Phenobarbital orally disintegrating micro-tablet based on 3D printing and preparation method of phenobarbital orally disintegrating micro-tablet

Abstract

The invention discloses a phenobarbital orally disintegrating micro-tablet based on 3D printing. The phenobarbital orally disintegrating micro-tablet is mainly prepared from, by mass, 15%-70% of phenobarbital, 10%-60% of filler, 0%-50% of disintegrating agent, 0.1%-2% of flavoring agent and 0%-15% of adhesive through the 3D printing technology. The invention also discloses a preparation method of the phenobarbital orally disintegrating micro-tablet. The phenobarbital orally disintegrating micro-tablet is high in drug release speed, can improve the drug taking compliance of patients, and is particularly convenient for infants and other persons with dysphagia to take.

Description

Technical Field

[0001] The present invention relates to a phenobarbital orally disintegrating microtablet, and in particular to a phenobarbital orally disintegrating microtablet based on 3D printing and a preparation method thereof. Background Art

[0002] 3D printing, also known as additive manufacturing, creates three-dimensional objects from digital models through a layer-by-layer process. Applied to the pharmaceutical field, 3D printing offers unique advantages over traditional formulation technologies in increasing the structural complexity of formulations and providing personalized drug delivery. Since the FDA approval of Spritam, the first 3D-printed oral dosage form, in 2015, 3D-printed formulations have garnered significant attention. 3D printing technologies currently used in the pharmaceutical industry typically include powder deposition modeling (3DP), fused deposition modeling (FDM), stereolithography (SLA), and semi-solid extrusion (SSE).

[0003] Orally disintegrating microtablets (ODMTs) are a novel pharmaceutical dosage form. Compared to traditional orally disintegrating tablets, they are significantly smaller, typically less than 5mm in height and diameter, improving their acceptability in pediatric patients. Furthermore, compared to directly splitting larger tablets, directly preparing them into microtablets can better ensure dosing accuracy.

[0004] Neonatal jaundice, also known as neonatal hyperbilirubinemia, is a condition characterized by yellowing of the skin, mucous membranes, and sclera due to abnormal bilirubin metabolism in the neonatal period. It is the most common clinical problem in newborns. Long-term hyperbilirubinemia can lead to chronic bilirubin encephalopathy (kernicterus). Infants with kernicterus may experience fever or seizures. Rapid and accurate treatment of neonatal jaundice helps reduce the risk of kernicterus in newborns.

[0005] Currently, phenobarbital is commonly used in clinical practice to treat neonatal jaundice, with common dosage forms including injections and oral tablets. Patient compliance with injections is poor, and oral administration is usually followed by an initial injection. However, the current tablet dosage specifications are 30mg, 50mg, and 100mg, and the maintenance treatment dose for infants and young children requires very precise dosage. Existing oral tablets are more difficult for infants and young children, and the therapeutic window of phenobarbital is narrow. The maintenance treatment concentration is usually 4-8mg / kg. Directly splitting large-sized tablets cannot guarantee the accuracy of the dosage.

[0006] It is of great significance to use 3D printing technology to prepare phenobarbital orally disintegrating microtablets that are convenient for administration and improve the accuracy of dosage. Summary of the Invention

[0007] One of the purposes of the present invention is to provide a 3D-printed orally disintegrating phenobarbital microtablet, which makes up for the shortcomings of existing phenobarbital dosage forms. It is small in size and disintegrates quickly, making it suitable for infants, the elderly, and patients with swallowing disorders caused by some special diseases.

[0008] A second object of the present invention is to provide a method for preparing the above-mentioned 3D phenobarbital orally disintegrating microtablets.

[0009] In order to achieve the first object of the present invention, the present invention adopts the following technical solution:

[0010] A 3D-printed orally disintegrating phenobarbital microtablet comprises the following components, calculated by mass percentage: 15% to 70% phenobarbital, 10% to 60% filler, 0% to 50% disintegrant, 0.1% to 2% flavoring agent, 0.05% to 15% binder, 0% to 2% glidant, 0% to 0.1% antioxidant, and 0% to 5% plasticizer, with the sum of the mass percentages of the components being equal to 100%.

[0011] Furthermore, using semi-solid extrusion printing technology, the weight percentages of the components are as follows: 15% to 55% phenobarbital, 10% to 60% filler, 0% to 50% disintegrant, 0.1% to 2% flavoring agent, 0% to 10% binder, and 0% to 2% plasticizer. Preferably, 40% to 50% phenobarbital, 10% to 50% filler, 0% to 46% disintegrant, 0.1% to 2% flavoring agent, 0% to 10% binder, and 0% to 2% plasticizer. The sum of the weight percentages of the components equals 100%.

