Expandable, structured drug delivery type

Abstract

Disclosed herein is a pharmaceutical dosage form comprising a three-dimensional framework of thin solid elements surrounded by interconnected voids. The elements comprise at least a drug, a water-absorbing polymer excipient, and a hydrophilic surface composition, such that upon immersion in a dissolving fluid, the three-dimensional framework transitions from solid to viscous and expands in all dimensions. Among other advantages, the dosage form of the present disclosure allows for better control of drug concentration in the bloodstream and improved therapeutic outcomes. In some embodiments, upon immersion in a physiological fluid, the drug-containing solid dissolves or disintegrates in the physiological fluid.

Description

[Technical Field]

[0001] Cross-reference of related inventions This application claims priority and benefits of U.S. Provisional Application No. 62 / 633,602 filed on 21 February 2018 and U.S. Provisional Application No. 62 / 733,624 filed on 19 September 2018, which are incorporated herein by reference in their entirety.

[0002] This application incorporates, by reference, the entirety of the jointly owned U.S. applications No. 15 / 482,776, filed on April 9, 2017, entitled “Fibrous dosage form”, No. 15 / 964,058, filed on April 26, 2018, entitled “Method and apparatus for the manufacture of fibrous dosage forms”, and No. 15 / 964,063, filed on April 26, 2018. [Background technology]

[0003] Currently, the most common forms of pharmaceutical administration, oral delivery tablets and capsules, are porous solids of compressed drug and excipient particles. Upon ingestion, digestive fluids penetrate the open pores of the drug delivery form, promoting its fragmentation and dissolution of the drug particles. The dissolved drug molecules are then absorbed through the bloodstream and distributed to disease-specific target sites in the human body.

[0004] Despite significant commercial success, compressed powders for drug delivery applications have an inherent limitation: their non-deterministic and non-interconnective porosity. As a result, the rate and extent of fluid infiltration into the drug delivery form cannot be precisely controlled. Consequently, the range and control of drug delivery rates into the bloodstream are limited.

[0005] Therefore, to overcome such limitations, in jointly owned U.S. Patent Application No. 15 / 482,776, the inventors (Blaesi and Saka) introduced fibrous drug delivery forms. As schematically shown in Figure 1, these drug delivery forms include solid skeletons 100, 102, 104 of a drug-excipient complex (or solid solution) surrounded by adjacent voids 130, 132, 134 (or empty spaces). When immersed in a solution 140, 142, 144, the fluids 140, 142, 144 can permeate into the interconnected empty spaces 130, 132, 134 and the solid skeletons 100, 102, 104 (e.g., water-soluble excipients), allowing the solutions 140, 142, 144 to interdiffuse. Two examples are shown below.

[0006] In the first example, schematically shown in Figure 1a, when the skeleton 100 dissolves, the dissolved molecules diffuse into the empty space 130 and convect in the freely flowing dissolving solution 140 through the empty space 130. When the skeleton 100 dissolves, the drug is released. This example is observed for skeletons 100 containing water-soluble, low-molecular-weight excipients that generally form dilute, low-viscosity solutions with water.

[0007] In the second example represented by Figures 1b and 1c, at least one water-soluble excipient has a larger molecular weight. As a result, upon immersion in the dissolution, the structural framework 102, 104 transitions from solid to viscous media 152, 154 (e.g., a viscous dispersion, a viscous solution, or a viscous mass having a viscosity higher or much higher than the viscosity of the dissolution). The drug can be released either by deformation and dissolution of the viscous media 152, as schematically shown in Figure 1b, or by diffusion of the drug molecule through the viscous media 154, as illustrated in Figure 1c.

[0008] This disclosure primarily focuses on solid-to-viscosity drug formulations that transform into a viscous medium when immersed in a dissolving solution. The type of transformation from solid to viscous significantly affects the rate at which the drug is delivered into the bloodstream, and is therefore an important design parameter for enhancing the efficacy of drug therapy and reducing its side effects.

[0009] Design considerations Four non-limiting types of solid-to-viscosity transitions are briefly described in the following paragraphs. Through the descriptions and any supplementary illustrations, those skilled in the art will be able to more readily understand the inventions presented through this disclosure. These are not limiting in any way.

[0010] In the first type, represented by Figure 2a, the solid drug delivery form 200 consists of a three-dimensional structural framework 202 of drug particles 210 and a water-soluble and water-absorbing polymer excipient 220. The framework 202 is surrounded by interconnected empty spaces 230. The volume occupied by the excipient 220 in the framework 202 is considerably smaller than the volume of the empty spaces 230.

[0011] When immersed in the dissolving solution 240, the fluid 240 rapidly permeates into the interconnected empty spaces 230. Next, the excipient 220 and the dissolving solution 240 interdiffuse to form a viscous medium 250 consisting of fluidized (or dissolved) excipient molecules 222, drug molecules 212, and drug particles 210. The concentration of excipient molecules 222 in the viscous medium 250 is very low. Therefore, the viscosity of the viscous medium 250 is also low. As a result, the medium 250 rapidly deforms and dissolves in the dissolving solution 240.

[0012] Furthermore, as shown in the schematic diagram in Figure 2b, upon ingestion, the drug form rapidly breaks down in gastric juices, releasing drug particles (and drug molecules). The drug particles then dissolve and simultaneously pass through the small intestine. The dissolved drug molecules are finally absorbed through the bloodstream.

[0013] This type of drug delivery form is suitable for the immediate delivery of drugs with high solubility and diffusion rates in the gastrointestinal tract. However, because the mass of water-soluble excipients in the drug delivery form is very small, it is not possible to adjust the drug's physicochemical properties (e.g., solubility in digestive fluids, permeability across the digestive wall, etc.) and the drug release rate determined by the drug delivery form using excipients. This limits the range of drug delivery rates into the bloodstream and the control of drug concentration in the bloodstream.

[0014] Therefore, as illustrated in Figure 3a, in the second type, the solid drug delivery form 300 also consists of a three-dimensional structural framework 302 of the drug and a water-soluble and water-absorbing polymer excipient surrounded by interconnected empty spaces 330. However, unlike the above example, the volume of the polymer excipient 320 in the drug delivery form 300 is considerably larger than the volume of the empty spaces 330 in this example. As a result, upon immersion in the dissolution, the drug delivery form 300 transforms into a viscous medium 350 with a high excipient concentration and viscosity. Thus, in this example, the viscous medium 350 is a highly viscous mass that is essentially indeformable by the dissolution 340 and gradually disintegrates from the outside. Consequently, the content of the water-soluble polymer excipient in the drug delivery form is higher than in the first example, and the drug release rate by the drug delivery form is slower. The range and control of the drug delivery rate into the bloodstream are also limited, and the efficacy and safety of drug therapy may be impaired, as detailed below.

[0015] As a non-exclusive example, as schematically shown in Figure 3b, when ingested, the drug form or viscous mass gradually disintegrates, passing from the stomach to the small intestine and moving downward along the digestive tract, thereby releasing the drug. If the drug release rate is too slow, some of the ingested drug will be released during the gastrointestinal transit time t tr It cannot be released or absorbed internally and is therefore excreted. As a result, the amount of drug absorbed can also be variable, due to the generally variable transit time through the gastrointestinal tract. Variations in the amount of drug absorbed (e.g., variations in bioavailability) can impair both the efficacy and safety of drug therapy. Therefore, these variations must be eliminated.

[0016] However, if the drug-dosing form expands during its transfer to the viscous medium, a compromise can be overcome between the rapid decomposition (or dissolution) of the drug-dosing form and the high content of the water-soluble polymer excipient. Thus, in the third type illustrated in Figure 4a, the volume of the polymer excipient 420 in the three-dimensional structural framework 402 is also greater than the volume of the empty space 430. However, unlike the above example, when immersed in the dissolution 440, the drug-dosing structure 402, 450 continue to expand. As a result, the concentration of the excipient in the drug-dosing structure 402 or the viscous medium 450 constantly decreases to a concentration low enough to eventually unravel or even lower. Thus, the viscosity of the “final” viscous medium 450 becomes very low, and the “final” medium 450 rapidly deforms and dissolves in the dissolution 440.

[0017] Upon ingestion, the drug form can be broken down and dissolved in the upper gastrointestinal tract, as schematically shown in Figure 4b. The dissolved drug molecules can then be absorbed via the bloodstream. Variations in drug delivery rates due to slow or inconsistent breakdown of the drug form can be eliminated.

[0018] Furthermore, in addition to rapid and consistent drug breakdown and drug release rates, bloating drug formulations can release large amounts of water-soluble functional excipients in a short time. Such functional excipients can enhance the delivery rate of released drug molecules, for example, by increasing the drug concentration or solubility in the digestive fluid, or by enhancing the rate of drug absorption into the bloodstream. Thus, bloating drug formulations enable higher and more consistent drug delivery rates into the bloodstream, improving the efficacy and safety of numerous drug therapies.

[0019] Solid drug formulations that transform into viscous media and thereby expand may have further advantages. As a non-limiting example, if a solid drug formulation has an initial size smaller than the esophagus (15-20 mm) to facilitate swallowing, but then transforms into a viscous medium in the stomach and thereby expands to a size considerably larger than the pylorus (approximately 13 mm), it will not pass from the stomach to the small intestine, provided its viscosity is sufficiently high. This allows the drug to be released / delivered over a long period in the upper gastrointestinal tract without impairing drug absorption or premature excretion.

[0020] Therefore, in the fourth type, as schematically shown in Figure 5a, structures 502, 550 also expand as the polymer excipient 520 and the solvent 540 interdiffuse. However, eventually, the pores (e.g., multiple voids or empty spaces) 530 close, the expansion of the viscous drug-dosing form or medium 550 stops, and an expanded viscous mass 550 is formed. The viscous mass 550 is a concentrated polymer solution or dispersion. It is essentially immutable and gradually disintegrates or dissolves in the solvent, thereby releasing the drug.

[0021] Therefore, as schematically shown in Figure 5b, if the drug form or viscous medium expands rapidly after ingestion but stops expanding as soon as it reaches a size considerably larger than the pylorus, the viscosity of the expanded medium may remain high enough to prevent passage into the small intestine. This allows the drug form to be retained in the stomach for a long period, enabling the drug to be delivered into the bloodstream at a precisely controlled rate over a long period. This allows for improved control of drug concentration in the bloodstream and improved efficacy or reduced side effects of various drug therapies. [Overview of the Initiative] [Means for solving the problem]

[0022] The above considerations suggest that a solid drug delivery form that, upon ingestion, transfers to a viscous medium and expands, thereby enabling improved control of drug concentration in the bloodstream and improved therapeutic outcomes. Accordingly, in one embodiment, the pharmaceutical delivery form of the present disclosure comprises a drug-containing solid having an external surface and an internal three-dimensional structural skeleton of one or more thin structural elements, wherein the skeleton is adjacent to and terminates thereon the external surface, the thin structural element comprising at least one active pharmaceutical component, at least one absorbent polymer excipient, and at least one hydrophilic surface composition, the thin structural element further having spatially separated sections from adjacent sections, thereby defining voids, and a plurality of adjacent voids bonding across the drug-containing solid to define one or more interconnected voids forming an open network structure, thereby enabling uniform wetting of the structural skeleton and transfer of the drug-containing solid to a viscous medium, thereby expanding in all dimensions.

[0023] In some embodiments, when immersed in a physiological fluid, the drug-containing solid dissolves or decomposes in the physiological fluid.

[0024] In some embodiments, the drug-containing solid dissolves or decomposes during or after the transfer to the viscous medium.

[0025] In some embodiments, the drug-containing solid expands due to the permeation of physiological fluids or bodily fluids into the three-dimensional structural framework of one or more elements.

[0026] In some embodiments, the drug-containing solid expands upon permeation of physiological fluids or bodily fluids into an absorbent polymer excipient.

[0027] In some embodiments, at least one dimension of the drug-containing solid expands to at least 1.12 times its initial length during the transfer to the viscous medium.

[0028] In some embodiments, the drug-containing solid expands to at least 1.4 times its initial volume during the transfer to the viscous medium.

[0029] In some embodiments, at least one dimension of the drug-containing solid expands to at least 1.12 times its initial length within 20 minutes of immersion in a physiological fluid or body fluid.

[0030] In some embodiments, the drug-containing solid expands to at least 1.4 times its initial volume within 20 minutes of being immersed in a physiological fluid or body fluid.

[0031] In some embodiments, the drug-containing solid expands isotropically during the transfer to the viscous medium.

[0032] In some embodiments, the geometric similarity of the three-dimensional structural framework of the elements is preserved when they expand and transition to a fluid or viscous medium.

[0033] In some embodiments, at least one structural element expands isotropically during the transition to a fluid or viscous medium.

[0034] In some embodiments, 80 percent of the drug content in the drug-containing solid is released within 45 minutes after immersion in a physiological fluid or body fluid.

[0035] In some embodiments, one or more elements expand substantially anisotropically, causing the drug-containing solid to transform into a viscous mass having a viscosity at least three orders of magnitude greater than that of the dissolved solution.

[0036] In some embodiments, 80 percent of the drug content in the drug-containing solid is released over a period of time between 30 minutes and 72 hours (for example, between 30 minutes and 48 hours, or between 30 minutes and 24 hours).

[0037] In some embodiments, one or more elements include an average thickness of 2.5 mm or less (for example, 1 mm or less, or in the range of 1 μm to 1 mm, 5 μm to 1 mm, or 10 μm to 1 mm).

[0038] In some embodiments, the effective space spacing between sections that span one or more spaces is greater than 1 μm on average (for example, greater than 5 μm, greater than 10 μm, or in the range of 1 μm to 2 mm, 10 μm to 2 mm, or 20 μm to 2 mm).

[0039] In some embodiments, the position of at least one element or at least one segment in the three-dimensional structural framework of one or more elements is precisely controlled.

[0040] In some embodiments, the volume fraction of an element or section having a precisely controlled position in the three-dimensional structural framework of one or more elements is greater than 0.3.

[0041] In some embodiments, the three-dimensional structural framework of one or more elements includes a regular structure.

[0042] In some embodiments, the effective clearance spacing and element thickness are precisely controlled.

[0043] In some embodiments, a three-dimensional structural framework of one or more thin structural elements includes multiple layers of elements or sections.

[0044] In some embodiments, at least one element is a fiber.

[0045] In some embodiments, fiber plies or fiber sections are stacked in a cross-ply arrangement to form a three-dimensional structural framework.

[0046] In some embodiments, the three-dimensional structural framework of one or more thin structural elements includes a plurality of cross-patterned laminations of fibrous structural elements.

[0047] In some embodiments, the spacing between adjacent fibers or between adjacent fiber sections in a layer or ply is uniform or equal.

[0048] In some embodiments, at least one element is a sheet.

[0049] In some embodiments, at least one element is a bead.

[0050] In some embodiments, the surface of at least one element or the surface of at least one section includes a coating.

[0051] In some embodiments, the coating includes a highly hydrophilic surface composition to enhance the wetting rate of the structural framework or the rate of fluid penetration into the perforated network structure.

[0052] In some embodiments, at least one highly hydrophilic coating composition is selected from the group comprising polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone, silicon dioxide, talc, magnesium stearate, mannitol, xylitol, maltitol, erythritol, sucrose, glucose, isomalt, maltodextrin, or lactitol.

[0053] In some embodiments, the spacing between sections and the composition of the surface of one or more elements are such that the penetration time of physiological fluids / body fluids into one or more interconnected spaces of the drug-containing solid is less than 200 seconds under physiological conditions.

[0054] In some embodiments, the rate of permeation of physiological fluids / body fluids into an element or absorbent excipient under physiological conditions is greater than the average value of the element's thickness divided by 3600 seconds.

[0055] In some embodiments, the effective diffusion rate of physiological fluids / body fluids in the element or absorbent excipient is 1 × 10⁻¹⁶ under physiological conditions.-12 m 2 Greater than / s

[0056] In some embodiments, at least one absorbent polymer excipient is selected from the group comprising hydroxypropyl methylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose succinate acetate, sodium alginate, hydroxypropylcellulose, methylcellulose, hydroxypropyl methyl ethercellulose, starch, chitosan, pectin, polymethacrylate (e.g., poly(methacrylic acid, ethyl acrylate) 1:1, or butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer), polyacrylic acid, or vinylpyrrolidone-vinyl acetate copolymer.

[0057] In some embodiments, at least one absorbent polymer excipient comprises a plurality of individual chains that unravel when immersed in a physiological fluid.

[0058] In some embodiments, the molecular weight of at least one absorbent polymer excipient is greater than 2 kg / mol (for example, greater than 5 kg / mol, or greater than 10 kg / mol, or greater than 20 kg / mol, or greater than 50 kg / mol).

[0059] In some embodiments, the molecular weight of at least one absorbent polymer excipient is between 2 kg / mol and 500 kg / mol (for example, in the range of 5 to 500 kg / mol, 10 to 500 kg / mol, 2 to 200 kg / mol, 5 to 200 kg / mol, 2 to 50 kg / mol, or 2 to 100 kg / mol).

[0060] In some embodiments, the weight fraction of the absorbent polymer excipient in the three-dimensional structural framework of one or more elements is greater than 0.1 (e.g., greater than 0.15, greater than 0.2, or greater than 0.25).

[0061] In some embodiments, drug molecules or drug particles are embedded in a matrix containing an absorbent polymer excipient.

[0062] In some embodiments, at least one pharmacokinetic component has a solubility of 5 g / l or less (for example, 2 g / l or less, or 1 g / l or less, or 0.5 g / l or less, or 0.2 g / l or less, or 0.1 g / l or less).

[0063] In some embodiments, at least one active pharmaceutical component has pH-dependent solubility in a physiological fluid or body fluid.

[0064] In some embodiments, at least one pharmacokinetic component has a solubility at least 5 times (e.g., at least 10 times) higher in an acidic solution than in a basic solution.

[0065] In some embodiments, at least one pharmacokinetic component is a basic compound.

[0066] In some embodiments, the tensile strength of the three-dimensional structural framework of one or more elements is between 0.01 MPa and 100 MPa (this includes, but is not limited to, the tensile strength of at least one element greater than 0.02 MPa, or greater than 0.05 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa, or greater than 0.5 MPa, or greater than 1 MPa, or greater than 1.5 MPa, or greater than 2 MPa, or greater than 3 MPa, or greater than 5 MPa).

[0067] In some embodiments, there are fewer than five walls that must be broken to obtain clusters in which empty spaces are interconnected from the external surface of the drug-containing solid to any point in the internal structure.

[0068] In some embodiments, at least one empty space is surrounded by walls to form a closed cell, and there are fewer than five walls that must be broken to obtain clusters in which the empty spaces are interconnected from the external surface of the drug-containing solid to any point in the internal structure.

[0069] In some embodiments, the average length, width, and thickness of the three-dimensional structural framework of the drug-containing solid or element are greater than 0.5 mm (for example, greater than 1 mm, or greater than 1.5 mm, or greater than 2 mm, or in the range of 1 mm to 30 mm, 1.5 mm to 30 mm, or 2 mm to 30 mm).

[0070] In another embodiment, the pharmaceutical dosing form of the present disclosure comprises a drug-containing solid having an external surface and an internal three-dimensional structural framework of one or more thin structural elements, wherein the framework is adjacent to and terminates adjacent to the external surface, the thin structural element comprising at least one active pharmaceutical component, at least one absorbent polymer excipient, and at least one hydrophilic surface composition, the thin structural element further having spatially separated sections from adjacent sections, thereby defining voids, and a plurality of adjacent voids bond across the drug-containing solid to define one or more interconnected voids that form an open network structure, thereby, when immersed in a physiological fluid, the open network structure allows for uniform wetting of the structural framework and transfer of the drug-containing solid to a viscous medium, thereby expanding in all dimensions, and during or after the transfer to the viscous medium, the drug-containing solid dissolves or decomposes.

