Ketotifen fumarate divided dose tablet based on 3D printing technology and preparation method

Abstract

The invention discloses a ketotifen fumarate divided-dose tablet based on a 3D printing technology and a preparation method thereof. The ketotifen fumarate clinical divided-dose tablet comprises the following components in percentage by mass: 1-10% of ketotifen fumarate tablet powder, 90-99% of cocoa butter and 0-5% of a flavoring agent, and the sum of the mass percentages of the components is equal to 100%. According to the technical scheme, a hot-melt extrusion type 3D printing technology is adopted to achieve rapid dissolution and clinical precise dose division of tablets, the 3D printing technology is applied to the field of dose division of commercially available tablets, and tablet powder and heated and melted pharmaceutic adjuvants are evenly mixed to prepare a printing material; the dose of the 3D printing divided dose tablet is accurately controlled by adjusting the drug content of the printing material and the volume of the printing model; the content of medicines in commercially available tablets is diluted by adding pharmaceutic adjuvants, and small-dose tablets with lower content are prepared again, so that precise dose-divided administration is realized, and the purpose of individualized administration is achieved.

Description

Summary of the invention

[0001] In order to overcome the shortcomings of the tablet dosage method in the prior art, a ketotifen fumarate clinical dosage tablet and a preparation method thereof are proposed.

[0002] A clinical divided-dose ketotifen fumarate tablet is prepared by 3D printing technology and comprises the following components in mass percentage: 1-10% of ketotifen fumarate tablet powder, 90-99% of cocoa butter, and 0-5% of flavoring agent, and the sum of the mass percentages of the components is equal to 100%.

[0003] Preferably, the flavoring agent includes any one of sucrose, glucose, fructose, aspartame, steviol glycoside, and lactose, or a combination of two or more thereof.

[0004] A method for preparing a clinical divided-dose ketotifen fumarate tablet, the method being used for preparing the clinical divided-dose ketotifen fumarate tablet, and comprising the following steps:

[0005] S1, designing a model: using computer-aided design software or a 3D modeling tool to create a tablet model to be printed; the shape and structure of the tablet model are pre-designed;

[0006] S2, preparing tablets: heating and melting the cocoa butter into liquid, grinding the ketotifen fumarate tablets into powder, and adding the powder into the liquid cocoa butter in a first preset ratio; then adding the flavoring agent in a second preset ratio, and mixing well;

[0007] S3, preheating the printer: preheating the preset 3D printer to a preset temperature;

[0008] S4, loading printing materials: loading the prepared printing materials into the ink cartridge or storage of the preset 3D printer;

[0009] S5, setting printing parameters: setting the parameters of the preset 3D printer according to the characteristics of the components and the shape and structure of the tablet model;

[0010] S6, start printing: send the tablet model to the preset 3D printer and start printing;

[0011] S7, cooling and solidifying: after printing is completed, ketotifen fumarate divided-dose tablets are obtained; the ketotifen fumarate divided-dose tablets are allowed to cool and solidify at room temperature to keep their shape;

[0012] S8, taking out the finished product: taking out the printed ketotifen fumarate divided-dose tablets from the preset 3D printer.

[0013] The clinical ketotifen fumarate divided-dose tablets and the preparation method thereof provided by the present invention adopt 3D printing technology to adjust the clinical precise ketotifen fumarate divided-dose tablets. The tablets not only have a fast dissolution speed and rapid absorption, but also do not require drinking water after taking the medicine, which is convenient for infants and young children to take; and the divided-dose is precise, and the dosage of the tablets can be individually controlled by changing the ratio of the drug to the excipients and the volume parameters of the printed model, and the dosage required by the patient can be provided according to the individualized medication of different patients, thereby realizing individualized drug administration and precise treatment; in addition, the 3D printing divided-dose method can also reduce the operation steps of the pharmacist and the patient for divided-dose, facilitate the patient to take, carry and store, increase the patient's medication compliance, improve the patient's efficacy, and reduce the patient's adverse reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is a schematic diagram of the design of a 3D printed tablet in an embodiment of the present invention;

[0015] The symbols in the drawings of the specification are as follows:

[0016] H: tablet thickness; h: layer thickness; r: tablet radius; n: number of layers. DETAILED DESCRIPTION

[0017] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0018] A clinical divided-dose ketotifen fumarate tablet, characterized in that the clinical divided-dose ketotifen fumarate tablet is prepared by 3D printing technology and comprises the following components in mass percentage: 1-10% of ketotifen fumarate tablet powder, 90-99% of cocoa butter, and 0-5% of flavoring agent, and the sum of the mass percentages of each component is equal to 100%.