[0012] Furthermore, using powder bonding printing technology, the weight percentages of the components are as follows: 15% to 70% phenobarbital, 10% to 60% filler, 0% to 30% disintegrant, 0.1% to 2% flavoring agent, 0.5% to 15% binder, 0% to 2% glidant, 0% to 0.1% antioxidant, and 0% to 5% plasticizer. More preferably, 50% to 70% phenobarbital, 10% to 30% filler, 1% to 10% disintegrant, 0.1% to 2% flavoring agent, 0.5% to 15% binder, 0% to 2% glidant, 0% to 0.1% antioxidant, and 0% to 5% plasticizer. The sum of the weight percentages of the components is equal to 100%.

[0013] Furthermore, the particle size range of the phenobarbital is d50<20 μm, and preferably, the particle size range of the phenobarbital is d90<20 μm. When the particle size range of the phenobarbital is d50<20 μm, the drug solubility can be increased and the taste can be improved to a certain extent.

[0014] Furthermore, the phenobarbital orally disintegrating microtablet has a diameter of 2.5 mm to 5 mm and a height of 1.9 mm to 6.2 mm. Preferably, the orally disintegrating microtablet has a diameter and a height of 2.5 to 4 mm. Considering the single tablet dosage and therapeutic dose, if the single tablet size is too small, more tablets may need to be taken each time the drug is administered, which in turn reduces patient compliance.

[0015] Furthermore, the filler includes one or more of lactose, mannitol, starch, sorbitol, sucrose, dextrin, microcrystalline cellulose, ethyl cellulose, sodium alginate, hypromellose, and sodium carboxymethyl starch;

[0016] The disintegrant comprises one or more of: polyvidone (PVP), sodium carboxymethyl starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium alginate, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvidone;

[0017] The flavoring agent includes one or more of sucralose, aspartame, saccharin sodium, strawberry flavor, and mint flavor;

[0018] The binder comprises one or more of: povidone, hydroxypropyl cellulose, lactose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose (HPMC), starch, gelatin, and polyethylene glycol;

[0019] The glidant includes: one or more of colloidal silicon dioxide, talc, and magnesium stearate;

[0020] The antioxidant includes: one or more of butylated hydroxytoluene and butylated hydroxyanisole;

[0021] The plasticizer includes one or more of polyethylene glycol, glycerol, and poloxamer.

[0022] The second object of the present invention is achieved by the following technical solution: the above-mentioned phenobarbital orally disintegrating microtablets are manufactured by semi-solid extrusion printing technology, comprising the following steps:

[0023] 1) Weigh the powder components according to the prescribed amount and mix them evenly in a mortar or a three-dimensional mixer to obtain a powder mixture;

[0024] 2) Weighing the liquid components according to the prescribed amount and uniformly mixing them to obtain a liquid mixture;

[0025] 3) adding the powder mixture in step 1) to the liquid mixture in step 2) and uniformly mixing to obtain a semi-solid mixture;

[0026] 4) Modeling the desired drug dosage according to pre-set printing parameters and importing it into the 3D printer software system, loading the semi-solid mixture from step 3) into the semi-solid extrusion 3D printer, and printing the desired tablets layer by layer from bottom to top;

[0027] 5) Drying at room temperature or a certain temperature;

[0028] The powder component comprises the active pharmaceutical ingredient phenobarbital and one or more of a filler, a disintegrant, a binder, and a flavoring agent; the liquid component comprises a solvent and / or a plasticizer, wherein the solvent is water or an ethanol solution, and the plasticizer is glycerol.

[0029] Furthermore, in step 4), the printing parameters are set as follows:

[0030] The number of shells (ie, the number of shell printing layers) is 1 to 3, preferably 2. The number of shells affects the shell thickness of the orally disintegrating microtablets. If the number of shells is too low, the tablet is fragile, and if the number of shells is too high, the disintegration speed of the tablet will be affected.

[0031] The printing temperature is 25°C to 50°C, preferably 25°C to 40°C. The applicant selects an appropriate printing temperature to ensure that the semi-solid material has good printability. Too low a temperature may result in poor extrudability of the material, while too high a temperature may cause the material to melt or the solvent to evaporate, leading to problems such as nozzle blockage, uneven material discharge, and unformed printing during the printing process.

[0032] The diameter of the printing nozzle is 0.2-0.8 mm, and preferably, the diameter of the printing nozzle is 0.4-0.6 mm.

[0033] The moving speed of the print head is 5 mm / s to 20 mm / s. Preferably, the moving speed of the print head is 5 mm / s to 8 mm / s.

