CN110833192A - 3D printing polysaccharide sustained-release tablet and preparation method thereof - Google Patents
3D printing polysaccharide sustained-release tablet and preparation method thereof Download PDFInfo
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- CN110833192A CN110833192A CN201910657060.3A CN201910657060A CN110833192A CN 110833192 A CN110833192 A CN 110833192A CN 201910657060 A CN201910657060 A CN 201910657060A CN 110833192 A CN110833192 A CN 110833192A
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P20/00—Coating of foodstuffs; Coatings therefor; Making laminated, multi-layered, stuffed or hollow foodstuffs
- A23P20/20—Making of laminated, multi-layered, stuffed or hollow foodstuffs, e.g. by wrapping in preformed edible dough sheets or in edible food containers
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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Molecular Biology (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a 3D printing polysaccharide sustained-release tablet which is prepared by adopting a three-dimensional printing forming technology. The invention fully utilizes the characteristic of 3D printing layer-by-layer stacking molding to axially design the release-resistant layer, changes the traditional three-dimensional release into two-dimensional release and greatly reduces the release area; by utilizing the characteristic that the 3D printing forming layer surface can be flexibly prepared, the density gradient design of the radial fine structure of the tablet compensates the process of slowing down the release rate caused by the reduction of the area of the tablet in the release process, and the tablet is slowly released in a certain release range.
Description
Technical Field
The invention belongs to the technical field of health food, and particularly relates to a 3D printed polysaccharide sustained-release tablet and a preparation method thereof.
Background
The 3DP forming technique has a high degree of process flexibility never seen in conventional manufacturing, does not require the various tools of conventional powder forming, and is not limited by any geometry. The spraying position, the spraying frequency and the spraying speed can be controlled at will; different materials can be sprayed by different spray heads; the spray material may be a solution, suspension, emulsion, melt, etc., so that the 3DP forming technique can easily control the local material composition, microstructure and surface characteristics.
Wu et al [ j.control.release, 1996, 40 (1): 77-87] firstly, 3DP shaping technology is adopted to carry out the preparation research of an implantation drug delivery system; katsta [ j.control.release, 2000 (66): 1-9] and Rowe [ Jcontrol. Release, 2000 (66): 11-17] and the like respectively adopt a 3DP forming technology to carry out preparation research on an oral sustained and controlled release drug delivery system; WO2000/29202 discloses a buccal fast dissolving disintegrating tablet prepared by 3DP forming techniques. The scale of 3D printing applications in the global pharmaceutical market since 2013 will grow at a compound growth rate of 15.4% per year. The first SPRITAM orally disintegrating tablet prepared by Aprecia pharmaceutical company using 3D printing technology on day 5/8 in 2015 was approved by the Food and Drug Administration (FDA) for marketing and will be officially released in 2016, which means that 3D printing technology is moving further into the pharmaceutical field.
At present, 3D printing of western medicine components is mostly carried out to form a medicine, and 3D printing products with traditional Chinese medicines are not found; the effect of rapid disintegration and dispersion of the tablets printed by ink-jet 3D is mostly realized by virtue of high porosity and loose structure, and how to utilize 3DP forming technology to solve the problem of slow release tablet preparation of high-dose traditional Chinese medicine components is not reported at home and abroad.
Disclosure of Invention
In view of this, the technical problem to be solved by the present invention is to provide a 3D printed polysaccharide sustained release tablet and a preparation method thereof, and the high-dose 3D printed polysaccharide sustained release tablet provided by the present invention can realize two-dimensional sustained release of a drug.
The invention provides a 3D printing polysaccharide sustained-release tablet, which is prepared by adopting a three-dimensional printing forming technology and comprises the following components:
a bottom layer;
a first transition layer compounded on the bottom layer;
an intermediate layer containing active polysaccharide and compounded on the first transition layer;
a second transition layer compounded on the intermediate layer;
a top layer composited with the second transition layer;
the middle layer is prepared from active polysaccharide and a controlled release material, and the central position of the middle layer is gradually compact towards an epitaxial structure;
the bottom layer and the top layer are prepared from insoluble polymers;
the first transition layer is prepared by mixing a bottom layer material and an intermediate layer material;
the second transition layer is prepared by mixing a top layer material and a middle layer material.
Preferably, the insoluble polymer is one or more of ethyl cellulose, vinyl acetate cellulose, acrylic resin, polylactic acid and epsilon-polylactone;
the active polysaccharide is selected from one or more of lentinan, lycium barbarum polysaccharide, ganoderma lucidum polysaccharide, tremella polysaccharide and pachyman;
the controlled release material is selected from one or more of ethyl cellulose, hydroxypropyl methyl cellulose and cetyl alcohol.
Preferably, the intermediate layer is prepared from the following raw materials in parts by mass:
preferably, the mass ratio of the middle layer material to the middle layer material in the first transition layer is 1: 0.5-0.5: 1;
the mass ratio of the top layer material to the middle layer material in the second transition layer is 1: 0.5-0.5: 1.
Preferably, the thickness of the bottom layer is 100-450 μm;
the thickness of the first transition layer is 150-600 mu m;
the thickness of the intermediate layer is 3000-3750 mu m;
the thickness of the second transition layer is 150-600 mu m;
the thickness of the top layer is 100-450 mu m.
Preferably, the mass percentage of the active polysaccharide in the 3D printing polysaccharide sustained-release tablet is 20-55%.
The invention also provides a preparation method of the 3D printed polysaccharide sustained-release tablet, which is characterized in that the polysaccharide sustained-release tablet is prepared by adopting a three-dimensional printing forming technology, and the preparation method comprises the following steps:
A) laying bottom layer material powder, spraying a binder and forming to obtain a bottom layer;
B) laying first transition layer material powder on the surface of the bottom layer, and spraying a binder for forming to obtain a first transition layer/bottom layer composite layer;
C) laying intermediate layer material powder on the surface of the first transition layer, spraying a binder for forming, and obtaining an intermediate layer/first transition layer/bottom layer composite layer, wherein the specific method comprises the following steps:
dividing the intermediate layer into a plurality of sequentially sleeved annular printing areas from the center to the outer extension, gradually increasing the number of layers of the intermediate layer material powder paved in the annular printing areas from the center of the intermediate layer to the outer extension, and spraying a binder to form after each layer of the intermediate layer material powder is paved;
D) laying second transition layer material powder on the surface of the intermediate layer, and spraying a binder for forming to obtain a second transition layer/intermediate layer/first transition layer/bottom layer composite layer;
E) and paving top layer material powder on the surface of the second transition layer, and spraying a binder for forming to obtain the 3D printing polysaccharide sustained-release tablet.
