CN113244181B - Method for rapidly preparing tablets by adopting large-spot heating and melting formula powder - Google Patents

Method for rapidly preparing tablets by adopting large-spot heating and melting formula powder Download PDF

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CN113244181B
CN113244181B CN202110470243.1A CN202110470243A CN113244181B CN 113244181 B CN113244181 B CN 113244181B CN 202110470243 A CN202110470243 A CN 202110470243A CN 113244181 B CN113244181 B CN 113244181B
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powder
layer
tablet
light
spot
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CN113244181A (en
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杨燕
韦赛楠
单伟光
董启航
陈姝晔
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Zhejiang University of Technology ZJUT
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/19—Acanthaceae (Acanthus family)
    • A61K36/195—Strobilanthes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
    • A61K36/315—Isatis, e.g. Dyer's woad
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/898—Orchidaceae (Orchid family)
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
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    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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    • A61K9/20—Pills, tablets, discs, rods
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    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P10/00—Technologies related to metal processing
    • Y02P10/25—Process efficiency

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a method for rapidly preparing tablets by adopting large-spot heating and melting formula powder. According to the method, the angle and the light path distance of the light homogenizing sheet are adjusted by adding the light homogenizing sheet on the path of the laser beam, so that the laser beam with concentrated energy is converted into uniform big light; simultaneously, the components of the formula powder are regulated to be melted and formed under the irradiation of large light spots, and a single-layer sheet is instantaneously prepared; the process of powder spreading and irradiation is repeated, the layer height is optimized according to the melting depth of the single layer, and the multi-layer sheet can be rapidly prepared by layer lamination. When each layer of powder is the same, a multi-layer tablet with uniform components can be obtained; when the powder of each layer is different, a non-uniform multi-layer tablet or compound tablet can be obtained. The tablet prepared by the method can be formed instantly, the powder is heated and melted uniformly, the surface of a sample is flat, the process is simple, the production equipment is simplified, the production cost is reduced, and the automatic production of small-sized equipment and the quality control of products are further realized.

Description

Method for rapidly preparing tablets by adopting large-spot heating and melting formula powder
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to a method for rapidly preparing tablets, in particular to a method for rapidly preparing tablets by adopting large-spot heating and melting formula powder.
Background
Selective Laser Sintering (SLS), in which powders such as metals and ceramics are selectively sintered by a laser beam, and samples having a specific three-dimensional morphology are prepared by layer-by-layer sintering. The prior related research uses SLS technology for pharmaceutical preparations, and successfully prepares quick-release tablets and sustained-release tablets, which are published in the publication Oral preparations with tunable dissolution behavior based on selective laser sintering technique. However, the thermal stability of the medicinal raw materials and auxiliary materials is poor, and the laser beam energy is too concentrated, so that the laser beam can only be used for processing partial medicinal raw materials and auxiliary materials with good thermal stability and large thermal operation temperature interval (large difference between melting temperature and decomposition temperature). In addition, the effective diameter of the laser beam irradiated on the powder bed is small (about 0.5 mm), the laser head is required to be continuously moved, the printing path is completely distributed in the whole printing area, the powder in the printing area can be completely melted, and the printing process is time-consuming and labor-consuming. In the laser beam scanning process, the temperature of a printing area is always uneven, only powder on a scanning path is partially melted, a strip-shaped belt consistent with the scanning path appears on the surface of a printing sample, and powder outside the scanning path is easy to melt incompletely, so that the mechanical strength is influenced. When the powder contains a medicine with a small thermal operation temperature range or a natural medicine (such as astragalus polysaccharide) with an inaccurate melting point, partial powder is not completely melted due to uneven heating of the powder, and partial powder is decomposed and carbonized at high temperature.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provides a method for rapidly preparing tablets by adopting large-light-spot heating and melting formula powder.
