A new 3D printing concept for pharmaceutical formulations using selective laser sintering.

Abstract

The present invention relates to a process for manufacturing pharmaceutical formulations by powder bed fusion selective laser three-dimensional printing, particularly selective laser sintering three-dimensional printing (SLS), and to pharmaceutical formulations produced by the same process.

Description

Technical Field

[0001] The present invention relates to a process for manufacturing pharmaceutical formulations by powder bed fusion selective laser three-dimensional printing, particularly selective laser sintering three-dimensional printing (SLS), and to pharmaceutical formulations produced by such a process.

Background Art

[0002] Selective laser sintering (SLS) is an additive manufacturing process that creates three-dimensional (3D) objects layer by layer. In this process, layers of powder material are applied sequentially and each powder layer is sintered or coalesced with a laser according to the shape of the computer-aided design (CAD) of the part.

[0003] SLS is a powder bed-based additive manufacturing technology for manufacturing complex three-dimensional parts. In SLS, a rasterized laser is used to scan a bed of polymer powder and sinter it layer by layer to form a solid shape. When the laser beam scans the powder, the powder melts due to the temperature rise, and the density of the final part should approach the maximum for each layer, and the properties of the bulk material (polymer) should be obtained. By controlling the energy input, the density of the sintered material can be controlled, and parts ranging from highly porous to almost fully dense can be realized.

[0004] Selective laser sintering (SLS) is a subset of powder bed fusion 3D printing that uses a laser beam to heat powder particles and fuse them on the surface to create a solid object. Currently, most commercially available SLS printers employ carbon dioxide (CO2) lasers, which enable low cost and high power, and allow the use of various powder thermoplastic materials. Therefore, the application of SLS spans many fields such as aerospace, automotive, military, medical, dental, engineering, and the electronics industry. In the pharmaceutical field, when the raw material is a powder blend of a drug and a thermoplastic polymer, SLS printing can be used to manufacture therapeutic products.

[0005] This means that, compared to other 3D printing technologies, the raw materials used in SLS printing are the closest to those used in conventional tableting. Therefore, SLS is expected to be more suitable for pharmaceutical applications. While other 3D printing technologies, such as binder jetting, are also based on powder materials, SLS, being a solvent-free process, is faster because it does not require an additional drying step to evaporate residual binder.

[0006] The currently described 3D printing concepts for creating pharmaceutical formulations by selective laser sintering typically utilize a layer-by-layer approach using a pre-mixed powder consisting of at least one polymer, API, and a specific absorbing material depending on the light / laser source (Awad et al., 2020; International Journal of Pharmaceutics 586:119594).

[0007] In this concept, all components must be pre-mixed in order to achieve homogeneous sintering. Because pre-mixing of the API and polymer is required, and separate mixtures need to be prepared for each printing step, formulation development becomes more complex. Furthermore, demixing may occur during the process. Using a prescribed pre-mix limits dosage adjustment and flexibility in formulation development.

[0008] Therefore, a process is needed to manufacture pharmaceutical formulations by powder-bed fusion selective laser 3D printing, which allows for individual adjustment of drug content within the printing step. Furthermore, a process that avoids separation effects during the process is required. In addition, it is desirable that such a process results in pharmaceutical formulations with improved structural consistency and / or high drug content compared to conventional processes. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] Surprisingly, a process for manufacturing pharmaceutical formulations by powder bed fusion selective laser 3D printing, comprising the following steps: (a) preparing a first sintered powder on a first reservoir platform such that it consists essentially of a pharmaceutically active ingredient or a mixture of at least two pharmaceutically active ingredients; (b) preparing a second sintered powder containing an excipient on a second reservoir platform, wherein the excipient absorbs electromagnetic radiation of wavelengths emitted by the laser; and (c) operating a selective laser sintering apparatus to fuse the layers of the first and second sintered powders, thereby manufacturing a pharmaceutical formulation, has been found to improve the production process and yield a pharmaceutical formulation with improved properties.

[0010] In preferred embodiments of the present invention, powder bed fusion selective laser 3D printing includes selective laser sintering 3D printing, selective laser melting 3D printing, electron beam melting 3D printing, or multi-jet fusion, or a combination thereof, preferably selective laser sintering 3D printing, preferably selective laser sintering 3D printing.

[0011] In a more preferred embodiment of the present invention, the excipient is a polymer, particularly a polymer selected from the group consisting of acrylic polymers, cellulosic polymers, polyvinyl polymers, and mixtures thereof. In another aspect, the present invention provides a pharmaceutical formulation manufactured by the process described above. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 shows the conventional method and the multi-compartment system. [Figure 2] Figure 2 shows the final structures printed using the conventional method and the multi-compartment method.

[0013] Detailed description of the invention Embodiments of the present invention relate to a process for manufacturing pharmaceutical formulations by powder bed fusion selective laser 3D printing, comprising the following steps: (a) A step of preparing a first sintered powder on a first reservoir platform such that it consists essentially of a pharmaceutical active ingredient or a mixture of at least two pharmaceutical active ingredients, (b) A second sintered powder containing an excipient is prepared on a second reservoir platform, wherein the excipient absorbs electromagnetic radiation of a wavelength emitted by the laser. (c) A step of manufacturing a pharmaceutical product by operating a selective laser sintering apparatus to fuse the layers of the first and second sintered powders. The process includes the above.