[0071] Furthermore, in another embodiment, the pharmaceutical delivery form comprises a drug-containing solid having an external surface and an internal three-dimensional structural framework comprising a plurality of cross-patterned stacks of fibrous structural elements, wherein the framework is adjacent to and terminates adjacent to the external surface, and the fibrous structural elements comprise at least one active pharmaceutical component, at least a polymer excipient, and at least one hydrophilic surface composition, and the fibrous structural elements further comprise spatially separated sections from similar sections of adjacent fibrous elements, thereby defining voids, wherein a plurality of adjacent voids in a continuous layer combine to define one or more interconnected voids that form an open network structure, thereby enabling uniform wetting of the structural framework by a physiological fluid and the transfer of the drug-containing solid to a viscous medium when immersed in a physiological fluid, thereby expanding in length and volume.

[0072] In another embodiment, the drug delivery form of the present disclosure comprises a drug-containing solid having an external surface and an internal three-dimensional structural framework comprising a plurality of cross-patterned stacks of fibrous structural elements, wherein the framework is adjacent to and terminates adjacent to the external surface, and the fibrous structural elements comprise at least one active pharmaceutically active ingredient, at least a polymer excipient, and at least one hydrophilic surface composition, wherein the fibrous structural elements further comprise spatially separated sections from similar sections of adjacent fibrous elements, thereby defining voids, wherein a plurality of adjacent voids in a continuous layer combine to define one or more interconnected voids that form an open network structure, thereby allowing the open network structure to allow uniform wetting of the structural framework and transfer of the drug-containing solid to a viscous medium, thereby expanding in all dimensions.

[0073] A non-limiting method for producing the drug formulation of the present disclosure includes the steps of: injecting at least one active ingredient and at least one absorbent polymer excipient into an extrusion channel having a cross section extending along its length inside a housing; injecting a solvent to solvate at least one injected granular solid so that one or more injected granular solids form a plasticizing matrix; transporting the plasticizing matrix toward the exit of the extrusion channel by applying a mechanical action to the plasticizing matrix; extruding the plasticizing matrix from the exit to form at least one plasticizing fiber; and structuring at least one plasticizing fiber into a three-dimensional structural skeleton of one or more drug-containing fibers, which, upon immersion in a physiological fluid, are uniformly wetted and transferred to a viscous medium, thereby expanding in all dimensions.

[0074] Another non-limiting method for manufacturing the drug formulation of the present disclosure includes the steps of: injecting one or more active ingredients and one or more excipients into an extrusion channel having a cross section extending along its length inside a housing, wherein at least one excipient melts upon heating; heating the injected one or more active ingredients and one or more excipients to form a plasticizing matrix; transporting the plasticizing matrix toward the exit of the extrusion channel by applying a mechanical action to the plasticizing matrix; extruding the plasticizing matrix from the exit to form at least one plasticizing fiber; and structuring the at least one plasticizing fiber into a three-dimensional structural network of one or more drug-containing fibers.

[0075] In some embodiments, the step of structuring at least one plasticized fiber into a three-dimensional network structure of one or more drug-containing fibers is carried out by 3D pattern formation on the substrate of the at least one plasticized fiber.

[0076] In some embodiments, the three-dimensional structural framework of one or more drug-containing fibers includes a plurality of cross-shaped laminations of fiber-like structural elements.

[0077] Furthermore, an apparatus for manufacturing the dosage form of the present disclosure is an internal hollow housing having an internal surface that encloses and defines an extrusion channel having a first end, a second end, and a cross section extending axially along its length from the first end to the second end and ending at an exit of the second end, the housing comprising at least a first feed port for injecting at least one solid component into the extrusion channel between the first end and the second end, and injecting at least one solvent into the extrusion channel between the first feed port and the exit to produce at least one injected solid The invention comprises an internal hollow housing having at least a second supply port for forming a plasticizing matrix by solvating constituent components; at least one transport element for extruding the plasticizing matrix from an outlet in an extrusion channel to form at least one plasticizing fiber; and a fiber structuring unit for structuring one or more plasticizing fibers into a three-dimensional structural network structure of one or more drug-containing fibers, wherein when immersed in a physiological fluid, the three-dimensional structural skeleton is uniformly wetted and transferred to a viscous medium, thereby expanding in all dimensions.

[0078] Another non-limiting apparatus for manufacturing the drug formulation of the present disclosure includes an internal hollow housing having an internal surface for enclosing and defining an extrusion channel having a first end, a second end, and a cross section extending axially along its length from the first end to the second end and terminating at an exit of the second end, the internal hollow housing having at least a first supply port for injecting at least one solid component into the extrusion channel between the first end and the second end; at least one heating element for fluidizing the at least one injected solid component so that the injected one or more solid components form a plasticizing matrix in the extrusion channel; at least one transport element for extruding the plasticizing matrix in the extrusion channel out of the exit to form at least one plasticizing fiber; and a fiber structuring unit for structuring the one or more plasticizing fibers into a three-dimensional structural network structure of one or more drug-containing fibers, which, when immersed in a physiological fluid, is uniformly wetted and transferred to a viscous medium, thereby expanding in all dimensions.

[0079] In some embodiments, the fiber structuring unit includes a translational or rotational stage.

[0080] In some embodiments, one or more plasticizable fibers are structured into a three-dimensional network structure of one or more drug-containing fibers by 3D patterning the one or more plasticizable fibers on a substrate defined by or attached to a translational or rotational stage.

[0081] In some embodiments, the three-dimensional structural framework of one or more drug-containing fibers includes a plurality of cross-shaped laminations of fiber-like structural elements.

[0082] Embodiments described in relation to one aspect of the present invention may be applied to other aspects. For example, a particular embodiment of the claims described in relation to the first aspect may include features of the claims described in relation to the second, third, fourth, fifth, sixth, or seventh aspect, and vice versa.

[0083] The present invention can be better understood by referring to the accompanying drawings, but it should be noted that the drawings are primarily for illustrative purposes and should not be considered limiting.

[0084] The object, embodiments, features, and advantages of the present invention will be better understood when considered in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0085] [Figure 1] Figure 1 illustrates non-limiting schematic diagrams of fibrous drug formulations: (a) fibrous drug formulations whose structure disintegrates during dissolution; (b) fibrous drug formulations that rapidly deform and form a viscous medium that dissolves; and (c) fibrous drug formulations that gradually form a highly viscous medium or mass that dissolves.

[0086] [Figure 2] Figure 2 illustrates (a) the solid drug delivery form including the three-dimensional structural framework of the drug and excipients, and its conversion (e.g., transfer) to a viscous medium when immersed in a dissolution, and (b) a non-limiting schematic diagram of the degradation of the drug delivery form after ingestion, drug release, and drug absorption processes.

[0087] [Figure 3] Figure 3 presents (a) a solid drug delivery form including the three-dimensional structural framework of the drug and excipients, and its transfer to a viscous medium when immersed in a dissolution, and (b) a non-limiting schematic diagram of the decomposition of the drug delivery form after ingestion, drug release, and drug absorption processes.

[0088] [Figure 4]Figure 4 illustrates (a) a solid drug delivery form containing a three-dimensional structural framework that expands when it transitions to a viscous medium during immersion in a dissolving solution, and (b) a non-limiting schematic diagram of the decomposition, drug release, and drug absorption processes of the drug delivery form after ingestion.

[0089] [Figure 5] Figure 5 shows (a) a solid drug delivery form containing a three-dimensional structural framework that expands when it transitions to a viscous medium in a dissolution solution, and (b) other non-limiting schematics of the degradation, drug release, and drug absorption processes of the drug delivery form after ingestion.

[0090] [Figure 6] Figure 6 presents non-limiting examples of pharmaceutically active drug forms according to the present invention as herein, as well as the expansion, decomposition, and drug release processes when immersed in a solvent: (a) the dry drug form and its microstructure, (b) the drug form and its microstructure immediately after immersion in a solvent, (c) the drug form and its microstructure during transfer to a viscous medium, (d) the drug form and its microstructure after transfer to a viscous medium, (e) the deformation of the viscous medium in the solvent, (f) the solvent after dissolution of the drug form, and (g) a sketch of the length L of the side of the drug form with respect to time after immersion in the solvent.

[0091] [Figure 7] Figure 7 illustrates another non-limiting pharmaceutically acceptable drug delivery form according to the present invention as herein, as well as the swelling, decomposition, and drug release processes after immersion in a solvent.

[0092] [Figure 8] Figure 8 shows further non-limiting pharmaceutically acceptable drug formulations according to the present invention as herein, as well as the swelling, decomposition, and drug release processes after immersion in a solvent.

[0093] [Figure 9] Figure 9 shows an unrestricted schematic diagram of the diffusion of the dissolve into the fibers and the profile of the fluid concentration in the fibers at different times.

[0094] [Figure 10] Figure 10 illustrates a non-limiting schematic diagram of an expanding drug-delivery-type skeleton according to the present invention, having (a) isotropically expanding fibers and (b) anisotropically expanding fibers.

[0095] [Figure 11] Figure 11 presents non-limiting examples of the deformation process of viscous media: (a) a homogeneous media with uniform shear stress and strain, and (b) a non-uniform media with non-uniform stress and strain.

[0096] [Figure 12] Figure 12 is an unrestricted schematic diagram of drug release by diffusion of drug molecules through a viscous mass or medium.

[0097] [Figure 13] Figure 13 presents non-limiting examples of the deformation process of viscous media: (a) a homogeneous media with uniform shear stress and strain, and (b) a non-uniform media with non-uniform stress and strain.

[0098] [Figure 14] Figure 14 is a schematic diagram of a method and apparatus for manufacturing a drug dosage form according to the present invention.

[0099] [Figure 15] Figure 15 is another schematic diagram of a method and apparatus for manufacturing a drug dosage form according to the present invention.

[0100] [Figure 16] Figure 16 schematically shows the apparatus and method applied to produce experimental drug formulations according to the present invention as described herein.

[0101] [Figure 17] Figure 17 shows scanning electron microscope images of the microstructure of experimental drug dosage form A according to the present invention: (a) top view and (b) side view.

[0102] [Figure 18]Figure 18 is a scanning electron microscope image of experimental single fiber A.

[0103] [Figure 19] Figure 19 presents a series of images illustrating the expansion and decomposition processes of experimental drug dosage form A.

[0104] [Figure 20] Figure 20 is a series of images illustrating the expansion and decomposition processes of single fiber A.

[0105] [Figure 21] Figure 21 shows the experimental drug dosage and the percentage of drug dissolved from single fiber A as a percentage of the time after immersion in the dissolution solution.

[0106] [Figure 22] Figure 22 shows scanning electron microscope images of experimental single fibers B and C.

[0107] [Figure 23] Figure 23 presents a series of images illustrating the expansion and decomposition processes of (a) experimental fiber B and (b) experimental fiber C.

[0108] [Figure 24] Figure 24 shows the expansion results for single fibers B and C: (a) normalized radial expansion ΔR / R0 with respect to time t, and (b) ΔR / R0 with respect to time t1 / 2 / R0.

[0109] [Figure 25] Figure 25 shows the results of drug release through experimental fibers B and C: (a) the ratio of dissolved drug md / M0 to time t, and (b) md / M0 to time t1 / 2 / R0.

[0110] [Figure 26]Figure 26 presents scanning electron micrographs of the microstructures of experimental drug delivery forms: (a) top view of drug delivery form B, (b) side view of drug delivery form B, (c) top view of drug delivery form C, and (d) side view of drug delivery form C.

[0111] [Figure 27] Figure 27 illustrates the expansion and decomposition processes of (a) experimental drug dosage B and (b) experimental drug dosage C.

[0112] [Figure 28] Figure 28 shows the expansion results for drug dosage forms B and C: (a) normalized longitudinal expansion ΔL / L0 with respect to time t, and (b) ΔL / L0 with respect to t1 / 2 / R0.

[0113] [Figure 29] Figure 29 shows the drug release results for drug formulations B and C: (a) the ratio of dissolved drug to time t, md / M0, and (b) md / M0 to t1 / 2.

[0114] [Figure 30] Figure 30 shows both the normalized longitudinal expansion ΔL / L0 and the percentage of dissolved drug by drug type B over time, md / M0.

[0115] [Figure 31] Figure 31 presents experimental results of the shear viscosity of an aqueous solution of HPMC 10k: (a) shear viscosity as a function of shear strain rate, and (b) shear viscosity at a shear strain rate of 1 / s as a function of the weight fraction fe of HPMC.

[0116] [Figure 32] Figure 32 shows experimental results of the shear viscosity μs of an HPMC120k aqueous solution at a shear strain rate of 1 / s with respect to the weight fraction fe of HPMC. [Modes for carrying out the invention]

[0117] definition To facilitate understanding of this disclosure, certain terms are first defined below. Additional definitions of the following terms and other terms are provided herein.

[0118] In this application, the use of “or” means “and / or” unless otherwise specified. In this application, the terms “comprise,” and variations such as “comprising” and “comprises,” are intended not to exclude other additives, components, integers, or steps. In this application, the terms “about” and “approximately” are used as equivalents. Any figures used in this application with or without about / approximately are intended to include any normal variation recognized by those skilled in the art.

[0119] Furthermore, in the disclosure herein, the terms “one or more active ingredients,” “at least one active ingredient,” “active ingredient,” “active pharmaceutical ingredient,” and “drug” are used interchangeably. As used herein, “active ingredient” or “activator” refers to an activator whose presence or level correlates with an increase in a target level or activity compared to when observed in the absence of the activator (or at different levels of the activator). In some embodiments, the active ingredient is an ingredient whose presence or level correlates with a target level or activity equivalent to or greater than a particular reference level or activity (e.g., a level or activity observed under appropriate reference conditions, such as in the presence of a known activator, e.g., a positive control).

[0120] Furthermore, in the context of embodiments herein where the average thickness of the structural elements is greater than approximately 30–100 μm, a three-dimensional structural skeleton of one or more thin structural elements includes a drug-containing structural skeleton (e.g., a reticular structure, skeleton, assembly, group, or arrangement) of one or more thin structural elements extending over lengths, widths, and thicknesses greater than 100 μm. This includes, but is not limited to, drug-containing structural skeletons extending over lengths, widths, and thicknesses greater than 200 μm, or greater than 300 μm, or greater than 500 μm, or greater than 700 μm, or greater than 1 mm, or greater than 1.25 mm, or greater than 1.5 mm, or greater than 2 mm.

[0121] In other embodiments where the average thickness of the structural elements is less than approximately 30–100 μm, the three-dimensional structural framework of one or more thin structural elements includes a drug-containing structural framework (e.g., a reticular structure, framework, assembly, group, or arrangement) of one or more thin structural elements that extends over lengths, widths, and thicknesses greater than the average thickness of at least one element (or at least one segment) in the structural framework. This includes, but is not limited to, structural frameworks that extend over lengths, widths, and thicknesses greater than 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times the average thickness of at least one element (or at least one segment) in the structural framework. It should be noted that the terms “three-dimensional structural framework of drug-containing elements,” “three-dimensional structural framework of elements,” “three-dimensional structural framework of one or more thin structural elements,” “three-dimensional structural framework of one or more elements,” “three-dimensional structural framework,” and “three-dimensional framework of elements” are used interchangeably herein.

[0122] Furthermore, in preferred embodiments, a three-dimensional structural framework of one or more thin structural elements includes multiple layers of thin structural elements (or segments). This includes, but is not limited to, layers of at least two layers of thin structural elements (or segments), or at least three layers of thin structural elements (or segments), or at least four layers of thin structural elements (or segments), or at least five layers of thin structural elements (or segments).

[0123] As used herein, the terms “element,” “multiple elements,” “one or more elements,” “one or more thin elements,” “one or more thin structural elements,” “structural element,” “one or more drug-containing elements,” and “drug-containing elements” are used interchangeably. They are understood as solid drug-containing structural elements (or building blocks) that constitute a three-dimensional structural framework (e.g., a drug-dosing structure or a drug-containing solid structure). Thin structural elements include two-dimensional elements (2D structural elements), one-dimensional elements (1D structural elements), or zero-dimensional elements (0D structural elements).

[0124] As used herein, a two-dimensional structural element or “sheet” refers to one having a length and width considerably greater than its thickness. More specifically, in this disclosure, the length and width of a two-dimensional structural element is greater than twice its thickness. This includes, but is not limited to, lengths and widths greater than three times, four times, five times, six times, eight times, ten times, or twelve times the thickness. Furthermore, in some embodiments included herein but not limited thereto, the length and width of a sheet is greater than 0.3 mm, or 0.5 mm, or 1 mm, or 2.5 mm.

[0125] One-dimensional structural elements or “fibers” are described herein as having a length considerably greater than their width and thickness. More specifically, in this disclosure, the length of a one-dimensional structural element or fiber is greater than twice its width and thickness (for example, the length is greater than twice its width and the length is greater than twice its thickness). This includes, but is not limited to, lengths greater than three times, four times, five times, six times, eight times, ten times, or twelve times the width and thickness. Furthermore, in some embodiments included herein but not limited to, the length of a fiber is greater than 0.3 mm, or 0.5 mm, or 1 mm, or 2.5 mm.

[0126] A zero-dimensional structural element or "bead" is described herein as having a length and width approximately equal to its thickness. In this disclosure, the length and width of a zero-dimensional structural element or bead is not more than twice its thickness. This includes, but is not limited to, lengths and widths not more than three times or four times the thickness. Furthermore, the thickness of a zero-dimensional element or bead is less than 2.5 mm.

[0127] The non-limiting shapes of the elements include "sheets," "rods," "cylinders," "fibers," "particles," "beads," "polyhedra," "spheroids," "ellipsoids," clusters, or combinations thereof. In preferred embodiments, the elements are joined or connected to each other to form a continuous solid structure or a three-dimensional structural skeleton.

[0128] Furthermore, as used herein, the term “segment” or “segments” refers to a piece of an element along its length and / or width. As a non-limiting example, a “segment” of a fiber may include a piece of the fiber along its length.

[0129] In the context of the present invention as herein, drug release from a solid element (or solid drug delivery form or solid matrix or drug-containing solid) refers to the conversion of a drug (e.g., one or more drug particles or drug molecules or clusters thereof) embedded in or attached to the solid element into a drug in a dissolving medium.

[0130] As used herein, the terms “solubilant,” “physiological fluid,” “body fluid,” “solvent,” “medium,” “fluid,” and “permeator” are used interchangeably. They are understood to be any fluid produced by or contained in the human body under physiological conditions, or any fluid similar to a fluid produced by or contained in the human body under physiological conditions. Examples include, but are not limited to, water, saliva, gastric juice, digestive juice, saline solution, etc., at a temperature of 37°C and a pH value adjusted to the associated physiological conditions.

[0131] Furthermore, in the present invention as herein, an excipient is described as a “polymer” if its molecular weight is greater than 1,000 kg / mol. This includes, but is not limited to, molecular weights greater than 1,500 kg / mol, 2,000 kg / mol, 3,000 kg / mol, 4,000 kg / mol, or 5,000 kg / mol. A polymer excipient is described as “absorbing the solution” if it transitions from a solid to a fluid or viscous medium upon contact with a physiological fluid or solution.