[0034] The internal filling pattern of the micro-tablet is solid, grid-shaped or concentrically circular, with a filling rate of 50% to 80%, preferably 50% to 70%. The porosity is coordinated with the disintegrant and the binder to achieve a balance between structural strength, drug loading and disintegration time.

[0035] The printing platform is made of stainless steel or glass, preferably glass. The material of the printing platform affects the degree of adhesion between the printing platform and the tablet material, which may cause the tablet to deviate or excessively adhere during the printing process, thereby affecting the quality of the tablet.

[0036] The second object of the present invention is achieved by the following technical solution: the above-mentioned phenobarbital orally disintegrating microtablets are manufactured by powder bonding printing technology, comprising the following steps:

[0037] 1) Weigh the powder components according to the prescribed amount and mix them evenly in a mortar or a three-dimensional mixer to obtain a powder mixture;

[0038] 2) The powder mixture in step 1) is loaded into a powder box of a 3D printer, and the binder is loaded into an ink cartridge of the 3D printer;

[0039] 3) Based on pre-set printing parameters, a model is created for the desired drug dosage and imported into the 3D printer software system. The powder spreading device first spreads a layer of drug powder on the powder bed to a predetermined layer height. The print head then sprays the adhesive liquid onto a specific area. Once completed, the printing platform descends on the Z axis to the predetermined layer height, and the above process is repeated until printing is complete.

[0040] 4) After drying at room temperature or a certain temperature, remove excess powder;

[0041] The powder component comprises the active pharmaceutical ingredient phenobarbital and one or more of a filler, a binder, a disintegrant, a flavoring agent, an antioxidant, and a glidant.

[0042] Furthermore, the adhesive liquid is an ethanol solution or an isopropyl alcohol solution, and further comprises 0% to 1.5% by weight of povidone and / or 0% to 5% by weight of glycerol. By selecting this ratio of organic solvent, povidone, and glycerol, the evaporation rate and viscosity are adjusted, so that the adhesive liquid has appropriate surface tension, viscosity, and density, and is sprayable.

[0043] Furthermore, the printing parameters in step 3) are set as:

[0044] The thickness of each layer of medicine powder is 100 to 300 μm, preferably, the thickness of each layer of medicine powder is 100 to 150 μm;

[0045] The unit ejection volume of the print head is 10 pL to 30 pL. Preferably, the unit ejection volume of the print head is 15 pL to 20 pL.

[0046] Compared with the prior art, the present invention has the following beneficial technical effects:

[0047] (1) Improve patient compliance. The miniaturized design of the microtablets and their rapid disintegration in the oral cavity enable drug administration without swallowing, which is particularly suitable for infants and elderly patients whose swallowing function is not fully developed, and reduces the risk of choking.

[0048] (2) Improve the accuracy of dosing. The unit tablet is small in size and does not need to be split from a large tablet. This solves the problem of large dose splitting errors caused by the narrow therapeutic window of existing phenobarbital dosage forms and facilitates accurate individualization of infants and young children according to their weight.

[0049] (3) Dual-process adaptability to multiple scenarios:

[0050] Without relying on a multi-layer design, semi-solid extrusion technology is used to achieve a balance between structural strength, drug loading and disintegration time. Low friability can reduce irritation to the oral mucosa, making it suitable for the elderly or patients with oral sensitivity. At the same time, orally disintegrating microtablets are physically stable during production, transportation and storage, and can meet the needs of industrial mass production.

[0051] The powder bonding technology is used to achieve high drug loading and rapid disintegration performance, meeting the immediate drug delivery needs of hospital pharmacies or patients with dysphagia. The dosage can be flexibly adjusted according to patient differences to achieve individual customization. DETAILED DESCRIPTION

[0052] The following examples are provided to further illustrate the above content of the present invention. However, it should not be understood that the scope of the present invention is limited to the following examples.

[0053] In the following examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or those recommended by the manufacturer. All reagents and instruments used, if the manufacturer is not specified, are commercially available conventional products.

[0054] Example 1

[0055] 1. The prescription is as follows:

[0056]

[0057]

[0058] 2. The printing parameters are set as follows:

[0059] Floor Height 0.4mm Number of shells 2 Printing temperature 25℃ Fill Pattern Concentric circles Fill rate 60％ Print head moving speed 5mm / s Printing platform material Glass Print head diameter 0.4mm Tablet Model Cylindrical, diameter 4mm, height 3.5mm

[0060] 3. Prepared by semi-solid extrusion printing technology, the preparation method is as follows:

[0061] (1) The phenobarbital raw material was pulverized by air flow to a particle size of d90 < 20 μm.

