A 3D printed olaparib tablet and its preparation method

Abstract

The present invention relates to the field of preparation of pharmaceutical preparations, and particularly to a 3D printed olaparib tablet, which comprises a composition composed of olaparib, a carrier material and a dissolution regulating material; the preparation method is as follows: the above components are uniformly mixed and put into a twin-screw hot melt extruder; the mixed composition is heated by the twin-screw hot melt extruder to become a molten state, forms a linear material at the die orifice, is drawn into a wire, and becomes solid after cooling, thus completing the preparation of the wire; the above wire is supplied to a 3D printer and printed into an olaparib tablet; the present invention improves the mechanical properties of the wire, improves the dust problem of highly active drugs, and improves the problem of dysphagia of large-sized tablets.

Description

Technical Field

[0001] The present invention relates to the field of preparation of pharmaceutical preparations, and particularly to a 3D printed olaparib tablet and a preparation method thereof. Background Art

[0002] The 3D printing technology is known as the "third technological revolution" due to its characteristics such as digitalization, networking, and customization. It is a new forming technology based on "layered printing and layer-by-layer stacking" of three-dimensional digital models, and is also known as rapid prototyping technology, additive manufacturing technology, or solid freeform fabrication technology. This technology integrates computer-aided design, numerical control technology, and new materials, and has developed rapidly in the applications such as personalized medication and preparation of compound preparations. The U.S. Food and Drug Administration (FDA) approved the listing of the world's first levetiracetam prepared by 3D printing technology in 2015. This rapidly dissolving tablet can disintegrate within 5 seconds and is clinically used to treat epileptic seizures in the elderly or children, which provides a basis for clinical innovation and preparation of high-end preparations. In recent years, 3D printing technology has been increasingly applied to the preparation of drugs. Thanks to its good micro-control and spatial design capabilities, the material extrusion molding technology can control drug release by constructing complex geometric shapes and internal three-dimensional structures, and the fused deposition modeling (FDM) technology is the most commonly used.

[0003] Olaparib is an oral poly (ADP-ribose) polymerase (PARP) inhibitor that preferentially kills cancer cells by taking advantage of the defects in the tumor DNA damage response (DDR) pathway and is clinically used to treat ovarian cancer. Olaparib is a BCS class IV drug with poor water solubility, resulting in low oral bioavailability. In the reference preparation patent ((CN 200980150172.4)), AstraZeneca prepared an amorphous solid dispersion (ASD) of olaparib and copovidone by hot melt extrusion technology, and then tableted through a series of process treatments, greatly improving its dissolution rate.

[0004] As one of the most popular 3D printing technologies, FDM technology is widely used in the research of drug 3D printing due to its advantages such as low equipment cost and flexible operation. However, its main disadvantage is the limited choice of materials. FDM requires the pre-preparation of drug-containing filaments, and the prepared filaments need to have suitable mechanical strength and elasticity to avoid bending or breaking under pressure when passing through the gear conveyor device after being placed in the FDM printer, thus affecting the printing quality and accuracy. In the reference preparation patent, copovidone with low hygroscopicity and high softening temperature was used as the carrier of ASD to prepare a binary ASD for improving the solubility of olaparib. However, due to the strong brittleness of the copovidone extrudate, it is prone to fracture during the feeding process (Journal of Pharmaceutical Sciences, 2018, 107(1): 390 - 401), so this formulation is not suitable for 3D printing.

[0005] In the production process of commercially available olaparib tablets The production process is relatively complex and time-consuming, including steps such as extrusion, granulation, pulverization, mixing, tabletting, and coating. And during this process, a large amount of dust is easily generated. The mechanism of action of olaparib is to target cancer cells with inherent defects, but it still has damage to normal cells. In in vitro studies by Nakamura et al., it was found that olaparib reduced the number of oocytes and the fertilization rate of in vitro fertilization, and the results showed that olaparib is toxic to the ovaries (Scientific reports, 2020, 10(1): 17058). Therefore, olaparib is a highly toxic drug with cytotoxicity and reproductive toxicity and belongs to a highly active drug. Highly active compounds are classified according to their inherent toxicity, pharmacological activity, and occupational exposure limit (OEL). From the perspective of occupational health, the eight-hour weighted average OEL should be below 10 μg / m 3 The following. Currently, the main solutions for occupational exposure and isolation protection in the production of highly active drugs are to use negative pressure closed isolators, and the air cannot be exchanged with the surrounding environment (unless through high-efficiency filters), which undoubtedly greatly increases the cost of drug production and also poses problems of safety hazards, environmental pollution, and labor protection.