The technical scheme adopted for solving the technical problems is as follows:
a method for rapidly preparing tablets using a large spot of heated melt formulation powder, comprising the steps of:
(1) Powder paving: spreading the formula powder on a powder bed;
(2) And (3) irradiation: converting the laser beam into a large light spot, vertically irradiating the formulation powder at the melting light spot position of 2-40s on the surface of the formulation powder layer paved in the step (1), stopping irradiation, and immediately solidifying the formulation powder at the light spot position;
(3) Removing the peripheral unmelted powder to obtain a single-layer sheet; or, the process of the step (1) of powder spreading and the step (2) of irradiation is repeated for a plurality of times without removing the peripheral unmelted powder, so that the formula powder at the light spots is overlapped layer by layer after being melted, and the peripheral unmelted powder is removed after the final step (2) of irradiation is finished, thus obtaining the multi-layer tablet.
Preferably, the powder layer thickness of the powder layer paved in the step (1) is 0.1-1.0mm.
Preferably, the laser beam is blue-violet light.
Preferably, the irradiation time of the step (2) is 5-20s.
Preferably, the thickness of the powder layer of the multi-layer sheet in the step (3) is 0.1-1.0mm, and the powder spreading and irradiating processes are repeated for 3-20 times.
Preferably, in the step (3), each layer of powder is the same to obtain a multi-layer tablet with uniform components, or each layer of powder is different to obtain a non-uniform multi-layer tablet or compound tablet.
Preferably, the particle size of the formula powder is 40-80 meshes, and the particles are round, compact and uniform in size.
Preferably, the formula powder comprises the following components in parts by weight: 0-100 parts of medicine, 0-100 parts of filler, 0-20 parts of disintegrating agent and 0-0.5 part of pigment. When the dosage of the medicine is 0, the formula powder is blank powder and can be used as an isolation layer and a slow release layer of a multilayer tablet.
Preferably, the medicine is a traditional Chinese medicine extract such as bletilla striata extract, ginkgo extract, astragalus polysaccharide or isatis root extract, and the like, and the weight parts of the medicine are 60-80 parts; the filler is polyethylene glycol 8000 (PEG 8000), 15-25 weight portions; the disintegrating agent is carboxymethyl starch sodium (CMS-Na), microcrystalline cellulose, mannitol or hydroxypropyl cellulose (HPC-LF) 10 weight parts; the pigment is lemon yellow lake, and the weight part is 0.1-0.3 part.
Preferably, the step (2) of converting the laser beam into a large spot includes the steps of: the beam splitter is arranged right below the laser head, the diameter d of the emitted light beam is adjusted, the diffusion angle theta of the beam splitter is adjusted, the light path distance L (the distance from the beam splitter to the formula powder) is adjusted, the emitted laser energy P is adjusted, and the large light spot with uniform energy and specific shape can be obtained on the powder bed.
Preferably, the diameter (d) of the emitted light beam is 5-7mm, the diffusion angle (theta) of the light homogenizing sheet is 1-3 degrees, and the light path distance (L) is 100-200mm. According to the formula (1), the corresponding spot diameter (D) can be calculated to be 8.5-20.7mm. The energy (P) of the laser emitted by the laser head is 1.4-5.5W, the loss of the laser energy after passing through the light homogenizing sheet is 40 percent, and the Energy Density (ED) of the corresponding light spot can be calculated to be 1.0-4.0W/cm according to the formula (2) 2 。
D (mm) =2l×tan θ+d formula (1)
Figure BDA0003045188910000031
Preferably, the laser head has an emission laser energy (P) of 3.0-4.0W.
Preferably, the single-layer melting depth of the formula powder is 0.6-1.0mm, the single-layer height of the multi-layer sheet is 0.1-0.2mm smaller than the single-layer melting depth for the purpose of combining interlayer adhesiveness and printing efficiency, the printing layer number of the multi-layer sheet is determined by the sheet thickness and the layer height, and the layer height of the multi-layer sheet refers to the powder layer thickness of each layer of powder paving of the multi-layer sheet.
Aiming at the difficulties in the prior art, the invention adds the light homogenizing sheet on the path of the laser beam, adjusts the angle of the light homogenizing sheet and the distance between the light homogenizing sheet and the powder, and converts the laser beam (the diameter is about 0.5 mm) with concentrated energy into uniform large light spots (the diameter is about 5-20 mm). The components of the formula powder are regulated to enable the powder to be melted and formed under the irradiation of large light spots, and a single-layer sheet is instantaneously prepared. The surface area of the tablet can be changed by adjusting the angle and the light path distance of the light homogenizing sheet; the thickness of the single-layer sheet can be changed by adjusting the emission energy of the laser head and the irradiation time of the light spots. The process of powder spreading and irradiation is repeated, the layer height is optimized according to the melting depth of the single layer, and the multi-layer sheet can be rapidly prepared by layer lamination. When each layer of powder is the same, a multi-layer tablet with uniform components can be obtained; when the powder of each layer is different, a non-uniform multi-layer tablet or compound tablet can be obtained.