[0019] Among them, 3D printing technology is used in computer software-aided design. Figure 1 The design of the 3D printed tablet shown. The tablet thickness, layer thickness, tablet radius, number of layers, and the shape and structure of the tablet can all be flexibly set.

[0020] Furthermore, the flavoring agent includes but is not limited to any one or a combination of two or more of sucrose, glucose, fructose, aspartame, steviol glycoside, and lactose.

[0021] Specifically, taking the more common clinical dosages of ketotifen fumarate, 0.25 mg, 0.5 mg, and 0.75 mg, as examples, the present invention is further illustrated and demonstrated through an embodiment of 3D printing divided-dose tablets and an experimental example of grinding and packaging divided-dose tablets.

[0022] Example 1, target dose: 0.25 mg of ketotifen fumarate, the formula is as follows:

[0023]

[0024] The parameters of 3D printed tablets are as follows:

[0025]

[0026]

[0027] The preparation method is as follows:

[0028] (1) Design model: Use computer-aided design (CAD) software or 3D modeling tools to create a tablet model to be printed.

[0029] (2) Preparation of tablets: Heat cocoa butter to melt into liquid, grind commercially available ketotifen fumarate tablets into powder, add the powder to liquid cocoa butter in a certain proportion, add appropriate amount of flavoring agent, and mix thoroughly.

[0030] (3) Preheat the printer: Preheat the 3D printer to an appropriate temperature.

[0031] (4) Loading printing materials: Load the prepared printing materials into the ink cartridge or storage of the printer.

[0032] (5) Set printing parameters: Set the printer parameters such as printing speed, temperature, nozzle size, etc. according to the characteristics of the printing components and the requirements of the model.

[0033] (6) Start printing: Send the designed model file to the printer and start the printing process. The printer will extrude the printing material point by point and layer by layer according to the shape and structure of the model to build a three-dimensional object.

[0034] (7) Cooling and curing: After printing is completed, the tablet is allowed to cool and solidify at room temperature so that it retains its shape.

[0035] (8) Take out the finished product: Carefully take out the printed ketotifen fumarate divided-dose tablets from the printer.

[0036] Content determination of 3D printed ketotifen fumarate split-dose tablets:

[0037] The content of ketotifen fumarate in ketotifen fumarate tablets was determined by high performance liquid chromatography (HPLC) to be 0.25±0.01 mg / tablet, which meets the content requirements of the 2020 edition of the "Chinese Pharmacopoeia" and the "Drug Dosage Operation Specifications".

[0038] Disintegration time test of 3D printed ketotifen fumarate split-dose tablets:

[0039] The disintegration time of the 3D printed ketotifen fumarate divided-dose tablets was measured by a disintegration instrument to be 3±1s, which meets the disintegration time requirements of the 2020 edition of the "Chinese Pharmacopoeia".

[0040] Example 2, target dose: 0.5 mg of ketotifen fumarate, the formula is as follows:

[0041]

[0042] The parameters of 3D printed tablets are as follows:

[0043]

[0044] The preparation method is the same as that in Example 1 and will not be described again here.

[0045] Content determination of 3D printed ketotifen fumarate split-dose tablets:

[0046] The content of ketotifen fumarate in ketotifen fumarate split-dose tablets was determined by high performance liquid chromatography (HPLC) to be 0.51±0.02 mg / tablet, which meets the requirements of the 2020 edition of the "Chinese Pharmacopoeia" and the "Drug Dosage Operation Specifications".

[0047] Disintegration time test of 3D printed ketotifen fumarate split-dose tablets:

[0048] The disintegration time of the 3D printed ketotifen fumarate divided-dose tablets was measured by a disintegration instrument to be 4±1s, which meets the disintegration time limit requirements of the 2020 edition of the "Chinese Pharmacopoeia".

[0049] Example 3, target dose: 0.75 mg of ketotifen fumarate, the formula is as follows:

[0050]

[0051] The parameters of 3D printed tablets are as follows:

[0052]

[0053] The preparation method is the same as that in Example 1 and will not be described again here.

