Expanding structured dosage form

Abstract

To provide expanding structured dosage forms.SOLUTION: In this specification, a pharmaceutical dosage form comprising a three-dimensional structural framework of thin, solid elements surrounded by interconnected void space is disclosed. The elements comprise at least a drug, a water-absorptive polymeric excipient, and a hydrophilic surface composition, so that upon immersion in a dissolution fluid, the three-dimensional structural framework transitions from solid to viscous and expands in all dimensions. The disclosed dosage form enables better control of drug concentration in the blood stream, and improved therapeutic outcomes, among other advantages. In some embodiments, upon immersion in a physiological fluid the drug-containing solid dissolves or disintegrates in said physiological fluid.SELECTED DRAWING: Figure 5

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED INVETIONS This application claims priority to and benefit of U.S. Provisional Application No. 62 / 633,602, filed February 21, 2018, and U.S. Provisional Application No. 62 / 733,624, filed September 19, 2018, which are incorporated by reference in their entireties.

[0002] This application is a jointly filed application entitled “Fibrous dosage form,” filed on April 9, 2017. No. 15 / 482,776, filed April 26, 2018, entitled "Method and Apparatus for the Manufacture of Fibrous Dosage Forms," ​​which is hereby incorporated by reference in its entirety. No. 15 / 964,058, filed April 26, 2018, and commonly owned U.S. patent application Ser. No. 15 / 964,058, entitled "Dosage form comprising two-dimensional structural elements," No. 15 / 964,063, the entirety of which is incorporated herein by reference. [Background technology]

[0003] Oral delivery tablets and capsules, currently the most common pharmaceutical dosage forms, are porous solids of compressed drug and excipient particles. When ingested, digestive fluids penetrate the open pores of the dosage form, promoting its fragmentation and drug particle dissolution. The dissolved drug molecules are then absorbed by the bloodstream and distributed to disease-specific target sites in the human body.

[0004] Despite the great commercial success of compressed powders for drug delivery applications, an inherent limitation is their non-deterministic and non-interconnected porosity. As a result, the rate and extent of fluid penetration into the dosage form cannot be precisely controlled. Thus, the range and control of drug delivery rate into the bloodstream is limited.

[0005] Therefore, to overcome such limitations, in commonly owned US patent application Ser. No. 15 / 482,776, the present inventors (Blaesi and Saka) introduced fiber-like dosage forms. As shown diagrammatically in FIG. 1, these dosage forms include a solid skeleton 100, 102, 104 of drug-excipient complexes (or solid solutions) surrounded by adjacent voids 130, 132, 134 (or open spaces). When immersed in a dissolution fluid 140, 142, 144, the fluid 140, 142, 144 can penetrate the interconnected open spaces 130, 132, 134 and the solid skeleton 100, 102, 104 (e.g., water-soluble excipients) and the dissolution fluids 140, 142, 144 can interdiffuse. Two examples are given below.

[0006] In the first example, shown diagrammatically in Figure 1a, as the scaffold 100 dissolves, the dissolved molecules diffuse into the void space 130 and convect through the free flowing dissolution fluid 140. As the scaffold 100 dissolves, the drug is released. This example is typically observed for scaffolds 100 that contain water-soluble, low molecular weight excipients that form dilute, low viscosity solutions with water.

[0007] In a 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 a dissolution liquid, the scaffolds 102, 104 transition from a solid to a viscous medium 152, 154 (e.g., a viscous dispersion, a viscous solution, or a viscous mass having a higher or much higher viscosity than that of the dissolution liquid). The drug can be released either by deformation and dissolution of the viscous medium 152, as shown diagrammatically in Figure 1b, or by diffusion of the drug molecules through the viscous medium 154, as illustrated in Figure 1c.

[0008] This disclosure focuses primarily on solid dosage forms that transition to a viscous medium when immersed in a dissolution fluid. The type of solid-to-viscous transition greatly influences the rate at which a drug is delivered to the bloodstream and is therefore an important design parameter for enhancing the efficacy and reducing the side effects of drug therapy.

[0009] Design Considerations Four non-limiting types of solid-to-viscous transitions are briefly described in the following paragraphs. The explanations and any supplemental illustrations will enable those skilled in the art to more readily understand the invention presented throughout this disclosure. They are not meant to be limiting in any way.

[0010] In the first type, represented by Figure 2a, the solid dosage form 200 consists of a three-dimensional structural scaffold 202 of drug particles 210 and water-soluble and water-absorbent polymeric excipients 220. The scaffold 202 is surrounded by interconnected void spaces 230. The volume occupied by the excipients 220 in the scaffold 202 is much smaller than the volume of the void spaces 230.

[0011] Upon immersion in the dissolution liquid 240, the fluid 240 rapidly penetrates into the interconnected void spaces 230. The excipients 220 and the dissolution liquid 240 then 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 the excipient molecules 222 in the viscous medium 250 is very low. Thus, the viscosity of the viscous medium 250 is also low. As a result, the medium 250 rapidly deforms and dissolves in the dissolution liquid 240.

[0012] Moreover, as shown diagrammatically in Figure 2b, once ingested, the dosage form rapidly disintegrates in the gastric fluids, releasing the drug particles (and drug molecules), which then dissolve and simultaneously pass through the small intestine, where the dissolved drug molecules are eventually absorbed by the bloodstream.

[0013] This type of dosage form is suitable for immediate delivery of drugs with high solubility and diffusivity in the digestive tract. However, the mass of water-soluble excipients in the dosage form is very small, so the physicochemical properties of the drug (e.g., the solubility of the drug in digestive fluids, the permeability of the drug across the digestive barrier, etc.) and the drug release rate from the dosage form cannot be matched by the excipients. This limits the range of drug delivery rate to the bloodstream and the control of the drug concentration in the bloodstream.

[0014] Thus, in the second type as illustrated in FIG. 3a, the solid dosage form 300 also consists of a three-dimensional structural framework 302 of drug and water-soluble and water-absorbent polymer excipients surrounded by interconnected empty spaces 330. However, unlike the above example, the volume of the polymer excipients 320 in the dosage form 300 is much larger than the volume of the empty spaces 330 in this example. As a result, when immersed in a dissolution liquid, the dosage form 300 transitions into a viscous medium 350 of high excipient concentration and viscosity. Thus, in this example, the viscous medium 350 is a highly viscous mass that is essentially undeformable by the dissolution liquid 340, which gradually disintegrates from the outside. As a result, the content of water-soluble polymer excipients in the dosage form is higher than in the first example, and the drug release rate by the dosage form is slower. The range and control of the drug delivery rate to the bloodstream is also limited, and the efficacy and safety of the drug treatment may be compromised as described in detail below.

[0015] As a non-limiting example, as shown diagrammatically in FIG. 3b, upon ingestion, a slowly disintegrating dosage form or viscous mass passes from the stomach into the small intestine and travels down the digestive tract, thereby releasing drug. If the drug release rate is too slow, a portion of the ingested drug will be lost within the digestive tract transit time t tr In the absence of a circulating drug, the drug cannot be released or absorbed into the body and, therefore, can be excreted. As a result, the mass of drug absorbed can also be variable, since the gastrointestinal transit time is generally variable. Variability in the mass of drug absorbed (e.g., variability in bioavailability) can compromise both the efficacy and safety of drug therapy. For this reason, variability must be eliminated.

[0016] However, if the dosage form expands during the transition into the viscous medium, the compromise between rapid dosage form degradation (or dissolution) and high content of water-soluble polymer excipients can be overcome. Thus, in the third type illustrated in FIG. 4a, the volume of the polymer excipients 420 in the three-dimensional structure scaffold 402 is also larger than the volume of the empty space 430. However, unlike the above examples, the dosage form structure 402, 450 continues to expand when immersed in the dissolution liquid 440. As a result, the concentration of the excipients in the dosage form structure 402 or the viscous medium 450 is constantly reduced, eventually reaching a concentration at or below the point of disintegration. Thus, the viscosity of the "final" viscous medium 450 becomes very low, and the "final" medium 450 is rapidly deformed and dissolved in the dissolution liquid 440.

[0017] Once ingested, the dosage form may disintegrate and dissolve in the upper part of the digestive tract, as shown diagrammatically in Figure 4b. The dissolved drug molecules may then be absorbed by the bloodstream. Variability in drug delivery rate due to slow or inconsistent dissolution of the dosage form may be eliminated.

[0018] Furthermore, along with the rapid and consistent dosage form disintegration and drug release rate, the swellable dosage form can release large amounts of water-soluble functional excipients in a short period of time. Such functional excipients can enhance the delivery rate of the released drug molecules, for example, by enhancing the drug concentration or drug solubility in digestive fluids, or by enhancing the drug absorption rate into the bloodstream. Thus, the swellable dosage form allows for a higher and more consistent drug delivery rate into the bloodstream to improve the efficacy and safety of many drug treatments.

[0019] Solid dosage forms that transition into a viscous medium and thereby expand may have additional advantages. As a non-limiting example, if a solid dosage form has an initial size smaller than the esophagus (15-20 mm) to facilitate swallowing, but in the stomach it transitions into a viscous medium and thereby expands to a size significantly larger than the pylorus (about 13 mm), it will not pass from the stomach to the small intestine as long as its viscosity is high enough. Thus, the drug can be released / delivered in the upper part of the digestive tract for a long period of time without compromising drug absorption or premature drug excretion.

[0020] Thus, in the fourth type, as shown diagrammatically in Figure 5a, the structures 502, 550 also expand as the polymer excipient 520 and the dissolution medium 540 interdiffuse. Eventually, however, the pores (e.g., open spaces or void spaces) 530 close, the expansion of the viscous dosage form or vehicle 550 stops, and an expanded viscous mass 550 is formed. The viscous mass 550 is a concentrated polymer solution or dispersion, which is essentially non-deformable and gradually disintegrates or dissolves in the dissolution medium, thereby releasing the drug.

[0021] Thus, as shown diagrammatically in Figure 5b, if a dosage form or viscous medium expands rapidly after ingestion, but stops expanding as soon as it reaches a size significantly larger than the pylorus, the viscosity of the expanded medium may remain high enough to prevent passage into the small intestine. The dosage form may then be retained in the stomach for an extended period of time, delivering drug to the bloodstream at a precisely controlled rate over an extended period of time. This allows for improved control of drug concentration in the bloodstream and improved efficacy or reduced side effects of many drug treatments. Summary of the Invention [Means for solving the problem]

[0022] The above discussion suggests that a solid dosage form that swells by transitioning into viscous medium when ingested can improve the control of drug concentration in bloodstream and improve therapeutic outcome.Therefore, in one aspect, the pharmaceutical dosage 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, said framework being adjacent to and terminating at said external surface, said thin structural elements comprising at least one active pharmaceutical ingredient, at least one absorbent polymer excipient, and at least one hydrophilic surface composition, said thin structural elements further have sections that are spatially separated from adjacent sections, thereby defining void space, and a plurality of adjacent void spaces are joined across the drug-containing solid to define one or more interconnected void spaces to form an open-pore network, whereby said open-pore network allows uniform wetting of the structural framework and transition of the drug-containing solid into viscous medium, thereby expanding in all dimensions when immersed in physiological fluid.

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

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

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

[0026] In some embodiments, the drug-containing solid swells due to the permeation of physiological or bodily fluids into the 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 transition to the viscous medium.

[0028] In some embodiments, the drug-containing solid expands to at least 1.4 times its initial volume during transition 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 physiological or bodily fluid.

[0030] In some embodiments, the drug-containing solid expands to at least 1.4 times its initial volume within 20 minutes of immersion in physiological or bodily fluids.

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

[0032] In some embodiments, the geometric similarity of the three-dimensional structural scaffold of the elements is preserved upon expansion and transition into a fluidized 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 in less than 45 minutes after immersion in physiological or bodily fluids.

[0035] In some embodiments, one or more elements expand substantially anisotropically such that the drug-containing solid transitions into a viscous mass having a viscosity at least three orders of magnitude greater than the viscosity of the dissolution liquid.

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

[0037] In some embodiments, one or more elements comprise an average thickness of 2.5 mm or less (eg, 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 free space spacing between one or more over-free space sections is, on average, greater than 1 μm (e.g., greater than 5 μm, or 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 elements or sections having precisely controlled positions 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 comprises an ordered structure.

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

[0043] In some embodiments, a three-dimensional structural scaffold of one or more thin structural elements comprises multiple stacks of elements or sections.

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

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

[0046] In some embodiments, the three-dimensional structural scaffold of one or more thin structural elements comprises multiple crisscross stacks of fiber-like structural elements.

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

[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, a surface of at least one element or a surface of at least one section comprises a coating.

[0051] In some embodiments, the coating comprises a highly hydrophilic surface composition to enhance the rate of wetting of the scaffold or the rate of penetration of fluids into the open pore network.

[0052] In some embodiments, the 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 open space spacing between the 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 open 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 thickness of said element divided by 3600 seconds.

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

[0056] In some embodiments, the at least one absorbent polymer excipient is selected from the group including hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, sodium alginate, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methyl ether cellulose, 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 upon immersion in physiological fluid.

[0058] In some embodiments, the molecular weight of at least one absorbent polymer excipient is greater than 2 kg / mol (eg, 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 the 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).

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

[0061] In some embodiments, drug molecules or particles are embedded in a matrix that includes absorbent polymer excipients.

[0062] In some embodiments, at least one active pharmaceutical ingredient comprises 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).

[0063] In some embodiments, at least one active pharmaceutical ingredient comprises a pH-dependent solubility in a physiological or bodily fluid.

[0064] In some embodiments, at least one active pharmaceutical ingredient comprises at least 5-fold (eg, at least 10-fold) greater solubility in an acidic solution than in a basic solution.

[0065] In some embodiments, at least one active pharmaceutical ingredient is a basic compound.

[0066] In some embodiments, the tensile strength of the three-dimensional structural scaffold of one or more elements is between 0.01 MPa and 100 MPa (including, but not limited to, a 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, fewer than five walls must be disrupted to obtain a cluster with interconnected void space from the outer surface of the drug-containing solid to any point in the internal structure.

[0068] In some embodiments, at least one void space is surrounded by a wall to form a closed cell, and fewer than five walls must be destroyed to obtain a cluster of interconnected void spaces from the exterior surface of the drug-containing solid to any point in the internal structure.