Preferably, in the step A), the binder is selected from 0-8 wt% of ethanol solution of insoluble polymer or 0-8 wt% of ethanol water solution of insoluble polymer;
in step B), the binder comprises: 0 to 10 wt% of polyvinylpyrrolidone; 40-60 wt% ethanol; 0-3 wt% of glycerol; the balance of water;
in step C), the binder comprises: 0 to 10 wt% of polyvinylpyrrolidone; 20 to 50 weight percent of ethanol; 0-3 wt% of glycerol; the balance of water;
in step D), the binder comprises: 0 to 10 wt% of polyvinylpyrrolidone; 0-40 wt% ethanol; 0-3 wt% of glycerol; the balance of water;
in the step E), the binder is selected from 0-8 wt% of ethanol solution of insoluble polymer or 0-8 wt% of ethanol solution of insoluble polymer.
Preferably, the repetition frequency of the step A) is 1-5 times when the bottom layer is prepared;
the repetition frequency of the step B) is 1-3 times when the first transition layer is prepared;
when preparing the second transition layer, the repetition frequency of the step D) is 1-3 times;
and (3) repeating the step E) for 1-5 times when preparing the top layer.
Compared with the prior art, the invention provides a 3D printing polysaccharide sustained-release tablet, which is prepared by adopting a three-dimensional printing forming technology and comprises the following components: a bottom layer; a first transition layer compounded on the bottom layer; an intermediate layer containing active polysaccharide and compounded on the first transition layer; a second transition layer compounded on the intermediate layer; a top layer composited with the second transition layer; the middle layer is prepared from active polysaccharide and a controlled release material, and the central position of the middle layer is gradually compact towards an epitaxial structure; the bottom layer and the top layer are prepared from insoluble polymers; the first transition layer is prepared by mixing a bottom layer material and an intermediate layer material; the second transition layer is prepared by mixing a top layer material and a middle layer material. The top layer and the bottom layer of the 3D printed polysaccharide sustained-release tablet provided by the invention are formed by bonding insoluble polymers, the middle layer is formed by jointly using a controlled-release material with a release-retarding or sustained-release effect and active polysaccharide powder, and the first transition layer and the second transition layer are formed by the bottom layer or the top layer and the middle layer powder in a certain proportion, so that the bonding effect of the bottom layer and the top layer with the middle layer is enhanced, and the phenomenon that the top layer and the bottom layer fall off in the corrosion process is avoided. The invention fully utilizes the characteristic of 3D printing layer-by-layer stacking molding to axially design the release-resistant layer, changes the traditional three-dimensional release into two-dimensional release and greatly reduces the release area; by utilizing the characteristic that the 3D printing forming layer surface can be flexibly prepared, the density gradient design of the radial fine structure of the tablet compensates the process of slowing down the release rate caused by the reduction of the area of the tablet in the release process, and the tablet is slowly released in a certain release range.
Drawings
FIG. 1 is a schematic structural diagram of a longitudinal section of a 3D printed polysaccharide sustained-release tablet provided by the invention;
fig. 2 is a schematic sectional view of a middle layer of a 3D printed polysaccharide sustained-release tablet provided in example 2;
figure 3 is a comparative graph of drug release behavior for the examples and comparative examples.
Detailed Description
The invention provides a 3D printing polysaccharide sustained-release tablet, which is prepared by adopting a three-dimensional printing forming technology and comprises the following components:
a bottom layer;
a first transition layer compounded on the bottom layer;
an intermediate layer containing active polysaccharide and compounded on the first transition layer;
a second transition layer compounded on the intermediate layer;
a top layer composited with the second transition layer;
the middle layer is prepared from active polysaccharide and a controlled release material, the central position of the middle layer is gradually compact towards an epitaxial structure, the structure at the central position is loosest, and the outermost structure is bonded and compacted;
the bottom layer and the top layer are prepared from insoluble polymers;
the first transition layer is prepared by mixing a bottom layer material and an intermediate layer material;
the second transition layer is prepared by mixing a top layer material and a middle layer material.
Referring to fig. 1, fig. 1 is a schematic structural view of a longitudinal section of a 3D printed polysaccharide sustained-release tablet provided by the present invention. 1 is a top layer, 2 is a second transition layer, 3 is a middle layer, 4 is a first transition layer, and 5 is a bottom layer.
The 3D printed polysaccharide sustained-release tablet provided by the invention is prepared by adopting a three-dimensional printing forming technology, and comprises a bottom layer, wherein the bottom layer is prepared from an insoluble polymer, the insoluble polymer is one or more of ethyl cellulose, vinyl acetate cellulose, acrylic resin, polylactic acid and epsilon-polylactone, and preferably ethyl cellulose. The thickness of the bottom layer is 300 μm.
The release retarding material insoluble polymer used for spraying is typically a low viscosity grade, preferably one or more of 3cps, 5cps, 7cps and 10cps ethylcellulose. This enables a more continuous and stable spraying process and a higher quality delivery system.
The 3D printed polysaccharide sustained-release tablet provided by the invention further comprises a first transition layer compounded on the bottom layer and an intermediate layer containing active polysaccharide compounded on the first transition layer.
The first transition layer is prepared by mixing a bottom layer material and a middle layer material, and the mass ratio of the bottom layer material to the middle layer material in the first transition layer is 1: 0.5-0.5: 1, preferably 1: 1.
The middle layer is prepared from active polysaccharide and controlled release material, wherein the active polysaccharide is selected from one or more of lentinan, lycium barbarum polysaccharide, ganoderma lucidum polysaccharide, tremella polysaccharide and pachyman.
In the invention, the active polysaccharide is not easy to dissolve after being wetted in water and has a certain three-dimensional structure, and the active polysaccharide is not only an active drug but also a slow-release auxiliary material, so that the high drug loading of the tablet can be realized.
The controlled release material is selected from one or more of ethyl cellulose, hydroxypropyl methyl cellulose and cetyl alcohol.
In some embodiments of the present invention, the intermediate layer is prepared from the following raw materials in parts by mass:
in some embodiments of the present invention, the intermediate layer is prepared from the following raw materials in parts by mass:
in some embodiments of the present invention, the intermediate layer is prepared from the following raw materials in parts by mass:
in the raw material of the middle layer, hydroxypropyl methylcellulose is a low-viscosity series product, and preferably one or more of HPMC E50, HPMC E100 and HPMC E15. This enables a more continuous and stable spraying process and a higher quality delivery system.
In the structure of the intermediate layer, the central position is gradually compact towards the epitaxial structure, the structure at the central position is loosest, and the outermost structure is compactest.
