CN106491551A - A kind of 3D printing multilamellar controlled-release pharmaceutical tablet and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of medical drugs, and discloses a 3D printed multilayer controlled-release tablet and a preparation method thereof. The preparation method of the present invention comprises the following steps: adding 1-3wt% hydroxypropyl methylcellulose, 5-10wt% alginate, 0.05-0.3wt% calcium chloride into water and magnetically stirring to obtain the printing material; The concentration of the drug required in the drug was added to the above printing materials, and mixed evenly; the shape parameters of the drug were designed by modeling software, and a multi-layer controlled-release tablet was obtained by printing with a 3D printer. The method of the invention prepares a multi-layer controlled-release tablet with a low drug load in the outer layer and a thin thickness, and a large drug load in the inner layer with a high content. By adjusting parameters, adjusting different surface area volume ratios, etc., the controlled release of drugs can be realized, and there is no restricted release zone, which is more convenient for controlled release. In addition, enteric-coated polymer materials are used as the basic material for printing, so as to avoid damage to the stomach and loss of some acid-resistant drugs.

Description

A kind of 3D printing multi-layer controlled-release tablet and preparation method thereof

technical field

The invention belongs to the technical field of medical drugs, in particular to a 3D printed multilayer controlled-release tablet and a preparation method thereof.

Background technique

The existing controlled-release preparation is a dosage form that releases the drug at a regular, quantitative, and uniform rate through a controlled-release coating, so that the blood drug concentration is kept constant, so that the curative effect can be better exerted. Traditional controlled-release preparations are generally coated or made into sustained-release microspheres, which is not only complicated in process, but also low in drug loading. As a new processing method, 3D printing has already begun to be applied in the field of pharmaceutical preparations. For example, SA Khaled et al. used materials such as hydroalcoholic gel as a carrier to prepare a multi-active tablet containing captopril, nifedipine and glipizide through 3D printing technology. The tablet can be used to treat diabetes complicated with high blood pressure. Blood pressure (International Journal of Pharmaceutics 494 (2015) 643–650); WeismanJA et al. added gentamicin or methotrexate powder to polylactic acid microspheres, and prepared flake-shaped and hollow beads by 3D printing technology. Drugs, these drugs show the effect of inhibiting the growth of Escherichia coli and cancer cells (Int JNanomedicine.2015,10:357-370); CN200510018844 is a cylindrical controlled-release tablet prepared by 3D printing. The establishment of drug gradient distribution.

3D printing is based on digitalization, which can well control the process and results of processing and production. Including controlling filling rate, specific surface area, texture uniformity, etc., it has high potential in the field of making controlled-release and sustained-release pharmaceutical preparations.

Contents of the invention

In order to overcome the shortcomings and deficiencies of the above-mentioned prior art, the primary purpose of the present invention is to provide a 3D printed multi-layer controlled-release tablet. In the multi-layer controlled-release tablet of the present invention, when the drug in the outer layer is released gradually, the drug in the inner layer is gradually filled to achieve the purpose of controlled release and sustained release.

Another object of the present invention is to provide a method for preparing the above-mentioned 3D printed multilayer controlled-release tablet. In the present invention, drug-loaded materials with different drug concentrations are directly prepared by 3D printing technology to obtain a multi-layer controlled-release tablet with a low drug-loaded outer layer and a thin thickness, and a large drug-loaded inner layer with a high content. Compared with others, the drug of the present invention does not have a release-restraining zone, but directly 3D prints different drug concentration gradients, which is more convenient for controlled release and more convenient for printing. In addition, enteric-coated polymer materials are used to avoid damage to the stomach and Loss of some acid-intolerant drugs.

The object of the present invention is achieved through the following solutions:

A preparation method for 3D printing multilayer controlled-release tablets, comprising the following steps:

(1) Preparation of printing materials: add 1-3 wt% hydroxypropyl methylcellulose, 5-10 wt% alginate, 0.05-0.3 wt% calcium chloride into water and magnetically stir evenly to obtain printing materials;

(2) Drug loading: according to the concentration of the required drug in different layers, add them to the above printing materials and mix them evenly;

(3) 3D printing: the shape parameters of the drug are designed by modeling software, and multi-layer controlled-release tablets are obtained by printing with a 3D printer.

