Propranolol sustained release tablet as well as preparation method and application thereof

Abstract

The present invention relates to a propranolol hydrochloride sustained release tablet, the sustained release tablet is prepared by filling a 3D printing shell with a 3D printing propranolol hydrochloride tablet core, and the tablet core contains 5-20% by weight of propranolol hydrochloride, 35-50% by weight of a lipid material, 20-35% by weight of a filler and 15-25% by weight of a plasticizer. The propranolol hydrochloride sustained-release tablet with the core-shell structure is prepared by filling the 3D printing shell with the 3D printing propranolol hydrochloride tablet core for the first time, medicine release is precisely regulated and controlled, precise administration is realized, plasma concentration release is stable, and bioavailability, medication safety and effectiveness and medication compliance are remarkably improved.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly relates to a propranolol sustained-release tablet, a preparation method thereof, and an application thereof. Background Art

[0002] Hypertension is the most important risk factor for cardiovascular and cerebrovascular diseases, commonly seen in middle-aged and elderly people. In recent years, the onset window of hypertension has gradually shifted forward, and the incidence of childhood hypertension has been increasing year by year. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, β-blockers, and diuretics have become the main antihypertensive drugs used clinically.

[0003] The liver and kidney functions, central nervous system, and endocrine system of children (especially infants and young children) are not fully developed, and there are significant differences in physiology, pathology, immunity, etc. between children and adults. Their pharmacokinetics and pharmacodynamics are significantly different from those of adults, and they are characterized by poor drug tolerance and a high incidence of drug adverse reactions. Factors such as the height, weight, and blood pressure of children are directly related to the dosage of antihypertensive drugs, and long-term medication is required. Therefore, it is crucial to ensure the dosage accuracy and medication safety of pediatric-specific dosage forms.

[0004] Pediatric preparations are characterized by a large number of clinical use specifications, small batch sizes, and high costs. The "2019-2025 China Pediatric Medicine Market Panorama Survey and Development Prospect Forecast Report" shows that more than 90% of chemical drug preparations in China do not have dosage forms suitable for pediatric use, and pediatric preparations are seriously insufficient. At present, clinical practice mostly solves the problem of pediatric medication by dividing the dosage of adult preparations or having pharmacists prepare adult preparations into suspensions, which leads to problems such as the destruction of the preparation structure, cross-contamination during dispensing, poor stability, poor distribution uniformity, interaction between the solvent and the drug, unstable bioavailability, inaccurate dosage, and adverse medication events.

[0005] Propranolol Hydrochloride, as a classic non-selective β-blocker and cardiovascular drug, is widely used clinically to treat various cardiovascular diseases such as arrhythmia, angina pectoris, hypertension, pheochromocytoma (preparation before surgery), supraventricular tachycardia, and tachycardia related to hyperthyroidism. It is preferentially recommended because of its broad spectrum of indications, definite efficacy, and excellent cost-effectiveness, and has been continuously included in the World Health Organization (WHO) Essential Medicines List (EML) since 1977. Although children need to use it with caution (such as metabolic differences and long-term side effect risks), propranolol is still used as an essential drug for treating supraventricular tachycardia in infants, postoperative complications of congenital heart disease, etc., and is indispensable especially in pediatric emergencies. Its efficacy in treating pediatric tachyarrhythmia (such as atrioventricular nodal reentrant tachycardia) is significant.

[0006] Propranolol hydrochloride ordinary tablets have low bioavailability (only about 25%), short half-life (about 3 - 4 h), and patients need to take the drug 2 - 3 times a day, resulting in large fluctuations in blood drug concentration. There may even be missed doses, drug side effects, and it affects the treatment effect. The propranolol hydrochloride sustained-release preparation prolongs the gastrointestinal residence time of the drug, significantly increases drug absorption, maintains a stable blood drug concentration, significantly improves bioavailability, drug safety and effectiveness, and medication compliance. However, there are defects such as poor sustained-release effect, the aqueous preparation affecting drug stability, large amounts of matrix materials (such as ethylcellulose, acrylic resin, lactose, microcrystalline cellulose, etc.), and complex preparation. Propranolol hydrochloride is slightly soluble in water and is sensitive to light, heat, and humidity. It needs to be stored under strict temperature control and light protection. It is necessary to improve its formulation performance and also take into account the dosage accuracy and medication safety of pediatric-specific dosage forms.

[0007] The American Academy of Pediatrics' "Clinical Practice Guidelines for the Screening and Management of Hypertension in Children and Adolescents" (2017) recommends that the daily dose of propranolol hydrochloride for outpatient antihypertensive treatment of children with hypertension is 0.06 - 0.30 mg / kg. The scored shaped tablets still cannot meet the medication needs of children, and the inaccurate dosage affects the effectiveness and safety of medication, and it is difficult to meet the clinical medication needs of patients with swallowing difficulties and poor medication compliance such as children, the elderly, and critically ill patients.

[0008] 3D printing technology (3D printing, 3DP) is an additive manufacturing and rapid prototyping technology. Based on a three-dimensional model of computer-aided design (Computer Aided Design, CAD), it is a manufacturing technology that constructs objects by printing materials layer by layer, including powder binding (Powder Binding, PB), fused deposition modeling (Fused Deposition Modeling, FDM), semi-solid extrusion (Semi Solid Extrusion, SSE), stereolithography (Stereolithography, SLA), etc. By selecting printing materials, optimizing process parameters, and model structure design (such as size, shape, structure, and dosage, etc.), it can precisely control the appearance, dosage, and release characteristics of drugs, providing more accurate, effective, and personalized therapeutic drugs for clinical use.

[0009] CN115414332A discloses a 3D printed immediate-release preparation of propranolol hydrochloride. Since the preparation contains water during preparation and requires drying treatment, the operation is cumbersome and cannot meet the diverse clinical medication needs. Therefore, there is an urgent need to develop a new preparation that is convenient for cardiovascular and cerebrovascular patients to use. Summary of the Invention

[0010] The object of the present invention is to provide a propranolol hydrochloride sustained-release tablet, which is prepared by filling a 3D-printed propranolol hydrochloride tablet core into a 3D-printed outer shell. Among them, by weight percentage, the tablet core contains 5-20% of propranolol hydrochloride, 35-50% of lipid material, 20-35% of filler, and 15-25% of plasticizer.

[0011] In a preferred technical solution of the present invention, by weight percentage, the propranolol hydrochloride contained in the tablet core is 8-12%.

[0012] In a preferred technical solution of the present invention, the lipid material is selected from any one or a combination of polyethylene glycol 32 stearate, phospholipid, cholesterol, and fat emulsion.

[0013] In a preferred technical solution of the present invention, by weight percentage, the lipid material contained in the tablet core is 40-45%.

[0014] In a preferred technical solution of the present invention, the filler is selected from any one or a combination of mannitol, starch, microcrystalline cellulose, MCC105, lactose, dextrin, powdered sugar, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch, calcium chloride, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, sorbitol, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sucrose, maltitol, crospovidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and calcium carboxymethyl cellulose.

[0015] In a preferred technical solution of the present invention, by weight percentage, the filler contained in the tablet core is 23-30%.

