CN115998699A - 3D printed Olaparib tablet and preparation method thereof - Google Patents

Abstract

The invention relates to the field of preparation of pharmaceutical preparations, in particular to a 3D printing Olaparib tablet, which comprises a composition composed of Olaparib, a carrier material and a dissolution regulating material; the preparation method comprises the following steps: mixing the above components uniformly, and putting into a double-screw hot-melt extruder; the mixed composition is heated by a double-screw hot-melt extruder to be in a molten state, a linear material is formed at a die orifice, the linear material is pulled into a wire rod, and the wire rod is cooled to be in a solid state, so that the wire rod preparation is completed; feeding the wire rod to a 3D printer to print into an Olaparib sheet; the invention improves the mechanical property of the wire rod, improves the dust problem of high-activity medicines and improves the dysphagia problem of large-size tablets.

Description

3D printed Olaparib tablet and preparation method thereof

Technical Field

The invention relates to the field of preparation of pharmaceutical preparations, in particular to a 3D printed Olaparib tablet and a preparation method thereof.

Background

The 3D printing technology is known as a third technical revolution due to the characteristics of digitalization, networking, customization and the like, and is a novel forming technology based on three-dimensional digital model layering printing and layering stacking, and is also known as a rapid forming technology, an additive manufacturing technology or a solid free forming technology. The technology integrates computer aided design, numerical control technology and novel materials, and has rapid application development in the aspects of personalized medicine application, compound preparation and the like. The U.S. Food and Drug Administration (FDA) approves the world's first example of 3D printing technology to prepare levetiracetam (levetiracetam) for marketing, and the instant tablet can be rapidly disintegrated within 5 seconds and is clinically used for treating epileptic seizures of old people or children, thereby providing basis for clinical innovation and preparation of high-end preparations. In recent years, 3D printing technology is increasingly applied to the preparation of pharmaceuticals. Thanks to the good microcosmic control and space design ability, material extrusion techniques can achieve control of drug release by constructing complex geometries and internal three-dimensional structures, with Fused Deposition Modeling (FDM) techniques being most commonly used.

Olaparib is an oral poly (adenosine diphosphate) ribose polymerase (PARP) inhibitor that uses defects in the tumor DNA Damage Response (DDR) pathway to preferentially kill cancer cells and is clinically used to treat ovarian cancer. Olaparib is a BCS IV type drug with poor water solubility, resulting in low oral bioavailability. In the reference formulation patent ((CN 200980150172.4)), the company of avaricone prepares the olapari and copovidone into Amorphous Solid Dispersion (ASD) by hot melt extrusion technique, and the dissolution and dissolution rates are greatly improved by tabletting after a series of process treatments.

As one of the most popular 3D printing technologies, FDM technology is widely applied to drug 3D printing research by virtue of advantages of low equipment cost, flexible operation, etc., but its most major disadvantage is few selectable materials. FDM needs to prepare the medicine-containing wire rod in advance, and the wire rod prepared needs to have proper mechanical strength and elasticity, so that the wire rod is prevented from being bent or broken under pressure when being put into an FDM printer and then passing through a gear conveying device, and the printing quality and the printing precision are further influenced. The reference formulation patent uses copovidone with low hygroscopicity and high softening temperature as a carrier of ASD, and the binary ASD is prepared for improving the solubility of the Olaparib. However, because copovidone extrudates are brittle, they are prone to breakage during feeding (Journal of Pharmaceutical Sciences,2018,107 (1): 390-401), and this formulation is not suitable for 3D printing.

In the commercial Olaparib tablet

In the production process, the production process is more time-consuming and comprises the steps of extrusion, granule finishing, crushing, mixing, tabletting, coating and the like. And in the process, a large amount of dust is easy to generate. Whereas the mechanism of action of olapari is targeted to cancer cells that are inherently defective, but still have damage to normal cells. Nakamura et al in vitro studies found that Olaparib decreased oocyte numbers and fertilization rates for in vitro fertilization, and the results indicated that Olaparib was toxic to the ovaries (Scientific reports,2020,10 (1): 17058). Thus, olapari is a highly toxic drug of 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 contact limit (OEL), from a occupational health point of view, eight hour weighted average OEL shouldAt 10. Mu.g/m ³ The following is given. The occupational contact and isolation protection solution of the existing high-activity drug production mainly adopts a negative pressure closed isolator, and air cannot be ventilated with the surrounding environment (except through a high-efficiency filter), so that the cost of drug production is obviously greatly increased, and the problems of potential safety hazard, environmental pollution and labor protection also exist.