[0132] A viscous medium refers to a viscous solution, viscous dispersion, or viscous mass having a shear viscosity that is considerably lower than the viscosity of the solid but considerably higher than the shear viscosity of the dissolving solution. For this reason, in some embodiments, the shear viscosity of the viscous medium is considerably lower than the shear viscosity of the solid but is greater than twice, four times, five times, six times, seven times, eight times, ten times, twelve times, or fifteen times the viscosity of the dissolving solution.

[0133] In other embodiments, the viscous medium is defined by a shear viscosity in the range of 0.005 to 100,000 Pa·s. This includes, but is not limited to, shear viscosities in the range of 0.01 to 100,000 Pa·s or 0.01 to 10,000 Pa·s. In the present invention as herein, “shear viscosity” is typically referred to as the average shear viscosity over a shear rate range of 1 to 100 1 / s under physiological conditions.

[0134] Furthermore, in viscous media, the concentration of water-soluble (or superabsorbent) polymer excipients is typically the concentration c of the disintegration agent. e * Higher, but generally the solid / semi-diluted boundary is c e ** Lower. For this reason, viscous media are typically semi-diluted solutions or dispersions containing at least entangled water-soluble or superabsorbent polymer molecules that dissolve in or by means of a physiological fluid (e.g., fluidize or viscous).

[0135] A hydrophilic surface composition is described herein as a solid surface (e.g., a solid surface composition, or a composition of the surface of one or more elements) that can be wetted by an aqueous physiological fluid or bodily fluid under physiological conditions. A solid surface is “wettable by fluid” if the contact angle of a droplet of the fluid on the solid surface in air is 90 degrees or less. This includes, but is not limited to, contact angles of a droplet of the fluid on the solid surface in air of 80 degrees or less, or 70 degrees or less, or 60 degrees or less, or 50 degrees or less, or 40 degrees or less, or 30 degrees or less. It should be noted that in some embodiments, the contact angle does not have to be static. In this example, a solid surface can be understood as “wettable by fluid” if the contact angle of a droplet of the fluid on the solid surface in air is 90 degrees or less for at least 20 to 360 seconds after the droplet is placed on the surface. A non-limiting example of droplets on a surface is presented in U.S. Patent Application No. 15 / 482,776, entitled “Fibrous dosage form”.

[0136] Scope of the Invention Any particular feature described individually or as part of an embodiment in this disclosure is intended to be combined with other individually described features or parts of other embodiments, even if other features and embodiments do not refer to that particular feature. For this reason, the invention as described herein also extends to such specific combinations not yet described. Furthermore, the drawings and embodiments of the invention as described herein are presented as examples and not as limitations. For this reason, the invention as described herein is understood to be not limited to these embodiments themselves. Other embodiments that are obvious to those skilled in the art are within the scope of the claimed invention.

[0137] As a non-limiting example, the compositions, systems, devices, methods, and processes of the claimed invention include variations and adaptations developed using information from the embodiments described herein. Adaptations and / or modifications of the compositions, systems, devices, methods, and processes described herein may be carried out by those skilled in the art.

[0138] Furthermore, where compositions, products, and devices are described as having, including, or comprising, certain components, or where processes and methods are described as having, including, or comprising, certain steps, it is intended that, in addition, there exist compositions, products, and devices of the present invention that are essentially composed of or consist of the listed components, and processes and methods according to the present invention that are essentially composed of or consist of the listed processing steps.

[0139] Similarly, where compositions, products, and devices are described as having, including, or comprising certain compounds and / or materials, it is intended that, in addition, there exist compositions, products, and devices of the present invention that are essentially composed of or comprise the listed compounds and / or materials.

[0140] The order of the steps or the order in which certain actions are performed should be understood to be irrelevant as long as the invention remains operational. Furthermore, two or more steps or actions may be performed simultaneously.

[0141] Any reference to any publication in this specification does not imply that such publication serves as prior art with respect to any of the claims presented herein. Headings are provided for constituent purposes only and are not limiting.

[0142] Detailed description of the invention Figure 6a illustrates a non-limiting example of a pharmaceutical dosing form according to the present invention. The dosing form 600 comprises a drug-containing solid 601 having an outer surface 602 and an internal structure 604 adjacent to and terminating thereon the outer surface 602. The internal structure 604 comprises a three-dimensional structural framework of one or more thin structural elements (e.g., fibers, sheets, etc.) 610. In the present invention, a structural element is understood to be “thin” if its thickness (e.g., its smallest dimension) is considerably smaller than the length, width, or thickness of the dosing form. This includes, but is not limited to, thicknesses less than half, one-third, one-quarter, or one-fifth of the length, width, or thickness of the dosing form. A thin structural element is also referred to herein as an “element.”

[0143] Element 610 comprises at least an active ingredient, at least a polymer excipient (e.g., an absorbent polymer excipient) that absorbs physiological fluids, and at least one hydrophilic surface composition. Element 610 further includes a section spaced apart from adjacent sections, thereby defining an open space 615. Multiple adjacent open spaces 615 combine across the drug-containing solid 601 to define one or more interconnected open spaces 615 that form an open network structure in the drug-containing solid 601.

[0144] In the present invention as described herein, the terms “interconnected voids” or “open network structure” in a drug-containing solid are also referred to as “interconnected network structure,” “network structure of opening channels,” or “open channels of voids” in a drug-containing solid. In some embodiments, the interconnected voids or a plurality of interconnected voids can be accessed from the external surface of the drug-containing solid. That is, there are no walls (e.g., walls containing the three-dimensional structural framework of elements) that must be broken to obtain the interconnected voids (e.g., open channels of voids) from the external surface of the drug-containing solid to a point (or any point) in the interconnected voids within the internal structure. Furthermore, it can be noted that if all the voids (e.g., the entirety of the voids in the drug-containing solid) are interconnected, the voids are also referred to herein as “continuous.” Drug-dosing forms having continuous voids include preferred embodiments of the present invention.

[0145] As shown in Figure 6b, when immersed in the dissolving solution, the perforated network structure allows the physiological fluid 620 to penetrate the drug-containing solid 601, enabling uniform wetting of the structural framework by the fluid. In the present invention as specified, a surface (e.g., the surface of the three-dimensional structural framework) is "wetted by the fluid" when the fluid comes into contact with the surface (e.g., touches it). The surface is "uniformly wetted" by the fluid when at least 30 to 60 percent of the surface area comes into contact with the fluid (e.g., direct contact). In a preferred embodiment, when the drug-containing solid is immersed in the physiological fluid, at least 70 percent of the surface of the three-dimensional structural framework is wetted by the fluid (e.g., by contact).

[0146] Next, the drug-containing solid having a uniformly moistened three-dimensional structural framework (e.g., the moistened element 610 or the moistened drug-containing solid 601) transitions from solid 630 to viscous media 640, 641, and 642, thereby expanding in all dimensions as schematically shown in non-limiting Figures 6c to 6e.

[0147] It should be noted that the drug-containing solid may be a “solid,” a combination of “solid” and “viscous medium,” a combination of “viscous medium,” a combination of “solid” and a diluent or dispersion, or a combination of “viscous medium” and a diluent or dispersion during the transition to the viscous medium. Furthermore, the terms “expansion in all dimensions,” “expansion in all dimensions,” or “expansion in all dimensions” are understood to mean an increase in the length of the sample (e.g., the length and / or width and / or thickness of the sample, etc.) and an increase in the volume of the sample. For this reason, deformation due to pure shear is not considered “expansion in all dimensions” as used herein.

[0148] In some embodiments, when immersed in a dissolving solution, the drug-containing solid dissolves or decomposes in the physiological fluid. Furthermore, in some embodiments, the drug-containing solid dissolves or decomposes in the physiological fluid or body fluid during or after the transfer to a viscous medium.

[0149] In some embodiments, the drug-containing solid expands due to the permeation (e.g., diffusion or inflow) of physiological fluids or bodily fluids into the three-dimensional structural framework of the element. Furthermore, in some embodiments, the drug-containing solid expands due to the permeation (e.g., diffusion or inflow) of physiological fluids or bodily fluids into an absorbent polymer excipient. Moreover, in some embodiments, the drug-containing solid expands due to the permeation (e.g., diffusion or inflow) of physiological fluids or bodily fluids into at least one structural element.

[0150] The expansion of the drug-containing solid can be quite substantial, as schematically shown in Figure 6g. Therefore, in some embodiments, at least one dimension of the drug-containing solid (e.g., the length of the side of the drug-containing solid, the thickness of the drug-containing solid, etc.) expands to at least 1.12 times its initial value (e.g., the initial length) during the transfer to the viscous media 641, 642. This includes, but is not limited to, at least one dimension of the drug-containing solid that expands to at least 1.15 times, at least 1.17 times, at least 1.2 times, at least 1.22 times, at least 1.25 times, at least 1.27 times, at least 1.3 times, at least 1.35 times, at least 1.4 times, at least 1.5 times, at least 1.6 times, or at least 1.7 times its initial value during the transfer to the fluid or viscous media 641, 642.

[0151] Furthermore, in some embodiments, the drug-containing solid expands to at least 1.4 times its initial volume during the transfer to the viscous medium. This includes, but is not limited to, drug-containing solids that expand to at least 1.5 times, or at least 1.6 times, or at least 1.7 times, or at least 1.8 times, or at least 1.9 times, or at least 2 times, or at least 2.2 times their initial volume.

[0152] The expansion rate generally depends on the rate at which the solution 620 is absorbed by the structural framework (e.g., by absorbent polymer excipients), as well as the presence and strictness of constraints on expansion. The absorption rate of the solution by the framework typically increases as the specific surface area of ​​the framework (e.g., the ratio of surface area to volume) increases. Therefore, when elements 630 and 640 are thin, the ratio of surface area to volume is large, and it is expected that the rate at which the solution is absorbed by the framework will be fast.

[0153] Constraints on expansion often arise from the non-uniformity of the solvent concentration throughout the three-dimensional structural framework. As a non-limiting example, a wet element or section may absorb the solvent, but its expansion may be constrained if it is connected to (e.g., attached to) a non-expanding dry solid element or section. Therefore, uniform wetting of elements in the structural framework is crucial to minimize constraints on expansion. Uniform wetting is achieved, in particular, by interconnected voids (e.g., by interconnected voids that form an open network structure through which the solvent can penetrate).

[0154] The drug delivery form according to the present invention as described herein includes a structural framework of thin elements having a hydrophilic surface composition surrounded by interconnected voids forming an open-pore network structure. Therefore, the expansion rate can be substantial.

[0155] Therefore, in some embodiments, at least one dimension of the drug-containing solid (e.g., side length or thickness) expands to at least 1.12 times its initial value (e.g., initial length) within 30 minutes of immersion in a physiological fluid or body fluid under physiological conditions when it is transferred to a fluid or viscous medium. This includes, but is not limited to, at least one dimension of the drug-containing solid that reaches at least 1.12 times its initial length within 20 minutes, or within 15 minutes, or within 10 minutes, or within 5 minutes of immersion in a physiological fluid or body fluid under physiological conditions. This also includes, but is not limited to, at least one dimension of the drug-containing solid that expands to at least 1.15 times, or at least 1.2 times, or at least 1.25 times, or at least 1.3 times, or at least 1.4 times, or at least 1.5 times, or at least 1.6 times its initial length within 20 minutes after immersion in a physiological fluid or body fluid under physiological conditions.

[0156] Furthermore, in some embodiments, the drug-containing solid expands to at least 1.4 times its initial volume within 20 minutes of immersion in a physiological fluid or body fluid under physiological conditions. This includes, but is not limited to, drug-containing solids that expand to at least 1.5 times, at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2 times, or at least 2.2 times their initial volume within 20 to 30 minutes of immersion in a physiological fluid or body fluid under physiological conditions.

[0157] During and after the transition to a fluid or viscous medium, the three-dimensional structural framework of the element and / or the viscous mediums 640, 641, 642 may further release the drug into the dissolution. Common drug release processes include, but are not limited to, disintegration in the dissolution 620 (Figures 6c-6f), diffusion of the drug through the viscous medium, and the like.

[0158] Furthermore, it should be noted that drug-containing solids or viscous media may expand and be diluted to such an extent that they essentially form a dilution solution or dilution dispersion. A dilution solution or dilution dispersion is described herein as a solution or dispersion of a physiological fluid with dissolved and unraveled polymer excipient molecules (e.g., polymer excipient molecules dissolved at a concentration lower than the unraveling concentration). Such dilution solutions or dispersions are generally deformable by and miscible with the physiological fluid. However, it should be noted that any deformation due to the application of external forces, including but not limited to shear stress due to the dissolving solution, buoyancy, gravity, etc., does not constitute "expansion" as defined herein. Moreover, a dilution solution or dilution dispersion is not considered a "viscous media" as defined herein.

[0159] Finally, further non-limiting examples of three-dimensional structural skeletons with interconnected open spaces, illustrating how elements (e.g., fibers, sheets, beads, etc.) may be structured, arranged, or assembled, are disclosed in the concurrently pending U.S. applications 15 / 482,776, “Fibrous dosage form,” 15 / 964,058, “Method and apparatus for the manufacture of fibrous dosage forms,” and 15 / 964,063, “Dosage form comprising two-dimensional structural elements.” More examples of how elements may be structured or arranged within a three-dimensional structural network or skeleton of one or more elements will be obvious to those skilled in the art. All of these are included in the spirit or scope of the present invention.

[0160] Modeling of drug decomposition, swelling, and drug release in drug formulations The following examples illustrate how the drug release and degradation behavior of the drug formulations of this disclosure may be modeled. The models will make it easier for those skilled in the art to understand the details and advantages of the present invention. The models are for illustrative purposes only and are not limiting in any way.

[0161] a) Drug delivery structure The non-limiting models presented refer to the pharmaceutical dosing forms schematically shown in Figures 7a and 8a. Dosing forms 700, 800 include drug-containing solids 701, 801 having external surfaces 702, 802 and internal three-dimensional structural skeletons 704, 804 comprising a plurality of cross-patterned stacks of fibrous structural elements 710, 810, the skeletons 704, 804 adjacent to and terminating at the external surfaces 702, 802. The fibrous structural elements 710, 810 include at least a drug 780, 880, at least one absorbent polymer excipient 790, 890, and a hydrophilic surface composition. The fibrous structural elements 710, 810 further have spatially separated sections from similar sections of adjacent fibrous elements 710, 810, thereby defining voids, and multiple adjacent voids in a continuous layer combine to define one or more interconnected voids 715, 815 that form an open network structure in the drug-containing solids 701, 801. The radius of the fibrous structural elements 710, 810 or fibrous sections, and the interfiber spacing in the layers of fibrous structural elements are uniform.

[0162] b) Medication-type composition Two non-restrictive dosing forms having different compositions and drug release mechanisms are considered. In the first 700, represented by Figure 7 and referred to herein as “Dosing Form A”, the fiber 710 consists of 10 wt% drug (ibuprofen), 60 wt% hydroxypropyl methylcellulose (HPMC) with a molecular weight of 10 kg / mol (also referred herein as “HPMC 10k”), and 30 wt% polyoxyl stearate. The surface of the fiber 710 is coated with a thin hydrophilic layer of polyvinylpyrrolidone (PVP) and silicon dioxide (SiO2).

[0163] In the second dosage form 800, represented by Figure 8 and referred to herein as “Dosage Form B”, the fiber 810 consists of 20% by weight of the drug (acetaminophen) and 80% by weight of a high molecular weight polymer excipient (HPMC with a molecular weight of 120 kg / mol, also referred herein as “HPMC 120k”). Furthermore, the surface of the fiber 810 is coated with a thin hydrophilic layer of polyvinylpyrrolidone (PVP) and silicon dioxide (SiO2).

[0164] c) Overview of drug release mechanism When drug type A is immersed in aqueous solution 720, the fluid 720 rapidly penetrates into the structure because the voids 715 (e.g., empty spaces) are continuous and the fiber surface is hydrophilic (Figure 7b). Furthermore, as schematically shown in Figure 7c, the fluid 720 (e.g., water, saliva, digestive fluid, etc.) then diffuses into the fiber 710. The thin fiber 710 and structure transition from solid 730 to viscous 740, and rapidly expand as the fluid 720 diffuses into it.

[0165] Furthermore, as the fibers and structure expand, the dissolving solution 720 continues to flow from the outside into the structure through the pores 716 (Figures 7c and 7d). However, eventually, when the fluid content in the drug formulation becomes very high and the viscosity of the expanded viscous media 741, 742 becomes very low, it deforms due to forces such as gravity and fluid shear (Figures 7d and 7e). Such deformation increases the ratio of the surface area to the volume of the viscous media 741, 742, accelerating their collapse and dissolution. When the excipients surrounding the drug molecules or drug particles in the viscous media 741, 742 dissolve or collapse, the drug is released. If the fibers 710 are thin, the diffusion length of the dissolving solution 720 molecules is small, and the structure expands and dissolves rapidly.

[0166] As shown schematically in FIGS. 8b and 8c, in the case of dosage form B, the decomposition, swelling, and drug release process 800 initially proceeds as in the first example: the dissolution solution 820 penetrates inside, diffuses between the fibers and the fluid, and due to the absorption of the fluid, swelling of the structure occurs. However, since the fibers 810 swell faster in the radial direction than in the axial direction, they finally fuse and the flow of fluid inside stops. Next, the dosage form forms a viscous mass 841 consisting of entangled high molecular weight excipient molecules, the drug, and the dissolution solution 820, as shown in FIG. 8d.

[0167] The viscous masses 841, 842, 843 disintegrate and dissolve very slowly (FIGS. 8d - 8f). Therefore, the drug is released mainly by the diffusion of drug molecules through the viscous masses 841, 842, 843. However, since the viscous masses are several millimeters thick, the diffusion process is slow and the drug release time is extended. After (and during) drug release, the dissolution solution continues to diffuse into the viscous mass 843, making it more fluid. Similarly, polymer molecules also diffuse from the viscous mass 843 into the external dissolution solution outside. Therefore, the viscous mass 843 finally disappears or dissolves (FIGS. 8f and 8g).

[0168] Any detailed analysis of the drug release mechanism or process is outside the scope of this disclosure. Therefore, in this specification, the individual process steps are separated and modeled with reasonable assumptions.

[0169] d) Penetration of the dissolution solution into the fiber - like dosage form The first step of the dosage form decomposition and drug release process herein is the penetration of the dissolution solution into the structure. The penetration of the dissolution solution into the voids 715, 815 (e.g., empty space or spaces) is driven by capillary forces and can be retarded by viscous forces. When treating the empty spaces 715, 815 with an assembly of capillaries exposed to the dissolution solution at one end and to air at the other end, an approximate value t of the penetration time perc can be obtained. In this case, the penetration time t perc can be expressed by the Lucas - Washburn equation.

number

[0170] Parameter (l perc = 5 mm, μ f For non-restrictive drug formulations and dissolving solutions having (=0.001 Pa·s, γ=0.072 N / m, r=100 μm, θ≈ 30°), the infiltration time t is given by formula (1). perc = 8ms. In the fibrous structures 700 and 800, the penetration time does not need to be that fast. Even in that case, the fiber surface is hydrophilic and the spacing between spaces λ f If it is larger than a few micrometers (for example, λ f If the size is greater than approximately 5-10 μm, the interconnected empty spaces 715, 815 will be permeated by the dissolving solutions 720, 820 almost immediately after the drug delivery form is immersed in the fluid.

[0171] It will be apparent to those skilled in the art that the models presented (and any of the models below) are approximations and may not accurately represent the underlying physical or chemical processes. Furthermore, any model presented herein may be adapted to other situations, designs, or examples not specifically modeled herein. For this reason, all more examples and models of the penetration of dissolutions into fibrous drug formulations that are apparent to those skilled in the art are within the scope of this disclosure.