[0069] In some embodiments, the average length, average width, and average thickness of the three-dimensional structural skeleton of the drug-containing solid or element is greater than 0.5 mm (e.g., 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 aspect, a pharmaceutical dosage form of the present disclosure comprises a drug-containing solid having an exterior surface and an internal three-dimensional structural framework of one or more thin structural elements, said framework terminating adjacent to said exterior surface, said thin structural elements comprising at least one active pharmaceutical ingredient, at least one absorbent polymer excipient, and at least one hydrophilic surface composition, said thin structural elements further having sections spatially separated from adjacent sections thereby defining void spaces, a plurality of adjacent void spaces defining one or more interconnected void spaces that join across the drug-containing solid to form an open pore network, whereby upon immersion in physiological fluid, said open pore network allows for uniform wetting of the structural framework and transition of the drug-containing solid into a viscous medium, thereby expanding in all dimensions and dissolving or degrading the drug-containing solid during or after transition into the viscous medium.

[0071] Moreover, in another aspect, a pharmaceutical dosage form comprises a drug-containing solid having an exterior surface and an internal three-dimensional structural framework comprising a plurality of crisscross stacks of fiber-like structural elements, said framework terminating adjacent to said exterior surface, said fiber-like structural elements comprising at least one active pharmaceutical ingredient, at least a polymeric excipient, and at least one hydrophilic surface composition, said fiber-like structural elements further having sections spatially separated from similar sections of adjacent fiber-like elements thereby defining void spaces, and a plurality of adjacent void spaces of successive layers defining one or more interconnected void spaces that combine to form an open pore network, whereby said open pore network allows for uniform wetting of the structural framework by physiological fluids and transition of the drug-containing solid into a viscous medium when immersed in a physiological fluid, thereby expanding in length and volume.

[0072] In yet another aspect, the dosage form of the present disclosure comprises a drug-containing solid having an exterior surface and an internal three-dimensional structural scaffold comprising a plurality of crisscross stacks of fibrous structural elements, said scaffold terminating adjacent to said exterior surface, said fibrous structural elements comprising at least one active pharmaceutical ingredient, at least a polymeric excipient, and at least one hydrophilic surface composition, said fibrous structural elements further having sections spatially separated from similar sections of adjacent fibrous elements thereby defining void spaces, wherein a plurality of adjacent void spaces of successive layers define one or more interconnected void spaces that combine to form an open pore network, whereby upon immersion in a physiological fluid, said open pore network allows for uniform wetting of the structural scaffold and transition of the drug-containing solid into a viscous medium thereby expanding in all dimensions.

[0073] A non-limiting method of manufacturing the dosage form 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 the at least one injected granular solid, such that the one or more injected granular solids form a plasticized matrix; conveying the plasticized matrix toward an outlet of the extrusion channel by applying a mechanical action to the plasticized matrix; extruding the plasticized matrix from the outlet to form at least one plasticized fiber; and structuring the at least one plasticized fiber into a three-dimensional structural framework of one or more drug-containing fibers, which upon immersion in a physiological fluid is uniformly wetted and transitions to a viscous medium, thereby expanding in all dimensions.

[0074] Another non-limiting method of manufacturing the dosage form 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 the housing, where at least one excipient melts when heated; heating the injected one or more active ingredients and one or more excipients to form a plasticized matrix; conveying the plasticized matrix toward an outlet of the extrusion channel by applying a mechanical action to the plasticized matrix; extruding the plasticized matrix from the outlet to form at least one plasticized fiber; and structuring the at least one plasticized 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 structured network of one or more drug-containing fibers is performed by 3D patterning of said at least one plasticized fiber on a substrate.

[0076] In some embodiments, the three-dimensional structural scaffold of the drug-containing fiber or fibers comprises multiple crisscross stacks of fiber-like structural elements.

[0077] Moreover, a non-limiting apparatus for producing the dosage forms of the present disclosure includes an interior hollow housing having an interior surface enclosing and defining an extrusion channel having a first end, a second end, and a cross-section extending axially along its length from said first end to said second end and terminating at an outlet at the second end, at least a first feed inlet for injecting at least one solid component into the extrusion channel between the first end and the second end, and at least one solvent for injecting at least one injected solid component into the extrusion channel between the first feed inlet and the outlet. the extrusion channel includes an inner hollow housing having at least one first feed port for forming a plasticized matrix by solvating the components; at least one conveying element for extruding the plasticized matrix in the extrusion channel through an outlet to form at least one plasticized fiber; and a fiber structuring unit for structuring the one or more plasticized fibers into a three-dimensional structured network of one or more drug-containing fibers, wherein when immersed in a physiological fluid, the three-dimensional structured scaffold is uniformly wetted and transitions into a viscous medium, thereby expanding in all dimensions.

[0078] Another non-limiting apparatus for manufacturing the dosage form of the present disclosure includes an internal hollow housing having an interior surface enclosing and defining an extrusion channel having a first end, a second end, and a cross-section extending axially along its length from said first end to said second end and terminating in an outlet at the second end, the internal hollow housing having at least a first feed inlet between the first end and the second end for injecting at least one solid component into the extrusion channel; at least one heating element for fluidizing the at least one injected solid component so that the injected solid component or components form a plasticized matrix in the extrusion channel; at least one conveying element for extruding the plasticized matrix in the extrusion channel through an outlet to form at least one plasticized fiber; and a fiber structuring unit for structuring the one or more plasticized fibers into a three-dimensional structured network of one or more drug-containing fibers, wherein when immersed in a physiological fluid, the three-dimensional structured scaffold is uniformly wetted and transitions to a viscous medium, thereby expanding in all dimensions.

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

[0080] In some embodiments, one or more plasticized fibers are structured into a three-dimensional structured network of one or more drug-containing fibers by 3D patterning said one or more plasticized fibers on a substrate defined by or attached to a translation or rotation stage.

[0081] In some embodiments, the three-dimensional structural scaffold of the drug-containing fiber or fibers comprises multiple crisscross stacks of fiber-like structural elements.

[0082] An embodiment described with respect to one aspect of the invention may be applied with respect to another aspect. By way of non-limiting example, a particular embodiment of a claim described with respect to the first aspect may include features of a claim described with respect to the second, third, fourth, fifth, sixth, or seventh aspect, and vice versa.

[0083] The invention may be better understood by referring to the attached drawings, in which attention should be paid to the fact that the drawings are primarily for illustration purposes and should not be considered as limiting.

[0084] The objects, embodiments, features and advantages of the present invention will be better understood when considered in conjunction with the accompanying drawings, in which: [Brief description of the drawings]

[0085] [Figure 1] FIG. 1 illustrates non-limiting schematic diagrams of (a) a fiber-like dosage form whose structure collapses during dissolution, (b) a fiber-like dosage form that forms a viscous medium that rapidly deforms and dissolves, and (c) a fiber-like dosage form that forms a highly viscous medium or mass that slowly dissolves.

[0086] [Diagram 2] FIG. 2 illustrates (a) a non-limiting schematic diagram of a solid dosage form comprising a three-dimensional structural framework of drug and excipients and its transformation (e.g., transition) into a viscous medium upon immersion in a dissolution fluid, and (b) the dosage form's disintegration, drug release, and drug absorption process following ingestion.

[0087] [Diagram 3] FIG. 3 provides a non-limiting schematic representation of (a) a solid dosage form comprising a three-dimensional structural scaffold of drug and excipients and its transition to a viscous medium upon immersion in a dissolution fluid, and (b) the dosage form's degradation, drug release, and drug absorption process after ingestion.

[0088] [Figure 4]FIG. 4 illustrates (a) a solid dosage form comprising a three-dimensional structural scaffold that expands upon immersion in a dissolution fluid and transitions to a viscous medium, and (b) a non-limiting schematic of the dosage form's degradation, drug release, and drug absorption process after ingestion.

[0089] [Diagram 5] FIG. 5 shows (a) a solid dosage form comprising a three-dimensional structural scaffold that expands upon transition to a viscous medium in a dissolution fluid, and (b) another non-limiting schematic of the dosage form's disintegration, drug release, and drug absorption process after ingestion.

[0090] [Figure 6] FIG. 6 presents a non-limiting example of a pharmaceutical dosage form according to the invention herein and the swelling, disintegration and drug release process when immersed in a dissolution liquid: (a) a dry dosage form and its microstructure, (b) a dosage form and its microstructure immediately after immersion in a dissolution liquid, (c) a dosage form and its microstructure during transition to a viscous medium, (d) a dosage form and its microstructure after transition to a viscous medium, (e) deformation of the viscous medium in the dissolution liquid, (f) the dissolution liquid after the dosage form dissolves, and (g) a sketch of the lateral length L of the dosage form versus time after immersion in the dissolution liquid.

[0091] [Figure 7] FIG. 7 illustrates another non-limiting pharmaceutical dosage form according to the invention herein and the swelling, disintegration, and drug release process after immersion in a dissolution fluid.

[0092] [Figure 8] FIG. 8 presents a further non-limiting pharmaceutical dosage form according to the invention herein and the swelling, disintegration, and drug release process after immersion in a dissolution fluid.

[0093] [Figure 9] FIG. 9 shows a non-limiting schematic representation of the diffusion of a dissolution fluid into a fiber and the profile of the fluid concentration in the fiber at different times.

[0094] [Figure 10] FIG. 10 depicts a non-limiting schematic diagram of an expanding dosage form scaffold according to the invention herein having (a) isotropically expanding fibers and (b) anisotropically expanding fibers.

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

[0096] [Figure 12] FIG. 12 is a non-limiting schematic illustration of drug release by diffusion of drug molecules through a viscous mass or medium.

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

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

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

[0100] [Figure 16] FIG. 16 shows diagrammatically the apparatus and methodology applied to produce experimental dosage forms according to the invention herein.

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

[0102] [Figure 18]FIG. 18 is a scanning electron micrograph of experimental single fiber A.

[0103] [Figure 19] FIG. 19 presents a series of images depicting the swelling and disintegration process of experimental dosage form A.

[0104] [Figure 20] FIG. 20 is a series of images presenting the swelling and degradation process of single fiber A.

[0105] [Figure 21] FIG. 21 shows the percentage of drug dissolved from the experimental dosage forms and single fiber A versus time after immersion in the dissolution medium.

[0106] [Figure 22] FIG. 22 presents scanning electron micrographs of experimental single fibers B and C.

[0107] [Diagram 23] FIG. 23 presents a series of images depicting the swelling and degradation process of (a) experimental fiber B and (b) experimental fiber C.

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

[0109] [Diagram 25] FIG. 25 shows the results of drug release from experimental fibers B and C: (a) fraction of dissolved drug md / M0 versus time t, and (b) md / M0 versus time t1 / 2 / R0.

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

[0111] [Figure 27] FIG. 27 depicts the swelling and disintegration process of (a) experimental dosage form B and (b) experimental dosage form C.

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

[0113] [Figure 29] FIG. 29 presents the drug release results from dosage forms B and C: (a) fraction of drug dissolved md / M0 versus time t, and (b) md / M0 versus t1 / 2.

[0114] [Diagram 30] FIG. 30 presents both the normalized longitudinal expansion ΔL / L0 and the fraction of drug dissolved md / M0 from dosage form B versus time.

[0115] [Diagram 31] FIG. 31 presents the experimental results of shear viscosity of HPMC10k aqueous solutions: (a) shear viscosity versus shear strain rate, and (b) shear viscosity at a shear strain rate of 1 / s versus the weight fraction of HPMC, fe.

[0116] [Diagram 32] FIG. 32 shows the experimental results of the shear viscosity μs of an aqueous HPMC120k solution at a shear strain rate of 1 / s versus the weight fraction f of HPMC. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0117] definition In order that this disclosure may be more readily understood, certain terms are first defined below. Additional definitions for the following terms, as well as other terms, are set forth throughout this specification.

[0118] In this application, the use of "or" means "and / or" unless otherwise stated. As used in this application, the term "comprise" and variations of terms such as "comprising" and "comprises" are not intended to exclude other additives, components, integers, or steps. As used in this application, the terms "about" and "approximately" are used as equivalents. Any numbers used in this application with or without about / approximately are meant to include any normal variations recognized by one of ordinary skill in the relevant art.

[0119] Moreover, in the present disclosure, 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 "active agent" refers to an agent whose presence or level correlates with an increase in the level or activity of a target compared to that observed in the absence of the agent (or a different level of the agent). In some embodiments, an active ingredient is an ingredient whose presence or level correlates with a target level or activity that is equal 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 active agent, e.g., a positive control).

[0120] Further, in the context of embodiments herein where the average thickness of the structural elements is greater than about 30-100 μm, a three-dimensional structural scaffold of one or more thin structural elements includes a drug-containing structural scaffold (e.g., a network, scaffold, assembly, population, or arrangement) of one or more thin structural elements that extends over a length, width, and thickness of greater than 100 μm, including, but not limited to, a drug-containing structural scaffold that extends over a length, width, and thickness of 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 about 30-100 μm, the three-dimensional structural framework of one or more thin structural elements comprises a drug-containing structural framework (e.g., a network, framework, assembly, grouping, or arrangement) of one or more thin structural elements that extend over a length, width, and thickness that is greater than the average thickness of at least one element (or at least one section) in said structural framework. This includes, but is not limited to, structural frameworks that extend over a length, width, and thickness that is greater than 1.5 times, or greater than 2 times, or greater than 2.5 times, or greater than 3 times, or greater than 3.5 times, or greater than 4 times, or greater than 5 times the average thickness of at least one element (or at least one section) in the structural framework. It may 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] Moreover, in a preferred embodiment, the three-dimensional structural scaffold of one or more thin structural elements comprises multiple stacks of thin structural elements (or sections), including but not limited to a stack of at least two layers of thin structural elements (or sections), or a stack of at least three layers of thin structural elements (or sections), or a stack of at least four layers of thin structural elements (or sections), or a stack of at least five layers of thin structural elements (or sections).

[0123] As used herein, the terms "element," "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 element" are used interchangeably. They are understood as solid drug-containing structural elements (or building blocks) that make up a three-dimensional structural scaffold (e.g., a dosage form structure or a drug-containing solid structure). Thin structural elements include two-dimensional elements (2-dimensional structural elements), one-dimensional elements (1-dimensional structural elements), or zero-dimensional elements (0-dimensional structural elements).

[0124] As used herein, a two-dimensional structural element or "sheet" is described as having a length and width that are significantly greater than the thickness. More specifically, in this disclosure, the length and width of the two-dimensional structural element are greater than twice the thickness. This includes, but is not limited to, the length and width are greater than three times, or greater than four times, or greater than five times, or greater than six times, or greater than eight times, or greater than ten times, or greater than twelve times the thickness. Moreover, in some embodiments, including but not limited to, the length and width of the sheet are greater than 0.3 mm, or greater than 0.5 mm, or greater than 1 mm, or greater than 2.5 mm.