[0006] In addition, commercially available olaparib tablets are 14.7×7.6×6.8 mm oval tablets with a tablet weight of about 630 mg. The size and tablet weight are relatively large, and there is a risk of difficulty in swallowing. It should be noted that ovarian cancer patients often experience difficulty in swallowing and severe pain during the treatment process, so this specification of tablets often causes problems with patient compliance (Archives of Gynecology and Obstetrics, 2019, 299(4): 1063 - 9).

[0007] Therefore, to solve the above problems, providing a 3D printed olaparib tablet and its preparation method has become an issue of concern in this technical field. Summary of the Invention

[0008] The object of the present invention is to provide a 3D printed olaparib tablet and its preparation method, which can improve the mechanical properties of the wire, improve the dust problem of highly active drugs, and improve the problem of dysphagia for large-sized tablets.

[0009] To solve the above technical problems, the technical solution of the present invention is as follows:

[0010] In the first aspect, a 3D printed olaparib tablet is provided, which comprises a composition composed of olaparib, a carrier material, and a dissolution regulating material;

[0011] Among them, the carrier material accounts for 45-70% by weight of the composition;

[0012] Among them, the dissolution regulating material accounts for 5-10% by weight of the composition;

[0013] The remaining component is olaparib.

[0014] Furthermore, the carrier material is a mixture of two polymers, including but not limited to hydroxypropyl methylcellulose, copovidone, polyvinyl alcohol, and hydroxypropyl cellulose.

[0015] Furthermore, the carrier material includes copovidone and polyvinyl alcohol, and the ratio between the two is 1:1 to 1:2.25.

[0016] Furthermore, the dissolution regulating material is any one of cross-linked polyvinylpyrrolidone, calcium carbonate, and mannitol.

[0017] In the second aspect, a preparation method of the above 3D printed olaparib tablet is provided, which is characterized in that:

[0018] Step S100: Mix olaparib, the carrier material, and the dissolution regulating material evenly, and put them into a twin-screw hot melt extruder;

[0019] Step S200: The mixed composition is heated by the twin-screw hot melt extruder to become a molten state, forms a linear material at the die orifice, is drawn into a wire, and becomes solid after cooling, completing the preparation of the wire;

[0020] Step S300: Supply the wire to a 3D printer and print it into an olaparib tablet.

[0021] Furthermore, in step S100, the parameters of the twin-screw hot melt extruder include: the screw rotation speed is 20-40 rpm, and the heating temperature is 180-220 °C.

[0022] Further, in step S200, the diameter of the wire is 2.85 ± 0.02 mm.

[0023] Further, in step S300, the parameters of the 3D printer include: temperature setting of 230 - 270 °C, printing speed setting of 30 - 60 mm / s, layer height setting of 0.20 - 0.40 mm, nozzle diameter of 0.20 - 0.40 mm.

[0024] The filling rate is 10 - 20%, the wall thickness is set at 0.20 - 0.40 mm, the platform temperature is set at 50 - 100 °C, and the outer wall printing speed is 30 - 60 mm / s.

[0025] Further, in step S300, before printing, it also includes the step of establishing a 3D printing model; the established 3D printing model is in the shape of a capsule - shaped ring and is divided into upper, middle, and lower layers.

[0026] Further, in step S300, the inter - layer bonding area of the 3D printing model is 52 - 65 mm 2 , and the specific surface area is 2.0 - 2.2.

[0027] The present invention has the following beneficial effects:

[0028] 1. The present invention uses the hot - melt extrusion method to prepare a ternary amorphous solid dispersion (ASD) as an FDM printing wire. In the reference preparation hot - melt extrusion formulation, olaparib forms a binary ASD with copovidone to improve the solubility of the drug. However, due to the poor mechanical properties of copovidone, it is difficult to achieve 3D printing feeding. The present invention improves the mechanical properties of the wire by adding polyvinyl alcohol and adjusts the dissolution rate using cross - linked povidone, realizing the development of 3D - printed olaparib tablets and achieving a similar in - vitro dissolution to the reference preparation. It initially has a market prospect;

[0029] The present invention controls the preparation structure microscopically through the fused deposition modeling technology (FDM), designs a model with a smaller inter - layer bonding area and a higher specific surface area, improves the dissolution behavior, and realizes a similar in - vitro dissolution release to the reference preparation.