[0062] (2) Add the raw materials in the prescription into a three-dimensional mixer, set the speed to 30 rpm, and mix for 20 min to obtain a powder mixture.

[0063] (3) Gradually add pure water to the powder mixture, grind and mix evenly in a mortar, with a liquid to solid mass ratio of 60:40 to obtain a semi-solid mixture.

[0064] (4) Based on pre-set printing parameters, a model is created for the desired drug dosage and imported into the 3D printer software system. The semi-solid mixture is loaded into a semi-solid extrusion 3D printer and the desired tablets are printed layer by layer from bottom to top. A single print contains 20 tablets, with 1 cm between tablets. After printing, the tablets are dried at room temperature for 6 h.

[0065] After drying, the tablets shrank slightly and measured 3.07 ± 0.21 mm in diameter and 2.62 ± 0.17 mm in thickness.

[0066] Example 2

[0067] 1. The prescription is as follows:

[0068]

[0069]

[0070] 2. The printing parameters are set as follows:

[0071] Floor Height 0.4mm Number of shells 2 Printing temperature 40℃ Fill Pattern Concentric circles Fill rate 70％ Print head moving speed 5mm / s Printing platform material Glass Print head diameter 0.4mm Tablet model Cylindrical, diameter 4mm, height 3.5mm

[0072] 3. Prepared by semi-solid extrusion printing technology, the preparation method is as follows:

[0073] (1) The phenobarbital raw material was pulverized by air flow to a particle size of d90 < 20 μm.

[0074] (2) Add the raw materials in the prescription into a three-dimensional mixer, set the speed to 30 rpm, and mix for 20 min to obtain a powder mixture.

[0075] (3) Gradually add pure water to the powder mixture, grind and mix evenly in a mortar, with a liquid to solid mass ratio of 60:40 to obtain a semi-solid mixture.

[0076] (4) Based on pre-set printing parameters, a model is created for the desired drug dosage and imported into the 3D printer software system. The semi-solid mixture is loaded into the printer and the desired tablets are printed layer by layer from bottom to top. A single print contains 20 tablets, with 1 cm between tablets. After printing, the tablets are dried at room temperature for 6 h.

[0077] After drying, the tablets shrank slightly and measured 3.42 ± 0.30 mm in diameter and 3.17 ± 0.23 mm in thickness.

[0078] Example 3

[0079] 1. The prescription is as follows:

[0080]

[0081]

[0082] 2. The printing parameters are set as follows:

[0083] Floor Height 0.4mm Number of shells 2 Printing temperature 25℃ Fill Pattern Concentric circles Fill rate 60％ Print head moving speed 5mm / s Printing platform material Glass Print head diameter 0.4mm Tablet Model Cylindrical, diameter 4mm, height 3.5mm

[0084] 3. Prepared by semi-solid extrusion printing technology, the preparation method is as follows:

[0085] (1) The phenobarbital raw material was pulverized by air flow to a particle size of d90 < 20 μm.

[0086] (2) Add the raw materials in the prescription into a three-dimensional mixer, set the speed to 30 rpm, and mix for 20 min to obtain a powder mixture.

[0087] (3) Gradually add pure water to the powder mixture, grind and mix evenly in a mortar, with a liquid to solid mass ratio of 60:40 to obtain a semi-solid mixture.

[0088] (4) Based on pre-set printing parameters, a model is created for the desired drug dosage and imported into the 3D printer software system. The semi-solid mixture is loaded into the printer and the desired tablets are printed layer by layer from bottom to top. A single print contains 20 tablets, with 1 cm between tablets. After printing, the tablets are dried at room temperature for 6 h.

[0089] After drying, the tablets shrank slightly and measured 3.18 ± 0.15 mm in diameter and 2.86 ± 0.11 mm in thickness.

[0090] Example 4

[0091] 1. The prescription is as follows:

[0092]

[0093] 2. The printing parameters are set as follows:

[0094] Floor Height 0.4mm Number of shells 2 Printing temperature 25℃ Fill Pattern Concentric circles Fill rate 50％ Print head moving speed 5mm / s Printing platform material Glass Print head diameter 0.4mm Tablet Model Cylindrical, diameter 4mm, height 3.5mm

[0095] 3. Prepared by semi-solid extrusion printing technology, the preparation method is as follows:

[0096] (1) The phenobarbital raw material was pulverized by air flow to a particle size of d90 < 20 μm.

[0097] (2) Add the raw materials in the prescription into a three-dimensional mixer, set the speed to 30 rpm, and mix for 20 min to obtain a powder mixture.