The thickness of the first transition layer is 100-450 mu m;
the thickness of the intermediate layer is 3000-3750 mu m;
the 3D printed polysaccharide sustained-release tablet provided by the invention further comprises a second transition layer compounded on the middle layer and a top layer compounded on the second transition layer.
The second transition layer is prepared by mixing a top layer material and a middle layer material.
The top layer is prepared from an insoluble polymer, the insoluble polymer is one or more of ethyl cellulose, vinyl acetate cellulose, acrylic resin, polylactic acid and epsilon-polylactone, and ethyl cellulose is preferred.
The mass ratio of the top layer material to the middle layer material in the second transition layer is 1: 0.5-0.5: 1, and preferably 1: 1.
The thickness of the second transition layer is 150-600 mu m;
the thickness of the top layer is 100-450 mu m.
In the invention, the mass percentage of the active polysaccharide in the 3D printing polysaccharide sustained-release tablet is 20-55%. The active polysaccharide content is higher in the 3D printed polysaccharide sustained-release tablet, so that the preparation of the high-dose polysaccharide sustained-release tablet is realized.
The shape of the 3D printed polysaccharide sustained-release tablet is not particularly limited, and the sustained-release tablet known to those skilled in the art can be in the shape of a tablet layer, and the radial cross-sectional shape can be, but is not limited to, a circle, a square, a diamond, an ellipse, and the like.
The invention also provides a preparation method of the 3D printing polysaccharide sustained-release tablet, the 3D printing polysaccharide sustained-release tablet provided by the invention is prepared by adopting a three-dimensional printing forming technology through 'layer-by-layer printing and layer-by-layer superposition': firstly, powder layering is carried out, then a three-dimensional printer is controlled by a computer to spray a binder, the powder is bonded together to form a two-dimensional layered sheet, then a new layer of powder layering is carried out on the two-dimensional layered sheet, the three-dimensional printer is controlled by the computer to spray the binder to bond the powder together, and the steps are repeated until the spraying and forming of the processed three-dimensional article are finished, so that the material gradient controlled-release drug delivery system is prepared.
Wherein, the top layer and the bottom layer are paved with the insoluble polymer powder of the controlled release material with the release-retarding function, and sprayed with the adhesive for bonding and forming. The transition layer is paved with mixed powder of the top layer or the bottom layer and the middle layer in a certain proportion, and is sprayed with adhesive for bonding and forming. The intermediate layer is paved with mixed powder containing medicine and excipient, and is sprayed with adhesive for bonding and forming, and the difference of inner domains of each layer is formed by different spraying times of different areas, so as to obtain structural gradient distribution. The structural gradient distribution of each layer of the middle layer of the polysaccharide sustained-release tablet means that the spraying times are different in different areas, namely the spraying times are gradually increased from the circle center to the circumference; the spraying frequency of the innermost layer is the least, and the bonding is the loosest; the outermost layer is sprayed for the most times and is bonded most tightly.
Specifically, the polysaccharide sustained-release tablet is prepared by adopting a three-dimensional printing forming technology, and comprises the following steps:
A) laying bottom layer material powder, spraying a binder and forming to obtain a bottom layer;
B) laying first transition layer material powder on the surface of the bottom layer, and spraying a binder for forming to obtain a first transition layer/bottom layer composite layer;
C) laying intermediate layer material powder on the surface of the first transition layer, spraying a binder for forming, and obtaining an intermediate layer/first transition layer/bottom layer composite layer, wherein the specific method comprises the following steps:
dividing the intermediate layer into a plurality of sequentially sleeved annular printing areas from the center to the outer extension, gradually increasing the number of layers of the intermediate layer material powder paved in the annular printing areas from the center of the intermediate layer to the outer extension, and spraying a binder to form after each layer of the intermediate layer material powder is paved;
D) laying second transition layer material powder on the surface of the intermediate layer, and spraying a binder for forming to obtain a second transition layer/intermediate layer/first transition layer/bottom layer composite layer;
E) and paving top layer material powder on the surface of the second transition layer, and spraying a binder for forming to obtain the 3D printing polysaccharide sustained-release tablet.
When the 3D printing polysaccharide sustained-release tablet is prepared, the computer terminal outputs an instruction to directly control the 3D printing equipment to operate and prepare.
Firstly, bottom layer material powder is paved on the surface of a powder bed of a printing workbench, and the single-layer powder paving thickness is 75-200 mu m. And then spraying a binder for forming, wherein the binder is selected from 0-8 wt% of ethanol solution of insoluble polymer or 0-8 wt% of ethanol solution of insoluble polymer. The frequency of spraying the binder can ensure that the bottom layer material powder is formed, and then, the bottom layer material powder is naturally dried. And then the piston rod drives the whole powder bed of the workbench to descend, a new layer of powder is prepared for powder paving, and the steps are repeated for 1-5 times to jointly form a bottom surface layer release-resistant layer.
And then, paving first transition layer material powder on the surface of the bottom layer, wherein the thickness of the single-layer powder paving is 100-200 mu m. Then spraying a binder for forming, wherein the binder comprises: 0 to 10 wt% of polyvinylpyrrolidone; 40-60 wt% ethanol; 0-3 wt% of glycerol; the balance being water. In some embodiments of the invention, the binder comprises: 1-7 wt% of polyvinylpyrrolidone; 45-55 wt% ethanol; 0.5-3 wt% of glycerol; the balance being water. The frequency of spraying the binder can ensure that the first transition layer material powder is formed, and then, the first transition layer material powder is naturally dried. And then the piston rod drives the whole powder bed of the workbench to descend, a new layer of powder is prepared for powder paving, the steps are repeated for 1-3 times, and a first transition layer is formed together to obtain a first transition layer/bottom layer composite layer.
Then, laying intermediate layer material powder on the surface of the first transition layer, spraying a binder for forming, and obtaining an intermediate layer/first transition layer/bottom layer composite layer, wherein the specific method comprises the following steps:
dividing the intermediate layer into a plurality of annular printing areas which are sequentially sleeved from the center to the outer extension, gradually increasing the number of layers of the intermediate layer material powder paved in the annular printing areas from the center of the intermediate layer to the outer extension, and spraying the adhesive after each layer of the intermediate layer material powder is paved for forming.
In the present invention, the annular printing areas have the same width in the radial direction, i.e., the intermediate layer is equally divided. In the two-dimensional release tablet which is only eroded in the radial direction, the release rate is relatively constant when the release rate constant k is oc 1/r. The release rate constant k of the tablet is related to the surface area of the particles, the more the spraying times are, the more compact the particles are bonded, the smaller the surface area is, the smaller the release rate constant is, and the r is continuously reduced and the k is continuously increased along with the radial erosion of the tablet. During the printing operation, the printing is performed in equally divided areas.
