WO2022021524A1 - 一种左乙拉西坦3d打印制剂及其制备方法 - Google Patents

一种左乙拉西坦3d打印制剂及其制备方法 Download PDF

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WO2022021524A1
WO2022021524A1 PCT/CN2020/111961 CN2020111961W WO2022021524A1 WO 2022021524 A1 WO2022021524 A1 WO 2022021524A1 CN 2020111961 W CN2020111961 W CN 2020111961W WO 2022021524 A1 WO2022021524 A1 WO 2022021524A1
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printing
levetiracetam
formulation
preparation
content
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PCT/CN2020/111961
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English (en)
French (fr)
Inventor
郑爱萍
王增明
陈如心
韩晓璐
张慧
高静
刘楠
高翔
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中国人民解放军军事科学院军事医学研究院
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Publication of WO2022021524A1 publication Critical patent/WO2022021524A1/zh

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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
    • A61K9/2072—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
    • 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
    • A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing
    • B33Y70/10—Composites of different types of material, e.g. mixtures of ceramics and polymers or mixtures of metals and biomaterials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing

Definitions

  • the invention belongs to the field of medicines and preparations, and relates to a 3D printing preparation of levetiracetam and a preparation method thereof.
  • the present invention relates to a levetiracetam tablet such as levetiracetam dispersible tablet, and a method for preparing the levetiracetam tablet such as levetiracetam dispersible tablet using 3D printing technology .
  • it relates to 3D printed tablets of levetiracetam suitable for administration to children.
  • Levetiracetam a pyrrolidone derivative
  • Levetiracetam is one of the most widely used broad-spectrum antiepileptic drugs in clinical practice.
  • Levetiracetam is easily soluble and highly osmotic. It is rapidly absorbed after oral administration. The absolute bioavailability is close to 100%. It is linearly metabolized, with little intra-individual and inter-individual differences, and no gender, ethnic, and circadian differences. Due to the completeness and linearity of levetiracetam absorption, its plasma concentration can be predicted based on oral doses in mg/kg.
  • the structural formula of levetiracetam is shown in formula A below:
  • Solid preparations have always been the most widely used dosage forms due to their advantages of good stability, convenient administration and portability.
  • Dysphagia has always been a major problem for children taking medicine.
  • the absorption system and metabolic system of children are not fully developed, and the pharmacodynamics, pharmacokinetics, and toxicokinetics characteristics of children are significantly different from those of adults.
  • Children are often referred to as "little adults", but they must not simply be regarded as miniature adults when it comes to medication.
  • paediatricians can only adjust the adult dose based on clinical experience.
  • the dosage description of "half tablet” often appears in the prescription, which brings a lot of inconvenience.
  • cutting the tablet may damage the structure of the preparation and cause risks.
  • 3D printing technology is a computer-aided design model, based on digital model files (usually in STL or PLY format), using different materials to construct objects by layer-by-layer printing, and finally turning the blueprint on the computer into a real technology. .
  • 3D printing is also known as "rapid prototyping", “solid free forming” and “additive manufacturing”.
  • 3D printing technology has high flexibility, can control the printing process through model design, and prepare personalized products with various geometric shapes and functions.
  • 3D printing has great advantages in product design complexity, product personalization and on-demand manufacturing, and can solve the shortcomings of existing formulation technologies.
  • the use of 3D printing technology to manufacture children's formulations is a This is a promising approach and could facilitate the transition to more personalized medicines.
  • binder jetting technology is the main 3D printing technology used for formulation production. Compared with other 3D printing technologies, binder jetting technology has a wide range of optional raw materials and has broad application prospects in pharmaceutical preparations due to its many similarities with the granulation technology used in traditional preparation production. Furthermore, with proper equipment modification and optimization, binder jetting technology is the most likely 3D printing technology to meet the commercial production of pharmaceuticals.
  • the process of printing medicines with binder jetting technology is as follows. First, the powder is evenly spread on the printer operating table with a powder spreading roller, and the print head sprays droplets containing binder or medicine at a precise speed under the set path. onto the powder bed. Then, the operating table is lowered for a certain distance, and then powder is spread and liquid is added dropwise. This is repeated, and the desired product is prepared according to the principle of "layered manufacturing and layer-by-layer stacking". Powder that is not bound during printing is used as a support material for the printed product; the liquid formulation inside the printer can contain only binders and other special materials, and the powder bed can contain Active Pharmaceutical Ingredient (API) and other excipients; API is sprayed onto the powder bed as a solution or nanoparticle suspension.
  • API Active Pharmaceutical Ingredient
  • CN 105188849 and US 9,339,489 disclose 3D printed fast-dispersing dosage forms containing different specifications of levetiracetam. Compared with traditional medicines, it has a large drug load, can provide flexible dosage and can make patients with swallowing disorders smooth of medication.
  • the rapidly dispersible tablets prepared by the invention have rough appearance, cannot well coordinate the requirements of rapid disintegration of tablets and smooth appearance, and cannot realize the printing of dispersible tablets with good appearance, especially delicate cartoon tablets.
  • the biggest defect of binder jet 3D printing is the appearance of the product. Due to the stacking of different polymers and powders, surface defects of the product may occur, such as insufficient mechanical properties such as tablet surface roughness, hardness, and friability. It may even affect the patient's medication experience, and there may even be differences in the dosage of medication caused by the drop of surface powder during tablet storage and transportation.
  • the inventors have made a 3D printing formulation of levetiracetam through in-depth research and creative work.
  • the inventors have surprisingly found that the surface of the 3D printing formulation of levetiracetam has significantly reduced roughness, and maintains good hardness and brittleness while obtaining good surface finish.
  • the inventors have also obtained a method for preparing the formulation. The following invention is thus provided:
  • One aspect of the present invention relates to a 3D printing formulation of levetiracetam, including levetiracetam, as well as fillers, disintegrants, flavoring agents, glidants, antioxidants and binders;
  • the content of levetiracetam is 40%-70%; preferably 45%-65%;
  • the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing preparation is not higher than 45 ⁇ m, the arithmetic mean height (Sa) is not higher than 40 ⁇ m, and the maximum height (Sz) is not higher than 40 ⁇ m. 350 ⁇ m;
  • the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing preparation is not higher than 40 ⁇ m, the arithmetic mean height (Sa) is not higher than 35 ⁇ m, and the maximum height (Sz) is not higher than 35 ⁇ m. 320 ⁇ m;
  • the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing formulation is 15-45 ⁇ m
  • the arithmetic mean height (Sa) is 10-40 ⁇ m
  • the maximum height (Sz) is 150- 350 ⁇ m
  • the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing formulation is 20-45 ⁇ m
  • the arithmetic mean height (Sa) is 15-40 ⁇ m
  • the maximum height (Sz) is 180- 350 ⁇ m;
  • the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing formulation is 15-40 ⁇ m
  • the arithmetic mean height (Sa) is 10-35 ⁇ m
  • the maximum height (Sz) is 180- 320 ⁇ m;
  • the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing formulation is 20-40 ⁇ m
  • the arithmetic mean height (Sa) is 15-35 ⁇ m
  • the maximum height (Sz) is 200- 320 ⁇ m;
  • the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing formulation is 20-35 ⁇ m
  • the arithmetic mean height (Sa) is 15-30 ⁇ m
  • the maximum height (Sz) is 200- 300 ⁇ m;
  • the root mean square height (Sq), the arithmetic mean height (Sa) and the maximum height (Sz) are measured by a three-dimensional white light interferometric topograph (eg, Nexview from ZYGO, USA).
  • the invention also relates to a levetiracetam 3D printing preparation, including levetiracetam, as well as fillers, disintegrants, flavoring agents, glidants, antioxidants and adhesives; wherein, according to the accounting Calculated as a percentage by weight of the preparation, the content of levetiracetam is 40%-70%; preferably, it is 45%-65%.
  • levetiracetam in the 3D printing formulation of levetiracetam, levetiracetam is the active ingredient; preferably, levetiracetam is the only active ingredient.
  • the 3D printing formulation of levetiracetam is composed of levetiracetam, filler, disintegrant, flavoring agent, glidant, antioxidant, adhesive agent and plasticizer.
  • the 3D printing formulation of levetiracetam is composed of levetiracetam, filler, disintegrant, flavoring agent, glidant, antioxidant, adhesive Agents, plasticizers and pigments.
  • the content of levetiracetam in the formulation is 45%-70%.
  • the content of levetiracetam in the formulation is 45%-65%.
  • the content of levetiracetam in the formulation is 50%-70%.
  • the content of levetiracetam in the formulation is 50%-65%.
  • the content of levetiracetam in the formulation is 55%-65%.
  • the content of levetiracetam in the formulation is 60%-65%.
  • the 3D printing formulation of levetiracetam is characterized by any one or more of the following items (1)-(6):
  • (1) described filler is one or more selected from sorbitol, mannitol, lactose, calcium hydrogen phosphate and starch, preferably sorbitol or mannitol;
  • the disintegrating agent is microcrystalline cellulose, preferably microcrystalline cellulose PH101;
  • the corrective agent is selected from one or more of aspartame, sucralose, sodium saccharin and essence; preferably, the essence is selected from mint essence, strawberry essence and cherry essence one or more;
  • (4) described glidant is one or more selected from colloidal silicon dioxide, hydrogenated vegetable oil, talc, magnesium stearate and polyethylene glycol;
  • the antioxidant is selected from one or more of L-ascorbyl palmitate (L-AP), butylated hydroxyanisole (BHA) and dibutylhydroxytoluene (BHT); and
  • the adhesive is one or more of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose and sodium alginate; preferably povidone , more preferably povidone K30.
  • the 3D printing formulation of levetiracetam is characterized by any one, any two, any three, any four, Any 5 or all 6:
  • the content of the filler is 10%-60%, preferably 10%-40%, 10%-30%, 10%-20% or 10%-15%;
  • the content of the disintegrant is 10%-30%, preferably 15%-25% or 18%-22%;
  • the content of the flavoring agent is 0.5%-5%
  • the content of the glidant is 0.2%-2%;
  • the content of the antioxidant is 0.01%-0.5%, preferably 0.01%-0.05%;
  • the content of the binder is 0.01%-2%, preferably 0.01%-1%.
  • the 3D printing formulation of levetiracetam is characterized in that:
  • the content of the filler is 10%-60%, preferably 10%-40%, 10%-30%, 10%-20% or 10%-15%;
  • the content of the disintegrant is 10%-30%, preferably 15%-25% or 18%-22%;
  • the dosage of the flavoring agent in the 3D printing formulation of levetiracetam, is 2% sucralose and 0.5% mint flavor.
  • the 3D printing formulation of levetiracetam wherein super disintegrants (such as crospovidone, sodium carboxymethyl starch and/or croscarmellose sodium ) is 0%-4%, 0%-3%, 0%-2% or 0%-1%.
  • the content of the super-disintegrant is 0, that is, no super-disintegrant is contained.
  • the 3D printing formulation of levetiracetam wherein the content of crospovidone, sodium carboxymethyl starch and croscarmellose sodium is 0%-4% , 0%-3%, 0%-2% or 0%-1%.