[0014] In conventional powder bed fusion selective laser 3D printing, particularly selective laser sintering 3D printing for pharmaceutical applications, a mixture of active pharmaceutical ingredients (APIs) and excipients is filled into one or more reservoirs.

[0015] According to the present invention, powder bed fusion selective laser 3D printing comprises two reservoirs, the first of which is filled with sintered powder consisting essentially of API. When API and excipients are used in separate chambers, there is no need to pre-mix the components. The API content and emission rate can be individually adjusted by selecting the compartment to be treated.

[0016] Variations can be created by changing the amount or height of individual layers. It is also possible to adjust the amount of individual drug or polymer layers. The new system will utilize a dedicated cartridge system that can be supplied directly to individual compartment chambers.

[0017] Furthermore, surprisingly, the process according to the present invention was found to yield pharmaceutical formulations with improved homogeneity and / or structural consistency. In addition, high drug filling was achieved in the resulting pharmaceutical formulations. The advantages of the process of the present invention and the improved properties of the pharmaceutical formulation are important aspects in the production of pharmaceuticals.

[0018] According to the present invention, the term "consisting essentially of a pharmaceutical active ingredient" means that the first sintered powder consists of an API or the first sintered powder mainly contains an API and at least one pharmaceutically acceptable additive. Preferably, the pharmaceutically acceptable additive is a flow control agent. A flow control agent such as silicon dioxide is required to ensure proper API flow and uniformity of the API content in the pharmaceutical formulation in APIs that do not have appropriate fluidity.

[0019] In one embodiment, the first sintered powder consists of a pharmaceutical active ingredient or consists of a mixture of at least two pharmaceutical active ingredients.

[0020] In a further embodiment, the first sintered powder consists of at least one API of 95 to 100 weight percent and a pharmaceutically acceptable additive of 5 to 0 weight percent. In a further embodiment, the first sintered powder consists of at least one API of 97 to 100 weight percent and a pharmaceutically acceptable additive of 3 to 0 weight percent.

[0021] In a further embodiment, the first sintered powder is composed of at least one API of 95 to 100 weight percent and a flow control agent of 5 to 0 weight percent. In a further embodiment, the first sintered powder consists of at least one API of 97 to 100 weight percent and a flow control agent of 3 to 0 weight percent.

[0022] In a further embodiment, the first sintered powder contains at least one API but does not contain excipients as defined below. In a more preferred embodiment, the first sintered powder contains at least one API but does not contain excipients as defined below that absorb electromagnetic radiation of the wavelength emitted by the laser. In a more preferred embodiment, the first sintered powder contains at least one API but does not contain excipients and pharmaceutically acceptable additives as defined below that absorb electromagnetic radiation of the wavelength emitted by the laser.

[0023] According to the present invention, the term "powder bed fusion selective laser three-dimensional printing" refers to a subset of four technologies: selective laser sintering (SLS), selective laser melting (SLM), electron beam melting (EBM), and multi-jet fusion (MJF). These technologies differ in the type of material used and the type and amount of light or radiation used to transfer energy to the powder bed.

[0024] In any case, the object is shaped layer by layer using the thermal energy generated from the combination of temperature rise and the use of a light source, and powder is used as its raw material. One of the direct advantages of this is that the loose powder particles inside the bed function as a support and maintain the integrity of the object during printing, so that overhang structures and complex structures can be fabricated without the need for a secondary support material.

[0025] In SLS printing, a thermoplastic polymer is used as the main raw material. The laser beam melts the surface of the powder particles and fuses them together. This process is called "sintering". Since a relatively low-power laser is used, the printer itself heats the raw material powder, and the laser only slightly raises the surface temperature of the powder to induce sintering. When the feed material is metal or alloy powder, this technique is usually called SLM or direct metal laser sintering (DMLS).

[0026] While EBM also uses metal powders and alloy powders as its main supply material, the energy required for sintering the particles is supplied by an electron beam, not a laser beam. The high-intensity electron beam completely melts the powder material during the printing process.

[0027] MJF uses only one raw material, nylon (such as PA12), and employs an infrared (IR) lamp as its energy source. MJF requires two additional components: (i) a fusion agent that is precisely deposited on the printing area by the inkjet head, and (ii) a detailing agent that absorbs heat from the edges of the object. As a result, only the areas coated with the fusion agent melt, improving printing efficiency and speed. Adding the detailing agent reduces heat leakage (e.g., heat diffusion to adjacent areas), improving print resolution and accuracy.

[0028] In preferred embodiments, powder bed fusion selective laser 3D printing includes selective laser sintering 3D printing, selective laser melting 3D printing, electron beam melting 3D printing, multi-jet fusion, or a combination thereof, preferably selective laser sintering 3D printing, and more preferably powder bed fusion selective laser 3D printing is selective laser sintering 3D printing (SLS).

[0029] According to the present invention, the terms “selective laser sintering,” “SLS,” “selective laser sintering 3D printing,” or “SLS 3DP” refer to a process that uses a laser beam to sinter a powder bed filled with sintering powder by scanning the laser along the cross-section of a digital model. The digital model version is manufactured layer by layer by laser scanning a continuous layer of powder.

