CN111840243B - Levetiracetam 3D printing preparation and preparation method thereof - Google Patents

Levetiracetam 3D printing preparation and preparation method thereof Download PDF

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CN111840243B
CN111840243B CN202010749741.5A CN202010749741A CN111840243B CN 111840243 B CN111840243 B CN 111840243B CN 202010749741 A CN202010749741 A CN 202010749741A CN 111840243 B CN111840243 B CN 111840243B
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printing
levetiracetam
formulation
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weight
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CN111840243A (en
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郑爱萍
王增明
陈如心
韩晓璐
张慧
高静
刘楠
高翔
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Academy of Military Medical Sciences AMMS of PLA
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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

Abstract

The invention belongs to the field of medicines and preparations, and relates to a levetiracetam 3D printing preparation and a preparation method thereof. Specifically, the invention relates to a levetiracetam 3D printing preparation, which comprises levetiracetam accounting for 40-70% of the weight of the preparation, a filler, a disintegrating agent, a flavoring agent, a flow aid, an antioxidant and an adhesive; wherein the levetiracetam 3D printing formulation has a roughness characteristic root mean square height (Sq) no greater than 45 μm, an arithmetic mean height (Sa) no greater than 40 μm, and a maximum height (Sz) no greater than 350 μm. The preparation of the invention has excellent surface smoothness, can realize rapid drug release within a few seconds, can realize flexible adjustment of drug dosage, and greatly improves the compliance of children drug administration.

Description

Levetiracetam 3D printing preparation and preparation method thereof
Technical Field
The invention belongs to the field of medicines and preparations, and relates to a levetiracetam 3D printing preparation and a preparation method thereof. In particular, the present invention relates to a levetiracetam tablet, such as a levetiracetam dispersible tablet, and a method for preparing the levetiracetam tablet, such as a levetiracetam dispersible tablet, using 3D printing technology. In particular, it relates to levetiracetam 3D printed tablets suitable for administration to children.
Background
Levetiracetam is a pyrrolidone derivative and is one of the most widely used broad-spectrum antiepileptic drugs in clinical application. Levetiracetam is very easy to dissolve and has high permeability, can be quickly absorbed after being orally taken, has the absolute bioavailability close to 100 percent, is linearly metabolized, has small difference between individuals and in vivo, and has no sex, ethnic difference and circadian rhythm difference. Due to the completeness of absorption and the linear relation of levetiracetam, the blood concentration can be predicted according to the oral dose of mg/kg. The structural formula of levetiracetam is shown in the following formula A:
Figure BDA0002609618360000011
pediatric patients are a special medication group, children of different age groups have different requirements for medication dosage, and child medication compliance can be affected by the taste, color and surface texture of the medication. For pediatric formulations, there are still a number of problems, such as lack of suitable dosage forms, lack of suitable dosages, poor compliance, inadequate clinical compliance, lack of excipients for pediatric safety data, and the like.
The solid preparation is always the most widely applied preparation formulation due to the advantages of good stability, convenient taking, convenient carrying and the like. In the case of solid preparations, more than 25% of patients have dysphagia even among adults, and even more so among children, the dysphagia is always a great problem for children to take medicines. The absorption system and the metabolic system of children are not completely developed, and the pharmacodynamics, the pharmacokinetics and the toxicokinetics characteristics of children are obviously different from those of adults. Children are often referred to as "adults," but are by no means simply regarded as miniature versions of adults on medication. Many times pediatricians can only take medication by clinical experience to adjust the dosage for adults, often the dosage description of "half-tablets" appears in the prescription, which causes inconvenience and the risk of breaking the structure of the preparation by cutting up the tablets.
In addition, children have high requirements on the shape, color and taste of the medicine, the dosage form on the market at present often refuses to take the medicine, if medical staff or parents adopt compulsive means when the baby is in the absence of the persuasion, the sick children struggle, refuse, cry and fear, so that the conditions of vomiting, insufficient medicine intake and the like can prevent the smooth proceeding of treatment, and the psychology of the children is wounded. The incomplete specification of the pediatric drug dosage form exists all over the world, and even the pediatric drug dosage form is not suitable for pediatric clinical use, which brings great difficulty to the treatment of children patients. Therefore, the current pharmaceutical preparation is far from meeting the requirements of children for medication. Despite the significant advances made in the formulation of children in recent years, the above problems remain a significant challenge that pharmaceutical technology has to face today. Therefore, innovative manufacturing techniques are needed to meet the personalized medication needs of children, and achieve "tailor-made" of children's preparations.
The 3D printing technology is a technology of constructing an object by printing layer by layer on the basis of a digital model file (usually STL or PLY format) using different materials through a computer aided design model, and finally changing a blueprint on a computer into a real object. 3D printing is also known as "rapid prototyping", "solid freeform" and "additive manufacturing". The 3D printing technology has higher flexibility, and can prepare personalized products with various geometric shapes and functions by controlling the printing process through model design. As a novel technical platform, 3D printing has great advantages in product design complexity, product individuation and on-demand manufacturing, can well solve the defects of the existing preparation technology, is a promising method for manufacturing the children preparation by using the 3D printing technology, and can promote the transition to more individualized treatment medicines.
The main 3D printing techniques currently applied in the field of pharmaceutical preparations include: adhesive spraying technology, material extruding technology and stereo light curing and forming technology. Among them, the binder jetting technology is the main 3D printing technology for formulation production. Because of having many similarities with the pelletization technique that uses in traditional preparation production, compare with other 3D printing techniques, binder injection technique has extensive optional raw and auxiliary material kind and the application prospect in the pharmaceutical preparation is wide. Furthermore, with appropriate equipment modifications and optimizations, the adhesive jetting technology is the 3D printing technology most likely to meet the commercial production of pharmaceuticals.
The adhesive jetting technology is used for printing medicine, and includes spreading powder onto the operation table of printer, and jetting adhesive or medicine liquid drop to the powder bed in the set path and in the precise speed. Then, the operation table is lowered for a certain distance, then powder is spread and liquid is dripped, and the steps are repeated, and the required product is prepared according to the principles of layered manufacturing and layer-by-layer superposition. The powder which is not combined in the printing process is used as a supporting material of a printing product; the liquid formulation in the printer may contain only binders and other particulate materials, the powder bed may contain Active Pharmaceutical Ingredients (API) and other excipients; the API may also be sprayed onto the powder bed as a solution or nanoparticle suspension.
In 2015, FDA approved the first 3D printing medicine worldwide-
Figure BDA0002609618360000031
(levetiracetam fast dissolving tablet).
CN 105188849 and US 9,339,489 disclose 3D printed fast-dispersing dosage forms containing levetiracetam in different specifications, which have larger drug loading capacity compared with traditional medicines, can provide flexible dosage and can ensure that patients with dysphagia can take medicines smoothly. However, the fast-dispersing tablet prepared by the invention has rough appearance, cannot well coordinate the requirements of fast disintegration and smooth appearance of the tablet, and cannot realize the printing of the fast-dispersing tablet with better appearance, particularly the exquisite cartoon tablet.
The biggest defect of the binder-jet type 3D printing is the appearance of the product, and surface defects of the product, such as insufficient mechanical properties of tablet surface roughness, hardness, friability and the like, may occur due to the stacking of different polymers and powders, thereby affecting the medication experience of patients and even causing the difference in medication dosage due to the falling of surface powder during the storage and transportation of tablets.
