinding machine for treatment, wherein the diameter of a discharge hole of the grinding machine is 12mm, and the rotating speed is 500 r/min;
(3) extruding: adding water or not to make the total water content of the mixture after grinding 43-44 wt%; mixing the ground mixture for 10 minutes by using a mixer, then putting the mixture into an extruder, wherein the pore plate of the extruder is 500 microns, and extruding the material into strips to obtain strips, wherein the moisture content of the strips is 43-44 wt%;
(4) rounding: transferring the strips into a rounding machine, processing for 20 seconds at the rotating speed of 1350 revolutions per minute, cutting the strips into small particles, and rounding for 8 minutes at the rotating speed of 120 revolutions per minute; obtaining a wet pill core;
(5) and (3) drying: transferring the wet pellet cores into a fluidized bed for drying, wherein the inlet air temperature of the fluidized bed is 75 ℃, the material temperature is 65 ℃, the rotating speed of a fan is 2200 rpm, and the material moisture is controlled within 6 percent to obtain crude pellet cores;
(6) sieving: the crude pellet cores are respectively screened by a 500-micron screen and a 300-micron screen, and the pellet cores screened by a 500-micron screen and a 300-micron screen are the target pellet cores of the comparative example.
Comparative example 3: investigating the influence of the overhigh water content of the material on the quality of the pellet core
Table 6: prescription of pill core
| Name (R) | Microcrystalline cellulose | Fumed silica |
| Weight ratio (in dry matter) | 20 | 80 |
The preparation method comprises the following steps:
(1) mixing: weighing 200 g of microcrystalline cellulose dry product and 800 g of fumed silica dry product according to the formula shown in the 6 in the table, adding 800 g of water, and mixing for 20 minutes in a mixer, wherein the mixing frequency is 10 Hz; controlling the water content in the mixing process to be 57-59 wt% (about 58 wt%) to obtain a mixture;
(2) grinding: transferring the mixture to a grinding machine for treatment, wherein the diameter of a discharge hole of the grinding machine is 12mm, and the rotating speed is 500 r/min;
(3) extruding: adding water or no water to a total moisture content of 57 wt% to 59 wt% (about 58 wt%) of the milled mixture; mixing the ground mixture by a mixer for 10 minutes, then putting the mixture into an extruder, wherein the pore plate of the extruder is 500 microns, and extruding the material into strips to obtain strips, wherein the moisture of the strips is 57-59 wt% (about 58 wt%);
(4) rounding: transferring the strips into a rounding machine, processing for 20 seconds at the rotating speed of 1350 revolutions per minute, cutting the strips into small particles, and rounding for 8 minutes at the rotating speed of 120 revolutions per minute; obtaining a wet pill core;
(5) and (3) drying: transferring the wet pellet cores into a fluidized bed for drying, wherein the inlet air temperature of the fluidized bed is 75 ℃, the material temperature is 65 ℃, the rotating speed of a fan is 2200 rpm, and the material moisture is controlled within 6 percent to obtain crude pellet cores;
(6) sieving: the crude pellet cores are respectively screened by a 500-micron screen and a 300-micron screen, and the pellet cores screened by a 500-micron screen and a 300-micron screen are the target pellet cores of the comparative example.