[0030] This process requires a selective laser sintering printer equipped with a laser light source and a galvanometric system for scanning the laser on the powder bed surface, or an XY motion system for moving the laser light source itself to additionally scan the powder bed, or mirrors for reflecting the laser light source to achieve XY motion of the laser spot within the powder bed.

[0031] The printer must also provide two reservoir platforms, a first reservoir platform with a first sintered powder and a second reservoir platform with a second sintered powder, a build platform, a powder application system (spreader) for spreading the powder in layers onto the build platform, and several heating functions for heating the surface of the build chamber and the powder bed.

[0032] Parameters that can be changed in SLS typically include the type and wavelength of the laser, as well as laser power, scan speed, print resolution (layer height), beam spot size, surface temperature, chamber temperature, initial position of the build platform, and its descent speed. Powder dispensers are also diverse, and the design of other tools such as scrapers and roller devices may vary.

[0033] A laser is a device that emits light through a process of light amplification based on stimulated emission of electromagnetic radiation. The term "laser" is an acronym for "light acceleration by stimulated emission of radiation." Lasers emit coherent light. The types of lasers used in SLS include, for example, CO2 lasers, infrared lasers, and diode lasers such as blue diode lasers. In preferred embodiments, the laser encompasses CO2 lasers.

[0034] The wavelength of electromagnetic radiation emitted from lasers suitable for SLS is typically in the range of 200 nm to 11 μm, and is typically in the near-ultraviolet to mid-infrared range of the electromagnetic spectrum. For example, a suitable laser can emit electromagnetic radiation in the range of 315 nm to 1.4 μm, for example, 400 to 610 nm, preferably 400 to 500 nm, and more preferably 430 to 470 nm.

[0035] Another suitable laser emits electromagnetic radiation in the range of 9.4–11 μm, for example 10.2–10.8 μm, preferably about 10.6 μm. Another suitable laser emits electromagnetic radiation in the range of 750–850 nm, for example about 800 nm.

[0036] Laser power is measured in watts. This refers to the optical output of the laser beam; for continuous-wave (CW) lasers, it refers to the continuous output, and for pulsed or modulated lasers, it refers to the average output. Typically, SLS 3D printers use continuous-wave lasers. The appropriate laser power for SLS according to this invention is typically in the range of 0.5W to 140W.

[0037] In all aspects and embodiments of the present invention, the laser output is preferably in the range of 1W or more and less than 80W, for example, 1.5 to 75W. More preferably, the laser output is in the range of 1 to 30W, for example, 2 to 20W, for example, 3 to 15W. A suitable SLS 3D printer can use multiple lasers. For example, a printer can use two lasers, or three or more.

[0038] In SLS, the scan speed is the speed at which the laser moves across the powder bed. Suitable scan speeds for the present invention are in the range of approximately 5 mm / second to approximately 50,000 mm / second. The scan speed is directly correlated with the interaction time of the laser beam. The slower the scan speed, the longer the interaction time of the laser beam. In a preferred embodiment applicable to all aspects of the present invention, the scan speed is in the range of 10 mm / second to 10,000 mm / second, preferably 20 to 7,000 mm / second, and more preferably 50 to 6,000 mm / second.

[0039] According to the present invention, it is preferable to use a layer height in the range of 0.001 mm to 10 mm, preferably 0.025 mm to 0.5 mm, more preferably 0.05 mm to 0.25 mm, for example, 0.1 mm. It is believed that reducing the thickness of the layer improves the print resolution (i.e., improves the resolution) of the printed object.

[0040] The beam spot size suitable for the present invention is typically in the range of 0.0025 mm to 1 mm, for example, 0.05 to 0.5 mm, preferably 0.1 to 0.3 mm, for example, 0.2 mm. Typically, this is affected by adjusting the scan speed.

[0041] The surface temperature is the temperature of the powder being sintered. Typically, the surface temperature is in the range of 0 to 200°C, but preferably 40 to 180°C, and most preferably 70 to 170°C. The chamber temperature is the temperature inside the chamber where printing is taking place. Typically, this is in the range of 20 to 200°C, but for low-melting-point polymers such as poloxamer and PEG, 20 to 50°C is preferred, and for high-melting-point polymers such as PVA, 50 to 200°C is preferred, and 60 to 150°C is more preferred.

[0042] The first and second sintered powders are loaded into the printer, and the printing process begins. During the printing process, parameters such as the temperature of the chamber and printing bed are set to appropriate values ​​obtained through experimental studies, and a printed pharmaceutical formulation with desirable mechanical and morphological properties is provided.

[0043] Other parameters that affect the process are the laser energy input and the layer height of each applied layer. The laser energy input can be controlled in various ways depending on the type of printer used, but is usually controlled by adjusting the laser scan speed, hatching space (distance between scanned laser lines), or the energy output from the laser.

[0044] Once the printing process is complete, the printed pharmaceutical product is slowly cooled within the printer and then removed from the surrounding unsintered powder.