After the printing materials described in step (1) are prepared, they can be stored in the refrigerator for later use.

The 3D printer described in step (1) is preferably a printer powered by air pressure, such as 3D-BIOPLOTTER.

The printing parameters may include printing pressure of 0.2-0.5kpa, nozzle moving speed of 5-25mm/s, and printing temperature of 4-25°C.

The modeling software described in step (3) can be CAD etc.

The drug shape parameters refer to the surface area, shape, size, thickness, number of layers, etc. of the tablet.

The preparation method of the present invention uses hydroxypropyl methylcellulose as the hydrogel skeleton, alginate as the filling and forming agent, and calcium chloride as the crosslinking agent. Multilayer controlled-release tablets of surface area, shape, size and thickness.

The present invention also provides the multi-layer controlled-release tablet prepared by the above method.

In one of the embodiments, the number of layers of the multi-layer controlled-release tablet is 3-5 layers.

In one embodiment, the thickness of the outer layer of the multi-layer controlled-release tablet is 1-3 mm, and the thickness of the inner layer is 3-5 mm.

In one embodiment, the drug concentration of the multi-layer controlled-release tablet is lower than that of the inner layer, and the concentration ratio of the outer layer to the inner layer is preferably 0.2:1-0.8:1. When the drug in the outer layer is gradually released, the drug in the inner layer is gradually filled to achieve the purpose of controlled release and sustained release.

In one of the embodiments, the thickness and drug loading of each layer of the multi-layer controlled-release tablet increase gradually from the outer layer to the inner layer. The drug controlled release can be effectively realized.

In one of the embodiments, the multi-layer controlled-release tablet can be regulated to obtain different shapes, surface area and volume ratios. Said shapes may include circles, triangles, crescents, hexagons, squares, and the like.

Compared with the prior art, the present invention has the following advantages and beneficial effects:

(1) The thickness and drug loading of each layer of the multi-layer controlled-release tablet of the present invention increase progressively from the outer layer to the inner layer, and the controlled release of the drug is realized by adjusting and controlling the parameters;

(2) The shape of the multi-layer controlled-release tablet of the present invention can be changed, and different surface area-to-volume ratios can be regulated to realize controlled drug release; at the same time, patients can also choose the shape they like according to their personal preferences, thereby increasing the enthusiasm for taking medicine (especially children) ;

(3) The multi-layer controlled-release tablet of the present invention uses enteric-coated polymer as the basic material for printing, thereby avoiding damage to the stomach and loss of some acid-resistant drugs;

(4) The multi-layer controlled-release tablet of the present invention can print out the drug loading suitable for the treatment of patients (especially for the elderly and children) by changing the thickness and drug loading of each layer according to the difference in the patient's condition.

Description of drawings

Fig. 1 is a schematic diagram of the design principle of the present invention (taking 3 layers as an example), wherein, A1, A2 are outer layers, and B is an inner layer;

Fig. 2 is the model design drawing (taking 3 layers as example) of sustained-release tablet of the present invention;

Fig. 3 is the cumulative drug release curve of water-soluble anti-tuberculosis drug isoniazid (with 3 layers, a circle is an example);

Fig. 4 is fat-soluble anti-inflammatory analgesic drug aspirin cumulative release curve (taking 3 layers, circular as example);

Figure 5 is a model diagram of different shapes and different layers obtained by 3D printing control;

Figure 6 is a schematic diagram of the 3D printing process (taking 3 layers as an example).

detailed description

The present invention will be further described in detail below in conjunction with examples, but the embodiments of the present invention are not limited thereto.

All reagents used in the following examples are available from commercial sources.

See Figure 1, Figure 2 and Figure 5 for the schematic diagram of the design principle and model design diagram of the present invention, and Figure 6 for the schematic diagram of the printing process.