  • the content of crospovidone, sodium carboxymethyl starch and croscarmellose sodium is 0, that is, it does not contain crospovidone, sodium carboxymethyl starch and croscarmellose Cellulose sodium.
  • the 3D printing formulation of levetiracetam wherein the content of surfactant is 0%-0.5% or 0%-0.2%; preferably, no surfactant is included.
  • the 3D printing formulation of levetiracetam further comprises a plasticizer; preferably, it further comprises a plasticizer and a pigment;
  • the plasticizer is glycerol
  • the plasticizer such as glycerol
  • the plasticizer is present in an amount of 0.5% to 1.5% by weight of the formulation.
  • the 3D printing formulation of levetiracetam is characterized in that:
  • the content of the filler is 10%-60%, preferably 10%-40%, 10%-30%, 10%-20% or 10%-15%;
  • the content of the disintegrant is 10%-30%, preferably 15%-25% or 18%-22%;
  • the content of the plasticizer is 0.5%-1.5%
  • the 3D printing formulation of levetiracetam further comprises pigment; preferably, the content of pigment is adjusted according to the required color of the printing model, preferably, the total amount of pigment does not exceed the weight of the formulation 1%.
  • the 3D printing formulation of levetiracetam is a tablet, preferably a non-solid tablet.
  • the external features of the tablet are designed using computer software according to children's compliance requirements, including but not limited to cartoon animal type, candy type, fruit type, etc., wherein the monochrome model is in STL format, and the color model is in PLY format.
  • the colorful cartoon model uses CMYK four primary colors and multi-channel joint supply to achieve fine matching of any color, that is, the printing liquid is divided into five kinds, namely cyan, magenta, yellow, black four kinds of printing liquid and transparent printing liquid, different colors
  • the printing liquid is realized by adding different pigments into the printing liquid.
  • the types of pigments include but are not limited to erythrosine, amaranth, carmine, bright blue, lemon yellow, etc.
  • the four primary colors used are all prepared from the above pigments.
  • the internal structure of the tablet can be designed as a lattice structure, a hollow structure or a hollow column structure (as shown in Figures 3A-3C), etc., to ensure the rapid disintegration of the tablet to interpret the drug, and the lattice structure refers to the tablet
  • the spraying amount of the outer shell and the inner printing liquid is different.
  • the inner spraying amount is 30%-80% of the spraying amount of the outer shell.
  • the hollow structure means that the middle part of the tablet is not sprayed with printing liquid, and the hollow column structure is that the middle part of the tablet is not sprayed.
  • the printing liquid is supported by a certain number of uprights inside the tablet to ensure the mechanical properties of the tablet.
  • the above tablet structures have solid top and bottom layers with a certain thickness, and the middle layer can be sprayed differently in different parts according to the model design, but all models have a solid shell.
  • the 3D printing software is used to control the size of the tablet model, so as to realize the flexible adjustment of the dose. It is found that the prescription and process determined by the present invention can ensure that the size of the tablet model has a good linear correlation with the tablet specification and weight. Thanks to the parameters determined in this study, the precise spraying of the printing liquid in a unit volume can be realized, so that the drug dose can be accurately predicted by the tablet size, and the individualized dispensing of the drug dose can be realized. At the same time, according to production requirements, drugs of different specifications and dosages can be produced in the same batch, which maximizes production cost savings.
  • FIGS. 1A-1D schematic diagrams of colorful cartoon and candy tablet models are shown in FIGS. 1A-1D .
  • the tablet of the present invention meets the requirements for hardness and friability of pharmacopoeia of various countries, especially the Chinese Pharmacopoeia (2015 edition).
  • 1000 mg tablets have a hardness of 50-80 N, 750 mg tablets have a hardness of 40-70 N, 500 mg tablets have a hardness of 35-65 N, 250 mg tablets have a hardness of 25-50 N, and 160 mg tablets have a hardness of 8-20 N.
  • the tablets of the present invention do not break or pulverize when measured for friability.
  • hardness and/or friability are measured using a tablet friability hardness tester (eg, Model CJY-2C, Shanghai Huanghai Drug Inspection Instrument Co., Ltd.).
  • a tablet friability hardness tester eg, Model CJY-2C, Shanghai Huanghai Drug Inspection Instrument Co., Ltd.
  • 6 pieces of each sample are taken and measured separately with a measuring instrument, and the average value is calculated as the average hardness.
  • the friability is measured by taking no less than 6.5 g (at least 10 tablets) of tablets, dusting them, and rotating them at 25 rpm for 4 minutes without breakage or pulverization.
  • the 3D printing formulation of levetiracetam because the final proportion of the components of the printing solution is small, the weight percent content of each component, especially the active ingredient and main excipients in the formulation, is different from the active ingredient.
  • the weight percentages of ingredients and main excipients in the drug powder are approximately the same or substantially the same.
  • Another aspect of the present invention relates to a printing liquid combination comprising a transparent printing liquid, and any one, any two, any three or four selected from the following printing liquids:
  • Cyan printing fluid magenta printing fluid, yellow printing fluid and black printing fluid
  • Each of the printing liquids contains a base solvent, a binder, a plasticizer and a pigment
  • the basic solvent is a mixed solution of an organic solvent and water; the organic solvent is one or more selected from ethanol, propylene glycol, isopropanol and acetone; the volume ratio of the organic solvent in the basic solvent is 35%- 55%, preferably 40%-50%; preferably, the content of the base solvent is at least 85%-97%, preferably 90%-96% by weight of the corresponding printing liquid;
  • the binder is one or more selected from povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium alginate and starch; ketone, more preferably povidone K30; preferably, the content of the binder is no more than 5% or no more than 2% by weight of the corresponding printing liquid, such as 0.01%-5%, 0.05%- 5%, 0.05%-4%, 0.05%-3%, 0.05%-2%, 0.05%-1%, 0.05%-0.5%, 0.05%-0.1%, 0.01%-0.5%, 0.03%-0.3% , 0.03%-0.2% or 0.03%-0.15%;
  • the plasticizer is glycerin, accounting for 1%-6% by weight of the corresponding printing liquid, preferably 2%-5%, such as 2%, 3%, 4% or 5%.
  • the printing liquid combination wherein,
  • the pigment in the cyan printing liquid is bright blue
  • the pigments in the magenta printing solution are erythrosine and carmine
  • the pigment in the yellow printing fluid is tartrazine; and/or
  • the pigments in the black printing fluid are amaranth and bright blue.
  • the content of the surfactant is 0%-2% or 0%-1% by weight of the corresponding printing liquid; preferably, no surfactant is included.
  • the printing liquid combination of the present invention is used to prepare the levetiracetam 3D printing formulation described in any one of the present invention.
  • Yet another aspect of the present invention relates to a method for preparing the levetiracetam 3D printing formulation of any one of the present invention, which is a binder jet 3D printing method;
  • the preparation method comprises the following steps:
  • Spread the drug powder on the printing platform, and the thickness of each powder layer during the printing process is 80 ⁇ m-200 ⁇ m, preferably 90 ⁇ m-150 ⁇ m or 100 ⁇ m-120 ⁇ m;
  • the printing nozzle finely sprays a certain number of printing liquid droplets on a specific part according to the instructions input by the 3D printer control software, the Z axis of the printing platform drops to a certain height, then spreads powder again, and prints again, repeating this process until the printing is completed;
  • the printing liquid is selected from the combination of printing liquids described in any one of the present invention.
  • the step of drying and packaging the preparation obtained after printing is also included.
  • the 3D printed row spacing is 0.4cm-0.6cm, preferably 0.5cm;
  • the column spacing of 3D printing is 0.4cm-0.6cm, preferably 0.5cm.
  • the ejection mechanism of the print head is piezoelectric
  • the unit ink droplet ejection volume is 5pL-40pL; preferably 6pL-30pL; more preferably, the volumes of large droplets, medium droplets and small droplets are about 30pL, about 15pL and about 6pL, respectively;
  • the spraying speed is 0.2g/min-0.8g/min, preferably 0.3g/min-0.5g/min, more preferably 0.4g/min.
  • the ejection mechanism of the print head is thermal bubble type
  • the unit ink droplet ejection volume is 15pL-25pL, preferably 18pL;
  • the spraying speed is 0.3g/min-0.8g/min, preferably 0.4g/min-0.6g/min, more preferably 0.5g/min.
  • the particle size of the drug powder is 30 ⁇ m-150 ⁇ m, preferably 60 ⁇ m-120 ⁇ m.
  • a preparation method of levetiracetam cartoon dispersible tablets based on full-color binder jet 3D printing technology is provided. Aiming at the common problems of binder jet 3D printing preparations, through the coordinated adjustment of printing liquid binder concentration, unit ink droplet ejection volume, powder layer thickness, and particle size of key materials, the 3D printing tablet is guaranteed to be smooth and clean. The appearance, strong mechanical properties and fast dispersing characteristics are obvious improvements to the existing technology. At the same time, in order to solve the problem of children's medication compliance, the present invention uses color inkjet technology to develop a colorful cartoon formulation of levetiracetam suitable for children.
  • the levetiracetam cartoon dispersible tablet can be completely dispersed within 10-20 seconds in a small sip of water or other fluid (eg, milk, juice, etc.).
  • the dosage form uses the binder jet 3D printing technology to prepare the required products according to the principle of "layered manufacturing, layer-by-layer stacking", and realizes the high drug-loading levetiracetam colorful cartoon dispersible tablets that are difficult to be completed by traditional processes.
  • the present invention is also applicable to other medicines with higher dosage and quick onset of action.
  • the dosage form provided by the present invention is designed by computer model according to the requirements.
  • the printer sprays the printing liquid on the surface of the medicine powder with a certain thickness according to the instruction, and repeats the powder spreading and spraying process until the desired preparation is obtained.
  • the present invention uses an on-demand jet printing head, the printing head used in the 3D printing tablet can be a thermal bubble type nozzle, or a piezoelectric type nozzle, the number of nozzle holes of a single print head is 300-3000, and the unit ink drop The spray volume was 15-50 pL.
  • the number of sprayed layers is determined according to the tablet specifications and the size of the tablet model, usually 30-100 layers.
  • the inventors also found that when the particle size of some auxiliary materials is slightly larger than the thickness of the powder layer, it does not affect the flatness of the powder layer and the overall powder coating effect.
  • the formulation is printed with a column spacing of 0.2-1.0 cm and a row spacing of 0.2-0.5 cm.
  • the flow chart of the preparation of colorful cartoon dispersible tablets by binder jet 3D printing technology is shown in FIG. 2 .
  • the printed tablets are collected after drying and powder removal, and the drying temperature is set at 30°C-50°C, preferably 35°C-45°C.
  • the vacuum suction system to recover the excess powder material. This part of the powder acts as a supporting material to play an important supporting role in the tablet printing process. Research shows that adding antioxidants to the powder material will help the powder Stable and reusable.
  • Another aspect of the present invention relates to a 3D printing formulation of levetiracetam, which is prepared by the preparation method described in any one of the present invention.