[0045] According to the present invention, the terms “pharmaceutical active ingredient” or “API” refer to a bioactive agent or dietary supplement, preferably a bioactive agent. An API may be a small molecule in the form of a weak base, weak acid, or neutral molecule, or it may be in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates thereof. The first sintered powder may contain a plurality of APIs. In one embodiment, the API is a sparingly soluble API or a lipophilic API.

[0046] As used herein, the terms “poorly soluble API,” “poorly water-soluble API,” and “lipophilic API” refer to APIs whose maximum therapeutic dose administered to an individual is so poorly soluble that it cannot be dissolved in 250 ml of an aqueous medium with a pH in the range of 1 to 8, according to the definition of low solubility in accordance with the Biopharmaceutical Classification System (BCS) Classes 2 and 4.

[0047] Poorly soluble APIs with weakly basic or weakly acidic properties have a pH-dependent solubility profile and can exhibit a wide range of solubility in the aqueous environment of the gastrointestinal tract. APIs corresponding to BCS class 2 or 4, respectively, are well known to those skilled in the art.

[0048] In one embodiment, the API is a weakly basic API. In this specification, the term "weakly basic API" refers to a basic pharmacoactive ingredient (API) that does not completely ionize in water.

[0049] The present invention provides for at least one active pharmaceutical ingredient (API) which can be dispersed in a pharmaceutical formulation to form an amorphous solid dispersion.

[0050] In this specification, the term "amorphous solid dispersion" refers to a dispersion of at least one amorphous API in the excipient matrix of a pharmaceutical formulation. Preferably, the amorphous API is distributed in a molecularly dispersed state within the excipient matrix. In this case, the solid dispersion is a solid solution. When dissolved, formulations containing amorphous solid dispersions may achieve higher solubility in aqueous media than crystalline APIs.

[0051] The amount of API contained in the pharmaceutical formulation of the present invention is sufficient to exert a therapeutic effect. For a particular API, the amount that is therapeutically effective is generally known or readily available to those skilled in the art. Typically, the API may be present in the pharmaceutical formulation in a weight ratio of API to excipient of 0.1:99.1 to 60:40, preferably 1:99 to 50:50, more preferably 5:95 to 40:60, and most preferably 10:90 to 30:70.

[0052] According to the present invention, the term "excipient" has the standard meaning in the art, that is, a substance that is combined with the active pharmaceutical ingredient of a pharmaceutical product for the purpose of enhancing the therapeutic effect of the active ingredient in the final dosage form, such as long-term stabilization, increasing the volume of a solid formulation containing a potent active ingredient, or promoting drug absorption, reducing viscosity, or improving solubility.

[0053] In a preferred embodiment, the excipient absorbs electromagnetic radiation of wavelengths emitted by the laser. The electromagnetic radiation is in the infrared, visible light, or ultraviolet region of the electromagnetic spectrum. In a preferred embodiment applicable to all aspects of the present invention, the excipient comprises or consists of a polymer.

[0054] A wide variety of polymer excipients are used in the production of solid pharmaceutical formulations. These include, for example, acrylic polymers, cellulosic polymers, polyvinyl polymers, and mixtures thereof. In this specification, the terms "polymer" and "polymer material" are used interchangeably.

[0055] Examples of suitable polymers include methyl acrylate-methacrylic acid copolymers, ethyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, shellac, cellulose acetate trimellitic acid, sodium alginate, zein, polyethylene oxide, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer, gelatin, polysaccharides, and mixtures thereof.

[0056] In preferred embodiments, the polymer is polyvinyl alcohol (PVA). Polyvinyl alcohol (PVA) has the ideal chemical formula -[CH2CH(OH)] n It is a synthetic water-soluble polymer with - properties. It possesses excellent film-forming, adhesive, and emulsifying properties. PVA is prepared from polyvinyl acetate, where the acetate functional groups are partially or completely hydrolyzed to alcohol functional groups. If not completely hydrolyzed, PVA is a random copolymer consisting of repeating units of vinyl alcohol -[CH2CH(OH)]- and repeating units of vinyl acetate -[CH2CH(OOCCH3)]-. The polarity of PVA is closely related to its molecular structure.

[0057] The molecular properties of PVA are determined by its degree of hydrolysis and molecular weight. As the degree of hydrolysis of the acetate group increases, the solubility, crystallinity, and melting point of the polymer in aqueous media increase. However, once the degree of hydrolysis exceeds 88%, the solubility of PVA decreases again. PVA is generally soluble in water, but is practically insoluble in almost all organic solvents except ethanol.

[0058] Typical PVA nomenclature indicates the viscosity of a 4% solution at 20°C and the degree of hydrolysis of the polymer. For example, PVA4-88 is a PVA grade with a viscosity of 4 mPa·s and 88% hydrolysis. That is, it contains 88% vinyl alcohol repeat units and 12% vinyl acetate repeat units.

[0059] Those skilled in the art will recognize that, according to common rounding methods, a degree of hydrolysis of 88% and a viscosity of 4 mPas corresponds to a calculated degree of hydrolysis of 87.50% to 88.49% and a calculated viscosity of 3.50 mPas to 4.49 mPas%. The viscosity according to the present invention is measured by the viscosity rotation method (912) according to the monograph "Polyvinyl Alcohols" of USP39.