In addition, commercially available olapari tablets

The tablet weight is about 630mg, and the size and the tablet weight are large, so that the dysphagia risk is provided. Notably, patients with ovarian cancer often experience dysphagia and concomitant severe pain problems during treatment, and thus tablets of this size often create patient compliance problems (Archives of Gynecology and Obstetrics,2019,299 (4): 1063-9).

Therefore, in order to solve the above problems, providing a 3D printed olapari tablet and a method for preparing the same is a concern in the technical field.

Disclosure of Invention

The invention aims to provide a 3D printed Olaparib tablet and a preparation method thereof, which can improve the mechanical property of wires, improve the dust problem of high-activity medicines and improve the dysphagia problem of large-size tablets.

In order to solve the technical problems, the technical scheme of the invention is as follows:

in a first aspect, there is provided a 3D printed olapari tablet comprising a composition consisting of olapari, a carrier material and a dissolution modifying material;

wherein the carrier material accounts for 45-70% of the weight of the composition;

wherein the dissolution regulating material accounts for 5-10% of the weight of the composition;

the remaining component is olapari.

Further, the carrier material is a mixture of two polymers including, but not limited to, hydroxypropyl methylcellulose, copovidone, polyvinyl alcohol, hydroxypropyl cellulose.

Further, the carrier material comprises copovidone and polyvinyl alcohol, and the ratio of the copovidone to the polyvinyl alcohol is 1:1-1:2.25.

Further, the dissolution regulating material is any one of crospovidone, calcium carbonate and mannitol.

In a second aspect, a method for preparing the 3D printed olapari tablet is provided, which is characterized in that:

step S100: uniformly mixing the olapari, the carrier material and the dissolution regulating material, and putting the mixture into a double-screw hot-melt extruder;

step S200: the mixed composition is heated by a double-screw hot-melt extruder to be in a molten state, a linear material is formed at a die orifice, the linear material is pulled into a wire rod, and the wire rod is cooled to be in a solid state, so that the wire rod preparation is completed;

step S300: the wire was fed to a 3D printer and printed into olapari tablets.

Further, in step S100, parameters of the twin-screw hot-melt extruder include: the rotating speed of the screw is 20-40 rpm, and the heating temperature is 180-220 ℃.

Further, in step S200, the diameter of the wire rod is 2.85±0.02mm.

Further, in step S300, parameters of the 3D printer include: the temperature is set at 230-270 ℃, the printing speed is set at 30-60 mm/s, the layer height is set at 0.20-0.40 mm, and the diameter of the spray head is 0.20-0.40 mm.

The filling rate is 10-20%, the wall thickness is 0.20-0.40 mm, the platform temperature is 50-100 ℃, and the outer wall printing speed is 30-60 mm/s.

Further, in step S300, a step of creating a 3D printing model is further included before printing; the established 3D printing model is a capsule-shaped circular ring and is divided into an upper layer, a middle layer and a lower layer.

Further, in step S300, the interlayer bonding area of the 3D printing model is 52-65 mm ² The specific surface area is 2.0-2.2.

The invention has the following beneficial effects:

1. the invention adopts a hot melt extrusion method to prepare ternary Amorphous Solid Dispersion (ASD) as FDM printing wires. In a reference preparation hot-melt extrusion prescription, the oxilapachone and the copovidone form binary ASD to improve the solubility of the medicine, but because the mechanical property of the copovidone is poor, the 3D printing feeding is difficult to realize. The method has market prospect preliminarily;

the invention controls the preparation structure in microcosmic through a Fused Deposition Modeling (FDM) technology, designs a model with smaller interlayer bonding area and higher specific surface area, improves dissolution behavior, and realizes in-vitro dissolution and release similar to that of a reference preparation.

2. The invention adopts FDM technology to prepare Olaparib tablet, which solves the problems of dust hazard and labor protection in the production process of high-activity medicines in the traditional preparation process; the 3D printing technology adopted by the invention can avoid the redundant processes of mixing, granulating, crushing, tabletting, coating and the like in the traditional process, realize one-step molding continuous production, and directly use the technology without crushing and the like after the hot melt extrusion process for printing, so that dust pollution is not generated, the harm of high active substances in the production process to operators is prevented, the pollution of the medicine environment is prevented, and a large amount of workshop construction and labor protection cost is saved.