[0098] (3) Gradually add 20% ethanol solution to the powder mixture, grind and mix evenly in a mortar, with a liquid to solid mass ratio of 3:1 to obtain a semi-solid mixture.

[0099] (4) Based on pre-set printing parameters, a model is created for the desired drug dosage and imported into the 3D printer software system. The semi-solid mixture is loaded into the printer and the desired tablets are printed layer by layer from bottom to top. A single print contains 20 tablets, with 1 cm between tablets. After printing, the tablets are dried at room temperature for 6 h.

[0100] After drying, the tablets shrank slightly and measured 2.98 ± 0.52 mm in diameter and 2.54 ± 0.41 mm in thickness.

[0101] Example 5

[0102] 1. The prescription is as follows:

[0103]

[0104] 2. The printing parameters are set as follows:

[0105] Thickness of powder layer 90μm Unit injection volume 18pL Tablet model Cylindrical, diameter 3mm, height 3mm

[0106] 3. Prepared by powder bonding printing technology, the preparation method is as follows:

[0107] (1) Pulverize the phenobarbital API by air flow to a particle size of d90 < 20 μm. Pass the colloidal silicon dioxide through a 40-mesh sieve, and pass the remaining excipients through a 100-mesh sieve.

[0108] (2) Add the powder components into a three-dimensional mixer, set the speed to 30 rpm, and mix for 20 min to obtain a powder mixture.

[0109] (3) The powder mixture is loaded into the powder box of the printer, and the binder is loaded into the ink cartridge of the printer.

[0110] (4) According to the pre-set printing parameters, the model is built according to the required drug dosage and imported into the 3D printer software system. The powder spreading device first spreads a layer of drug powder on the powder bed with a thickness of the set layer height. Then the printing nozzle sprays the adhesive liquid on a specific area. After completion, the printing platform descends a certain height on the Z axis and repeats the above operation until printing is completed.

[0111] (5) After printing, dry at 40°C for 3 hours and remove excess powder.

[0112] After drying, the tablets shrank slightly and measured 2.91 ± 0.30 mm in diameter and 2.67 ± 0.23 mm in thickness.

[0113] Example 6

[0114] 1. The prescription is as follows:

[0115]

[0116] 2. The printing parameters are set as follows:

[0117] Thickness of powder layer 120μm Unit injection volume 18pL Tablet Model Cylindrical, diameter 3mm, height 3mm

[0118] 3. Prepared by powder bonding printing technology, the preparation method is as follows:

[0119] (1) Pulverize the phenobarbital API by air flow to a particle size of d90 < 20 μm. Pass the colloidal silicon dioxide through a 40-mesh sieve, and pass the remaining excipients through a 100-mesh sieve.

[0120] (2) Add the powder components into a three-dimensional mixer, set the speed to 30 rpm, and mix for 20 min to obtain a powder mixture.

[0121] (3) The powder mixture is loaded into the powder box of the printer, and the binder is loaded into the ink cartridge of the printer.

[0122] (4) According to the pre-set printing parameters, the model is built according to the required drug dosage and imported into the 3D printer software system. The powder spreading device first spreads a layer of drug powder on the powder bed with a thickness of the set layer height. Then the printing nozzle sprays the adhesive liquid on a specific area. After completion, the printing platform descends a certain height on the Z axis and repeats the above operation until printing is completed.

[0123] (5) After printing, dry at 40°C for 3 hours and remove excess powder.

[0124] After drying, the tablets shrank slightly and measured 2.77 ± 0.41 mm in diameter and 2.52 ± 0.36 mm in thickness.

[0125] Example 7

[0126] 1. The prescription is as follows:

[0127]

[0128] 2. The printing parameters are set as follows:

[0129] Thickness of powder layer 90μm Unit injection volume 18pL Tablet Model Cylindrical, diameter 3mm, height 3mm

[0130] 3. Prepared by powder bonding printing technology, the preparation method is as follows:

[0131] (1) The phenobarbital raw material was pulverized by air flow to a particle size of d90 < 20 μm, the colloidal silicon dioxide was passed through a 40-mesh sieve, and the remaining excipients were passed through a 100-mesh sieve.

[0132] (2) Add the powder components into a three-dimensional mixer, set the speed to 30 rpm, and mix for 20 min to obtain a powder mixture.

[0133] (3) The powder mixture is loaded into the powder box of the printer, and the binder is loaded into the ink cartridge of the printer.

[0134] (4) According to the pre-set printing parameters, the model is built according to the required drug dosage and imported into the 3D printer software system. The powder spreading device first spreads a layer of drug powder on the powder bed with a thickness of the set layer height. Then the printing nozzle sprays the adhesive liquid on a specific area. After completion, the printing platform descends a certain height on the Z axis and repeats the above operation until printing is completed.