[0060] The degree of hydrolysis according to the present invention is measured by measuring the saponification value of polyvinyl alcohol, as described, for example, in the section on "Degree of Hydrolysis" in the monograph for "Polyvinyl Alcohol" in USP39.

[0061] Sample: 1 g of polyvinyl alcohol (dried to constant weight at 110°C) analysis: The sample was transferred to a 250 ml wide-mouth Erlenmeyer flask fitted to a reflux condenser with a suitable glass tube. 35 ml of dilute methanol (3 in 5) was added, and the mixture was gently mixed until the solid was completely moistened. Three drops of phenolphthalein reagent were added, and neutralization was performed with 0.2 N hydrochloric acid or 0.2 N sodium hydroxide if necessary. 25.0 ml of 0.2 N sodium hydroxide VS was added, and reflux was performed on a hot plate for just under 1 hour. The condenser was washed with 10 ml of water, the washing solution was collected in the flask and cooled, and titrated with 0.2 N hydrochloric acid VS. Simultaneously, a blank measurement was performed using the same volume of 0.2 N sodium hydroxide VS in the same manner.

[0062] Calculation of saponification value: Calculate the saponification value: Result=[(V B -V S )xNxM r ] / W V B = Volume (ml) of 0.2N hydrochloric acid VS used in the blank titration V S = Volume (ml) of 0.2N hydrochloric acid VS used for titration of the sample solution N = Actual normality of hydrochloric acid VS M r = Molecular weight of potassium hydroxide, 56.11 W = Weight of the collected polyvinyl alcohol (g) Calculation of the degree of hydrolysis: The degree of hydrolysis, expressed as the hydrolysis rate (%) of polyvinyl acetate, is calculated. Result=100-[7.84xS / (100-0.075xS)) S = saponification value of polyvinyl alcohol

[0063] The use of PVA grade according to the present invention is of interest for formulations of solid oral pharmaceutical preparations involving immediate, rapid, or long-term API release. Preferred PVA has a degree of hydrolysis of 70% to 90%, a viscosity of 3 mPa·s to 8 mPa·s in a 4% solution at 20°C, more preferably 3 mPa·s to 5 mPa·s in a 4% solution at 20°C, and most preferably 3 mPa·s to 4 mPa·s in a 4% solution at 20°C.

[0064] In a further embodiment of the present invention, the polyvinyl alcohol has a degree of hydrolysis of 70% to 90%, preferably 80% to 90%, and the viscosity described above. In a further embodiment of the present invention, the polyvinyl alcohol has a degree of hydrolysis of 80% to 90% and a viscosity of 3 mPa·s in a 4% solution at 20°C, or a degree of hydrolysis of 80% to 90% and a viscosity of 4% solution at 20°C of 4 mPa·s.

[0065] In further embodiments of the present invention, the polyvinyl alcohol is PVA3-80, PVA3-82, PVA4-88, PVA5-88, PVA8-88, or PVA5-74, preferably PVA3-80, PVA3-82, or PVA4-88, and more preferably PVA4-88. In further embodiments of the present invention, the polyvinyl alcohol is PVA3-82, PVA4-88, or PVA5-74, more preferably PVA3-82 or PVA4-88, and most preferably PVA3-82. In a more preferred embodiment, the polymer is poloxamer (PLX).

[0066] Poloxamers are amphiphilic polymers, comprising two hydrophilic blocks and one hydrophobic block in the center. Poloxamers are triblock copolymers of polyethylene glycol (PEG) / polypropylene glycol (PPG), with one PPG block flanked by two PEG blocks. The polyethylene glycol (PEG) part is also called the polyethylene oxide (PEO) part. The polypropylene glycol (PPG) part is also called the polypropylene oxide (PPO) part.

[0067] Poloxamers are typically graded using the letter P (poloxamer) followed by a three-digit number formally used in USP and EP. This represents the polymer composition as follows: the first two digits multiplied by 100 represent the molecular weight of the PO block, and the last digit multiplied by 10 represents the percentage of EO.

[0068] Poloxamer P188 is composed of an average of 80% EO and the remaining 20% ​​PO, making up 1800 g / mol. Poloxamer P407 is a poloxamer with an average polyoxypropylene molecular weight of 4000 g / mol and a polyoxyethylene content of 70%. Poloxamers are represented by the general formula (I). [ka]

[0069] In different poloxamers, the number of x(PEO), y(PPO chain), and z(PEO) units varies widely depending on the type of poloxamer. In the case of poloxamer P188, the PPO chain contains an average of 25-30 units, each PEO consists of an average of 75-85 EO units, and the molecular weight is 7680-9510 Da. In the case of poloxamer P407, the PPO chain contains an average of 56 units, each PEO consists of an average of approximately 101 EO units, and the molecular weight is in the range of 9840-14600 Da. Poloxamer 407 (a=101, b=56) has molecular weights ranging from 9840 to 14600 Da.

[0070] Table 1 shows the types of poloxamers listed in the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopoeia (USP). [Table 1] The preferred poloxamers are P188 and P407.

[0071] In further embodiments of the present invention, the second sintered powder may contain further pharmaceutically acceptable additives. These pharmaceutically acceptable additives include flow control agents such as silicon dioxide, fillers, plasticizers, surfactants, light-absorbing materials such as ruby ​​red and candurine pigments, and other suitable components well known to those skilled in the art. In one embodiment of the present invention, the second sintered powder further comprises a light-absorbing material.