Compared with the prior art, the invention has the beneficial effects that:
(1) And the instant forming is performed, and the production efficiency is high. The large light spots adopted by the invention have the same shape and uniform energy with the surface of the tablet, and the formula powder of the whole printing plane can be heated and melted uniformly by direct irradiation, so that a single-layer tablet with smaller thickness is prepared instantaneously; the process of powder spreading and irradiation is repeated, so that the multilayer sheet with larger thickness can be rapidly prepared by laminating layers. Compared with the existing SLS technology, the method does not need to spread the printing path on the surface of the tablet (the diameter is 5-20 mm) through scanning of the laser beam (the diameter is about 0.5 mm), but directly irradiates the powder layer by using large light spots (the diameter is 5-20 mm) with uniform energy, instantly heats and melts the formula powder, prepares the tablet, and greatly improves the production efficiency.
(2) The powder is heated and melted uniformly, and the surface of the sample is flat. Compared with the laser beam, the energy density of the large light spot is uniform, and all the powder covered by the light spot can be heated and melted uniformly. Ensures the temperature uniformity of the melting area, and is beneficial to the surface leveling and mechanical strength of the tablet. Can prevent the thermal degradation or carbonization of partial powder caused by the overhigh local temperature; partial powder melting incompletely caused by too low local temperature can also be prevented; and the internal stress of the sample caused by uneven temperature of the melting zone can be prevented, so that the edge buckling and deformation can be prevented. The method is suitable for medicines with small thermal operation temperature range or no accurate melting point, and is especially suitable for traditional Chinese medicine extracts, medicinal macromolecular polymers and complex components. Considering that many traditional Chinese medicine extracts have complex components and strong hygroscopicity, powder 3D printing by spraying an adhesive is easy to absorb moisture and agglomerate, and SLS printing heating uneven active ingredients are easy to damage and carbonize. The invention discloses a technology for heating and melting formula powder with large light spots, which provides a novel method for rapid forming of traditional Chinese medicine extract powder, can realize solvent-free processing and forming of the traditional Chinese medicine extract powder, has a uniform temperature field, is beneficial to stabilization of active ingredients, and has the advantages of rapid preparation, personalized preparation of a small amount of powder and the like.
(3) The process is simple and the equipment is simplified. According to the invention, only the light homogenizing sheets (usually circular and elliptical) with different shapes are required to be replaced, and the large light spots with different shapes and sizes can be obtained by adjusting the angles and the light path distances of the light homogenizing sheets. The modeling is not needed to set a printing area, the large light spot is directly adopted to irradiate the formula powder, and the powder in the printing area can be instantaneously heated and melted to prepare the monolayer tablet. The melting depth can be increased by prolonging the illumination time, and the thickness of the single-layer sheet is increased; the layer by layer superposition can prepare uniform multi-layer tablets with larger thickness or multi-layer tablets or compound tablets with different components of each layer. The invention does not need laser beam to scan filling printing area, the laser head can be fixed (XY axis movement is not needed), and the powder bed area can be reduced, thereby greatly simplifying production equipment, saving materials and reducing production cost. And also provides possibility for further realizing automatic production and product quality control of small-sized equipment.
Drawings
FIG. 1 is an external view of a single-layer tablet (left) and a multi-layer tablet (right) of the astragalus polysaccharide quick-release tablet of example 1;
FIG. 2 is a graph showing the effect of the different formulations of example 2 on the appearance of indomethacin tablets (left) and of comparative example 2 on the appearance of astragalus polysaccharide tablets (right)
FIG. 3 is a graph showing the effect of SLS (left) and spot melting technique (right) on tablet formability in comparative example 1;
Detailed Description
The technical scheme of the invention is further specifically described below through specific embodiments and with reference to the accompanying drawings.