[0016] In a preferred technical solution of the present invention, the plasticizer is selected from any one or a combination of glycerol, polyethylene glycol (PEG), PEG200, PEG400, PEG600, PEG800, PEG1000, PEG1000, PEG1200, PEG1400, PEG1600, PEG1800, PEG2000, PEG4000, PEG6000, PEG8000, dibutyl sebacate, sorbitol, dioctyl phthalate (DOP), dibutyl phthalate (DBP), dioctyl adipate (DOA), dioctyl sebacate (DOS), tricresyl phosphate (TCP), and trioctyl phosphate (TOP).

[0017] In a preferred technical solution of the present invention, by weight percentage, the plasticizer contained in the tablet core is 17-23%.

[0018] In a preferred technical solution of the present invention, by weight percentage, the tablet core contains 8-12% of propranolol hydrochloride, 40-45% of lipid material, 23-30% of filler and 17-23% of plasticizer.

[0019] In a preferred technical solution of the present invention, by weight percentage, the tablet core contains 10% of propranolol hydrochloride, 44% of Gelucire 48 / 16, 29% of MCC 105 and 17% of PEG 400.

[0020] In a preferred technical solution of the present invention, the filling rate of the tablet core is 10-30%, preferably 20-30%.

[0021] In a preferred technical solution of the present invention, the shape of the tablet core is selected from any one or a combination of circular, annular, square, rhombus, pea-shaped, capsule-shaped, cloud-shaped, petal-shaped, heart-shaped, animal-shaped.

[0022] In a preferred technical solution of the present invention, the material for forming the 3D printed outer shell is selected from any one or a combination of polylactic acid (PLA) and acrylonitrile-butadiene-styrene copolymer (ABS).

[0023] In a preferred technical solution of the present invention, the release window area of the 3D printed outer shell is 9-126 mm 2 , preferably 36-63 mm 2 .

[0024] In a preferred technical solution of the present invention, the size of the release window of the 3D printed outer shell is (1-3) mm * (1-3) mm, preferably (2-3) mm * (2-3) mm.

[0025] In a preferred technical solution of the present invention, the number of release windows of the 3D printed outer shell is 5-25.

[0026] In a preferred technical solution of the present invention, the preparation of the sustained release tablets comprises the following steps:

[0027] (1) Prepare 3D printed propranolol hydrochloride tablet cores by semi-solid extrusion (SSE) technology;

[0028] (2) Obtain the 3D printed outer shell by fused deposition modeling (FDM);

[0029] (3) Fill the propranolol hydrochloride tablet cores into the 3D printed outer shell to obtain the product.

[0030] In the preferred technical solution of the present invention, the preparation of the tablet core includes the following steps: Under stirring conditions, heat the required amount of lipid material to 60-80 °C. After melting, add the required amount of propranolol hydrochloride, filler and plasticizer, mix evenly, and prepare the propranolol hydrochloride tablet core by semi-solid extrusion technology.

[0031] In the preferred technical solution of the present invention, the stirring speed is 50-300 rpm, preferably 70-200 rpm.

[0032] In the preferred technical solution of the present invention, the preparation of the propranolol hydrochloride tablet core includes the following steps: Use 3ds Max software to design the tablet core model, export it in the format of (.stl) file, and load it into Repetier-Host V2.0.5 for slicing.

[0033] In the preferred technical solution of the present invention, the tablet core model is a cylinder with a diameter of (13.00 mm) * height of (3.00 mm).

[0034] In the preferred technical solution of the present invention, the size of the 3D printing nozzle in the tablet core preparation is 0.6-0.8 mm.

[0035] In the preferred technical solution of the present invention, the tablet core is preheated at the printing temperature for 20-50 min, preferably 30-40 min.

[0036] In the preferred technical solution of the present invention, the printing temperature of the tablet core is 40-50 °C, preferably 41-46 °C.

[0037] In the preferred technical solution of the present invention, the printing layer height of the tablet core is 0.5-1.0 mm, preferably 0.6-0.8 mm.

[0038] In the preferred technical solution of the present invention, the printing rate of the tablet core is 10-45 mm / s, preferably 15-40 mm / s.

[0039] In the preferred technical solution of the present invention, the filling method of the tablet core is selected from any one or a combination of grid filling, concentric circle filling, and honeycomb filling.

[0040] In the preferred technical solution of the present invention, PLA is used to prepare the 3D printing outer shell.

[0041] In the preferred technical solution of the present invention, the size of the printing nozzle in the preparation of the 3D printing outer shell is 0.2-0.4 mm.

[0042] In the preferred technical solution of the present invention, the printing layer height in the preparation of the 3D printing outer shell is 0.1-0.5 mm.

[0043] In the preferred technical solution of the present invention, the printing temperature in the preparation of the 3D printed outer shell is 150 - 200 °C.

[0044] In the preferred technical solution of the present invention, the printing rate in the preparation of the 3D printed outer shell is 50 - 70 mm / s.

[0045] In the preferred technical solution of the present invention, the hardness of the sustained release tablet is greater than 150 N.

[0046] Another object of the present invention is to provide a method for preparing a propranolol hydrochloride sustained release tablet, wherein the sustained release tablet is made by filling a 3D printed propranolol hydrochloride tablet core into a 3D printed outer shell. Among them, by weight percentage, the tablet core contains 5 - 20% of propranolol hydrochloride, 35 - 50% of lipid material, 20 - 35% of filler and 15 - 25% of plasticizer. The method includes the following steps:

[0047] (1) Prepare a 3D printed propranolol hydrochloride tablet core by using semi - solid extrusion (SSE) technology;

[0048] (2) Prepare a 3D printed outer shell by using fused deposition modeling (FDM);

[0049] (3) Fill the propranolol hydrochloride tablet core into the 3D printed outer shell to obtain the product.

[0050] In the preferred technical solution of the present invention, the preparation of the tablet core includes the following steps: Under stirring conditions, heat the required amount of lipid material to 60 - 80 °C, and after melting, add the required amount of propranolol hydrochloride, filler and plasticizer. After uniform mixing, prepare the propranolol hydrochloride tablet core by using semi - solid extrusion technology.

[0051] In the preferred technical solution of the present invention, the stirring speed is 50 - 300 rpm, preferably 70 - 200 rpm.

[0052] In the preferred technical solution of the present invention, the preparation of the propranolol hydrochloride tablet core includes the following steps: Use 3dsMax software to design the tablet core model, export it in the format of (.stl) file, and load it into Repetier - Host V2.0.5 for slicing.

[0053] In the preferred technical solution of the present invention, the tablet core model is a cylinder with a diameter of (13.00 mm) * height of (3.00 mm).

[0054] In the preferred technical solution of the present invention, the size of the 3D printing nozzle in the preparation of the tablet core is 0.60 - 0.8 mm.

[0055] In the preferred technical solution of the present invention, the tablet core is pre - heated at the printing temperature for 20 - 50 min, preferably 30 - 40 min.

[0056] In the preferred technical solution of the present invention, the printing temperature of the tablet core is 40 - 50 °C, preferably 41 - 46 °C.