[0072] Depending on the wavelength of light emitted from a laser, a light-absorbing material (pigment) that absorbs light of that wavelength may be required. These light-absorbing materials contain transition metals for absorption at approximately 450 nm, or carbon for absorption over a wider range, from visible light to near-infrared. Light absorption is the process by which light is absorbed and converted into energy. When light is absorbed, heat is generated. Selective absorption of light by certain materials occurs because the frequency of the light wave matches the vibration frequency of electrons within the atoms of that material.

[0073] The light-absorbing material is any material known to those skilled in the art that is suitable for the SLS method, as described above. Preferably, a light-absorbing material that has been demonstrated to be effective with 455 nm laser irradiation is used, such as Candurin NXT, ruby ​​red, Candurin Gold Sheen, aluminum lake, activated carbon (which is also effective at 808 nm), or iron oxide (Fe2O3). More preferably, ruby ​​red is used.

[0074] In carbon dioxide lasers emitted at approximately 9-10 microns, CH bonds absorb energy at this wavelength, and since this type of bond is found in most polymers, there is usually no need to add light-absorbing materials.

[0075] To avoid any doubt, the further pharmaceutically acceptable additives defined above are not necessary for the beneficial properties of the present invention. However, these additives can also be used for other purposes, such as optimizing the production process of the pharmaceutical composition or oral dosage form according to the present invention. Furthermore, the pharmaceutical composition according to the present invention may contain additional pharmaceutically acceptable hydrophilic or lipophilic polymers.

[0076] As used herein, the term “pharmaceutically acceptable” generally refers to all excipients, additives, polymers, compounds, solvents, dispersion media, flow regulators, carriers, coatings, activators, isotonic agents, and absorption retarders that do not cause allergic reactions or similar undesirable reactions when administered to humans. The use of such materials in pharmaceutical compositions is well known in the art.

[0077] In a preferred embodiment, the particle size of the first and second sintered powders is such that D50 is 200 μm or less. Preferably, the particle size (D50) of the sintered powder is 20 μm to 200 μm, 20 μm to 150 μm, or 20 μm to 100 μm.

[0078] In a preferred embodiment, the PVA particle size D50 is 200 μm or less. Preferably, the PVA particle size (D50) is 20 μm to 200 μm, 20 μm to 150 μm, or 20 μm to 100 μm.

[0079] In a more preferred embodiment, the PVA particle size has a D90 of 250 μm or less. Preferably, the PVA particle size (D90) is 100 μm to 250 μm, and more preferably 140 μm to 220 μm. A further embodiment of the present invention is a pharmaceutical formulation obtained by the above process.

[0080] In this invention, "pharmaceutical preparation" means a dosage form or unit containing a drug for pharmaceutical use. Typically, dosage forms can be cylindrical, spherical, prismatic, elliptical, capsule-shaped, elongated, or diamond-shaped. Pharmaceutical preparations can be prepared in various physical forms, such as tablets, capsules, orally disintegrating tablets, films, masks, and patches.

[0081] Pharmaceutical formulations can be prepared with various release behaviors. The pharmaceutical formulation according to the present invention can provide at least one of controlled release, immediate release, colonic delivery, enteric-coated delivery, or gastric retention drug delivery performance. Preferably, immediate release or controlled release is provided.

[0082] The pharmaceutical formulation is suitable for administration via oral, intraoral, topical, transdermal, sublingual, enteral, dental, rectal, urethral, ​​or vaginal route. Preferably, oral, intraoral, topical, or transdermal administration is used, and more preferably, oral administration is used.

[0083] Surprisingly, pharmaceutical formulations printed using the multi-compartment method were found to have improved structural consistency. The tablets had a more precise shape, and for example, there was no curvature at the bottom of the structure compared to pharmaceutical formulations printed using conventional methods.

[0084] Furthermore, improved surface quality and parameters can be measured using scanning electron microscopy (SEM), BET (gas adsorption), or μCT measurements.

[0085] Furthermore, pharmaceutical formulations printed using the multi-compartment method exhibit faster and higher API release and / or improved API amorphousness compared to pharmaceutical formulations printed using conventional methods. API release can be tested by dissolution experiments in aqueous media.

[0086] When comparing powder X-ray diffraction (PXRD) data and / or differential scanning calorimetry (DSC) data with those of pharmaceutical formulations produced by conventional methods, improved amorphous properties can be observed in pharmaceutical formulations produced by the multi-compartment method.

[0087] Furthermore, in the multi-compartment system, the drug content of individual formulations can be adjusted within the same printing step or between different printing steps, using the same powder mixture. This can be achieved by adjusting the amounts of the first and second sintered powders. This adaptation is not possible with the conventional methods described above.

[0088] Furthermore, conventional methods can lead to separation of the API and excipients, potentially resulting in poor uniformity of content. This effect is less likely to be observed with the multi-compartment method.