When intermediate layer printing is underway, the adhesive includes: 0 to 10 wt% of polyvinylpyrrolidone; 20 to 50 weight percent of ethanol; 0-3 wt% of glycerol; the balance being water. In some embodiments of the invention, the binder comprises: 1-8 wt% of polyvinylpyrrolidone; 25 wt% -40 wt% of ethanol; 0.5-2 wt% of glycerol; the balance being water.
The frequency of spraying the binder can ensure that the intermediate layer material powder is formed, and then, the intermediate layer material powder is naturally dried.
And paving second transition layer material powder on the surface of the intermediate layer, spraying a binder for forming, paving the second transition layer material powder on the surface of the intermediate layer, and paving the single-layer powder with the thickness of 100-150 mu m. Then spraying a binder for forming, wherein the binder comprises: 0 to 10 wt% of polyvinylpyrrolidone; 0-40 wt% ethanol; 0-3 wt% of glycerol; the balance being water. In some embodiments of the invention, the binder comprises: 1-7 wt% of polyvinylpyrrolidone; 40-60 wt% ethanol; 0.5-3 wt% of glycerol; the balance being water. The frequency of spraying the binder can ensure that the second transition layer material powder is formed, and then, the second transition layer material powder is naturally dried. And then the piston rod drives the whole powder bed of the workbench to descend, a new layer of powder is prepared for powder paving, the steps are repeated for 1-3 times, and a second transition layer is formed together to obtain a second transition layer/middle layer/first transition layer/bottom layer composite layer.
And finally, paving top layer material powder on the surface of the second transition layer, spraying a binder for forming, and obtaining the 3D printing polysaccharide sustained-release tablet. Specifically, top layer material powder is paved on the surface of the second transition layer, and the thickness of the single layer paved powder is 100-200 mu m. And then spraying a binder for forming, wherein the binder is selected from 0-8 wt% of ethanol solution of insoluble polymer or 0-8 wt% of ethanol solution of insoluble polymer. The frequency of spraying the binder can ensure that the top layer material powder is formed, and then, the top layer material powder is naturally dried. And then the piston rod drives the whole powder bed of the workbench to descend, a new layer of powder is prepared for powder paving, the steps are repeated for 1-5 times, and a top layer release-retarding layer is formed together to obtain the 3D printed polysaccharide sustained-release tablet.
By adopting the technical scheme, the medicine is only released from the radial direction through the release resistance of the top and the bottom surfaces; the radial gradient distribution of the bonding compactness is realized by a printing process, and the drug release at a relatively constant rate is controlled.
The top layer and the bottom layer of the 3D printed polysaccharide sustained-release tablet provided by the invention are formed by bonding insoluble polymers, the middle layer is formed by jointly using a controlled-release material with a release-retarding or sustained-release effect and active polysaccharide powder, and the first transition layer and the second transition layer are formed by the bottom layer or the top layer and the middle layer powder in a certain proportion, so that the bonding effect of the bottom layer and the top layer with the middle layer is enhanced, and the phenomenon that the top layer and the bottom layer fall off in the corrosion process is avoided. The invention fully utilizes the characteristic of 3D printing layer-by-layer stacking molding to axially design the release-resistant layer, changes the traditional three-dimensional release into two-dimensional release and greatly reduces the release area; by utilizing the characteristic that the 3D printing forming layer surface can be flexibly prepared, the density gradient design of the radial fine structure of the tablet compensates the process of slowing down the release rate caused by the reduction of the area of the tablet in the release process, and the slow release of the tablet in a certain release range is realized.
For further understanding of the present invention, the following examples are provided to illustrate the 3D printed polysaccharide sustained-release tablet and the preparation method thereof, and the scope of the present invention is not limited by the following examples.
Example 1: three-dimensional printing powder and adhesive blending
Top and bottom layer powder 1 composition: sieving ethyl cellulose with 5cps with 200 mesh sieve, and collecting powder with particle size less than 74 μm for top and bottom layer layering;
top and bottom adhesive 1 consists of: weighing 2 g of 5cps ethyl cellulose powder, dissolving in a mixed solution of 10g of ethanol and 90g of water to prepare a top layer and a bottom layer powder forming binder 1;
the intermediate mixed powder 2 comprises the following raw materials in parts by weight:
52 parts of active polysaccharide (the mass ratio of lentinan, pachyman and tremella polysaccharide is 1:1:1, the specific formula is shown in patent CN105747232A, which is not described in detail here)
Sieving each raw material and adjuvant with 200 mesh sieve, mixing, and sieving for 3 times
transition layer mixed powder 3 composition: weighing 50 parts of middle layer powder and 50 parts of middle layer powder, and uniformly mixing
example 2: preparation of 3D printing polysaccharide sustained-release tablet
The computer terminal outputs instructions to directly control the operation and preparation. Laying a layer of powder 1 with the thickness of 100 mu m, spraying 5 times of adhesive 1 for forming to form the bottom surface of the medicine film, naturally drying for 30s, then driving the whole powder bed of the workbench to descend by the piston rod, preparing a new layer of laid powder, and repeatedly printing the 2 nd and 3 rd layers to jointly form a bottom surface layer release-resistant layer (with the thickness of 300 mu m).
The powder 3 was mixed in 4,5 subsequent layers of transition layer, a single layer of 150 μm thick, and bonded with the binder 3, and the binder 3 was sprayed 5 times per layer to form a bottom transition region (300 μm).
6-30 layers are middle layers containing active polysaccharide, the powder is spread in a single layer with the thickness of 150 mu m, bonding forming is carried out by using an adhesive 2, the section view of the middle layer is shown in figure 2, and the radial structure gradient is prepared by the change of the spraying times as follows: dividing the round surface of the tablet into 8 areas according to the diameter (10mm) of the tablet, wherein the first spraying is performed in 1-8 areas, the second spraying is performed in 2-8 areas, the 3 rd spraying is performed in 3-8 areas, the 4 th spraying is performed in 4-8 areas, and the like, and the 8 th spraying is performed in 8 areas, so that the 8 areas from the most central periphery to the outside are sprayed for 1, 2,3,4,5,6,7 and 8 times, and the structural gradient distribution with the most compact periphery and the relatively loose center is obtained. The number of intermediate layer sprays is shown in table 1.