Comparative example 4: influence of too high proportion of silicon dioxide on quality of pellet core
Table 7: pill core prescription
| Name (R) | Microcrystalline cellulose | Fumed silica |
| Weight ratio (in dry matter) | 10 | 90 |
The preparation method comprises the following steps:
(1) mixing: weighing 100 g of microcrystalline cellulose dry product and 900 g of fumed silica dry product according to the formula shown in Table 7, adding 1000 g of water, and mixing in a mixer for 20 minutes at the mixing frequency of 10 Hz; controlling the water content in the mixing process to be 48-51 wt% (about 49 wt%) to obtain a mixture;
(2) grinding: transferring the mixture to a grinding machine for treatment, wherein the diameter of a discharge hole of the grinding machine is 12mm, and the rotating speed is 500 r/min;
(3) extruding: adding water or not to make the total water content of the mixture after grinding 45-55 wt% (about 50 wt%); mixing the ground mixture by a mixer for 10 minutes, then putting the mixture into an extruder, wherein the pore plate of the extruder is 500 microns, and extruding the material into strips to obtain strips, wherein the moisture of the strips is 45-55 wt% (about 50 wt%);
(4) rounding: transferring the strips into a rounding machine, processing for 20 seconds at the rotating speed of 1350 revolutions per minute, cutting the strips into small particles, and rounding for 8 minutes at the rotating speed of 120 revolutions per minute; obtaining a wet pill core;
(5) and (3) drying: transferring the wet pellet cores into a fluidized bed for drying, wherein the inlet air temperature of the fluidized bed is 75 ℃, the material temperature is 65 ℃, the rotating speed of a fan is 2200 rpm, and the material moisture is controlled within 6 percent to obtain crude pellet cores;
(6) sieving: the crude pellet cores are respectively screened by a 500-micron screen and a 300-micron screen, and the pellet cores screened by a 500-micron screen and a 300-micron screen are the target pellet cores of the comparative example.
Comparative example 5: influence of too low a proportion of silica on the quality of the cores
Table 8: pill core prescription
| Name (R) | Microcrystalline cellulose | Fumed silica |
| Weight ratio (in dry matter) | 90 | 10 |
The preparation method comprises the following steps:
(1) mixing: weighing 900 g of microcrystalline cellulose dry product and 100 g of fumed silica dry product according to the formula shown in the table 8, adding 1000 g of water, and mixing in a mixer for 20 minutes at the mixing frequency of 10 Hz; controlling the water content in the mixing process to be 48-51 wt% (about 49 wt%) to obtain a mixture;
(2) grinding: transferring the mixture to a grinding machine for treatment, wherein the diameter of a discharge hole of the grinding machine is 12mm, and the rotating speed is 500 r/min;
(3) extruding: adding water or not to make the total water content of the mixture after grinding 45-55 wt% (about 50 wt%); mixing the ground mixture by a mixer for 10 minutes, then putting the mixture into an extruder, wherein the pore plate of the extruder is 500 microns, and extruding the material into strips to obtain strips, wherein the moisture of the strips is 45-55 wt% (about 50 wt%);
(4) rounding: transferring the strips into a rounding machine, processing for 20 seconds at the rotating speed of 1350 revolutions per minute, cutting the strips into small particles, and rounding for 8 minutes at the rotating speed of 120 revolutions per minute; obtaining a wet pill core;
(5) and (3) drying: transferring the wet pellet cores into a fluidized bed for drying, wherein the inlet air temperature of the fluidized bed is 75 ℃, the material temperature is 65 ℃, the rotating speed of a fan is 2200 rpm, and the material moisture is controlled within 6 percent to obtain crude pellet cores;
(6) sieving: the crude pellet cores are respectively screened by a 500-micron screen and a 300-micron screen, and the pellet cores screened by a 500-micron screen and a 300-micron screen are the target pellet cores of the comparative example.
Example 4: preparation of pellet cores
Table 9: pill core prescription
| Name (R) | Microcrystalline cellulose | Fumed silica |
| Weight ratio (in dry matter) | 40 | 60 |
The preparation method comprises the following steps:
(1) mixing: weighing 400 g of microcrystalline cellulose dry product and 600 g of fumed silica dry product according to the formula shown in the table 9, adding 1000 g of water, and mixing in a mixer for 20 minutes at the mixing frequency of 10 Hz; controlling the water content in the mixing process to be 48-51 wt% (about 49 wt%) to obtain a mixture;
(2) grinding: transferring the mixture to a grinding machine for treatment, wherein the diameter of a discharge hole of the grinding machine is 20mm, and the rotating speed is 500 r/min;
(3) extruding: adding water or not to make the total water content of the mixture after grinding to be 48-51 wt% (about 49 wt%); mixing the ground mixture by a mixer for 10 minutes, then putting the mixture into an extruder, wherein the pore plate of the extruder is 1000 microns, and extruding the material into strips to obtain strips, wherein the moisture of the strips is 48-51 wt% (about 49 wt%);
(4) rounding: transferring the strips into a rounding machine, processing for 5 seconds at the rotating speed of 1350 revolutions per minute, cutting the strips into small particles, and rounding for 4 minutes at the rotating speed of 100 revolutions per minute; obtaining a wet pill core;
(5) and (3) drying: transferring the wet pellet cores into a fluidized bed for drying, wherein the inlet air temperature of the fluidized bed is 75 ℃, the material temperature is 65 ℃, the rotating speed of a fan is 2200 rpm, and the material moisture is controlled within 6 percent to obtain crude pellet cores;
(6) sieving: the crude pellet cores are respectively screened by a 1100 micron screen and a 850 micron screen, and the pellet cores screened by a screen with the size of 1100 microns but not larger than 850 microns are the target pellet cores of the embodiment.