[0172] e) Interdiffusion of fibers and dissolving solution After the dissolving solution penetrates through a drug delivery structure (e.g., an open network structure defined by interconnected empty spaces), the hydrophilic coating on the fiber can dissolve. Then, the dissolving solution (e.g., water) and the excipients in the fiber can interdiffuse.

[0173] Water diffusivity D in fibers w Assuming that it does not depend on concentration, the differential equation for the diffusion of water in cylindrical coordinates is: [Number] is, where c w (r, t) is the water concentration in the fiber at time t, and R(t) is the fiber radius at time t.

[0174] Assume that the water concentration at the fiber-fluid interface is c b . As shown in Fig. 9, the initial conditions and boundary conditions are: c w = 0 at t = 0, 0 ≤ r < R0(2b) c w = c b for t ≥ 0, r = R(t) (2b) where R0 is the initial fiber radius. It can be immediately noticed that this is a moving interface problem. Analytical solutions of equation (2a) that satisfy the initial condition (2b) and the moving interface condition (2c) may not be available at present. However, under the very approximate assumption that the concentration of the diffusing liquid is very low (i.e., the fiber radius is constant), as schematically shown in non-limiting Fig. 9, the water concentration profile is

[0175] [[ID=%32]] given by [[ID=%,35]] [Number] where J0 and J1 are the zero-order and first-order Bessel functions of the first kind, respectively, and α is the root of n J0(Rα n ) = 0 (4) .

[0176] Integrating equation (3) over the fiber volume gives the mass ratio of water M w (t) per unit length of the fiber at time t, and the mass ratio of water M w,∞ in the fiber at infinite time. Following Crank, for short times (i.e., t << R0 2 / D w ), [Number]​ That is the case.

[0177] From equation (5), the mass of water in the fiber is,

number

[0178] For further information regarding diffusion models, see, for example, J. Crank, *The Mathematics of Diffusion*, 2nd edn., Oxford University Press, 1975. Further examples of models for the diffusion of dissolves into fibers will be obvious to those skilled in the art. All of these are within the scope of the present invention.

[0179] f) Swelling of fibrous drug delivery type When a substantial amount of the solution diffuses or permeates into the fibers (or absorbent polymer excipients), the mass and volume of the fibers increase (e.g., the fibers expand or swell). Fiber-like drug formulations may also expand or swell if individual fibers expand. However, the precise derivation of the expansion rate of drug formulations is outside the scope of this disclosure. An estimate based on the expansion of a single fiber is given below.

[0180] f1) Monofiber Assuming no volume change during mixing (e.g., during permeation of the dissolution solution into the fibers or the absorbent polymer excipient), the normalized difference between the fiber volume V(t) at time t and the initial fiber volume V0 is related to the normalized mass of the dissolution solution permeated into the fibers.

Number

[0181] Moreover, in the case of small swelling (i.e., when the boundary concentration c b of the dissolution solution is very low compared to the density ρ w of the dissolution solution (c b << ρ w )), the normalized volume swelling of the fiber at "infinite" or "long" time is

Number

[0182] Multiplying equations (5) and (7) together gives equation (8), which provides the normalized volume swelling of the fiber:

Number

[0183] Furthermore, in the case of small isotropic swelling, the normalized radial and axial swelling is approximately one-third of the volume swelling. Thus, from equation (9), for short times, [[ID=4...]]

Number

[0184] Similarly, in the case of small completely anisotropic swelling in the radial direction, the radial swelling is approximately half of the volume swelling. Thus, for short times,

number

[0185] From equations (10) and (11a), the normalized expansion of the fiber is approximately proportional to the square root of time and the reciprocal of the initial fiber radius. Furthermore, the parameter value c b Approximately 930mg / ml, ρ w =1000mg / ml, D w Approximately 3×10 -11 m 2 For a speed of / s and an R0 of approximately 100 μm, equation (9) shows that ΔR / R0 = ΔL / L0 = 0.3 in one minute. Therefore, thin fibers rapidly interdiffusing with the solution can expand to a radius or length greater than 30 percent of their initial value within just a few minutes.

[0186] However, even in this case, it should be noted that the accuracy of the above model is very limited. As an example where it is not limited, equations (3) to (11) are bounding factors c b The density of water or a solution ρ w Much lower (c b <<ρ w This assumption is generally not met when the excipients and the solvent (e.g., water) are mutually soluble.

[0187] Any other model of single-fiber expansion that is obvious to those skilled in the art falls within the scope of this invention.

[0188] f2) Medication type Figure 10 shows schematic diagrams of cross-sections of fibers in the fibrous structure before (before immersion in the dissolving solution) and after immersion in the dissolving solution.

[0189] Regarding the structure of the isotropically expanding fibers, as shown in Figure 10a, the geometric similarity of the structure is preserved during expansion. Therefore, the dissolution continues to flow inward as the structure expands and is readily available around all the expanding fibers. Next, the length L of the viscous, expanding drug dosing form. v and thickness H vIt increases at the same rate as the radius or length of the single fiber. Therefore,

number

[0190] In the case of anisotropically expanding fibers in a cross-ply structure, as schematically shown in Figure 10b, the normalized expansion of the interfiber distance can grow more slowly but approximately proportionally to the normalized expansion of the fiber radius. Next, the normalized expansion ΔL in the longitudinal direction of the viscous, expandable drug dosage form. v / L0 can be written as follows:

number

[0191] Further models of drug-induced expansion during transfer to a viscous medium are obvious to those skilled in the art. All of them are within the scope of the present invention.

[0192] g) Formation of a viscous medium As described above, the solid dosing form can be transferred to a viscous medium during expansion. The approximate viscosity of the medium is calculated based on the concentration of the main polymer excipient c. e,vThis is determined by [the following]. As an example, the primary polymer excipient may be the polymer excipient that contributes most significantly to the viscosity of the viscous medium, or the polymer excipient with the highest molecular weight, or the polymer excipient with the highest concentration in the viscous medium. In the non-limiting dosing forms A and B modeled herein, c e,v This is typically the concentration of HPMC in a viscous medium. e,v teeth,

number

[0193] The mass of the excipient is the weight fraction of the excipient in the solid drug formulation w e and the weight M of the solid drug delivery type sdf It is the product of the two. M e =w e M sdf (15a) Furthermore, M sdf The density ρ of the solid material in the drug administration form s and volume fraction φ s Regarding this, it can be written as follows: M sdf =ρ s φ s V sdf (15b) In the formula, V sdf This is the volume of the solid drug delivery form. Combining equations (15a) and (15b), M e =w e ρ s φ s V sdf (15b) It is given.

[0194] Similarly, the volume of the viscous medium is V v =V sdf (1+ΔV v / V sdf) (16a) can be expressed as, where ΔV v =V v -V sdf is the difference between the volume of the viscous medium and the volume of the solid dosage form. When the dosage form expands isotropically and the expansion is small, V v =V sdf (1 + 3ΔL v / L0) (16b) where ΔL v / L0 can be obtained from either equation (12) or equation (13).

[0195] Combining equations (15) and (16) with equation (14), the concentration of the excipient in the viscous medium is

Number

[0196] For non-limiting parameters of dosage form A, when w e is about 0.6, φ s is about 0.5, ΔL v / L0 is about 0.5, and ρ s is about 1200 mg / ml, according to equation (17), c e,v is about 144 mg / ml. This is only about twice the dissolution concentration c e * derived in non-limiting experimental example 11a. Therefore, the viscous medium is quite dilute. Moreover, an aqueous and viscous solution of 144 mg / ml HPMC ₁₀k has a viscosity of about 598 mPa (see, for example, experimental example 11a). This is only about two to three orders of magnitude greater than the viscosity of water.

[0197] For non-limiting parameters of dosage form B, when w e is about 0.8, φ sApproximately 0.4, ΔL v / L0 is approximately 1, and ρ s When it is approximately 1200 mg / ml, according to Equation (17), c e,v is approximately 96 mg / ml. This is approximately two orders of magnitude greater than the release concentration c e * derived in Non-limiting Experimental Example 11b. Therefore, the viscous medium is concentrated. Furthermore, water and a viscous solution of 96 mg / ml HPMC 120k have a viscosity of approximately 1.45×10 3 Pa·s (see, for example, Experimental Example 11b). This is more than six orders of magnitude greater than the viscosity of water.

[0198] More examples and models of the viscous medium will be apparent to those skilled in the art. All of them are within the scope of the present disclosure.

[0199] h) Viscous deformation of the viscous medium The viscous medium is exposed to forces such as shear due to gravity or fluid flow. Therefore, it can deform over time. The derivation of the exact equations for shear stress, strain rate, and strain in the medium is outside the scope of the present disclosure. However, when the viscous medium is fixed at the bottom and exposed to a unidirectional flow of a Newtonian fluid, as schematically shown in FIG. 11, the average wall shear stress τ is

Number

[0200] Assuming that the viscous medium is a Newtonian viscous medium, the shear strain rate is approximately

Number

[0201] Furthermore, if the viscous medium is homogeneous, the viscous flow can thin it down to a sheet, as shown in the non-limiting schematic diagram of Figure 11a. Geometry shows that the time t required to thin the medium down to a sheet of thickness h is... def teeth,

number

number

[0202] Typical parameters of medium A (τ = 2.3 × 10) -3 Pa, L v =10mm, h=200μm, and μ v In the case of =598mPas), according to equation (19b), t def = 6.6 minutes. Typical parameters of medium B (τ = 2.3 × 10) -3 Pa, L v =10mm, h=200μm, and μ v = 1.45 × 10 3 In the case of Pas), t def = 266 hours. Therefore, viscous medium A deforms very rapidly, while viscous medium B deforms very slowly. However, the calculation for medium B was t def It should be noted that this is not always very important in practice. At such low deformation rates, the dissolving solution may diffuse into the viscous medium, becoming less viscous and potentially accelerating its deformation rate over time.

[0203] Another non-limiting example of a deformable viscous medium is shown in 11b. The viscous medium is heterogeneous, containing higher viscosity regions at the initial fiber locations and lower viscosity regions between fibers. As a result, stress, strain rate, and strain can also be heterogeneous, and the lower viscosity areas may be sheared faster than the remaining areas, potentially causing void growth. Ultimately, the voids can fuse together and decompose the structure. The rate at which the structure can decompose increases significantly if the strain rate increases and the viscosity of the viscous medium decreases (for example, if the concentration of the main polymer excipient in the viscous medium decreases).

[0204] All further examples and models relating to the deformation of viscosity solutions of viscous gels, which will be obvious to those skilled in the art, are within the scope of this disclosure.

[0205] i) Disintegration of viscous media by convective mass transfer Simultaneously with viscous deformation, the viscous medium and the dissolving solution can continue to interdiffuse. For this reason, since the shear strain rate in the surrounding dissolving solution is generally considerably greater than the shear strain rate in the viscous medium, the viscous medium may be considered a "stagnant" body for the purpose of estimating the decay rate by convection diffusion.

[0206] In convection-diffusion, the decay rate of a viscous medium can be approximated by the decay rate of a rotating solid disk, as follows:

number

[0207] Time until the viscous medium breaks down:

number

[0208] Typical parameter value of medium A (μ f = 0.001 Pa·s, D e about 10 -10 m2 / s, ρ f =1000mg / ml, Ω=50rpm, c e,v =144 mg / ml, and c e * In the case of (70 mg / ml), the decay rate E is approximately 1.5 μm / s. Therefore, a 200 μm thick coating of this medium will dissolve in approximately 2 minutes. Typical parameter values ​​of medium B (μ f = 0.001 Pa·s, D e about 10 -10 m 2 / s, ρ f =1000mg / ml, Ω=50rpm, c e,v =96 mg / ml, and c e * If the concentration is 1.67 mg / ml, then E is approximately 0.053 μm / s. It would take about 63 minutes for a thickness of exactly 200 μm to disintegrate. Furthermore, a 5 mm thick viscous medium of this composition, which disintegrates from two sides, would dissolve in 63 × 2.5 / 0.2 = 788 minutes (13 hours).

[0209] More examples and models relating to the disintegration or dissolution of drug-containing solids or viscous media, which are obvious to those skilled in the art, are all within the scope of this disclosure.

[0210] j) Drug release Drugs can be released from a viscous medium into a solvent either by the breakdown of the viscous medium (e.g., by the breakdown or dissolution of excipients surrounding drug molecules or drug particles in the viscous medium) or by the diffusion of drug molecules into the solvent through the viscous medium. The faster of these two mechanisms is typically referred to herein as the “dominant drug release mechanism.” j1) Drug release due to the breakdown of the viscous medium

[0211] The time it takes for the drug to be released through disintegration is t d,er =t perc +t dif +t def +t E,v (twenty three) It can be approximated as follows.

[0212] Related parameter values ​​for drug administration type A (t perc Approximately 1 second, t dif Approximately 26 seconds, t def Approximately 6.6 minutes, t E,v (Approximately 2 minutes) Drug release time due to disintegration t d,er ≈ 9.1 minutes. However, in the case of drug administration type B, t d,er It will likely be longer than 10 hours.

[0213] All other models and examples for estimating drug release time, which are obvious to those skilled in the art, are within the scope of this disclosure.

[0214] j2) Drug release by drug diffusion through a viscous medium Figure 12 illustrates a schematic diagram illustrating drug release from a viscous mass governed by the diffusion of drug molecules through it. If all the drugs dissolve in the viscous mass, the diffusion equation is:

number

[0215] From the solutions to equations (24a) to (24d) given by Crank, when the time is short, the proportion of drug released is:

number

[0216] Equation (25) suggests that the proportion of drug released by the viscous mass is directly proportional to the square root of time and inversely proportional to its thickness.

[0217] D d It is approximately 5 x 10 -10 m 2 At a rate of 0.2 / s and a height of 5 mm, 80 percent of the drug content is released in 105 minutes. Therefore, when immersed in the solvent, drug delivery type B expands rapidly due to the diffusion of the solvent into the thin fibers, but releases the drug quite slowly due to the diffusion of drug molecules through the thick viscous mass.

[0218] The drug delivery form possesses several desirable characteristics. Due to the rapid diffusion of the dissolution into thin fibers, it can expand from a diameter of less than 12 mm to greater than 20 mm within 10-15 minutes after immersion in the dissolution. The drug delivery form further transforms from a solid to a viscous state during expansion, eliminating any risk of damage to the gastrointestinal mucosa. Moreover, it can release the drug at a controlled rate over a long period of time. Furthermore, it has sufficient mechanical strength to significantly delay passage through the pylorus during drug release, and still decomposes completely thereafter.

[0219] For more examples and models of drug release by diffusion of drug molecules through viscous media, see, for example, J. Siepmann, NA Peppas, "Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC)," Advanced Drug Delivery Reviews 48 (2001), pp. 139-157. All other examples and models of drug release by diffusion of drug molecules through viscous media that are obvious to those skilled in the art are within the spirit and scope of this disclosure.

[0220] k) Model summary The above model suggests that, when the drug dosage form of the present disclosure is immersed in a dissolving solution, the fluid penetrates uniformly and rapidly into the interior of the structure, provided that the surface of the fibers (e.g., the surface of the elements) is hydrophilic, the voids are interconnected, and the void spacing (e.g., the effective void spacing) is on a micro, meso, or macro scale.

[0221] After penetration, the fluid diffuses inward from the surface of the fiber. As a result, the fiber absorbs water and transforms into a viscous or gel-like substance or medium. Furthermore, upon absorbing water, the fiber expands. Therefore, if constraints that stop the expansion of the drug-administered structure, such as non-uniform wetting, are removed, the fiber-like structure can expand in approximately proportion to the expansion rate of a single fiber. Two non-restrictive types of single-fiber and drug-administered expansion can be distinguished.

[0222] Firstly, the single fibers expand isotropically. Secondly, the fibrous structure expands at approximately the same rate as the single fibers, the geometric similarity of the structures is preserved during expansion, and the porous network structure remains open. As a result, the dissolving agent continues to flow through the structure during expansion, and the absorbent polymer excipient in the viscous medium (or structural or viscous framework) is constantly diluted. Consequently, the viscosity of the viscous medium is constantly reduced until it becomes low enough for the medium to deform and dissolve easily. Dosage forms with this type of fiber generally dissolve rapidly, even if the fibers are densely packed and loaded with large amounts of water-soluble or water-absorbent polymer excipients.

[0223] Secondly, the individual fibers expand anisotropically. If the fibers expand more rapidly radially than longitudinally, they may fuse together as the drug-administered form expands. The voids and openings may close after the fibers fuse, and the flow of the solution into the interior may be stopped or greatly reduced. As a result, expanded viscous masses with very high polymer excipient concentrations and viscosities may be formed. The viscous masses may not deform or dissolve in the solution, or they may deform or dissolve very slowly. The drug may be released through the thick viscous mass by slow diffusion of drug molecules. The thick viscous masses eventually dissolve or decompose.

[0224] Therefore, the fibrous drug delivery form rapidly expands due to the diffusion of water into the thin fibers, but slowly releases the drug through the diffusion of drug molecules via the thick, expanded viscous medium. As a result, the drug delivery form can satisfy the two functional requirements of a gastrointestinal-retaining, sustained-release drug delivery form: rapid drug delivery form expansion and sustained drug release.

[0225] Embodiments of the present invention In consideration of the above theoretical models and considerations, which are suggestive and more approximate than precise, the drug dosage forms and embodiments disclosed herein may further include:

[0226] a) Three-dimensional structural framework of drug-containing solids and elements In some embodiments, the average length, width, and / or thickness of a drug-containing solid (e.g., a three-dimensional structural skeleton of one or more elements) is greater than 1 mm. This includes, but is not limited to, average lengths, and / or widths, and / or thicknesses of drug-containing solids in the range of 1 mm to 30 mm, 1.5 mm to 30 mm, or 2 mm to 30 mm. In the present invention as described herein, length usually refers to a measurement of distance in the direction of the longest distance, thickness usually refers to a measurement of distance in the direction of the shortest distance, and width is less than length but greater than thickness.

[0227] In some embodiments, the perforated network structure is continuous, and therefore there are no walls (e.g., walls containing the three-dimensional structural framework of the elements) that must be broken to obtain interconnected clusters of voids (e.g., void opening channels) from the external surface of the drug-containing solid to a point (or any point) in the voids within the internal structure.

[0228] However, in some embodiments, at least one empty space is enclosed by a wall, forming a closed cell. In this case, there are fewer than five walls that can be broken to obtain clusters of interconnected empty spaces from the external surface of the drug-containing solid to any point in the internal structure.

[0229] Furthermore, elements or divisions in the three-dimensional structural framework of one or more elements may be defined by their position relative to a reference point or reference frame (e.g., the position of the center of the mass, the position of its central axis, the path of the line formed by its central axis, or the central plane, etc.). In the invention as described herein, the reference frame may be understood as a reference coordinate system. The origin and orientation of the reference point or reference frame may be specified on the external surface or within the internal structure of the drug-containing solid.

[0230] In some embodiments, the position of at least one element or at least one segment in the three-dimensional structural framework of one or more elements is precisely controlled. Such embodiments include, but are not limited to, a three-dimensional structural framework of one or more elements in which the positions of the element or segment fragments are precisely controlled. The volume fraction of the element or segment whose position is precisely controlled (with respect to the total volume of the elements or segments constituting the three-dimensional structural framework of one or more elements) may be greater than 0.1, or greater than 0.3, or greater than 0.5, or greater than 0.7, or greater than 0.9.