[0057] In the preferred technical solution of the present invention, the printing layer height of the tablet core is 0.5 - 1.0 mm, preferably 0.6 - 0.8 mm.

[0058] In the preferred technical solution of the present invention, the printing rate of the tablet core is 10 - 45 mm / s, preferably 15 - 40 mm / s.

[0059] In the preferred technical solution of the present invention, the filling method of the tablet core is selected from any one or a combination of grid filling, concentric circle filling, and honeycomb filling.

[0060] In the preferred technical solution of the present invention, PLA is used to prepare the 3D printing shell.

[0061] In the preferred technical solution of the present invention, the size of the printing nozzle in the preparation of the 3D printing shell is 0.2 - 0.4 mm.

[0062] In the preferred technical solution of the present invention, the printing layer height in the preparation of the 3D printing shell is 0.1 - 0.5 mm.

[0063] In the preferred technical solution of the present invention, the printing temperature in the preparation of the 3D printing shell is 150 - 200 °C.

[0064] In the preferred technical solution of the present invention, the printing rate in the preparation of the 3D printing shell is 50 - 70 mm / s.

[0065] In the preferred technical solution of the present invention, the hardness of the sustained-release tablet is greater than 150 N.

[0066] In the preferred technical solution of the present invention, calculated by weight percentage, the propranolol hydrochloride contained in the tablet core is 8 - 12%.

[0067] In the preferred technical solution of the present invention, the lipid material is selected from any one or a combination of polyethylene glycol 32 stearate, phospholipid, cholesterol, and fat emulsion.

[0068] In the preferred technical solution of the present invention, calculated by weight percentage, the lipid material contained in the tablet core is 40 - 45%.

[0069] In the preferred technical solution of the present invention, the filler is selected from any one or a combination of mannitol, starch, microcrystalline cellulose, MCC105, lactose, dextrin, powdered sugar, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch, calcium chloride, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, sorbitol, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, sucrose, maltitol, sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose.

[0070] In the preferred technical solution of the present invention, based on weight percentage, the filler contained in the tablet core is 23-30%.

[0071] In the preferred technical solution of the present invention, the plasticizer is selected from any one or a combination of glycerol, polyethylene glycol (PEG), PEG200, PEG400, PEG600, PEG800, PEG1000, PEG1000, PEG1200, PEG1400, PEG1600, PEG1800, PEG2000, PEG4000, PEG6000, PEG8000, dibutyl sebacate, sorbitol, dioctyl phthalate (DOP), dibutyl phthalate (DBP), dioctyl adipate (DOA), dioctyl sebacate (DOS), tricresyl phosphate (TCP), trioctyl phosphate (TOP).

[0072] In the preferred technical solution of the present invention, based on weight percentage, the plasticizer contained in the tablet core is 17-23%.

[0073] In the preferred technical solution of the present invention, based on weight percentage, the tablet core contains 8-12% propranolol hydrochloride, 40-45% lipid material, 23-30% filler, and 17-23% plasticizer.

[0074] In the preferred technical solution of the present invention, based on weight percentage, the tablet core contains 10% propranolol hydrochloride, 44% Gelucire 48 / 16, 29% MCC 105, and 17% PEG 400.

[0075] In the preferred technical solution of the present invention, the filling rate of the tablet core is 10-30%, preferably 20-30%.

[0076] In the preferred technical solution of the present invention, the shape of the tablet core is selected from any one or a combination of circular, annular, square, rhombic, pea-shaped, capsule-shaped, cloud-shaped, petal-shaped, heart-shaped, animal-shaped.

[0077] In the preferred technical solution of the present invention, the material for forming the 3D printed outer shell is selected from any one of polylactic acid (PLA) and acrylonitrile-butadiene-styrene copolymer (ABS) or a combination thereof.

[0078] In the preferred technical solution of the present invention, the release window area of the 3D printed outer shell is 9 - 126 mm 2 , preferably 36 - 63 mm 2 .

[0079] In the preferred technical solution of the present invention, the size of the release window of the 3D printed outer shell is (1 - 3) mm * (1 - 3) mm, preferably (2 - 3) mm * (2 - 3) mm.

[0080] In the preferred technical solution of the present invention, the number of release windows of the 3D printed outer shell is 5 - 25.

[0081] Another object of the present invention is to provide the use of propranolol hydrochloride sustained release tablets in the preparation of drugs for the treatment of cardiovascular and cerebrovascular diseases.

[0082] In the preferred technical solution of the present invention, the propranolol hydrochloride sustained release tablets are 3D printed preparations.

[0083] In the preferred technical solution of the present invention, the cardiovascular and cerebrovascular diseases are selected from any one of hypertension, coronary heart disease, chronic stable angina pectoris, variant angina pectoris, arrhythmia caused by various reasons, angina pectoris, hypertension, pheochromocytoma (preoperative preparation), supraventricular tachycardia, tachycardia related to hyperthyroidism, supraventricular tachycardia in infants, postoperative complications of congenital heart disease, rapid arrhythmia in children, atrioventricular nodal reentrant tachycardia in children or a combination or complication thereof.

[0084] In the preferred technical solution of the present invention, the patients with cardiovascular and cerebrovascular diseases are selected from any one of infant patients, child patients, adult patients, elderly patients, and critically ill patients.

[0085] In the preferred technical solution of the present invention, the patients with cardiovascular and cerebrovascular diseases are any one or a combination of patients who need precise dose adjustment and patients with dysphagia.

[0086] In the preferred technical solution of the present invention, the propranolol hydrochloride sustained release tablets are used in combination with other cardiovascular and cerebrovascular disease drugs.

[0087] In the preferred technical solution of the present invention, the other cardiovascular and cerebrovascular disease drugs are selected from any one or a combination of hydrochlorothiazide, bendroflumethiazide, chlorthalidone, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, aspirin, clopidogrel, tirofiban, unfractionated heparin, low molecular weight heparin, fondaparinux sodium, bivalirudin, streptokinase, urokinase, tissue-type plasminogen activator, metoprolol, atenolol, bisoprolol, carvedilol, arotinolol, verapamil, nifedipine, diltiazem, enalapril, benazepril, captopril, lisinopril, trandolapril, imidapril, ramipril, fosinopril, valsartan, telmisartan, irbesartan, losartan, candesartan, lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, indapamide, lidocaine, levodopa.

[0088] The present invention uses high performance liquid chromatography to detect the content of propranolol hydrochloride in the tablet core: Weigh an appropriate amount of the tablet core precisely, and use the mobile phase to prepare a propranolol hydrochloride solution with a concentration of 0.2 mg / mL. The chromatographic column is packed with octadecylsilane chemically bonded silica gel (C18 column, 4.6×250 mm, 5 μm). The detection wavelength is 292 nm; the flow rate is 1.8 mL / min; the column temperature is 30 °C; the injection volume is 20 μL, and the injection time is 7 min.