[0030] 2. The present invention specifically uses the FDM technology to prepare olaparib tablets, solving the problems of relatively complex production processes in traditional preparation processes and the dust hazards and labor protection problems in the production process of highly active drugs; the 3D printing technology adopted by the present invention can avoid the cumbersome processes such as mixing, granulation, pulverization, tableting, and coating in traditional processes, realize one - step continuous production. After the hot - melt extrusion process, there is no need for processes such as pulverization and can be directly used for printing, without generating dust pollution, preventing the highly active substances in the production process from harming the operators, preventing drug environmental pollution, and saving a large amount of workshop construction and labor protection costs.

[0031] III. The 3D printing technology adopted by the present invention does not require the use of external excipients and coatings, and can directly print using the extrudate. The tablet weight and size can be reduced by about 20%. The size and weight of the prepared olaparib tablets are relatively small, which solves the problem of difficult swallowing of the reference preparation and is conducive to improving patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is the overall flow chart of the preparation method of the 3D printed olaparib tablets of the present invention;

[0033] Figure 2 It is the structural schematic diagram of the 3D printing model established in this embodiment;

[0034] Figure 3 It is the comparison chart of the fracture distance and fracture stress of the reference preparation prescription and the wire material of the 3D printed tablet prescription of the present invention;

[0035] Figure 4 It is the external structure diagram of the 3D printed olaparib tablets prepared in Example 1;

[0036] Figure 5 It is the size comparison chart of the 3D printed olaparib tablets prepared in Example 1 and the reference preparation;

[0037] Figure 6 It is the DSC chart of the olaparib raw material drug, physical mixture, hot melt extrudate, and ground powder of the 3D printed tablet in Example 1;

[0038] Figure 7 It is the PXRD chart of the hot melt extrusion product, physical mixture, and olaparib raw material drug in Example 1;

[0039] Figure 8 It is the FTIR chart of the olaparib raw material drug, polyvinyl alcohol, copovidone, olaparib, physical mixture of polyvinyl alcohol and copovidone, and hot melt extrudate in Example 1;

[0040] Figure 9 It is the polarized light microscope chart of the hot melt extrusion products of the olaparib raw material drug and different polymers;

[0041] Figure 10 It is the DSC chart of the physical mixture, hot melt extrudate with 30% drug loading, hot melt extrudate with 40% drug loading, hot melt extrudate with 45% drug loading, and hot melt extrudate with 50% drug loading;

[0042] Figure 11 It is the comparison chart of the dissolution curves of the 3D printed olaparib tablets and the reference preparation in 0.1M hydrochloric acid solution;

[0043] Figure 12 It is the comparison chart of the dissolution curves of the 3D printed olaparib tablets and the reference preparation in pH 6.8 phosphate buffer solution;

[0044] Figure 13 It is a comparison graph of the dissolution curves of 3D printed olaparib tablets in water and the reference preparation. Detailed implementation mode

[0045] In order to make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0046] The present invention provides a 3D printed olaparib tablet, which comprises a composition composed of olaparib, a carrier material and a dissolution regulating material; wherein, the proportion of the carrier material in the composition is 45-70%, and this proportion is by weight percentage; the proportion of the dissolution regulating material in the composition is 5-10%, and the proportion is by weight percentage; the remaining component is olaparib.

[0047] Among them, the carrier material is a mixture of two polymers, including but not limited to hydroxypropyl methylcellulose, copovidone, polyvinyl alcohol, hydroxypropyl cellulose; preferably, the present invention uses copovidone and polyvinyl alcohol; the ratio of the two is 1:1-1:2.25.

[0048] Among them, the dissolution regulating material is any one of crospovidone, calcium carbonate, and mannitol; preferably, the present invention uses crospovidone.

[0049] The olaparib raw material used in the present invention is provided by Nanjing FangShengHe Pharmaceutical Technology Co., Ltd.; the copovidone used is purchased from BASF (China) Co., Ltd.; the polyvinyl alcohol used is purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.; the crospovidone used is purchased from Chongqing Sterck Rohm & Haas Material Technology Co., Ltd.; the mannitol used is purchased from Roquette France; the calcium carbonate used is purchased from Hunan Xinlvfang Pharmaceutical Co., Ltd.; the hydroxypropyl methylcellulose used is purchased from Shanghai Colorcon Coating Technology Co., Ltd.; the ethyl cellulose used is purchased from Shanghai Colorcon Coating Technology Co., Ltd.; the polyethylene oxide used is purchased from Shanghai Colorcon Coating Technology Co., Ltd.; the hydroxypropyl cellulose used is purchased from Nippon Soda Co., Ltd.

[0050] For reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.