Disclosure of Invention
The inventor prepares a levetiracetam 3D printing preparation through intensive research and creative work. The inventors have surprisingly found that the levetiracetam 3D printing formulation surface has significantly reduced roughness while maintaining good hardness and friability. The inventors also have obtained a process for preparing the formulation. The following invention is thus provided:
one aspect of the invention relates to a levetiracetam 3D printing formulation comprising levetiracetam, as well as fillers, disintegrants, flavoring agents, glidants, antioxidants and binders;
wherein, the levetiracetam accounts for 40 to 70 percent of the weight of the preparation; preferably 45% -65%;
preferably, the levetiracetam 3D printing formulation has a roughness characteristic value with a root mean square height (Sq) of no more than 45 μm, an arithmetic mean height (Sa) of no more than 40 μm, and a maximum height (Sz) of no more than 350 μm;
preferably, the levetiracetam 3D printing formulation has a roughness characteristic value with a root mean square height (Sq) of no more than 40 μm, an arithmetic mean height (Sa) of no more than 35 μm, and a maximum height (Sz) of no more than 320 μm;
preferably, the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing preparation is 15-45 μm, the arithmetic mean height (Sa) is 10-40 μm, and the maximum height (Sz) is 150-350 μm;
preferably, the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing preparation is 20-45 μm, the arithmetic mean height (Sa) is 15-40 μm, and the maximum height (Sz) is 180-350 μm;
preferably, the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing preparation is 15-40 μm, the arithmetic mean height (Sa) is 10-35 μm, and the maximum height (Sz) is 180-320 μm;
preferably, the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing preparation is 20-40 μm, the arithmetic mean height (Sa) is 15-35 μm, and the maximum height (Sz) is 200-320 μm;
preferably, the root mean square height (Sq) of the roughness characteristic value of the levetiracetam 3D printing preparation is 20-35 μm, the arithmetic mean height (Sa) is 15-30 μm, and the maximum height (Sz) is 200-300 μm;
preferably, the root mean square height (Sq), the arithmetic mean height (Sa) and the maximum height (Sz) are measured by a three-dimensional white light interferometer (e.g., Nexview of ZYGO, usa).
The invention also relates to a levetiracetam 3D printing preparation, which comprises levetiracetam, a filler, a disintegrating agent, a flavoring agent, a flow aid, an antioxidant and an adhesive; wherein, the levetiracetam accounts for 40 to 70 percent of the weight of the preparation; preferably 45% -65%.
In some embodiments of the invention, the levetiracetam 3D printing formulation, wherein levetiracetam is the active ingredient; preferably, levetiracetam is the only active ingredient.
In some embodiments of the invention, the levetiracetam 3D printing formulation consists of levetiracetam, a filler, a disintegrant, a flavoring agent, a glidant, an antioxidant, a binder, and a plasticizer.
In some embodiments of the invention, the levetiracetam 3D printing formulation consists of levetiracetam, a filler, a disintegrant, a flavoring agent, a glidant, an antioxidant, a binder, a plasticizer, and a pigment.
In some embodiments of the invention, the levetiracetam 3D printing formulation, wherein the levetiracetam is present in the formulation in an amount of 45% to 70%.
In some embodiments of the invention, the levetiracetam 3D printing formulation, wherein the levetiracetam is present in the formulation in an amount of 45% to 65%.
In some embodiments of the invention, the levetiracetam 3D printing formulation, wherein the levetiracetam is present in the formulation in an amount of 50% to 70%.
In some embodiments of the invention, the levetiracetam 3D printing formulation, wherein the levetiracetam is present in the formulation in an amount of 50% to 65%.
In some embodiments of the invention, the levetiracetam 3D printing formulation, wherein the levetiracetam is present in the formulation in an amount of 55% to 65%.
In some embodiments of the invention, the levetiracetam 3D printing formulation, wherein the levetiracetam is present in the formulation in an amount of 60% to 65%.
In some embodiments of the invention, the levetiracetam 3D printing formulation is characterized by any one or more of the following items (1) - (6):
(1) the filler is one or more selected from sorbitol, mannitol, lactose, calcium hydrogen phosphate and starch, preferably sorbitol or mannitol;
(2) the disintegrant is microcrystalline cellulose, preferably microcrystalline cellulose PH 101;
(3) the flavoring agent is selected from one or more of aspartame, sucralose, saccharin sodium and essence; preferably, the flavour is selected from mint flavour, strawberry flavour and cherry flavour;
(4) the glidant is one or more selected from colloidal silicon dioxide, hydrogenated vegetable oil, talcum powder, magnesium stearate and polyethylene glycol;
(5) the antioxidant is selected from one or more of L-ascorbyl palmitate (L-AP), Butyl Hydroxy Anisole (BHA) and dibutyl hydroxy toluene (BHT); and
(6) the adhesive is one or more of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose and sodium alginate; preferably povidone, more preferably povidone K30.
In some embodiments of the invention, the levetiracetam 3D printing formulation is characterized by any 1, any 2, any 3, any 4, any 5, or all 6 of items 1) to 6) as follows:
calculated as a percentage of the weight of the formulation,
1) the content of the filler is 10-60%, preferably 10-40%, 10-30%, 10-20% or 10-15%;
2) the content of the disintegrant is 10 to 30 percent, preferably 15 to 25 percent or 18 to 22 percent;
3) the content of the flavoring agent is 0.5% -5%;
4) the content of the glidant is 0.2% -2%;
5) the content of the antioxidant is 0.01-0.5%, preferably 0.01-0.05%;
6) the content of the adhesive is 0.01-2%, preferably 0.01-1%.
In some embodiments of the invention, the levetiracetam 3D printing formulation is characterized by:
calculated as a percentage of the weight of the formulation,
1) the content of the filler is 10-60%, preferably 10-40%, 10-30%, 10-20% or 10-15%;
2) the content of the disintegrant is 10 to 30 percent, preferably 15 to 25 percent or 18 to 22 percent; and
comprises a proper amount of flavoring agent, glidant and/or antioxidant.
In some embodiments of the invention, the levetiracetam 3D printing formulation comprises 2% sucralose and 0.5% peppermint flavor.
In some embodiments of the invention, the levetiracetam 3D printing formulation wherein the super disintegrant (e.g., crospovidone, sodium carboxymethyl starch, or sodium croscarmellose) is present in an amount of 0% to 4%, 0% to 3%, 0% to 2%, or 0% to 1%. Preferably, the content of the super disintegrant is 0, i.e. no super disintegrant.
In some embodiments of the invention, the levetiracetam 3D printing formulation, wherein the surfactant is present in an amount of 0% to 0.5% or 0% to 0.2%; preferably, no surfactant is present.
In some embodiments of the invention, the levetiracetam 3D printing formulation further comprises a plasticizer; preferably, it further comprises a plasticizer and a pigment;
preferably, the plasticizer is glycerol;
preferably, the plasticizer, such as glycerin, is present in an amount of 0.5% to 1.5% by weight of the formulation.
In some embodiments of the invention, the levetiracetam 3D printing formulation is characterized by:
calculated as a percentage of the weight of the formulation,
1) the content of the filler is 10-60%, preferably 10-40%, 10-30%, 10-20% or 10-15%;
2) the content of the disintegrant is 10 to 30 percent, preferably 15 to 25 percent or 18 to 22 percent;
3) the content of the pigment plasticizer is 0.5 to 1.5 percent; and
comprises a proper amount of flavoring agent, glidant, antioxidant and/or pigment.
In some embodiments of the invention, the levetiracetam 3D printing formulation further comprises a pigment; preferably, the pigment content is adjusted according to the color required by the printing model, and preferably, the total pigment dosage does not exceed 1 percent of the weight of the preparation.
In some embodiments of the invention, the levetiracetam 3D-printed formulation is a tablet, preferably a non-solid tablet.
In the present invention, the external features of the tablet are designed using computer software according to the child 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 realizes fine collocation of any color by using CMYK four primary colors and multi-channel joint supply, namely printing liquids are divided into five types, namely cyan printing liquid, magenta printing liquid, yellow printing liquid and black printing liquid and transparent printing liquid, the printing liquids with different colors are realized by adding different pigments into the printing liquids, the types of the pigments include but are not limited to erythrosine, amaranth, carmine, brilliant blue, lemon yellow and the like, and the four primary colors are prepared by blending the pigments.
In the invention, the internal structure of the tablet can be designed into a lattice structure, a hollow structure or a hollow upright post structure (as shown in fig. 3A-3C) and the like to ensure the rapid disintegration and drug release of the tablet, wherein the lattice structure means that the spraying amount of the tablet shell and the internal printing liquid is different, the spraying amount of the internal part is 30-80% of the spraying amount of the shell, the hollow structure means that the printing liquid is not sprayed in the middle part of the tablet, and the hollow upright post structure means that the printing liquid is not sprayed in the middle part of the tablet but a certain number of upright posts are supported in the tablet to ensure the mechanical property of the tablet. The tablet structure has a solid top layer and a solid bottom layer with certain thickness, the middle layer realizes the differential spraying of different parts according to the model design, but all models have solid shells.