Example 1

It is confirmed that a patient needs to take isoniazid to treat tuberculosis, and the doctor formulates the daily dosage according to the specific situation of the patient. Patients like round tablets, so they use 3D printers to customize three-layer round sustained-release tablets. Patients only need to take one tablet a day to meet their needs. The specific method is:

(1) Preparation of printing materials: magnetically stir 2wt% hydroxypropyl methylcellulose, 5wt% alginate, 0.05wt% calcium chloride, and 92.95wt% deionized water as a solvent to obtain printing materials;

(2) Drug loading: set the concentrations of the drugs in the three-layer materials to 0.5wt%, 1wt%, and 0.5wt%, respectively, and dissolve isoniazid in the above-mentioned printing materials according to the concentrations to obtain three-layer printing materials;

(3) 3D printing: Design the medicine as a three-layer circle through modeling software. Its diameter is 12mm, and the heights of the three layers are 2mm, 4mm, and 2mm in turn. Three-layer controlled-release tablets were obtained by printing directly with the 3D-BIOPLOTTER 3D printing head, the printing pressure was 0.2kpa, the moving speed of the nozzle was 20mm/s, and the printing temperature was 10°C.

The drug release performance of the obtained tablets was studied, and the drug release curve is shown in Figure 3. It can be seen from the figure that the in vitro drug release presents zero-order release within 0 to 8 hours, followed by effective sustained release. The metabolism in the body is relatively fast during the daytime activities, and stable administration is achieved; during the night, the metabolism is relatively slow as the human body is dormant, and the second half of the drug is slowly released to meet the demand.

Example 2

A person who is diagnosed with arthritis needs to take aspirin for a long time. This design uses enteric-coated materials to avoid stomach damage caused by long-term medication. The doctor formulates the daily dosage according to the specific situation of the patient. Patients like round tablets, so they use 3D printers to customize three-layer round sustained-release tablets. Patients only need to take one tablet a day to meet their needs. The specific methods are as follows:

(1) Preparation of printing materials: magnetically stir 2wt% hydroxypropyl methylcellulose, 5wt% alginate, 0.05wt% calcium chloride, and 92.95wt% deionized water as a solvent to obtain printing materials;

(2) Drug loading: set the concentrations of the drugs in the three-layer materials to 0.5wt%, 1wt%, and 0.5wt%, respectively, and dissolve aspirin in the above-mentioned printing materials according to the concentrations to obtain three-layer printing materials;

(3) 3D printing: Design the medicine as a three-layer circle through modeling software. Its diameter is 12mm, and the heights of the three layers are 2mm, 4mm, and 2mm in turn. The three-layer controlled-release tablet was directly printed with the 3D printing head, the printing pressure was 0.2kpa, the moving speed of the nozzle was 15mm/s, and the printing temperature was 4°C.

The drug release performance of the obtained tablets was studied, and the drug release curve is shown in Figure 4. It can be seen from the figure that the in vitro drug release presents zero-order release within 0 to 8 hours, followed by effective sustained release. The metabolism in the body is relatively fast during the daytime activities, and stable administration is achieved; during the night, the metabolism is relatively slow as the human body is dormant, and the second half of the drug is slowly released to meet the demand.

Embodiment 3: the preparation of five-layer square controlled-release doxorubicin tablet

(1) Preparation of printing materials: magnetically stir 1wt% hydroxypropyl methylcellulose, 10wt% alginate, 0.05wt% calcium chloride with 88.95wt% deionized water as a solvent to obtain printing materials;

(2) Drug loading: respectively set the concentration of the drug in the five-layer materials to 0.2wt%, 0.4wt%, 0.8wt%, 0.4wt%, 0.2wt%, and dissolve adriamycin in the above-mentioned printing materials according to the concentration, Get five layers of printing materials;

(3) 3D printing: Design the drug into a five-layer square through modeling software. Its diameter is 12mm, and the heights of the three layers are 1mm, 2mm, 3mm, 2mm, and 1mm. Directly use the 3D printing head to print to obtain five-layer controlled-release tablets, the printing pressure is 0.3kpa, the moving speed of the nozzle is 5mm/s, and the printing temperature is 20°C.