TABLE 1 interlayer gradient printing
31, 32 layers of transition layer mixed powder 3 with a single layer powder thickness of 150 μm are bonded and formed by using the adhesive 3, and each layer is sprayed for 5 times to form a top transition layer (300 μm)
Spreading release-resistant powder 1 in 33-36 layers with a thickness of 100 μm, bonding with adhesive 1, and spraying 5 times to form a top release-resistant layer (400 μm)
And after printing, naturally drying, and removing the powder to obtain the 3D printed polysaccharide sustained-release tablet.
TABLE 23D printing parameters for each layer of polysaccharide sustained-release tablets
The quality standard inspection of the tablets is carried out according to the appendix of the 'Chinese pharmacopoeia' 2015 edition, and the result shows that the hardness and the friability both meet the requirements. The same batch of drug delivery systems were checked for drug content, SD ═ 0.042(n ═ 6), and different batches of drug delivery systems were checked for drug content, SD ═ 0.047(n ═ 6), meeting the standard.
Comparative example 1: comparative tablet 1 without transition layer
The powder preparation was the same as example 1, the bottom top middle layer was printed the same as example 2, the transition layer was not designed, and the specific printing process is shown in table 3.
Table 3 print parameters for each layer of comparative example 1
The quality standard inspection of the tablets is carried out according to the appendix of the 'Chinese pharmacopoeia' 2015 edition, and the result shows that the hardness and the friability both meet the requirements. The same batch of drug delivery systems were checked for drug content, SD 0.037(n 6), and different batch of drug delivery systems were checked for drug content, SD 0.056(n 6), meeting the standard.
Comparative example 2: comparative tablet 2 without Release layer
The powder preparation was the same as example 1, the transition layer and the intermediate layer were printed the same as example 2, the release-retarding layer was not designed, and the specific printing process is shown in table 4.
Table 4 print parameters for each layer of comparative example 2
The quality standard inspection of the tablets is carried out according to the appendix of the 'Chinese pharmacopoeia' 2015 edition, and the result shows that the hardness and the friability both meet the requirements. The same batch of drug delivery systems were checked for drug content, SD ═ 0.046(n ═ 6), and different batch of drug delivery systems were checked for drug content, SD ═ 0.057(n ═ 6), and met the standard.
Comparative example 3: comparative tablet 3 with non-gradient bonding of intermediate layer structure
The powder preparation is the same as example 1, the top layer, the bottom layer and the transition layer are printed as in example 2, no structural gradient is designed in the middle, and the specific printing process is shown in Table 5.
Table 5 comparative film 3 printing parameters for each layer
The quality standard inspection of the tablets is carried out according to the appendix of the 'Chinese pharmacopoeia' 2015 edition, and the result shows that the hardness and the friability both meet the requirements. The same batch of drug delivery systems were checked for drug content, SD 0.067(n 6), and different batch of drug delivery systems were checked for drug content, SD 0.066(n 6), meeting the standard.
Comparative example 4: conventional direct compression comparative tablet 4
The powder of the intermediate layer in example 1 was used for direct compression, and the tablet size and weight were not significantly different from those of the tablet in example 2. The quality standard inspection of the tablets is carried out according to the appendix of the 'Chinese pharmacopoeia' 2015 edition, and the result shows that the hardness and the friability both meet the requirements. The same batch of drug delivery systems were tested for drug content, SD 0.027(n 6), and different batches of drug delivery systems were tested for drug content, SD 0.034(n 6), meeting the standard.
Example 3 Slow Release of tablets based on the powder composition modification Process design in example 1
The computer terminal outputs instructions to directly control the operation and preparation. Laying a layer of powder 1 with the thickness of 150 mu m, spraying 10 times of binder 1 for forming to form the bottom surface of the medicine film, naturally drying for 60s, then driving the whole powder bed of the workbench to descend by the piston rod, preparing a new layer of laid powder, and repeatedly printing the layer 2 to jointly form the bottom surface layer release-resistant layer.
Then 3,4,5 layers of transition layer mixed powder 3 are paved, the single layer of powder is paved with the thickness of 150 mu m, bonding forming is carried out by the adhesive 3, and each layer is sprayed for 10 times, thus forming a bottom transition area.
6-30 layers are layers containing active polysaccharide in the middle, the powder is spread in a single layer with the thickness of 150 mu m, bonding forming is carried out by using an adhesive 2, and the radial structure gradient is prepared by the change of spraying times as follows: dividing the round surface of the tablet into 10 areas according to the diameter (10mm) of the tablet, wherein the first spraying is performed in a 1-10 area, the second spraying is performed in a 2-10 area, the 3 rd spraying is performed in a 3-10 area, the 4 th spraying is performed in a 4-10 area, and the like, and the 10 th spraying is performed in a 10 area, so that the 10 areas from the most central periphery to the outside are sprayed for 1, 2,3,4,5,6,7, 8, 9 and 10 times, and the structural gradient distribution with the most compact periphery and the relatively loose center is obtained. The number of intermediate layer sprays is shown in table 6.
TABLE 6 intermediate layer gradient printing
29, 30 and 31 layers of transition layer mixed powder 3 are paved, the single layer powder paving thickness is 150 mu m, bonding forming is carried out by the adhesive 3, each layer is sprayed for 5 times, and the top transition layer is formed
Spreading release-resistant powder 1 in 32-33 layers with a thickness of 150 μm, bonding with adhesive 1, and spraying 10 times to form top release-resistant layer
And after printing, naturally drying, and removing the powder to obtain the 3D printed polysaccharide sustained-release tablet.
TABLE 73D printing parameters for each layer of polysaccharide sustained-release tablets
The quality standard inspection of the tablets is carried out according to the appendix of the 'Chinese pharmacopoeia' 2015 edition, and the result shows that the hardness and the friability both meet the requirements. The same batch of drug delivery system was checked for drug content, SD is 0.074(n is 6), and the different batch of drug delivery system was checked for drug content, SD is 0.067(n is 6), meeting the standard. The printed polysaccharide sustained-release tablet basically realizes the slow release from 60 minutes to 460 minutes by adopting the first method for measuring XD release in appendix of 2015 edition of Chinese pharmacopoeia.
Example 4 Slow Release of tablets based on the powder composition modification Process design in example 1
The computer terminal outputs instructions to directly control the operation and preparation. Laying a layer of powder 1 with the thickness of 100 mu m, spraying 10 times of binder 1 for forming to form the bottom surface of the medicine film, naturally drying for 60s, then driving the whole powder bed of the workbench to descend by the piston rod, preparing a new layer of laid powder, and repeatedly printing the 2 nd, 3 rd and 4 th layers to jointly form the bottom surface layer release-resistant layer.