Example 5: preparation of pellet cores
Table 10: pill core prescription
| Name (R) | Microcrystalline cellulose | Fumed silica |
| Weight ratio (in dry matter) | 30 | 70 |
The preparation method comprises the following steps:
(1) mixing: weighing 300 g of microcrystalline cellulose dry product and 700 g of fumed silica dry product according to the formula shown in Table 10, adding 1000 g of water, and mixing in a mixer for 20 minutes at the mixing frequency of 20 Hz; controlling the water content in the mixing process to be 48-51 wt% (about 49 wt%) to obtain a mixture;
(2) grinding: transferring the mixture to a grinding machine for treatment, wherein the diameter of a discharge hole of the grinding machine is 12mm, and the rotating speed is 500 r/min;
(3) extruding: adding water or not to make the total water content of the mixture after grinding to be 48-51 wt% (about 49 wt%); mixing the ground mixture by a mixer for 10 minutes, then putting the mixture into an extruder, wherein the pore plate of the extruder is 700 microns, and extruding the material into strips to obtain strips, wherein the moisture of the strips is 48-51 wt% (about 49 wt%);
(4) rounding: transferring the strips into a rounding machine, processing for 20 seconds at the rotating speed of 1400 revolutions per minute, cutting the strips into small particles, and rounding for 6 minutes at the rotating speed of 120 revolutions per minute; obtaining a wet pill core;
(5) and (3) drying: transferring the wet pellet cores into a fluidized bed for drying, wherein the inlet air temperature of the fluidized bed is 75 ℃, the material temperature is 65 ℃, the rotating speed of a fan is 2200 rpm, and the material moisture is controlled within 6 percent to obtain crude pellet cores;
(6) sieving: the crude pellet cores are respectively screened by a 700 micron screen and a 500 micron screen, and the pellet cores screened by a screen with the size of 700 microns but not more than 500 microns are the target pellet cores of the embodiment.
Example 6: quality detection
The operation is as follows: the objective cores obtained in examples 1 to 5 and comparative examples 1 to 5 were examined for sphericity, hardness, water absorption, 24-hour swelling rate in water, friability and angle of repose, respectively, and the results are shown in Table 11.
Table 11: the result of the detection
And (4) analyzing results:
(1) as is clear from the results of comparative example 1 and example 1 in Table 11, the pellet core obtained by the grinding step had a better true sphericity, higher hardness, higher water absorption, smaller expansion rate in 24 hours upon contact with water, better friability, and smaller angle of repose (i.e., better fluidity) than the pellet core obtained without the grinding step
(2) As is apparent from the results of comparative example 2 and example 1 in Table 11, too low a moisture content during the preparation of the pellet core results in deterioration of the true sphericity of the pellet core and increase in the angle of repose (i.e., deterioration in flowability); and the water content range provided by the application can ensure that the obtained pill core has better true sphericity and smaller angle of repose (namely better fluidity).
(3) As is clear from the results of comparative example 3 and example 1 in Table 11, in the process of preparing pellet cores, too high a moisture content causes deterioration of true sphericity, decrease in hardness, decrease in water absorption, increase in expansion ratio and increase in angle of repose (i.e., deterioration in fluidity) at 24 hours upon contact with water; the water content range provided by the application can ensure that the obtained pellet core has better true sphericity, improves the hardness and the water absorption rate, and reduces the 24-hour expansion rate and the angle of repose when meeting water.