[0231] In the context of the present invention as herein, a variable or parameter (e.g., the position of an element, or the spacing between elements, or the thickness of an element) is precisely controlled if it is deterministic and not probabilistic (or random). A variable or parameter may be deterministic if, when a step involving the variable is repeated multiple times (e.g., multiple drug formulations are produced under identical or nearly identical conditions), the standard deviation of the values ​​of the variable is less than the mean. This includes, but is not limited to, a standard deviation of the values ​​of the variable that is less than half the mean of the variable, or less than one-third the mean of the mean, or less than one-quarter the mean of the mean, or less than one-fifth the mean of the mean, or less than one-sixth the mean of the mean.

[0232] In some embodiments, the spacing λ between elements or sections, and / or the thickness h of at least one element, are precisely (or deterministically) controlled. Therefore, in some embodiments of this specification, when elements are produced multiple times under identical or nearly identical conditions, the standard deviation of the element thickness is less than the average value of the element thickness. Similarly, in certain embodiments, when elements or sections are produced multiple times under identical or nearly identical conditions, the standard deviation of the spacing between elements or sections is less than the average value. It should be noted that the spacing between elements or sections may vary along the length or width of the element or section. Similarly, the thickness of an element or section may also vary along the length of the element or section.

[0233] An unrestricted example of a three-dimensional structural skeleton of one or more elements in which the position of a large proportion (or all) of the elements, the spacing between elements, and the thickness of the elements are controlled (or precisely controlled) is a regular structure.

[0234] As a non-limiting example, such a typical or regular structure may include multiple layers of stacked fibers or fiber divisions. Furthermore, the fibers or fiber divisions in the layers may be oriented parallel (or nearly parallel) to one another. The distance between adjacent fiber divisions across empty space, also referred herein as "λ" or "λ0", may be further constant or essentially constant in the layers.

[0235] Furthermore, it should be noted that preferred embodiments of regular structures in this specification include plies (e.g., layers) of stacked fibers or fiber segments in a cross-ply arrangement (e.g., a cross-patterned stacking of fiber-like structural elements). In a cross-ply arrangement, the fibers (or fiber segments) in the layer (or ply) are oriented or at an angle (e.g., at an angle greater than 0 degrees, or at an angle greater than 0 degrees but less than or equal to 90 degrees) with respect to the fibers in the upper or lower plies. Non-limiting examples of cross-ply structures or arrangements are shown in Figures 7 and 8.

[0236] In a cross-ply structure, if the fiber radius is uniform (e.g., constant) and the distance λ between adjacent fiber sections across the voids is further constant (e.g., uniform or equidistant) or nearly constant, the voids form an interconnected, highly regular and highly uniform open network structure with respect to the drug-containing solid. For example, such a highly uniform and regular structure is expected to allow for uniform wetting of the three-dimensional structural framework, removing constraints on expansion and ensuring repeatable optimal properties.

[0237] Therefore, compared to irregular or random structures, a general advantage of regular structures, especially cross-ply structures, is that they allow for better control over relevant properties, such as the expansion rate and / or drug release rate of the drug formulation.

[0238] Further non-limiting embodiments of the dosage form structure are presented in U.S. Patent Application No. 15 / 482,776, entitled “Fibrous dosage form”, U.S. Patent Application No. 15 / 964,058, entitled “Method and apparatus for the manufacture of fibrous dosage forms”, and U.S. Patent Application No. 15 / 964,063, entitled “Dosage form comprising two-dimensional structural elements”.

[0239] b) Element thickness and spacing between sections To obtain a sufficiently large specific surface area (i.e., ratio of surface area to volume) to ensure rapid expansion of the drug-dosed form, in some embodiments, one or more elements (e.g., fibers, etc.) have an average thickness h0 of 2.5 mm or less. This includes, but is not limited to, h0 of 2 mm or less, or 1.5 mm or less, or 1.25 mm or less, or 1 mm or less, or 750 μm or less.

[0240] However, it should be noted that if the elements are very thin and densely packed, the spacing between elements and the gaps between them can become very small, limiting the rate at which the dissolving solution penetrates or flows into the gaps. Furthermore, drug formulations with very thin elements may be difficult to manufacture, for example, by 3D micropattern formation. For this reason, in some embodiments, one or more elements have an average thickness h0 in the range of 0.1 μm to 2.5 mm, 0.5 μm to 2.5 mm, 1 μm to 2.5 mm, 5 μm to 2.5 mm, 10 μm to 2.5 mm, 2.5 μm to 2 mm, 5 μm to 2 mm, 5 μm to 1.5 mm, 5 μm to 1 mm, 10 μm to 1 mm, 10 μm to 750 μm, 20 μm to 1.5 mm, or 20 μm to 1 mm.

[0241] The element thickness h can be considered as the smallest dimension of the element (i.e., h ≤ w and h ≤ l, where h, w, and l are the thickness, width, and length of the element, respectively). The average element thickness h0 is the average of the element thicknesses along the length or width of one or more elements. A non-limiting example for deriving the average element thickness is presented in U.S. Patent Application No. 15 / 482,776, entitled "Fibrous dosage form".

[0242] Similarly, to ensure rapid penetration of the dissolving solution into the drug-dosing structure, an effective empty space λ between adjacent compartments is required. f,e This must typically be on a micro or mesoscale. For this reason, in some embodiments, an effective free space interval λ f,e This is greater than 0.1 μm on average. This is greater than 0.25 μm, or greater than 0.5 μm, or greater than 1 μm, or greater than 2 μm, or greater than 5 μm, or greater than 7 μm, or greater than 10 μm, or greater than 15 μm, or greater than 20 μm, or greater than 25 μm, or greater than 30 μm, or greater than 40 μm, or greater than 50 μm on average λ f,e This includes, but is not limited to, these items.

[0243] However, since the volume of the drug form is generally limited, the mass of drugs and excipients that can be loaded into the drug form can be very small when the effective space spacing is very large. For this reason, in some embodiments, the effective space spacing may be in the range of 0.1 μm to 5 mm, 0.1 μm to 3 mm, 0.25 μm to 5 mm, 0.5 μm to 5 mm, 1 μm to 3 mm, 5 μm to 2.5 mm, 10 μm to 2 mm, 10 μm to 4 mm, 5 μm to 4 mm, 10 μm to 3 mm, 15 μm to 3 mm, 20 μm to 3 mm, 30 μm to 4 mm, 40 μm to 4 mm, or 50 μm to 4 mm.

[0244] The effective clearance between adjacent sections (hereinafter referred to as the “effective clearance distance”) is defined as the maximum diameter of a sphere that fits into the corresponding clearance when the element or section is considered as a solid, fixed body. A non-limiting example illustrating how the effective clearance distance may be derived or measured is presented in U.S. Patent Application No. 15 / 482,776, entitled “Fibrous dosage form”.

[0245] c) Surface properties of elements and sections Furthermore, in some embodiments, the surface composition of at least one element is hydrophilic in order to allow penetration into the interior of the structure of the dissolution (e.g., into empty spaces). In this disclosure, a surface or surface composition is hydrophilic and also described as “wettable with a physiological fluid” if the contact angle of a droplet of a physiological fluid on the surface in air is 90 degrees or less. This includes, but is not limited to, contact angles of a droplet of the fluid on the solid surface in air of 80 degrees or less, or 70 degrees or less, or 60 degrees or less, or 50 degrees or less, or 40 degrees or less, or 30 degrees or less. It should be noted that in some embodiments, the contact angle does not have to be static. In this case, the solid surface may be understood as “hydrophilic” if the contact angle of a droplet of a physiological fluid on the solid surface in air for at least 20 to 360 seconds after the droplet is placed on the surface is 90 degrees or less. A non-limiting example of a droplet on a surface is presented in U.S. Patent Application No. 15 / 482,776, entitled “Fibrous dosage form”.

[0246] Generally, the penetration rate of physiological fluids into interconnected open spaces increases as the contact angle between the fluid and the surface of the three-dimensional structural framework of one or more elements decreases. For this reason, in some embodiments, at least one element or at least one segment of an element includes a hydrophilic or highly hydrophilic coating to enhance the fluid penetration rate into the drug-dosing structure. In the context of this specification, a solid surface (e.g., a solid material or solid compound or surface or coating) is understood to be "highly hydrophilic" if the contact angle of a droplet of physiological fluid on the solid surface in air is 45 degrees or less. This includes, but is not limited to, contact angles of the droplet of the fluid on the solid surface in air that are 35 degrees or less, or 30 degrees or less, or 25 degrees or less, or 20 degrees or less, or 15 degrees or less.

[0247] Non-limiting examples of hydrophilic (or highly hydrophilic) compounds that can serve as coatings for elements (or segments of elements) include polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone, silicon dioxide, talc, magnesium stearate, and polyols (e.g., mannitol, maltitol, xylitol, isomalt, lactitol, sucrose, glucose, erythritol, etc.).

[0248] Ultimately, it can be noted that in some embodiments, the spacing between sections and the composition of the surface of one or more elements are such that the penetration time of physiological fluids / body fluids into one or more interconnected spaces of the drug-containing solid is 200 seconds or less under physiological conditions. This includes, but is not limited to, penetration times of physiological fluids / body fluids into one or more interconnected spaces of the drug-containing solid that are 100 seconds or less, or 50 seconds or less, or 25 seconds or less, or 10 seconds or less under physiological conditions.

[0249] d) Composition of elements and properties of excipients In some embodiments, the weight fraction of the drug in at least one element (e.g., fiber, sheet, bead, etc.) relative to the total weight of the element is 0.9 or less. This includes, but is not limited to, weight fractions of the drug in the element relative to the total weight of the element of 0.85 or less, or 0.8 or less, or 0.75 or less, or 0.7 or less, or 0.65 or less.

[0250] Similarly, in some embodiments, the weight fraction of the drug in the three-dimensional structural skeleton of one or more elements relative to the total weight of the skeleton is 0.9 or less. This includes, but is not limited to, a weight fraction of the drug in the skeleton relative to the total weight of the structural skeleton of 0.85 or less, or 0.8 or less, or 0.75 or less, or 0.7 or less, or 0.65 or less.

[0251] Furthermore, in some embodiments, the weight fraction of the absorbent polymer excipient in at least one element with respect to the total weight of the element is greater than 0.1. This includes, but is not limited to, weight fractions of the absorbent polymer excipient in the element with respect to the total weight of the element that are greater than 0.15, or greater than 0.2, or greater than 0.25, or greater than 0.3, or greater than 0.35, or greater than 0.4.

[0252] Similarly, in some embodiments, the weight fraction of the absorbent polymer excipient in the three-dimensional structural framework of one or more elements with respect to the total weight of the framework is greater than 0.1. This includes, but is not limited to, weight fractions of the absorbent polymer excipient in the framework with respect to the total weight of the structural framework that are greater than 0.15, or greater than 0.2, or greater than 0.25, or greater than 0.3, or greater than 0.35, or greater than 0.4.

[0253] In some embodiments, the effective dispersion rate of physiological fluids / body fluids in the absorbent excipient is 0.1 × 10⁻⁶ under physiological conditions. -11 m 2 It is greater than / s. This is 0.2 × 10 under physiological conditions. -11 m2 Greater than / s, or 0.5 × 10 -11 m 2 Greater than / s, or 0.75 × 10 -11 m 2 Greater than / s, or 1 × 10 -11 m 2 Greater than / s, or 2 × 10 -11 m 2 Greater than / s, or 3 × 10 -11 m 2 Greater than / s, or 4 × 10 -11 m 2 This includes, but is not limited to, the effective diffusion rate of physiological fluids / body fluids in absorbent excipients (and / or elements or segments) greater than / s.

[0254] Alternatively, in the case of absorbent excipients whose diffusion into the physiological fluid / body fluid is not of the Fick type, the permeation rate may be specified. In some embodiments, the permeation rate of physiological fluid / body fluid into the solid absorbent excipient (and / or element or segment) is greater than the average thickness of one or more drug-containing elements divided by 3600 seconds (i.e., h0 / 3600 μm / s). In other examples that are not limited, the permeation rate may be greater than h0 / 1800 μm / s, greater than h0 / 1200 μm / s, greater than h0 / 800 μm / s, greater than h0 / 600 μm / s, or greater than h0 / 500 μm / s.

[0255] To determine the effective diffusion rate (and / or permeation rate) of a dissolution medium in a solid absorbent excipient (and / or element or segment), the following procedure may be applied: An element (e.g., an element or segment of a drug-dosing structure, or an element or segment consisting of an absorbent excipient itself) may be fixed at both ends and placed in a static dissolution medium at 37°C. The time t1 until the element substantially decomposes or deforms may be recorded. (As a non-limiting example, generally, if the length, width, or thickness of the element differs by more than 10-20 percent from its initial value, the deformation of the element may be considered substantial.) e , or volume fraction φ eFor elements having the length, width, or thickness of the element or section, any of these values ​​is 25 × φ from its first value. e Percentage or 25 × w e If the difference is greater than a percent, the deformation of the element or segment may be considered substantial. Next, the effective diffusion rate D eff D eff =h init 2 It may also be determined according to / 4t1, where h init is the thickness of the first element or section (e.g., the thickness of the dry element or section). Similarly, the rate of permeation of physiological fluids / body fluids into the element or section is given by h init It is equal to / 2t1. Further non-limiting examples for deriving the effective diffusion rate or transmission rate are presented in U.S. Patent Application No. 15 / 482,776, entitled "Fibrous dosage form".

[0256] Furthermore, in some embodiments, the solubility of at least one absorbent polymer excipient is greater than about 0.1 g / l in physiological fluids / body fluids under physiological conditions. This includes, but is not limited to, solubility greater than 0.5 g / l, or greater than 1 g / l, or greater than 5 g / l, or greater than 10 g / l, or greater than 20 g / l, or greater than 30 g / l, or greater than 50 g / l, or greater than 70 g / l, or greater than 100 g / l in physiological fluids / body fluids under physiological conditions.

[0257] The solubility of a material or compound in a fluid is generally described herein as the ratio of the maximum mass of the material that can be dissolved in a given volume of the fluid at equilibrium, obtained by dividing the fluid by a given volume of the fluid. Solubility can be determined, for example, by optical methods.

[0258] Furthermore, with respect to polymers that form viscous solutions when combined with a dissolving medium, "solubility" in the context of this invention refers to the polymer concentration in the physiological fluid / body fluid such that the average shear viscosity of the polymer-physiological fluid / body fluid solution is 5 Pa·s under physiological conditions at a shear rate range of 1 to 100 ¹ / s. The pH value of the physiological fluid / body fluid may be adjusted to suit the specific physiological conditions of the choice.

[0259] In some embodiments, to ensure that the drug formulation eventually dissolves or decomposes in a physiological fluid (for example, to avoid the expanded drug formulation or viscous medium clogging the digestive tract, etc.), at least one absorbent polymer excipient comprises a plurality of individual chains or molecules that dissolve or unravel upon immersion in a physiological fluid.

[0260] Furthermore, in some embodiments, the molecular weight of at least one absorbent polymer excipient is greater than 2 kg / mol (e.g., greater than 5 kg / mol, or greater than 10 kg / mol, or greater than 20 kg / mol, or greater than 50 kg / mol). In addition, in some embodiments, the molecular weight of at least one absorbent polymer excipient is between 2 kg / mol and 1000 kg / mol (e.g., in the range of 5 to 750 kg / mol, 5 to 500 kg / mol, 10 to 500 kg / mol, 2 to 200 kg / mol, 5 to 200 kg / mol, 2 to 50 kg / mol, or 2 to 100 kg / mol).

[0261] Non-limiting examples of excipients that meet some or all of the requirements of polymer excipients include, but are not limited to, hydroxypropyl methylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose succinate acetate, sodium alginate, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropyl methyl ethercellulose, starch, chitosan, pectin, polymethacrylates (e.g., poly(methacrylic acid, ethyl acrylate) 1:1, or butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer), vinylpyrrolidone-vinyl acetate copolymer.

[0262] e) Microstructure and three-dimensional structural framework of elements Non-limiting examples of elemental microstructures and three-dimensional structural skeletons of one or more elements are presented in U.S. Patent Application No. 15 / 482,776 entitled "Fibrous dosage form", U.S. Patent Application No. 15 / 964,058 entitled "Method and apparatus for the manufacture of fibrous dosage forms", and U.S. Patent Application No. 15 / 964,063 entitled "Dosage form comprising two-dimensional structural elements".

[0263] However, in some preferred embodiments, the drug is embedded within the element as either particles or molecules in the matrix of an absorbent polymer excipient.

[0264] Similarly, in some preferred embodiments, the drug is embedded in a three-dimensional structural framework of one or more elements as either particles or molecules in the matrix of an absorbent polymer excipient.

[0265] In some embodiments, the elements swell due to the dilution of the polymer excipient with physiological fluids or bodily fluids.

[0266] Similarly, in some embodiments, the three-dimensional structural framework of one or more elements expands due to dilution of the polymer excipient with physiological fluids or bodily fluids.

[0267] f) Characteristics of drug-containing solids and drug-dosing forms In some embodiments, a drug-containing solid (or three-dimensional structural skeleton) expands isotropically (e.g., uniformly in all directions) during a transition to a fluid or viscous medium. In the present invention, a solid, viscous mass, or viscous medium is understood to expand isotropically if its normalized expansion (e.g., the ratio of the length difference to the initial length, e.g., (L(t)-L0) / L0, (H(t)-H0) / H0, etc.) deviates by less than 50 percent from its maximum value by changing direction or orientation. Thus, in a solid, viscous mass, viscous medium, or skeleton that expands isotropically, the normalized expansion is substantially the same in all directions. Figure 13a is a non-limiting schematic diagram of a drug-containing solid that expands isotropically.

[0268] Furthermore, in some embodiments, the geometric similarity of the three-dimensional structural framework is preserved during the transition to a fluid or viscous medium. In the present invention, a microstructure or three-dimensional structural framework is geometrically similar to the original structure or framework if the expanded microstructure or expandable framework can be obtained by scaling or enlarging the original structure or framework (for example, by uniformly scaling or enlarging the original structure or framework in all directions). Thus, in an expandable framework where geometric similarity is preserved, interconnected voids remain open and interconnected even as the structure expands. This allows the framework to absorb more water (e.g., physiological fluid) during expansion, thereby allowing it to expand to a greater extent.

[0269] The geometric similarity of an expandable skeleton can be preserved if the elements (or segments) are uniformly wetted by the dissolving solution, and / or if the individual elements (or segments) expand substantially isotropically upon contact with the dissolving solution. An expandable skeleton is understood to exist if the geometric similarity can be "preserved" or "almost preserved" only at the beginning. All such skeletons in which geometric similarity is partially, somewhat, or initially preserved are referred to herein as "skeletons in which geometric similarity is preserved during expansion." Figures 6b and 6c present non-limiting examples of two geometrically similar three-dimensional structural skeletons.

[0270] Figure 13a presents a non-limiting example of a drug-containing solid including a geometrically similar, expandable three-dimensional structural skeleton 1302 and interconnected empty spaces 1330 that form an open network structure. When immersed in a dissolving solution 1340, the skeleton 1302 is uniformly wetted by the fluid 1340. As a result, the skeleton 1302 absorbs the water 1340, transitions to viscosity, and expands. Furthermore, since geometric similarity is preserved during expansion, the empty spaces 1330 remain open, and the dissolving solution 1340 continues to flow into the structure as the skeleton 1302 expands. As a result, when the framework (or drug-containing solid) is transferred to the viscous medium 1350, the viscosity always decreases (for example, the viscosity or "mean viscosity" of the drug-containing solid always decreases during the transfer to the viscous medium, and this can also be repeated when the drug-containing solid is a "solid", a combination of "solid" and "viscous medium", a combination of "viscous medium", "solid" and a dilution solution or dispersion, or a combination of "viscous medium" and a dilution solution or dispersion). Therefore, ultimately, the viscosity of the viscous medium 1350 can become very low, so 1350 deforms and thins due to the forces applied by the dissolving solution (e.g., shear tensile force, pressure imbalance, buoyancy, gravity, etc.). This increases the specific surface area of ​​the viscous medium 1350 and, therefore, increases the disintegration rate into the dissolving solution 1340. Note that in some examples, the drug-containing solid or viscous medium 1350 may expand and be diluted to the extent that a "dilution solution" or "dilution dispersion" is formed. Furthermore, it must be reiterated that "deformation due to external forces" and "thinning" are not considered "expansion" in this specification.