3. The 3D printing technology adopted by the invention does not need to use external auxiliary materials and coating, can directly print by using extrudate, can reduce the weight and size of tablets by about 20%, has smaller size and weight of tablets of the prepared Olaparib tablets, solves the problem of dysphagia of reference preparations, and is beneficial to improving the compliance of patients.

Drawings

FIG. 1 is a flow chart of an overall process for preparing a 3D printed Olaparib tablet according to the present invention;

fig. 2 is a schematic diagram of a 3D printing model structure established in the present embodiment;

FIG. 3 is a graph comparing the breaking distance and breaking stress of a reference formulation recipe and a 3D printed sheet recipe wire of the present invention;

FIG. 4 is a diagram of the appearance of a 3D printed Olaparib tablet prepared in example 1;

FIG. 5 is a graph comparing the size of 3D printed Olaparib tablets prepared in example 1 with a reference formulation;

FIG. 6 is a DSC of the Olaparib drug substance, physical blend, hot melt extrudate, 3D printed tablet grind of example 1;

FIG. 7 is a PXRD pattern for the hot melt extrusion product, physical mixture, and Olaparib drug substance of example 1;

FIG. 8 is a FTIR plot of the physical mixture of Olaparib drug substance, polyvinyl alcohol, copovidone, olaparib, polyvinyl alcohol and copovidone, hot melt extrudate of example 1;

FIG. 9 is a polarized light microscope image of hot melt extrusion products of an Olaparib drug substance and different polymers;

FIG. 10 is a DSC plot of a physical blend, 30% drug-loaded hot-melt extrudate, 40% drug-loaded hot-melt extrudate, 45% drug-loaded hot-melt extrudate, 50% drug-loaded hot-melt extrudate;

FIG. 11 is a graph comparing dissolution curves of 3D printed Olaparib tablets in 0.1M hydrochloric acid solution with a reference formulation;

FIG. 12 is a graph of dissolution profile of 3D printed Olaparib in pH 6.8 phosphate buffer versus a reference formulation;

fig. 13 is a graph comparing dissolution curves of 3D printed olapari tablet in water with a reference formulation.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.

The invention provides a 3D printing Olaparib tablet, which comprises a composition composed of Olaparib, a carrier material and a dissolution regulating material; wherein the carrier material accounts for 45-70% of the composition, and the weight percentage of the carrier material is; the dissolution regulating material accounts for 5-10% of the composition, and the proportion is weight percent; the remaining component is olapari.

Wherein the carrier material is a mixture of two polymers including, but not limited to, hydroxypropyl methylcellulose, copovidone, polyvinyl alcohol, hydroxypropyl cellulose; preferred in the present invention are copovidone and polyvinyl alcohol; the ratio of the two is 1:1-1:2.25.

Wherein the dissolution regulating material is any one of crosslinked povidone, calcium carbonate and mannitol; preferred for the present invention are crospovidone.

The Olaparib bulk drug used in the invention is provided by Nanjing Fang Sheng and medical science and technology limited company; the copovidone used was purchased from basf (china) limited; the polyvinyl alcohol used was purchased from Jiangxi alpha-high pharmaceutical Co., ltd; the crospovidone used was purchased from Chongqing Texak Redenmel materials technologies Co.Ltd; mannitol used was purchased from french Luo Gaite company; the calcium carbonate used was purchased from Hunan New Green prescription pharmaceutical Co., ltd; hydroxypropyl methylcellulose used was purchased from Shanghai Carlekang coating technologies Co., ltd; the ethyl cellulose used was purchased from Shanghai Carlekang coating technologies Co., ltd; the polyoxyethylene used was purchased from Shanghai Carlekang coating technology Co., ltd; the hydroxypropyl cellulose used was purchased from Caesada Japan.

The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

The invention also provides a preparation method of the 3D printed Olaparib tablet, which is used for preparing the 3D printed Olaparib tablet, referring to FIG. 1, and comprises the following steps:

step S100: uniformly mixing the olapari, the carrier material and the dissolution regulating material, and putting the mixture into a double-screw hot-melt extruder;

step S200: the mixed composition is heated by a double-screw hot-melt extruder to be in a molten state, a linear material is formed at a die orifice, the linear material is pulled into a wire rod, and the wire rod is cooled to be in a solid state, so that the wire rod preparation is completed;

step S300: the wire was fed to a 3D printer and printed into olapari tablets.