According to the invention, 3D printing software is used for controlling the size of the tablet model, so that the flexible adjustment of the dosage is realized, researches show that the prescription and the process determined by the invention can ensure that the size of the tablet model has better linear correlation with the specification and the weight of the tablet, and the parameters determined by the researches can realize the precise spraying of the printing liquid in unit volume, so that the dosage of the medicine can be accurately predicted through the size of the tablet, and the individualized preparation of the dosage of the medicine is realized. Meanwhile, medicines with different specifications and dosages can be produced in the same batch according to production requirements, and the production cost is saved to the maximum extent.
In some embodiments of the invention, a schematic representation of a colorful cartoon and candy tablet model is shown in fig. 1A-1D.
In some embodiments of the present invention, since the final ratio of the components of the printing solution is small, the weight percentage content of each component, in particular, the active ingredient and the main adjuvant, in the preparation is about the same as or substantially the same as the weight percentage content of the active ingredient and the main adjuvant in the drug powder.
Another aspect of the invention relates to a printing fluid combination comprising a transparent printing fluid and any 1, any 2, any 3 or 4 of the printing fluids selected from the group consisting of:
cyan printing liquid, magenta printing liquid, yellow printing liquid and black printing liquid;
each printing liquid comprises 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 base solvent is at least 85% to 97%, preferably 90% to 96%, by weight of the respective printing fluid;
the adhesive is one or more selected from povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium alginate and starch; preferably povidone, more preferably povidone K30; preferably, the binder is present in an amount of not more than 5% or not more than 2%, for example 0.01% to 5%, 0.05% to 4%, 0.05% to 3%, 0.05% to 2%, 0.05% to 1%, 0.05% to 0.5%, 0.05% to 0.1%, 0.01% to 0.5%, 0.03% to 0.3%, 0.03% to 0.2% or 0.03% to 0.15% by weight of the respective printing fluid;
the plasticizer is glycerol and represents 1% to 6%, preferably 2% to 5%, for example 2%, 3%, 4% or 5% by weight of the respective printing fluid.
In some embodiments of the invention, the printing fluid is a combination, wherein,
the pigment in the cyan printing liquid is a bright blue pigment;
pigments in the magenta printing liquid are erythrosine and carmine;
the pigment in the yellow printing liquid is lemon yellow; and/or
The pigment in the black printing liquid is amaranth pigment and bright blue pigment.
In some embodiments of the invention, the printing fluid combination comprises 0% to 2% or 0% to 1% by weight of the respective printing fluid of a surfactant; preferably, no surfactant is present.
Yet another aspect of the invention relates to a method of preparing a levetiracetam 3D printing formulation according to any of the invention, said method being a binder jet type 3D printing method;
preferably, the preparation method comprises the following steps:
spreading the medicine powder on a printing platform, wherein the thickness of each powder spreading layer is 80-200 μm, preferably 90-150 μm or 100-120 μm in the printing process;
the printing nozzle finely sprays a certain amount of printing liquid drops on a specific part according to an instruction input by 3D printer control software, the Z axis of the printing platform descends by a certain height, then powder is spread again, printing is carried out again, and the process is repeated until printing is finished;
preferably, the printing fluid is selected from the printing fluid combinations described in any one of the present invention;
preferably, the method further comprises the steps of drying and packaging the finished printed preparation.
In some embodiments of the invention, the method of making, wherein,
the line spacing is 0.4cm-0.6cm, preferably 0.5 cm; and
the column pitch is 0.4cm to 0.6cm, preferably 0.5 cm.
In some embodiments of the invention, the method of making, wherein,
the print head ejection mechanism is piezoelectric;
the unit ink drop ejection volume is 5pL-40 pL; preferably 6pL-30 pL; more preferably, the volumes of the large, medium 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, and more preferably 0.4 g/min.
In some embodiments of the invention, the method of making, wherein,
the jet mechanism of the printing head is a thermal bubble type;
the unit ink drop ejection volume is 15pL-25pL, preferably 18 pL;
the spraying speed is 0.3g/min-0.8g/min, preferably 0.4g/min-0.6g/min, and more preferably 0.5 g/min.
In some embodiments of the present invention, the particle size of the drug powder is 30 μm to 150 μm, preferably 60 μm to 120 μm.
In some embodiments of the invention, a preparation method of levetiracetam cartoon dispersible tablets based on full-color binder-jet 3D printing technology is provided. Aiming at the problems commonly existing in a binder jet type 3D printing preparation, the 3D printing tablet is ensured to have smooth appearance, strong mechanical property and fast dispersion characteristic by the synergistic adjustment of the binder concentration of a printing liquid, the jet volume of unit ink drop, the thickness of a powder laying layer and the particle size of a key material, and the prior art is obviously improved. Meanwhile, in order to solve the problem of compliance of children in medication, the invention uses the color ink-jet technology to develop the levetiracetam colorful cartoon preparation suitable for children. Through flexible model design and printing mode, not only can manufacture the medicine with accurate dosage and rapid medicine release, but also can manufacture tablets with different colors and shapes according to the favor of children, thereby realizing the individual administration of the children preparation and obviously improving the compliance of the children medicine administration.
The levetiracetam cartoon dispersible tablet can be completely dispersed in small-mouth water or other fluids, such as milk, fruit juice and the like, within 10-20 seconds.
The preparation formulation uses a binder jet type 3D printing technology, a required product is prepared according to the principles of layered manufacturing and layer-by-layer superposition, the preparation of the levetiracetam colorful cartoon dispersible tablet with high drug loading rate, which is difficult to complete by the traditional process, is realized, and the invention is also suitable for other drugs with higher drug dosage and needing quick effect.
The dosage form provided by the invention is designed according to a computer model according to requirements, a printer sprays printing liquid on the surface of medicine powder with a certain thickness according to instructions, and the powder spreading and spraying processes are repeated until the required preparation is obtained.
The invention uses the 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 the jet holes of a single printing head is 300-3000, and the unit ink drop jet volume is 15-50 pL.
The inventors have found that a reduction in the thickness of the powder layer can increase the print fineness of the tablet surface. The number of spray layers is determined by the tablet size and the tablet model size, and is usually 30-100 layers.
The inventor also finds that the particle size of partial auxiliary materials is slightly larger than the thickness of the powder laying layer, so that the flatness of the powder layer and the whole powder laying effect are not influenced.
In the invention, the column spacing and the line spacing of the printing and typesetting of the preparation are 0.2-1.0cm and 0.2-0.5cm, and researches show that the larger the size of the tablet is, the larger the column spacing and the line spacing are required to avoid the mutual influence between the tablets caused by the penetration of ink drops.
In some embodiments of the invention, a flow chart for a binder-jetting 3D printing technique for preparing a multicolored cartoon dispersible tablet is shown in fig. 2.
In the invention, the printed tablets are dried and collected after powder removal, and the drying temperature is set to be 30-50 ℃, preferably 35-45 ℃. The vacuum material sucking system is used for recycling redundant powder materials, the powder serves as a supporting material to play an important supporting role in the tablet printing process, and researches show that the antioxidant is added into the powder materials to contribute to the stability and the reutilization of the powder. Yet another aspect of the invention relates to a levetiracetam 3D printing formulation, made by the method of preparation described in any of the present inventions.
In the present invention,
the term "unit drop ejection volume" refers to the volume of a single drop formed after ejection of a printing fluid from an orifice on a printhead, and the drop size generally affects the fineness of the final product.
The term "ejection speed of the printing liquid" refers to the mass of the printing liquid ejected from the print head per unit time, which is expressed in g/min, and refers to only the liquid ejection time, excluding the powder spreading time and the roll homing time.
The term "powder spreading layer thickness" refers to the layer spreading thickness of each layer of medicine powder in the printing process, namely, after each layer is printed, the Z axis descends for a certain distance, and the powder spreading roller spreads the powder with a certain thickness.