[0125] One-dimensional structural elements or "fibers" are described herein as having a length that is significantly greater than their width and thickness. More specifically, in this disclosure, the length of one-dimensional structural elements or fibers is greater than twice their width and thickness (e.g., the length is greater than twice their width and the length is greater than twice their thickness). This includes, but is not limited to, lengths that are greater than three times their width and thickness, or greater than four times their width and thickness, or greater than five times their width and thickness, or greater than six times their width and thickness, or greater than eight times their width and thickness, or greater than ten times their width and thickness, or greater than twelve times their width and thickness. Moreover, in some embodiments, including but not limited to, the length of the fibers is greater than 0.3 mm, or greater than 0.5 mm, or greater than 1 mm, or greater than 2.5 mm.

[0126] Zero-dimensional structural elements or "beads" are described herein as having a length and width on the order of their thickness. In this disclosure, the length and width of a zero-dimensional structural element or bead is no more than twice its thickness. This includes, but is not limited to, a length and width that is no more than three or four times its thickness. Additionally, the thickness of a zero-dimensional element or bead is less than 2.5 mm.

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

[0128] Moreover, as used herein, the term "segment" or "segments" refers to a segment of an element along the length and / or width of the element. As a non-limiting example, a "segment" of a fiber can include a segment of the fiber along the length of the fiber.

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

[0130] As used herein, the terms "dissolution medium", "physiological fluid", "body fluid", "dissolution liquid", "medium", "fluid" and "permeation agent" are used interchangeably. They are understood to be any fluid produced or contained by the human body under physiological conditions, or any fluid similar to a fluid produced or contained by the human body under physiological conditions. Examples include, but are not limited to, water, saliva, gastric fluid, digestive fluid, saline, etc., at a temperature of 37° C. and pH value adjusted to relevant physiological conditions.

[0131] Moreover, in the present invention herein, an excipient is said to be "polymeric" 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, or greater than 2,000 kg / mol, or greater than 3,000 kg / mol, or greater than 4,000 kg / mol, or greater than 5,000 kg / mol. A polymeric excipient is said to "imbibe a dissolution fluid" if it transitions from a solid to a fluid or viscous medium upon contact with a physiological fluid or dissolution fluid.

[0132] A viscous medium refers to a viscous solution, viscous dispersion, or viscous mass that has a shear viscosity that is significantly less than the "viscosity" of a solid, but significantly greater than the shear viscosity of a melt. Thus, in some embodiments, the shear viscosity of a viscous medium is significantly less than the shear viscosity of a solid, but more than 2 times, or more than 4 times, or more than 5 times, or more than 6 times, or more than 7 times, or more than 8 times, or more than 10 times, or more than 12 times, or more than 15 times the viscosity of a melt.

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

[0134] Moreover, in viscous media, the concentration of water-soluble (or water-absorbent) polymeric excipients is typically greater than the disentanglement concentration c e * Higher, but generally within the solid / semi-dilute boundary c e ** Thus, a viscous medium is typically a semi-dilute solution or dispersion that includes at least entangled water-soluble or water-absorbent polymer molecules that are dissolved in or fluidized (e.g., fluidized or viscous) by physiological fluids.

[0135] A hydrophilic surface composition is referred to herein as a solid surface (e.g., a solid surface composition, or a composition of a surface of an element or elements) that is wettable by an aqueous physiological or bodily fluid under physiological conditions. A solid surface is "wettable by a fluid" if the contact angle of a droplet of said fluid on said solid surface in air is 90 degrees or less. This includes, but is not limited to, contact angles of a droplet of said fluid on said solid surface in air that are 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 may be noted that in some embodiments, the contact angle need not be static. In this example, a solid surface may be understood to be "wettable by a fluid" if the contact angle of a droplet of said fluid on said 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 provided in US application Ser. No. 15 / 482,776, entitled "Fibrous dosage form."

[0136] Scope of the invention It is contemplated that specific features described in this disclosure individually or as part of an embodiment can be combined with other individually described features or parts of other embodiments, even if the other features and embodiments do not refer to the specific feature. Therefore, the invention herein extends to such specific combinations not yet described. Furthermore, the drawings and embodiments of the invention herein are presented by way of example and not by way of limitation. Therefore, it is understood that the invention herein is not limited to these exact embodiments. Other embodiments that are obvious to those skilled in the art are within the scope of the invention as claimed.

[0137] By way of non-limiting example, the compositions, systems, devices, methods, and processes of the claimed invention encompass 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 performed by one of ordinary skill in the relevant art.

[0138] Furthermore, when compositions, articles, and devices are described as having, including, or comprising certain components, or processes and methods are described as having, including, or comprising certain steps, it is contemplated that there are additionally compositions, articles, and devices of the invention that consist essentially of, or consist of, the recited components, and processes and methods according to the invention that consist essentially of, or consist of, the recited processing steps.

[0139] Similarly, when compositions, articles, and devices are described as having, including, or comprising particular compounds and / or materials, it is contemplated that there are additionally compositions, articles, and devices of the invention that consist essentially of, or consist of, the recited compounds and / or materials.

[0140] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0141] The citation of any publication in this specification is not an admission that the publication serves as prior art with respect to any of the claims presented herein. Headings are provided for organizational purposes and are not meant to be limiting.

[0142] Detailed Description of the Invention FIG. 6a presents a non-limiting example of a pharmaceutical dosage form according to the invention herein. The dosage form 600 comprises a drug-containing solid 601 having an exterior surface 602 and an interior structure 604 adjacent to and terminating at said exterior surface 602. The interior structure 604 comprises a three-dimensional structural framework of one or more thin structural elements (e.g., fibers, sheets, etc.) 610. In the invention herein, a structural element is understood to be "thin" if its thickness (e.g., its smallest dimension) is significantly less than the length, or width, or thickness of the dosage form. This includes, but is not limited to, a thickness less than half, or less than a third, or less than a quarter, or less than a fifth of the length, or width, or thickness of the dosage form. A thin structural element is also referred to herein as an "element."

[0143] The element 610 includes at least an active ingredient, at least a polymeric excipient (e.g., an absorbent polymeric excipient) that absorbs physiological fluid, and at least one hydrophilic surface composition. The element 610 further includes sections spaced apart from adjacent sections, thereby defining void spaces 615. A plurality of adjacent void spaces 615 join across the drug-containing solid 601 to define one or more interconnected void spaces 615 that form an open pore network in the drug-containing solid 601.

[0144] In the present invention herein, the term "interconnected void space" or "open pore network" in the drug-containing solid is also referred to as "interconnected pore network", "network of open channels" or "open channels of void space" in the drug-containing solid. In some embodiments, the interconnected void space or multiple interconnected void spaces can be accessed from the external surface of the drug-containing solid. That is, there is no wall (e.g., a wall including the three-dimensional structural framework of the element) that must be broken to obtain the interconnected void space (e.g., open channels of void space) from the external surface of the drug-containing solid to a point (or any point) in the interconnected void space in the internal structure. Moreover, it may be noted that if all void spaces (e.g., the entire void space in the drug-containing solid) are interconnected, the void space is also referred to as "continuous" herein. The dosage form having continuous void space comprises a preferred embodiment of the present invention.

[0145] As shown in FIG. 6b, when immersed in a dissolution solution, the open pore network allows physiological fluid 620 to penetrate the drug-containing solid 601, allowing uniform wetting of the scaffold by the fluid. In the invention herein, a surface (e.g., a surface of a three-dimensional scaffold) is "wetted by a fluid" if the fluid contacts (e.g., touches) the surface. A surface is "uniformly wetted" by a fluid if at least 30-60 percent of the area of ​​the surface is in contact (e.g., direct contact) with the fluid. In a preferred embodiment, at least 70 percent of the surface of the three-dimensional scaffold is wetted (e.g., by contact) by the fluid upon immersion of the drug-containing solid in a physiological fluid.

[0146] The drug-containing solid having a uniformly wetted three-dimensional structural framework (e.g., wet element 610 or wet drug-containing solid 601) then transitions from solid 630 into viscous medium 640, 641, 642, thereby expanding in all dimensions as shown diagrammatically in non-limiting Figures 6c-6e.

[0147] It may be noted that the drug-containing solid may be a "solid", a combination of a "solid" and a "viscous medium", a combination of a "viscous medium", a "solid" and a dilute solution or dispersion, or a combination of a "viscous medium" and a dilute solution or dispersion. Moreover, the term "swelling in all dimensions", "swelling in all dimensions", or "swelling in all dimensions" is understood to be an increase in the length of the sample (e.g., the length and / or width and / or thickness of said sample, etc.) and an increase in the volume of said sample. Thus, deformation due to pure shear is not considered to be "swelling in all dimensions" in this specification.

[0148] In some embodiments, when immersed in a dissolution liquid, the drug-containing solid dissolves or dissolves in said physiological fluid. Moreover, in some embodiments, the drug-containing solid dissolves or dissolves in physiological or bodily fluids during or after transition to a viscous medium.

[0149] In some embodiments, the drug-containing solid expands by the permeation (e.g., diffusion or inflow) of physiological fluids or bodily fluids into the three-dimensional structural framework of the element. Additionally, in some embodiments, the drug-containing solid expands by the permeation (e.g., diffusion or inflow) of physiological fluids or bodily fluids into the absorbent polymer excipient. Moreover, in some embodiments, the drug-containing solid expands by 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 shown diagrammatically in FIG. 6g. Thus, in some embodiments, at least one dimension of the drug-containing solid (e.g., length of a side of the drug-containing solid, thickness of the drug-containing solid, etc.) expands to at least 1.12 times its initial value (e.g., initial length) during transition to the viscous medium 641, 642. This includes, but is not limited to, at least one dimension of the drug-containing solid expanding to at least 1.15 times, or at least 1.17 times, or at least 1.2 times, or at least 1.22 times, or at least 1.25 times, or at least 1.27 times, or at least 1.3 times, or at least 1.35 times, or at least 1.4 times, or at least 1.5 times, or at least 1.6 times, or at least 1.7 times its initial value during transition to the flowable or viscous medium 641, 642.

[0151] Additionally, in some embodiments, the drug-containing solid expands to at least 1.4 times its initial volume during transition to the viscous medium, including but 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 its initial volume.

[0152] The rate of expansion generally depends on the rate at which the dissolution fluid 620 is absorbed by the structural scaffold (e.g., by absorbent polymer excipients) and the presence and severity of constraints on expansion. The rate at which dissolution fluid is absorbed by the scaffold typically increases when the specific surface area (e.g., the ratio of surface area to volume) of the scaffold increases. Thus, when the elements 630, 640 are thin, the surface area to volume ratio is large and the rate at which dissolution fluid is absorbed by the scaffold is expected to be faster.

[0153] Constraints on expansion often result from non-uniformity of dissolution liquid concentration throughout the three-dimensional scaffold. As a non-limiting example, a wetting element or section may absorb dissolution liquid, but the expansion of said wetting element or section may be constrained if it is connected (e.g., attached) to a dry solid element or section that does not expand. For this reason, uniform wetting of the elements in the scaffold is crucial to minimize constraints on expansion. Uniform wetting is made possible, among other things, by interconnected void spaces (e.g., interconnected void spaces forming an open-pore network through which the dissolution liquid can penetrate).

[0154] The dosage forms according to the invention herein comprise a structural framework of thin elements having a hydrophilic surface composition surrounded by interconnected void spaces forming an open pore network, so that the rate of expansion can be substantial.

[0155] Thus, in some embodiments, at least one dimension of the drug-containing solid (e.g., lateral length or thickness) expands to at least 1.12 times its initial value (e.g., initial length) within 30 minutes of immersion in physiological fluid or body fluid under physiological conditions when it transitions to a flowable or viscous medium. This includes, but is not limited to, at least one dimension of the drug-containing solid reaching a length of 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 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 expanding to at least 1.15 times its initial length, or at least 1.2 times its initial length, or at least 1.25 times its initial length, or at least 1.3 times its initial length, or at least 1.4 times its initial length, or at least 1.5 times its initial length, or at least 1.6 times its initial length within 20 minutes of immersion in physiological fluid or body fluid under physiological conditions.

[0156] Further, 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, including, but not limited to, a drug-containing solid that expands 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 its initial volume within 20-30 minutes of immersion in a physiological fluid or body fluid under physiological conditions.

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

[0158] It may further be noted that the drug-containing solid or viscous medium may swell to such an extent that it essentially forms a dilute solution or dispersion. A dilute solution or dispersion is described herein as a solution or dispersion of a physiological fluid and a polymeric excipient molecule that has dissolved and disentangled (e.g., a dissolved polymeric excipient molecule at a concentration lower than the concentration of disentanglement). Such a dilute solution or dispersion is generally deformable by and miscible with a physiological fluid. However, it is noted that any deformation due to the application of an external force, including but not limited to shear stress due to a dissolving liquid, buoyancy, gravity, etc., does not include "swelling" herein. Moreover, a dilute solution or dispersion is not considered a "viscous medium" herein.

[0159] Finally, further non-limiting examples of three-dimensional structural scaffolds having interconnected void spaces that illustrate how elements (e.g., fibers, sheets, beads, etc.) can be structured, arranged, or assembled are described in co-pending U.S. application Ser. No. 09 / 299,333, entitled "Fibrous Dosage Forms." No. 15 / 482,776, U.S. application Ser. No. 15 / 964,058 entitled "Method and apparatus for the manufacture of fibrous dosage forms," ​​and U.S. application Ser. No. 15 / 964,063 entitled "Dosage form comprising two-dimensional structural elements." Many more examples of how elements can be structured or arranged in a three-dimensional structural network or scaffold of one or more elements will be apparent to one of ordinary skill in the art, all of which are within the spirit or scope of the present invention.

[0160] Modeling the disintegration, swelling, and drug release of dosage forms The following examples provide methods by which the drug release and dissolution behavior of the dosage forms of the present disclosure can be modeled. The models allow those skilled in the art to more easily understand the details and advantages of the present invention. The models are for illustrative purposes and are not meant to be limiting in any way.