In the invention, a double-screw hot-melt extruder is purchased from Suzhou Pu Pasan science and technology Co., ltd, and the model is PPS TSE Elf; the 3D printer used was a fused deposition modeling 3D printer.

Two specific examples are given below for the preparation process.

Example 1:

step S100: uniformly mixing the powder of the olapari bulk drug (45%), the copolyvidone (25%), the polyvinyl alcohol (25%) and the crospovidone (5%) and putting the mixture into a double-screw hot-melt extruder, wherein the screw speed is set to be 30rpm, and the heating temperature is set to be 180 ℃, 190 ℃ and 200 ℃;

step S200: continuously feeding raw materials into a feed inlet, heating the mixed raw materials to be in a molten state, forming a linear material at a die opening, cooling to be in a solid state, and drawing the composite material into a wire rod with the diameter of 2.85+/-0.02 mm. The appearance of the wire rod is photographed by a camera, the wire rod is smooth and flat, and the diameter is uniform.

Step S300: step S300: feeding the wire to a 3D printer for printing into olapari tablets; the method specifically comprises the following steps:

step S310: establishing a 3D printing model;

because of the technological characteristics of 3D printing layer by layer, the interlayer combination is tight, no gap exists, and a tablet with a compact structure is often obtained, and a dissolution medium is difficult to permeate in the dissolution process; thus, a multi-layer porous model is established, and the surface area and the gaps of the 3D printing sheet are increased.

And (3) establishing a model by using computer CAD 2014 software, and establishing a capsule-shaped circular ring which is divided into an upper layer, a middle layer and a lower layer, wherein the layers are 2mm in height, 7mm in width and 11mm in length respectively. As shown in fig. 2, (a) in fig. 2 is a front view of the model, (b) is a left view of the model, and (c) is a top view of the model. The established 3D printing model has the characteristics of small interlayer bonding area and higher 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 of overlapping between the layers of the three layers; specific surface area refers to the ratio of surface area to volume. It is believed that a reduction in interlayer bonding area contributes to an increase in the surface area of the model, and furthermore it has been documented that models with larger specific surface areas often have faster release rates. (International Journal of Pharmaceutics), 2015,494 (2): 657-63.

Step S320: printing:

exporting the designed model into a stl format file, importing the stl format file into 3D printing slicing software Ultimaker Cura, designing a spray head printing sequence and a printing path, and setting the printing speed to be 30-60 mm/s, preferably 40mm/s; the height of the printing layer is 0.20-0.40 mm, preferably 0.20mm; the filling rate is 10% -20%, preferably 10%; export preparation for printing for gcode format

And filling the printing wire into a feeding device of the 3D printer, guiding the gcode format file into the printer, starting the printer to work, and printing out the Olaparib 3D printing sheet by stacking layer by layer.

Example 2:

step S100: uniformly mixing the powder of the olapari bulk drug (30%), the copovidone (20%), the polyvinyl alcohol (45%) and the cross-linked povidone (5%) and putting the mixture into a double-screw hot-melt extruder, wherein the screw speed is set to be 30rpm, and the heating temperature is set to be 200, 210 and 220 ℃.

Step S200: continuously feeding raw materials into a feed inlet, heating the mixed raw materials to be in a molten state, forming a linear material at a die opening, cooling to be in a solid state, and drawing the composite material into a wire rod with the diameter of 2.85+/-0.02 mm to finish wire rod preparation. The appearance of the wire rod is photographed by a camera, the wire rod is smooth and flat, and the diameter is uniform.

Step S300: feeding the wire to a 3D printer for printing into olapari tablets; the method specifically comprises the following steps:

step S310: establishing a 3D printing model;

because of the technological characteristics of 3D printing layer by layer, the interlayer combination is tight, no gap exists, and a tablet with a compact structure is often obtained, and a dissolution medium is difficult to permeate in the dissolution process. Thus, a multi-layer porous model is established, and the surface area and the gaps of the 3D printing sheet are increased.

And (3) establishing a model by using computer CAD 2014 software, and establishing a capsule-shaped circular ring which is divided into an upper layer, a middle layer and a lower layer, wherein the layers are 2mm in height, 7mm in width and 11mm in length respectively. As shown in fig. 2. The established 3D printing model has the characteristics of small interlayer bonding area and higher porosity.