In the present invention, "about" means, if not specifically stated, a fluctuation in the range of 20% of the modified numerical value or physical quantity, for example, about 100 minutes, which means 80 minutes to 120 minutes.
In the present invention, the content (including but not limited to the content of levetiracetam as an active ingredient or an auxiliary material) is calculated by percentage based on the weight of the preparation if not specifically stated.
Advantageous effects of the invention
The present invention achieves any one or more of the following technical effects (1) to (5):
(1) the preparation has a relatively smooth surface, so that the roughness is obviously reduced, and the difference of the dosage caused by the falling of powder on the surface of the preparation in the storage and transportation processes is reduced; the medication experience of patients is improved; the medication compliance of children is remarkably improved;
(2) good hardness and friability are maintained;
(3) the rapid disintegration in a small amount of liquid is realized through the design of the internal structure, and the problem of dysphagia of children is solved;
(4) the size of the model has good linear correlation with the dosage, the flexible adjustment of the dosage can be realized, and the requirement of individuation of the dosage for children is met;
(5) the cartoon appearance that children like can be set, and the children can accept the cartoon appearance more easily.
Drawings
Fig. 1A to fig. 1D: schematic diagrams of colorful cartoon and candy tablet models.
FIG. 2: a flow chart of a binder jetting type 3D printing technology for preparing the multicolor cartoon dispersible tablet.
Fig. 3A-3C: sectional schematic diagram of tablet model with different internal space structures. Wherein, fig. 3A, a lattice structure; FIG. 3B, a hollow structure; 3C, hollow upright column structure.
Fig. 4A-4C: dose model schematic. Wherein, FIG. 4A is a side view; FIG. 4B is a three-dimensional sectional view; fig. 4C top view.
FIG. 5: personalized dosing models. The abscissa in the figure is the computer designed model volume and the ordinate is the actual printed tablet specification.
Fig. 6A to 6D: surface roughness 3D topography. FIG. 6A: the formulation of the invention (250 mg); FIG. 6B:
Figure BDA0002609618360000133
(250 mg); FIG. 6C: the formulation of the invention (1000 mg); FIG. 6D:
Figure BDA0002609618360000134
(1000mg)。
fig. 7A-7L: SEM tablet microstructure. Wherein, FIGS. 7A-7F are 1000mg specifications; FIGS. 7G-7L are 250mg format. Wherein:
FIG. 7A: shell upper surface-50 x; FIG. 7B: housing upper surface-300 x;
FIG. 7C: shell side-50 x; FIG. 7D: housing side-300 x;
FIG. 7E: interior hollow region-50 x; FIG. 7F: inner hollow area-300 x
FIG. 7G: shell upper surface-50 x; FIG. 7H: housing upper surface-300 x;
FIG. 7I: shell side-50 x; FIG. 7J: housing side-300 x;
FIG. 7K: interior hollow region-50 x; FIG. 7L: the interior hollow region-300 x.
FIG. 8: and (3) detecting the result by an X-ray powder diffractometer (XRD). Wherein the meaning of API is raw material; LEV tablets means levetiracetam tablets; the meaning of Excipients is that the Excipients are present with an abscissa of 2 theta angle.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Preparation example 1: preparation of samples 1-1, 1-2, 1-3, and 1-4
1. Preparation of pharmaceutical powder
Levetiracetam is crushed and sieved by a 120-mesh sieve, colloidal silicon dioxide is sieved by a 40-mesh sieve, and other auxiliary materials are sieved by a 120-mesh sieve. Adding the raw materials and the auxiliary materials into a hopper mixer, setting the rotating speed to be 20rpm, and mixing for 20min to ensure that the medicine powder is uniformly mixed. The medicine powder material comprises the following components:
Figure BDA0002609618360000141
2. preparation of printing liquid
A50% ethanol solution (v/v) was used as a base solvent.
The printing liquids had the following composition:
(1) transparent printing liquid:
50% ethanol solution 95.95% (w/w)
Povidone K300.05% (w/w)
Glycerol 4% (w/w)
(2) Cyan printing liquid (C):
Figure BDA0002609618360000142
Figure BDA0002609618360000151
(3) magenta printing liquid (M):
Figure BDA0002609618360000152
(4) yellow printing liquid (Y):
Figure BDA0002609618360000153
(5) black printing liquid (K):
Figure BDA0002609618360000154
3. model design
A model file is created by using computer aided design software 3D Sprint (3D systems, USA), a circular tablet or a tablet model which is liked by children and has different colors and shapes is firstly designed, a three-dimensional model is generated by using a 'generating geometric shape function', and the size of the model is adjusted in three axial directions according to the reality. The establishment of the special-shaped model usually uses the functions of 'segmentation' and 'Boolean operation', the segmentation function can cut out the required shape, and the Boolean operation function can fit a plurality of models with different shapes into an integral model. And coloring the model after the model is built, so that the color of the model is increased. Designing levetiracetam dispersible tablets with different doses according to requirements and calculating the size data of the tablets, wherein the model file is in a single color (STL format) or a color (PLY format). The preparation example designs 250mg and 1000mg standard round tablets respectively, wherein the diameter of the 250mg standard tablet is 11.50mm, the thickness of the tablet is 5.18mm, and the volume is 0.537cm3(ii) a The 1000mg size tablet has a diameter of 18.50mm, a thickness of 8.33mm, and a volume of 2.24cm3. Two colorful cartoon models (model patterns are shown in figure 1B and figure 1D) are designed in the preparation example, and are both 1000mg in specification, wherein the long diameter of each small bear tablet is 19.20mm, and the thickness of each tablet is 8.28 mm; the diameter of the candy tablet is 18.50mm, and the thickness of the tablet is 8.33 mm.
4. Tablet printing
Transmitting the model data to 3D printer control software, setting the printing quantity and typesetting, wherein the printing parameters are set as follows:
Figure RE-GDA0002654590260000011
firstly, medicine powder with a certain thickness is spread on a printing platform to serve as a support at the bottom of a printing model and simultaneously ensure that a single powder layer can be uniformly spread in the printing process, and the thickness of the powder layer is 2-5 mm. And in the printing process, the thickness of each powder spreading layer is 100 micrometers, the printing spray head finely sprays a certain amount of liquid drops on a specific part according to an instruction input by 3D printer control software, the Z axis of the printing platform descends by a certain height, then the powder is spread again, the printing is carried out again, and the process is repeated until a required model is formed. The printing of the color cartoon model realizes the combination of CMYK four primary colors and the spraying of color patterns through different printing heads, wherein the color patterns are only sprayed on the surface of the shell of the model, and the spraying inside the model is completely finished by using transparent printing liquid.
5. Drying and working up
And drying the tablets after printing, setting the drying temperature to be 40 ℃, maintaining for 120min, and controlling the drying weight loss to be lower than 2%. And after drying, recovering the redundant drug powder by using a vacuum suction system, and removing the powder attached to the surface of the tablet.
6. Package (I)
The tablets were packaged using an aluminium-plastic blister.
Samples 1-1, 1-2, 1-3, and 1-4 were prepared:
sample 1-1: 250mg size round tablets; samples 1 to 2: 1000mg size round tablets; samples 1 to 3: 1000mg size small bear tablets; samples 1 to 4: 1000mg size candy tablets.
Preparation example 2: preparation of sample 2-1, sample 2-2, sample 2-3, and sample 2-4
1. Preparation of pharmaceutical powder
Levetiracetam is crushed and sieved by a 120-mesh sieve, colloidal silicon dioxide is sieved by a 40-mesh sieve, and other auxiliary materials are sieved by a 120-mesh sieve. Adding the raw materials and the auxiliary materials into a hopper mixer, setting the rotating speed to be 20rpm, and mixing for 20min to ensure that the medicine powder is uniformly mixed. The medicine powder material comprises the following components:
Figure BDA0002609618360000171
2. preparation of printing liquid
A40% isopropanol solution (v/v) was used as the base solvent.