[0051] The present invention also provides a preparation method of a 3D printed olaparib tablet for preparing the above-mentioned 3D printed olaparib tablet, see Figure 1 , the steps include:

[0052] Step S100: Mix olaparib, the carrier material and the dissolution regulating material evenly and put them into a twin-screw hot melt extruder;

[0053] Step S200: The mixed composition is heated by a twin-screw hot melt extruder to become a molten state, forming a linear material at the die orifice, drawn into a wire, and cooled to a solid state to complete the preparation of the wire.

[0054] Step S300: Supply the wire to a 3D printer and print it into olaparib tablets.

[0055] In the present invention, the twin-screw hot melt extruder used in the present invention is purchased from Suzhou Pupeshan Technology Co., Ltd., and the model is PPS TSE Elf; the 3D printer used is a fused deposition modeling 3D printer.

[0056] Next, two specific embodiments are given for the preparation method.

[0057] Example 1:

[0058] Step S100: Mix the powders of olaparib API (45%), copovidone (25%), polyvinyl alcohol (25%), and crospovidone (5%) evenly and put them into a twin-screw hot melt extruder. The screw speed is set to 30 rpm, and the heating temperature setting gradient is 180 °C, 190 °C, and 200 °C.

[0059] Step S200: Continuously input raw materials at the feed inlet. The mixed raw materials are heated to a molten state, form a linear material at the die orifice, and become solid after cooling. The composite material is drawn into a wire with a diameter of 2.85 ± 0.02 mm. Take a picture of the appearance of the above wire. The wire is smooth and flat, and the diameter is uniform.

[0060] Step S300: Step S300: Supply the wire to a 3D printer and print it into olaparib tablets; specifically including:

[0061] Step S310: Establish a 3D printing model;

[0062] Due to the process characteristics of 3D printing with layer-by-layer printing, the interlayer bonding is tight and there are no voids, and tablets with a relatively dense structure are often obtained. During the dissolution process, the dissolution medium is difficult to penetrate; therefore, a multi-layer porous model is established to increase the surface area and voids of the 3D printed tablets.

[0063] Use computer CAD 2014 software to establish a model. Establish a capsule-shaped ring, which is divided into upper, middle, and lower layers. The layer height is 2 mm for each layer, the width is 7 mm for each layer, and the lengths are 11, 13, and 11 mm respectively. As Figure 2 shown, Figure 2 (a) in is the front view of the model, (b) is the left view of the model, and (c) is the top view of the model. The established 3D printing model has the characteristics of a small interlayer bonding area and a relatively high porosity; the interlayer bonding area is 52 - 65 mm 2, the specific surface area is 2.0 - 2.2. The interlayer bonding area refers to the area where the three layers overlap with each other; the specific surface area refers to the ratio of the surface area to the volume. Generally, it is considered that a decrease in the interlayer bonding area is beneficial to an increase in the surface area of the model. In addition, there is literature proving that models with a relatively large specific surface area often have a faster release rate. (International Journal of Pharmaceutics, 2015, 494(2): 657 - 63).

[0064] Step S320: Conduct printing:

[0065] Export the designed model as an stl - format file, import it into the 3D printing slicing software Ultimaker Cura, design the nozzle printing sequence and printing path, set the printing speed to 30 - 60 mm / s, preferably 40 mm / s; the printing layer height is 0.20 - 0.40 mm, preferably 0.20 mm; the filling rate is 10% - 20%, preferably 10%; export it as a gcode - format file for preparation of printing.

[0066] Fill the printing wire into the feeding device of the 3D printer, import the gcode - format file into the printer, the printer starts to work, and through layer - by - layer stacking, print out the olaparib 3D - printed tablets.

[0067] Example 2:

[0068] Step S100: Uniformly mix the powders of olaparib API (30%), copovidone (20%), polyvinyl alcohol (45%), and crospovidone (5%) and put them into a twin - screw hot - melt extruder. Set the screw rotation speed to 30 rpm, and set the heating temperature gradient to 200, 210, 220 °C.

[0069] Step S200: Continuously input raw materials at the feeding port. The mixed raw materials become molten after heating, form a linear material at the die orifice, and become solid after cooling. Pull the composite material into a wire with a diameter of 2.85 ± 0.02 mm to complete the wire preparation. Take a photo of the appearance of the above - mentioned wire. The wire is smooth and flat, and the diameter is uniform.

[0070] Step S300: Supply the wire to the 3D printer to print into olaparib tablets; specifically including:

[0071] Step S310: Establish a 3D printing model;

[0072] Due to the process characteristics of 3D printing with layer - by - layer printing, the interlayer bonding is tight and there are no voids, and tablets with a relatively dense structure are often obtained. During the dissolution process, it is difficult for the dissolution medium to penetrate. Therefore, establish a multi - layer porous model to increase the surface area and voids of the 3D - printed tablets.