[0161] a) Dosage Form Structure The presented non-limiting model refers to the pharmaceutical dosage form shown in the schematic diagrams in Figures 7a and 8a. The dosage form 700, 800 comprises a drug-containing solid 701, 801 having an outer surface 702, 802 and an internal three-dimensional structural framework 704, 804 comprising a plurality of crisscross stacks of fiber-like structural elements 710, 810, said framework 704, 804 being adjacent to and terminating at said outer surface 702, 802. The fiber-like structural elements 710, 810 comprise at least a drug 780, 880, at least one absorbent polymer excipient 790, 890, and a hydrophilic surface composition. The fiber-like structural elements 710, 810 further have sections that are spatially separated from similar sections of adjacent fiber-like elements 710, 810, thereby defining void spaces, and multiple adjacent void spaces in successive layers combine to define one or more interconnected void spaces 715, 815 that form an open network in the drug-containing solid 701, 801. The radius of the fiber-like structural elements 710, 810 or fiber sections and the inter-fiber spacing in the layers of the fiber-like structural elements are uniform.

[0162] b) Dosage Form Composition Consider two non-limiting dosage forms with different compositions and drug release mechanisms. In the first 700, represented by FIG. 7 and referred to herein as "Dosage Form A", the fiber 710 is composed of 10 wt.% drug (ibuprofen), 60 wt.% hydroxypropylmethylcellulose (HPMC) with a molecular weight of 10 kg / mol (also referred to 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 a second dosage form 800, represented by Figure 8 and referred to herein as "Dosage Form B", the fiber 810 is composed of 20% by weight drug (acetaminophen) and 80% by weight high molecular weight polymer excipient (HPMC with a molecular weight of 120 kg / mol, also referred to herein as "HPMC 120k"). Additionally, 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 dosage form A is immersed in an aqueous dissolution fluid 720, the fluid 720 penetrates rapidly into the interior of the structure (FIG. 7b) due to the continuous voids 715 (e.g., open spaces) and hydrophilic fiber surface. Moreover, the fluid 720 (e.g., water, saliva, digestive fluids, etc.) then diffuses into the fibers 710, as shown diagrammatically in FIG. 7c. The thin fibers 710 and structure transition from solid 730 to viscous 740 and expand rapidly as the fluid 720 diffuses into them.

[0165] Moreover, as the fibers and structures expand, the dissolution fluid 720 continues to flow from the outside into the structure through the pores 716 (FIGS. 7c and 7d). Eventually, however, when the fluid content in the dosage form becomes so high that the viscosity of the expanded viscous medium 741, 742 becomes so low, it deforms due to forces such as gravity, fluid shear, etc. (FIGS. 7d ​​and 7e). Such deformation increases the surface area to volume ratio of the viscous medium 741, 742, facilitating its collapse and dissolution. The drug is released when the drug molecules in the viscous medium 741, 742 or excipients around the drug particles dissolve or collapse. When the fibers 710 are thin, the diffusion length of the dissolution fluid 720 molecules is small, and the structure expands and dissolves quickly.

[0166] As shown diagrammatically in Figures 8b and 8c, for dosage form B, the degradation, swelling, and drug release process 800 initially proceeds as in the first example: dissolution fluid 820 penetrates the interior, there is fiber-fluid interdiffusion, and the absorption of fluid causes the structure to expand. However, because the fibers 810 expand radially faster than axially, they eventually coalesce and the inward flow of fluid stops. The dosage form then forms a viscous mass 841 consisting of entangled high molecular weight excipient molecules, drug, and dissolution fluid 820, as shown in Figure 8d.

[0167] The viscous masses 841, 842, 843 disintegrate and dissolve very slowly (Figures 8d-8f). Thus, the drug is released mainly by 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 fluid continues to diffuse into the viscous mass 843, making it more fluid. Similarly, polymer molecules also diffuse outward from the viscous mass 843 into the external dissolution fluid. Thus, the viscous mass 843 eventually disappears or dissolves (Figures 8f and 8g).

[0168] A detailed analysis of any drug release mechanism or process is outside the scope of this disclosure. Therefore, individual process steps are isolated and modeled herein with reasonable assumptions.

[0169] d) Penetration of dissolution fluid into fiber-like dosage forms The first step in the dosage form degradation and drug release process herein is the penetration of the dissolution fluid into the interior of the structure. The penetration of the dissolution fluid into the voids 715, 815 (e.g., an empty space or spaces) may be driven by capillary forces and retracted by viscous forces. If the empty spaces 715, 815 are treated by an assembly of capillaries exposed to the dissolution fluid at one end and air at the other end, the approximate penetration time t perc 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 an unrestricted dosage form and dissolution solution with a viscosity of 0.05 Pa·s, γ=0.072 N / m, r=100 μm, and θ≒30°, the penetration time t perc = 8 ms. In the fiber-like structures 700, 800, the penetration time does not have to be very fast. Even in that case, the fiber surface is hydrophilic and the free space interval λ f is larger than a few micrometers (e.g., λ f In the case where the particle size is greater than about 5-10 μm, the interconnected void spaces 715, 815 will be permeated by the dissolution fluid 720, 820 almost immediately after immersion of the dosage form in said fluid.

[0171] It will be clear to those skilled in the art that the presented model (and any of the following models) 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. Thus, more examples and models of dissolution fluid penetration into fiber-like dosage forms that are clear to those skilled in the art are all within the scope of this disclosure.

[0172] e) Interdiffusion of fibers and solution After penetration of the dissolution fluid through the dosage form structure (e.g., an open network defined by interconnected void spaces), the hydrophilic coating on the fibers may dissolve. The dissolution fluid (e.g., water) and the excipients in the fibers may then interdiffuse.

[0173] Diffusivity of water in the fiber D w Assuming that is concentration independent, the differential equation for water diffusion in cylindrical coordinates is

number

[0174] If the water concentration at the fiber-fluid interface is c b As shown in Figure 9, the initial and boundary conditions are: c w =0 t=0, 0≦r <R0(2b) c w =c b t ≥ 0, r = R(t) (2b) and where R0 is the initial fiber radius.

[0175] One can immediately notice that this is a moving interface problem. An analytical solution to equation (2a) subject to the first condition (2b) and the moving interface condition (2c) may not currently be available. However, under the very approximate assumption that the concentration of the diffusing liquid is very low (i.e., the fiber radius is constant), the water concentration profile, as shown diagrammatically in the non-limiting Figure 9, is

number

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

number

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

number

[0178] For more information on diffusion models, see, e.g., J. Crank, The Mathematics of Diffusion, 2nd edn., Oxford University Press, 1975. Further examples of models of dissolve diffusion into fibers will be apparent to those skilled in the art, all of which are within the scope of the present invention.

[0179] f) Swelling of Fiber-Like Dosage Forms When a substantial amount of dissolved fluid diffuses or penetrates into the fiber (or absorbent polymer excipient), the mass and volume of the fiber increases (e.g., the fiber grows or swells). Fiber-like dosage forms can also grow or swell as individual fibers swell. However, the exact derivation of dosage form expansion rates is outside the scope of this disclosure. An estimate based on the expansion of a single fiber is provided below.

[0180] f1) Single fiber Assuming no volume change upon mixing (e.g., permeation of the dissolution fluid into the fiber or 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 dissolution fluid that has permeated the fiber.

number

[0181] Moreover, in the case of small expansion (i.e., the boundary concentration c b is the density of the solution, ρ w If it is much lower than (c b <<ρ w )), the normalized volume expansion of the fiber at "infinite" or "long" times is

number

[0182] Combining equations (5) and (7) and multiplying them by equation (8) gives the normalized volumetric expansion of the fiber:

number

[0183] Furthermore, for small isotropic expansions, the normalized radial and axial expansions are approximately one-third of the volume expansion. Thus, from equation (9), for short times,

number

[0184] Similarly, for a perfectly anisotropic expansion with small radial expansion, the radial expansion is approximately half the volume expansion. 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 inverse of the initial fiber radius. Moreover, the parameter value c b Approximately 930mg / ml, ρ w = 1000mg / ml, D w Approximately 3×10 -11 m 2For a flow rate of 1 / s and R about 100 μm, ΔR / R0 = ΔL / L0 = 0.3 at 1 min, according to equation (9). Thus, a thin fiber that rapidly interdiffuses with a melt can expand to a radius or length that is 30 percent greater than its initial value within just a few minutes.

[0186] However, it should be noted that the accuracy of the above model is very limited. As a non-limiting example, Equations (3)-(11) are b is the density of water or the solution, ρ w Much lower than (c b <<ρ w ) This assumption is generally not met when the excipient and the solvent (e.g., water) are mutually soluble.

[0187] Any other models of monofilament expansion apparent to one skilled in the art are within the scope of the present invention.

[0188] f2) Dosage form FIG. 10 presents a schematic representation of the cross-section of fibers in the fiber-like structure initially (before immersion in the dissolution solution) and after immersion in the dissolution solution.

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

number

[0190] For anisotropically expanding fibers in a cross-ply structure, the normalized expansion of the interfiber distance may grow slower but approximately proportional to the normalized expansion of the fiber radius, as shown diagrammatically in FIG. 10b. Next, the longitudinal normalized expansion ΔL of the viscous expandable dosage form v / L0 can be written as follows:

number

[0191] Additional models of dosage form expansion during transition to a viscous medium will be apparent to those skilled in the art, all of which are within the scope of the present invention.

[0192] g) Formation of viscous media As mentioned above, the solid dosage form may transition into a viscous medium during swelling. The viscosity of the medium is estimated by multiplying the concentration of the main polymer excipient, c e,v By way of non-limiting example, the predominant polymer excipient may be the polymer excipient that contributes most 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, etc. In the non-limiting dosage forms A and B modeled herein, c e,v is typically the concentration of HPMC in the viscous medium. e,v teeth,

number

[0193] The mass of an excipient is the weight fraction of the excipient in the solid dosage form w e and the weight of the solid dosage form M sdf It is the product of. M e =w e M sdf (15a) Furthermore, M sdf is the density ρ of the solid material in the dosage form s and volume fraction φ s can be written in terms of M sdf =ρ s φ s V sdf (15b) In the formula, V sdf is the volume of the solid dosage form. Combining equations (15a) and (15b), we get M e =w e ρ s φ s V sdf (15b) is given.

[0194] Similarly, the volume of a viscous medium is V v =V sdf (1+ΔV v / V sdf ) (16a) 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. If the dosage form expands isotropically and the expansion is small, V v =V sdf (1+3ΔL v / L0) (16b) Wherein, 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 given by:

number

[0196] Non-limiting parameters of dosage form A are w e Approximately 0.6, φ s Approximately 0.5, ΔL v / L0 approx. 0.5, and ρ s When the concentration is about 1200 mg / ml, according to formula (17), c e,v is about 144 mg / ml. This is the concentration of disentanglement c derived in non-limiting experimental Example 11a. e * The viscosity of the solution is only about twice that of water. Thus, the viscous medium is quite dilute. Moreover, a viscous solution of water and 144 mg / ml HPMC 10k has a viscosity of about 598 mPa (see, e.g., Experimental Example 11a). This is only about two to three orders of magnitude greater than the viscosity of water.

[0197] Non-limiting parameters of dosage form B are w e Approximately 0.8, φ s Approximately 0.4, ΔL v / L0 approx. 1, and ρ s When the concentration is about 1200 mg / ml, according to formula (17), c e,v is about 96 mg / ml. This is the concentration of disentanglement c derived in non-limiting experimental example 11b. e * This is about two orders of magnitude greater than the concentration of 1.45×10 3 It has a viscosity of 10 Pa·s (see, for example, Experimental Example 11b), which is six orders of magnitude greater than the viscosity of water.

[0198] Many more examples and models of viscous media will be apparent to those of skill in the art, all of which are within the scope of this disclosure.

[0199] h) Viscous deformation of viscous media A viscous medium is exposed to forces such as gravity or shear due to fluid flow. Because of this, it may deform over time. The derivation of exact expressions for shear stress, strain rate, and strain in a medium is outside the scope of this disclosure. However, when a viscous medium is fixed at the bottom and exposed to a unidirectional flow of a Newtonian fluid, the average wall shear stress τ is given by:

number

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

number

[0201] Furthermore, if the viscous medium is homogeneous, the viscous flow can thin it into a sheet, as shown in the non-limiting schematic diagram of FIG. 11a. From the geometry, it takes time t to thin the medium into a sheet of thickness h. def teeth,

number

number

[0202] Representative parameters of medium A (τ = 2.3 × 10 -3 Pa, L v = 10 mm, h = 200 μm, and μ v = 598 mPas), according to equation (19b), t def = 6.6 min. Representative parameters for medium B (τ = 2.3 × 10 -3 Pa, L v = 10 mm, h = 200 μm, and μ v =1.45×10 3 Pas), t def = 266 hours. Thus, viscous medium A deforms very rapidly, while viscous medium B deforms very slowly. However, the t calculated for medium B is def Note that θ may not be of much importance in practice: at such low deformation rates, the melt may diffuse into the viscous medium, making it less viscous, accelerating its deformation rate over time.

[0203] Another non-limiting example of a deforming viscous medium is shown in 11b. The viscous medium is heterogeneous, containing higher viscosity regions at the initial fiber location and lower viscosity regions between the fibers. Because of this, the stress, strain rate, and strain may also be heterogeneous, and the lower viscosity areas may be sheared faster than the remaining areas, causing void growth. Eventually, the voids may heal and break down the structure. The rate at which the structure may break down increases greatly when the strain rate increases and the viscosity of the viscous medium decreases (e.g., when the concentration of the main polymer excipient in the viscous medium decreases).

[0204] Many more examples and models of modification of viscous gel consistency solutions that are obvious to one of ordinary skill in the art are all within the scope of this disclosure.

[0205] i) Collapse of a viscous medium due to convective mass transfer Concurrent with viscous deformation, the viscous medium and the melt may continue to interdiffuse, and thus the viscous medium may be considered a "stagnant" body for the purposes of estimating collapse rates by convective diffusion, since the shear strain rate in the surrounding melt is typically much larger than the shear strain rate in the viscous medium.

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

number

[0207] Time to disintegrate a viscous medium:

number

[0208] Representative parameter values ​​for medium A (μ f =0.001 Pa·s, D e about 10 -10 m 2 / s, ρ f =1000mg / ml, Ω=50rpm, c e,v = 144 mg / ml, and c e * = 70mg / ml), the disintegration rate E is about 1.5μm / s. Therefore, a 200μm thick film of this medium dissolves in about 2 minutes. Typical parameter values ​​for 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* = 1.67 mg / ml), E is about 0.053 μm / s. To disintegrate just 200 μm thick would require about 63 minutes. Moreover, a 5 mm thick viscous medium of this composition disintegrating from two sides would dissolve in 63 × 2.5 / 0.2 = 788 minutes (13 hours).