The printing liquids had the following composition:
(1) transparent printing liquid:
40% isopropanol solution 95.9% (w/w)
Povidone K300.1% (w/w)
Glycerol 4% (w/w)
(2) Cyan printing liquid (C):
Figure BDA0002609618360000172
Figure BDA0002609618360000181
(3) magenta printing liquid (M):
Figure BDA0002609618360000182
(4) yellow printing liquid (Y):
Figure BDA0002609618360000183
(5) black printing liquid (K):
Figure BDA0002609618360000184
3. model design
Reference is made to preparation example 1 above.
4. Tablet printing
Transmitting the model data to 3D printer control software, setting the printing quantity and typesetting, wherein the printing parameters are set as follows:
Figure BDA0002609618360000185
Figure BDA0002609618360000191
firstly, medicine powder with a certain thickness is spread on a printing platform to serve as a support at the bottom of a printing model and simultaneously ensure that a single powder layer can be uniformly spread in the printing process, and the thickness of the powder layer is 2-5 mm. And in the printing process, the thickness of each powder spreading layer is 100 micrometers, the printing nozzle finely sprays a certain amount of liquid drops on a specific part according to an instruction input by 3D printer control software, the Z axis of the printing platform descends by a certain height, then the powder is spread again, the printing is carried out again, and the process is repeated until a required model is formed.
5. Drying and working up
And drying the tablets after printing, setting the drying temperature to be 40 ℃, maintaining for 120min, and controlling the drying weight loss to be lower than 2%. And after drying, recovering the redundant drug powder by using a vacuum suction system, and removing the powder attached to the surface of the tablet.
6. Package (I)
The tablets were packaged using an aluminium-plastic blister.
Samples 2-1, 2-2, 2-3, and 2-4 were prepared:
sample 2-1: 250mg size round tablets; sample 2-2: 1000mg size round tablets; samples 2 to 3: 1000mg size small bear tablets; samples 2 to 4: 1000mg size candy tablets.
Preparation example 3: preparation of sample 3-1, sample 3-2, sample 3-3, and sample 3-4
1. Preparation of pharmaceutical powder
The same as in preparation example 2.
2. Preparation of printing liquid
The same as in preparation example 2.
3. Model design
The same as in preparation example 1.
4. Tablet printing
Transmitting the model data to 3D printer control software, setting the printing quantity and typesetting, wherein the printing parameters are set as follows:
Figure BDA0002609618360000192
Figure BDA0002609618360000201
firstly, medicine powder with a certain thickness is spread on a printing platform to serve as a support at the bottom of a printing model and simultaneously ensure that a single powder layer can be uniformly spread in the printing process, and the thickness of the powder layer is 2-5 mm. And in the printing process, the thickness of each powder spreading layer is 150 micrometers, the printing nozzle finely sprays a certain amount of liquid drops on a specific part according to an instruction input by 3D printer control software, the Z axis of the printing platform descends by a certain height, then the powder is spread again, the printing is carried out again, and the process is repeated until a required model is formed.
5. Drying and working up
And drying the tablets after printing, setting the drying temperature to be 40 ℃, maintaining for 120min, and controlling the drying weight loss to be lower than 2%. And after drying, recovering the redundant drug powder by using a vacuum suction system, and removing the powder attached to the surface of the tablet.
6. Package (I)
The tablets were packaged using an aluminium-plastic blister.
Samples 3-1, 3-2, 3-3, and 3-4 were prepared:
sample 3-1: 250mg size round tablets; sample 3-2: 1000mg size round tablets; sample 3-3: 1000mg size small bear tablets; samples 3 to 4: 1000mg size candy tablets.
Preparation example 4: preparation of sample 4-1, sample 4-2 and sample 4-3
The samples obtained in preparation examples 1 to 3 were all solid tablets. The inventor adjusts the internal structure of the model on the basis of the preparation example 2 (except that the internal space structure is different, the powder, the printing liquid and the preparation method are completely the same as the 1000mg standard sample of the preparation example 2) to further accelerate the dispersion time of the tablet in the liquid.
The following are three model structure designs (as shown in fig. 3A-3C) in this experiment, the three tablet models are different from each other in the inside and the outside, and the tablet printing process is divided into three parts for printing, namely a tablet bottom layer, a tablet middle layer and a tablet top layer. Wherein the bottom layer and the top layer are both solid layers, and the printing saturation is 100% so as to maintain the overall mechanical properties of the tablet; the middle layer is used for carrying out fine spraying on each printing area according to the structural design of the model, the shell has 100% of printing saturation, the inner layer has a special structure, and the printing saturation is low, so that the aim of rapid disintegration and drug release is fulfilled.
(1) And the dot matrix structure model (figure 3A) realizes the difference of the printing saturation of the inner part and the shell of the tablet through the adjustment of the structure of the inner model, the printing saturation of the shell is 100 percent, and the printing saturation of the inner part of the tablet is flexibly adjustable. In this experiment, the tablet had an internal print saturation of 50% and the shell size was one-fourth of the tablet size, requiring adjustment to the tablet size. In the experiment, the diameter of a 1000mg standard tablet is 18.50mm, the thickness of the tablet is 8.33mm, the wall thickness of the upper surface and the lower surface of a tablet shell are both 2.08mm, and the wall thickness of the outer side surface of the tablet shell is 4.63 mm.
(2) And (3B) a hollow structure model (figure 3B), wherein the printing liquid is not sprayed in the structure, and the printing liquid is sprayed only on the shell part, namely the printing saturation of the tablet shell is 100%, and the printing saturation of the hollow part in the structure is 0%. The shell size is one fourth of the tablet size and needs to be adjusted according to the tablet size. In the experiment, the diameter of a 1000mg standard tablet is 18.50mm, the thickness of the tablet is 8.33mm, the wall thickness of the upper surface and the lower surface of a tablet shell are both 2.08mm, and the wall thickness of the outer side surface of the tablet shell is 4.63 mm.
(3) Hollow column structural model (fig. 3C): on the basis of the hollow structure model, 3 support columns are additionally arranged at the hollow part of the structure and are distributed in a triangular shape; meanwhile, the area of the shell interior 1/2 of the hollow structure model is adjusted to be a hollow structure, and 6 supporting columns are added to surround the hollow structure in a circular ring shape.
The samples prepared in the above (1), (2) and (3) were designated as sample 4-1, sample 4-2 and sample 4-3, respectively.
Preparation example 5: preparation of sample 5-1, sample 5-2, sample 5-3, sample 5-4, and sample 5-5
The 3D printing technology can realize flexible adjustment of the drug dose through the design of the model size, but has a high requirement on the matching degree of the printing liquid and the drug powder (the applicability of the printing liquid and the drug powder, namely whether a high-precision tablet can be printed or not), and the requirement on the printing precision must be met. The inventors examined the linear relationship between the model size design and the tablet specification using the hollow structure model of preparation example 4, and established the correlation between the model size and the dose. The 3D Sprint is used for establishing tablet models with different sizes, the designed theoretical doses are respectively 160mg, 250mg, 500mg, 750mg and 1000mg, corresponding dose model schematic diagrams are shown in figures 4A-4C, tablets with different sizes are respectively printed by using the prescription and the process in the preparation example 2, and a sample 5-1, a sample 5-2, a sample 5-3, a sample 5-4 and a sample 5-5 are obtained, wherein the specifications are respectively 160mg, 250mg, 500mg, 750mg and 1000mg in sequence.
And measuring the content and specification of each size of tablet, taking the volume of the tablet model as an X axis, and actually measuring the specification of the tablet as a Y axis, and establishing the correlation between the model size and the dosage. The results of the experiment are shown in FIG. 5. The results show that the linear relation between the model volume and the tablet specification is better, and r is 0.999, so that the drug dosage can be flexibly adjusted through model size design.
Experimental example 1: testing mechanical properties of tablets
(1) Tablet appearance and surface roughness
Experimental samples:
samples 1 to 3(1000mg) and samples 1 to 4(1000mg) obtained in the foregoing production example 1, samples 2 to 3(1000mg) and samples 2 to 4(1000mg) obtained in production example 2, samples 3 to 3(1000mg) and 3 to 4(1000mg) obtained in production example 3, and samples 5 to 2(250mg) and samples 5 to 5(1000mg) obtained in production example 5.