EXAMPLE 1 preparation of quick-Release tablets of Astragalus polysaccharide
70g of astragalus polysaccharide, 20g of PEG8000 and 10g of CMS-Na are uniformly mixed, the mixture is sieved by a 80-mesh sieve to prepare formula powder, and a spot melting technology is adopted to prepare single-layer tablets and multi-layer tablets. The laser wavelength is 450nm, the beam emission aperture is 5mm, the diffusion angle (theta) is 1 DEG, the working distance, namely the optical path distance (L), is 150mm, and the corresponding spot diameter (D) is about 10mm. The energy (P) of the emitted laser is 3.5W, and the Energy Density (ED) of the corresponding light spot is 2.5W/cm 2 The irradiation time was 20s, the single layer melt depth was measured to be 0.83mm, the single layer height was set to be 0.8mm, and five layers were co-printed. The single-layer sheet and the multilayer sheet as shown in FIG. 1 were obtained, and the appearance was good. The multi-layered tablet was placed in 200mL of purified water (37 ℃ C.), and the time required for the tablet to disperse into granules (disintegration time) was measured to be 5s.
EXAMPLE 2 preparation of Indometacin tablets
2.0g of indomethacin is taken to be sieved by a 40-mesh sieve, and is powder of formula I. 1.9g of indomethacin and 0.1g of CMS-Na were combinedMixing, and sieving with 40 mesh sieve to obtain formula II powder. 1.9g of indomethacin and 0.1g of PEG were uniformly mixed and sieved by a 40-mesh sieve to obtain a powder of formula III. The three formula powders are prepared into a single-layer tablet by adopting a spot melting technology. The beam emitting aperture is 6mm, the diffusion angle is 1 degree, the working distance is 130mm, the corresponding light spot diameter is about 9.5mm, the emitted laser energy is 10.0W, and the corresponding light spot energy density is 8.4W/cm 2 The irradiation time is 35s, the powder laying height is 1.0mm, and a single-layer sheet is printed. The appearance of the indomethacin tablets is shown in the left part of FIG. 2, and the melting depth is about 0.5mm. Indomethacin was dispersed in 200mL of a buffer solution (37 ℃) at ph=7.2, and the absorbance was measured at 320nm from the filtrate, and the tablet content was calculated. Wherein, the standard curve of the content measurement of the indomethacin solution (10-35 ug/ml) is A=0.0193C. The marked content of indomethacin in the three tablets is 100.1% ± 0.3%,99.8% ± 0.3% and 100.0% ± 0.3%, respectively. The results show that: different formulations affect the tablet formability, but the drug indomethacin is stable and has no degradation in the preparation process.
Example 3 preparation of Ginkgo biloba extract tablet
5g of ginkgo extract, 5g of PEG8000 and 0.3g of lemon yellow starch are uniformly mixed, and are sieved by a 40-mesh sieve to prepare formula powder, and a light spot melting technology is adopted to prepare a multi-layer tablet. The beam emission aperture is 7mm, the diffusion angle is 3 degrees, the working distance is 100mm, the corresponding spot diameter is about 15.5mm, the emitted laser energy is 3.0W, and the corresponding spot energy density is 1.0W/cm 2 The irradiation time was 25s, the layer height was set to 0.5mm, and 8 layers were printed in total. The multi-layered tablet of ginkgo extract has good appearance.
Example 4 preparation of Bletillae radix extract tablet
90g of bletilla striata extract, 10g of PEG8000 and 0.2g of lemon yellow lake are uniformly mixed and pass through a 60-mesh sieve to prepare medicine-containing formula powder. 100g PEG8000 and 0.2g lemon yellow lake were mixed uniformly and sieved through a 60 mesh sieve to prepare a blank formulation powder. And preparing a multilayer sheet with a blank layer and a medicine-containing layer at intervals by adopting a spot melting technology. The beam emitting aperture is 5mm, the diffusion angle is 1 degree, the working distance is 200mm, the corresponding light spot diameter is about 12mm, the emitted laser energy is 5.5W, and the corresponding light spot energy density is 2.9W/cm 2 The irradiation time was 10s, and the layer height was set to 0.5mm. In the 1 st step of the method,the 3,5,7 and 9 layers of powder are made of blank formula powder, the 2,4,6 and 8 layers of powder are made of medicine-containing formula powder, and the prepared multi-layer tablet of the bletilla striata extract has good appearance and moisture-proof and instant effects.