The subsequent 4,5,6 layers of the mixed powder 3 of the transition layer are paved, the single layer is paved, the powder thickness is 100 mu m, the bonding forming is carried out by the adhesive 3, and each layer is sprayed for 8 times, so as to form the bottom transition area.
7-30 layers are layers containing active polysaccharide in the middle, the powder is spread in a single layer with the thickness of 150 mu m, bonding forming is carried out by using an adhesive 2, and the radial structure gradient is prepared by the change of spraying times as follows: dividing the round surface of the tablet into 7 areas according to the diameter (10mm) of the tablet, wherein the first spraying and the second spraying are carried out in 1-7 areas, the third spraying and the fourth spraying are carried out in 2-7 areas, the 5 th spraying and the 4-7 areas are carried out in 4-7 areas, and the like, and the 8 th spraying and the 7 th spraying are carried out in 7 areas, so that the 7 areas from the most central periphery to the outside are sprayed for 2,3,4,5,6,7 and 8 times, and the structural gradient distribution with the most compact periphery and the relatively loose center is obtained. The number of intermediate layer sprays is shown in table 8.
TABLE 8 interlayer gradient printing
31, 32 and 33 layers of transition layer mixed powder 3 are paved, the single layer of the mixed powder is paved with the thickness of 100 mu m, the bonding forming is carried out by the adhesive 3, each layer is sprayed for 8 times, and the top transition layer is formed
Spreading release-resistant powder 1 in 34-36 layers with a thickness of 100 μm, bonding with adhesive 1, and spraying 10 times to form top release-resistant layer
And after printing, naturally drying, and removing the powder to obtain the 3D printed polysaccharide sustained-release tablet.
TABLE 93D printing parameters for each layer of polysaccharide sustained-release tablets
The quality standard inspection of the tablets is carried out according to the appendix of the 'Chinese pharmacopoeia' 2015 edition, and the result shows that the hardness and the friability both meet the requirements. The same batch of drug delivery system was checked for drug content, SD is 0.074(n is 6), and the different batch of drug delivery system was checked for drug content, SD is 0.074(n is 6), meeting the standard. The printed polysaccharide sustained-release tablet basically realizes the slow release from 60 minutes to 400 minutes by adopting the first method for measuring XD release in appendix of 2015 edition of Chinese pharmacopoeia.
Example 5 printing of lentinan sustained release tablet 1 by changing powder composition based on the process design in example 2
Top and bottom layer powder a composition: respectively sieving 10cps ethyl cellulose and hydroxypropyl methyl cellulose with 200 mesh sieve, collecting powder with particle size less than 74 μm, and mixing with ethyl cellulose: hydroxypropyl methylcellulose 8:2 blend for top and bottom layering;
top and bottom adhesive a composition: weighing ethyl cellulose: dissolving 2 g of hydroxypropyl methyl cellulose (8: 2) mixed powder in a mixed solution of 5g of ethanol and 95g of water to prepare a top layer powder forming binder A and a bottom layer powder forming binder A;
the intermediate mixed powder B comprises the following raw materials in parts by weight:
sieving each raw material and adjuvant with 200 mesh sieve, mixing, and sieving for 3 times
Interlayer adhesive B composition: weighing 5g of polyvinylpyrrolidone K30 powder and 1mL of glycerol, dissolving in a mixed solution of 30g of ethanol and 70g of water, and preparing an intermediate layer binder B;
transition layer mixed powder C composition: weighing 50 parts of middle layer powder and 50 parts of middle layer powder, and uniformly mixing
Transition layer adhesive C composition: weighing 3 g of polyvinylpyrrolidone K30 powder and 1mL of glycerol, dissolving in a mixed solution of 50g of ethanol and 50g of water, and preparing a transition layer adhesive C;
the computer terminal outputs instructions to directly control the operation and preparation. Laying a layer of powder A with the thickness of 100 mu m, spraying 5 times of the binder A for forming to be the bottom surface of the medicine film, naturally drying for 30s, then driving the whole powder bed of the workbench to descend by the piston rod, preparing a new layer of laid powder, and repeatedly printing the 2 nd and 3 rd layers to jointly form a bottom surface layer release-resistant layer (with the thickness of 300 mu m).
Subsequently, 4,5 layers of the transition layer mixed powder C were laid to a single layer thickness of 150 μm, and bonded and formed with the adhesive C, and the adhesive C was sprayed 5 times per layer to form a bottom surface transition region (300 μm).
6-30 layers are layers containing lentinan in the middle, the powder spreading thickness of a single layer is 150 mu m, bonding forming is carried out by using an adhesive B, and the radial structure gradient is prepared by the change of spraying times as follows: dividing the round surface of the tablet into 8 areas according to the diameter (10mm) of the tablet, wherein the first spraying is performed in 1-8 areas, the second spraying is performed in 2-8 areas, the 3 rd spraying is performed in 3-8 areas, the 4 th spraying is performed in 4-8 areas, and the like, and the 8 th spraying is performed in 8 areas, so that the 8 areas from the most central periphery to the outside are sprayed for 1, 2,3,4,5,6,7 and 8 times, and the structural gradient distribution with the most compact periphery and the relatively loose center is obtained. The number of intermediate layer sprays is shown in table 1.
TABLE 10 intermediate layer gradient printing
31, 32 layers of transition layer mixed powder 3 with a single layer powder thickness of 150 μm are bonded and formed by using the adhesive 3, and each layer is sprayed for 5 times to form a top transition layer (300 μm)
Spreading release-resistant powder 1 in 33-35 layers with a thickness of 100 μm, bonding with adhesive 1, and spraying 5 times to form top release-resistant layer (400 μm)
And after printing, naturally drying, and removing the dried powder to form bonding powder to obtain the 3D printed lentinan sustained-release tablet 1.
Table 113D prints the print parameters of each layer of lentinan sustained release tablet 1
The quality standard inspection of the tablets is carried out according to the appendix of the 'Chinese pharmacopoeia' 2015 edition, and the result shows that the hardness and the friability both meet the requirements. The same batch of drug delivery systems were checked for drug content, SD ═ 0.052(n ═ 6), and different batch of drug delivery systems were checked for drug content, SD ═ 0.057(n ═ 6), meeting the standard.
Example 6 lentinan sustained release tablet 2 printed based on the powder composition change process design of example 5
The computer terminal outputs instructions to directly control the operation and preparation. Laying a layer of powder A with the thickness of 100 mu m, spraying 10 times of binder 1 for forming to form the bottom surface of the medicine film, naturally drying for 30s, then driving the whole powder bed of the workbench to descend by the piston rod, preparing a new layer of laid powder, and repeatedly printing the 2 nd and 3 rd layers to jointly form the bottom surface layer release-resistant layer.