Figure BDA0002609618360000223
(250mg) and
Figure BDA0002609618360000224
(1000mg) was obtained commercially.
The appearance of the tablet is observed visually, and the tablet is complete, smooth and free of interlayer displacement and projections or depressions outside the design of the model; the colorful cartoon tablet has beautiful appearance and uniform color; the appearance of the tablets in the above preparation examples can meet the requirements.
The surface roughness of the samples was tested using a three-dimensional white light interferometric topographer (Nexview, ZYGO, usa), a 2.75x objective lens, and a 1x eyepiece lens, and surface roughness characterization parameters such as root mean square height (Sq), arithmetic mean height (Sa), and maximum height (Sz), where Sz is the sum of Sp (maximum peak height) and Sv (maximum valley depth) were evaluated. The surface roughness analysis of the tablets in the above preparation examples was performed separately, and simultaneously with the 3D printed product on the market in the United states
Figure BDA0002609618360000225
The comparison between the specification of 250mg and the specification of 1000mg shows that the preparation of the invention has the typical value Sq of 20-35 μm, Sa of 15-30 μm, Sz of 200-300 μm,
Figure BDA0002609618360000231
sq is 60-80 μm, Sa is 50-70 μm, Sz is 350-500 μm, the preparation of the invention is obviously superior to
Figure BDA0002609618360000232
. Meanwhile, it can be seen from the 3D topography (see FIG. 6) (as in preparation example 5, samples 5-2 and 5-5 and
Figure BDA0002609618360000233
for example), the surface roughness of the inventive formulation is significantly better than that of the inventive formulation
Figure BDA0002609618360000234
Solving the problem of poor surface roughness common to binder-jetting type 3D printing preparations, an
Figure BDA0002609618360000235
Compared with the prior art, the method has obvious improvement.
(2) Hardness and friability
The hardness and friability of the product were measured using a tablet friability tester (model CJY-2C, Shanghai Huanghai pharmaceutical testing Instrument Co., Ltd.). And 6 pieces of each sample are respectively measured by using a measuring instrument during the hardness measurement, and the average value is calculated to be the average hardness. Friability measurement A tablet of not less than 6.5g (at least 10 pieces) was dusted and rotated at 25rpm for 4 minutes without breaking or crushing.
Hardness and friability measurements were performed on the tablets of different sizes in preparation examples 1-5, wherein the hardness of 1000mg size tablets was 50-80N, the hardness of 750mg tablets was 40-70N, the hardness of 500mg tablets was 35-65N, the hardness of 250mg size tablets was 25-50N, and the hardness of 160mg size tablets was 8-20N.
Tablets of different specifications in preparation examples 1 to 5 and
Figure BDA0002609618360000236
the fracture or crushing phenomenon does not occur in the brittle degree measurement.
In addition, measure
Figure BDA0002609618360000237
The hardness of the 1000mg standard tablet is 40-70N, the hardness of the 750mg standard tablet is 30-60N, the hardness of the 500mg standard tablet is 20-40N, and the hardness of the 250mg standard tablet is 10-30N.
The above results demonstrate, with
Figure BDA0002609618360000238
In contrast, the formulations of the present invention have higher hardness and comparable friability while reducing surface roughness.
Experimental example 2: tablet microstructure
The morphology of the printed tablets was studied using a high resolution thermal field emission scanning electron microscope. The microstructures of 250mg size sample (sample 5-2) and 1000mg size sample (sample 5-5) in preparation example 5 were observed at magnifications of 50x and 300x, respectively, after plating a conductive layer on the surface of the sample using a vacuum evaporator and then adjusting the accelerating voltage to 5.0 kV.
Through SEM observation (fig. 7A-7L), the surfaces of the shells of the tablets with the 250mg specification and the tablets with the 1000mg specification have more pores, but the overall structure is compact, the surfaces are smooth, the better appearance and mechanical property of the tablets can be ensured, meanwhile, the rapid penetration of moisture is facilitated, so that the tablets can be rapidly disintegrated, the hollow areas in the tablets are not bonded and are uniform powder and porous, and the moisture can be rapidly released after being penetrated through the external pores and being contacted with the powder.
Experimental example 3: analysis of crystal form
The crystal form of the 1000mg size levetiracetam dispersible tablet (sample 5-5) in preparation example 5 was monitored using an X-ray powder diffractometer (XRD), and the crystal form change of levetiracetam before and after 3D printing was observed while comparing with the crystal forms of levetiracetam (API) and Excipients (Excipients).
The XRD detection result is shown in figure 8, and the result shows that the levetiracetam crystal form in the levetiracetam dispersible tablets (LEV tables) is the same as that of the raw material (API) and does not change, which indicates that the levetiracetam crystal form does not change in the tablet printing process.
Experimental example 4: determination of content
The content determination method comprises the following steps: high Performance Liquid Chromatography (HPLC).
A chromatographic column: and (3) a reversed phase chromatographic column with octyl silane bonded silica gel as a filling agent.
Mobile phase: acetonitrile: the buffer solution is 10:90, wherein the buffer solution is 1.4g/L anhydrous.
Aqueous disodium hydrogen phosphate solution, adjusted to ph3.5 with phosphoric acid.
Detection wavelength: 205 nm.
Flow rate: 1.5 ml/min.
Column temperature: at 30 ℃.
The quantitative method comprises the following steps: and (4) an external standard method.
The results show that the content of each standard tablet in the above preparation examples 1 to 5 is in the range of 95 to 105% of the designed dosage, and the requirement of the Chinese pharmacopoeia (2015 edition) on the content of the tablet is met.
Experimental example 5: uniformity of dispersion and drug release
(1) Measurement of Dispersion uniformity
According to the chinese pharmacopoeia (2015 edition) dispersion uniformity determination method, the tablet dispersion uniformity was determined using an intelligent disintegration apparatus. The stainless steel wire net of the measuring apparatus has an inner diameter of 710 μm and is measured at 15 to 25 ℃ with purified water (usually 20 ℃) at 6 pieces each time. The results showed that the printed tablets in preparation examples 1 to 5 above all had a dispersion uniformity in the range of 15. + -.5 s, and were rapidly dispersible in a liquid.
(2) Dissolution determination
The dissolution curve of the tablets was measured by using a dissolution apparatus according to the dissolution method II of Chinese pharmacopoeia (2015 edition), 6 tablets were measured each time, and the measurement parameters are shown in Table 1 below.
TABLE 1
Figure BDA0002609618360000251
The results show that the dissolution rates of the printed tablets in the preparation examples 1 to 5 in four dissolution media within 2.5min are all more than 80%, and extremely rapid drug release can be realized.
Experimental example 6: evaluation of mouthfeel
The taste evaluation is a key ring in the compliance evaluation of the children preparation, an ASTREE electronic tongue of French Alpha MOS company is used, and based on the principle of potential measurement, objective analysis on the taste quality of a sample to be tested (the dosages of sucralose and mint essence are 0.5%/0.5%, 0.5%/0.2%, 2%/0.5%, 1%/0.2%, 0.5%/0.3%, 2%/0.3%, 1%/0.5%, and 1%/0.3%, respectively) is realized, and the optimal flavoring agent dosage is 2% of sucralose and 0.5% of mint essence through prescription screening.