Step S320: printing:

exporting the designed model into a stl format file, importing the stl format file into 3D printing slicing software Ultimaker Cura, designing a spray head printing sequence and a printing path, and setting the printing speed to be 30-60 mm/s, preferably 40mm/s; the height of the printing layer is 0.20-0.40 mm, preferably 0.40mm; filling 10-20%, preferably 20%; the export prepares the print for gcode format.

And filling the printing wire into a feeding device of the 3D printer, guiding the gcode format file into the printer, starting the printer to work, and printing out the 3D printed Olaparib sheet by stacking layer by layer.

Test example 1: comparison of the reference formulation with the inventive formulation wire mechanical Properties

In the reference formulation patent (CN 200980150172.4), VA64, which is low in hygroscopicity and high in softening temperature, was used as a carrier for the solid dispersion. However, because VA64 extrudate is brittle, it is prone to fracture during feeding (Journal of Pharmaceutical Sciences,2018,107 (1): 390-401), and this formulation is not suitable for 3D printing. The present invention contemplates the use of a combination of two different polymers to enhance the mechanical properties of the extrudate.

The mechanical properties of the wire prepared in example 1 of the present invention and the reference formulation recipe were studied using a three-point bending test, and the results are shown in fig. 3. It is considered that a wire rod having a large breaking distance and a large breaking stress has stronger toughness. Literature reports that when the fracture distance is>1mm and breaking stress>2941g/mm ² The wire can meet the requirements of 3D printing (International Journal of Pharmaceutics,2017,519 (1): 186-97). The results show that the breaking distance and the breaking stress of the wire rod of the reference preparation prescription are low, and the wire rod cannot be printed in a 3D mode. The invention uses the composition of two different polymers, greatly improves the mechanical property of the wire rod, and can be used for 3D printing.

Test example 2:3D printing of topographical features of Olaparib tablets

The appearance of the olaparib tablet prepared in example 1 was photographed with a camera. As shown in fig. 4, the 3D printing sheet has a capsule-like appearance, a complete appearance, smooth and flat contour lines, a length of about 13mm, a width of about 7mm, and a height of about 7mm, and is light-yellowish in color, and the size of the 3D printing preparation prepared by the model is significantly smaller than that of the reference preparation, as shown in fig. 5. In consideration of the problem that dysphagia and pain accompany swallowing often occur after patients with ovarian cancer undergo treatment means such as chemotherapy, the invention can solve the problem and improve the patient compliance.

Test example 3: solid characterization study of 3D printed Olaparib tablets

The extrudate strands prepared in example 1 were subjected to solid state characterization studies. The wire rod was ground and pulverized, and then passed through a 100-mesh sieve to obtain wire rod powder, which was subjected to Differential Scanning Calorimetry (DSC), fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction study (PXRD) to examine the solid state properties of the wire rod.

DSC parameters: the initial temperature was 40℃and the temperature was raised to 250℃at 10℃per minute.

FTIR parameters: scanning range is 4000-400 cm ^-1 The obtained spectral data were smoothed by Nicolet Omnic 8.0 infrared spectrum analysis software.

PXRD parameters: the copper target is adopted, the step size is 0.02 DEG, and the scanning speed is 1 DEG/min.

As shown in fig. 6, fig. 6 (a) is an olapari drug substance, (b) is a physical mixture, (c) is a hot melt extrudate, and (D) is a 3D print sheet milled powder; according to the DSC result of FIG. 6, the extrudate wire prepared in example 1 and the 3D printing plate milled powder have no crystal melting peak and have a single T _g It is presumed that an amorphous solid dispersion is formed.

As shown in fig. 7, (a) is a hot melt extrusion product, (b) is a physical mixture, and (c) is an olapari drug substance; the PXRD results from fig. 7 show that the wire prepared in example 1 does not contain crystalline melting peaks, appears as broad diffraction rings, presumably forming an amorphous solid dispersion, consistent with DSC results.