[0073] A model was established using computer CAD 2014 software. A toroid in the shape of a capsule was created, divided into three layers: upper, middle, and lower. The height of each layer is 2 mm, the width is 7 mm, and the lengths are 11, 13, and 11 mm respectively. As Figure 2 shown. The 3D printed model established has the characteristics of a small interlayer bonding area and a relatively high porosity.

[0074] Step S320: Conduct printing:

[0075] Export the designed model as an stl format file, import it into the 3D printing slicing software Ultimaker Cura, design the nozzle printing sequence and printing path. The printing speed is set to 30 - 60 mm / s, preferably 40 mm / s; the printing layer height is 0.20 - 0.40 mm, preferably 0.40 mm; the filling is 10 - 20%, preferably 20%; export it as a gcode format for preparation of printing.

[0076] Fill the printing wire into the feeding device of the 3D printer, and import the gcode format file into the printer. The printer starts to work, and through layer - by - layer stacking, a 3D printed olaparib tablet is printed.

[0077] Test Example 1: Comparison of the mechanical properties of the reference preparation prescription and the prescription wire of the present invention

[0078] In the reference preparation patent (CN 200980150172.4), VA64 with low hygroscopicity and high softening temperature was used as the carrier of the solid dispersion. However, due to the strong brittleness of the VA64 extrudate, it is prone to breakage during the feeding process (Journal of Pharmaceutical Sciences, 2018, 107(1): 390 - 401), so this formulation is not suitable for 3D printing. The present invention plans to use a composition of two different polymers to improve the mechanical properties of the extrudate.

[0079] The mechanical properties of the wire of the reference preparation formulation and the wire prepared in Example 1 of the present invention were studied using a three - point bending experiment. The results are as Figure 3 shown. Generally, it is considered that a wire with a larger fracture distance and fracture stress has stronger toughness. Literature reports that when the fracture distance > 1 mm and the fracture stress > 2941 g / mm 2 , the wire can meet the requirements of 3D printing (International Journal of Pharmaceutics, 2017, 519(1): 186 - 97). The results show that both the fracture distance and fracture stress of the wire of the reference preparation formulation are low, and the wire cannot be 3D printed. However, the present invention uses a composition of two different polymers, which greatly improves the mechanical properties of the wire and can be used for 3D printing.

[0080] Test Example 2: Morphological characteristics of 3D printed olaparib tablets

[0081] The appearance of the olaparib tablets prepared in Example 1 was photographed with a camera. As Figure 4 shown, the 3D printed tablets are capsule-shaped, with a complete appearance, smooth and flat contour lines, a length of about 13 mm, a width of about 7 mm, and a height of about 7 mm. The overall color is light creamy yellow. The size of the 3D printed preparation prepared with this model is significantly smaller than that of the reference preparation, as Figure 5 shown. Considering that ovarian cancer patients often experience difficulty swallowing and pain during swallowing after treatment such as chemotherapy, the present invention can solve this problem and improve patient compliance.

[0082] Test Example 3: Solid characterization study of 3D printed olaparib tablets

[0083] The extruded wire prepared in Example 1 was studied by solid-state characterization. After grinding and pulverizing the wire, it was passed through a 100-mesh sieve. After obtaining the wire powder, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction studies (PXRD) were carried out to investigate the solid-state properties of the wire.

[0084] DSC parameters: Initial temperature 40 °C, heated to 250 °C at a rate of 10 °C / min.

[0085] FTIR parameters: Scanning range is 4000~400 cm -1 , and the obtained spectral data was smoothed using Nicolet Omnic 8.0 infrared spectroscopy analysis software.

[0086] PXRD parameters: Using a copper target, step size 0.02 °, scanning speed 1 ° / min.

[0087] As Figure 6 shown, Figure 6 in (a) is the olaparib raw material drug, (b) is the physical mixture, (c) is the hot melt extrudate, and (d) is the ground powder of the 3D printed tablet; according to Figure 6 the DSC results, neither the extruded wire prepared in Example 1 nor the ground powder of the 3D printed tablet has a crystal melting peak, and has a single T g , it is speculated that an amorphous solid dispersion is formed.

[0088] As Figure 7 shown, Figure 7 in (a) is the hot melt extrusion product, (b) is the physical mixture, and (c) is the olaparib raw material drug; according to Figure 7 the PXRD results show that the wire prepared in Example 1 does not contain a crystal melting peak and shows a broad diffraction ring, and it is speculated that an amorphous solid dispersion is formed, which is consistent with the DSC results.