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (93)

1. A levetiracetam 3D printing preparation comprises levetiracetam, a filler, a disintegrant, a flavoring agent, a glidant, an antioxidant and an adhesive;
wherein, the levetiracetam accounts for 40 to 70 percent of the weight of the preparation; the content of the adhesive is 0.01% -2%;
wherein the levetiracetam 3D printing formulation has a roughness characteristic value having a root mean square height of no more than 45 μm, an arithmetic mean height of no more than 40 μm, and a maximum height of no more than 350 μm;
the levetiracetam 3D printing preparation is prepared by a binder jet type 3D printing method, and the method comprises the following steps:
spreading the medicine powder on a printing platform, wherein the thickness of each powder spreading layer is 80-200 μm in the printing process; the grain diameter of the medicine powder is 30-150 μm;
the printing nozzle finely sprays a certain amount of printing liquid drops on a specific part according to an instruction input by 3D printer control software, the Z axis of the printing platform descends by a certain height, then powder is spread again, printing is carried out again, and the process is repeated until printing is finished;
the print head ejection mechanism is piezoelectric; the unit ink drop ejection volume is 5pL-40 pL; the spraying speed is 0.2g/min-0.8 g/min;
or the jet mechanism of the printing head is a thermal bubble type; the unit ink drop ejection volume is 15pL-20 pL; the spraying speed is 0.3g/min to 0.8 g/min;
the printing liquid is selected from the following printing liquid combinations:
a printing fluid combination comprising a transparent printing fluid and optionally 1, 2, 3 or 4 printing fluids selected from:
cyan printing liquid, magenta printing liquid, yellow printing liquid and black printing liquid;
each printing liquid comprises 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 of the organic solvent in the basic solvent accounts for 35 to 55 percent;
the adhesive is one or more selected from povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium alginate and starch; wherein, the content of the adhesive is 0.01 to 0.5 percent of the weight of the corresponding printing liquid;
the plasticizer is glycerol and accounts for 1-6% of the weight of the corresponding printing liquid.
2. The levetiracetam 3D printing formulation according to claim 1, wherein the levetiracetam is present in an amount of 45-65%.
3. The levetiracetam 3D printing formulation according to claim 1, wherein the roughness characteristics of the levetiracetam 3D printing formulation have a root mean square height of no more than 40 μ ι η, an arithmetic mean height of no more than 35 μ ι η, and a maximum height of no more than 320 μ ι η.
4. The levetiracetam 3D-printing formulation according to claim 1, wherein the roughness characteristics of the levetiracetam 3D-printing formulation have a root mean square height of 20-40 μ ι η, an arithmetic mean height of 15-35 μ ι η, and a maximum height of 200-320 μ ι η.
5. The levetiracetam 3D-printing formulation according to claim 1, wherein the roughness characteristics of the levetiracetam 3D-printing formulation have a root mean square height of 20-35 μ ι η, an arithmetic mean height of 15-30 μ ι η, and a maximum height of 200-300 μ ι η.
6. The levetiracetam 3D printing formulation according to any one of claims 1 to 5, wherein the root mean square height, arithmetic mean height and maximum height are measured by a three-dimensional white light interferometric topographer.
7. The levetiracetam 3D printing formulation of claim 6, wherein the three-dimensional white light interferometer is Nexview, ZYGO, usa.
8. The levetiracetam 3D printing formulation according to claim 1, wherein the powder layer is 90-150 μ ι η thick.
9. The levetiracetam 3D printing formulation according to claim 1, wherein the powder layer is 100-120 μ ι η thick.
10. The levetiracetam 3D printing formulation of claim 1, wherein the drug powder has a particle size of 60-120 μ ι η.
11. The levetiracetam 3D printing formulation of claim 1, wherein for a printhead ejection mechanism of piezoelectric type, the unit drop ejection volume is 6pL-30 pL.
12. The levetiracetam 3D printing formulation of claim 1, wherein for the case where the printhead ejection mechanism is piezoelectric, the volumes of large, medium, and small drops are 30pL, 15pL, and 6pL, respectively.
13. The levetiracetam 3D printing formulation of claim 1, wherein for printhead ejection mechanisms that are piezoelectric, the jet velocity is between 0.3g/min and 0.5 g/min.
14. The levetiracetam 3D printing formulation of claim 1, wherein for a printhead ejection mechanism that is piezoelectric, the jet velocity is 0.4 g/min.
15. The levetiracetam 3D printing formulation of claim 1, wherein for a printhead ejection mechanism that is hot-bubble, the unit drop ejection volume is 18 pL.
16. The levetiracetam 3D printing formulation of claim 1, wherein for a printhead ejection mechanism that is hot-bubble, the jet velocity is between 0.4g/min and 0.6 g/min.
17. The levetiracetam 3D printing formulation of claim 1, wherein the jet velocity is 0.5g/min for the case where the printhead ejection mechanism is hot bubble.
18. The levetiracetam 3D-printing formulation according to claim 1, wherein the organic solvent is present in the base solvent in a proportion of 40% to 50% by volume.
19. The levetiracetam 3D printing formulation according to claim 1, wherein the base solvent is present in an amount of at least 85% -97% by weight of the respective printing fluid.
20. The levetiracetam 3D printing formulation according to claim 1, wherein the base solvent is present in an amount of 90-96% by weight of the respective printing fluid.
21. The levetiracetam 3D printing formulation of claim 1, wherein the binder is povidone.
22. The levetiracetam 3D printing formulation of claim 1, wherein the binder is povidone K30.
23. The levetiracetam 3D printing formulation of claim 1, wherein the binder is present in an amount of 0.05% -0.5% by weight of the respective printing fluid.
24. The levetiracetam 3D printing formulation of claim 1, wherein the binder is present in an amount of 0.05% -0.1% by weight of the respective printing fluid.
25. The levetiracetam 3D printing formulation according to claim 1, wherein the binder is present in an amount of 0.03-0.3% by weight of the respective printing fluid.
26. The levetiracetam 3D printing formulation according to claim 1, wherein the binder is present in an amount of 0.03-0.2% by weight of the respective printing fluid.
27. The levetiracetam 3D printing formulation according to claim 1, wherein the binder is present in an amount of 0.03-0.15% by weight of the respective printing fluid.
28. The levetiracetam 3D printing formulation according to claim 1, wherein glycerol represents 2-5% of the weight of the respective printing fluid.
29. The levetiracetam 3D printing formulation of claim 1, wherein,
the pigment in the cyan printing liquid is a bright blue pigment;
pigments in the magenta printing liquid are erythrosine and carmine;
the pigment in the yellow printing liquid is lemon yellow; and/or
The pigment in the black printing liquid is amaranth pigment and bright blue pigment.
30. The levetiracetam 3D printing formulation according to claim 1, wherein the surfactant is present in an amount of 0-2% by weight of the respective printing fluid.
31. The levetiracetam 3D printing formulation according to claim 1, wherein the surfactant is present in an amount of 0-1% by weight of the respective printing fluid.
32. The levetiracetam 3D printing formulation of claim 1, wherein the printing fluid combination is surfactant free.
33. The levetiracetam 3D-printed formulation according to claim 1, wherein the process further comprises the step of drying and packaging the formulation resulting from the printing.
34. The levetiracetam 3D printing formulation of claim 1, wherein,
the line spacing is 0.4cm-0.6 cm; and
the row spacing is 0.4cm-0.6 cm.
35. The levetiracetam 3D printing formulation of claim 34, wherein the row spacing is 0.5 cm.
36. The levetiracetam 3D printing formulation of claim 34, wherein the column-to-column spacing is 0.5 cm.
37. A levetiracetam 3D printing formulation according to claim 1, characterized by any one or more of the following items (1) - (6):
(1) the filler is one or more selected from sorbitol, mannitol, lactose, calcium hydrogen phosphate and starch;
(2) the disintegrant is microcrystalline cellulose;
(3) the flavoring agent is selected from one or more of aspartame, sucralose, saccharin sodium and essence;
(4) the glidant is one or more selected from colloidal silicon dioxide, hydrogenated vegetable oil, talcum powder, magnesium stearate and polyethylene glycol;
(5) the antioxidant is selected from one or more of L-ascorbyl palmitate, butyl hydroxy anisol and dibutyl hydroxy toluene; and
(6) the adhesive is one or more of polyvidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose and sodium alginate.
38. The levetiracetam 3D printing formulation of claim 37, wherein, in item (1), the filler is sorbitol or mannitol.
39. The levetiracetam 3D printing formulation of claim 37, wherein, in item (2), the disintegrant is microcrystalline cellulose PH 101.
40. The levetiracetam 3D-printing formulation according to claim 37, wherein, in item (3), the essence is selected from mint essence, strawberry essence, and cherry essence.