The subsequent 4,5 layers of mixed powder C are spread with a single layer thickness of 200 μm, and are bonded and formed by using the adhesive C, and each layer is sprayed 12 times to form a bottom transition area.
6-30 layers are layers containing lentinan in the middle, the powder spreading thickness of a single layer is 150 mu m, bonding forming is carried out by using an adhesive B, and the radial structure gradient is prepared by the change of spraying times as follows: dividing the round surface of the tablet into 12 areas according to the diameter (10mm) of the tablet, wherein the first spraying is carried out in the area 1-12, the second spraying is carried out in the area 2-12, the 3 rd spraying is carried out in the area 3-12, the 4 th spraying is carried out in the area 4-12, and the like, and the 12 th spraying is carried out in the area 12, so that the 12 areas from the most central periphery to the outside are sprayed for 1, 2,3,4,5,6,7, 8, 9, 10, 11 and 12 times, and the structural gradient distribution with the most compact periphery and the relatively loose center is obtained. The number of intermediate layer sprays is shown in table 12.
TABLE 12 intermediate layer gradient printing
31, 32 layers of mixed powder C of transition layer are paved, the thickness of single layer of spread powder is 200 mu m, bonding forming is carried out by the adhesive C, each layer is sprayed for 5 times, and the top transition layer is formed
Spreading release-resistant powder A in 33-35 layers with a thickness of 100 μm, bonding with adhesive A, and spraying 10 times to form top release-resistant layer
And after printing, naturally drying, and removing the bonding powder to obtain the 3D printed lentinan sustained-release tablet 2.
Table 133D printing parameters of each layer of lentinan sustained release tablet 2
The quality standard inspection of the tablets is carried out according to the appendix of the 'Chinese pharmacopoeia' 2015 edition, and the result shows that the hardness and the friability both meet the requirements. The same batch of drug delivery systems were checked for drug content, SD 0.053(n 6), and different batch of drug delivery systems were checked for drug content, SD 0.049(n 6), meeting the standard. The printed lentinan sustained-release tablet 2 basically realizes the slow release from 60 minutes to 460 minutes by adopting the first method for measuring XD release in appendix of 2015 edition of Chinese pharmacopoeia.
Example 7 the lentinan of the powder of example 5 was replaced by lycium barbarum polysaccharide: process design is carried out on tremella polysaccharide 7:3 compound to print compound polysaccharide sustained-release tablets
The lentinan in the powder of example 5 was replaced by lycium barbarum polysaccharide: the tremella polysaccharide 7:3 complex polysaccharide, the three powders used for printing are marked a ', B ', C ' respectively. As the adhesive, A, B, C used in example 5 was used
The computer terminal outputs instructions to directly control the operation and preparation. Laying a layer of powder A with the thickness of 100 mu m, spraying 10 times of binder 1 for forming to form the bottom surface of the medicine film, naturally drying for 30s, then driving the whole powder bed of the workbench to descend by the piston rod, preparing a new layer of laid powder, and repeatedly printing the 2 nd and 3 rd layers to jointly form the bottom surface layer release-resistant layer.
The subsequent 4,5 layers of mixed powder C are spread with a single layer thickness of 200 μm, and are bonded and formed by using the adhesive C, and each layer is sprayed 12 times to form a bottom transition area.
6-30 layers are layers containing composite polysaccharide in the middle, the powder spreading thickness of a single layer is 150 mu m, bonding forming is carried out by using an adhesive B, and the radial structure gradient is prepared by the change of spraying times as follows: dividing the round surface of the tablet into 10 areas according to the diameter (10mm) of the tablet, wherein the first spraying is performed in a 1-10 area, the second spraying is performed in a 2-10 area, the 3 rd spraying is performed in a 3-10 area, the 4 th spraying is performed in a 4-10 area, and the like, and the 10 th spraying is performed in a 12 area, so that the 10 areas from the most central periphery to the outside are sprayed for 1, 2,3,4,5,6,7, 8, 9 and 10 times, and the structural gradient distribution with the most compact periphery and the relatively loose center is obtained. The number of intermediate layer sprays is shown in table 14.
TABLE 14 intermediate layer gradient printing
31, 32 layers of mixed powder C of transition layer are paved, the thickness of single layer of spread powder is 200 mu m, bonding forming is carried out by the adhesive C, each layer is sprayed for 5 times, and the top transition layer is formed
Spreading release-resistant powder A in 33-35 layers with a thickness of 100 μm, bonding with adhesive A, and spraying 10 times to form top release-resistant layer
And after printing, naturally drying, and removing the powder to obtain the 3D printed composite polysaccharide sustained-release tablet.
Table 153D printing parameters of each layer of the composite polysaccharide sustained-release tablet
The quality standard inspection of the tablets is carried out according to the appendix of the 'Chinese pharmacopoeia' 2015 edition, and the result shows that the hardness and the friability both meet the requirements. The same batch of drug delivery systems are checked for drug content, SD is 0.061(n is 6), and different batches of drug delivery systems are checked for drug content, SD is 0.058(n is 6), meeting the standard. The printed composite polysaccharide sustained-release tablet basically realizes the slow release from 60 minutes to 420 minutes by adopting a first method for measuring XD release in an appendix of 2015 edition of Chinese pharmacopoeia.
Example 8: tablet Release behavior study
Preparation of a standard curve: accurately weighing appropriate amount of glucose, respectively, adding pure water to obtain glucose reference solutions with concentrations of 5, 10, 20, 30, 40, 50, and 60 mg/L. Precision transfer of control solutions2mL into a test tube, 1mL phenol and 5mL concentrated sulfuric acid were added, shaken, and left at room temperature (25 ℃) for 40 min. After cooling, the absorbance at 490nm was measured with a UV-Vis spectrophotometer. Obtaining a standard curve equation of C-58.259A +4.154 and a correlation coefficient R2The linear range is 0.9990 and 10-40 mu g/mL.
The first method for measuring XD release rate in appendix of Chinese pharmacopoeia 2015 edition is adopted, the dissolution medium is 900mL, the pH value is 6.8, 0.1mol/mL phosphate buffer solution (using pre-ultrasonic degassing) is adopted, the rotating speed is 100r/min, and the temperature is (37.0 +/-0.1) DEG C. Sampling 5.0mL every 1h, supplementing fresh medium (finished in 30 s) with the same amount and temperature, filtering the sampled product with a 0.45 μm filter membrane, diluting 1.0mL of the subsequent filtrate for several times, measuring absorbance, and calculating the cumulative release percentage of the drug. The drug release profile of a portion of the tablet is shown in figure 3.