Comparative example 1: influence of the preparation technique on the production efficiency and the formability
80g of astragalus polysaccharide, 10g of PEG8000 and 10g of CMS-Na are uniformly mixed, and are sieved by a 80-mesh sieve to obtain formula powder A, and a single-layer tablet is printed by adopting an SLS technology. The process conditions are as follows: the laser wavelength is 450nm, the emitted laser energy is 2.0-4.0W, the printing model is a circle with the diameter of 10mm, the filling mode (optical scanning path) is Z-shaped, the printing interval is 0.1mm (the effective diameter of the high-energy center of the laser beam is about 0.2 mm), and the printing speed is 56.3mm/s. The single-layer printing time is determined by the movement speed of the laser head and the path length, and the printing time corresponding to different laser energy (2.0-4.0W) is 48s. The appearance of the single-layer sheet is shown in the left diagram of fig. 3: at a laser energy of 2.0W, the powder could not be melt formed (only trace of the path was left on the powder bed); at a laser energy of 3.0W, the powder was locally carbonized. At a laser energy of 4.0W, the powder was completely carbonized.
The formula powder A is printed into a single-layer sheet by adopting a spot melting technology. The process conditions are as follows: the laser wavelength is 450nm, the beam emission aperture is 5mm, the diffusion angle of the light homogenizing sheet is 1 degree, the laser head is fixed (the moving speed is 0 mm/s), the working distance is 150mm, and the corresponding light spot diameter is 10mm. The energy of the emitted laser is 2.0-4.0W, and the energy density of corresponding light spots is 1.5-2.9W/cm 2 The irradiation time was 15s. The single-layer printing time is determined by the laser irradiation time, and the printing time corresponding to different laser energy (2.0-4.0W) is 15s. The appearance of the single-layer sheet is shown in the right diagram of fig. 3: when the laser energy is 2.0W, the powder cannot be melt-molded; the laser energy of 3.0W and 4.0W was excellent in formability.
As mentioned above, the existing SLS technique fails to print a formulation powder containing 80% astragalus polysaccharide. The spot melting method provided by the invention can be used for melting and forming the formula powder containing 80% of astragalus polysaccharide, and can be used for rapidly preparing a single-layer tablet, and the production time is obviously shortened.
Comparative example 2: influence of the type and amount of filler in the formulation powder
Uniformly mixing 90g of astragalus polysaccharide and 10g of different types of fillers, sieving with a 80-mesh sieve to prepare formula powder B, and printing a single-layer sheet by adopting a spot melting technology. The process conditions are as follows: the beam emission aperture is 5mm, the diffusion angle is 1 degree, the laser head is fixed, the working distance is 150mm, and the corresponding spot diameter is about 10mm. The energy of the emitted laser is 4.0W, and the energy density of the corresponding light spot is 2.9W/cm 2 The irradiation time was 15s. As can be seen from table 1: the four fillers can be formed in an auxiliary way; when PEG is the filler, the appearance, hardness and color uniformity of the single layer sheet are best.
TABLE 1 influence of filler types on monolayer sheet quality
Figure BDA0003045188910000071
Uniformly mixing 100-80g of astragalus polysaccharide and 0-20g of PEG, sieving with a 80-mesh sieve to prepare formula powder C, and printing a single-layer sheet by adopting a spot melting technology. The process conditions are as follows: the beam emission aperture is 5mm, the diffusion angle is 1 degree, the laser head is fixed, the working distance is 150mm, and the corresponding spot diameter is about 10mm. The energy of the emitted laser is 4.0W, and the energy density of the corresponding light spot is 2.9W/cm 2 The irradiation time was 15s. As can be seen from table 2: when the PEG amount is 0%, the melt molding cannot be performed; when the PEG dosage is 5%, the irregular shape of partial melting is prepared; when the PEG amount was 10% -20%, a single-layer sheet with good round appearance was obtained (right in FIG. 2).