[0089] As Figure 8 shown,Figure 8 In (a) is olaparib bulk drug, (b) is polyvinyl alcohol, (c) is copovidone, (d) is the physical mixture of olaparib, polyvinyl alcohol and copovidone, and (e) is the hot melt extrusion product; According to Figure 8 The FTIR results show that the characteristic peaks of olaparib bulk drug mainly occur in the range of 3300 - 2800 cm -1 and 1800 - 600 cm -1 . The ν C＝O peak of the amide group in olaparib bulk drug is at 1662 cm -1 and 1633 cm -1 , which is the amide I absorption band. The δ N-H peak is located at 1495 cm -1 , which is called the amide II absorption band. In addition, there are multiple medium-intensity peaks in the range of 1500 - 1450 cm C-N for the ν -1 peak, which is called the amide III absorption band. The amide II and III absorption bands are generated due to the vibrational coupling of δ N-H and ν C-N .

[0090] In polyvinyl alcohol, the broad and strong absorption peak at 3292 cm -1 frequency belongs to the OH stretching vibration mode (ν OH ) of polyvinyl alcohol molecules. The asymmetric stretching vibration of CH2 in polyvinyl alcohol molecules (ν as CH2- ) is at 2943 cm -1 . The symmetric stretching vibration of CH2 (ν s CH2- ) is at 2904 cm -1 frequency. The characteristic absorption peak of hydroxyl group caused by C - O stretching vibration is at 1093 cm -1 . The stretching vibration peak of C - C bond is at 1142 cm -1 .

[0091] Copovidone has two hydrogen bond acceptor groups. The cyclic amide stretching band ν C＝O of the lactam group is at 1667 cm -1 . The ν C＝O peak of the vinyl acetate group is at 1739 cm -1 . In addition, the ν C-N peak of the amide group is at 1496 cm -1 . The ν C-O peak of the ester group is at 1242 cm -1 and 1290 cm -1 , which is a doublet.

[0092] The FTIR spectrum of the physical mixture of olaparib API, polyvinyl alcohol, and copovidone is merely a simple superposition of the spectra of olaparib crystals, polyvinyl alcohol, and copovidone.

[0093] The infrared spectrum of the amorphous solid dispersion formed after hot melt extrusion is significantly different from that of the physical mixture. Among them, the ν C＝O peak of the amide group shifts from 1663 cm -1 to a higher wavenumber, blue-shifting to 1678 cm -1 and the peak shape becomes broader and blunter. The original ν -1 peak at 1633 cm C＝O shifts to a higher wavenumber, blue-shifting to 1643 cm -1 and the ν N-H peak shifts from 3163 cm -1 to 3278 cm -1 , and the peak shape becomes broader and blunter. The ν C-N peak shifts from 1433 cm -1 to 1454 cm -1 . All these indicate that a new solid form of olaparib API is formed after hot melt extrusion. Combining with the PXRD results, it further shows that an amorphous form is formed. The originally long-range ordered crystal lattice of olaparib API is damaged, and the molecules inside rearrange, showing a long-range disordered arrangement.

[0094] For copovidone, the ν C＝O peak of the amide group shifts from 1667 cm -1 to 1678 cm -1 , and the ν C＝O peak of the vinyl acetate group shifts from 1738 cm -1 to 1740 cm -1 . In polyvinyl alcohol, the characteristic absorption peak of -OH existing in the form of intermolecular or intramolecular association at 3292 cm -1 disappears. Therefore, it is speculated that the amide carbonyl of olaparib, the amide carbonyl of copovidone, and the vinyl acetate carbonyl may form intermolecular hydrogen bonds with polyvinyl alcohol.

[0095] Test Example 4: Prescription and process research

[0096] 1. Influence of carrier material on 3D printed olaparib tablets:

[0097] Replace polyvinyl alcohol in Example 1 with other carrier materials, including: hypromellose, hydroxypropyl cellulose, and polyethylene oxide, and conduct hot melt extrusion to obtain the corresponding wire rods. The mechanical properties of the wire rods can all meet the requirements for 3D printing. Conduct polarized light microscopy solid state characterization on the wire rods, see Figure 9, where (a) is hydroxypropyl methylcellulose, (b) is hydroxypropyl cellulose, and (c) is polyethylene oxide. The results show that the extrudates prepared all exhibit birefringence. The above carrier materials have poor miscibility with the drug and cannot form amorphous solid dispersions.