As shown in fig. 8, fig. 8 (a) shows the crude drug of olapari, (b) shows polyvinyl alcohol, (c) shows copovidone, (d) shows olapari,A physical mixture of polyvinyl alcohol and copovidone, (e) a hot melt extrudate; the FTIR results according to FIG. 8 show that the characteristic peaks of the Olaparib drug substance occur mainly at 3300-2800 cm ^-1 And 1800-600 cm ^-1 Within the range. V of amide group in Olaparib bulk drug _C＝O Peak at 1662cm ^-1 、1633cm ^-1 The amide I absorption band is shown. Delta _N-H The peak is at 1495cm ^-1 Where it is called the amide ii absorption band. In addition v _C-N The peak is 1500-1450 cm ^-1 There are several peaks of moderate intensity in the range called the amid iii band. The two absorption bands of amides II and III are due to delta _N-H And v _C-N Is generated by vibration coupling of the (c).

3292cm in polyvinyl alcohol ^-1 Broad and strong absorption peaks at the frequency are attributed to the OH stretching vibration mode (v) of the polyvinyl alcohol molecule _OH ) Polyvinyl alcohol molecule CH ₂ Asymmetric telescopic vibration (v) _{as CH2-} ) At 2943cm ^-1 CH2 symmetrical telescopic vibration (v) _{s CH2-} ) At 2904cm ^-1 At a frequency of 1093cm ^-1 Is characterized in that the absorption peak of hydroxyl characteristic caused by C-O stretching vibration is 1142cm ^-1 The stretching vibration peak of the C-C bond is shown.

Copovidone has two hydrogen bond acceptor groups, wherein the cyclic amide extension of the lactam group has v _C＝O At 1667cm ^-1 Where v of vinyl acetate group _C＝O Peak at 1739cm ^-1 Where it is located. In addition, v of the amide group _C-N The peak is at 1496cm ^-1 Where v of the ester group _C-O The peak is at 1242cm ^-1 、1290cm ^-1 Where it is bimodal.

The FTIR spectrum of the physical mixture of the olapari drug substance, the polyvinyl alcohol, and the copovidone is simply a superposition of the olapari crystal, the polyvinyl alcohol, and the copovidone spectrum.

The infrared spectrum of the amorphous solid dispersion formed after hot melt extrusion is clearly different from that of the physical mixture. Wherein v of the amide group _C＝O Peak from 1663cm ^-1 Shift to higher wavenumbers, blue shift to 1678cm ^-1 Where, and the peak shape becomes wider and duller. Is originally positioned at 1633cm ^-1 V at _C＝O The peak shifts to higher wavenumbers, blue to 1643cm ^-1 Where v _N-H Peak from 3163cm ^-1 Move to 3278cm ^-1 And the peak shape becomes wider and duller. V (v) _C-N The peak is 1433cm ^-1 Move to 1454cm ^-1 All show that the oxilapatinib drug substance forms a new solid form after hot melt extrusion, and further show that the oxilapatinib drug substance forms an amorphous form by combining with a PXRD result. The original long-range ordered crystal lattice of the olapari bulk drug is destroyed, and the inside of the molecule is rearranged to be in long-range disordered arrangement.

And v of amide group in copovidone _C＝O Peak from 1667cm ^-1 Move to 1678cm ^-1 Where v of vinyl acetate group _C＝O Peak from 1738cm ^-1 Move to 1740cm ^-1 Where it is located. 3292cm in polyvinyl alcohol ^-1 The absorption peak characteristic of-OH, which exists at a frequency in the form of intermolecular or intramolecular association, disappears. It is speculated that the olapamide carbonyl, copolyvidone amide carbonyl, and vinyl acetate carbonyl may produce intermolecular hydrogen bonds with polyvinyl alcohol.

Test example 4: prescription and Process study

1. Effect of carrier material on 3D printed olapari tablets:

the substitution of polyvinyl alcohol in example 1 with other carrier materials, including: and carrying out hot melt extrusion on the hydroxypropyl methylcellulose, the hydroxypropyl cellulose and the polyethylene oxide to obtain the corresponding wire rod. The wire rod mechanical properties can meet the 3D printing requirement, and the wire rod is subjected to solid state characterization of a polarized light microscope, as shown in fig. 9, wherein (a) is hydroxypropyl methylcellulose, (b) is hydroxypropyl cellulose, and (c) is polyethylene oxide. The results show that the prepared extrudates have birefringence, and the carrier materials have poor miscibility with drugs, so that amorphous solid dispersions cannot be formed.