[0089] example Example 1: Conventional SLS printing method Preparation of formulations Conventional SLS 3D printing formulations consist of a blend of PVA-based polymers (PVA), active pharmaceutical ingredients (APIs), and fluidity enhancers (silicon dioxide colloids (SD)). Detailed information regarding the composition is provided in Table 2 below. [Table 2] Table 2: Composition of formulations using the conventional method

[0090] The following formulation preparation sequence was used: 1. PVA-based polymers, SD, and APIs were manually weighed and mixed. 2. The blend was sieved using a 315 μm stainless steel test sieve (VWR International AB, Stockholm, Sweden). This step is necessary to remove large particle aggregates of the SD lamp and API and PVA-based polymers. 3. Next, the sieved blends were mixed for 3 hours using a Turbula shaker (Turbula T2F shaker, Glen Mills, Inc., Clifton, New Jersey, USA). 4. The mixed blend was heat-treated at 70°C to remove the temperature memory (TME) effect of the polymer and residual moisture. 5. Next, the blend was mixed again for 2 hours using a Turbula shaker. 6. The final formulation was filled into the printer's powder compartment.

[0091] Hardware setup and SLS printing procedure The operating system used is a SNOWWHITE2 selective laser sintering (SLS) 3D printer (SHAREBOT SRL, Nibionno, Lecco, Italy). This printer performs sintering via a CO2 (λ=10.6μm, P=14W) galvanometer laser system. The printer is equipped with an F-theta lens to avoid aberrations such as image field curvature. The inside of the printer is divided into three compartments: left, right, and the build compartment. The left and right compartments are used for powder supply, and the actual sintering occurs on the surface of the build compartment.

[0092] SLS printing procedure: 1. In the conventional method, the same powder formulation is filled into the left and right powder supply compartments. 2. The heating lamp warms the powder inside the printer to the set temperature. 3. Five "warm-up" powder layers are applied alternately to the build compartment from the left and right compartments. This is necessary to avoid temperature gradients within the build compartment. A spreader (black triangle in Figure 1) is used to apply the powder layers. The sequence of the layer application process is the same throughout the entire printing process. a) The left or right powder supply compartment rises, forming an excess layer of powder (Step 1 in Figure 1). b) The central structural compartment descends (the distance is equal to the height of the structural layer), forming space for the structural layer. c) The spreader moves along the powder surface, distributing the excess powder layer into the build compartment. This powder fills the space in the build compartment. 4. Next, sintering occurs on the powder surface inside the molding chamber (Step 2 in Figure 1). 5. This sequence is then repeated in the opposite compartment to create a new layer. 6. After that, the entire printer chamber is cooled, and the printer structure can be removed.

[0093] Print settings The print settings are as shown in Table 3 below. [Table 3] Table 3: Conventional print settings

[0094] Example 2: SLS printing using a multi-compartment system Preparation of formulations The multi-compartment method assumes the use of compound excipients without prior mixing. Each compartment is filled with a different excipient. APIs and polymers were used as compartment fillers. SD was added to each excipient to maintain flow properties. Details regarding the composition are shown in Table 4 below. [Table 4] Table 4: Composition of formulations for the multi-compartment method

[0095] The following formulation preparation sequence was used: Left compartment compound (PVA) 1. The PVA-based polymer was weighed manually and mixed with SD. 2. The blend was sieved using a 315 μm stainless steel test sieve (VWR International AB, Stockholm, Sweden). This step is necessary to remove aggregates of large particles of the SD lamp and PVA-based polymer. 3. Next, the sieved blends were mixed for 3 hours using a Turbula shaker (Turbula T2F shaker, Glen Mills, Inc., Clifton, New Jersey, USA). 4. The mixed blend was heat-treated at 70°C to remove the temperature memory (TME) effect of the polymer and residual moisture. 5. The blend was then mixed again for 2 hours using a Turbula shaker. 6. The final mixture was filled into the left and center compartments.

[0096] Right compartment formulation (API) 1. The API was weighed manually and mixed with the SD. 2. The blend was sieved using a 315 μm stainless steel test sieve (VWR International AB, Stockholm, Sweden). This step is necessary to remove large particle aggregates from the SD lamp and API. 3. Next, the sieved blends were mixed for 3 hours using a Turbula shaker (Turbula T2F shaker, Glen Mills, Inc., Clifton, New Jersey, USA). 4. The final mixture was filled into the right-hand compartment.

[0097] Hardware setup and SLS printing procedure The operating system used is a SNOWWHITE2 selective laser sintering (SLS) 3D printer (SHAREBOT SRL, Nibionno, Lecco, Italy). This printer performs sintering via a CO2 (λ=10.6μm, P=14W) galvanometer laser system. The printer is equipped with an F-theta lens to avoid aberrations such as field curvature. The internal space of the printer is divided into three compartments: left, right, and the build compartment. The left and right compartments are used for powder supply, and the actual sintering takes place on the surface of the build compartment.