[0135] (5) After printing, dry at 40°C for 3 hours and remove excess powder.

[0136] After drying, the tablets shrank slightly and measured 2.81 ± 0.13 mm in diameter and 2.78 ± 0.09 mm in thickness.

[0137] Comparative Example 1

[0138] 1. The prescription is as follows:

[0139]

[0140] 2. The printing parameters are set as follows:

[0141] Floor Height 0.4mm Number of shells 2 Printing temperature 40℃ Fill Pattern Concentric circles Fill rate 100％ Print head moving speed 5mm / s Printing platform material Glass Print head diameter 0.4mm Tablet Model Cylindrical, diameter 4mm, height 3.5mm

[0142] 3. Prepared by semi-solid extrusion printing technology, the preparation method is as follows:

[0143] (1) The phenobarbital raw material was pulverized by air flow to a particle size of d90 < 20 μm.

[0144] (2) Add the raw materials in the prescription into a three-dimensional mixer, set the speed to 30 rpm, and mix for 20 min to obtain a powder mixture.

[0145] (3) Gradually add pure water to the powder mixture, grind and mix evenly in a mortar, with a liquid to solid mass ratio of 60:40 to obtain a semi-solid mixture.

[0146] (4) Based on pre-set printing parameters, a model is created for the desired drug dosage and imported into the 3D printer software system. The semi-solid mixture is loaded into the printer and the desired tablets are printed layer by layer from bottom to top. A single print contains 20 tablets, with 1 cm between tablets. After printing, the tablets are dried at room temperature for 6 h.

[0147] After drying, the tablets shrank slightly and measured 3.83 ± 0.12 mm in diameter and 3.31 ± 0.15 mm in thickness.

[0148] Comparative Example 2

[0149] 1. The prescription is as follows:

[0150]

[0151] 2. The printing parameters are set as follows:

[0152] Thickness of powder layer 90μm Unit injection volume 18pL Tablet Model Cylindrical, diameter 3mm, height 3mm

[0153] 3. Prepared by powder bonding printing technology, the preparation method is as follows:

[0154] (1) Pulverize the phenobarbital API by air flow to a particle size of d90 < 20 μm. Pass the colloidal silicon dioxide through a 40-mesh sieve, and pass the remaining excipients through a 100-mesh sieve.

[0155] (2) Add the powder components into a three-dimensional mixer, set the speed to 30 rpm, and mix for 20 min to obtain a powder mixture.

[0156] (3) The powder mixture is loaded into the powder box of the printer, and the binder is loaded into the ink cartridge of the printer.

[0157] (4) According to the pre-set printing parameters, the model is built according to the required drug dosage and imported into the 3D printer software system. The powder spreading device first spreads a layer of drug powder on the powder bed with a thickness of the set layer height. Then the printing nozzle sprays the adhesive liquid on a specific area. After completion, the printing platform descends a certain height on the Z axis and repeats the above operation until printing is completed.

[0158] (5) After printing, dry at 40°C for 3 hours and remove excess powder.

[0159] The powder layer cannot be effectively bonded, the tablets are loose and fragile, and the printing fails.

[0160] Comparative Example 3

[0161] 1. The prescription is as follows:

[0162]

[0163] 2. The printing parameters are set as follows:

[0164] Floor Height 0.4mm Number of shells 2 Printing temperature 40℃ Fill Pattern Concentric circles Fill rate 70％ Print head moving speed 5mm / s Printing platform material Glass Print head diameter 0.4mm Tablet Model Cylindrical, diameter 4mm, height 3.5mm

[0165] 3. Prepared by semi-solid extrusion printing technology, the preparation method is as follows:

[0166] (1) The phenobarbital raw material was pulverized by air flow to a particle size of d90 < 20 μm.

[0167] (2) Add the raw materials in the prescription into a three-dimensional mixer, set the speed to 30 rpm, and mix for 20 min to obtain a powder mixture.

[0168] (3) Gradually add pure water to the powder mixture, grind and mix evenly in a mortar, with a liquid to solid mass ratio of 60:40 to obtain a semi-solid mixture.

[0169] (4) Based on pre-set printing parameters, a model is created for the desired drug dosage and imported into the 3D printer software system. The semi-solid mixture is loaded into the printer and the desired tablets are printed layer by layer from bottom to top. A single print contains 20 tablets, with 1 cm between tablets. After printing, the tablets are dried at room temperature for 6 h.

[0170] After drying, the tablets shrank slightly and measured 3.36 ± 1.34 mm in diameter and 3.12 ± 0.87 mm in thickness.