[0098] 2. Influence of drug content on 3D printed olaparib tablets:

[0099] Table 1 Formulations of 3D printed olaparib tablets with different drug contents

[0100]

[0101] The olaparib content in Example 1 was used to prepare filaments according to Table 1, and the prepared filaments were studied by solid state characterization. The DSC results show that the filaments with a drug loading of 30 - 50% all have a single T g , and both the drug and the carrier can form amorphous solid dispersions, as shown in Figure 10 , where (a) is a physical mixture, (b) is a hot melt extrudate with a 30% drug loading, (c) is a hot melt extrudate with a 40% drug loading, (d) is a hot melt extrudate with a 45% drug loading, and (e) is a hot melt extrudate with a 50% drug loading.

[0102] The filaments prepared above were supplied to a 3D printer for printing. The printing temperature was set at 270 °C, the printing speed was set at 40 mm / s, the layer height was set at 0.20 mm, and the nozzle diameter was 0.20 mm. The dissolution of the printed tablets was determined. The results are shown in Table 2.

[0103] Table 2 Dissolution of 3D printed olaparib tablets with different drug loadings

[0104]

[0105] The dissolution experiment results show that a drug loading of 30 - 45% can achieve 100% dissolution, while the dissolution end point of a 50% drug loading is only 85%. As the drug loading increases, the dissolution rate accelerates.

[0106] Since the dissolution of 3D printed olaparib tablets with a drug loading of 30% - 45% is similar to that of the reference preparation, a drug loading of 40% - 45% is preferably selected.

[0107] 3. Influence of dissolution regulating material on 3D printed olaparib tablets:

[0108] Replace the crospovidone in Example 1 with other carrier materials, including: mannitol, calcium carbonate, and investigate the dosage of crospovidone. After mixing the above raw materials evenly, melt extrusion is carried out to obtain the corresponding wire. The mechanical properties of the wire can meet the requirements of 3D printing. Supply the prepared wire to a 3D printer for printing. The printing temperature is set at 270 °C, the printing speed is set at 40 mm / s, the layer height is set at 0.20 mm, and the nozzle diameter is 0.20 mm. The dissolution of the printed tablets is determined. The results are shown in Table 3.

[0109] Table 3 Dissolution of 3D printed olaparib tablets with different dissolution regulating materials

[0110]

[0111] The dissolution experiment results show that 5% crospovidone has the most significant effect on improving the dissolution rate. Therefore, the preferred content of crospovidone is 5% - 10%.

[0112] 4. Influence of printing temperature on 3D printed olaparib tablets:

[0113] Supply the wire prepared in Example 2 to a 3D printer for printing. The printing temperatures are set at 230, 250, 270 °C, the printing speed is set at 40 mm / s, the layer height is set at 0.20 mm, and the nozzle diameter is 0.20 mm. The dissolution of the printed tablets is determined. The results are shown in Table 4.

[0114] Table 4 Dissolution of 3D printed olaparib tablets at different printing temperatures

[0115]

[0116] The dissolution experiment results show that different printing temperatures in the range of 230 - 270 °C have no obvious effect on the dissolution of 3D printed tablets, and no drug degradation occurs. Considering the printability and energy consumption issues, 230 - 250 °C is preferred.

[0117] 5. Influence of printing filling on 3D printed olaparib tablets:

[0118] Supply the wire prepared in Example 2 to a 3D printer for printing. The printing temperature is set at 270 °C, the printing speed is set at 40 mm / s, the layer height is set at 0.20 mm, and the nozzle diameter is 0.20 mm. The filling rates are 10, 20% respectively. The dissolution of the printed tablets is determined. The results are shown in Table 5.

[0119] Table 5 Dissolution of 3D printed olaparib tablets with different filling densities

[0120]

[0121] The dissolution experiment results show that increasing the filling rate slightly raises the tablet weight and slightly reduces the dissolution rate, with no obvious impact. The preferred filling rate is 10 - 20%.

[0122] 6. Influence of nozzle diameter on 3D printed olaparib tablets:

[0123] The nozzle diameter affects the diameter of the printed filament. During the experiment using a 0.40 mm nozzle, it was found that the diameter of the printed filament was larger, resulting in smearing, which changed the structure of the 3D printed tablet and affected the dissolution experiment.

[0124] The wire prepared in Example 2 was supplied to a 3D printer for printing. The printing temperature was set at 270 °C, the printing speed was set at 40 mm / s, the layer height was set at 0.20 mm, and the nozzle diameters were 0.40 and 0.20 mm. The dissolution degrees of the printed tablets were measured. The results are shown in Table 6.

[0125] Table 6 Dissolution Degrees of 3D Printed Olaparib Tablets with Different Nozzle Diameters

[0126]

[0127] The dissolution experiment results show that when the nozzle diameter of 0.20 mm is selected, the dissolution rate of the tablets is improved. Therefore, the preferred nozzle diameter is 0.20 - 0.40 mm.