  • levetiracetam According to the 3D printing formulation of levetiracetam according to any one of the present invention, it is used for treating and/or preventing epilepsy.
  • Yet another aspect of the present invention relates to the use of the 3D printing formulation of levetiracetam according to any one of the present invention in the preparation of a medicament for treating and/or preventing epilepsy.
  • Yet another aspect of the present invention relates to a method for treating and/or preventing epilepsy, comprising the step of administering to a subject in need thereof an effective amount of the 3D printing formulation of levetiracetam according to any one of the present inventions; Preferably, the subject in need is a child.
  • the 3D printing formulation of levetiracetam of the present invention can be administered once or several times a day in different doses.
  • the dose to be administered depends on many factors, such as the severity of the condition to be treated or adjuvantly treated or prevented, such as epilepsy, the sex, age, weight and individual response of the patient, the route of administration and the number of times of administration.
  • the above doses may be administered in a single dose or divided into several, eg, two, three, or four doses. It is common practice to administer the active ingredient levetiracetam in an art-recognized (eg, pharmacopeia or textbook) dose or as prescribed by a physician or pharmacist.
  • the actual dosage level of the main drug (levetiracetam) in the pharmaceutical composition of the present invention can be varied so as to be effective in obtaining the desired therapeutic response for a particular patient, composition and mode of administration. Dosage levels will be selected based on the route of administration, the severity of the condition being treated, and the condition and past medical history of the patient to be treated. However, it is the practice in the art to start at a dose below that required to obtain the desired therapeutic effect and to gradually increase the dose until the desired effect is obtained.
  • unit drop ejection volume refers to the volume of a single drop formed after printing liquid is ejected from an orifice on a print head.
  • printing liquid ejection speed refers to the mass of the printing liquid ejected by the print head per unit time, expressed in g/min, and this time only refers to the liquid ejection time, excluding the powder spreading time and the roller return time.
  • binder layer thickness refers to the layer thickness of each layer of drug powder during the printing process, that is, after each layer is printed, the Z-axis drops a certain distance, and the powder roller spreads the powder of a certain thickness.
  • the term "effective amount” refers to an amount that will effect treatment, prevention, mitigation and/or amelioration of the disease or disorder (epilepsy) of the present invention in a subject.
  • the content (including but not limited to the content of the active ingredient levetiracetam or auxiliary materials), unless otherwise specified, the content is calculated as a percentage of the weight of the preparation.
  • the present invention has achieved any one or more of the following technical effects (1)-(5):
  • the dosage form of the present invention has a relatively smooth surface, which significantly reduces the roughness and reduces the dosage difference caused by the falling of the surface powder of the preparation during storage and transportation; improves the patient's medication experience; significantly improves children's medication compliance sex;
  • 1A-1D Schematic diagrams of colorful cartoon and candy tablet models.
  • Figure 2 Flow chart of the preparation of colorful cartoon dispersible tablets by binder jet 3D printing technology.
  • Figures 3A-3C schematic cross-sectional views of tablet models with different internal spatial structures. Among them, Fig. 3A, a lattice structure; Fig. 3B, a hollow structure diagram; 3C, a hollow column structure.
  • Figures 4A-4C Schematic diagrams of dose models. Among them, Fig. 4A is a side view; Fig. 4B is a three-dimensional sectional view; Fig. 4C is a top view.
  • Figure 5 Individualized dosing model.
  • the abscissa in the figure is the model volume designed by the computer, and the ordinate is the actual printed tablet specification.
  • FIGS 6A-6D 3D topography of surface roughness.
  • Figure 6A formulation of the invention (250 mg);
  • Figure 6B (250 mg);
  • Figure 6C formulation of the invention (1000 mg);
  • Figure 6D (1000 mg).
  • Figures 7A-7L SEM tablet microstructure. Among them, Fig. 7A-Fig. 7F are 1000 mg specifications; Fig. 7G-Fig. 7L are 250 mg specifications. in:
  • Fig. 7A Top surface of housing - 50x
  • Fig. 7B Top surface of housing - 300x;
  • Figure 7C Shell side - 50x
  • Figure 7D Shell side - 300x
  • Fig. 7G Upper surface of housing - 50x
  • Fig. 7H Upper surface of housing - 300x;
  • Figure 7I Shell side - 50x
  • Figure 7J Shell side - 300x
  • Figure 7K Internal hollow area - 50x
  • Figure 7L Internal hollow area - 300x.
  • Figure 8 X-ray powder diffractometer (XRD) detection results.
  • API is raw materials
  • LEV tablets is levetiracetam tablets
  • Excipients is excipients
  • abscissa is the 2 ⁇ angle.
  • Levetiracetam was pulverized and passed through a 120-mesh sieve, colloidal silicon dioxide was passed through a 40-mesh sieve, and the remaining auxiliary materials were passed through a 120-mesh sieve.
  • the composition of the drug powder material is as follows:
  • composition of each printing liquid is as follows:
  • the model file is monochrome (STL format) or color (PLY format).
  • 250mg and 1000mg round tablets are designed respectively.
  • the 250mg tablet has a diameter of 11.50mm, a thickness of 5.18mm and a volume of 0.537cm 3 ;
  • a 1000mg tablet has a diameter of 18.50mm, a thickness of 8.33mm and a volume of 2.24cm 3 .
  • Two colorful cartoon models are also designed in this preparation example (see Figure 1B and Figure 1D for the model pattern), both of which are 1000 mg in size.
  • the bear tablet has a length of 19.20 mm and a thickness of 8.28 mm;
  • the candy tablet has a diameter of 18.50 mm and a thickness of 8.28 mm. 8.33mm.
  • the printing platform spreads a certain thickness of drug powder on the printing platform as a support for the bottom of the printing model and ensure that a single powder layer can be spread evenly during the printing process.
  • the thickness of the powder layer is 2-5mm.
  • the thickness of each powder layer is 100 ⁇ m.
  • the printing nozzle sprays a certain number of droplets on a specific part according to the instructions input by the 3D printer control software.
  • the Z axis of the printing platform drops to a certain height, and then powder is applied again, and the printing is repeated. This process until the desired model is formed.
  • the printing of color cartoon models realizes the combination of CMYK four primary colors and the spraying of color patterns through different print heads. The color patterns are only sprayed on the surface of the model shell, and the spraying inside the model is all done with transparent printing liquid.
  • the tablet was dried, and the drying temperature was set at 40° C., maintained for 120 min, and the weight loss on drying was controlled to be less than 2%. After drying, use the vacuum suction system to recover the excess drug powder and remove the powder attached to the surface of the tablet.
  • Tablets are packaged in aluminum-plastic blister packs.
  • Sample 1-1 250 mg round tablet
  • Sample 1-2 1000 mg round tablet
  • Sample 1-3 1000 mg bear tablet
  • Sample 1-4 1000 mg candy tablet.
  • Levetiracetam was pulverized and passed through a 120-mesh sieve, colloidal silicon dioxide was passed through a 40-mesh sieve, and the remaining auxiliary materials were passed through a 120-mesh sieve.
  • the composition of the drug powder material is as follows:
  • composition of each printing liquid is as follows:
  • the printing platform spreads a certain thickness of drug powder on the printing platform as a support for the bottom of the printing model and ensure that a single powder layer can be spread evenly during the printing process.
  • the thickness of the powder layer is 2-5mm.
  • the thickness of each powder layer is 100 ⁇ m.
  • the printing nozzle sprays a certain number of droplets on a specific part according to the instructions input by the 3D printer control software.
  • the Z axis of the printing platform drops to a certain height, and then powder is applied again, and the printing is repeated. This process until the desired model is formed.
  • the tablet was dried, and the drying temperature was set at 40° C., maintained for 120 min, and the weight loss on drying was controlled to be less than 2%. After drying, use the vacuum suction system to recover the excess drug powder and remove the powder attached to the surface of the tablet.
  • Tablets are packaged in aluminum-plastic blister packs.
  • Sample 2-1, Sample 2-2, Sample 2-3 and Sample 2-4 were prepared:
  • Sample 2-1 250 mg round tablet
  • Sample 2-2 1000 mg round tablet
  • Sample 2-3 1000 mg bear tablet
  • Sample 2-4 1000 mg candy tablet.
  • the printing platform spreads a certain thickness of drug powder on the printing platform as a support for the bottom of the printing model and ensure that a single powder layer can be spread evenly during the printing process.
  • the thickness of the powder layer is 2-5mm.
  • the thickness of each powder layer is 150 ⁇ m.
  • the printing nozzle sprays a certain number of droplets on a specific part according to the instructions input by the 3D printer control software.
  • the Z axis of the printing platform drops to a certain height, and then powder is applied again, and the printing is repeated. This process until the desired model is formed.
  • the tablet was dried, and the drying temperature was set at 40° C., maintained for 120 min, and the weight loss on drying was controlled to be less than 2%. After drying, use the vacuum suction system to recover the excess drug powder and remove the powder attached to the surface of the tablet.
  • Tablets are packaged in aluminum-plastic blister packs.
  • Sample 3-1, Sample 3-2, Sample 3-3 and Sample 3-4 were prepared:
  • Sample 3-1 250 mg round tablet
  • Sample 3-2 1000 mg round tablet
  • Sample 3-3 1000 mg bear tablet
  • Sample 3-4 1000 mg candy tablet.
  • the following three model structures are designed in this experiment (as shown in Figure 3A-3C).
  • the interior and exterior of these three tablet models are different.
  • the tablet printing process is divided into three parts for printing, namely tablet Bottom, middle and top layers.
  • the bottom layer and the top layer are both solid layers, and the printing saturation is 100% to maintain the overall mechanical properties of the tablet;
  • the middle layer is finely sprayed on each printing area according to the structural design of the model, the outer shell is 100% printing saturation, and the inner layer is finely sprayed.
  • the layer is a special structure, and the printing saturation is low to achieve the purpose of rapidly disintegrating drug release.
  • Dot matrix structure model (Fig. 3A), this structure realizes the difference in the printing saturation between the inside of the tablet and the outer shell through the adjustment of the internal model structure.
  • the printing saturation of the outer shell is 100%, and the printing saturation inside the tablet is flexible and adjustable. tune.
  • the inner print saturation of the tablet is 50%, and the shell size is a quarter of the tablet size, which needs to be adjusted according to the tablet size.
  • the diameter of the 1000 mg tablet is 18.50 mm
  • the thickness is 8.33 mm
  • the wall thickness of the upper and lower surfaces of the tablet shell is 2.08 mm
  • the wall thickness of the outer side is 4.63 mm.
  • the hollow structure model (Fig. 3B), the printing liquid is not sprayed inside the structure, and the printing liquid is only sprayed on the shell part, that is, the printing saturation of the tablet shell is 100%, and the printing saturation of the inner hollow part is 0%.
  • the shell size is one quarter of the tablet size and needs to be adjusted for the tablet size.
  • the diameter of the 1000 mg tablet is 18.50 mm
  • the thickness is 8.33 mm
  • the wall thickness of the upper and lower surfaces of the tablet shell is 2.08 mm
  • the wall thickness of the outer side is 4.63 mm.