[0089] Preparation of the mobile phase: Under stirring conditions, add 1.6 g of sodium dodecyl sulfate and 0.31 g of tetrabutylammonium dihydrogen phosphate to 400 mL of water. Slowly add 1 mL of concentrated sulfuric acid, then add 550 mL of acetonitrile. After mixing evenly, adjust the pH to 3.3 with 2 mol / L sodium hydroxide solution, and make up the volume to 1000 mL with water to obtain it.

[0090] Unless otherwise specified, when the present invention involves the percentage between liquids, the percentage is volume / volume percentage; when the present invention involves the percentage between a liquid and a solid, the percentage is volume / weight percentage; when the present invention involves the percentage between a solid and a liquid, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[0091] Compared with the prior art, the present invention has the following beneficial effects:

[0092] 1. The present invention first uses the SSE printing technology and scientifically selects polyethylene glycol-32-stearate, microcrystalline cellulose 105 (MCC105), polyethylene glycol 400 (PEG400) and their ratios, and the core filling rate to prepare the propranolol hydrochloride core. The FDM printing technology is used and any one or a combination of biodegradable polylactic acid (PLA) and acrylonitrile-butadiene-styrene copolymer (ABS) is scientifically selected to prepare the 3D printing shell. Moreover, the release area, size, quantity, etc. of the release window of the shell are scientifically screened, and the propranolol hydrochloride core is loaded into the shell to obtain the core-shell structured sustained-release tablets (CSRT) of propranolol hydrochloride, accurately regulating drug release and achieving precise drug delivery, with a stable release of blood drug concentration, significantly improving bioavailability, the safety and effectiveness of drug use, and drug compliance.

[0093] 2. The preparation method of the propranolol hydrochloride sustained-release tablets of the present invention has the advantages of simple operation, environmental friendliness, better cost, and suitability for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Figure 1 Observation results of the propranolol hydrochloride core of the present invention;

[0095] Figure 2 Observation results of the release window of the shell of the propranolol hydrochloride sustained-release tablets of the present invention;

[0096] Figure 3 XRD diffraction test results of the crystal form of the propranolol hydrochloride core of the present invention;

[0097] FIG. 4 Investigation of the dissolution behavior of the propranolol hydrochloride sustained-release tablets of the present invention. A is the dissolution curve of the 3D printed propranolol hydrochloride core prepared in Examples 3-7; B is the dissolution curve of the propranolol hydrochloride sustained-release tablets prepared in Examples 5 and 8. DETAILED DESCRIPTION OF THE INVENTION

[0098] The present invention will be specifically described below with reference to the examples. The examples of the present invention are only used to illustrate the technical solutions of the present invention and do not limit the essence of the present invention.

[0099] UP BOX+Fused Deposition 3D Printer (Beijing Tiertime Technology Co., Ltd.); M3DI MAKER Semi-Solid Extrusion 3D Printer (FABRX Biotechnology Co., Ltd., UK). Gelucire 48 / 16 (Gattefossé, France).

[0100] Example 1 Preparation of the propranolol hydrochloride sustained-release tablets of the present invention

[0101] The preparation of propranolol hydrochloride sustained-release tablets includes the preparation of the 3D-printed propranolol hydrochloride tablet core and the preparation of the 3D-printed outer shell.

[0102] 1. Preparation of the 3D-printed propranolol hydrochloride tablet core

[0103] Composition of the 3D-printed propranolol hydrochloride tablet core:

[0104] Component Dosage (g) Propranolol Hydrochloride 10 PEG 400 20 MCC 105 30 Gelucire 48 / 16 40

[0105] The preparation of the 3D-printed propranolol hydrochloride tablet core includes the following steps:

[0106] (1) Under stirring (200 rpm), heat the required amount of Gelucire 48 / 16 to 60 °C until melted, then add the required amount of propranolol hydrochloride, PEG400, and MCC105. After mixing evenly, fill it into a 20 mL 3D-printing special syringe. After sealing the syringe plunger and the screw cap, pack it in a polyester / aluminum / polyethylene bag and seal it for storage;

[0107] (2) Use 3ds Max software to design a cylindrical core model (diameter 13.00 mm * height 3.00 mm), export it in the (.stl) format file, load it into Repetier-Host V2.0.5 for slicing. Printing parameters: 0.60 mm tapered stainless steel needle, printing temperature 42 °C, initial layer height 0.60 mm, layer thickness 0.60 mm, nozzle movement speed for the outer circle: 20 mm·s -1 , for the inner part: 16 mm·s-1, number of outer circles 2, import the generated g-code file into the M3DI MAKER semi-solid extrusion 3D printer, and set the filling rate to 10% for printing to obtain the 3D-printed propranolol hydrochloride tablet core.

[0108] After testing, the filling fluidity and printing feasibility of the 3D-printed propranolol hydrochloride tablet core are good, the average weight is 0.314 g ± 3.79%, and the disintegration time is 3 min 48 s - 4 min 10 s.

[0109] 2. Preparation of the 3D-printed outer shell

[0110] (1) Import the model (cylinder: 13.00 mm * 13.00 mm * 3.00 mm, release window size 2.00 mm * 2.00 mm, 9 release windows, release window area 36 mm 2 ) in the (.stl) format file into the slicing software Repetier-Host V2.0.5, generate a g-code file and import it into the UP BOX+ fused deposition 3D printer;

[0111] (2) Use PLA as the shell material for printing, with a nozzle diameter of 0.20 mm, a layer height of 0.10 mm, a printing temperature of 195 °C, and a printing speed of 70 mm·s -1 , and obtain a 3D printed shell;

[0112] 3. Load the 3D printed propranolol hydrochloride tablet core into the 3D printed shell for assembly to obtain the propranolol hydrochloride sustained release tablet.

[0113] Example 2 Preparation of the propranolol sustained release tablet of the present invention

[0114] The preparation of the propranolol hydrochloride sustained release tablet includes the preparation of the 3D printed propranolol hydrochloride tablet core and the preparation of the 3D printed shell.

[0115] 1. Preparation of the 3D printed propranolol hydrochloride tablet core

[0116] Composition of the 3D printed propranolol hydrochloride tablet core:

[0117] Component Dosage (g) Propranolol Hydrochloride 10 PEG 400 20 MCC 105 26 Gelucire 48 / 16 44

[0118] The preparation of the 3D printed propranolol hydrochloride tablet core includes the following steps:

[0119] (1) Under stirring (200 rpm), heat Geluci re 48 / 16 to 60 °C until melted, add the required amount of propranolol hydrochloride, PEG400, and MCC105, mix evenly, fill it into a 20 mL 3D printing special syringe, seal the syringe plunger and screw cap, and then pack and seal it in a polyester / aluminum / polyethylene bag for storage;

[0120] (2) Use 3ds Max software to design a cylindrical core model (diameter 13.00 mm * height 3.00 mm), export it in the format of a (.stl) file, load it into Repet ier-Host V2.0.5 for slicing, and the printing parameters are: a 0.60 mm tapered stainless steel needle, a printing temperature of 42 °C, an initial layer height of 0.60 mm, a layer thickness of 0.60 mm, the nozzle moving speed of the outer circle: 20 mm·s -1 , the inner circle: 16 mm·s-1, the number of outer circles is 2, import the generated g-code file into the M3DI MAKER semi-solid extrusion 3D printer, and set the filling rate to 10% for printing to obtain the 3D printed propranolol hydrochloride tablet core.