[0054] Content determination of 3D printed ketotifen fumarate split-dose tablets: The content of ketotifen fumarate in the split-dose tablets is 0.77±0.02 mg / tablet, which meets the requirements of the 2020 edition of the "Chinese Pharmacopoeia" and the "Drug Split-Dose Operation Specifications".

[0055] Disintegration time test of 3D printed ketotifen fumarate split-dose tablets:

[0056] The disintegration time of the 3D printed ketotifen fumarate divided-dose tablets was measured by a disintegration instrument to be 4±1s, which meets the disintegration time limit requirements of the 2020 edition of the "Chinese Pharmacopoeia".

[0057] To verify the feasibility of the present invention, a comparison experiment was conducted on the above embodiments. The experimental example is a commonly used clinical dosage method for commercially available ketotifen fumarate tablets. Because the tablets are extremely small and there are no scratches on the surface of the tablets, in order to facilitate children to take them, they are often ground and packaged clinically.

[0058] The dosages (0.25 mg, 0.5 mg, and 0.75 mg) of the above three examples were selected for experimental comparison.

[0059] According to the "Drug Dosage Operation Specifications": According to the "Filling Difference" requirements of the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Rules 0115 Powders, a filling difference test is conducted. Take 10 packages of the test sample, accurately weigh the weight of the contents of each package, and calculate the filling volume of the contents. Compared with the average theoretical filling volume, no more than 2 packages shall exceed the filling volume difference by 15%, and no package shall exceed the filling volume difference by 30%.

[0060] The experimental results are as follows:

[0061] Split Dose Exceeding the filling volume difference by 15% Exceeding the filling volume difference by 30% result 0.25mg 5 3 Failure 0.5mg 4 2 Failure 0.75mg 6 4 Failure

[0062] The experiment proved that the results of the experimental cases using the traditional dosing method were all unqualified, while the dosing tablets prepared by 3D printing technology were accurate in dosage, fast in dissolution, intact in appearance, and convenient for patients to take, carry and store. It can be concluded that the use of 3D printing technology to prepare dosing tablets can replace the traditional dosing method and solve the problem of accurate dosing of infants and young children.

[0063] The above is an explanation of the ketotifen fumarate split-dose tablets and preparation method based on 3D printing technology of the present invention, which is used to help understand the present invention; however, the embodiments of the present invention are not limited to the above embodiments, and any changes, modifications, substitutions, combinations, and simplifications made without departing from the principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A clinical divided-dose tablet of ketotifen fumarate, characterized in that: The clinical divided-dose ketotifen fumarate tablets are prepared by 3D printing technology and include the following components in mass percentage: 1-10% ketotifen fumarate tablet powder, 90-99% cocoa butter, and 0-5% flavoring agent, and the sum of the mass percentages of the components is equal to 100%.

2. The ketotifen fumarate clinical divided-dose tablet according to claim 1, characterized in that: The flavor corrector includes any one of sucrose, glucose, fructose, aspartame, steviol glycoside and lactose, or a combination of two or more thereof.

3. A method for preparing a clinical divided-dose ketotifen fumarate tablet, characterized in that: The preparation method is used to prepare clinical divided-dose ketotifen fumarate tablets, and comprises the following steps: S1, designing a model: using computer-aided design software or a 3D modeling tool to create a tablet model to be printed; the shape and structure of the tablet model are pre-designed; S2, preparing tablets: heating and melting the cocoa butter into liquid, grinding the ketotifen fumarate tablets into powder, and adding the powder into the liquid cocoa butter in a first preset ratio; then adding the flavoring agent in a second preset ratio, and mixing well; S3, preheating the printer: preheating the preset 3D printer to a preset temperature; S4, loading printing materials: loading the prepared printing materials into the ink cartridge or storage of the preset 3D printer; S5, setting printing parameters: setting the parameters of the preset 3D printer according to the characteristics of the components and the shape and structure of the tablet model; S6, start printing: send the tablet model to the preset 3D printer and start printing; S7, cooling and solidifying: after printing is completed, ketotifen fumarate divided-dose tablets are obtained; the ketotifen fumarate divided-dose tablets are allowed to cool and solidify at room temperature to keep their shape; S8, taking out the finished product: taking out the printed ketotifen fumarate divided-dose tablets from the preset 3D printer.

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