  • 3D printing technology can realize the flexible adjustment of drug dosage through the design of model size, but the matching degree of printing liquid and drug powder (the applicability of printing liquid and drug powder, that is, whether it can print high-precision tablets) requires Higher, must be able to meet the requirements of printing accuracy.
  • the inventors used the hollow structure model of Preparation Example 4 to investigate the linear relationship between model size design and tablet specifications, and to establish the correlation between model size and dose.
  • Use 3D Sprint to establish tablet models of different sizes, and the designed theoretical doses are 160 mg, 250 mg, 500 mg, 750 mg, and 1000 mg, respectively.
  • the schematic diagrams of the corresponding dose models are shown in Figure 4A-4C, using the recipe and process in Preparation Example 2, respectively. Tablets of different sizes were printed to obtain sample 5-1, sample 5-2, sample 5-3, sample 5-4 and sample 5-5, and the specifications were 160 mg, 250 mg, 500 mg, 750 mg, and 1000 mg respectively.
  • the content and specifications of tablets of each size were determined, taking the tablet model volume as the X-axis and the measured tablet specifications as the Y-axis to establish the correlation between the model size and the dose.
  • the specifications are compared with the specifications of 1000 mg, and the results show that the typical value of the surface roughness of the preparation of the present invention is Sq is 20-35 ⁇ m, Sa is 15-30 ⁇ m, Sz is 200-300 ⁇ m, Sq is 60-80 ⁇ m, Sa is 50-70 ⁇ m, Sz is 350-500 ⁇ m, the preparation of the present invention is obviously better than At the same time, it can be seen from the 3D topography (see Fig. 6) (with the sample 5-2 and the sample 5-5 in the preparation example 5 and For example), the surface roughness of the preparation of the present invention is obviously better than Solve the problem of poor surface roughness, a common problem of binder jet 3D printing formulations, and Compared with the obvious improvement.
  • the hardness and friability of this product were measured by a tablet friability hardness tester (CJY-2C type, Shanghai Huanghai Drug Inspection Instrument Co., Ltd.). In the hardness measurement, 6 pieces of each sample were taken and measured separately with a measuring instrument, and the average value was calculated as the average hardness. Determination of friability Take no less than 6.5g (at least 10 pieces) of tablets for dust removal, rotate at 25rpm for 4 minutes, and there shall be no breakage or crushing.
  • the hardness and friability of the tablets of different specifications in Preparation Examples 1-5 were measured, among which the hardness of the 1000mg tablet was 50-80N, the hardness of the 750mg tablet was 40-70N, the hardness of the 500mg tablet was 35-65N, and the hardness of the 250mg tablet was 25 -50N, 160mg strength tablets 8-20N.
  • the morphology of the printed tablets was investigated using high-resolution thermal field emission scanning electron microscopy. Use a vacuum evaporator to spray a conductive layer on the surface of the sample, then adjust the accelerating voltage to 5.0kV, and observe the 250mg specification sample (sample 5-2) and the 1000mg specification sample (sample 5 in Preparation Example 5 at magnifications of 50x and 300x, respectively. 5-5) Microstructure.
  • X-ray powder diffractometer X-ray powder diffractometer
  • HPLC high performance liquid chromatography
  • Chromatographic column a reversed-phase chromatographic column with octanylsilane-bonded silica gel as filler.
  • Aqueous disodium hydrogen phosphate adjusted to pH 3.5 with phosphoric acid.
  • Quantitative method external standard method.
  • the tablet dispersion uniformity was measured using an intelligent disintegrator.
  • the inner diameter of the mesh of the stainless steel wire mesh of the measuring device is 710 ⁇ m, and it is measured at 15° C.-25° C. (usually 20° C.) using purified water, and 6 pieces are measured each time.
  • the results show that the dispersion uniformity of the printed tablets in the above preparation examples 1-5 are all within the range of 15 ⁇ 5s, and they can be rapidly dispersed in the liquid.
  • Taste evaluation is a key part of the compliance evaluation of children's preparations.
  • the samples to be tested (the dosage of sucralose and mint flavor are 0.5%/0.5%, 0.5%/0.2%, 2%/0.2%, 2%/0.5%, 1%/0.2%, 0.5%/0.3%, 2%/0.3%, 1%/0.5%, 1%/0.3%) taste quality Objective analysis, through the screening of prescriptions to determine the optimal dosage of sucralose 2%, peppermint flavor 0.5%.

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Abstract

一种左乙拉西坦3D打印制剂及其制备方法。具体地，一种左乙拉西坦3D打印制剂，包括占制剂重量40％-70％的左乙拉西坦，以及填充剂、崩解剂、矫味剂、助流剂、抗氧剂和粘合剂；其中，所述左乙拉西坦3D打印制剂的粗糙度特征值根均方高度(Sq)不高于45μm、算术平均高度(Sa)不高于40μm、最大高度(Sz)不高于350μm。该制剂具有优越的表面光洁度，可以实现十几秒甚至几秒内的快速释药，还可以实现药物剂量的灵活调整，并极大地提高了儿童用药的顺应性。

Description

一种左乙拉西坦3D打印制剂及其制备方法 技术领域
本发明属于药物和制剂领域，涉及一种左乙拉西坦3D打印制剂及其制备方法。具体地，本发明涉及一种左乙拉西坦片剂例如左乙拉西坦分散片，以及一种利用3D打印技术制备该左乙拉西坦片剂例如左乙拉西坦分散片的方法。特别地，涉及适用于儿童给药的左乙拉西坦3D打印片剂。
背景技术
左乙拉西坦是一种吡咯烷酮衍生物，是临床上应用最为广泛的广谱抗癫痫药物之一。左乙拉西坦极易溶解并且具有高渗透性，口服后迅速吸收，绝对生物利用度接近100％，呈线性代谢，个体内和个体间差异小，没有性别、种族差异性和生理节奏差异。由于左乙拉西坦的吸收完全性和线性关系，其血药浓度可以根据口服剂量mg/kg进行预测。左乙拉西坦的结构式如下面的式A所示：
Figure PCTCN2020111961-appb-000001