[0098] SLS printing procedure: 1. Both the left side and the build compartment are filled with PVA-based polymer powder, while the right side is filled with API powder. In Figure 1, the amount of powder used varies depending on the type of powder. 2. The heating lamp warms the powder inside the printer to the set temperature. 3. To avoid temperature gradients within the build compartment, apply five layers of "warm-up" powder to the build compartment only from the left compartment. This is necessary to avoid temperature gradients within the build compartment. Use a spreader (black triangle in Figure 1) to apply the powder layers. The layer application process sequence is the same throughout the entire printing process. a) The left or right powder supply compartment rises to create an excess layer of powder (Step 1 in Figure 1). b) The central building compartment descends (the distance is equal to the height of the structural layer), creating space for the structural layer. c) The spreader moves along the powder surface, distributing the excess powder layer into the build compartment. This powder fills the voids within the build compartment. 4. Sintering occurs on the powder surface inside the molding chamber (Step 2 in Figure 1). 5. This sequence is then repeated in the opposite compartment, creating a new layer every two layers. 6. After that, the entire printer chamber is cooled, and the printer structure can be removed.

[0099] Print settings The print settings are shown in Table 5 below. [Table 5] Table 5. Print settings for the multi-compartment method

[0100] Both the conventional method and the multi-compartment method use the same materials for compound preparation, but the optical and thermal properties of the blend and the pure material differ. Therefore, the conventional method and the multi-compartment method cannot be performed with the same printing settings, and the printing settings were adjusted to avoid over-sintering due to temperature gradients and powder layer entanglement. The following details the differences in speed, powder, and plate temperature parameters between the conventional method and the multi-compartment method.

[0101] Due to the pure polymer wrapping issue, a high rate (85,000 pps) and low energy (26%) were selected. These two values ​​define the amount of laser energy transferred to the powder surface in the build chamber. In the case of blended formulations, the energy is distributed between the polymer and the API, requiring more energy than when the polymer and API are used individually. In the multi-compartment method, the plate temperature decreases because the top layer of API in the right compartment melts. In the case of blends, this is not a problem because there are polymers that require a higher temperature for melting.

[0102] Example 3: Characterization of 3D printed dosage forms structural consistency The printed model is cylindrical with a diameter of 10 mm and a height of 4 mm. In both methods, the total number of layers is 32 (4 / 0.125=32, where 4 is the height (mm) and 0.125 is the layer height (mm)). In the conventional method, all layers consist of a blended formulation. In the multi-compartment method, 16 layers are polymer-based and 16 layers are API-based. The API layers and polymer layers are arranged alternately in pairs.

[0103] Figure 2 shows the final structures printed using both methods. Figure 2 shows the final structures of tablets printed using the conventional method (right) and the multi-compartment method (left). It can be seen that the tablets printed using the conventional method are darker because energy transfer is higher, resulting in more intense melting of the API and polymer. However, the multi-compartment method shows improved structural consistency; for example, these tablets do not show curvature at the bottom of the structure compared to tablets printed using the conventional method.

Claims

1. A process for manufacturing pharmaceutical formulations by powder bed fusion selective laser 3D printing, comprising the following steps: (a) A step of preparing a first sintered powder on a first reservoir platform such that it consists essentially of a pharmaceutical active ingredient or a mixture of at least two pharmaceutical active ingredients, (b) A second sintered powder containing an excipient is prepared on a second reservoir platform, wherein the excipient absorbs electromagnetic radiation of a wavelength emitted by the laser. (c) A step of manufacturing a pharmaceutical product by operating a selective laser sintering apparatus to fuse the layers of the first and second sintered powders. The process including the process described above.

2. Laser CO ２ The process according to claim 1, wherein the laser is used.

3. The process according to claim 1 or 2, wherein the second sintered powder further comprises at least one light-absorbing material.

4. The process according to any one of claims 1 to 3, wherein the powder bed fusion selective laser three-dimensional printing includes selective laser sintering three-dimensional printing, selective laser melting three-dimensional printing, electron beam melting three-dimensional printing, or multi-jet fusion, or a combination thereof.

5. The process according to any one of claims 1 to 4, wherein the powder bed fusion selective laser three-dimensional printing is selective laser sintering three-dimensional printing.

6. The process according to any one of claims 1 to 5, wherein the excipient comprises a polymer.

7. The process according to claim 6, wherein the polymer is selected from the group consisting of acrylic-derived polymers, cellulose-derived polymers, poloxamers and polyvinyl-derived polymers, and mixtures thereof.

8. The process according to claim 6 or 7, wherein the polymer is selected from the group consisting of methyl acrylate-methacrylic acid copolymer, ethyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalic acid, methyl methacrylate-methacrylic acid copolymer, shellac, cellulose acetate trimellitic acid, sodium alginate, zein, polyethylene oxide, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, poloxamer, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, gelatin, polysaccharides, and mixtures thereof.

9. The process according to any one of claims 6 to 8, wherein the polymer is polyvinyl alcohol.

10. The process according to any one of claims 6 to 9, wherein the polymer is a polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of 3 mPa·s to 8 mPa·s in a 4% solution at 20°C.

11. The process according to any one of claims 6 to 10, wherein the polymer is polyvinyl alcohol PVA4-88 or P3-82.

12. The process according to any one of claims 1 to 11, wherein the electromagnetic radiation is electromagnetic radiation in the infrared, visible light, or ultraviolet region of the electromagnetic spectrum.

13. A pharmaceutical preparation manufactured by the process described in any one of claims 1 to 12.

14. The pharmaceutical preparation according to claim 13, wherein the pharmaceutical preparation is an orally administered formulation.

Images