[0121] After testing, the filling fluidity and printing feasibility of the 3D printed propranolol hydrochloride tablet core are good, the average weight is 0.313 g ± 4.37%, and the disintegration time is 4 min 9 s - 5 min 34 s.

[0122] 2. Preparation of the 3D printed shell

[0123] (1) Import the model (cylinder: 13.00 mm * 13.00 mm * 3.00 mm, release window size 2.00 mm * 2.00 mm, 9 release windows, release window area 36 mm 2 ) into the slicing software Repetier-Host V2.0.5 in the form of a (.stl) file, and generate a g-code file to be imported into the UP BOX+ fused deposition 3D printer;

[0124] (2) Use PLA as the shell material for printing, with a nozzle diameter of 0.20 mm, a layer height of 0.10 mm, a printing temperature of 195 °C, and a printing speed of 70 mm·s -1 , and obtain a 3D printed shell;

[0125] 3. Load the 3D printed propranolol hydrochloride tablet core into the 3D printed shell for assembly to obtain the propranolol hydrochloride sustained release tablet.

[0126] Example 3 Preparation of the propranolol sustained release tablet of the present invention

[0127] The preparation of the propranolol hydrochloride sustained release tablet includes the preparation of the 3D printed propranolol hydrochloride tablet core and the preparation of the 3D printed shell.

[0128] 1. Preparation of the 3D printed propranolol hydrochloride tablet core

[0129] Composition of the 3D printed propranolol hydrochloride tablet core:

[0130] Component Dosage (g) Propranolol Hydrochloride 10 PEG 400 17 MCC 105 29 Gelucire 48 / 16 44

[0131] The preparation of the 3D printed propranolol hydrochloride tablet core includes the following steps:

[0132] (1) Under stirring (150 rpm), heat Gelucire 48 / 16 to 60 °C until melted, add the required amount of propranolol hydrochloride, PEG400, and MCC105, mix evenly, fill it into a 20 mL 3D printing special syringe, seal the syringe plunger and screw cap, and then pack and seal it in a polyester / aluminum / polyethylene bag for storage;

[0133] (2) Use 3ds Max software to design a cylinder core model (diameter 13.00 mm * height 3.00 mm), export it in the form of a (.stl) file, load it into Repetier-Host V2.0.5 for slicing, printing parameters: 0.60 mm tapered stainless steel needle, printing temperature 42 °C, initial layer height 0.60 mm, layer thickness 0.60 mm, nozzle movement speed of the outer circle: 20 mm·s -1, Inside: 16 mm·s-1, number of outer rings: 2. Import the generated g-code file into the M3DI MAKER semi-solid extrusion 3D printer, set the filling rate to 10% for printing, and obtain the 3D printed propranolol hydrochloride tablet core.

[0134] After testing, the filling fluidity and printing feasibility of the 3D printed propranolol hydrochloride tablet core are good, the average weight is 0.309 g ± 3.56%, and the disintegration time is 5 min 6 s - 5 min 54 s.

[0135] 2. Preparation of the 3D printed outer shell

[0136] (1) Import the model (cylinder: 13.00 mm * 13.00 mm * 3.00 mm, release window size 2.00 mm * 2.00 mm, 9 release windows, release window area 36 mm 2 ) in the form of a (.stl) file into the slicing software Repetier-Host V2.0.5, generate a g-code file and import it into the UP BOX+ fused deposition 3D printer;

[0137] (2) Use PLA as the outer shell material for printing, the nozzle diameter is 0.20 mm, the layer height is 0.10 mm, the printing temperature is 195 °C, and the printing speed is 70 mm·s -1 , and obtain the 3D printed outer shell;

[0138] 3. Load the 3D printed propranolol hydrochloride tablet core into the 3D printed outer shell for assembly to obtain the propranolol hydrochloride sustained-release tablet. After testing, the average content of propranolol in the propranolol hydrochloride sustained-release tablet is 99.15 ± 0.07%.

[0139] Example 4 Preparation of the propranolol sustained-release tablet of the present invention

[0140] The preparation of the propranolol hydrochloride sustained-release tablet includes the preparation of the 3D printed propranolol hydrochloride tablet core and the preparation of the 3D printed outer shell.

[0141] 1. Preparation of the 3D printed propranolol hydrochloride tablet core

[0142] Composition of the 3D printed propranolol hydrochloride tablet core:

[0143] Component Dosage (g) Propranolol Hydrochloride 10 PEG 400 17 MCC 105 29 Gelucire 48 / 16 44

[0144] The preparation of the 3D printed propranolol hydrochloride tablet core includes the following steps:

[0145] (1) Under stirring (250 rpm), Gelucire 48 / 16 was placed at 60 °C to be heated and melted. After that, the required amount of propranolol hydrochloride, PEG 400 and MCC 105 were added. After mixing evenly, it was filled into a 20 mL special syringe for 3D printing. After the syringe plunger and the screw cap were sealed, it was packed and sealed in a polyester / aluminum / polyethylene bag for storage;

[0146] (2) The cylinder core model (diameter 13.00 mm * height 3.00 mm) was designed using 3ds Max software and exported as a file in (.stl) format. It was loaded into Repetier-Host V2.0.5 for slicing. Printing parameters: 0.60 mm tapered stainless steel needle, printing temperature 42 °C, initial layer height 0.60 mm, layer thickness 0.60 mm, nozzle movement speed for the outer circle: 20 mm·s -1 , with 2 circles for the outer circle. The generated g-code file was imported into an M3DI MAKER semi-solid extrusion 3D printer, and printing was carried out with a filling rate of 15% to obtain the 3D printed propranolol hydrochloride tablet core.

[0147] After detection, the filling fluidity and printing feasibility of the 3D printed propranolol hydrochloride tablet core were good.

[0148] 2. Preparation of the 3D printed outer shell

[0149] (1) The model (cylinder: 13.00 mm * 13.00 mm * 3.00 mm, release window size 2.00 mm * 2.00 mm, 9 release windows, release window area 36 mm 2 ) was imported into the slicing software Repetier-Host V2.0.5 as a file in (.stl) format, and the generated g-code file was imported into a UP BOX+ fused deposition 3D printer;

[0150] (2) PLA was used as the outer shell material for printing. The nozzle diameter was 0.20 mm, the layer height was 0.10 mm, the printing temperature was 195 °C, and the printing speed was 70 mm·s -1 , to obtain the 3D printed outer shell;

[0151] 3. The 3D printed propranolol hydrochloride tablet core was loaded into the 3D printed outer shell for assembly to obtain the propranolol sustained-release tablets. After detection, the average content of propranolol contained in the propranolol sustained-release tablets was 102.85 ± 0.12%.

[0152] Example 5 Preparation of the propranolol sustained-release tablets of the present invention

[0153] The preparation of propranolol hydrochloride sustained-release tablets includes the preparation of the 3D printed propranolol hydrochloride tablet core and the preparation of the 3D printed outer shell.