儿科患者是一个特殊的用药群体，不同年龄段的儿童对于药物剂量的需求不同，而且儿童用药顺应性会受到药物味道、颜色和表面纹理的影响。对于儿童制剂，目前仍存在一系列的问题，比如缺乏合适的剂型、缺乏合适的剂量、用药依从性较差、临床用药依据不足、赋形剂缺乏儿科人群安全性数据等等。
固体制剂以其稳定性好、服用方便、便于携带等诸多优势，一直是应用最为广泛的一类剂型。对于固体制剂，即使成年人也会有25％以上的患者出现吞咽困难的情况，儿童则更甚，吞咽困难一直是儿童服药的一大难题。儿童的吸收系统和代谢系统均未发育完全，药效学、药物代谢动力学、毒物代谢动力学特征与成人都有明显的差异。儿童常常被称作“小大人”，但在用药上绝不能简单视为微缩版的成人。很多时候儿科 医师只能凭借临床经验用药，将成人剂量进行调整，处方中经常出现“半片”的用量描述，带来很多不便，而且切碎片剂有可能破坏制剂结构从而导致风险。
此外，儿童对药物的形状、色彩、味道要求较高，对于目前上市的剂型经常拒绝服药，如果医务人员或家长在哄劝无效时采用强迫手段，造成患儿的挣扎、拒绝、哭闹、恐惧，从而导致呕吐、药物摄入量不足等情况就会阻碍治疗的顺利进行，并使儿童心理蒙受创伤。世界范围内都存在儿科药物剂型规格不完整，甚至不适合儿科临床使用的情况，给儿童患者的治疗带来很大困难。因此，现在的药物制剂远远不能满足儿童用药的需求。尽管近些年在儿童制剂方面取得了重大进展，但以上问题仍然是目前制药技术不得不面对的巨大挑战。因此，需要创新的制造技术来满足儿童个性化的用药需求，实现儿童制剂的“量身定制”。
3D打印技术是通过计算机辅助设计模型，以数字模型文件(通常是STL或PLY格式)为基础，运用不同材料，通过逐层打印的方式来构造物体，最终把计算机上的蓝图变成实物的技术。3D打印也被称作“快速成型”，“固体自由成型”和“增材制造”。3D打印技术具有较高的灵活性，可通过模型设计控制打印过程，制备出具有各种几何形状和功能的个性化产品。作为一种新型技术平台，3D打印在产品设计复杂度、产品个性化和按需制造方面具有极大的优势，可以很好的解决现有制剂技术的不足，使用3D打印技术制造儿童制剂是一种很有前途的方法，并且可以促进向更个性化治疗药物的过渡。
目前应用在药物制剂领域的主要3D打印技术包括：粘结剂喷射技术、材料挤压技术和立体光固化成型技术。其中，粘结剂喷射技术是用于制剂生产的主要3D打印技术。由于与传统制剂生产中使用的制粒技术有诸多相似之处，与其他3D打印技术相比，粘结剂喷射技术有广泛可选的原辅料种类并且在药物制剂中的应用前景广阔。此外，通过适当的设备改造和优化，粘结剂喷射技术是最可能满足药品商业生产的3D打印技术。
粘结剂喷射技术打印药品流程如下，首先用铺粉辊将粉末均匀地铺在打印机操作台上，打印头在设定好的路径下，以精确的速度将含有粘结剂或者药物的液滴喷射到粉末床上。然后，操作台下降一定距离，再铺洒粉末、滴加液体，如此反复，按照“分层制造、逐层叠加”的原理制备出所需产品。打印过程中未结合的粉末用作打印产品的支撑材料；打印机内的液体制剂可以仅含有粘结剂和其他特殊材料，粉末床可含有活性药物成分(API)和其他赋形剂；也可以将API作为溶液或纳米颗粒悬浮液喷射 到粉末床上。
2015年，FDA批准了全球第一款3D打印药品-
Figure PCTCN2020111961-appb-000002
(左乙拉西坦速溶片)。
CN 105188849、US 9,339,489公开了包含左乙拉西坦不同规格的3D打印快速分散剂型，相较传统药品，它有很大的载药量，可以提供灵活的剂量并且能让有吞咽障碍的患者顺利的服药。但该发明所制备的快速分散片剂外观粗糙，未能很好的协调片剂快速崩散和外观光洁的需求，无法实现外观较好的分散片剂特别是精致的卡通片剂的打印。
粘结剂喷射型3D打印最大的缺陷是产品外观，由于不同聚合物及粉体的彼此堆叠而可能出现产品的表面缺陷，如片剂表面粗糙度、硬度、脆碎度等机械性能不足，从而影响患者的用药体验甚至可能存在片剂储存及运输过程中表面粉体掉落导致用药剂量差异。
发明内容
本发明人经过深入的研究和创造性的劳动，制得了一种左乙拉西坦3D打印制剂。本发明人惊奇地发现，该左乙拉西坦3D打印制剂表面具有显著降低的粗糙度，在获得良好的表面光洁度的同时还保持了良好的硬度和脆碎度。本发明人还得到了制备该制剂的方法。由此提供了下述发明：
本发明的一个方面涉及一种左乙拉西坦3D打印制剂，包括左乙拉西坦，以及填充剂、崩解剂、矫味剂、助流剂、抗氧剂和粘合剂；
其中，按照占制剂重量的百分比计算，左乙拉西坦的含量为40％-70％；优选为45％-65％；
优选地，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度(Sq)不高于45μm、算术平均高度(Sa)不高于40μm、最大高度(Sz)不高于350μm；
优选地，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度(Sq)不高于40μm、算术平均高度(Sa)不高于35μm、最大高度(Sz)不高于320μm；
优选地，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度(Sq)为15-45μm、算术平均高度(Sa)为10-40μm、最大高度(Sz)为150-350μm；
优选地，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度(Sq)为20-45μm、算术平均高度(Sa)为15-40μm、最大高度(Sz)为180-350μm；
优选地，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度(Sq)为15-40μm、算术平均高度(Sa)为10-35μm、最大高度(Sz)为180-320μm；
优选地，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度(Sq)为20-40μm、算术平均高度(Sa)为15-35μm、最大高度(Sz)为200-320μm；
优选地，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度(Sq)为20-35μm、算术平均高度(Sa)为15-30μm、最大高度(Sz)为200-300μm；
优选地，所述根均方高度(Sq)、算术平均高度(Sa)和最大高度(Sz)通过三维白光干涉形貌仪(例如美国ZYGO的Nexview)测得。
本发明还涉及一种左乙拉西坦3D打印制剂，包括左乙拉西坦，以及填充剂、崩解剂、矫味剂、助流剂、抗氧剂和粘合剂；其中，按照占制剂重量的百分比计算，左乙拉西坦的含量为40％-70％；优选为45％-65％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中，左乙拉西坦是活性成分；优选地，左乙拉西坦是唯一活性成分。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其由左乙拉西坦、填充剂、崩解剂、矫味剂、助流剂、抗氧剂、粘合剂和增塑剂组成。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其由左乙拉西坦、填充剂、崩解剂、矫味剂、助流剂、抗氧剂、粘合剂、增塑剂和色素组成。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中，左乙拉西坦在制剂中的含量为45％-70％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中，左乙拉西坦在制剂中的含量为45％-65％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中，左乙拉西坦在制剂中的含量为50％-70％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中，左乙拉西坦在制剂中的含量为50％-65％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中，左乙拉西坦在制剂中的含量为55％-65％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中，左乙拉西坦在制剂中的含量为60％-65％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其特征在于如下的 (1)-(6)项中的任意一项或者多项：
(1)所述填充剂为选自山梨醇、甘露醇、乳糖、磷酸氢钙和淀粉中的一种或多种，优选为山梨醇或甘露醇；
(2)所述崩解剂为微晶纤维素，优选为微晶纤维素PH101；
(3)所述矫味剂选自阿斯巴甜、三氯蔗糖、糖精钠和香精中的一种或者多种；优选地，所述香精为选自薄荷香精、草莓香精和樱桃香精中的一种或多种；
(4)所述助流剂为选自胶态二氧化硅、氢化植物油、滑石粉、硬脂酸镁和聚乙二醇中的一种或多种；
(5)所述抗氧剂选自L-抗坏血酸棕榈酸酯(L-AP)、丁基羟基茴香醚(BHA)和二丁基羟基甲苯(BHT)中的一种或多种；和
(6)所述粘合剂为聚维酮、羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠和海藻酸钠中的一种或多种；优选为聚维酮，更优选为聚维酮K30。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其特征在于如下的1)-6)项中的任意1项、任意2项、任意3项、任意4项、任意5项或者全部6项：
按照占制剂重量的百分比计算，
1)所述填充剂的含量为10％-60％，优选为10％-40％、10％-30％、10％-20％或10％-15％；
2)所述崩解剂的含量为10％-30％，优选为15％-25％或18％-22％；
3)所述矫味剂的含量为0.5％-5％；
4)所述助流剂的含量为0.2％-2％；
5)所述抗氧剂的含量为0.01％-0.5％，优选为0.01％-0.05％；
6)所述粘合剂的含量为0.01％-2％，优选为0.01％-1％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其特征在于：
按照占制剂重量的百分比计算，
1)所述填充剂的含量为10％-60％，优选为10％-40％、10％-30％、10％-20％或10％-15％；
2)所述崩解剂的含量为10％-30％，优选为15％-25％或18％-22％；以及
包括适量的矫味剂、助流剂和/或抗氧剂。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中，矫味剂用量为三氯蔗糖2％，薄荷香精0.5％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中超级崩解剂(例如交联聚维酮、羧甲基淀粉纳和/或交联羧甲基纤维素钠)的含量为0％-4％、0％-3％、0％-2％或0％-1％。优选地，所述超级崩解剂的含量为0，即不含超级崩解剂。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中交联聚维酮、羧甲基淀粉纳和交联羧甲基纤维素钠的含量为0％-4％、0％-3％、0％-2％或0％-1％。优选地，所述交联聚维酮、羧甲基淀粉纳和交联羧甲基纤维素钠的含量为0，即不含交联聚维酮、羧甲基淀粉纳和交联羧甲基纤维素钠。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其中表面活性剂的含量为0％-0.5％或0％-0.2％；优选地，不含表面活性剂。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其还包含增塑剂；优选地，其还包含增塑剂和色素；
优选地，增塑剂为甘油；
优选地，所述增塑剂例如甘油含量为占制剂重量的0.5％-1.5％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其特征在于：
按照占制剂重量的百分比计算，
1)所述填充剂的含量为10％-60％，优选为10％-40％、10％-30％、10％-20％或10％-15％；
2)所述崩解剂的含量为10％-30％，优选为15％-25％或18％-22％；
3)所述增塑剂的含量为0.5％-1.5％；以及