[0271] Therefore, with respect to the immediate release and delivery of the drug in its prescribed dosage form, the viscosity of the expanded dilution solution 1360 can be very low, causing it to rapidly deform and disintegrate in the solvent 1340. The expansion of the drug-containing solid 1300 reduces the viscosity of the viscous medium 1350 or the formed dilution solution 1360, accelerating the disintegration and drug release rate.

[0272] Therefore, in some embodiments, 80 percent of the drug content in a drug-containing solid is released within 45 minutes after immersion in a physiological fluid or body fluid under physiological conditions. This includes, but is not limited to, drug-containing solids that release 80 percent of their drug content within 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, or 1 to 45 minutes, 1 to 30 minutes, 2 to 45 minutes, or 2 to 30 minutes after immersion in a physiological fluid under physiological conditions.

[0273] However, in some embodiments, the geometric similarity of the expandable skeleton may not be preserved at all, or not at all, or hardly at all, if the individual elements 230, 240 (or individual sections) expand substantially anisotropically when in contact with the solvent 220.

[0274] Figure 13b shows a non-limiting example of a drug-containing solid 1305 comprising a three-dimensional structural skeleton 1307 of elements that expand more rapidly along its thickness than along its length, and interconnected voids 1335 defining an open network structure. When immersed in a dissolving solution 1345, the skeleton 1307 is uniformly wetted by the fluid 1345. As a result, the skeleton 1307 absorbs the water 1345, transitions to viscosity, and expands. Due to the anisotropic expansion of the elements, as the skeleton 1307 expands, they fuse together, closing the voids 1335 and openings. Subsequently, the flow into the interior of the dissolving solution 1345 can be stopped or greatly reduced. As a result, an expanded viscous mass 1355 can be formed with a polymer excipient concentration considerably higher than the unraveling concentration and a viscosity considerably higher than the viscosity of the dissolving solution 1345. The viscous mass 1355 may not deform in the solvent 1345, or it may deform very slowly, or it may not dissolve, or it may dissolve very slowly. The drug may be released by the slow diffusion of drug molecules through the thick viscous mass 1355.

[0275] Therefore, in some embodiments, 80 percent of the drug content in a drug-containing solid is released after immersion in a physiological fluid or body fluid under physiological conditions for a period of longer than 30 minutes. This includes, but is not limited to, drug-containing solids that release 80 percent of their drug content after immersion in a physiological fluid under physiological conditions for a period of longer than 40 minutes, or longer than 50 minutes, or longer than 60 minutes, or longer than 100 minutes, or within 30 minutes to 48 hours, 30 minutes to 36 hours, 30 minutes to 24 hours, or 45 minutes to 24 hours.

[0276] Finally, in some embodiments, the tensile strength of the drug-containing solid or the three-dimensional structural framework of one or more elements is between 0.01 MPa and 100 MPa (this includes, but is not limited to, the tensile strength of at least one element greater than 0.02 MPa, or greater than 0.05 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa, or greater than 0.5 MPa, or greater than 1 MPa, or greater than 1.5 MPa, or greater than 2 MPa, or greater than 3 MPa, or greater than 5 MPa).

[0277] Method and apparatus for manufacturing drug dosage forms (a) Method Figure 14 illustrates a non-limiting example of a method for producing a pharmaceutically solid dosing form according to the present invention. One or more drugs 1410 and / or one or more absorbent polymer excipients 1420 (a combination of one or more drugs 1410 and / or one or more excipients 1420 is also referred to herein as "one or more solid components") are injected into an extrusion channel 1430 having a cross section that extends along its length inside a housing 1440. Similarly, at least one solvent that solvates at least one injected solid component is injected into the extrusion channel 1430. The rate at which the solvent is injected, and the volume fraction of at least one solvated solid component with respect to the total volume of one or more injected solid components, are such that one or more injected solid components form a plasticizing matrix upon contact and mixing with the solvent. The plasticizing matrix is ​​transported toward the outlet 1450 of the extrusion channel 1430 (after or simultaneously with its formation) by applying mechanical action to the plasticizing matrix (for example, by applying a shear force to the plasticizing matrix along the division of the extrusion channel 1430, or by applying a pressure gradient in the direction of the extrusion channel 1430). The plasticizing matrix is ​​then extruded from the outlet 1450 to form at least one plasticizing fiber 1460. The at least one plasticizing fiber 1460 (e.g., one or more plasticizing fibers) is then structured into a three-dimensional lattice structure of one or more fibers. In some embodiments, the three-dimensional lattice structure of one or more fibers solidifies by evaporating the solvent to form a fibrous drug-doped form with sufficient rigidity. Furthermore, upon immersion in a physiological fluid, the three-dimensional lattice structure is uniformly wetted and transferred to a viscous medium, thereby expanding in all dimensions.

[0278] Another non-limiting example of a method for producing a pharmaceutically solid dosing form according to the present invention is shown in Figure 15. One or more drugs 1510 and / or one or more solid excipients 1520 (e.g., one or more solid components) are supplied or injected into an extrusion channel 1530 having a cross section extending along its length inside a housing 1540. The injected one or more solid components are then heated to a temperature higher than the melting temperature of at least one of the injected solid components. Thus, at least one of the injected solid components becomes fluid upon heating (e.g., transitions from solid or solid-like to fluid or fluid-like). The volume fraction of the fluidized solid components (or more fluidized solid components) relative to the volume of one or more injected solid components is such that, upon heating (and mixing), one or more injected solid components form a plasticizing matrix. The plasticizing matrix is ​​transported toward the outlet 1550 of the extrusion channel 1530 (after or simultaneously with its formation) by applying mechanical action to the plasticizing matrix (for example, by applying a shear force to the plasticizing matrix along the division of the extrusion channel 1530, or by applying a pressure gradient in the direction of the extrusion channel 430, etc.). The plasticizing matrix is ​​then extruded from the outlet 1550 to form at least one plasticizing fiber 1560. The at least one plasticizing fiber 1560 (e.g., one or more plasticizing fibers) is then structured into a three-dimensional lattice structure of one or more fibers. In some embodiments, the three-dimensional lattice structure of one or more fibers is solidified by cooling it to a temperature below the solidification temperature. Furthermore, upon immersion in a physiological fluid, the three-dimensional lattice structure is uniformly wetted and transferred to a viscous medium, thereby expanding in all dimensions.

[0279] In some embodiments, the structuring of at least one plasticized fiber into a three-dimensional network structure of one or more drug-containing fibers is carried out by 3D pattern formation of the at least one plasticized fiber on a substrate.

[0280] In some embodiments, the three-dimensional structural framework of one or more drug-containing fibers includes a plurality of cross-shaped laminations of fiber-like structural elements.

[0281] It should be noted that in any example presented herein, the extrusion channels 1430, 1530 may include one or more outlets through which the plasticizing material can be extruded. Similarly, a three-dimensional network structure of one or more fibers may be combined with other elements of the drug-dosing form, such as one or more drug-containing solids, one or more non-drug-containing solids, one or more coating shells, liquids, gases, etc. Furthermore, in the present invention herein, the terms “plasticizing fiber” and “fibrous extruder” are used interchangeably. Moreover, any order of the steps described herein may be performed simultaneously (e.g., at least one step simultaneously with another) or sequentially (e.g., one step is performed at a certain time, and subsequent steps are started after the completion of the previous step). In addition, any process step described in relation to one aspect of the present invention may be applied to another aspect. As a non-limiting example, solid components may be plasticized by a combination of solvation and melting.

[0282] Further non-limiting examples of methods for manufacturing the dosage forms disclosed herein are presented in concurrently pending U.S. applications 15 / 482,776, entitled “Fibrous dosage form”, 15 / 964,058, entitled “Method and apparatus for the manufacture of fibrous dosage forms”, and 15 / 964,063, entitled “Dosage form comprising two-dimensional structural elements”. Any more examples of process steps for manufacturing the disclosed dosage forms will be obvious to those skilled in the art. All of them are within the scope of the present invention.

[0283] (b) Equipment Figure 14 also presents a non-limiting example of an apparatus 1400 for manufacturing a pharmaceutical solid-dosage form according to the present invention. The apparatus 1400 includes an internally hollow housing 1440 having an internal surface that encloses and defines an extrusion channel 1430 having a first end 1445, a second end 1450, and a cross section that extends axially along its length from the first end 1445 to the second end 1450 and terminates at the exit 1450 of the second end 1450. The housing 1440 further has at least a first feed port 1455 between the first end 1445 and the second end 1450 for supplying or injecting at least one solid component into the extrusion channel 1430. Furthermore, the housing 1440 has at least a second feed port 1456 between the first feed port 1455 and the outlet 1450 for injecting at least one liquid into the extrusion channel 1430 to solvate at least one injected solid component and form a plasticizing matrix. The apparatus 1400 further includes at least one transport element 1470 for extruding the plasticizing matrix in the extrusion channel out of the outlet 1450 to form at least one plasticizing fiber 1460. The apparatus 1400 further includes a fiber structuring unit 1480 for structuring the at least one plasticizing fiber 1460 (e.g., one or more plasticizing fibers) into a three-dimensional structural network structure of one or more fibers. In some embodiments, the apparatus 1400 further includes a solid component supply unit 1485 for injecting at least one solid component into the extrusion channel 1430 through the first feed port 1455. Furthermore, in some embodiments, the apparatus further includes a solvent supply unit 1486 attached to a second supply port 1456 for injecting at least one solvent into the extrusion channel 1430. Moreover, when immersed in a physiological fluid, the three-dimensional structural framework is uniformly wetted and transferred to a viscous medium, thereby expanding in all dimensions.

[0284] Figure 15 shows another non-limiting schematic diagram of apparatus 1500 for the manufacture of a pharmaceutical solid-dosage form according to the present invention. Apparatus 1500 includes an internal hollow housing 1540 having an internal surface that encloses and defines an extrusion channel 1530 having a first end 1545, a second end 1550, and a cross section that extends axially along its length from the first end 1545 to the second end 1550 and terminates at the exit 1550 of the second end 1550. The housing 1540 further has at least a first feed port 1555 between the first end 1545 and the second end 1550 for supplying or injecting at least one solid component into the extrusion channel 1530. Apparatus 1500 further includes at least one heating element 1586 for fluidizing at least one injected solid component so that the injected one or more solid components form a plasticizing matrix in the extrusion channel 1530. The apparatus 1500 further includes at least one transport element 1570 for extruding the plasticizing matrix in the extrusion channel 1530 from the outlet 1550 to form at least one plasticizing fiber 1560. The apparatus 1500 further includes a fiber structuring unit 1580 for structuring the at least one plasticizing fiber 1560 (e.g., one or more plasticizing fibers) into a three-dimensional structural network structure of one or more fibers. In some embodiments, the apparatus 1500 further includes a solid component supply unit 1585 for injecting at least one solid component into the extrusion channel 1530 through a first supply port 1555. Furthermore, when immersed in a physiological fluid, the three-dimensional structural skeleton is uniformly wetted and transferred to a viscous medium, thereby expanding in all dimensions.

[0285] In some embodiments, the fiber structuring unit includes a translational or rotational stage.

[0286] In some embodiments, one or more plasticizable fibers are structured into a three-dimensional network structure of one or more drug-containing fibers by 3D patterning the one or more plasticizable fibers on a substrate defined by or attached to a translational or rotational stage.

[0287] In some embodiments, the three-dimensional structural framework of one or more drug-containing fibers includes a plurality of cross-shaped stacks of fibrous structural elements.

[0288] In any example presented herein, the extrusion channels 1430, 1530 may include one or more outlets through which plasticizing fibers can be extruded. Furthermore, any feature described in reference to one aspect of the present invention can be applied to another aspect. In a non-limiting example, the apparatus may include at least a supply port for injecting a solvent into the extrusion channel to form a plasticizing matrix, and at least a heating element for fluidizing at least one injected solid component to form a plasticizing matrix.

[0289] Further non-limiting examples of apparatus for manufacturing the dosage forms disclosed herein are presented in concurrently pending U.S. applications 15 / 482,776, entitled “Fibrous dosage form”, 15 / 964,058, entitled “Method and apparatus for the manufacture of fibrous dosage forms”, and 15 / 964,063, entitled “Dosage form comprising two-dimensional structural elements”. Any many more examples of apparatus for manufacturing fibrous dosage forms will be apparent to those skilled in the art. All of them are within the scope of the present invention. [Examples]

[0290] The following examples present methods for preparing and analyzing fibrous drug formulations, thereby making the principles more readily understandable to those skilled in the art. The following examples are presented for illustrative purposes only and are not intended to be limiting.

[0291] (Example 1) Preparation of drug dosage and fiber A The drug used in the dosage form and fiber A was ibuprofen, which was received as solid particles (particle size approximately 20 μm) from BASF, Ludwigshafen, Germany. The excipient was a mixture of 67 wt% hydroxypropyl methylcellulose (HPMC) and 33 wt% polyoxyl stearate (trade name: Gelucire 48 / 16, Gattefosse) with a molecular weight of 10 kg / mol. The common solvent used was dimethyl sulfoxide (DMSO).

[0292] Dosage form A was prepared as follows: First, the ibuprofen drug particles as received were dissolved in DMSO at a concentration of 123 mg drug / ml DMSO. Next, the solution was combined with the excipient at a concentration of 1.11 g excipient / ml DMSO. The mixture was then extruded through a desktop extruder to form a uniform viscous paste.

[0293] As schematically shown in Figure 16, the paste was then filled into a syringe at point O and extruded through a subcutaneous needle to form a moist fibrous drug delivery form and pattern at point P. The drug delivery form included a cross-ply arrangement of fibers with uniform inter-fiber distances in the ply (or layer). The nominal radius of the moist fibers (inner radius of the subcutaneous needle) R n The nominal interfiber distance λ was 130 μm; n The particle size was 500 μm, as shown in Table 1. After pattern formation, warm air at a temperature of approximately 50°C and a speed of 2.3 m / s was blown onto the material to evaporate the solvent and solidify the structure. Drying time t dry The reaction time was approximately 35 minutes, after which the fibers were a homogeneous solid solution of drug and excipient molecules.

[0294] After drying, the structure was molded into a dosage form in the shape of a square disc with nominal volume of 8 mm × 8 mm × 3.6 mm. The weight fraction of the drug in the dosage form was 0.1, the weight fraction of HPMC was 0.6, and the weight fraction of polyoxyl stearate was 0.3.

[0295] Single fiber A was prepared as described above (for example, as drug dosage type A), but the fibrous extruded material was not structured into a drug dosage type.

[0296] (Example 2) Preparation of drug dosage forms and fibers B and C Dosage forms B and C were prepared as follows: First, 20% by weight acetaminophen drug particles were mixed with an excipient, 80% by weight HPMC with a molecular weight of 120 kg / mol. Next, the mixture was combined with a solvent, either DMSO (for preparing dosage form B) or water (for dosage form C). The volume of solvent per mass of excipient for preparing dosage forms B and C was 5.5 ml / g and 3.33 ml / g, respectively. Next, the drug-excipient-solvent mixture was extruded in a laboratory extruder to form a uniform viscous paste. The viscous paste was then extruded to an inner radius R n =130 μm (to prepare drug dosage form B) or R n The paste was placed in a syringe equipped with a 500 μm subcutaneous injection needle (for preparing drug delivery type C). The paste was then extruded from the needle to form a pattern as a fibrous drug delivery type with a cross-ply arrangement of fibers. The nominal inter-fiber distance in the plies was uniform, equal to 730 μm (for preparing drug delivery type B) or 2800 μm (for preparing drug delivery type C). During and after pattern formation, warm air at 60°C and a speed of approximately 2.3 m / s was blown over the fibrous drug delivery type for a period of time t dry The solvent was evaporated and the structure was fixed by spraying for approximately 40 minutes. The process parameters for preparing the drug dosage forms are summarized in Table 1. After drying, the structure was molded into a square disc-shaped drug dosage form with a side length L0 of approximately 8 mm. The thickness H0 of drug dosage forms B and C was approximately 3 mm.

[0297] Single fibers B and C were prepared as drug-dosing types B and C, but the fibrous extruded material was not structured into a drug-dosing type. [Table 1]

[0298] (Example 3) Fiber coating in drug-administered structures To ensure that the dissolving solution penetrates the drug-doped structures uniformly and rapidly after immersion, all fibers of the drug-doped structures were coated with a thin hydrophilic coating. The coating was applied by dropping a few drops of the hydrophilic coating solution onto the drug-doped structures and then drying them immediately afterward. The drying step was carried out by blowing hot air at a temperature of 50°C and a speed of 2.3 m / s onto the drug-doped structures.

[0299] To coat the fibers of drug formulation A, the hydrophilic coating solution consisted of polyvinylpyrrolidone (PVP) with a molecular weight of 10 kg / mol (received from BASF, Ludwigshafen, Germany), mannitol, and ethanol. The concentration of PVP was 10 mg per 1 ml of ethanol, and the concentration of mannitol was 20 mg per 1 ml of ethanol.

[0300] To coat the fibers of drug formulations B and C, the hydrophilic coating solution consisted of polyvinylpyrrolidone (PVP) with a molecular weight of 10 kg / mol (as received from BASF, Ludwigshafen, Germany), silicon dioxide (as received from Evonik, Essen, Germany), and acetone. The concentrations of both PVP and silicon dioxide were 10 mg per 1 ml of acetone.

[0301] (Example 4) Scanning electron microscope images of drug administration and fiber A. Drug-treated and single-fiber A samples were imaged using a Zeiss Merlin High Resolution SEM equipped with a GEMINI column. The top view image was taken without sample preparation. However, when imaging cross-sections, the sample was cut in the imaging plane with a thin blade (MX35 Ultra, Thermo Scientific, Waltham, MA). Imaging was performed using an in-lens secondary electron detector. The acceleration voltage was 5kV and the probe current was 95pA.

[0302] Figure 17 shows scanning electron microscope images of the microstructure of drug-dosage type A. Figure 17a is a top view, and Figure 17b is a front view (e.g., a cross-sectional view). From Figures 17a and 17b, the fiber radius R0 = 104 μm and the interfiber distance λ0 = 385 μm in the drug-dosage type microstructure. The fiber radius is approximately 80 percent of the nominal value, and the interfiber distance is approximately 77 percent (Tables 1 and 2).

[0303] As the solvent is removed during drying, the wet formulation shrinks, so the microstructural parameters of the dry formulation are smaller than their nominal values. In the case of isotropic shrinkage, the ratio is:

number

[0304] Drug dosage form A has a solvent concentration of c solv = 550 kg / m 3 , and solvent density ρ solv = 1100 kg / m 3 It was prepared using [this method]. Therefore, the calculated R / R n =λ / λ n =0.79 is almost the same as the measured value.