[0154] 1. Preparation of the 3D printed propranolol hydrochloride tablet core

[0155] Composition of the 3D printed propranolol hydrochloride tablet core:

[0156] Component Dosage (g) Propranolol Hydrochloride 10 PEG 400 17 MCC 105 29 Gelucire 48 / 16 44

[0157] The preparation of the 3D printed propranolol hydrochloride tablet core includes the following steps:

[0158] (1) Under stirring (200 rpm), Gelucire 48 / 16 was placed in a water bath at 60 °C and melted. The required amount of propranolol hydrochloride, PEG 400 and MCC 105 were added, and after mixing evenly, it was filled into a 20 mL 3D printing special syringe. After sealing the syringe plunger and screw cap, it was packed and sealed in a polyester / aluminum / polyethylene bag for storage;

[0159] (2) The cylinder core model (diameter 13.00 mm * height 3.00 mm) was designed using 3ds Max software and exported as a file in the (.stl) format. It was loaded into Repetier-Host V2.0.5 for slicing. Printing parameters: 0.60 mm tapered stainless steel needle, printing temperature 42 °C, initial layer height 0.60 mm, layer thickness 0.60 mm, nozzle movement speed for the outer circle: 20 mm·s -1 , 2 circles for the outer circle, and the generated g-code file was imported into an M3DI MAKER semi-solid extrusion 3D printer. The filling rate was set at 20% for printing to obtain the 3D printed propranolol hydrochloride tablet core.

[0160] After testing, the filling fluidity and printing feasibility of the 3D printed propranolol hydrochloride tablet core were good.

[0161] 2. Preparation of the 3D printed outer shell

[0162] (1) The model (cylinder: 13.00 mm * 13.00 mm * 3.00 mm, release window size 2.00 mm * 2.00 mm, 9 release windows, release window area 36 mm 2 ) was imported into the slicing software Repetier-Host V2.0.5 as a file in the (.stl) format, and the generated g-code file was imported into a UP BOX+ fused deposition 3D printer;

[0163] (2) PLA was used as the outer shell material for printing. The nozzle diameter was 0.20 mm, the layer height was 0.10 mm, the printing temperature was 195 °C, and the printing speed was 70 mm·s-1 , a 3D printed outer shell was prepared;

[0164] 3. The 3D printed core of propranolol hydrochloride tablets was loaded into the 3D printed outer shell for assembly to prepare sustained-release propranolol hydrochloride tablets. After testing, the average content of propranolol contained in the sustained-release propranolol hydrochloride tablets was 100.39 ± 0.20%.

[0165] Example 6 Preparation of the sustained-release propranolol tablets of the present invention

[0166] The preparation of the sustained-release propranolol hydrochloride tablets includes the preparation of the 3D printed core of propranolol hydrochloride tablets and the preparation of the 3D printed outer shell.

[0167] 1. Preparation of the 3D printed core of propranolol hydrochloride tablets

[0168] Composition of the 3D printed core of propranolol hydrochloride tablets:

[0169] Component Dosage (g) Propranolol Hydrochloride 10 PEG 400 17 MCC 105 29 Gelucire 48 / 16 44

[0170] The preparation of the 3D printed core of propranolol hydrochloride tablets includes the following steps:

[0171] (1) Under stirring (200 rpm), Gelucire 48 / 16 was placed in a water bath at 60 °C and melted. Then, the required amount of propranolol hydrochloride, PEG 400 and MCC 105 were added. After mixing evenly, the mixture was filled into a 20 mL 3D printing special syringe. After sealing the syringe plunger and the screw cap, it was packed and sealed in a polyester / aluminum / polyethylene bag for storage;

[0172] (2) Use 3ds Max software to design a cylindrical core model (diameter 13.00 mm * height 3.00 mm) and export it in the (.stl) file format. Load it into Repetier-Host V2.0.5 for slicing. Printing parameters: 0.60 mm tapered stainless steel needle, printing temperature 42 °C, initial layer height 0.60 mm, layer thickness 0.60 mm, nozzle movement speed for the outer circle: 20 mm·s-1, internal: 16 mm·s-1, number of outer circles 2. The generated g-code file was imported into a M3DI MAKER semi-solid extrusion 3D printer, and printing was carried out with a filling rate of 25% to obtain the 3D printed core of propranolol hydrochloride tablets.

[0173] After testing, the filling fluidity and printing feasibility of the 3D printed core of propranolol hydrochloride tablets were good.

[0174] 2. Preparation of the 3D printed outer shell

[0175] (1) Import the model (cylinder: 13.00 mm * 13.00 mm * 3.00 mm, release window size 2.00 mm * 2.00 mm, 9 release windows, release window area 36 mm 2 ) into the slicing software Repetier-Host V2.0.5 in the form of a (.stl) file, and generate a g-code file to import into the UP BOX+ fused deposition 3D printer;

[0176] (2) Use PLA as the shell material for printing, with a nozzle diameter of 0.20 mm, a layer height of 0.10 mm, a printing temperature of 195 °C, and a printing speed of 70 mm·s -1 , and obtain a 3D printed shell;

[0177] 3. Load the 3D printed propranolol hydrochloride tablet core into the 3D printed shell for assembly to obtain the propranolol hydrochloride sustained release tablet. After testing, the average content of propranolol contained in the propranolol hydrochloride sustained release tablet is 100.64 ± 0.10%.

[0178] Example 7 Preparation of the propranolol sustained release tablet of the present invention

[0179] The preparation of the propranolol hydrochloride sustained release tablet includes the preparation of the 3D printed propranolol hydrochloride tablet core and the preparation of the 3D printed shell.

[0180] 1. Preparation of the 3D printed propranolol hydrochloride tablet core

[0181] Composition of the 3D printed propranolol hydrochloride tablet core:

[0182] Component Dosage (g) Propranolol Hydrochloride 10 PEG 400 17 MCC 105 29 Gelucire 48 / 16 44

[0183] The preparation of the 3D printed propranolol hydrochloride tablet core includes the following steps:

[0184] (1) Under stirring (200 rpm), place Gelucire 48 / 16 in a 60 °C water bath to heat and melt it, then add the required amount of propranolol hydrochloride, PEG 400, and MCC 105. After mixing evenly, fill it into a 20 mL 3D printing special syringe. After sealing the syringe plunger and screw cap, pack it in a polyester / aluminum / polyethylene bag and seal it for storage;

[0185] (2) Design a cylindrical core model (diameter 13.00 mm * height 3.00 mm) using 3ds Max software, export it as a file in (.stl) format, load it into Repetier-Host V2.0.5 for slicing. Printing parameters: 0.60 mm tapered stainless steel needle, printing temperature 42 °C, initial layer height 0.60 mm, layer thickness 0.60 mm, nozzle movement speed for the outer circle: 20 mm·s-1, inside: 16 mm·s-1, number of outer circles 2. Import the generated g-code file into an M3DIMAKER semi-solid extrusion 3D printer, set the filling rate to 30% for printing, and obtain a 3D printed propranolol hydrochloride tablet core.

[0186] After testing, the filling fluidity and printing feasibility of the 3D printed propranolol hydrochloride tablet core are good.