包括适量的矫味剂、助流剂、抗氧剂和/或色素。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其还包含色素；优选地，色素的含量根据打印模型所需色彩调节，优选地，色素总用量不超过制剂重量的1％。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，其为片剂，优选为非实心的片剂。
本发明中，片剂的外部特征根据儿童顺应性需求使用计算机软件设计，包括但不限于卡通动物型、糖果型、水果型等，其中单色模型为STL格式，彩色模型为PLY格式。
所述多彩卡通模型使用CMYK四原色以及多通路联供实现任意颜色的精细搭配，即打印液分为五种，分别为青、品红、黄、黑四种打印液以及透明打印液，不同色彩 的打印液通过在打印液中加入不同色素实现，色素种类包括但不限于赤藓红、苋菜红、胭脂红、亮蓝、柠檬黄等，所用四原色均为以上色素调配而成。
本发明中，片剂的内部结构可以设计为点阵结构、中空结构或中空立柱结构(如图3A-3C)等，以保证片剂的快速崩解释药，所述点阵结构是指片剂外壳及内部打印液喷涂量不同，内部喷涂量为外壳喷涂量的30％-80％，所述中空结构是指片剂中间部分不喷涂打印液，所述中空立柱结构为片剂中间部分不喷涂打印液但在片剂内部有一定数量的立柱支撑以确保片剂的机械性能。以上片剂结构均有一定厚度的实心顶层和底层，中间层根据模型设计实现不同部位的差异化喷涂，但所有模型均具有实心外壳。
本发明中，使用3D打印软件控制片剂模型尺寸，从而实现剂量的灵活可调，研究发现本发明确定的处方及工艺可以保证药片模型尺寸与药片规格和重量具有较好的线性相关性，这得益于本研究确定的参数可以实现打印液在单位体积内的精密喷涂，从而可以通过药片尺寸精确预测药物剂量，实现药物剂量的个体化调配。同时可以根据生产需求，在同一批次生产不同规格剂量的药品，最大化的节约生产成本。
在本发明的一些实施方式中，多彩卡通及糖果片剂模型示意图如图1A-图1D所示。
本发明的片剂满足各国药典特别是中国药典(2015版)对于硬度和脆碎度的要求。
在本发明的一些实施方式中，1000mg规格片剂硬度50-80N，750mg片剂硬度40-70N，500mg片剂硬度35-65N，250mg规格片剂25-50N，160mg规格片剂8-20N。
在本发明的一些实施方式中，本发明的片剂(例如上述规格的片剂)经脆碎度测定均未出现断裂或粉碎现象。
在本发明的一些实施方式中，使用片剂脆碎硬度测定仪(例如CJY-2C型，上海黄海药检仪器有限公司)测定硬度和/或脆碎度。
在本发明的一些实施方式中，硬度测定时每个样品均取6片使用测定仪分别测定，计算平均值即为平均硬度。
在本发明的一些实施方式中，脆碎度测定取不少于6.5g(至少10片)的片剂除尘，以25rpm旋转4分钟，不得有断裂或粉碎发生。
在本发明的一些实施方式中，所述的左乙拉西坦3D打印制剂，由于打印液组分最终占比较小，各成分特别是活性成分和主要辅料在制剂中的重量百分比含量，与活性成分和主要辅料在药物粉体中的重量百分比含量大致相同或者基本相同。
本发明的另一方面涉及一种打印液组合，其包含透明打印液，以及选自如下打印液中的任意1种、任意2种、任意3种或者4种：
青色打印液、品红打印液、黄色打印液和黑色打印液；
所述各打印液包含基础溶剂、粘合剂、增塑剂和色素；
所述基础溶剂为有机溶剂与水的混合溶液；所述有机溶剂为选自乙醇、丙二醇、异丙醇和丙酮中的一种或多种；有机溶剂在基础溶剂中的体积占比为35％-55％，优选为40％-50％；优选地，基础溶剂的含量为占相应打印液重量的至少85％-97％，优选90％-96％；
所述粘合剂为选自聚维酮、羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠、海藻酸钠和淀粉中的一种或多种；优选为聚维酮，更优选为聚维酮K30；优选地，所述粘合剂的含量为占相应打印液重量的不高于5％或不高于2％，例如为0.01％-5％、0.05％-5％、0.05％-4％、0.05％-3％、0.05％-2％、0.05％-1％、0.05％-0.5％、0.05％-0.1％、0.01％-0.5％、0.03％-0.3％、0.03％-0.2％或者0.03％-0.15％；
所述增塑剂为甘油，占相应打印液重量的1％-6％，优选为2％-5％，例如2％、3％、4％或5％。
在本发明的一些实施方式中，所述的打印液组合，其中，
青色打印液中的色素为亮蓝色素；
品红打印液中的色素为赤藓红和胭脂红；
黄色打印液中的色素为柠檬黄；和/或
黑色打印液中的色素为苋菜红色素和亮蓝色素。
在本发明的一些实施方式中，所述的打印液组合，其中表面活性剂的含量为占相应打印液重量的0％-2％或0％-1％；优选地，不含表面活性剂。
本发明的打印液组合用于制备本发明中任一项所述的左乙拉西坦3D打印制剂。
本发明的再一方面涉及一种制备本发明中任一项所述的左乙拉西坦3D打印制剂的方法，所述方法为粘结剂喷射型3D打印方法；
优选地，所述制备方法包括如下步骤：
在打印平台上铺展药物粉体，打印过程中每一铺粉层厚为80μm-200μm，优选为90μm-150μm或100μm-120μm；
打印喷头根据3D打印机控制软件输入的指令在特定部位精细喷涂一定数量的打印液液滴，打印平台Z轴下降一定高度，之后再次铺粉，再次打印，重复这一过程直至打印完成；
优选地，所述打印液选自本发明中任一项所述的打印液组合；
优选地，还包括对打印完成得到的制剂进行干燥和包装的步骤。
在本发明的一些实施方式中，所述的制备方法，其中，
3D打印的行间距为0.4cm-0.6cm，优选为0.5cm；和
3D打印的列间距为0.4cm-0.6cm，优选为0.5cm。
在本发明的一些实施方式中，所述的制备方法，其中，
打印头喷射机制为压电式；
单位墨滴喷射体积为5pL-40pL；优选为6pL-30pL；更优选地，大液滴、中液滴和小液滴的体积分别约30pL、约15pL和约6pL；
喷液速度为0.2g/min-0.8g/min，优选为0.3g/min-0.5g/min，更优选为0.4g/min。
在本发明的一些实施方式中，所述的制备方法，其中，
打印头喷射机制为热泡式；
单位墨滴喷射体积为15pL-25pL，优选为18pL；
喷液速度0.3g/min-0.8g/min，优选为0.4g/min-0.6g/min，更优选为0.5g/min。
在本发明的一些实施方式中，所述的制备方法，其中，所述药物粉体的粒径为30μm-150μm，优选为60μm-120μm。
在本发明的一些实施方式中，提供了一种基于全彩色粘结剂喷射型3D打印技术的左乙拉西坦卡通分散片的制备方法。针对粘结剂喷射型3D打印制剂普遍存在的问题，通过打印液粘结剂浓度、单位墨滴喷射体积、铺粉层厚、关键物料粒径的协同调整，同时保证了3D打印片剂具有光洁的外观、较强的机械性能以及快速分散的特性，对现有技术有明显的改进。同时，为解决儿童用药顺应性的问题，本发明使用彩色喷墨技术开发适合儿童的左乙拉西坦多彩卡通制剂。通过灵活的模型设计和打印方式，不仅可以制造出快速释药的精确剂量的药品，而且可以根据儿童的喜好，制备出不同颜色及形状的药片，实现儿童制剂的个体化给药，显著提高儿童用药的顺应性。
在本发明的一些实施方式中，所述左乙拉西坦卡通分散片可以在一小口的水或其它流体(例如牛奶、果汁等)中，在10-20秒内完全分散。
所述剂型使用粘结剂喷射型3D打印技术，按照“分层制造、逐层叠加”的原理制 备出所需产品，实现传统工艺难以完成的高载药量左乙拉西坦多彩卡通分散片的制备，本发明同样适用于其他用药剂量较高、需快速起效的药物。
本发明提供的剂型是根据需求进行计算机模型设计，打印机按照指令将打印液喷涂于一定厚度的药物粉体表面，重复铺粉及喷涂过程，直至获得所需的制剂。
本发明使用按需喷射打印头，所述3D打印药片中使用的打印头可以是热泡式喷头，也可以是压电式喷头，单个打印头的喷孔数量为300-3000个，单位墨滴喷射体积为15-50pL。
本发明人发现，粉层厚度降低能够增加片剂表面的打印精细度。喷涂层数根据片剂规格以及片剂模型尺寸确定，通常为30-100层。
本发明人还发现，部分辅料粒径略大于铺粉层厚时并未影响粉层平整度和整体铺粉效果。
在本发明的一些实施方式中，制剂打印排版列间距为0.2-1.0cm，行间距为0.2-0.5cm。本发明人发现，体积越大的片剂所需的列间距及行间距越大，以避免墨滴渗透造成的片剂之间的相互影响。
在本发明的一些实施方式中，粘结剂喷射型3D打印技术制备多彩卡通分散片剂的流程图如图2所示。
本发明中，打印完成的药片经干燥及除粉后收集，干燥温度设定为30℃-50℃，优选35℃-45℃。使用真空吸料系统回收多余的粉体材料，该部分粉体作为支撑材料在片剂打印过程中起到重要的支撑作用，研究表明，在粉体材料中加入抗氧剂有助于粉体的稳定及重复利用。
本发明的再一方面涉及一种左乙拉西坦3D打印制剂，其由本发明中任一项所述的制备方法制得。
根据本发明中任一项所述的左乙拉西坦3D打印制剂，其用于治疗和/或预防癫痫。
本发明的再一方面涉及本发明中任一项所述的左乙拉西坦3D打印制剂在制备治疗和/或预防癫痫的药物中的用途。
本发明的再一方面涉及一种治疗和/或预防癫痫的方法，包括给予有需求的受试者以有效量的本发明中任一项所述的左乙拉西坦3D打印制剂的步骤；优选地，所述有需求的受试者为儿童。
本发明的左乙拉西坦3D打印制剂可以以不同剂量每日一次或者多次给药。给药剂量取决于许多因素，例如所要治疗或辅助治疗或预防的病症例如癫痫症的严重程度，患者的性别、年龄、体重及个体反应，给药途径及给药次数等。上述剂量可以单一剂量形式或分成几个，例如二、三、四个剂量形式给药。通常的做法是，按照本领域公认的(例如药典或者教科书)的活性成分左乙拉西坦的给药剂量或者遵循医师或药师指定的剂量给药。
可改变本发明药物组合物中主药(左乙拉西坦)的实际剂量水平，以便能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据给药途径、所治疗病况的严重程度以及待治疗患者的病况和既往病史来选定。但是，本领域的做法是，给药剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。
本发明中，
术语“单位墨滴喷射体积”是指打印液从打印头上的喷孔喷射后形成的单个液滴的体积。
术语“打印液喷射速度”是指单位时间内打印头喷射出的打印液质量，用g/min表示，该时间仅指喷液时间，不包括铺粉时间及滚轴归位时间。
术语“铺粉层厚”是指打印过程中每层药物粉体的铺层厚度，即每层打印完成后Z轴下降一定距离，铺粉辊铺展一定厚度的粉体。
术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症(癫痫症)的剂量。
本发明中，如果没有特别说明，“约”是指在所修饰的数值或者物理量的20％的范围内上下浮动，例如，约100分钟，表示80分钟-120分钟。
本发明中，对于含量(包括但不限于活性成分左乙拉西坦或者辅料的含量)，如果没有特别说明，均为按照占制剂重量的百分比计算的含量。
发明的有益效果
本发明取得了如下技术效果(1)-(5)中的任意一项或者多项：
(1)本发明的剂型具有较为光洁的表面，显著降低了粗糙度，减少了制剂在储存及运输过程中表面粉体掉落导致用药剂量差异；提高了患者的用药体验；显著提升 儿童用药顺应性；
(2)保持了良好的硬度和脆碎度；
(3)通过内部结构的设计实现了少量液体中的快速崩散，解决了儿童吞咽困难的问题；特别适用于儿童用药或者吞咽困难的患者用药；
(4)模型尺寸与剂量之间具有很好的线性相关性，可以实现剂量的灵活调整，实现了儿童用药剂量个体化的要求；
(5)可以设置儿童喜爱的卡通外观，更容易被儿童所接受。
附图说明
图1A-图1D：多彩卡通及糖果片剂模型示意图。
图2：粘结剂喷射型3D打印技术制备多彩卡通分散片剂的流程图。
图3A-图3C：不同内部空间结构片剂模型剖面示意图。其中，图3A，点阵结构；图3B，中空结构图；3C，中空立柱结构。
图4A-图4C：剂量模型示意图。其中，图4A侧视图；图4B三维切面图；图4C上视图。
图5：个体化给药剂量模型。图中横坐标为计算机设计的模型体积，纵坐标为实际打印的片剂规格。
图6A-图6D：表面粗糙度3D形貌图。图6A：本发明制剂(250mg)；图6B:
Figure PCTCN2020111961-appb-000003
(250mg)；图6C：本发明制剂(1000mg)；图6D：
Figure PCTCN2020111961-appb-000004
(1000mg)。
图7A-图7L：SEM片剂微结构。其中，图7A-图7F为1000mg规格；图7G-图7L为250mg规格。其中：
图7A：外壳上表面-50x；图7B：外壳上表面-300x；
图7C：外壳侧面-50x；图7D：外壳侧面-300x；