[0128] Test Example 5: Dissolution curve determination

[0129] Samples from Example 1 were taken for the determination of the dissolution curve. According to the first method (basket method) for the determination of dissolution and release degrees in the Chinese Pharmacopoeia 2020 Edition, 900 mL of 0.1 M hydrochloric acid solution, pH 6.8 phosphate buffer solution, and water were used as dissolution media, the rotation speed was 100 rpm, 5 mL of samples were taken at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, and 120 min respectively, and the same volume of dissolution medium was replenished at the same time. After the samples were filtered through a 0.45 μm microporous filter membrane, the absorbance was measured at 276 nm, and the cumulative dissolution degree was calculated. The results are shown in Table 7, Figures 11 to 13 as shown, where Figure 11 (a) represents the dissolution curve of the 3D printed olaparib tablet in 0.1 M hydrochloric acid solution, and (b) represents the dissolution curve of the reference preparation in 0.1 M hydrochloric acid solution; where Figure 12 (a) represents the dissolution curve of the 3D printed olaparib tablet in pH 6.8 phosphate buffer solution, and (b) represents the dissolution curve of the reference preparation in pH 6.8 phosphate buffer solution; Figure 13Among them, (a) shows the dissolution curve of 3D-printed olaparib tablets in water, and (b) shows the dissolution curve of the reference preparation in water. The results show that the self-made 3D-printed olaparib tablets are similar to the reference preparation in all three dissolution media.

[0130] Table 7 Similarity factors of 3D-printed olaparib tablets and reference preparations in different media

[0131]

[0132] Parts not involved in the present invention are the same as the prior art or implemented using the prior art.

[0133] The above content is a further detailed description of the present invention in combination with specific implementation manners. It cannot be determined that the specific implementation of the present invention is only limited to these descriptions. For those of ordinary skill in the technical field to which the present invention belongs, without departing from the concept of the present invention, several simple deductions or substitutions can still be made, and all should be regarded as belonging to the protection scope of the present invention.

Claims

1. A 3D printed olaparib tablet, characterized in that: A composition comprising olaparib, a carrier material, and a dissolution regulating material; wherein the carrier material accounts for 45 - 70% by weight of the composition; wherein the dissolution regulating material accounts for 5 - 10% by weight of the composition; the remaining component is olaparib; the carrier material includes copovidone and polyvinyl alcohol, and the ratio between the two is 1:1 - 1:2.25; the dissolution regulating material is any one of crospovidone, calcium carbonate, and mannitol; the 3D printed olaparib tablets are printed using a fused deposition modeling 3D printer.

2. The method for preparing 3D printed olaparib tablets according to claim 1, characterized in that: Step S100: Mix olaparib, the carrier material, and the dissolution regulating material evenly, and put them into a twin - screw hot - melt extruder; Step S200: The mixed composition is heated by the twin - screw hot - melt extruder to become a molten state, forms a linear material at the die orifice, is drawn into a wire, and becomes solid after cooling, completing the preparation of the wire; Step S300: Supply the wire to a 3D printer and print it into olaparib tablets.

3. The preparation method of the 3D printed olaparib tablets according to claim 2, characterized in that: In step S100, the parameters of the twin - screw hot - melt extruder include: the screw speed is 20 - 40 rpm, and the heating temperature is 180 - 220 °C.

4. The preparation method of 3D printed olaparib tablets according to claim 2, characterized in that: In step S200, the diameter of the wire is 2.85 ± 0.02 mm.

5. The preparation method of 3D printed olaparib tablets according to claim 2, characterized in that: In step S300, the parameters of the 3D printer include: the temperature is set at 230 - 270 °C, the printing speed is set at 30 - 60 mm / s, the layer height is set at 0.20 - 0.40 mm, the nozzle diameter is 0.20 - 0.40 mm; the filling rate is 10 - 20%, the wall thickness is set at 0.20 - 0.40 mm, the platform temperature is set at 50 - 100 °C, and the outer wall printing speed is 30 - 60 mm / s.

6. The preparation method of the 3D printed olaparib tablets according to claim 2, wherein: In step S300, before printing, there is also a step of establishing a 3D printing model; the established 3D printing model is a capsule - shaped ring, divided into upper, middle, and lower layers.

7. The preparation method of 3D printed olaparib tablets according to claim 6, characterized in that: In step S300, the interlayer bonding area of the 3D printing model is 52 - 65 mm 2 , and the specific surface area is 2.0 - 2.2.

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