[0187] 2. Preparation of the 3D printed outer shell

[0188] (1) Import the model (cylinder: 13.00 mm * 13.00 mm * 3.00 mm, release window size 2.00 mm * 2.00 mm, 9 release windows, release window area 36 mm 2 ) into the slicing software Repetier-Host V2.0.5 as a file in (.stl) format, generate a g-code file and import it into a UP BOX+ fused deposition 3D printer;

[0189] (2) Use PLA as the outer shell material for printing, nozzle diameter 0.20 mm, layer height 0.10 mm, printing temperature 195 °C, printing speed 70 mm·s -1 , and obtain a 3D printed outer shell;

[0190] 3. Load the 3D printed propranolol hydrochloride tablet core into the 3D printed outer shell for assembly to obtain a propranolol hydrochloride sustained-release tablet. After testing, the average content of propranolol contained in the propranolol hydrochloride sustained-release tablet is 101.14 ± 0.15%.

[0191] Example 8 Preparation of the propranolol sustained-release tablet of the present invention

[0192] The preparation of the propranolol hydrochloride sustained-release tablet includes the preparation of the 3D printed propranolol hydrochloride tablet core and the preparation of the 3D printed outer shell.

[0193] 1. Preparation of the 3D printed propranolol hydrochloride tablet core

[0194] Composition of the 3D printed propranolol hydrochloride tablet core:

[0195] Component Dosage (g) Propranolol Hydrochloride 10 PEG 400 17 MCC 105 29 Gelucire 48 / 16 44

[0196] The preparation of the 3D printed propranolol hydrochloride tablet core includes the following steps:

[0197] (1) Under stirring (200 rpm), Gelucire 48 / 16 was placed in a 60 °C water bath to melt, and the required amount of propranolol hydrochloride, PEG 400, and MCC 105 were added. After mixing evenly, it was filled into a 20 mL 3D printing syringe. After sealing the syringe plunger and screw cap, it was packed and sealed in a polyester / aluminum / polyethylene bag for storage;

[0198] (2) Use 3ds Max software to design a cylindrical core model (diameter 13.00 mm * height 3.00 mm), export it as a file in the (.stl) format, load it into Repetier-Host V2.0.5 for slicing. Printing parameters: 0.60 mm tapered stainless steel needle, printing temperature 42 °C, initial layer height 0.60 mm, layer thickness 0.60 mm, nozzle movement speed for the outer circle: 20 mm·s-1, inside: 16 mm·s-1, number of outer circles 2. Import the generated g-code file into the M3DI MAKER semi-solid extrusion 3D printer, and set the filling rate to 30% for printing to obtain the 3D printed propranolol hydrochloride tablet core.

[0199] After testing, the filling fluidity and printing feasibility of the 3D printed propranolol hydrochloride tablet core are good.

[0200] 2. Preparation of the 3D printed outer shell

[0201] (1) Import the model (cylindrical size: 13.00 mm * 13.00 mm * 3.00 mm, release window size 3.00 mm * 3.00 mm, number of release windows 7, release window area 63 mm 2 ) into the slicing software Repetier-Host V2.0.5 as a file in the (.stl) format, and generate a g-code file to be imported into the UP BOX+ fused deposition 3D printer;

[0202] (2) Use PLA as the outer shell material for printing, nozzle diameter 0.20 mm, layer height 0.10 mm, printing temperature 195 °C, printing speed 70 mm·s -1 , to obtain the 3D printed outer shell;

[0203] 3. Load the 3D printed propranolol hydrochloride tablet core into the 3D printed outer shell for assembly to obtain the propranolol hydrochloride sustained release tablet. After testing, the average content of propranolol in the propranolol hydrochloride sustained release tablet is 99.15 ± 0.07%.

[0204] Example 9 Preparation of the propranolol sustained release tablet of the present invention

[0205] The preparation of propranolol hydrochloride sustained-release tablets includes the preparation of the 3D-printed propranolol hydrochloride tablet core and the preparation of the 3D-printed shell.

[0206] 1. Preparation of the 3D-printed propranolol hydrochloride tablet core

[0207] Composition of the 3D-printed propranolol hydrochloride tablet core:

[0208]

[0209]

[0210] The preparation of the 3D-printed propranolol hydrochloride tablet core includes the following steps:

[0211] (1) Under stirring (200 rpm), Gelucire 48 / 16 was placed in a water bath at 60 °C and melted. The required amount of propranolol hydrochloride, PEG 400, and MCC 105 were added, and after mixing evenly, it was filled into a 20 mL 3D printing special syringe. After sealing the syringe plunger and screw cap, it was packed and sealed in a polyester / aluminum / polyethylene bag for storage;

[0212] (2) The cylinder core model (diameter 13.00 mm * height 3.00 mm) was designed using 3ds Max software and exported as a file in the (.stl) format. It was loaded into Repetier-Host V2.0.5 for slicing. Printing parameters: 0.60 mm tapered stainless steel needle, printing temperature 42 °C, initial layer height 0.60 mm, layer thickness 0.60 mm, nozzle movement speed for the outer circle: 20 mm·s-1, internal: 16 mm·s-1, number of outer circles 2. The generated g-code file was imported into an M3DI MAKER semi-solid extrusion 3D printer, and printing was carried out with a filling rate of 10% to obtain the 3D-printed propranolol hydrochloride tablet core.

[0213] After testing, the filling fluidity and printing feasibility of the 3D-printed propranolol hydrochloride tablet core were good, with an average weight of 0.315 g ± 4.88% and a disintegration time of 4 min 30 s - 5 min 18 s.

[0214] 2. Preparation of the 3D-printed shell

[0215] (1) The model (cylinder size: 13.00 mm * 13.00 mm * 3.00 mm, release window size 3.00 mm * 3.00 mm, number of release windows 7, release window area 63 mm 2 ) was imported into the slicing software Repetier-Host V2.0.5 as a file in the (.stl) format, and the generated g-code file was imported into a UP BOX+ fused deposition 3D printer;

[0216] (2) Use PLA as the shell material for printing, with a nozzle diameter of 0.20 mm, a layer height of 0.10 mm, a printing temperature of 195 °C, and a printing speed of 70 mm·s -1 , and obtain a 3D printed shell;

[0217] 3. Load the 3D printed propranolol hydrochloride tablet core into the 3D printed shell for assembly to obtain the propranolol hydrochloride sustained release tablet.

[0218] Comparative Example 1 Preparation of the 3D printed tablet core carrier

[0219] Composition of the 3D printed tablet core carrier:

[0220] Component Dosage (g) PEG 400 17 MCC 105 29 Gelucire 48 / 16 44

[0221] The preparation of the 3D printed tablet core carrier includes the following steps:

[0222] (1) Under stirring (200 rpm), heat Gelucire 48 / 16 to 60 °C until melted, add the required amounts of PEG 400 and MCC 105, mix evenly, fill into a 20 mL 3D printing special syringe, seal the syringe plunger and screw cap, and pack and seal it in a polyester / aluminum / polyethylene bag for storage;

[0223] (2) Use 3ds Max software to design a cylinder core model (diameter 13.00 mm * height 3.00 mm), export it as a file in (.stl) format, load it into Repetier-Host V2.0.5 for slicing, printing parameters: 0.60 mm tapered stainless steel needle, printing temperature 42 °C, initial layer height 0.60 mm, layer thickness 0.60 mm, nozzle movement speed outside circle: 20 mm·s-1, inside: 16 mm·s-1, number of outside circles 2, import the generated g-code file into a M3DIMAKER semi-solid extrusion 3D printer, and set the filling rate to 10% for printing to obtain the 3D printed tablet core carrier.