[0171] Too high API content leads to uneven extrusion, rough tablet surface and large dosage fluctuation.

[0172] Performance testing

[0173] 1. Appearance

[0174] The appearance of the tablets was visually observed. The appearance of the tablets obtained in the above examples is recorded in the following table. Tablets with intact morphology and no obvious collapse or cracking were considered acceptable:

[0175] Example 1 The tablets are complete in shape and have visible layers on the surface. Example 2 The tablets are complete in shape and have visible layers on the surface. Example 3 The tablets are complete in shape and have visible layers on the surface. Example 4 The tablet is intact, slightly collapsed, and layers are visible on the surface. Example 5 The tablet shape is complete and the surface has a powdery feel Example 6 The tablet shape is complete and the surface has a powdery feel Example 7 The tablet shape is complete and the surface has a powdery feel Comparative Example 1 The tablets are complete in shape and have visible layers on the surface. Comparative Example 2 Tablets are loose and cannot maintain structure Comparative Example 3 Tablets have rough surfaces and large morphological variations

[0176] 2. Hardness

[0177] Hardness: The radial crushing force (cylindrical microtablets, n=10) was measured using a Huanghai Drug Testing YPD-200C tablet hardness tester.

[0178] The tablets obtained in the above examples were tested for hardness, and the results are shown in the following table:

[0179]

[0180]

[0181] 3. Disintegration time limit

[0182] According to the disintegration time test method of the 2020 edition of the Chinese Pharmacopoeia, a disintegration instrument (Tianjin Tianda Tianfa KB-1 orally disintegrating tablet disintegration instrument) was used to measure the disintegration time of the tablets in the above embodiment. The results are as follows:

[0183] Disintegration time Example 1 26.3±2.1s Example 2 34.2±3.6s Example 3 53.5±1.5s Example 4 28.0±4.2s Example 5 14.8±3.4s Example 6 24.6±6.7s Example 7 36.8±1.2s Comparative Example 1 72.4±3.4s Comparative Example 2 / Comparative Example 3 38.6±12.1s

[0184] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

Claims

1. A phenobarbital orally disintegrating microtablet based on 3D printing, characterized in that: Contains phenobarbital, filler, disintegrant, flavoring, binder, glidant, antioxidant, and plasticizer; Calculated by mass percentage, the phenobarbital content is 15% to 70%, the filler content is 10% to 60%, the disintegrant content is 0% to 50%, the binder content is 0% to 15%, the flavoring content is 0.1% to 2%, the glidant content is 0% to 2%, the antioxidant content is 0% to 0.1%, and the plasticizer content is 0% to 5%. The sum of the mass percentages of each component is equal to 100%.

2. The phenobarbital orally disintegrating microtablet based on 3D printing according to claim 1, wherein The semi-solid extrusion printing technology is used, and the mass percentages of the components are: 15% to 55% of phenobarbital, 10% to 60% of filler, 0% to 50% of disintegrant, 0.1% to 2% of flavoring agent, 0% to 10% of binder, and 0% to 2% of plasticizer; preferably, 40% to 50% of phenobarbital, 10% to 50% of filler, 0% to 46% of disintegrant, 0.1% to 2% of flavoring agent, 0% to 10% of binder, and 0% to 2% of plasticizer; Alternatively, powder bonding printing technology is used, and the mass percentages of the components are: 15% to 70% phenobarbital, 10% to 60% filler, 0% to 30% disintegrant, 0.1% to 2% flavoring agent, 0.5% to 15% binder, 0% to 2% flow aid, 0% to 0.1% antioxidant, and 0% to 5% plasticizer; preferably, 50% to 70% phenobarbital, 10% to 30% filler, 1% to 10% disintegrant, 0.1% to 2% flavoring agent, 0.5% to 15% binder, 0% to 2% flow aid, 0% to 0.1% antioxidant, and 0% to 5% plasticizer.

3. The phenobarbital orally disintegrating microtablet based on 3D printing according to claim 1, wherein The particle size range of the phenobarbital is d90<20 μm.

4. The phenobarbital orally disintegrating microtablet based on 3D printing according to claim 1, characterized in that The phenobarbital orally disintegrating microtablet has a diameter of 2.5 mm to 5 mm and a height of 1.9 mm to 6.2 mm. Preferably, the phenobarbital orally disintegrating microtablet has a diameter and a height of 2.5 to 4 mm.