[0209] Many more examples and models of disintegration or dissolution of drug-containing solids or viscous media that are apparent to one of ordinary skill in the art are all within the scope of this disclosure.

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

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

[0212] The relevant parameter values ​​for dosage form A (t perc Approximately 1 second, t dif Approximately 26 seconds, t def Approximately 6.6 minutes, t E,v 2 minutes), the drug release time due to disintegration t d,er However, for dosage form B, t d,er would be longer than 10 hours.

[0213] Many more models and examples for estimating drug release time that are apparent to one of ordinary skill in the art are all within the scope of this disclosure.

[0214] j2) Drug release by drug diffusion through a viscous medium Drug release from a viscous mass governed by the diffusion of drug molecules therethrough is illustrated diagrammatically in Figure 12. If all the drug is dissolved in the viscous mass, the diffusion equation is:

number

[0215] From the solution of equations (24a)-(24d) given by Crank, for short times the fraction of drug released is

number

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

[0217] D d is about 5×10 -10 m 2 / s and H=5 mm, 80 percent of the drug content is released in 105 minutes. Thus, when immersed in a dissolution solution, dosage form B swells rapidly due to diffusion of the dissolution solution into the thin fibers, but releases drug much more slowly due to diffusion of the drug molecules through the thick viscous mass.

[0218] The dosage form has several desirable characteristics. Rapid diffusion of the dissolution medium into the thin fiber allows it to expand from a diameter of less than 12 mm to a diameter of more than 20 mm within less than 10-15 minutes after immersion in the dissolution medium. The dosage form further transitions from a solid to a viscous state upon expansion, eliminating any risk of damaging the gastrointestinal mucosa. It further allows it to release drug at a controlled rate over an extended period of time. Yet it has sufficient mechanical strength to significantly slow passage through the pylorus during drug release, yet still completely degrades thereafter.

[0219] For more examples and models of drug release by diffusion of drug molecules through a viscous medium, 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. Many more examples and models of drug release by diffusion of drug molecules through a polymeric medium are all within the spirit and scope of the present disclosure.

[0220] k) Model summary The above model suggests that upon immersion of the dosage forms of the present disclosure in a dissolution medium, the fluid will uniformly and rapidly penetrate into the interior of the structure, provided that the surfaces of the fibers (e.g., the surfaces of the elements) are hydrophilic, the void spaces are interconnected, and the void space spacing (e.g., effective void space spacing) is on the micro-, meso-, or macro-scale.

[0221] After penetration, the fluid diffuses inwards from the surface of the fiber. As a result, the fiber absorbs water and transforms into a viscous or gel-like substance or medium. Moreover, absorbing water causes the fiber to expand. Thus, if constraints that stop the expansion of the dosage form structure, such as non-uniform wetting, are removed, the fiber-like structure can expand approximately proportionally to the expansion rate of the single fiber. Two non-limiting types of single fiber and dosage form expansion can be distinguished:

[0222] First, the single fiber expands isotropically. Second, the fiber-like structure expands at approximately the same rate as the single fiber, the geometric similarity of the structure is preserved during expansion, and the pore network remains open. Thus, the dissolution fluid continues to flow into the structure during expansion, constantly diluting the absorbent polymer excipients in the viscous medium (or structural scaffold or viscous scaffold). As a result, the viscosity of the viscous medium constantly decreases until it becomes small enough that the medium can easily deform and dissolve. 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] Second, the single fibers expand anisotropically. If the fibers expand more rapidly in the radial direction than in the longitudinal direction, they may coalesce as the dosage form expands. The void spaces and open pores may close after the fibers coalesce, and the inward flow of the solution may stop or be greatly reduced. As a result, an expanded viscous mass of very high polymer excipient concentration and viscosity may be formed. The viscous mass may not deform or dissolve in the solution, or may deform or dissolve very slowly. The drug may be released by slow diffusion of the drug molecules through the thick viscous mass. The thick viscous mass eventually dissolves or degrades.

[0224] Thus, the fiber-like dosage form swells rapidly by diffusion of water into the thin fibers, but slowly releases drug by diffusion of drug molecules through the thick swollen viscous medium, so that the dosage form can meet the twin functional requirements of a gastrointestinal sustained release dosage form: rapid dosage form expansion and sustained drug release.

[0225] EMBODIMENTS OF THE PRESENT DISCLOSURE In view of the above theoretical models and considerations, which are suggestive and approximate rather than precise, the designs and embodiments of the dosage forms disclosed herein may further include the following:

[0226] a) Three-dimensional structural framework of drug-containing solids and elements In some embodiments, the average length, average width, and / or average thickness of the drug-containing solid (e.g., the three-dimensional structural backbone of one or more elements) is greater than 1 mm. This includes, but is not limited to, the average length, average width, and / or average thickness of the drug-containing solid being 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. In the invention herein, length generally refers to the measurement of distance in the direction of the longest distance, thickness generally refers to the 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 open pore network is continuous, such that no walls (e.g., walls comprising the three-dimensional structural framework of the elements) must be broken to obtain clusters of interconnected void spaces (e.g., open channels of void space) from the exterior surface of the drug-containing solid to a point (or any point) in the void space within the internal structure.

[0228] However, in some embodiments, at least one void space is surrounded by a wall to form a closed cell, in which case fewer than five walls can be disrupted to obtain a cluster of interconnected void spaces from the exterior surface of the drug-containing solid to any point in the internal structure.

[0229] Moreover, an element or section in the three-dimensional structural framework of one or more elements can be defined, for example, by its position relative to a reference point or frame of reference (e.g., the position of its center of mass, or the position of its central axis, or the path of the line formed by its central axis, or the central plane, etc.). In the present invention herein, a reference frame can be understood as a reference coordinate system. The origin and orientation of the reference point or frame of reference can 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 partition in the three-dimensional structural framework of one or more elements is precisely controlled. Such embodiments include, but are not limited to, three-dimensional structural frameworks of one or more elements in which the position of a fragment of an element or partition is precisely controlled. The volume fraction of the element or partition whose position is precisely controlled (with respect to the total volume of the elements or partitions that make up the three-dimensional structural framework of one or more elements) can 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 invention herein, a variable or parameter (e.g., the position of an element, or the spacing between elements, or the thickness of an element, etc.) is precisely controlled if it is deterministic and not stochastic (or random). A variable or parameter may be deterministic if, when a step involving said variable is repeated multiple times (e.g., when multiple dosage forms are produced under identical or nearly identical conditions), the standard deviation of the values ​​of said variable is less than the mean value. This includes, but is not limited to, a standard deviation of the values ​​of said variable that is less than half the mean value of said variable, or less than one-third the mean value, or less than one-quarter the mean value, or less than one-fifth the mean value, or less than one-sixth the mean value.

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

[0233] A non-limiting example of a three-dimensional structural scaffold of one or more elements in which the positions of a large percentage (or all) of the elements, the spacing between the elements, and the thickness of the elements are controlled (or precisely controlled) is an ordered structure.

[0234] By way of non-limiting example, such regular or ordered structures may include multiple layers of stacked fibers or fiber segments. Moreover, the fibers or fiber segments in the layers may be oriented parallel (or nearly parallel) to one another. The distance between adjacent fiber segments across an open space, also referred to herein as "λ" or "λ0", may further be constant or essentially constant in the layers.

[0235] It should further be mentioned that preferred embodiments of the ordered structures herein include plies (e.g., layers) of fibers or fiber segments stacked in a cross-ply arrangement (e.g., a crisscross stack of fiber-like structural elements). In a cross-ply arrangement, the fibers (or fiber segments) in a layer (or ply) are oriented transversely or at an angle (e.g., at an angle greater than 0 degrees, or greater than 0 degrees but less than or equal to 90 degrees) to the fibers in the ply above or below. 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 radii are uniform (e.g., constant) and the distance λ between adjacent fiber sections across the void space is also constant (e.g., uniform or equidistant) or nearly constant, the void spaces form an interconnected open pore network that is highly ordered and highly uniform for the drug-containing solid. For example, such a highly uniform and ordered structure is expected to remove constraints on expansion and allow uniform wetting of the three-dimensional structural scaffold ensuring repeatable optimal properties.

[0237] Thus, a general advantage of ordered structures, particularly cross-ply structures, compared to non-ordered or random structures is the ability to better control relevant properties, such as the rate of expansion and / or drug release of the dosage form.

[0238] Further non-limiting embodiments of dosage form structures are described in US Pat. No. 6,393,363 entitled "Fibrous dosage form." Application No. 15 / 482,776, "Method and apparatus for the manufacture of No. 15 / 964,058, entitled "Fibrous Dosage Forms," ​​and U.S. Patent Application No. No. 15 / 964,063, entitled "Polyurethane foam comprising two-dimensional structural elements."

[0239] b) Element thickness and spacing between segments To obtain a sufficiently large specific surface area (i.e., ratio of surface area to volume) to ensure rapid expansion of the dosage form, in some embodiments, one or more elements (e.g., fibers, etc.) have an average thickness h0 that is 2.5 mm or less, including, but 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 may be noted that if the elements are very thin and closely packed, the spacing between elements and the free space spacing may be very small, limiting the rate at which dissolution fluids can penetrate or flow into the free space. Furthermore, dosage forms with very thin elements may be difficult to manufacture, for example, by 3D micropatterning. 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 thickness h of an element can be considered to be 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 thickness h0 of an element is the average thickness of the element along one or more lengths or widths of the element. A non-limiting example for deriving the average thickness of an element is the "Fibrous Dosage Form" formula: No. 15 / 482,776, entitled "Polymer Form."

[0242] Similarly, to ensure rapid penetration of the dissolution fluid into the interior of the dosage form structure, the effective free space spacing λ between adjacent sections should be f,e must typically be on the micro- or mesoscale. Thus, in some embodiments, the effective free space spacing λ f,e is on average greater than 0.1 μm. This means that the average λ 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. f,e Including but not limited to:

[0243] However, since the volume of a dosage form is generally limited, the mass of drug and excipients that can be loaded into the dosage form can be very small if the effective free space interval is very large. Thus, in some embodiments, the effective free space interval can 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 open space spacing between adjacent segments (herein referred to as "effective open space spacing") is defined as the maximum diameter of a sphere that would fit into the corresponding open space if the element or segment were considered to be a rigid, fixed body. A non-limiting example illustrating how the effective open space spacing can be derived or measured is provided in U.S. application Ser. No. 10 / 200,333, entitled "Fibrous Dosage Forms." Presented in No. 5 / 482,776.

[0245] c) Surface characteristics of elements and segments Further, to allow penetration of the dissolution fluid into the interior (e.g., into the void spaces) of the structure, in some embodiments, the surface composition of at least one element is hydrophilic. In the present disclosure, a surface or surface composition is hydrophilic, also referred to as "wettable by physiological fluid," if the contact angle of a drop of physiological fluid on said surface in air is 90 degrees or less. This includes, but is not limited to, a contact angle of a drop of said fluid on said solid surface in air that is 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 may be noted that in some embodiments, the contact angle does not have to be static. In this case, a solid surface may be understood to be "hydrophilic" if the contact angle of a drop of physiological fluid on said solid surface in air is 90 degrees or less at least 20 to 360 seconds after the drop is placed on said surface. A non-limiting illustration of a drop on a surface is provided in U.S. Application Serial No. 15 / 482,776, entitled "Fibrous dosage form."

[0246] In general, the penetration rate of physiological fluid into interconnected void spaces increases when the contact angle between said 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 section of an element includes a hydrophilic or highly hydrophilic coating to enhance the fluid penetration rate into the dosage form 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" when the contact angle of a drop of physiological fluid on said solid surface in air is 45 degrees or less. This includes, but is not limited to, a contact angle of a drop of said fluid on said solid surface in air that is 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 may serve as a coating for an element (or a section of an element) include polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone, silicon dioxide, talc, magnesium stearate, polyols (e.g., mannitol, maltitol, xylitol, maltitol, isomalt, lactitol, sucrose, glucose, erythritol, etc.), and the like.

[0248] Finally, it may be noted that in some embodiments, the open space spacing between the sections and the composition of the surface of one or more of the elements are such that the penetration time of physiological fluids / body fluids into one or more interconnected open spaces of the drug-containing solid is 200 seconds or less under physiological conditions, including but not limited to, penetration times of physiological fluids / body fluids into one or more interconnected open spaces of the drug-containing solid of 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 characteristics of excipients In some embodiments, the weight fraction of drug in at least one element (e.g., fiber, sheet, bead, etc.) with respect to the total weight of said element (e.g., total weight of fiber, sheet, etc.) is 0.9 or less, including but not limited to, a weight fraction of drug in said element with respect 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 drug in one or more elements of a three-dimensional structural scaffold relative to the total weight of said scaffold is 0.9 or less, including but not limited to a weight fraction of drug in said scaffold relative to the total weight of said scaffold 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] Additionally, in some embodiments, the weight fraction of absorbent polymer excipients in at least one element relative to the total weight of said element is greater than 0.1, including, but not limited to, a weight fraction of absorbent polymer excipients in said element relative to the total weight of said element 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 absorbent polymer excipients in one or more elements of a three-dimensional structural scaffold relative to the total weight of said scaffold is greater than 0.1, including but not limited to, a weight fraction of absorbent polymer excipients in said scaffold relative to the total weight of the structural scaffold is 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 diffusion rate of physiological fluids / body fluids in the absorbent excipient is less than 0.1×10 under physiological conditions. -11 m 2 / s, which is greater than 0.2 × 10 -11 m 2 / s or greater than 0.5×10 -11 m 2 / s or greater than 0.75×10 -11 m 2 / s or greater than 1×10 -11 m 2 / s or greater than 2×10 -11 m 2 / s or greater than 3×10 -11 m 2 / s or greater than 4×10 -11 m 2 This includes, but is not limited to, the effective diffusivity of physiological fluids / body fluids in an absorbent excipient (and / or element or compartment) that is greater than 1 / s.

[0254] Alternatively, for absorbent excipients in which the diffusion of physiological fluids / bodily fluids into them is not Fickian, a permeation rate may be specified. In some embodiments, the permeation rate of physiological fluids / bodily fluids into a solid absorbent excipient (and / or element or section) 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 non-limiting examples, 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 diffusivity (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 dosage form structure, or even an element or segment consisting of an absorbent excipient) may be fixed at both ends and placed in a static dissolution medium at 37°C. The time t1 until the element is substantially degraded or deformed may be recorded. (As a non-limiting example, deformation of an element may generally be considered substantial if either the length, width, or thickness of the element differs from its initial value by more than 10-20 percent. Weight fraction w of absorbent / expandable excipient less than 0.4.) e , or the volume fraction φ e For elements having a length, width, or thickness of the element or section, the length, width, or thickness is increased by 25 × φ from its initial value. e percent or 25 x w e (If the difference is more than a percent, the deformation of the element or section may be considered substantial.) Next, the effective diffusivity D eff D eff =h init 2 / 4t1, where h init is the thickness of the initial element or section (e.g., the thickness of the dry element or section). Similarly, the permeation rate of physiological fluids / body fluids into an element or section is h initA further non-limiting example for deriving the effective diffusivity or permeation rate is provided in U.S. application Ser. No. 15 / 482,776, entitled "Fibrous dosage form." As shown.