[0224] Test Example 1 Observation of the propranolol hydrochloride tablet core and shell of the present invention

[0225] Use a hand-held microscope to observe the structure of the 3D printed propranolol hydrochloride tablet core prepared in Examples 3-7, and the results are shown in Figure 1 . After extrusion and curing, the filaments are arranged neatly, the pore diameters are uniform, and there is no obvious expansion or shrinkage of the material during the extrusion process.

[0226] Observe Example 5( Figure 2 a) and Example 8( Figure 2b) The prepared sustained-release propranolol hydrochloride tablets have a good appearance of the shell, without obvious defects, and have a good matching degree with the tablet core.

[0227] Test Example 2 Crystal changes of the 3D printed propranolol hydrochloride tablet core of the present invention

[0228] The crystal morphology of propranolol hydrochloride, the 3D printed tablet core carrier prepared in Comparative Example 1, and the 3D printed propranolol hydrochloride tablet core prepared in Example 8 was detected by X-ray diffraction method (Rigaku Ultima IV, Rigaku Corporation, Tokyo, Japan). The angle scanning range was 10 - 80, 2θ = 0.02°, the detection wavelength was 1.5418, and the voltage was 40 kV. The results are shown in Figure 3 。

[0229] Propranolol hydrochloride has sharp peaks at 12°, 16°, 19°, and 25°. The 3D printed tablet core carrier has sharp peaks at 19° and 23°. The 3D printed propranolol hydrochloride tablet core has sharp peaks at 12°, 16°, 19°, 23°, and 25°.

[0230] The crystal morphology of the 3D printed propranolol hydrochloride tablet core did not change before and after preparation.

[0231] Test Example 3 Investigation on the dissolution behavior of the sustained-release propranolol hydrochloride tablets of the present invention

[0232] The dissolution curves of the 3D printed propranolol hydrochloride tablet core and the sustained-release propranolol hydrochloride tablets were detected using a dissolution tester. pH 6.8 phosphate buffer solution was used as the dissolution medium, the volume of the medium was 500 mL, the medium temperature was (37 ± 0.5) °C, the paddle method with a sedimentation basket was used, and the rotation speed was 50 r·min -1 , during the determination process, 2.5 mL was taken at each sampling point, 1 mL was discarded, and an equal volume of phosphate buffer solution was added. The sample was filtered through a 0.45 μm filter membrane, and the filtrate was collected.

[0233] The set sampling times for the 3D printed propranolol hydrochloride tablet core were 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, 120 min, and 240 min. The set sampling times for the 3D printed sustained-release propranolol hydrochloride tablets were 1.5 h, 4 h, 8 h, 14 h, and 24 h. The content of propranolol was detected (3 parallel samples were set for each sample, and the chromatographic conditions were the same as those of the content detection method, where the injection volume was changed from 20 μL to 100 μL), and the drug release curve was plotted. The results are shown in Figure 4.

[0234] Figure 4A It is the dissolution curve of the 3D printed propranolol hydrochloride tablet core prepared in Examples 3 - 7; Figure 4BThe dissolution curves of the propranolol hydrochloride sustained-release tablets prepared in Example 5 and Example 8 meet the quality requirements for the release rate in propranolol sustained-release tablets.

[0235] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or deformations according to the present invention. As long as they do not depart from the spirit of the present invention, they shall fall within the scope of protection of the claims of the present invention.

Claims

1. A propranolol hydrochloride sustained-release tablet, which is prepared by filling a 3D-printed propranolol hydrochloride tablet core into a 3D-printed outer shell, wherein, By weight percentage, the tablet core contains 5-20% of propranolol hydrochloride, 35-50% of lipid material, 20-35% of filler and 15-25% of plasticizer.

2. The sustained-release tablet according to claim 1, wherein the lipid material is selected from any one or a combination of polyethylene glycol-32-stearate, phospholipid, cholesterol, and fat emulsion.

3. The sustained-release tablet according to any one of claims 1-2, wherein the filler is selected from any one or a combination of mannitol, starch, microcrystalline cellulose, MCC105, lactose, dextrin, powdered sugar, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch, calcium chloride, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, sorbitol, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, sucrose, maltitol, crospovidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and calcium carboxymethyl cellulose.

4. The sustained-release tablet according to any one of claims 1-3, wherein the plasticizer is selected from any one or a combination of glycerol, polyethylene glycol (PEG), PEG200, PEG400, PEG600, PEG800, PEG1000, PEG1000, PEG1200, PEG1400, PEG1600, PEG1800, PEG2000, PEG4000, PEG6000, PEG8000, dibutyl sebacate, sorbitol, dioctyl phthalate, dibutyl phthalate, dioctyl adipate, dioctyl sebacate, tricresyl phosphate, and trioctyl phosphate.

5. The sustained-release tablet according to any one of claims 1-4, wherein the filling rate of the tablet core is 10-30%, preferably 20-30%.

6. The sustained-release tablet according to any one of claims 1-5, wherein the material for forming the 3D printing shell is selected from any one or a combination of polylactic acid and acrylonitrile-butadiene-styrene copolymer.

7. The sustained-release tablet according to any one of claims 1-6, wherein the area of the release window of the 3D printed outer shell is 9-126 mm 2 , preferably 36-63 mm 2 .

8. The preparation method of the propranolol hydrochloride sustained-release tablets according to any one of claims 1-7, wherein the sustained-release tablets are prepared by filling a 3D-printed propranolol hydrochloride tablet core into a 3D-printed outer shell, wherein, By weight percentage, the tablet core contains 5-20% of propranolol hydrochloride, 35-50% of lipid material, 20-35% of filler and 15-25% of plasticizer. The preparation method of the sustained-release tablet is as follows: (1) Prepare a 3D printed propranolol hydrochloride tablet core by using a semi-solid extrusion technique; (2) Prepare a 3D printed shell by using fused deposition modeling; (3) Fill the propranolol hydrochloride tablet core into the 3D printed shell to obtain the product.

9. The method according to claim 8, wherein the preparation of the tablet core comprises the following steps: under stirring conditions, heat the required amount of lipid material to 60-80 °C, add the required amounts of propranolol hydrochloride, filler, and plasticizer after melting, mix evenly, and prepare the propranolol hydrochloride tablet core by using a semi-solid extrusion technique.

10. The application of the propranolol hydrochloride sustained-release tablet according to any one of claims 1-7 and / or the propranolol hydrochloride sustained-release tablet prepared by the method according to any one of claims 8-9 in the preparation of a drug for treating cardiovascular and cerebrovascular diseases.

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