TABLE 2 influence of filler amount on print quality of single-layer sheets
Figure BDA0003045188910000072
Comparative example 3: influence of the type and amount of disintegrant in the formulation powder
Uniformly mixing 70g of astragalus polysaccharide, 20g of PEG8000 and 10g of different disintegrating agents, sieving with a 80-mesh sieve to prepare formula powder D, and printing a multilayer tablet by adopting a spot melting technology. The process conditions are as follows: the beam emission aperture is 5mm, the diffusion angle is 1 DEG, the laser head is fixed, and the working distance is 150mm, corresponding spot diameter about 10mm. The energy of the emitted laser is 4.0W, and the energy density of the corresponding light spot is 2.9W/cm 2 . The thickness of the powder layer of each powder spreading is 0.8mm, the irradiation time is 15s each time, the powder spreading and irradiation processes are repeated for 5 times, and the peripheral unmelted powder is removed to obtain the multi-layer tablet. As can be seen from table 3: different kinds of disintegrating agents are added to form, but when CMS-Na is taken as the disintegrating agent, the disintegrating time of the multi-layer tablet is shortest, and the multi-layer tablet is completely disintegrated within 5 seconds.
TABLE 3 influence of disintegrant type on the formability and disintegration time of multilayered tablets
Figure BDA0003045188910000081
Uniformly mixing 60-75g of astragalus polysaccharide, 20g of PEG8000 and 5-20g of CMS-Na, sieving with a 80-mesh sieve to prepare formula powder E, and printing a multilayer sheet by adopting a spot melting technology. The process conditions are as follows: the beam emission aperture is 5mm, the diffusion angle is 1 degree, the laser head is fixed, the working distance is 150mm, and the corresponding spot diameter is about 10mm. The energy of the emitted laser is 4.0W, and the energy density of the corresponding light spot is 2.9W/cm 2 . The thickness of the powder layer of each powder spreading is 0.8mm, the irradiation time is 15s each time, the powder spreading and irradiation processes are repeated for 5 times, and the peripheral unmelted powder is removed to obtain the multi-layer tablet. As can be seen from table 4: the CMS-Na can be formed when the dosage of CMS-Na is 5% and 10%, and the disintegration time is shorter when the dosage is 10%; CMS-Na was not formed at 15% and 20%.
TABLE 4 influence of disintegrant amount on the formability and disintegration time of the multilayered tablet
Figure BDA0003045188910000082
Comparative example 4: influence of process parameters
70g of astragalus polysaccharide, 20g of PEG and 10g of CMS-Na are uniformly mixed, the mixture is sieved by a 80-mesh sieve to prepare formula powder F, and a single-layer tablet is printed by adopting a spot melting technology. The process conditions are as follows: the beam emitting aperture is 5mm, the diffusion angle is 1 degree, the laser head is fixed, the working distance is 100-150mm, and the corresponding spot diameter is about8-10mm. The energy of the emitted laser is 2.5-5.0W, and the corresponding energy density of the light spot is about 1.7-3.6W/cm 2 The irradiation time was 15s. The appearance (spheroidization degree, warpage degree and carbonization degree) of the single-layer sheet was evaluated: "-" means no spheroidization, no warpage, no carbonization; the more "+" represents the more pronounced. Scoring the comprehensive quality of the single-layer sheet: all three indexes are "-" 10 points, and one "+" button 2 points appears; the comprehensive quality score is more than or equal to 8, and the comprehensive quality is considered to be better. Considering that the working distance and the laser energy jointly affect the spot energy density, the spot energy density is calculated according to formula (2). As can be seen from table 5: when the energy density is less than 2.0W/cm 2 In the case of excessive spheroidization of the powder. When the energy density is 2.0-3.0W/cm 2 When the score is more than or equal to 8, the comprehensive quality is better; wherein the energy density is 2.5W/cm 2 Score = 10 score, best overall quality (no spheroidization, carbonization, and warping). When the energy density is more than 3.0W/cm 2 Local powder carbonization (darkening of the intermediate color) begins to develop warp deformations. Thus, for the formulation powder F, the energy density is optimized to be 2.0-3.0W/cm 2 . If the fixed working distance is 150mm, the corresponding laser energy should be in the range of 3.0-4.0W. If the fixed laser energy is 4.0W, the corresponding working distance should be not less than 150mm.