5. The phenobarbital orally disintegrating microtablet based on 3D printing according to claim 1, characterized in that, Any one or more of the following ag items: a. The filler comprises: lactose, mannitol, starch, sorbitol, sucrose, dextrin, microcrystalline cellulose, ethyl cellulose, sodium alginate, hypromellose, sodium carboxymethyl starch or more; b. The disintegrant comprises: povidone, sodium carboxymethyl starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium alginate, cross-linked sodium carboxymethyl cellulose, one or more of cross-linked polyvinylpyrrolidone; c. The flavoring agent includes: one or more of sucralose, aspartame, saccharin sodium, strawberry flavor, and mint flavor; d. The binder comprises: one or more of povidone, hydroxypropyl cellulose, lactose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, starch, gelatin, and polyethylene glycol; e. The glidant comprises: colloidal silicon dioxide, talc, magnesium stearate or more; f. The antioxidant comprises: butylated hydroxytoluene, butylated hydroxyanisole or more; g. The plasticizer includes one or more of polyethylene glycol, glycerol, and poloxamer.

6. The method for preparing phenobarbital orally disintegrating microtablets based on 3D printing according to any one of claims 1 to 5, characterized in that: The phenobarbital orally disintegrating microtablets are manufactured by semi-solid extrusion printing technology, comprising the following steps: 1) Weigh the powder components according to the prescribed amount and mix them evenly in a mortar or a three-dimensional mixer to obtain a powder mixture; 2) Weighing the liquid components according to the prescribed amount and uniformly mixing them to obtain a liquid mixture; 3) adding the powder mixture in step 1) to the liquid mixture in step 2) and uniformly mixing to obtain a semi-solid mixture; 4) Modeling the desired drug dosage according to pre-set printing parameters and importing it into the 3D printer software system, loading the semi-solid mixture from step 3) into the semi-solid extrusion 3D printer, and printing the desired tablets layer by layer from bottom to top; 5) Drying at room temperature or a certain temperature; The powder component comprises the active pharmaceutical ingredient phenobarbital and one or more of a filler, a disintegrant, a binder, and a flavoring agent; the liquid component comprises a solvent and / or a plasticizer, wherein the solvent is water or an ethanol solution, and the plasticizer is glycerol.

7. The method for preparing phenobarbital orally disintegrating microtablets based on 3D printing according to claim 6, wherein: In step 4), the printing parameters are set as follows: The number of shells is 1 to 3, preferably, the number of shells is 2; The printing temperature is 25°C to 50°C, preferably 25°C to 40°C; The print head diameter is 0.2 to 0.8 mm, preferably, the print head diameter is 0.4 to 0.6 mm; The moving speed of the print head is 5 mm / s to 20 mm / s, preferably, the moving speed of the print head is 5 mm / s to 8 mm / s; The internal filling pattern of the micro-sheet is solid, grid-shaped or concentrically circular, with a filling rate of 50% to 80%, preferably, a filling rate of 50% to 70%; The printing platform is made of stainless steel or glass. Preferably, the platform is made of glass.

8. The method for preparing phenobarbital orally disintegrating microtablets based on 3D printing according to any one of claims 1 to 5, characterized in that: Orally disintegrating microtablets are manufactured using a powder bonding printing technique, which includes the following steps: 1) Weigh the powder components according to the prescribed amount and mix them evenly in a mortar or a three-dimensional mixer to obtain a powder mixture; 2) The powder mixture in step 1) is loaded into a powder box of a 3D printer, and the binder is loaded into an ink cartridge of the 3D printer; 3) Based on pre-set printing parameters, a model is created for the desired drug dosage and imported into the 3D printer software system. The powder spreading device first spreads a layer of drug powder on the powder bed to a predetermined layer height. The print head then sprays the adhesive liquid onto a specific area. Once completed, the printing platform descends on the Z axis to the predetermined layer height, and the above process is repeated until printing is complete. 4) After drying at room temperature or a certain temperature, remove excess powder; The powder component comprises the active pharmaceutical ingredient phenobarbital and one or more of a filler, a binder, a disintegrant, a flavoring agent, an antioxidant, and a glidant.

9. The method for preparing phenobarbital orally disintegrating microtablets based on 3D printing according to claim 8, wherein The bonding liquid is an ethanol solution or an isopropanol solution, and further contains 0% to 1.5% by mass of povidone and / or 0% to 5% by mass of glycerol.

10. The method for preparing phenobarbital orally disintegrating microtablets based on 3D printing according to claim 8, characterized in that: The printing parameters in step 3) are set as follows: The thickness of each layer of medicine powder is 100 to 300 μm, preferably, the thickness of each layer of medicine powder is 100 to 150 μm; The unit ejection volume of the print head is 10 pL to 30 pL. Preferably, the unit ejection volume of the print head is 15 pL to 20 pL.

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