[0256] Moreover, 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, including but not limited to, 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 referred to herein as the ratio of the maximum mass of said material that can be dissolved in a given volume of said fluid at equilibrium divided by the volume of said fluid. Solubility can be determined, for example, by optical methods.

[0258] Moreover, for polymers that form viscous solutions when combined with a dissolution medium, "solubility" in the context of the present invention is the concentration of polymer in a physiological fluid / body fluid at which the average shear viscosity of the polymer-physiological fluid / body fluid solution is 5 Pa·s at shear rates in the range 1-100 1 / s under physiological conditions. The pH value of the physiological fluid / body fluid may thereby be adjusted to suit the particular physiological conditions of interest.

[0259] In some embodiments, to ensure that the dosage form will eventually dissolve or disintegrate in physiological fluid (e.g., to avoid clogging of the swollen dosage form or viscous medium in the gastrointestinal system, etc.), at least one absorbent polymer excipient comprises multiple individual chains or molecules that dissolve or unravel upon immersion in physiological fluid.

[0260] Moreover, in some embodiments, the molecular weight of the 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). Furthermore, in some embodiments, the molecular weight of the at least one absorbent polymer excipient is between 2 kg / mol and 1000 kg / mol (e.g., in the range of 5-750 kg / mol, 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).

[0261] Non-limiting examples of excipients that meet some or all of the requirements of a polymer excipient include, but are not limited to, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, sodium alginate, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, hydroxypropyl methyl ether cellulose, 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, among others.

[0262] e) Microstructure and three-dimensional structural framework of the elements Non-limiting examples of the microstructure of the elements and the three-dimensional structural scaffold of one or more elements are provided in U.S. application Ser. No. 15 / 482,776, entitled "Fibrous dosage form," U.S. application Ser. No. 15 / 964,058, entitled "Method and apparatus for the manufacture of fibrous dosage forms," ​​and U.S. application Ser. 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 a matrix of absorbent polymer excipients.

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

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

[0266] Similarly, in some embodiments, the three-dimensional structural scaffold of one or more elements swells upon dilution of the polymer excipient with physiological or bodily fluids.

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

[0268] Furthermore, in some embodiments, the geometric similarity of the three-dimensional structure scaffold is preserved during the transition to a fluid or viscous medium. In the present invention, a microstructure or three-dimensional structure scaffold is geometrically similar to an initial structure or scaffold if the expanded microstructure or expansive scaffold can be approximately obtained by scaling or enlarging the initial structure or scaffold (e.g., by uniformly scaling or enlarging all directions of the initial structure or scaffold). Thus, in an expansive scaffold with preserved geometric similarity, interconnected void spaces remain open and interconnected as the structure expands. This allows the scaffold to absorb more water (e.g., physiological fluid) during expansion, thereby expanding to a greater extent.

[0269] The geometric similarity of an expandable scaffold can be preserved when the elements (or sections) are uniformly wetted by the dissolving liquid and / or when the individual elements (or individual sections) are substantially isotropically expanded when in contact with said dissolving liquid. An expandable scaffold is understood to exist when the geometric similarity can be "preserved" or "approximately preserved" only initially. All such scaffolds in which the geometric similarity is partially or somewhat or initially preserved are referred to herein as "skeletons in which the geometric similarity is preserved during expansion". Figures 6b and 6c provide non-limiting examples of two three-dimensional structural scaffolds that are geometrically similar.

[0270] 13a presents a non-limiting example of a drug-containing solid comprising a geometrically similar, expandable three-dimensional structure scaffold 1302 and interconnected void spaces 1330 forming an open-pore network. When immersed in a dissolution fluid 1340, the scaffold 1302 is uniformly wetted by said fluid 1340. As a result, the scaffold 1302 absorbs water 1340, transitions to a viscous form, and expands. Moreover, due to the preservation of the geometric similarity during expansion, the void spaces 1330 remain open and the dissolution fluid 1340 continues to flow into the structure as the scaffold 1302 expands. As a result, the viscosity always decreases as the scaffold (or drug-containing solid) transitions into the viscous medium 1350 (e.g., the viscosity or "average viscosity" of the drug-containing solid always decreases while transitioning into the viscous medium, but this can be repeated where the drug-containing solid can be a "solid", a combination of a "solid" and a "viscous medium", a combination of a "viscous medium", a "solid" and a dilute solution or dispersion, or a combination of a "viscous medium" and a dilute solution or dispersion while transitioning into the viscous medium). Thus, eventually, the viscosity of the viscous medium 1350 can be so low that 1350 deforms and thins due to the forces applied by the dissolution liquid (e.g., shear tensile forces, pressure imbalance, buoyancy, gravity, etc.). This increases the specific surface area of ​​the viscous medium 1350 and therefore the rate of disintegration into the dissolution liquid 1340. Note that in some cases, the drug-containing solid or viscous medium 1350 can expand and be diluted to such an extent that a "dilute solution" or "dilute dispersion" is formed. Moreover, it must be reiterated that "deformation due to external forces" and "thinning" are not considered "expansion" in this specification.

[0271] Thus, for immediate release and delivery of drug by the dosage form, the viscosity of the swollen dilute solution 1360 can be so low that it will rapidly deform and disintegrate in the dissolution fluid 1340. The swelling of the drug-containing solid 1300 reduces the viscosity of the viscous medium 1350 or the formed dilute solution 1360, accelerating the disintegration and drug release rate.

[0272] Thus, in some embodiments, 80 percent of the drug content in the drug-containing solid is released in less than 45 minutes after immersion in a physiological or bodily fluid under physiological conditions, including, but not limited to, drug-containing solids that release 80 percent of the drug content in less than 40 minutes, or less than 35 minutes, or less than 30 minutes, or less than 25 minutes, or less than 20 minutes, or less than 15 minutes, or less than 10, or between 1 and 45 minutes, 1 and 30 minutes, 2 and 45 minutes, or 2 and 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 to a great extent, or at all, when individual elements 230, 240 (or individual sections) expand substantially anisotropically upon contact with the dissolving liquid 220.

[0274] FIG. 13b is a non-limiting example of a drug-containing solid 1305 that includes a three-dimensional structural scaffold 1307 of elements that expand more rapidly along its thickness than along its length, and interconnected void spaces 1335 that define an open pore network. When immersed in a dissolution fluid 1345, the scaffold 1307 is uniformly wetted by said fluid 1345. As a result, the scaffold 1307 absorbs water 1345, transitions to a viscous form, and expands. Because the elements expand anisotropically, they coalesce as the scaffold 1307 expands, closing the void spaces 1335 and open pores. The inward flow of the dissolution fluid 1345 may then be stopped or greatly reduced. As a result, an expanded viscous mass 1355 may be formed that has a polymer excipient concentration significantly greater than the dissolution concentration, and a viscosity significantly greater than the viscosity of the dissolution fluid 1345. The viscous mass 1355 may not deform or may deform very slowly, or may not dissolve or may dissolve very slowly in the dissolution fluid 1345. The drug may be released by slow diffusion of the drug molecules through the thick viscous mass 1355.

[0275] Thus, in some embodiments, 80 percent of the drug content in the drug-containing solid is released in greater than 30 minutes after immersion in a physiological or bodily fluid under physiological conditions, including, but not limited to, drug-containing solids that release 80 percent of their drug content in greater than 40 minutes, or greater than 50 minutes, or greater than 60 minutes, or greater than 100 minutes, or between 30 minutes and 48 hours, between 30 minutes and 36 hours, between 30 minutes and 24 hours, or between 45 minutes and 24 hours after immersion in a physiological fluid under physiological conditions.

[0276] Finally, in some embodiments, the tensile strength of the drug-containing solid or three-dimensional structural scaffold of one or more elements is between 0.01 MPa and 100 MPa (including, but not limited to, a 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 dosage forms - Patents.com (a) Method 14 presents a non-limiting example of a method for manufacturing a pharmaceutical solid dosage form according to the present invention. One or more drugs 1410 and / or one or more absorbent polymer excipients 1420 (the 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 extending along its length inside a housing 1440. Similarly, at least one solvent that solvates the 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 the at least one solvated solid component with respect to the total volume of the one or more injected solid components are such that the one or more injected solid components form a plasticized matrix upon contact and mixing with the solvent. The plasticized matrix is ​​conveyed (after its formation or simultaneously with its formation) towards the outlet 1450 of the extrusion channel 1430 by applying a mechanical action to the plasticized matrix (e.g., by applying a shear force to the plasticized matrix along the division of the extrusion channel 1430, or by applying a pressure gradient in the direction of the extrusion channel 1430, etc.). The plasticized matrix is ​​then extruded from the outlet 1450 to form at least one plasticized fiber 1460. The at least one plasticized fiber 1460 (e.g., one or more plasticized fibers) is then structured into a three-dimensional network of one or more fibers. In some embodiments, the three-dimensional network of one or more fibers is solidified by evaporating the solvent to form a fiber-like dosage form with sufficient rigidity. Furthermore, when immersed in a physiological fluid, the three-dimensional structural scaffold is uniformly wetted and transitions to a viscous medium, thereby expanding in all dimensions.

[0278] Another non-limiting example of a method for producing a pharmaceutical solid dosage 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 fed 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 injected solid component. Thus, at least one injected solid component becomes fluid (e.g., transitions from solid or solid-like to flowable or fluid-like) upon heating. The volume fraction of the fluidized solid component (or multiple fluidized solid components) relative to the volume of the injected one or more solid components is such that, upon heating (and mixing), the injected one or more solid components form a plasticized matrix. The plasticized matrix is ​​conveyed (after its formation or simultaneously with its formation) towards the outlet 1550 of the extrusion channel 1530 by applying a mechanical action to the plasticized matrix (e.g., by applying a shear force to the plasticized 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 plasticized matrix is ​​then extruded from the outlet 1550 to form at least one plasticized fiber 1560. The at least one plasticized fiber 1560 (e.g., one or more plasticized fibers) is then structured into a three-dimensional network of one or more fibers. In some embodiments, the three-dimensional network of one or more fibers is solidified by cooling it to a temperature below the solidification temperature. Furthermore, when immersed in a physiological fluid, the three-dimensional structural scaffold is uniformly wetted and transitions into a viscous medium, thereby expanding in all dimensions.

[0279] In some embodiments, structuring of at least one plasticized fiber into a three-dimensional structured network of one or more drug-containing fibers is performed by 3D patterning of said at least one plasticized fiber on a substrate.

[0280] In some embodiments, the three-dimensional structural scaffold of the drug-containing fiber or fibers comprises multiple crisscross stacks of fiber-like structural elements.

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

[0282] Further non-limiting examples of methods for producing the dosage forms disclosed herein are described in co-pending U.S. application Ser. No. 15 / 482,776, entitled "Fibrous dosage forms," ​​entitled "Methods for Producing Fibrous Dosage Forms." No. 15 / 964,058, entitled "A method and apparatus for the manufacture of fibrous dosage forms," ​​and U.S. Ser. No. 15 / 964,063, entitled "Dosage form comprising two-dimensional structural elements." Any number of more examples of process steps for manufacturing the dosage forms described above will be apparent to one of ordinary skill in the art, all of which are within the scope of the present invention.

[0283] (b) Equipment 14 also presents a non-limiting example of an apparatus 1400 for manufacturing pharmaceutical solid dosage forms according to the present invention. The apparatus 1400 includes an internal hollow housing 1440 having an interior surface enclosing and defining an extrusion channel 1430 having a first end 1445, a second end 1450, and a cross-section extending axially along its length from said first end 1445 to said second end 1450 and terminating at an outlet 1450 at 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 feeding or injecting at least one solid component into the extrusion channel 1430. Moreover, the housing 1440 has at least a second inlet 1456 between the first inlet 1455 and the outlet 1450 for injecting at least one liquid into the extrusion channel 1430 to form a plasticized matrix by solvating at least one injected solid component. The apparatus 1400 further includes at least one conveying element 1470 for extruding the plasticized matrix in the extrusion channel through the outlet 1450 to form at least one plasticized fiber 1460. The apparatus 1400 further includes a fiber structuring unit 1480 for structuring the at least one plasticized fiber 1460 (e.g., one or more plasticized fibers) into a three-dimensional structured network 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 inlet 1455. Additionally, in some embodiments, the device further includes a solvent supply unit 1486 attached to the second supply inlet 1456 for injecting at least one solvent into the extrusion channel 1430. Furthermore, upon immersion in a physiological fluid, the three-dimensional scaffold is uniformly wetted and transitions into a viscous medium, thereby expanding in all dimensions.

[0284] Another non-limiting schematic diagram of an apparatus 1500 for the manufacture of pharmaceutical solid dosage forms according to the present invention is shown in Figure 15. The apparatus 1500 includes an internal hollow housing 1540 having an internal surface enclosing and defining an extrusion channel 1530 having a first end 1545, a second end 1550, and a cross-section extending axially along its length from said first end 1545 to said second end 1550 and terminating at an outlet 1550 at the second end 1550. The housing 1540 further has at least a first feed inlet 1555 between the first end 1545 and the second end 1550 for feeding or injecting at least one solid component into the extrusion channel 1530. The apparatus 1500 further includes at least one heating element 1586 for fluidizing the at least one injected solid component such that the injected solid component or components form a plasticized matrix in the extrusion channel 1530. The device 1500 further comprises at least one conveying element 1570 for extruding the plasticized matrix in the extrusion channel 1530 through the outlet 1550 to form at least one plasticized fiber 1560. The device 1500 further comprises a fiber structuring unit 1580 for structuring the at least one plasticized fiber 1560 (e.g., one or more plasticized fibers) into a three-dimensional structured network of one or more fibers. In some embodiments, the device 1500 further comprises a solid component supplying unit 1585 for injecting at least one solid component into the extrusion channel 1530 through the first supply port 1555. Furthermore, when immersed in a physiological fluid, the three-dimensional structural scaffold is uniformly wetted and transitions into a viscous medium, thereby expanding in all dimensions.