图7E：内部中空区域-50x；图7F：内部中空区域-300x
图7G：外壳上表面-50x；图7H：外壳上表面-300x；
图7I：外壳侧面-50x；图7J：外壳侧面-300x；
图7K：内部中空区域-50x；图7L：内部中空区域-300x。
图8：X射线粉末衍射仪(XRD)检测结果。其中，API的含义是原料；LEV tablets的含义是左乙拉西坦片；Excipients的含义是辅料，横坐标为2θ角。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
制备例1：样品1-1、样品1-2、样品1-3和样品1-4的制备
1.药物粉体的准备
左乙拉西坦粉碎过120目筛，胶态二氧化硅过40目筛，其余辅料过120目筛。将原辅料加入料斗混合机，设定转速20rpm，混合20min，保证药物粉体混合均匀。药物粉体材料组成如下：
Figure PCTCN2020111961-appb-000005
2.打印液的配制
使用50％乙醇溶液(v/v)作为基础溶剂。
各打印液组成如下：
(1)透明打印液：
50％乙醇溶液   95.95％(w/w)
聚维酮K30      0.05％(w/w)
甘油           4％(w/w)
(2)青色打印液(C)：
Figure PCTCN2020111961-appb-000006
Figure PCTCN2020111961-appb-000007
(3)品红打印液(M)：
Figure PCTCN2020111961-appb-000008
(4)黄色打印液(Y)：
Figure PCTCN2020111961-appb-000009
(5)黑色打印液(K)：
Figure PCTCN2020111961-appb-000010
3.模型设计
使用计算机辅助设计软件3D Sprint(3D systems,USA)创建模型文件，首先设计圆形片剂或儿童喜爱的不同色彩和形状的片剂模型，使用“生成几何形状功能”，生成三维模型，模型的尺寸根据实际进行三个轴方向的调整。异型模型的建立通常会用到“分割”，“布尔运算”功能，分割功能可以切割出需要的形状，布尔运算功能可以将多个不同形状的模型拟合成一个整体模型。模型建立好之后对模型进行上色，使模型本身增加色彩。根据需求设计不同剂量的左乙拉西坦分散片并计算药片的尺寸数据，模型文件为单色(STL格式)或彩色(PLY格式)。本制备例分别设计了250mg和1000mg规格圆形片剂，其中250mg规格片剂直径11.50mm，片厚5.18mm，体积为0.537cm 3；1000mg规格片剂直径18.50mm，片厚8.33mm，体积为2.24cm 3。本制备例还设计了两种多彩卡通模型(模型图案见图1B、图1D)，均为1000mg规格，其中小熊片剂 长径19.20mm，片厚8.28mm；糖果片剂直径18.50mm，片厚8.33mm。
4.片剂打印
将模型数据传输至3D打印机控制软件，设定打印数量并排版，打印参数设定如下：
Figure PCTCN2020111961-appb-000011
首先在打印平台上铺展一定厚度的药物粉体，作为打印模型底部的支撑同时确保打印过程中单一粉层能够均匀的铺展，该粉层厚度为2-5mm。打印过程中每一铺粉层厚为100μm，打印喷头根据3D打印机控制软件输入的指令在特定部位精细喷涂一定数量的液滴，打印平台Z轴下降一定高度，之后再次铺粉，再次打印，重复这一过程直至形成所需的模型。彩色卡通模型的打印通过不同打印头实现CMYK四原色的组合以及彩色图案的喷涂，其中彩色图案仅喷涂于模型外壳表面，模型内部的喷涂全部使用透明打印液完成。
5.干燥及后处理
打印完成后对片剂进行干燥，设置干燥温度40℃，维持120min，控制干燥失重低于2％。干燥完成后使用真空吸料系统回收多余药物粉体，除去片剂表面附着的粉体。
6.包装
使用铝塑泡罩对片剂进行包装。
制得样品1-1、样品1-2、样品1-3和样品1-4：
样品1-1：250mg规格圆形片剂；样品1-2：1000mg规格圆形片剂；样品1-3：1000mg规格小熊片剂；样品1-4：1000mg规格糖果片剂。
制备例2：样品2-1、样品2-2、样品2-3和样品2-4的制备
1.药物粉体的准备
左乙拉西坦粉碎过120目筛，胶态二氧化硅过40目筛，其余辅料过120目筛。 将原辅料加入料斗混合机，设定转速20rpm，混合20min，保证药物粉体混合均匀。药物粉体材料组成如下：
Figure PCTCN2020111961-appb-000012
2.打印液的配制
使用40％异丙醇溶液(v/v)作为基础溶剂。
各打印液组成如下：
(1)透明打印液：
40％异丙醇溶液   95.9％(w/w)
聚维酮K30        0.1％(w/w)
甘油             4％(w/w)
(2)青色打印液(C)：
Figure PCTCN2020111961-appb-000013
(3)品红打印液(M)：
Figure PCTCN2020111961-appb-000014
(4)黄色打印液(Y)：
Figure PCTCN2020111961-appb-000015
Figure PCTCN2020111961-appb-000016
(5)黑色打印液(K)：
Figure PCTCN2020111961-appb-000017
3.模型设计
参照前面的制备例1进行。
4.片剂打印
将模型数据传输至3D打印机控制软件，设定打印数量并排版，打印参数设定如下：
Figure PCTCN2020111961-appb-000018
首先在打印平台上铺展一定厚度的药物粉体，作为打印模型底部的支撑同时确保打印过程中单一粉层能够均匀的铺展，该粉层厚度为2-5mm。打印过程中每一铺粉层厚为100μm，打印喷头根据3D打印机控制软件输入的指令在特定部位精细喷涂一定数量的液滴，打印平台Z轴下降一定高度，之后再次铺粉，再次打印，重复这一过程直至形成所需的模型。
5.干燥及后处理
打印完成后对片剂进行干燥，设置干燥温度40℃，维持120min，控制干燥失重低于2％。干燥完成后使用真空吸料系统回收多余药物粉体，除去片剂表面附着的粉体。
6.包装
使用铝塑泡罩对片剂进行包装。
制得样品2-1、样品2-2、样品2-3和样品2-4：
样品2-1：250mg规格圆形片剂；样品2-2：1000mg规格圆形片剂；样品2-3：1000mg规格小熊片剂；样品2-4：1000mg规格糖果片剂。
制备例3：样品3-1、样品3-2、样品3-3和样品3-4的制备
1.药物粉体的准备
同制备例2。
2.打印液的配制
同制备例2。
3.模型设计
同制备例1。
4.片剂打印
将模型数据传输至3D打印机控制软件，设定打印数量并排版，打印参数设定如下：
Figure PCTCN2020111961-appb-000019
首先在打印平台上铺展一定厚度的药物粉体，作为打印模型底部的支撑同时确保打印过程中单一粉层能够均匀的铺展，该粉层厚度为2-5mm。打印过程中每一铺粉层厚为150μm，打印喷头根据3D打印机控制软件输入的指令在特定部位精细喷涂一定数量的液滴，打印平台Z轴下降一定高度，之后再次铺粉，再次打印，重复这一过程直至形成所需的模型。
5.干燥及后处理
打印完成后对片剂进行干燥，设置干燥温度40℃，维持120min，控制干燥失重低于2％。干燥完成后使用真空吸料系统回收多余药物粉体，除去片剂表面附着的粉体。
6.包装
使用铝塑泡罩对片剂进行包装。
制得样品3-1、样品3-2、样品3-3和样品3-4：
样品3-1：250mg规格圆形片剂；样品3-2：1000mg规格圆形片剂；样品3-3：1000mg规格小熊片剂；样品3-4：1000mg规格糖果片剂。
制备例4：样品4-1、样品4-2和样品4-3的制备
制备例1-3制得的样品均是实心片剂。本发明人在制备例2的基础上(除了内部空间结构不同，粉体、打印液、制备方法与制备例2的1000mg规格的样品完全相同)，通过调节模型的内部结构，以进一步加快药片在液体中的分散时间。
以下为本实验中的三种模型结构设计(如图3A-图3C)，这三种片剂模型内部和外部均有所不同，片剂打印过程分为三个部分进行打印，分别为片剂底层、中间层和顶层。其中底层和顶层均为实心层，打印饱和度为100％，以保持片剂的整体机械性能；中间层根据模型的结构设计对各打印区域进行精细喷涂，外壳为100％的打印饱和度，内层为特殊结构，打印饱和度较低，以实现快速崩散释药的目的。
(1)点阵结构模型(图3A)，该结构通过内部模型结构的调整实现片剂内部和外壳打印饱和度的差异，外壳的打印饱和度为100％，片剂内部的打印饱和度灵活可调。在本实验中，片剂内部打印饱和度为50％，外壳尺寸为片剂尺寸的四分之一，需要根据片剂尺寸调整。本实验中，1000mg规格片剂直径为18.50mm，厚度为8.33mm，片剂外壳上表面和下表面壁厚均为2.08mm，外侧面壁厚为4.63mm。
(2)中空结构模型(图3B)，该结构内部不喷涂打印液，仅在外壳部分喷涂打印液，即片剂外壳的打印饱和度为100％，内部中空部分的打印饱和度为0％。外壳尺寸为片剂尺寸的四分之一，需要根据片剂尺寸调整。本实验中，1000mg规格片剂直径为18.50mm，厚度为8.33mm，片剂外壳上表面和下表面壁厚均为2.08mm，外侧面壁厚为4.63mm。
(3)中空立柱结构模型(图3C)：该结构在上述中空结构模型的基础上在中空部位增加3根支撑柱，呈三角形分布；同时将中空结构模型的外壳内部1/2的区域调整为中空结构并增加6根支撑柱，呈圆环状围绕。
上述(1)、(2)、(3)制得的样品分别命名为样品4-1、样品4-2和样品4-3。
制备例5：样品5-1、样品5-2、样品5-3、样品5-4和样品5-5的制备
3D打印技术可以通过模型尺寸的设计实现药物剂量的灵活调整，但对打印液与药物粉体的匹配度(打印液与药物粉体的适用性，也就是能否打印出高精度的药片)要求较高，必须能够满足打印精度的要求。本发明人使用制备例4的中空结构模型，考察模型尺寸设计与片剂规格的线性关系，建立模型尺寸与剂量的相关性。使用3D Sprint建立不同尺寸的片剂模型，设计的理论剂量分别为160mg、250mg、500mg、750mg、1000mg，对应的剂量模型示意图见图4A-图4C，使用制备例2中的处方和工艺，分别打印不同尺寸的片剂，得到样品5-1、样品5-2、样品5-3、样品5-4和样品5-5，规格依次分别是160mg、250mg、500mg、750mg、1000mg。
测定各尺寸片剂的含量和规格，以片剂模型体积为X轴，实测片剂规格为Y轴，建立模型尺寸与剂量的相关性。实验结果见图5。结果显示，模型体积与片剂规格线性关系较好，r＝0.999，可通过模型尺寸设计灵活调整药物剂量。
实验例1：片剂机械性能检测
(1)片剂外观及表面粗糙度
实验样品：
前面的制备例1制得的样品1-3(1000mg)和样品1-4(1000mg)，制备例2制得的样品2-3(1000mg)和样品2-4(1000mg)，制备例3制得的样品3-3(1000mg)和3-4(1000mg)，制备例5制得的样品5-2(250mg)和样品5-5(1000mg)。
Figure PCTCN2020111961-appb-000020
(250mg)以及
Figure PCTCN2020111961-appb-000021
(1000mg)为商购得到。
目视观察片剂外观，应完整光洁，无层间位移及模型设计以外的突起或凹陷；多彩卡通片剂应外形美观，色彩均一；以上制备例中的片剂外观均能满足要求。
使用三维白光干涉形貌仪(Nexview,美国ZYGO)，2.75x物镜，1x目镜测试样品表面粗糙度，评价表面粗糙度特征参数，如根均方高度(Sq)、算术平均高度(Sa)、最大高度(Sz)，其中Sz为Sp(最大峰高)和Sv(最大谷深)之和。分别对以上制备例中片剂进行表面粗糙度分析，同时与美国上市3D打印产品
Figure PCTCN2020111961-appb-000022
规格和1000mg规格进行比较，结果本发明制剂表面粗糙度典型值Sq为20-35μm，Sa为15-30μm，Sz为200-300μm，
Figure PCTCN2020111961-appb-000023
Sq为60-80μm，Sa为50-70μm，Sz为350-500μm，本发明制剂明显优于
Figure PCTCN2020111961-appb-000024
同时，由3D形貌图(见图6)可以看到(以制备例5中样品5-2和样品5-5以及
Figure PCTCN2020111961-appb-000025
为例)，本发明制剂表面粗糙度明显好于