[0305] Furthermore, due to gravity, the wet fibers deform at the contact points, and the inter-fiber distance in the vertical direction decreases. As a result, the solid volume fraction of dry fibers with contact on a flat surface is greater than that of the nominal cross-ply structure with cylindrical fibers. Therefore, for all drug formulations, the volume fraction of solid fibers is

number

[0306] Finally, Figure 18 is a scanning electron microscope image of a typical single fiber A. The fiber radius was 102 μm, as shown in Table 2.

[0307] (Example 5) Drug administration and expansion and decomposition of fiber A For imaging of the drug administration method and the expansion and decomposition process of fiber A, the sample was first immersed in a beaker containing 500 ml of dissolving solution (0.1 M HCl in deionized water, 37°C). The fluid was stirred with a paddle rotating at 50 rpm. Next, the sample was continuously imaged with a Nikon DX camera until it dissolved.

[0308] Figure 19 shows an image of drug delivery type A expanding and decomposing. Upon immersion of the drug delivery type, the dissolving solution penetrated into the void almost immediately. Next, the solid drug delivery type transitioned to a viscous medium and expanded uniformly in all directions. The normalized expansion of the drug delivery type was 0.43 after 2 minutes of immersion, which was approximately the same as the radial and longitudinal expansion of a single fiber at that time (Figure 20).

[0309] After immersion for approximately 2-3 minutes, the administered substance began to deform viscously due to gravity and fluid shear. The material disintegrated from the surface, and its structure collapsed. Next, a viscous drug-excipient-solvent solution formed along the flat surface. The viscous solution disintegrated continuously in the solvent, and this dissolved after immersion for approximately 10-15 minutes.

[0310] (Example 6) Drug delivery form and drug release from fiber A The drug release by the drug delivery form and single fiber A was determined under the same conditions as in the expansion and decomposition experiment (Experimental Example 5). The drug concentration in the solution over time was measured by UV absorption using a Perkin Elmer Lambda 1050 spectrophotometer.

[0311] Figure 21 shows the drug concentration in the medium against time. As is clear, the fibrous drug delivery form and the single fiber continuously released the drug until they dissolved. Time t to dissolve 80 percent of the drug content 0.8The drug release time was 3 minutes for single fibers and 9 minutes for drug-administered forms (Table 2). Therefore, the drug release time for drug-administered forms was about the same as that for single fibers.

[0312] (Example 7) Scanning electron microscope images of fibers B and C Scanning electron microscope images of single fibers B and C were obtained under the above conditions in Experimental Example 4. From Figures 22a and 22b, the fiber radii were 73 μm (fiber B) and 309 μm (fiber C), as shown in Table 2. It should be noted that the inner radii of the needles used to prepare fibers B and C were 130 μm and 500 μm, respectively (Table 1).

[0313] (Example 8) Swelling and decomposition of fibers B and C Images of the decomposing single fibers B and C were obtained under the conditions described in Experimental Example 4. From Figure 23, when the fibers were immersed in the dissolution solution, a viscous layer developed at the fiber-fluid interface. The layer grew inward and outward over time and expanded in the fibers. The expansion of the fibers was anisotropic. The fibers expanded radially, but the axial expansion was essentially negligible.

[0314] Figure 24a is a plot of normalized radial expansion ΔR / R0 against time t, where ΔR / R0 steadily increased with time at a gradually decreasing rate. Furthermore, this increased as the initial fiber radius R0 decreased. A fiber with an initial radius of 73 μm (fiber B) expanded to 2.62 times its initial radius after 3 minutes. The same normalized expansion was achieved after approximately 15-20 minutes for a fiber with an initial radius of 309 μm (fiber C).

[0315] Figure 24b shows the t of △R / R0. 1 / 2 This is a plot against / R0. The data was not entirely independent of the fiber radius. Nevertheless, for all fibers, t of △R / R0 1 / 2 The approximate correlation with / R0 is:

number

[0316] Combining equation (28) with the model of equation (11a), the diffusion rate of the dissolution in the fiber is:

number

[0317] Therefore, thin fibers expand rapidly due to the diffusion of water into them. Excipients do not substantially stop the diffusion of water.

[0318] (Example 9) Drug release via fibers B and C Drug release by single fibers B and C was determined using the conditions and equipment described in Experimental Examples 5 and 6.

[0319] Figure 25a shows the percentage of drug released into the dispersion medium. d This is a plot of / M0 against time t. For all fibers, the drug was released steadily at a gradually decreasing rate. Time t until 80 percent of the initial drug content was released. 0.8 The time interval increased with increasing fiber radius, rising from 2.7 minutes for R0=73 μm to 24.5 minutes for R0=309 μm (Table 2).

[0320] Furthermore, as shown in Figure 25b, the proportion of drug released by the fiber was proportional to the square root of time and the reciprocal of the fiber radius. Therefore,

number

[0321] Combining equations (25) and (30), the diffusion rate of the drug in the fiber is:

number

[0322] Therefore, when water enters the thin fibers, the drug diffuses from the gelled fibers into the solution. Due to the thinness of the fibers, the drug is released rapidly.

[0323] (Example 10) Scanning electron microscope images of drug dosage forms B and C Scanning electron microscope images of drug-dosing types B and C were obtained using the equipment and conditions described in Experimental Example 4. From Figures 26a and 26b, the fiber radius R0 and interfiber distance λ0 in the microstructure of drug-dosing type B were 71 μm and 456 μm, respectively. Furthermore, from Figures 26c and 26d, the fiber radius R0 was 315 μm and the interfiber distance λ0 was 1466 μm in the microstructure of drug-dosing type C, as shown in Table 2. The microstructure parameters measured in the solid-dosing types were approximately 0.52 to 0.72 times the nominal values ​​(Tables 1 and 2).

[0324] (Example 11) Expansion and decomposition of drug dosage forms B and C Images of the decomposed drug formulations B and C were obtained using the equipment and conditions described in Experimental Example 5.

[0325] Figures 27a and 27b show top views of drug formulations B and C after immersion in the dissolution. In this case as well, the fluid penetrates the void almost immediately after immersion. Next, the solid drug formulations transformed into viscous masses, simultaneously expanding uniformly in all directions. The viscous masses gradually disintegrated in the dissolution, and thus their geometric shape was roughly preserved for longer than one hour. However, eventually, the viscous masses disappeared, and the drug formulations dissolved.

[0326] Figure 28a plots the normalized longitudinal expansion △L / L0 against time t. For all drug formulations, △L / L0 increased with time at a gradually decreasing rate. The ratio L of the length of the drug formulation at 15 minutes to the initial length. 15 / L0 is listed in Table 2. 15 / L0 increased as the fiber radius decreased, rising from 1.12 for R0=315μm (drug dosage type C) to 2.06 for R0=71μm (drug dosage type B).

[0327] Therefore, with the expansion rate of the drug formulation (drug formulation B) with an initial fiber radius of 71 μm, the diameter of a 9.7 mm diameter disc increases to 20 mm in just 15 minutes after immersion. This expansion rate is expected to be fast enough to ensure the drug formulation is easily swallowed and to prevent the viscous medium from passing too quickly through the intestines.

[0328] Figure 28b shows the t of △L / L0. 1 / 2 This is a plot for / R0. △L / L0 is initially t 1 / 2 A curve proportional to / R0, with the following form:

number

[0329] Passing through the linear region, t of △L / L0 1 / 2 The curve for / R0 reached equilibrium at a nearly constant value. The curve reached equilibrium as soon as the drug delivery form was converted to a uniform viscous mass. The "final" ΔL / L0 value was between 0.52 and 1.3 for the presented drug delivery forms (delivery forms B and C). The curve reaches equilibrium because the diffusion of water into the thick viscous mass is considerably slower than the diffusion of the fibrous drug delivery form into the thin fibers, thus greatly reducing the expansion rate of the viscous mass (for example, the expansion rate of the drug-containing solid during the transition to the viscous mass is considerably greater than the expansion rate of the uniform or nearly uniform viscous mass). [Table 2]

[0330] (Example 12) Drug release by drug delivery forms B and C The drug release for drug formulations B and C was determined using the conditions and equipment described in Experimental Examples 5 and 6.

[0331] Figure 29a shows the percentage of drug released by the fibrous drug delivery form over time. In all cases, the curve steadily increased with time, but with a decreasing slope. Time t to release 80 percent of the drug content 0.8 As shown in Table 2, the response time ranged from 110 minutes (R0=71 μm, drug dosage type B) to 502 minutes (R0=315 μm, drug dosage type C). This is approximately 20 to 41 times longer than the values ​​for the corresponding single fibers.

[0332] Figure 29b is a plot of the rate of drug release against the square root of time. The curve is essentially linear and takes the following form:

number

[0333] Combining equations (24) and (33), the diffusion rate of the drug through the viscous mass is:

number

[0334] The estimated diffusion rate in a viscous mass is the degree of diffusion of small drug molecules in water. Furthermore, the drug diffusion rate through a viscous mass increases as the fiber radius decreases, the expansion rate is more rapid, and the volume fraction of water in the viscous mass is larger. Thus, drug release and expansion rate are linked: drug formulations with thin, small-radius fibers expand and release the drug more rapidly than drug formulations with larger-radius fibers.

[0335] Nevertheless, because the diffusion length of drug molecules varies from the fiber radius to the thickness of the viscous mass, the drug release rate depending on the drug delivery form is considerably slower than the release rate due to single fibers.

[0336] As a result, as shown in Figure 30, drug delivery form B in thin fibers rapidly expands due to the diffusion of the solution into the thin fibers and its transfer to a viscous mass. The drug is then slowly released by the diffusion of drug molecules through the thick, expanded viscous mass.

[0337] Therefore, drug formulation B satisfies a pair of functional requirements for a gastrointestinal-retaining, sustained-release drug formulation, namely rapid formulation expansion and sustained drug release.

[0338] (Example 13) Viscosity of viscous media and solutions (a) Water and HPMC with a molecular weight of 10 kg / mol The shear viscosity of water containing HPMC with a molecular weight of 10 kg / mol was determined using a shear rheometer (TA Instruments, ARG2 Rheometer, stress-controlled) equipped with a 60 mm diameter cone with an apex angle of 178°. The concentrations of the excipient (HPMC with a molecular weight of 10 kg / mol) in the analyzed viscous solutions were 1, 2, 5, 10, and 20 wt%. The temperature during the experiment was 37°C, and the shear strain rate ranged from 1 to 100 / s.

[0339] Figure 31 shows various weight fractions f of excipients. e Shear viscosity μ s The following is presented. Figure 31a shows viscosity as a function of shear rate in the range of 1 to 100 / s, and Figure 31b shows f at a shear rate of 1 / s. e μ s This shows that in the dilution region described herein, where the weight fraction of the excipient is smaller than the weight fraction that is loosened, the viscosity is given by Einstein's viscosity formula μ. s =0.253f e The equation followed the form of +0.001 Pa·s. In the semi-dilution region, μ s =2089f e 4.21 The dilution and semi-dilution regions are the weight fraction f that is unraveled. e * Separation was performed by =0.062. Therefore, the concentration c of the excipient was determined. e * It is approximately 70 mg / ml.

[0340] (b) Water and HPMC with a molecular weight of 120 kg / mol The shear viscosity of water containing HPMC with a molecular weight of 120 kg / mol was determined using the same shear rheometer. The rheometer was equipped with either a 60 mm diameter cone with an apex angle of 178° (for measuring the viscosity of mixtures with an excipient weight fraction less than 0.1) or a 20 mm diameter cone with an apex angle of 176° (for measuring the viscosity of mixtures with an excipient weight fraction greater than 0.1). The tested solution consisted of water and HPMC excipient (molecular weight = 120 kg / mol), with an excipient weight fraction f e is 5 x 10 -4 The values ​​were in the range of ~0.5. The temperature was 37°C during the experiment.

[0341] When the weight fraction of the excipient was 0.3 or less, the sample flowed like a fluid between the rotating cone and the plate. However, when the weight fraction of the excipient was 0.5, the solution behaved essentially like a solid block; the rotating cone rotated on the surface of the sample, but the sample did not deform.

[0342] Figure 32 shows 5 × 10 -4 ≤f e Excipient weight fraction f at a shear rate of 1 / s in the range of ≤0.3 e Shear viscosity μ s The results are presented. Two regions could be identified: a dilution region and a semi-dilution region. In the dilution region, viscosity is given by Einstein's viscosity formula: μ s =0.001+9.95f e In accordance with Pa·s, in the semi-dilution region, which is described as the region where the weight fraction of the excipient is greater than the weight fraction that is loosened but less than the semi-dilution / solid boundary, μ s =10 6 f e 2.79 The dilution and semi-dilution regions are the weight fraction f that is unraveled. e * = 1.67 × 10 -3 It was bounded by this. Therefore, the concentration c of the excipient's disintegration e * It is approximately 1.67 mg / ml. The concentration of the excipient in water after dissolving is c. w * It is approximately 998 mg / ml.

[0343] Since the sample essentially behaved like a solid block when the excipient weight fraction was 0.5, this weight fraction may be used as the semi-dilution / solid boundary in this specification. Excipient concentration c at the semi-dilution / solid boundary e ** It is approximately 500 mg / ml. Water concentration c at the semi-dilution / solid boundary. w ** It is approximately 500 mg / ml.

[0344] Application Examples In some embodiments, the amount of the active ingredient contained in the drug formulation disclosed herein is appropriate for administration in a treatment regimen that has a statistically significant probability of achieving a predetermined therapeutic effect when administered to the relevant population. (As a non-exclusive example, the active ingredient may be selected from the group consisting of acetaminophen, aspirin, caffeine, ibuprofen, analgesics, anti-inflammatory agents, anthelmintics, antiarrhythmics, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antihistamines, antihypertensives, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics and sedatives, beta-adrenergic receptor blockers, cardiotropic agents, corticosteroids, antitussives, diuretics, dopamine agonists, immunosuppressants, lipid regulators, muscle relaxants, parasympathomimetic agents, parathyroid agents, calcitonin and biphosphonates, prostaglandins, radiopharmaceuticals, antiallergic agents, sympathomimetic agents, thyroid agents, PDE IV inhibitors, CSBP / RK / p38 inhibitors, or vasodilators.)

[0345] The drug formulations disclosed herein have predictable microstructures and drug release behaviors. They allow for a wider range and improved control of drug delivery rates into the bloodstream. While useful for improving almost any drug therapy, the drug formulations disclosed herein are particularly beneficial for increasing the delivery rate of drugs that are poorly soluble (e.g., poorly soluble) in digestive fluids. For this reason, in some embodiments, at least one active pharmaceutical ingredient contains a solubility of 5 g / l or less in physiological fluids / body fluids under physiological conditions. This includes, but is not limited to, at least one active ingredient having a solubility of 2 g / l or less, or 1 g / l or less, or 0.5 g / l or less, or 0.2 g / l or less, or 0.1 g / l or less in physiological fluids / body fluids under physiological conditions.

[0346] Furthermore, the drug delivery methods of this disclosure may be particularly useful for delivering drugs that are more soluble in acidic solutions (e.g., stomach or duodenum) than in basic solutions (e.g., intestine or large intestine).

[0347] Therefore, in some embodiments, at least one active pharmaceutical component has pH-dependent solubility in physiological fluids or body fluids.

[0348] Furthermore, in some embodiments, at least one active pharmaceutical ingredient has a solubility at least five times greater in an acidic solution than in a basic solution. This includes, but is not limited to, at least one active ingredient having a solubility at least ten times, or at least fifteen times, or at least twenty times, or at least thirty times, or at least fifty times greater in an acidic solution than in a basic solution. In the present invention as herein, a solution is understood to be "acidic" if its pH value is 5.5 or less. A solution is understood to be "basic" if its pH value is greater than 5.5.

[0349] Furthermore, in some embodiments, at least one pharmacokinetic component is a basic compound. In the present invention as herein, a compound is understood to be "basic" if its acid dissociation constant (e.g., pKa value) is greater than about 5.5.