Table 5: influence of process parameters on quality of single-layer sheet
Figure BDA0003045188910000091
Figure BDA0003045188910000101
70G of astragalus polysaccharide, 20G of PEG and 10G of CMS-Na are uniformly mixed, the mixture is sieved by a 80-mesh sieve to prepare a formula powder G, and a single-layer tablet is printed by adopting a spot melting technology. The process conditions are as follows: the beam emission aperture is 5mm, the diffusion angle is 1 degree, the laser head is fixed, the working distance is 150mm, and the corresponding spot diameter is about 10mm. The energy of the emitted laser is 2.7-4.1W, and the energy density of corresponding light spots is 2.0-3.0W/cm 2 The irradiation time is 15-25s. From Table 6It is known that: (1) When the fixed energy density is 2.5W/cm 2 When the irradiation time is 10s, the powder cannot be melt-molded; the irradiation time is prolonged from 15s to 25s, and the thickness (powder melting depth) of the single-layer sheet is increased from 0.77mm to 0.86mm; when the irradiation time was 30s, the powder was locally carbonized. (2) When the fixed irradiation time was 20s, the energy density was increased to 2.5W at 2.0W, and the single-layer sheet thickness (powder melt depth) was increased from 0.73mm to 0.91mm. The layer height is set to be smaller than the single-layer melting depth, so that interlayer melting can be ensured, and the multi-layer sheet can be prepared.
TABLE 6 influence of printing parameters on Single-layer sheet melt depth
Figure BDA0003045188910000102
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the invention in any way, but other variations and modifications are possible without exceeding the technical solutions described in the claims.

Claims (6)

1. A method for rapidly preparing tablets using a large spot of heated melt formulation powder, comprising the steps of:
(1) Powder paving: spreading the formula powder on a powder bed;
(2) And (3) irradiation: converting the laser beam into a large light spot, vertically irradiating the surface of the formula powder paved in the step (1) for 2-40s, melting the formula powder at the light spot, stopping irradiation, and immediately solidifying the formula powder at the light spot;
(3) Removing the peripheral unmelted powder to obtain a single-layer sheet; or, not removing the peripheral unmelted powder, repeating the processes of the step (1) and the step (2) for a plurality of times, so that the formula powder at the light spots is overlapped layer by layer after being melted, and removing the peripheral unmelted powder after the process of the step (2) is finished for the last time to obtain a multilayer sheet;
wherein the formula powder comprises the following components in parts by weight: the weight parts of the medicines are 60-80 parts; 15-25 parts of filler; 10 parts of disintegrating agent; the pigment is lemon yellow lake, and the weight part is 0.1-0.3 part;
the medicine is bletilla striata extract, ginkgo extract, astragalus polysaccharide or isatis root extract; the filler is polyethylene glycol 8000; the disintegrating agent is sodium carboxymethyl starch, microcrystalline cellulose, mannitol or hydroxypropyl cellulose;
the step (2) of converting the laser beam into a large light spot comprises the following steps: the beam splitter is arranged right below the laser head, the diameter d of the emitted light beam is adjusted to be 5-7mm, the diffusion angle theta of the beam splitter is adjusted to be 1-3 degrees, the light path distance L is adjusted to be 100-200mm, the emitted laser energy P is adjusted, and the large light spot with uniform energy and specific shape is obtained on the powder bed.
2. A method for rapid manufacture of tablets using a large spot heat melt formulation according to claim 1, wherein the laser beam is blue-violet light.
3. The method for rapid tablet formulation using hot melt formulation with large spots according to claim 1, wherein the irradiation time in step (2) is from 5 to 20 seconds.
4. The method for rapid preparation of tablets using large spot heat-melted formulation powder according to claim 1, wherein the multi-layered tablet in step (3) is repeated 3-20 times with each "powder-spreading" of 0.1-1.0mm in powder layer thickness.
5. The method for preparing a tablet according to claim 1, wherein each layer of powder in the step (3) is the same to obtain a multi-layered tablet having a uniform composition, or each layer of powder is different to obtain a non-uniform multi-layered tablet or compound tablet.
6. A method for rapid manufacture of tablets using a large spot heat melt formulation according to claim 1, wherein the formulation has a particle size of 40-80 mesh.
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