Example 4: Preparation of five-layer triangular controlled-release isoniazid tablets

(1) Preparation of printing materials: magnetically stir 1wt% hydroxypropyl methylcellulose, 5wt% alginate, 0.3wt% calcium chloride with 93.7wt% deionized water as a solvent to obtain printing materials;

(2) Drug loading: respectively set the concentration of the drug in the five-layer materials to 0.1wt%, 0.2wt%, 0.4wt%, 0.2wt%, 0.1wt%, and dissolve adriamycin in the above-mentioned printing materials according to the concentration, Get five layers of printing material;

(3) 3D printing: Design the drug as a five-layer triangle through modeling software. The side length is 10mm, and the heights of the three layers are 1mm, 2mm, 3mm, 2mm, and 1mm in turn. Directly use the 3D printing head to print to obtain five-layer controlled-release tablets, the printing pressure is 0.3kpa, the moving speed of the nozzle is 5mm/s, and the printing temperature is 20°C.

Example 5: Preparation of five-layer circular controlled-release doxorubicin tablets

(1) Preparation of printing materials: magnetically stir 1wt% hydroxypropyl methylcellulose, 7wt% alginate, 0.2wt% calcium chloride with 91.8wt% deionized water as a solvent to obtain printing materials;

(2) Drug loading: respectively set the concentration of the drug in the five-layer materials to 0.1wt%, 0.2wt%, 0.4wt%, 0.2wt%, 0.1wt%, and dissolve adriamycin in the above-mentioned printing materials according to the concentration, Get five layers of printing materials;

(3) 3D printing: Design the drug into a five-layer circle through modeling software. Its diameter is 10mm, and the heights of the three layers are 1mm, 2mm, 3mm, 2mm, and 1mm. Directly use the 3D printing head to print to obtain five-layer controlled-release tablets, the printing pressure is 0.3kpa, the moving speed of the nozzle is 15mm/s, and the printing temperature is 15°C.

Example 6: Preparation of three-layer star-shaped controlled-release isoniazid tablets

(1) Preparation of printing materials: magnetically stir 3wt% hydroxypropyl methylcellulose, 6wt% alginate, 0.1wt% calcium chloride, and 90.9wt% deionized water as a solvent to obtain printing materials;

(2) Drug loading: set the concentrations of the drugs in the three-layer materials to 0.5wt%, 1wt%, and 0.5wt%, respectively, and dissolve aspirin in the above-mentioned printing materials according to the concentrations to obtain three-layer printing materials;

(3) 3D printing: Design the drug into a three-layer star shape through modeling software. The side length is 10mm, and the heights of the three layers are 2mm, 4mm, and 2mm in turn. A three-layer controlled-release tablet was obtained by printing directly with a 3D printing head. The printing pressure was 0.3kpa, the moving speed of the nozzle was 20mm/s, and the printing temperature was 20°C.

Example 7: Preparation of three-layer square controlled-release isoniazid tablets

(1) Preparation of printing materials: magnetically stir 3wt% hydroxypropyl methylcellulose, 8wt% alginate, 0.05wt% calcium chloride, and 88.95wt% deionized water as a solvent to obtain printing materials;

(2) Drug loading: set the concentrations of the drugs in the three-layer materials to 0.5wt%, 1wt%, and 0.5wt%, respectively, and dissolve aspirin in the above-mentioned printing materials according to the concentrations to obtain three-layer printing materials;

(3) 3D printing: Design the drug into a three-layer square through modeling software. The side length is 10mm, and the heights of the three layers are 1mm, 2mm, and 1mm in turn. The three-layer controlled-release tablet was obtained by printing directly with the 3D printing head, the printing pressure was 0.5kpa, the moving speed of the nozzle was 10mm/s, and the printing temperature was 25°C.

Embodiment 8: Preparation of three-layer triangular controlled-release doxorubicin tablet

(1) Preparation of printing materials: magnetically stir 2wt% hydroxypropyl methylcellulose, 9wt% alginate, 0.05wt% calcium chloride, and 88.95wt% deionized water as a solvent to obtain printing materials;

(2) Drug loading: set the concentrations of the drugs in the three-layer materials to 0.5wt%, 1wt%, and 0.5wt%, respectively, and dissolve aspirin in the above-mentioned printing materials according to the concentrations to obtain three-layer printing materials;

(3) 3D printing: Design the drug as a three-layer triangle through modeling software. The side length is 10mm, and the heights of the three layers are 2mm, 4mm, and 2mm in turn. The three-layer controlled-release tablet was obtained by printing directly with the 3D printing head, the printing pressure was 0.3kpa, the moving speed of the nozzle was 18mm/s, and the printing temperature was 15°C.