(4) As is clear from the results of comparative example 4 and examples 1 to 5 in Table 11, too high a proportion of silica causes deterioration in true sphericity, deterioration in hardness, deterioration in water absorption and deterioration in friability; the content range of the silicon dioxide provided by the invention can improve the true sphere rate and improve the hardness, the water absorption and the friability.
(5) As is clear from the results of comparative example 4 and examples 1 to 5 in Table 11, too low a silica ratio causes deterioration of the true spherical ratio and increase of the expansion ratio in 24 hours upon contact with water; the content range of the silicon dioxide provided by the invention can improve the true sphere rate and reduce the 24-hour expansion rate when meeting water.
(6) From the results in Table 11, it is understood that the bulk density is increased with the increase of the ratio of microcrystalline cellulose, and if the dry weight mass ratio of silicon dioxide to microcrystalline cellulose is less than 1: 4, the obtained pellet core has high density and high mechanical strength, but is not favorable for floating and increasing the drug loading; if the dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose is higher than 4: 1, the obtained pill core has low density, high drug loading, but low mechanical strength, which is not beneficial to storage and transportation; the dry weight mass ratio of the silicon dioxide to the microcrystalline cellulose is 1: 4-4: 1, which is beneficial to ensuring that the density of the pill core is moderate, improving the floating and drug-loading capacity and simultaneously improving the mechanical strength, hardness and friability of the pill core.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A method of making a pellet core comprising: mixing silicon dioxide and microcrystalline cellulose, grinding, extruding, rounding and fluidizing; the water content of the microcrystalline cellulose is 50 wt% -56 wt% or the total water content of the silicon dioxide and the microcrystalline cellulose before mixing is 45 wt% -55 wt%.
2. The production method according to claim 1, the grinding comprising grinding with a grinder or an extruder; and/or
The aperture of the sieve mesh at the discharge port of the grinder is 6mm-20 mm; and/or
The rotating speed of the grinding machine is 300-600 rpm; and/or
The aperture of the discharge hole of the extruder in the grinding step is 6.0mm-20.0 mm; and/or
The rotation speed of the extruder in the grinding step is 300-1200 rpm; or the rotation speed of the extruder in the grinding step is 500-1000 rpm.
3. The production method according to any one of claims 1 to 2, wherein the dry weight mass ratio of silicon dioxide to microcrystalline cellulose is from 1: 4 to 4: 1.
4. The method according to any one of claims 1 to 3, wherein the mixing comprises mixing with a mixer, and/or
The mixing time for the mixing is 10-30 minutes, preferably 15-20 minutes; and/or
The frequency of the mixing mixer is 10Hz-60Hz, and the frequency of the mixing mixer is preferably 20Hz-50 Hz.
5. The production method according to any one of claims 1 to 4, wherein the extruding comprises adding or not adding water to make the total moisture of the silicon dioxide and the microcrystalline cellulose to be 45 wt% to 55 wt%, extruding the mixture by using an extruder to form a bar, and the moisture content of the bar is 45 wt% to 55 wt%; preferably 47 wt% -53 wt%; and/or
The pore size of the mesh of the extruder in the extrusion step is 150 to 1100 μm.
6. The method according to any one of claims 1-5, wherein the rounding comprises rounding with a rounding machine at a speed of 1000-1500 rpm for 5-120 seconds, cutting into pellets, and rounding at a speed of 50-1500 rpm for 10-15 minutes.
7. The preparation method according to any one of claims 1 to 6, wherein the fluidization comprises fluidization by using a fluidized bed, the inlet air temperature of the fluidized bed is 55 ℃ to 95 ℃, the material temperature of the fluidized bed is 40 ℃ to 80 ℃, and the fan speed of the fluidized bed is 1500-; the water content of the fluidized pill core is less than or equal to 6wt percent.
8. The production method according to any one of claims 1 to 7, wherein the silica is fumed silica or colloidal silica; and/or
The pellet core does not comprise a binder.
9. A pellet core obtained by the method of preparation according to any one of claims 1-8.
10. Use of a pellet core obtained by the process according to any one of claims 1 to 8 or a pellet core according to claim 9 for the preparation of a pharmaceutical preparation.
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