[0350] Finally, the drug formulations of this disclosure can be manufactured by economic processes that enable more personalized medicines. In certain embodiments, for example, the following items are provided: (Item 1) A pharmaceutical dosing form comprising a drug-containing solid having an external surface and an internal three-dimensional structural framework of one or more thin structural elements, wherein the framework is adjacent to and terminates at the external surface; The thin structural element comprises at least one pharmacokinetic component, at least one absorbent polymer excipient, and at least one hydrophilic surface composition; The thin structural element further has sections spatially separated from adjacent sections, thereby defining empty spaces, and a plurality of adjacent empty spaces connect across the drug-containing solid to define one or more interconnected empty spaces that form an open network structure; A pharmaceutical dosing form wherein, when immersed in a physiological fluid, the perforated network structure allows for uniform wetting of the structural framework and transfer of the drug-containing solid to a viscous medium, thereby expanding in all dimensions. (Item 2) The drug delivery form according to item 1, wherein, when immersed in a physiological fluid, the drug-containing solid dissolves or decomposes in the physiological fluid. (Item 3) The drug delivery form according to item 2, wherein the drug-containing solid dissolves or decomposes during or after transfer to a viscous medium. (Item 4) The drug delivery form according to item 1, wherein the drug-containing solid expands due to the permeation of a physiological fluid or bodily fluid into the three-dimensional structural framework of one or more elements. (Item 5) The drug delivery form according to item 1, wherein the drug-containing solid expands upon permeation of physiological fluids or body fluids into an absorbent polymer excipient. (Item 6) The drug delivery form according to item 1, wherein at least one dimension of the drug-containing solid expands to at least 1.12 times its initial length during the transfer to a viscous medium. (Item 7) The drug delivery form according to item 1, wherein the drug-containing solid expands to at least 1.4 times its initial volume during the transfer to a viscous medium. (Item 8) The drug delivery form according to item 1, wherein at least one dimension of the drug-containing solid expands to at least 1.12 times its original length within 20 minutes of immersion in a physiological fluid or body fluid. (Item 9) The drug-containing solid according to item 1, wherein the solid expands to at least 1.4 times its initial volume within 20 minutes of being immersed in a physiological fluid or body fluid. (Item 10) The drug delivery form according to item 1, wherein the drug-containing solid expands isotropically during the transfer to a viscous medium. (Item 11) The drug delivery form according to item 1, wherein the geometric similarity of the three-dimensional structural framework of the element is preserved when it expands and transfers to a fluid or viscous medium. (Item 12) The drug delivery form according to item 1, wherein at least one structural element expands isotropically during the transfer to a fluid or viscous medium. (Item 13) The drug delivery form described in item 1, wherein 80 percent of the drug content in the drug-containing solid is released within 45 minutes after immersion in a physiological fluid or body fluid. (Item 14) The drug delivery form according to item 1, wherein one or more of the elements expand substantially anisotropically, thereby causing the drug-containing solid to transform into a viscous mass having a viscosity at least three orders of magnitude greater than the viscosity of the dissolving solution. (Item 15) The drug delivery form according to item 1, wherein 80 percent of the drug content in the drug-containing solid is released over a period of time between 30 minutes and 48 hours (for example, between 30 minutes and 24 hours). (Item 16) The drug delivery type described in item 1, wherein one or more of the elements include an average thickness of 2.5 mm or less (for example, 1 mm or less, or in the range of 1 μm to 1 mm, 5 μm to 1 mm, or 10 μm to 1 mm). (Item 17) The drug administration type described in item 1, wherein the effective space spacing between the sections that cross the one or more empty spaces is greater than 1 μm on average (for example, greater than 5 μm, greater than 10 μm, or in the range of 1 μm to 2 mm, 10 μm to 2 mm, or 20 μm to 2 mm). (Item 18) The drug delivery form according to item 1, wherein the position of at least one element or at least one segment in the three-dimensional structural framework of one or more elements is precisely controlled. (Item 19) The drug formulation according to item 1, wherein the volume fraction of elements or sections having precisely controlled positions in the three-dimensional structural framework of one or more elements is greater than 0.3. (Item 20) The drug delivery form according to item 1, wherein the three-dimensional structural framework of one or more elements includes a regular structure. (Item 21) The drug delivery type described in item 1, in which the effective clearance spacing and element thickness are precisely controlled. (Item 22) The drug delivery type according to item 1, wherein the three-dimensional structural framework of one or more thin structural elements comprises a plurality of layers of elements or sections. (Item 23) The drug formulation described in item 1, wherein at least one element is a fiber. (Item 24) The drug delivery type described in item 1, wherein fiber plies or fiber sections are stacked in a cross-ply arrangement to form a three-dimensional structural framework. (Item 25) The drug delivery type according to item 1, wherein the three-dimensional structural skeleton of one or more thin structural elements comprises a plurality of cross-patterned laminations of fibrous structural elements. (Item 26) The dosage form according to item 24 or item 25, wherein the spacing between adjacent fibers or between adjacent fiber sections in a layer or ply is uniform or equally spaced. (Item 27) The medication form described in item 1, wherein at least one element is a sheet. (Item 28) The drug delivery form described in item 1, wherein at least one element is a bead. (Item 29) The drug delivery form according to item 1, wherein the surface of at least one element or the surface of at least one section includes a coating. (Item 30) The drug delivery form according to item 1, wherein the coating comprises a highly hydrophilic surface composition to enhance the wetting rate of the structural framework or the penetration rate of fluid into the perforated network structure. (Item 31) The dosage form according to item 1, wherein at least one highly hydrophilic coating composition is selected from the group comprising polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone, silicon dioxide, talc, magnesium stearate, mannitol, xylitol, maltitol, erythritol, sucrose, glucose, isomalt, maltodextrin, or lactitol. (Item 32) The drug delivery form according to item 1, wherein the spacing between compartments and the composition of the surface of one or more elements are such that the penetration time of physiological fluids / body fluids into one or more interconnected spaces of the drug-containing solid is less than 200 seconds under physiological conditions. (Item 33) The drug delivery form according to item 1, wherein the rate of permeation of physiological fluids / body fluids into the element or absorbent excipient under physiological conditions is greater than the average value of the element's thickness divided by 3600 seconds. (Item 34) The effective diffusion rate of physiological fluids / body fluids in an element or absorbent excipient is 1 × 10⁻⁶ under physiological conditions. -12 m 2 Drug administration forms greater than / s, as described in item 1. (Item 35) The dosage form described in item 1, wherein at least one absorbent polymer excipient is selected from the group comprising hydroxypropyl methylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose succinate acetate, sodium alginate, hydroxypropylcellulose, methylcellulose, hydroxypropyl methyl ethercellulose, starch, chitosan, pectin, polymethacrylate (e.g., poly(methacrylic acid, ethyl acrylate) 1:1, or butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer), polyacrylic acid, or vinylpyrrolidone-vinyl acetate copolymer. (Item 36) The drug delivery form according to item 1, wherein at least one absorbent polymer excipient comprises multiple individual chains that are unraveled when immersed in a physiological fluid. (Item 37) The dosage form described in item 1, wherein the molecular weight of at least one absorbent polymer excipient is greater than 2 kg / mol (e.g., greater than 5 kg / mol, or greater than 10 kg / mol, or greater than 20 kg / mol, or greater than 50 kg / mol). (Item 38) The dosage form described in item 1, wherein the molecular weight of at least one absorbent polymer excipient is between 2 kg / mol and 500 kg / mol (e.g., in the range of 5-500 kg / mol, 10-500 kg / mol, 2-200 kg / mol, 5-200 kg / mol, 2-50 kg / mol, or 2-100 kg / mol). (Item 39) The dosage form according to item 1, wherein the weight fraction of the absorbable polymer excipient in the three-dimensional structural skeleton of one or more elements is greater than 0.1 (e.g., greater than 0.15, or greater than 0.2, or greater than 0.25). (Item 40) The drug delivery form described in item 1, wherein drug molecules or drug particles are embedded in a matrix containing an absorbent polymer excipient. (Item 41) The dosage form described in item 1, wherein at least one active pharmaceutical ingredient has a solubility of 5 g / l or less (e.g., 2 g / l or less, or 1 g / l or less, or 0.5 g / l or less, or 0.2 g / l or less, or 0.1 g / l or less) in physiological fluids or body fluids under physiological conditions. (Item 42) The dosage form described in item 1, wherein at least one active pharmaceutical ingredient has pH-dependent solubility in physiological fluids or body fluids. (Item 43) The drug formulation according to item 42, wherein at least one active pharmaceutical ingredient has at least five times (e.g., at least ten times) higher solubility in an acidic solution than in a basic solution. (Item 44) The dosage form described in item 42, wherein at least one active pharmaceutical ingredient is a basic compound. (Item 45) The dosage form described in item 1 or any other item, wherein the tensile strength of the three-dimensional structural framework of one or more elements is between 0.01 MPa and 100 MPa (this includes, but is not limited to, the tensile strength of at least one element greater than 0.02 MPa, or greater than 0.05 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa, or greater than 0.5 MPa, or greater than 1 MPa, or greater than 1.5 MPa, or greater than 2 MPa, or greater than 3 MPa, or greater than 5 MPa). (Item 46) The drug delivery type according to item 1, wherein fewer than five walls must be broken in order to obtain a cluster in which empty spaces are interconnected from the external surface of the drug-containing solid to any point in the internal structure. (Item 47) The drug delivery form according to item 1, wherein at least one empty space is surrounded by a wall to form a closed cell, and fewer than five walls must be broken to obtain a cluster in which the empty spaces are interconnected from the outer surface of the drug-containing solid to any point in the internal structure. (Item 48) The drug delivery type described in item 1, wherein the average length, average width, and average thickness of the three-dimensional structural skeleton of the drug-containing solid or element are greater than 0.5 mm (for example, greater than 1 mm, or greater than 1.5 mm, or greater than 2 mm, or in the range of 1 mm to 30 mm, 1.5 mm to 30 mm, or 2 mm to 30 mm). (Item 49) A pharmaceutical dosing form comprising a drug-containing solid having an external surface and an internal three-dimensional structural framework of one or more thin structural elements, wherein the framework is adjacent to and terminates at the external surface; The thin structural element comprises at least one pharmacokinetic component, at least one absorbent polymer excipient, and at least one hydrophilic surface composition; The thin structural element further has sections spatially separated from adjacent sections, thereby defining empty spaces, and a plurality of adjacent empty spaces connect across the drug-containing solid to define one or more interconnected empty spaces that form an open network structure; A pharmaceutical dosing form wherein, when immersed in a physiological fluid, the perforated network structure allows for uniform wetting of the structural framework and transfer of the drug-containing solid to a viscous medium, thereby expanding in all dimensions, and during or after the transfer to the viscous medium, the drug-containing solid dissolves or decomposes in the physiological fluid. (Item 50) A drug-containing solid having an external surface and an internal three-dimensional structural skeleton comprising a plurality of cross-shaped layers of fibrous structural elements, wherein the skeleton is adjacent to and terminates at the external surface. A pharmaceutical dosing form that includes; The fibrous structural element comprises at least one pharmaceutically active ingredient, at least one polymer excipient, and at least one hydrophilic surface composition; The fibrous structural element further has a section spatially separated from similar sections of adjacent fibrous elements, thereby defining an empty space, and defining one or more interconnected empty spaces in which multiple adjacent empty spaces in a continuous layer are joined to form an open network structure; As a result, the perforated network structure is uniformly moistened by physiological fluids; and A pharmaceutical dosage form that allows the drug-containing solid to transfer to a viscous medium when immersed in a physiological fluid, thereby expanding in length and volume. (Item 51) A drug-containing solid having an external surface and an internal three-dimensional structural skeleton comprising a plurality of cross-shaped layers of fibrous structural elements, wherein the skeleton is adjacent to and terminates at the external surface. A pharmaceutical dosing form that includes; The fibrous structural element comprises at least one pharmaceutically active ingredient, at least one polymer excipient, and at least one hydrophilic surface composition; The fibrous structural element further has a section spatially separated from similar sections of adjacent fibrous elements, thereby defining an empty space, and a plurality of adjacent empty spaces in a continuous layer are joined together to define one or more interconnected empty spaces that form an open network structure; A pharmaceutical dosing form wherein, when immersed in a physiological fluid, the perforated network structure allows for uniform wetting of the structural framework and transfer of the drug-containing solid to a viscous medium, thereby expanding in all dimensions. (Item 52) A method for manufacturing a pharmaceutical dosage form, A step of injecting at least one active ingredient and at least one absorbent polymer excipient into an extrusion channel having a cross-section that extends along its length inside the housing; A step of heating one or more injected granular solids to form a plasticizing matrix, or a step of injecting a solvent to solvate at least one injected granular solid so that one or more injected granular solids form a plasticizing matrix; A step of transporting the plasticizing matrix toward the exit of the extrusion channel by applying a mechanical action to the plasticizing matrix; The steps of extruding the plasticizing matrix from the exit to form at least one plasticizing fiber; and Steps include structuring at least one plasticized fiber into a three-dimensional structural framework of one or more drug-containing fibers. Includes, A method wherein, when immersed in a physiological fluid, the three-dimensional structural framework is uniformly moistened and transferred to a viscous medium, thereby expanding in all dimensions. (Item 53) The method according to item 52, wherein the step of structuring at least one plasticized fiber into a three-dimensional network structure of one or more drug-containing fibers is carried out by 3D pattern formation on a substrate of the at least one plasticized fiber. (Item 54) The method according to item 52, wherein the three-dimensional structural skeleton of one or more drug-containing fibers comprises a plurality of cross-shaped laminations of fibrous structural elements. (Item 55) Apparatus for manufacturing pharmaceutical solid-dosage forms, An internal hollow housing having an internal surface that encloses and defines an extrusion channel having a first end, a second end, and a cross section extending axially along its length from the first end to the second end and ending at the exit of the second end, the internal hollow housing having at least a first supply port for injecting at least one solid component into the extrusion channel between the first end and the second end, and at least a second supply port for injecting at least one solvent into the extrusion channel between the first supply port and the exit to solvate the at least one injected solid component and form a plasticizing matrix; At least one transport element for extruding the plasticizing matrix from the exit of the extrusion channel to form at least one plasticizing fiber; and Fiber structuring unit for structuring one or more plasticizable fibers into a three-dimensional network structure of one or more drug-containing fibers A device that, when immersed in a physiological fluid, uniformly wets the three-dimensional structural framework, transforms into a viscous medium, and thereby expands in all dimensions. (Item 56) The apparatus according to item 55, wherein the fiber structuring unit includes a translational or rotational stage. (Item 57) The apparatus according to item 56, wherein the one or more plasticizable fibers are structured into a three-dimensional network structure of one or more drug-containing fibers by 3D patterning the one or more plasticizable fibers on a substrate defined by or attached to a translational or rotational stage. (Item 58) The apparatus according to item 55, wherein the three-dimensional structural skeleton of one or more drug-containing fibers comprises a plurality of cross-shaped laminations of fiber-like structural elements. (Item 59) Apparatus for manufacturing pharmaceutical solid-dosage forms, An internal hollow housing having an internal surface that encloses and defines an extrusion channel having a first end, a second end, and a cross section extending axially along its length from the first end to the second end and terminating at the exit of the second end, the internal hollow housing having at least a first supply port between the first end and the second end for injecting at least one solid component into the extrusion channel; A heating element for fluidizing at least one injected solid component, so that one or more injected solid components form a plasticizing matrix in the extrusion channel; At least one transport element for extruding the plasticizing matrix from the exit of the extrusion channel to form at least one plasticizing fiber; and Fiber structuring unit for structuring one or more plasticizable fibers into a three-dimensional network structure of one or more drug-containing fibers A device that, when immersed in a physiological fluid, uniformly wets the three-dimensional structural framework, transforms into a viscous medium, and thereby expands in all dimensions. (Item 60) The apparatus according to item 59, wherein the fiber structuring unit includes a translational or rotational stage. (Item 61) The apparatus according to item 60, wherein the one or more plasticizable fibers are structured into a three-dimensional network structure of one or more drug-containing fibers by 3D patterning the one or more plasticizable fibers on a substrate defined or mounted by a translational or rotational stage. (Item 62) The apparatus according to item 59, wherein the three-dimensional structural skeleton of one or more drug-containing fibers comprises a plurality of cross-shaped laminations of fiber-like structural elements.

Claims

1. A pharmaceutical dosing form for oral administration comprising a drug-containing solid having an internal three-dimensional network structure of one or more fibers, wherein the one or more fibers are stacked in a substantially regular cross-ply structure; The one or more of the aforementioned fibers have an average thickness in the range of 5 μm to 2.5 mm; The one or more fibers comprise the drug and at least one body fluid-absorbing polymer excipient comprising hydroxypropyl methylcellulose having a molecular weight greater than 20 kg / mol, and at least one of the one or more fibers has a substantially hydrophilic surface; As a result, when the pharmaceutical drug form is immersed in the bodily fluid, the three-dimensional network structure of one or more fibers is substantially uniformly moistened by the bodily fluid, and as a result, the drug-containing solid transforms into a viscous mass or viscous medium, thereby expanding in all dimensions. A pharmaceutical administration method wherein the time it takes for the drug-containing solid, viscous mass, or viscous medium to release the drug into the body fluid, releasing 80 percent of the drug content in the drug-containing solid, is longer than 50 minutes.

2. The drug delivery form according to claim 1, wherein when immersed in the body fluid, the drug-containing solid dissolves or decomposes in the body fluid.

3. The drug delivery form according to claim 1, wherein the drug-containing solid dissolves or decomposes during or after the transformation into a viscous mass or viscous medium.

4. The drug delivery method according to claim 1, wherein the drug-containing solid expands upon permeation of bodily fluids into the three-dimensional network structure of one or more fibers.

5. The drug delivery method according to claim 1, wherein the drug-containing solid expands upon permeation of body fluids into the at least one absorbent polymer excipient.

6. The drug delivery form according to claim 1, wherein at least one dimension of the drug-containing solid expands to at least 1.12 times its initial length during the transformation into a viscous mass or viscous medium.

7. The drug delivery form according to claim 1, wherein the drug-containing solid expands to at least 1.4 times its initial volume during the transformation into a viscous mass or viscous medium.

8. The drug delivery method according to claim 1, wherein at least one dimension of the drug-containing solid expands to at least 1.12 times its initial length within 30 minutes of immersion in the body fluid.

9. The drug delivery method according to claim 1, wherein the viscous mass or viscous medium has a viscosity at least three orders of magnitude greater than the viscosity of the body fluid.

10. The drug delivery method according to claim 1, wherein 80 percent of the drug content in the drug-containing solid is released over a period of time between 50 minutes and 48 hours.

11. The drug delivery type according to claim 1, wherein the effective space spacing between one or more fibers is greater than 1 μm on average.

12. The drug delivery type according to claim 1, wherein the three-dimensional network structure of one or more fibers includes a regular structure.

13. The drug delivery type according to claim 1, wherein the spacing between adjacent fibers in a layer or ply is uniform or equally spaced.

14. The drug delivery type according to claim 1, wherein the surface of at least one fiber includes a coating.

15. The drug delivery form according to claim 1, wherein the spacing between one or more fibers and the hydrophilic surface of the one or more fibers allow the penetration time of body fluids into one or more interconnected spaces of the drug-containing solid to be less than 200 seconds under physiological conditions.

16. The drug delivery type according to claim 1, wherein the rate of permeation of the body fluid into the fiber or absorbent polymer excipient under physiological conditions is greater than the average value of the fiber thickness divided by 3600 seconds.

17. The drug delivery form according to claim 1, wherein at least one absorbent polymer excipient comprises a plurality of individual polymer chains that are unraveled when immersed in a body fluid.

18. The drug delivery type according to claim 1, wherein the weight fraction of the absorbent polymer excipient in the three-dimensional network structure of one or more fibers is greater than 0.

1.

19. The drug delivery form according to claim 1, wherein drug molecules or drug particles are embedded in a matrix containing an absorbent polymer excipient.

20. The drug delivery form according to claim 1, wherein at least one drug has a solubility of 5 g / l or less in body fluids under physiological conditions.

21. The drug delivery form according to claim 1, wherein at least one drug has pH-dependent solubility in body fluids.

22. The drug delivery form according to claim 21, wherein at least one drug has at least five times higher solubility in an acidic solution than in a basic solution.

23. The drug delivery form according to claim 21, wherein at least one drug is a basic compound.

24. The drug delivery type according to claim 1, wherein the average length, average width, and average thickness of the three-dimensional network structure of the drug-containing solid or one or more fibers are greater than 0.5 mm.

25. A pharmaceutical dosing form for oral administration comprising a drug-containing solid having an internal three-dimensional network structure of one or more fibers, wherein the one or more fibers are stacked in a substantially regular cross-ply structure; The one or more of the aforementioned fibers have an average thickness in the range of 5 μm to 2.5 mm; The one or more fibers comprise the drug and at least one body fluid-absorbing polymer excipient comprising hydroxypropyl methylcellulose having a molecular weight greater than 20 kg / mol, and at least one of the one or more fibers has a substantially hydrophilic surface; As a result, when the pharmaceutical drug form is immersed in the body fluid, the three-dimensional network structure of one or more fibers is substantially uniformly wetted by the body fluid, and as a result, the drug-containing solid transforms into a viscous mass or viscous medium, thereby expanding in all dimensions, and during or after the transformation into a viscous mass or viscous medium, the drug-containing solid dissolves or decomposes in the body fluid. A pharmaceutical administration method wherein the time it takes for the drug-containing solid, viscous mass, or viscous medium to release the drug into the body fluid, releasing 80 percent of the drug content in the drug-containing solid, is longer than 50 minutes.

26. A method for producing a pharmaceutically solid drug form for oral administration, Steps include injecting at least one drug and at least one fluid-absorbing polymer excipient, comprising hydroxypropyl methylcellulose having a molecular weight greater than 20 kg / mol, into an extrusion channel; A step of heating the injected at least one drug and at least one fluid-absorbing polymer excipient to form a plasticizing matrix, or a step of injecting a solvent to solvate the at least one fluid-absorbing polymer excipient so that the at least one drug, the at least one fluid-absorbing polymer excipient, and the solvent form a plasticizing matrix; A step of transporting the plasticizing matrix toward the exit of the extrusion channel by applying a mechanical action to the plasticizing matrix; The steps of extruding the plasticizing matrix from the outlet to form at least one drug-containing fiber; and The step of structuring at least one drug-containing fiber to form a three-dimensional structural network structure including a cross-patterned stack of one or more substantially regularly arranged drug-containing fibers. Includes, The surface of at least one of the drug-containing fibers is substantially hydrophilic; When the three-dimensional network structure of one or more drug-containing fibers is immersed in the bodily fluid, the three-dimensional network structure is substantially uniformly moistened by the bodily fluid and transforms into a viscous mass or viscous medium, thereby expanding in all dimensions. A method wherein 80 percent of the drug content in the drug-containing fibers is released within a time longer than 50 minutes from immersion of the three-dimensional network structure of one or more drug-containing fibers in the bodily fluid.

27. The method according to claim 26, wherein the step of structuring at least one drug-containing fiber into a three-dimensional network structure of one or more drug-containing fibers is carried out by 3D pattern formation on a substrate of the at least one drug-containing fiber.

28. The drug delivery type according to any one of claims 1 to 25, wherein the surface of one or more fibers is substantially hydrophilic.

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