41. The levetiracetam 3D-printing formulation according to claim 37, wherein, in item (6), the binder is povidone.
42. The levetiracetam 3D-printing formulation according to claim 37, wherein, in item (6), the binder is povidone K30.
43. A levetiracetam 3D printing formulation according to claim 1, characterized by any one or more of the following 1) -5):
calculated as a percentage of the weight of the formulation,
1) the content of the filler is 10% -60%;
2) the content of the disintegrating agent is 10% -30%;
3) the content of the flavoring agent is 0.5% -5%;
4) the content of the glidant is 0.2% -2%;
5) the content of the antioxidant is 0.01-0.5%.
44. The levetiracetam 3D printing formulation according to claim 43, wherein in item 1), the filler is present in an amount of 10-20%.
45. The levetiracetam 3D printing formulation according to claim 43, wherein in item 2) the disintegrant is present in an amount of 15-25%.
46. The levetiracetam 3D-printing formulation according to claim 43, wherein in item 5), the antioxidant is present in an amount of 0.01% -0.05%.
47. The levetiracetam 3D printing formulation of claim 1, wherein the binder is present in an amount of 0.01% -1%.
48. The levetiracetam 3D printing formulation according to claim 1, wherein the content of super disintegrant is between 0% and 4%.
49. The levetiracetam 3D printing formulation of claim 48, wherein the super disintegrant is crospovidone, sodium carboxymethyl starch, or croscarmellose sodium.
50. The levetiracetam 3D printing formulation according to claim 48 or 49, wherein the content of super disintegrant is between 0% and 3%.
51. The levetiracetam 3D printing formulation according to claim 48 or 49, wherein the content of super disintegrant is between 0% and 2%.
52. The levetiracetam 3D printing formulation according to claim 48 or 49, wherein the content of super disintegrant is between 0% and 1%.
53. The levetiracetam 3D printing formulation according to claim 48 or 49, wherein super disintegrant is absent.
54. The levetiracetam 3D printing formulation according to claim 1, wherein the surfactant is present in an amount of 0% to 2%.
55. The levetiracetam 3D printing formulation according to claim 1, wherein the surfactant is present in an amount of 0% to 1%.
56. The levetiracetam 3D printing formulation according to claim 1, wherein no surfactant is present.
57. The levetiracetam 3D-printing formulation according to claim 1, further comprising a plasticizer.
58. The levetiracetam 3D printing formulation according to claim 1, further comprising a plasticizer and a pigment.
59. The levetiracetam 3D printing formulation according to claim 57 or 58, wherein the plasticizer is glycerol present in an amount of 0.5% to 1.5%.
60. The levetiracetam 3D printing formulation according to claim 58, wherein the pigment is present in an amount of no more than 1% by weight of the formulation.
61. The levetiracetam 3D-printing formulation according to claim 1, which is a tablet.
62. The levetiracetam 3D-printing formulation according to claim 61, which is a non-solid tablet.
63. A method of making the levetiracetam 3D printing formulation of any one of claims 1 to 62, the method being a binder jet type 3D printing method;
and the preparation method comprises the following steps:
spreading the medicine powder on a printing platform, wherein the thickness of each powder spreading layer is 80-200 μm in the printing process; the grain diameter of the medicine powder is 30-150 μm;
the printing nozzle finely sprays a certain amount of printing liquid drops on a specific part according to an instruction input by 3D printer control software, the Z axis of the printing platform descends by a certain height, then powder is spread again, printing is carried out again, and the process is repeated until printing is finished;
the print head ejection mechanism is piezoelectric; the unit ink drop ejection volume is 5pL-40 pL; the spraying speed is 0.2g/min-0.8 g/min;
or the jet mechanism of the printing head is a thermal bubble type; the unit ink drop ejection volume is 15pL-20 pL; the spraying speed is 0.3g/min to 0.8 g/min;
the printing liquid is selected from the following printing liquid combinations:
a printing fluid combination comprising a transparent printing fluid and optionally 1, 2, 3 or 4 printing fluids selected from:
cyan printing liquid, magenta printing liquid, yellow printing liquid and black printing liquid;
each printing liquid comprises 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 of the organic solvent in the basic solvent accounts for 35 to 55 percent;
the adhesive is one or more selected from povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium alginate and starch; wherein, the content of the adhesive is 0.01 to 0.5 percent of the weight of the corresponding printing liquid;
the plasticizer is glycerol and accounts for 1-6% of the weight of the corresponding printing liquid.
64. The method of claim 63, wherein the powder coating layer has a thickness of 90 μm to 150 μm.
65. The method of claim 63, wherein the powder coating layer has a thickness of 100 μm to 120 μm.
66. The method of claim 63, wherein the particle size of the drug powder is 60 μm to 120 μm.
67. The production method according to claim 63, wherein the unit droplet ejection volume is 6pL to 30pL for a case where the head ejection mechanism is piezoelectric.
68. The production method according to claim 63, wherein the volumes of the large droplet, the medium droplet and the small droplet are 30pL, 15pL and 6pL, respectively, in the case where the head ejection mechanism is of a piezoelectric type.
69. A producing method according to claim 63, wherein in a case where the head ejection mechanism is of piezoelectric type, the liquid ejection speed is 0.3g/min to 0.5 g/min.
70. The production method according to claim 63, wherein the ejection speed is 0.4g/min in the case where the head ejection mechanism is piezoelectric.
71. A production method according to claim 63, wherein the unit ink droplet ejection volume is 18pL for a case where the head ejection mechanism is a thermal bubble type.
72. A production method according to claim 63, wherein, in the case where the head ejection mechanism is of a thermal bubble type, the liquid ejection speed is 0.4g/min to 0.6 g/min.
73. A production method according to claim 63, wherein, in the case where the head ejection mechanism is of a thermal bubble type, the liquid ejection speed is 0.5 g/min.
74. The method according to claim 63, wherein the organic solvent is present in the base solvent in an amount of 40 to 50% by volume.
75. A method of making a composite ink according to claim 63, wherein the base solvent is present in an amount of at least 85% to 97% by weight of the respective printing fluid.
76. A method of making a composite ink according to claim 63, wherein the base solvent is present in an amount of 90% to 96% by weight of the respective printing fluid.
77. The method of claim 63, wherein the binder is povidone.
78. The method of claim 63, wherein the binder is povidone K30.
79. A method of making a composite ink jet printhead according to claim 63, wherein the binder is present in an amount of 0.05 to 0.5% by weight of the respective printhead fluid.
80. A method of making a composite ink jet printhead according to claim 63, wherein the binder is present in an amount of 0.05 to 0.1% by weight of the respective printhead fluid.
81. A method of making a composite ink jet printhead according to claim 63, wherein the binder is present in an amount of 0.03 to 0.3% by weight of the respective printhead fluid.
82. A method of making a composite ink jet printhead according to claim 63, wherein the binder is present in an amount of 0.03% to 0.2% by weight of the respective printhead fluid.
83. A method of making a composite ink jet printhead according to claim 63, wherein the binder is present in an amount of 0.03 to 0.15% by weight of the respective printhead fluid.
84. A method of making as claimed in claim 63 wherein glycerol comprises 2% to 5% by weight of the respective printing fluid.
85. The method of claim 63, wherein,
the pigment in the cyan printing liquid is a bright blue pigment;
pigments in the magenta printing liquid are erythrosine and carmine;
the pigment in the yellow printing liquid is lemon yellow; and/or
The pigment in the black printing liquid is amaranth pigment and bright blue pigment.
86. The method of claim 63, wherein the surfactant is present in an amount of 0% to 2% by weight of the respective printing fluid.
87. The method of claim 63, wherein the surfactant is present in an amount of 0% to 1% by weight of the respective printing fluid.
88. The method of claim 63, wherein the printing fluid combination is surfactant free.
89. The production method according to claim 63, wherein the method further comprises a step of drying and packaging the print-finished preparation.
90. The method of claim 63, wherein,
the line spacing is 0.4cm-0.6cm and
the row spacing is 0.4cm-0.6 cm.
91. The method of claim 90, wherein the row spacing is 0.5 cm.
92. The method of claim 90, wherein the column pitch is 0.5 cm.
93. A levetiracetam 3D printing formulation made by the method of making of any of claims 63-92.
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