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

[0286] In some embodiments, one or more plasticized fibers are structured into a three-dimensional structured network of one or more drug-containing fibers by 3D patterning said one or more plasticized fibers on a substrate defined by or attached to a translation or rotation stage.

[0287] In some embodiments, the three-dimensional structural scaffold of the one or more drug-containing fibers comprises multiple crisscross stacks of fiber-like structural elements.

[0288] In any of the examples presented herein, the extrusion channel 1430, 1530 may include one or more outlets through which the plasticized fiber may be extruded. Moreover, any feature described with respect to one embodiment of the present invention may be applied with respect to another embodiment. As a non-limiting example, the apparatus may include at least a feed port for injecting a solvent into the extrusion channel to form a plasticized matrix, and at least a heating element for fluidizing at least one injected solid component to form a plasticized matrix.

[0289] A further non-limiting example of an apparatus for producing the dosage forms disclosed herein is the "Fibrous No. 15 / 482,776, entitled "Method and Apparatus for the Manufacture of Fibrous Dosage Forms," ​​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." Any number of other examples of devices for manufacturing dosage forms will be apparent to those skilled in the art, all of which are within the scope of the present invention. EXAMPLES

[0290] The following examples provide methods by which fiber-like dosage forms can be prepared and analyzed, thereby enabling those skilled in the art to more readily understand the principles. The following examples are presented for illustrative purposes and are not meant to be limiting in any way.

[0291] Example 1 Preparation of Dosage Form 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% hydroxypropylmethylcellulose (HPMC) with a molecular weight of 10 kg / mol and 33 wt% polyoxyl stearate (trade name: Gelucire 48 / 16, Gattefosse). The common solvent used was dimethyl sulfoxide (DMSO).

[0292] Dosage Form A was prepared as follows: as-received ibuprofen drug particles were first dissolved in DMSO at a concentration of 123 mg drug / ml DMSO. The solution was then combined with excipients 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] The paste was then loaded into a syringe at point O and extruded through a hypodermic needle to form and pattern a wet fiber-like dosage form at P, as shown diagrammatically in Figure 16. The dosage form included a cross-ply arrangement of fibers with uniform inter-fiber distance in the plies (or layers). The nominal radius of the wet fiber (the inner radius of the hypodermic needle) R n was 130 μm; the nominal interfiber distance λ n The thickness of the dosing agent was 500 μm, as described in Table 1. After patterning, hot air at a temperature of about 50° C. and a speed of 2.3 m / s was blown onto the dosage form to evaporate the solvent and solidify the structure. The drying time t dry The time required for the gelation was approximately 35 min, after which the fibers were a homogenous solid solution of drug and excipient molecules.

[0294] After drying, the structures were molded into square disk-shaped dosage forms with a nominal volume of 8 mm x 8 mm x 3.6 mm. The weight fraction of 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] Monofilament A was prepared as described above (eg, as dosage form A), except that the fiber-like extrudate was not structured into a dosage form.

[0296] Example 2 Preparation of Dosage Forms and Fibers B and C Dosage forms B and C were prepared as follows: 20 wt% acetaminophen drug particles were first mixed with an excipient, 80 wt% HPMC with a molecular weight of 120 kg / mol. The mixture was then combined with a solvent, either DMSO (to prepare 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. The drug-excipient-solvent mixture was then extruded in a laboratory extruder to form a uniform viscous paste. The viscous paste was then extruded into a 300 ml tube with an inner radius of R n = 130 μm (to prepare dosage form B) or R n The paste was then placed in a syringe equipped with a hypodermic needle of 500 μm (to prepare dosage form C). The paste was then extruded through the needle and patterned as a fiber-like dosage form with a cross-ply arrangement of fibers. The nominal inter-fiber distance in the plies was uniform and equal to 730 μm (to prepare dosage form B) or 2800 μm (to prepare dosage form C). During and after patterning, hot air at a temperature of 60° C. and a velocity of about 2.3 m / s was blown over the fiber-like dosage form for a period of time t dry The solvent was evaporated and the structures were fixed by spraying for about 40 minutes. The process parameters for preparing the dosage forms are summarized in Table 1. After drying, the structures were molded into square disk-shaped dosage forms with a side length L0 of about 8 mm. The thickness H0 of dosage forms B and C was about 3 mm.

[0297] Single fibers B and C were prepared as dosage forms B and C, but the fiber-like extrudates were not structured into a dosage form. [Table 1]

[0298] Example 3 Coating of fibers in dosage form construction To ensure that the dissolution liquid penetrates the dosage form structure uniformly and quickly after immersion, the fibers of all dosage form structures were coated with a thin hydrophilic coating. The coating was applied by dropping a few drops of the hydrophilic coating solution onto the dosage form structure and immediately drying. The drying step was performed by blowing hot air at a temperature of 50° C. and a speed of 2.3 m / s onto the dosage form structure.

[0299] To coat the fibers of dosage form 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 ml of ethanol, and the concentration of mannitol was 20 mg per ml of ethanol.

[0300] To coat the fibers of dosage forms 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 ml of acetone.

[0301] Example 4 Scanning electron micrographs of dosage form and fiber A The dosage form and single fiber A were imaged with a Zeiss Merlin High Resolution SEM equipped with a GEMINI column. Top views were imaged without sample preparation. However, when imaging cross sections, the samples were imaged with a thin blade (MX35 Sections were taken using a 300 nm TEM microscope (Ultra, Thermo Scientific, Waltham, MA). Imaging was performed with an in-lens secondary electron detector. The accelerating voltage was 5 kV and the probe current was 95 pA.

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

[0303] As the solvent is removed during drying, the wet dosage form shrinks, so the microstructural parameters of the dry dosage form are less than the nominal values. For isotropic shrinkage, the ratio is:

number

[0304] Dosage form A has a solvent concentration of c solv =550kg / m 3 , and the solvent density ρ solv =1100kg / m 3 Therefore, the calculated R / R n = λ / λ n =0.79, which is almost the same as the measured value.

[0305] Moreover, due to gravity, the wet fibers deform at the contact points, decreasing the vertical interfiber distance. As a result, the solid volume fraction of dry fibers with flat surface contact is greater than that of a nominal cross-ply structure with cylindrical fibers. Thus, for all dosage forms, the solid fiber volume fraction is:

number

[0306] Finally, Figure 18 is a scanning electron micrograph of a representative single fiber A. The fiber radius was 102 μm as reported in Table 2.

[0307] Example 5 Swelling and Degradation of Dosage Form and Fiber A For imaging the swelling and dissolution process of the dosage form and fiber A, the sample was first immersed in a beaker containing 500 ml of dissolution solution (0.1 M HCl in deionized water at 37° C.). The fluid was stirred with a paddle rotating at 50 rpm. The sample was then continuously imaged with a Nikon DX camera until dissolution.

[0308] Images of dosage form A swelling and disintegrating are shown in Figure 19. Upon immersion of the dosage form, the dissolution fluid penetrated into the voids almost immediately. The solid dosage form then transitioned into a viscous medium and expanded uniformly in all directions. The normalized expansion of the dosage form was 0.43 after 2 minutes of immersion, approximately the same as the radial and longitudinal expansion of a single fiber over that time (Figure 20).

[0309] After about 2-3 minutes of immersion, the dosage form began to deform viscously due to gravity and fluid shear. The material collapsed and became destructured from the surface. A viscous drug-excipient-solvent solution then formed along the flat surface. The viscous solution continued to collapse in the solvent, which dissolved after about 10-15 minutes of immersion.

[0310] Example 6 Drug release from dosage forms and fiber A Drug release from the dosage form and single fiber A was determined under the same conditions as in the swelling and degradation experiments (Experimental Example 5). Drug concentration in the dissolution medium versus time was measured using a Perkin Elmer Measurements were made by UV absorption using a Lambda 1050 spectrophotometer.

[0311] The drug concentration in the medium versus time is shown in Figure 21. As is evident, the fiber-like dosage forms and the single fiber released drug continuously until they were dissolved. The time to dissolve 80 percent of the drug content, t 0.8 was 3 min for the single fiber and 9 min for the dosage form, Table 2. Thus, the drug release time from the dosage form was comparable to that of the single fiber.

[0312] Example 7 Scanning electron micrographs of fibers B and C Scanning electron micrographs of single fibers B and C were obtained under the conditions described above in Experimental Example 4. From Figures 22a and 22b, the fiber radii were 73 μm (fiber B) and 309 μm (fiber B), as listed in Table 2. It can be noted that the inner radii of the needles for preparing 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 decomposing single fibers B and C were obtained under the conditions described in Experimental Example 4. From Figure 23, when the fiber was immersed in the dissolution solution, a viscous layer developed at the fiber-fluid interface. The layer grew inward and outward with time and expanded with the fiber. The fiber expansion was anisotropic; the fiber expanded radially, but the axial expansion was essentially negligible.

[0314] Figure 24a is a plot of normalized radial expansion ΔR / R0 versus time t, where ΔR / R0 steadily increased with time at a gradually decreasing rate. Furthermore, this increased as the initial fiber radius R0 decreased. The 73 μm initial radius fiber (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 the 309 μm initial radius fiber (Fiber C).

[0315] Figure 24b shows the t 1 / 2The data are plotted against fiber radius. Nevertheless, the t of ΔR / R for all fibers was 1 / 2 The approximate correlation to / R0 is

number

[0316] Combining Eq. (28) with the model in Eq. (11a), the diffusivity of the solute in the fiber is given by

number

[0317] Thus, thin fibers expand rapidly due to the diffusion of water inwards, and the excipients do not substantially stop the diffusion of water.

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

[0319] Figure 25a shows the fraction of drug released into the dispersion medium, m d Figure 1 shows a plot of / M0 versus time t. For all fibers, the drug was released steadily at a gradually decreasing rate. The time to release 80 percent of the initial drug content, t0.8 , increased with increasing fiber radius, from 2.7 min for R0 = 73 μm to 24.5 min for R0 = 309 μm (Table 2).

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

number

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

number

[0322] Thus, when water enters the thin fiber, the drug diffuses out of the gelled fiber into the dissolution liquid, and because the fiber is thin, the drug is released rapidly.

[0323] Example 10 Scanning electron micrographs of dosage forms B and C Scanning electron micrographs of dosage forms B and C were obtained with the equipment and under the conditions described in Experimental Example 4. From Figures 26a and 26b, the fiber radius R0 and interfiber distance λ0 in the microstructure of dosage form B were 71 μm and 456 μm, respectively. Moreover, from Figures 26c and 26d, in the microstructure of dosage form C, the fiber radius R0 = 315 μm and interfiber distance λ0 = 1466 μm, as listed in Table 2. The microstructural parameters measured in the solid dosage forms were about 0.52-0.72 times the nominal values ​​(Tables 1 and 2).

[0324] Example 11 Swelling and disintegration of dosage forms B and C Images of the degrading dosage forms B and C were obtained using the equipment and conditions described in Experimental Example 5.

[0325] Figures 27a and 27b present top-view images of dosage forms B and C after immersion in the dissolution fluid. Again, fluid penetrates into the voids almost immediately after immersion. The solid dosage form then transitions into a viscous mass that simultaneously expands uniformly in all directions. The viscous mass gradually disintegrates in the dissolution fluid, thus preserving its geometry more or less for more than an hour. Eventually, however, the viscous mass disappears and the dosage form dissolves.

[0326] FIG. 28a is a plot of normalized longitudinal expansion ΔL / L0 versus time t. For all dosage forms, ΔL / L0 increased with time at a gradually decreasing rate. The ratio of the dosage form length at 15 minutes to the initial length, L 15 / L0 is shown in Table 2. 15 / L0 increased with decreasing fiber radius, increasing from 1.12 for R0 = 315 μm (dosage form C) to 2.06 for R0 = 71 μm (dosage form B).

[0327] Thus, the swelling rate of a dosage form with an initial fiber radius of 71 μm (Dosage Form B) is such that the diameter of a 9.7 mm disk increases to 20 mm just 15 minutes after immersion, which is expected to be fast enough to ensure ease of swallowing of the dosage form and prevent too rapid passage of the viscous medium into the intestine.

[0328] Figure 28b shows the t 1 / 2 / R0. △L / L0 is initially t 1 / 2 / R0 and has the following morphology:

number

[0329] Passing through the linear region, t of △L / L0 1 / 2 The curves for / R0 reached equilibrium at a nearly constant value. The curves reached equilibrium as soon as the dosage forms were transformed into homogeneous viscous masses. The "final" ΔL / L0 values ​​were between 0.52 and 1.3 for the presented dosage forms (dosage forms B and C). The curves reached equilibrium because the diffusion of water into a thick viscous mass is much slower than the diffusion into the thin fibers of the fiber dosage forms, and thus the swelling rate of the viscous mass is greatly reduced (e.g., the swelling rate of the drug-containing solid during the transition to a viscous mass is much greater than the swelling rate of a homogeneous or nearly homogeneous viscous mass). [Table 2]

[0330] Example 12 Drug release by dosage forms B and C Drug release from dosage forms B and C was determined according to the conditions and experimental equipment described in Experimental Examples 5 and 6.

[0331] The percentage of drug released by the fiber-like dosage forms versus time is shown in Figure 29a. In all cases, the curves increased steadily with time but with a decreasing slope. The time to release 80 percent of the drug content, t 0.8 ranged from 110 min (R = 71 μm, dosage form B) to 502 min (R = 315 μm, dosage form C) as listed in Table 2, which is approximately 20 to 41 times longer than the corresponding values ​​for single fibers.

[0332] Figure 29b is a plot of the percentage of drug released versus the square root of time. The curve is essentially linear and has the following form:

number

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

number

[0334] The estimated diffusivity in the viscous mass is on the order of the diffusivity of small drug molecules in water. Furthermore, the drug diffusivity through the viscous mass increases when the fiber radius decreases due to the more rapid swelling rate and the greater volume fraction of water in the viscous mass. Thus, drug release and swelling rates are coupled: dosage forms with thin, small radius fibers swell and release drug more rapidly than dosage forms with larger radius fibers.

[0335] Nevertheless, the drug release rate from the dosage form is much slower than that from a single fiber because the diffusion length of the drug molecules varies from the fiber radius to the thickness of the viscous mass.

[0336] As a result, the thin fiber dosage form B swells rapidly due to diffusion of the solution into the thin fiber and transition to a viscous mass, as shown in Figure 30. The drug is then released slowly by diffusion of the drug molecules through the thick, swollen viscous mass.