2. Effect of drug content on 3D printed olapari tablets:

table 1 3D printed olapari tablet formulations with different drug content

The olapari content of example 1 was subjected to wire preparation according to table 1, and the prepared wire was subjected to solid state characterization studies. DSC results show that the wires with the drug loading rate of 30-50% all have single T _g Both the drug and the carrier can form an amorphous solid dispersion, see fig. 10, (a) is a physical mixture, (b) is a 30% drug loading hot melt extrudate, (c) is a 40% drug loading hot melt extrudate, (d) is a 45% drug loading hot melt extrudate, and (e) is a 50% drug loading hot melt extrudate.

And feeding the prepared wire rod to a 3D printer for printing. The printing temperature was set at 270℃and the printing speed was set at 40mm/s, the layer height was set at 0.20mm, and the nozzle diameter was 0.20mm. The resulting tablets were printed and tested for dissolution. The results are shown in Table 2.

TABLE 2 3D printed Oxiaparil tablet dissolution for different drug loading rates

The dissolution experiment result shows that the drug loading rate of 30-45% can reach 100% dissolution, and the dissolution end point of 50% drug loading rate is only 85%. With the increase of drug loading, the dissolution speed is increased.

Since the dissolution of the 3D printed olaparib tablet at 30% -45% drug loading is similar to the reference formulation, it is preferred that the drug loading is 40% -45%.

3. Effect of dissolution modifying material on 3D printed olapari tablets:

the replacement of crospovidone in example 1 with other carrier materials includes: mannitol, calcium carbonate and the amount of crospovidone used were examined. And uniformly mixing the raw materials, and performing hot-melt extrusion to obtain the corresponding wire rod. The mechanical properties of the wire can meet the 3D printing requirement, and the prepared wire is supplied to a 3D printer for printing. The printing temperature was set at 270℃and the printing speed was set at 40mm/s, the layer height was set at 0.20mm, and the nozzle diameter was 0.20mm. The resulting tablets were printed and tested for dissolution. The results are shown in Table 3.

Table 3 dissolution of different dissolution modifying materials 3D printed olapari tablets

The dissolution test result shows that 5% of the crospovidone has the most remarkable effect on improving the dissolution rate, so that the content of the crospovidone is preferably 5% -10%.

4. Effect of printing temperature on 3D printed olapari tablets:

the wire rod prepared in example 2 was fed to a 3D printer for printing. The printing temperature was set at 230, 250, 270 ℃, the printing speed was set at 40mm/s, the layer height was set at 0.20mm, the nozzle diameter was 0.20mm, and the resulting tablets were printed for dissolution measurement. The results are shown in Table 4.

Table 4 dissolution of 3D printed olapari tablets at different printing temperatures

The dissolution experiment results show that the dissolution of the 3D printing piece is not obviously affected by different printing temperatures at 230-270 ℃, and the dissolution of the 3D printing piece is not degraded by medicines, and the printing performance and the energy consumption are considered, and the temperature of 230-250 ℃ is preferred.

5. Effect of print fill on 3D printed olapari tablets:

the wire rod prepared in example 2 was fed to a 3D printer for printing. The printing temperature is set to 270 ℃, the printing speed is set to 40mm/s, the layer height is set to 0.20mm, the diameter of the spray head is 0.20mm, and the filling rate is respectively 10% and 20%. The resulting tablets were printed and tested for dissolution. The results are shown in Table 5.

Table 5 dissolution of 3D printed olapari tablets at different packing densities

The dissolution experiment result shows that the filling rate is increased, the tablet weight is slightly increased, the dissolution speed is slightly reduced, and no obvious influence is caused. The filling ratio is preferably 10 to 20%.

6. Effect of spray head diameter on 3D printed olapari tablets:

the diameter of the nozzle influences the diameter of the printing filament, and the experiment process using the nozzle with the diameter of 0.40mm finds that the diameter of the printing filament is larger, so that the smearing phenomenon is generated, the structure of the 3D printing sheet is changed, and the dissolution experiment is influenced.

The wire rod prepared in example 2 was fed to a 3D printer for printing. The printing temperature was set at 270℃and the printing speed was set at 40mm/s, the layer height was set at 0.20mm, and the nozzle diameters were 0.40 and 0.20mm. The resulting tablets were printed and tested for dissolution. The results are shown in Table 6.

TABLE 6 dissolution of 3D printed Olaparib tablets for different spray head diameters

The dissolution experiment result shows that the diameter of the spray nozzle is 0.20mm, and the dissolution speed of the tablets is improved, so that the diameter of the spray nozzle is preferably 0.20-0.40 mm.