Figure PCTCN2020111961-appb-000026
解决了表面粗糙度差这一粘结剂喷射型3D打印制剂普遍存在的问题，与
Figure PCTCN2020111961-appb-000027
相比具有明显的改进。
(2)硬度和脆碎度
使用片剂脆碎硬度测定仪(CJY-2C型，上海黄海药检仪器有限公司)测定本品硬度和脆碎度。硬度测定时每个样品均取6片使用测定仪分别测定，计算平均值即为平均硬度。脆碎度测定取不少于6.5g(至少10片)的片剂除尘，以25rpm旋转4分钟，不得有断裂、粉碎现象。
对制备例1-5中不同规格片剂进行硬度及脆碎度测定，其中1000mg规格片剂硬度50-80N，750mg片剂硬度40-70N，500mg片剂硬度35-65N，250mg规格片剂25-50N，160mg规格片剂8-20N。
制备例1-5中不同规格片剂及
Figure PCTCN2020111961-appb-000028
经脆碎度测定均未出现断裂或粉碎现象。
另外，测得
Figure PCTCN2020111961-appb-000029
规格片剂硬度40-70N，750mg片剂硬度30-60N，500mg片剂硬度20-40N，250mg规格片剂10-30N。
以上结果说明，与
Figure PCTCN2020111961-appb-000030
相比，本发明的制剂在降低表面粗糙度的同时具有更高的硬度和相当的脆碎度。
实验例2：片剂微结构
使用高分辨热场发射扫描电镜研究了打印片剂的形态。使用真空蒸发器在样品表面喷镀导电层，然后将加速电压调节为5.0kV，分别在放大倍数为50x和300x下观察制备例5中250mg规格样品(样品5-2)及1000mg规格样品(样品5-5)微结构。
通过SEM观察(图7A-图7L)，250mg规格和1000mg规格片剂外壳表面均有较多孔隙，但整体结构较为紧密，表面光洁，可以保证片剂较好的外观和机械性能，同时有利于水分的快速进入从而实现片剂的快速崩散，片剂内部中空区域未经粘结，为均一粉体，呈疏松多孔状，水分通过外部孔隙进入与粉体接触后可以实现更加快速的药物释放。
实验例3：晶型分析
使用X射线粉末衍射仪(XRD)对制备例5中1000mg规格左乙拉西坦分散片(样品5-5)的晶型进行监测，同时与左乙拉西坦(API)和辅料(Excipients)的晶型进行比较，观察3D打印前后左乙拉西坦的晶型变化。
XRD检测结果见图8，结果表明，左乙拉西坦分散片(LEV tablets)中左乙拉西 坦晶型与原料(API)相同，未发生变化，说明片剂打印过程并未引起左乙拉西坦晶型的变化。
实验例4：含量测定
含量测定方法：高效液相色谱法(HPLC)。
色谱柱：辛烷基硅烷键合硅胶为填充剂的反相色谱柱。
流动相：乙腈：缓冲液为10:90，其中缓冲液为1.4g/L无水。
磷酸氢二钠水溶液，用磷酸调节至pH3.5。
检测波长：205nm。
流速：1.5ml/min。
柱温：30℃。
定量方法：外标法。
结果显示，以上制备例1-5中各个规格的片剂含量均在所设计剂量的95％-105％范围内，满足中国药典(2015版)对于片剂含量的要求。
实验例5：分散均匀性及药物释放
(1)分散均匀性测定
按照中国药典(2015版)分散均匀性测定法，使用智能崩解仪测定片剂分散均匀性。测定装置的不锈钢丝网的筛孔内径为710μm，使用纯化水在15℃-25℃(通常使用20℃)下测定，每次测定6片。结果显示，上述制备例1-5中打印片剂的分散均匀性均在15±5s范围内，在液体中可以快速分散。
(2)溶出度测定
按照中国药典(2015版)溶出度测定法二法，使用溶出仪测定片剂溶出曲线，每次测定6片，测定参数见下面的表1。
表1
Figure PCTCN2020111961-appb-000031
Figure PCTCN2020111961-appb-000032
结果显示，上述制备例1-5中打印片剂在四个溶出介质中的2.5min溶出度均在80％以上，可以实现极快速释药。
实验例6：口感评价
口感评价是儿童制剂顺应性评价中的关键一环，使用法国Alpha MOS公司的ASTREE电子舌，基于电位测量原理，实现了对待测样品(三氯蔗糖与薄荷香精用量分别为0.5％/0.5％、0.5％/0.2％、2％/0.2％、2％/0.5％、1％/0.2％、0.5％/0.3％、2％/0.3％、1％/0.5％、1％/0.3％)滋味品质的客观分析，通过处方筛选确定了最佳矫味剂用量为三氯蔗糖2％，薄荷香精0.5％。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解，根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (19)

  1. 一种左乙拉西坦3D打印制剂，包括左乙拉西坦，以及填充剂、崩解剂、矫味剂、助流剂、抗氧剂和粘合剂；
    其中，按照占制剂重量的百分比计算，左乙拉西坦的含量为40％-70％；优选为45％-65％；
    其中，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度不高于45μm、算术平均高度不高于40μm、最大高度不高于350μm；
    优选地，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度不高于40μm、算术平均高度不高于35μm、最大高度不高于320μm；
    优选地，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度为20-40μm、算术平均高度为15-35μm、最大高度为200-320μm；
    优选地，所述左乙拉西坦3D打印制剂的粗糙度特征值的根均方高度为20-35μm、算术平均高度为15-30μm、最大高度为200-300μm；
    优选地，所述根均方高度、算术平均高度和最大高度通过三维白光干涉形貌仪(例如美国ZYGO的Nexview)测得。
  2. 根据权利要求1所述的左乙拉西坦3D打印制剂，其特征在于如下的(1)-(6)项中的任意一项或者多项：
    (1)所述填充剂为选自山梨醇、甘露醇、乳糖、磷酸氢钙和淀粉中的一种或多种，优选为山梨醇或甘露醇；
    (2)所述崩解剂为微晶纤维素，优选为微晶纤维素PH101；
    (3)所述矫味剂选自阿斯巴甜、三氯蔗糖、糖精钠和香精中的一种或者多种；优选地，所述香精为选自薄荷香精、草莓香精和樱桃香精中的一种或多种；
    (4)所述助流剂为选自胶态二氧化硅、氢化植物油、滑石粉、硬脂酸镁和聚乙二醇中的一种或多种；
    (5)所述抗氧剂选自L-抗坏血酸棕榈酸酯、丁基羟基茴香醚和二丁基羟基甲苯中的一种或多种；和
    (6)所述粘合剂为聚维酮、羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠和海藻酸钠中的一种或多种；优选为聚维酮，更优选为聚维酮K30。
  3. 根据权利要求1至2中任一权利要求所述的左乙拉西坦3D打印制剂，其特征在于如下的1)-6)项中的任意一项或者多项：
    按照占制剂重量的百分比计算，
    1)所述填充剂的含量为10％-60％，优选为10％-20％；
    2)所述崩解剂的含量为10％-30％，优选为15％-25％；
    3)所述矫味剂的含量为0.5％-5％；
    4)所述助流剂的含量为0.2％-2％；
    5)所述抗氧剂的含量为0.01％-0.5％，优选为0.01％-0.05％；
    6)所述粘合剂的含量为0.01％-2％，优选为0.01％-1％。
  4. 根据权利要求1至3中任一权利要求所述的左乙拉西坦3D打印制剂，其中超级崩解剂(例如交联聚维酮、羧甲基淀粉纳和/或交联羧甲基纤维素钠)的含量为0％-4％、0％-3％、0％-2％或0％-1％；优选地，不含超级崩解剂。
  5. 根据权利要求1至4中任一权利要求所述的左乙拉西坦3D打印制剂，其中表面活性剂的含量为0％-2％或0％-1％；优选地，不含表面活性剂。
  6. 根据权利要求1至5中任一权利要求所述的左乙拉西坦3D打印制剂，其还包含增塑剂；优选地，包含增塑剂以及色素；
    优选地，增塑剂为甘油，其含量为0.5％-1.5％；
    优选地，色素的含量为不超过制剂重量的1％。
  7. 根据权利要求1至6中任一权利要求所述的左乙拉西坦3D打印制剂，其为片剂，优选为非实心的片剂。
  8. 一种打印液组合，其包含透明打印液，优选地，还包含选自如下打印液中的任意1种、任意2种、任意3种或者4种：
    青色打印液、品红打印液、黄色打印液和黑色打印液；
    所述各打印液包含基础溶剂、粘合剂、增塑剂和色素；
    所述基础溶剂为有机溶剂与水的混合溶液；所述有机溶剂为选自乙醇、丙二醇、 异丙醇和丙酮中的一种或多种；有机溶剂在基础溶剂中的体积占比为35％-55％，优选为40％-50％；优选地，基础溶剂的含量为占相应打印液重量的至少85％-97％，优选90％-96％；
    所述粘合剂为选自聚维酮、羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠、海藻酸钠和淀粉中的一种或多种；优选为聚维酮，更优选为聚维酮K30；优选地，所述粘合剂的含量为占相应打印液重量的不高于5％或不高于2％，例如为0.01％-5％、0.05％-2％、0.05％-1％、0.05％-0.5％、0.05％-0.1％、0.01％-0.5％、0.03％-0.3％、0.03％-0.2％或者0.03％-0.15％；
    所述增塑剂为甘油，占相应打印液重量的1％-6％，优选为2％-5％。
  9. 根据权利要求8所述的打印液组合，其中，
    青色打印液中的色素为亮蓝色素；
    品红打印液中的色素为赤藓红和胭脂红；
    黄色打印液中的色素为柠檬黄；和/或
    黑色打印液中的色素为苋菜红色素和亮蓝色素。
  10. 根据权利要求8或9所述的打印液组合，其中表面活性剂的含量为占相应打印液重量的0％-2％或0％-1％；优选地，所述打印液组合不含表面活性剂。
  11. 一种制备权利要求1至7中任一权利要求所述的左乙拉西坦3D打印制剂的方法，所述方法为粘结剂喷射型3D打印方法；
    优选地，所述制备方法包括如下步骤：
    在打印平台上铺展药物粉体，打印过程中每一铺粉层厚为80μm-200μm，优选为90μm-150μm或100μm-120μm；
    打印喷头根据3D打印机控制软件输入的指令在特定部位精细喷涂一定数量的打印液液滴，打印平台Z轴下降一定高度，之后再次铺粉，再次打印，重复这一过程直至打印完成；
    优选地，所述打印液选自权利要求8至10中任一权利要求所述的打印液组合；
    优选地，还包括对打印完成得到的制剂进行干燥和包装的步骤。
  12. 根据权利要求11所述的制备方法，其中，
    3D打印的行间距为0.4cm-0.6cm，优选为0.5cm；和
    3D打印的列间距为0.4cm-0.6cm，优选为0.5cm。
  13. 根据权利要求11所述的制备方法，其中，
    打印头喷射机制为压电式；
    单位墨滴喷射体积为5pL-40pL；优选为6pL-30pL；更优选地，大液滴、中液滴和小液滴的体积分别约30pL、约15pL和约6pL；
    喷液速度为0.2g/min-0.8g/min，优选为0.3g/min-0.5g/min，更优选为0.4g/min。
  14. 根据权利要求11所述的制备方法，其中，
    打印头喷射机制为热泡式；
    单位墨滴喷射体积为15pL-20pL，优选为18pL；
    喷液速度0.3g/min-0.8g/min，优选为0.4g/min-0.6g/min，更优选为0.5g/min。
  15. 根据权利要求11所述的制备方法，其中，所述药物粉体的粒径为30μm-150μm，优选为60μm-120μm。
  16. 一种左乙拉西坦3D打印制剂，其由权利要求11至15中任一权利要求所述的制备方法制得。
  17. 权利要求1至7和16中任一权利要求所述的左乙拉西坦3D打印制剂在制备治疗和/或预防癫痫的药物中的用途。
  18. 根据权利要求1至7和16中任一权利要求所述的左乙拉西坦3D打印制剂，其用于治疗和/或预防癫痫。
  19. 一种治疗和/或预防癫痫的方法，包括给予有需求的受试者以有效量的权利要求1至7和16中任一权利要求所述的左乙拉西坦3D打印制剂的步骤；优选地，所述有需求的受试者为儿童。
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