The release profile shows that the 3D printed tablets release relatively slowly compared to direct compression (comparative example 4) because there is one powder compaction process on the powder spreading shaft during printing, while the layer-by-layer binder spray during 3D printing makes the internal structure of the tablets tighter. Compared with the polysaccharide sustained-release tablet, the early-stage release of the tablet 1 (comparative example 1) is basically similar to that of the printed polysaccharide sustained-release tablet, and in the release process, because the difference between the components of the release-resistant layer and the middle layer is large, a strong interface gap exists, the release-resistant layer is easy to fall off, and the later-stage release is accelerated. Comparative tablet 2 (comparative example 2) was designed without a release barrier, or in a conventional three-dimensional release pattern; compared with the tablet 3 (comparative example 3), the intermediate structure is not designed by gradient adhesion, and the release is faster due to larger release area in the early stage, and the release area is reduced and the release rate is also gradually reduced along with the gradual erosion of the tablet. The printed polysaccharide extended release tablet (example 2) achieved substantially constant release rates from 60 to 460 minutes.
Examples 2,3,4,5,6,7 constant release of the tablet was achieved by maintaining the printed tablet to have a bottom layer-first transition layer-intermediate drug-containing layer-second transition layer-top layer structure, with the intermediate layer structure being distributed in a gradient manner, the center structure being the loosest and the outermost structure being the most tightly bonded.
The invention fully utilizes the characteristic of 3D printing layer-by-layer stacking molding to axially design the release-resistant layer, changes the traditional three-dimensional release into two-dimensional release and greatly reduces the release area; by utilizing the characteristic that the 3D printing forming layer surface can be flexibly prepared, the density gradient design of the radial fine structure of the tablet compensates the process of slowing down the release rate caused by the reduction of the area of the tablet in the release process, and the slow release of the tablet in a certain release range is realized.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. The 3D printing polysaccharide sustained-release tablet is characterized in that the polysaccharide sustained-release tablet is prepared by adopting a three-dimensional printing forming technology, and comprises the following components:
a bottom layer;
a first transition layer compounded on the bottom layer;
an intermediate layer containing active polysaccharide and compounded on the first transition layer;
a second transition layer compounded on the intermediate layer;
a top layer composited with the second transition layer;
the middle layer is prepared from active polysaccharide and a controlled release material, and the central position of the middle layer is gradually compact towards an epitaxial structure;
the bottom layer and the top layer are prepared from insoluble polymers;
the first transition layer is prepared by mixing a bottom layer material and an intermediate layer material;
the second transition layer is prepared by mixing a top layer material and a middle layer material.
2. The 3D printed polysaccharide extended release tablet of claim 1, wherein the insoluble polymer is one or more of ethyl cellulose, vinyl acetate cellulose, acrylic resin, polylactic acid, and epsilon-polylactone;
the active polysaccharide is selected from one or more of lentinan, lycium barbarum polysaccharide, ganoderma lucidum polysaccharide, tremella polysaccharide and pachyman;
the controlled release material is selected from one or more of ethyl cellulose, hydroxypropyl methyl cellulose and cetyl alcohol.
3. The 3D printed polysaccharide sustained-release tablet according to claim 1, wherein the intermediate layer is prepared from the following raw materials in parts by mass:
4. the 3D printed polysaccharide sustained-release tablet according to claim 1, wherein the mass ratio of the middle layer material to the middle layer material in the first transition layer is 1: 0.5-0.5: 1;
the mass ratio of the top layer material to the middle layer material in the second transition layer is 1: 0.5-0.5: 1.
5. The 3D printed polysaccharide sustained-release tablet according to claim 1, wherein the thickness of the bottom layer is 100-450 μm;
the thickness of the first transition layer is 150-600 mu m;
the thickness of the intermediate layer is 3000-3750 mu m;
the thickness of the second transition layer is 150-600 mu m;
the thickness of the top layer is 100-450 mu m.
6. The 3D printed polysaccharide sustained-release tablet according to claim 1, wherein the active polysaccharide is 20-55% by mass of the 3D printed polysaccharide sustained-release tablet.
7. The preparation method of the 3D printed polysaccharide sustained-release tablet according to any one of claims 1 to 6, wherein the polysaccharide sustained-release tablet is prepared by adopting a three-dimensional printing forming technology, and comprises the following steps:
A) laying bottom layer material powder, spraying a binder and forming to obtain a bottom layer;
B) laying first transition layer material powder on the surface of the bottom layer, and spraying a binder for forming to obtain a first transition layer/bottom layer composite layer;
C) laying intermediate layer material powder on the surface of the first transition layer, spraying a binder for forming, and obtaining an intermediate layer/first transition layer/bottom layer composite layer, wherein the specific method comprises the following steps:
dividing the intermediate layer into a plurality of sequentially sleeved annular printing areas from the center to the outer extension, gradually increasing the number of layers of the intermediate layer material powder paved in the annular printing areas from the center of the intermediate layer to the outer extension, and spraying a binder to form after each layer of the intermediate layer material powder is paved;
D) laying second transition layer material powder on the surface of the intermediate layer, and spraying a binder for forming to obtain a second transition layer/intermediate layer/first transition layer/bottom layer composite layer;
E) and paving top layer material powder on the surface of the second transition layer, and spraying a binder for forming to obtain the 3D printing polysaccharide sustained-release tablet.
8. The method according to claim 7, wherein in step A), the binder is selected from 0 to 8 wt% ethanol solution of insoluble polymer or 0 to 8 wt% ethanol water solution of insoluble polymer;
in step B), the binder comprises: 0 to 10 wt% of polyvinylpyrrolidone; 40-60 wt% ethanol; 0-3 wt% of glycerol; the balance of water;
in step C), the binder comprises: 0 to 10 wt% of polyvinylpyrrolidone; 20 to 50 weight percent of ethanol; 0-3 wt% of glycerol; the balance of water;
in step D), the binder comprises: 0 to 10 wt% of polyvinylpyrrolidone; 0-40 wt% ethanol; 0-3 wt% of glycerol; the balance of water;
in the step E), the binder is selected from 0-8 wt% of ethanol solution of insoluble polymer or 0-8 wt% of ethanol solution of insoluble polymer.
9. The method according to claim 7, wherein the step A) is repeated 1 to 5 times when preparing the primer layer;
the repetition frequency of the step B) is 1-3 times when the first transition layer is prepared;
when preparing the second transition layer, the repetition frequency of the step D) is 1-3 times;
and (3) repeating the step E) for 1-5 times when preparing the top layer.
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