Embodiment 9: Preparation of three-layer square controlled-release doxorubicin tablet

(1) Preparation of printing materials: magnetically stir 3wt% hydroxypropyl methylcellulose, 8wt% alginate, 0.05wt% calcium chloride, and 88.95wt% deionized water as a solvent to obtain printing materials;

(2) Drug loading: set the concentrations of the drugs in the three-layer materials to 0.5wt%, 1wt%, and 0.5wt%, respectively, and dissolve aspirin in the above-mentioned printing materials according to the concentrations to obtain three-layer printing materials;

(3) 3D printing: Design the drug into a three-layer square through modeling software. The side length is 10mm, and the heights of the three layers are 1mm, 2mm, and 1mm in turn. The three-layer controlled-release tablet was obtained by printing directly with the 3D printing head, the printing pressure was 0.5kpa, the moving speed of the nozzle was 10mm/s, and the printing temperature was 25°C.

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included in the protection scope of the present invention.

Claims (10)

1. a kind of preparation method of 3D printing multilamellar controlled-release pharmaceutical tablet, it is characterised in that comprise the following steps：

(1) preparation of printed material：By 1～3wt% hydroxypropyl methyl celluloses, 5～10wt% alginates, 0.05～ 0.3wt% calcium chloride is added to the water magnetic agitation uniformly, obtains printed material；

(2) medicine is carried：The concentration of medicine according to needed for different layers, is separately added in above-mentioned printed material, mix homogeneously；

(3) 3D printing：By modeling software design medicine form parameter, printed using 3D printer and obtain multilamellar controlled-release pharmaceutical tablet.

2. the preparation method of 3D printing multilamellar controlled-release pharmaceutical tablet according to claim 1, it is characterised in that：Institute in step (1) The 3D printer that states is the printer with air pressure as power.

3. the preparation method of 3D printing multilamellar controlled-release pharmaceutical tablet according to claim 1, it is characterised in that：Institute in step (1) It is 0.2～0.5kpa that the parameter of printing is stated for printing pressure, and shower nozzle translational speed is 5～25mm/s, 4～25 DEG C of print temperature.

4. the preparation method of 3D printing multilamellar controlled-release pharmaceutical tablet according to claim 1, it is characterised in that：Described medicine shape Shape parameter refers to the surface area of tablet, shape, size, thickness, the number of plies.

5. a kind of 3D printing multilamellar controlled-release pharmaceutical tablet, it is characterised in that the preparation method according to any one of Claims 1 to 4 is obtained Arrive.

6. 3D printing multilamellar controlled-release pharmaceutical tablet according to claim 5, it is characterised in that：The number of plies of the multilamellar controlled-release pharmaceutical tablet For 3～5 layers.

7. 3D printing multilamellar controlled-release pharmaceutical tablet according to claim 5, it is characterised in that：The outer layer of the multilamellar controlled-release pharmaceutical tablet Thickness is 1～3mm, and internal layer thickness is 3～5mm.

8. 3D printing multilamellar controlled-release pharmaceutical tablet according to claim 5, it is characterised in that：The multilamellar controlled-release pharmaceutical tablet carries medicine Concentration is that outer layer concentration is low with respect to internal layer load concentration.

9. 3D printing multilamellar controlled-release pharmaceutical tablet according to claim 5, it is characterised in that：The multilamellar controlled-release pharmaceutical tablet carries medicine Concentration, outer layer are 0.2 with internal layer concentration ratio：1～0.8：1.

10. 3D printing multilamellar controlled-release pharmaceutical tablet according to claim 5, it is characterised in that：The shape of the multilamellar controlled-release pharmaceutical tablet Shape includes circle, triangle, crescent, hexagon, square.