Test example 5: dissolution Curve determination

The dissolution profile was determined by taking a sample of example 1. According to the first method (basket method) of dissolution and release measurement of the 2020 edition of Chinese pharmacopoeia, 900mL of 0.1M hydrochloric acid solution, pH 6.8 phosphate buffer solution and water are respectively taken as dissolution media, the rotation speed is 100rpm, 5mL of dissolution media are respectively sampled at 5min, 10min, 15min, 20min, 30min, 45min, 60min, 90min and 120min, the same volume of dissolution media is supplemented at the same time, and after the sample is filtered by a 0.45 mu m microporous filter membrane, absorbance is measured at 276nm, and the cumulative dissolution rate is calculated. The results are shown in Table 7, and FIGS. 11 to 13, wherein (a) in FIG. 11 shows the dissolution profile of 3D-printed Olaparib in 0.1M hydrochloric acid solution, and (b) shows the dissolution profile of the reference formulation in 0.1M hydrochloric acid solution; wherein, (a) shows the dissolution profile of 3D printed olapari tablets in pH 6.8 phosphate buffer and (b) shows the dissolution profile of the reference formulation in pH 6.8 phosphate buffer; in fig. 13, (a) shows the dissolution profile of 3D printed olaparib in water and (b) shows the dissolution profile of a reference formulation in water. The results showed that homemade 3D printed olapari tablets were similar to the reference formulation in all 3 dissolution media.

TABLE 7 similarity factors for 3D printed Olaparib and reference formulations in different media

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The invention is not related in part to the same or implemented in part by the prior art.

The foregoing is a further detailed description of the invention in connection with specific embodiments, and it is not intended that the invention be limited to such description. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.

Claims (10)

1. A 3D printed olapari tablet, characterized by: comprising a composition of olapari, a carrier material and a dissolution modifying material;

wherein the carrier material accounts for 45-70% of the weight of the composition;

wherein the dissolution regulating material accounts for 5-10% of the weight of the composition;

the remaining component is olapari.

2. The 3D printed olapari tablet of claim 1, wherein: the carrier material is a mixture of two polymers including, but not limited to, hydroxypropyl methylcellulose, copovidone, polyvinyl alcohol, hydroxypropyl cellulose.

3. The 3D printed olapari tablet of claim 2, wherein: the carrier material comprises copovidone and polyvinyl alcohol, and the ratio of the copovidone to the polyvinyl alcohol is 1:1-1:2.25.

4. The 3D printed olapari tablet of claim 1, wherein: the dissolution regulating material is any one of crosslinked povidone, calcium carbonate and mannitol.

5. A method of preparing a 3D printed olapari tablet according to any of claims 1 to 4, wherein:

step S100: uniformly mixing the olapari, the carrier material and the dissolution regulating material, and putting the mixture into a double-screw hot-melt extruder;

step S200: the mixed composition is heated by a double-screw hot-melt extruder to be in a molten state, a linear material is formed at a die orifice, the linear material is pulled into a wire rod, and the wire rod is cooled to be in a solid state, so that the wire rod preparation is completed;

step S300: the wire was fed to a 3D printer and printed into olapari tablets.

6. The method for preparing 3D printed olapari tablet of claim 5, wherein: in step S100, parameters of the twin-screw hot-melt extruder include: the rotating speed of the screw is 20-40 rpm, and the heating temperature is 180-220 ℃.

7. The method for preparing 3D printed olapari tablet of claim 5, wherein: in step S200, the diameter of the wire rod is 2.85.+ -. 0.02mm.

8. The method for preparing 3D printed olapari tablet of claim 5, wherein: in step S300, parameters of the 3D printer include: the temperature is set at 230-270 ℃, the printing speed is set at 30-60 mm/s, the layer height is set at 0.20-0.40 mm, and the diameter of the spray head is 0.20-0.40 mm.

The filling rate is 10-20%, the wall thickness is 0.20-0.40 mm, the platform temperature is 50-100 ℃, and the outer wall printing speed is 30-60 mm/s.

9. The method for preparing 3D printed olapari tablet of claim 5, wherein: in step S300, the method further includes a step of creating a 3D printing model before printing; the established 3D printing model is a capsule-shaped circular ring and is divided into an upper layer, a middle layer and a lower layer.

10. The method for preparing 3D printed olapari tablet of claim 9, wherein: in step S300, the interlayer bonding area of the 3D printing model is 52-65 mm ² The specific surface area is 2.0-2.2.

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