[0337] Thus, dosage form B meets a pair of functional requirements for a gastrointestinal sustained release dosage form: rapid dosage form 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 with HPMC of molecular weight 10 kg / mol was determined by a shear rheometer (TA Instruments, ARG2 Rheometer, stress control) equipped with a 60 mm diameter cone with an apex angle of 178°. The concentrations of 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 experiments was 37°C and the shear strain rate ranged from 1 to 100 / s.

[0339] FIG. 31 shows the results of the experiment with various weight fractions of excipients, f e Shear viscosity μ at sFigure 31a shows the viscosity versus shear rate in the range of 1 to 100 / s, and Figure 31b shows the f at a shear rate of 1 / s. e μ for s In the dilute region, described herein as the region where the weight fraction of the excipient is less than the disentangled weight fraction, the viscosity is calculated according to Einstein's viscosity equation μ s =0.253f e +0.001 Pa s. In the semi-dilute region, μ s =2089f e 4.21 The dilute and semi-dilute regions are determined by the weight fraction f e * = 0.062. Therefore, the concentration of the excipient that disentangles the e * ≒70mg / ml.

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

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

[0342] Figure 32 shows the 5×10 -4 ≦f eExcipient weight fraction f at shear rates 1 / s in the range of ≦0.3 e Shear viscosity μ s Two regions can be identified: dilute and semi-dilute. In the dilute region, the viscosity is given by Einstein's viscosity formula: μ s =0.001+9.95f e In the semi-dilute region, described herein as the region where the excipient weight fraction is greater than the disentangled weight fraction but less than the semi-dilute / solid boundary, μ s =10 6 f e 2.79 The dilute and semi-dilute regions are determined by the weight fraction f e * =1.67×10 -3 Therefore, the concentration of the excipient that disentangles the e * ≒1.67mg / ml. Concentration of excipient in water for disintegration c w * ≒998mg / 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 herein as the semi-dilute / solid boundary. e ** ≒500mg / ml. Water concentration at semi-dilute / solid boundary c w ** ≒500mg / ml.

[0344] Application examples In some embodiments, the amount of active ingredient contained in the dosage forms disclosed in the present invention is appropriate for administration in a treatment regimen that has a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. By way of non-limiting example, the active ingredient may be selected from the group consisting of acetaminophen, aspirin, caffeine, ibuprofen, analgesics, anti-inflammatories, anthelmintics, antiarrhythmics, antibiotics, anticoagulants, antidepressants, antidiabetics, antiepileptics, antihistamines, antihypertensives, antimuscarinics, antimycobacterials, antineoplastics, immunosuppressants, antithyroids, antivirals, anxiolytics and sedatives, beta-adrenergic receptor blockers, cardiac inotropes, corticosteroids, antitussives, diuretics, dopaminergics, immunologicals, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid agents, calcitonin and biphosphonates, prostaglandins, radiopharmaceuticals, antiallergics, sympathomimetics, thyroid agents, PDE IV inhibitors, CSBP / RK / p38 inhibitors, or vasodilators).

[0345] The dosage forms disclosed herein have a predictable microstructure and drug release behavior. They allow a larger range and improved control of the drug delivery rate to the bloodstream. Although useful for improving almost any drug therapy, the dosage forms disclosed herein are particularly beneficial for increasing the delivery rate of drugs that are poorly soluble (e.g., poorly soluble) in digestive fluids. Thus, in some embodiments, at least one active pharmaceutical ingredient comprises a solubility of 5 g / l or less in physiological fluid / body fluid 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 fluid / body fluid under physiological conditions.

[0346] Additionally, the dosage forms of the present disclosure may be particularly useful for delivery of drugs that are more soluble in acidic solutions (eg, the stomach or duodenum) than in basic solutions (eg, the intestine or large intestine).

[0347] Thus, in some embodiments, at least one active pharmaceutical ingredient comprises a pH-dependent solubility in physiological or bodily fluids.

[0348] Furthermore, in some embodiments, at least one active pharmaceutical ingredient comprises at least 5 times greater solubility in acidic solution than in basic solution. This includes, but is not limited to, at least one active ingredient having at least 10 times, or at least 15 times, or at least 20 times, or at least 30 times, or at least 50 times greater solubility in acidic solution than in basic solution. In the present invention herein, if the pH value of the solution is 5.5 or less, the solution is considered to be "acidic". If the pH value of the solution is greater than 5.5, the solution is considered to be "basic".

[0349] Moreover, in some embodiments, at least one active pharmaceutical ingredient is a basic compound. In the present invention, a compound is understood to be "basic" if the acid dissociation constant (e.g., pKa value) of said compound is greater than about 5.5.

[0350] Finally, the dosage forms of the present disclosure can be manufactured by economical processes that allow for more personalized medicine. In certain embodiments, for example, the following items are provided: (Item 1) 1. A pharmaceutical dosage form comprising: a drug-containing solid having an exterior surface and an internal three-dimensional structural framework of one or more thin structural elements, said framework terminating adjacent to said exterior surface; the thin structural element comprises at least one active pharmaceutical ingredient, at least one absorbent polymer excipient, and at least one hydrophilic surface composition; the thin structural element further having sections spatially separated from adjacent sections thereby defining void spaces, a plurality of adjacent void spaces joining across the drug-containing solid to define one or more interconnected void spaces forming an open pore network; A pharmaceutical dosage form whereby, upon immersion in physiological fluid, the open pore network allows for uniform wetting of the scaffold and transfer of the drug-containing solids into the viscous medium, thereby expanding in all dimensions. (Item 2) 13. The dosage form according to item 1, wherein when immersed in a physiological fluid, the drug-containing solid dissolves or disintegrates in the physiological fluid. (Item 3) 3. The dosage form according to item 2, wherein the drug-containing solid dissolves or disintegrates during or after transition into the viscous medium. (Item 4) 2. The dosage form of item 1, wherein the drug-containing solid expands due to permeation of physiological or bodily fluids into the three-dimensional structural framework of one or more elements. (Item 5) 2. The dosage form of item 1, wherein the drug-containing solid expands due to permeation of physiological or bodily fluids through the absorbent polymer excipient. (Item 6) 2. The dosage form of item 1, wherein at least one dimension of the drug-containing solid expands to at least 1.12 times its initial length during transition to a viscous medium. (Item 7) 2. The dosage form according to item 1, wherein the drug-containing solid expands to at least 1.4 times its initial volume during transition to a viscous medium. (Item 8) 2. The dosage form of item 1, wherein 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 physiological or bodily fluid. (Item 9) 2. The dosage form according to item 1, wherein the drug-containing solid expands to at least 1.4 times its initial volume within 20 minutes of immersion in a physiological or bodily fluid. (Item 10) 2. The dosage form according to item 1, wherein the drug-containing solid expands isotropically during transition to a viscous medium. (Item 11) 2. The dosage form according to item 1, wherein the geometric similarity of the three-dimensional structural framework of the elements is preserved upon expansion and transition into a fluidized or viscous medium. (Item 12) 2. The dosage form according to item 1, wherein at least one structural element expands isotropically during the transition to a fluid or viscous medium. (Item 13) 2. The dosage form of item 1, wherein 80 percent of the drug content in the drug-containing solid is released in less than 45 minutes after immersion in physiological or body fluid. (Item 14) 2. The dosage form of item 1, wherein the one or more elements expand substantially anisotropically such that the drug-containing solid transitions into a viscous mass, the viscous mass having a viscosity at least three orders of magnitude greater than the viscosity of the dissolution liquid. (Item 15) 2. The dosage form of item 1, wherein 80 percent of the drug content in the drug-containing solid is released in a time period between 30 minutes and 48 hours (e.g., between 30 minutes and 24 hours). (Item 16) 2. The dosage form of item 1, wherein the one or more elements comprise an average thickness of 2.5 mm or less (e.g., 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) 2. The dosage form according to item 1, wherein the effective free space spacing between the sections over the one or more free spaces is on average greater than 1 μm (e.g., greater than 5 μm, or 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) 2. The dosage 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) 2. The dosage form 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) 2. The dosage form according to item 1, wherein the three-dimensional structural framework of one or more elements comprises an ordered structure. (Item 21) 2. The dosage form of item 1, wherein the effective free space spacing and thickness of the elements are precisely controlled. (Item 22) 2. The dosage form according to item 1, wherein the three-dimensional structural framework of one or more thin structural elements comprises multiple stacks of elements or sections. (Item 23) 2. The dosage form according to item 1, wherein at least one element is a fiber. (Item 24) 2. The dosage form according to item 1, wherein the plies of fiber or fiber sections are layered in a cross-ply arrangement to form a three-dimensional structural scaffold. (Item 25) 2. The dosage form according to item 1, wherein the three-dimensional structural framework of one or more thin structural elements comprises a plurality of crisscross stacks of fiber-like structural elements. (Item 26) 26. The dosage form according to item 24 or item 25, wherein the spacing between adjacent fibers or adjacent fiber sections in a layer or ply is uniform or equally spaced. (Item 27) 2. The dosage form according to item 1, wherein at least one element is a sheet. (Item 28) 2. The dosage form according to item 1, wherein at least one element is a bead. (Item 29) 2. The dosage form according to item 1, wherein the surface of at least one element or the surface of at least one segment comprises a coating. (Item 30) 2. The dosage form according to item 1, wherein the coating comprises a highly hydrophilic surface composition to enhance the wetting rate of the scaffold or the penetration rate of fluids into the open pore network. (Item 31) 2. The dosage form according to item 1, wherein the 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) 2. The dosage form according to item 1, wherein the free space spacing between the sections and the composition of the surface of one or more of the elements are such that the penetration time of physiological fluids / body fluids into one or more interconnected free spaces of the drug-containing solid is less than 200 seconds under physiological conditions. (Item 33) 2. The dosage 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 thickness of said element divided by 3600 seconds. (Item 34) The effective diffusivity of physiological fluids / body fluids in an element or absorbent excipient is 1×10 under physiological conditions -12 m 2 13. The dosage form according to item 1, wherein the dosage form is greater than / s. (Item 35) 2. The dosage form according to item 1, wherein the at least one absorbent polymer excipient is selected from the group comprising hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, sodium alginate, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methyl ether cellulose, 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) 2. The dosage form of item 1, wherein at least one absorbent polymer excipient comprises a plurality of individual chains that unravel upon immersion in physiological fluid. (Item 37) 2. The dosage form according to 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) 2. The dosage form according to item 1, wherein the molecular weight of the 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) 2. The dosage form of claim 1, wherein the weight fraction of absorbent polymer excipient in the three-dimensional structural scaffold 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) 2. The dosage form according to item 1, wherein the drug molecules or drug particles are embedded in a matrix comprising an absorbent polymer excipient. (Item 41) 2. The dosage form according to 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 or body fluids under physiological conditions. (Item 42) 2. The dosage form according to item 1, wherein at least one active pharmaceutical ingredient comprises a pH-dependent solubility in physiological or bodily fluids. (Item 43) 43. The dosage form according to item 42, wherein at least one active pharmaceutical ingredient has at least 5-fold (e.g., at least 10-fold) higher solubility in an acidic solution than in a basic solution. (Item 44) 43. The dosage form according to item 42, wherein at least one active pharmaceutical ingredient is a basic compound. (Item 45) The dosage form of item 1 or any other item, wherein the tensile strength of the three-dimensional structural scaffold of one or more elements is between 0.01 MPa and 100 MPa (including but not limited to a 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) 2. The dosage form according to item 1, wherein less than five walls must be destroyed to obtain a cluster of interconnected void spaces from the outer surface to any point in the internal structure of the drug-containing solid. (Item 47) 2. The dosage form according to item 1, wherein at least one void space is surrounded by a wall to form a closed cell, and less than five walls must be destroyed to obtain a cluster of interconnected void spaces from the exterior surface to any point in the internal structure of the drug-containing solid. (Item 48) 2. The dosage form according to item 1, wherein the three-dimensional structural framework of the drug-containing solid or element has an average length, an average width, and an average thickness greater than 0.5 mm (e.g., 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) 1. A pharmaceutical dosage form comprising: a drug-containing solid having an exterior surface and an internal three-dimensional structural framework of one or more thin structural elements, said framework terminating adjacent to said exterior surface; the thin structural element comprises at least one active pharmaceutical ingredient, at least one absorbent polymer excipient, and at least one hydrophilic surface composition; the thin structural element further having sections spatially separated from adjacent sections thereby defining void spaces, a plurality of adjacent void spaces joining across the drug-containing solid to define one or more interconnected void spaces forming an open pore network; A pharmaceutical dosage form whereby, when immersed in a physiological fluid, the open pore network allows for uniform wetting of the structural framework and transition of the drug-containing solid into the viscous medium, thereby expanding in all dimensions, and during or after transition into the viscous medium, the drug-containing solid dissolves or disintegrates in the physiological fluid. (Item 50) 1. A drug-containing solid having an exterior surface and an internal three-dimensional structural framework comprising a plurality of crisscross laminated layers of fiber-like structural elements, said framework terminating adjacent to said exterior surface. 1. A pharmaceutical dosage form comprising: the fiber-like structural elements comprising at least one active pharmaceutical ingredient, at least one polymeric excipient, and at least one hydrophilic surface composition; the fiber-like structural elements further having sections spatially separated from similar sections of adjacent fiber-like elements, thereby defining void spaces, and a plurality of adjacent void spaces of successive layers defining one or more interconnected void spaces that combine to form an open pore network; The open pore network thereby allows for uniform wetting of the scaffold by physiological fluids; and A pharmaceutical dosage form that when immersed in a physiological fluid allows for the transition of said drug-containing solid into a viscous medium, thereby expanding in length and volume. (Item 51) 1. A drug-containing solid having an exterior surface and an internal three-dimensional structural framework comprising a plurality of crisscross laminated layers of fiber-like structural elements, said framework terminating adjacent to said exterior surface. 1. A pharmaceutical dosage form comprising: the fiber-like structural elements comprising at least one active pharmaceutical ingredient, at least one polymeric excipient, and at least one hydrophilic surface composition; the fiber-like structural elements further having sections spatially separated from similar sections of adjacent fiber-like elements, thereby defining void spaces, and a plurality of adjacent void spaces of successive layers joining to define one or more interconnected void spaces forming an open pore network; A pharmaceutical dosage form whereby, upon immersion in physiological fluid, the open pore network allows for uniform wetting of the scaffold and transfer of the drug-containing solids into the viscous medium, thereby expanding in all dimensions. (Item 52) 1. A method of making a pharmaceutical dosage form, comprising: 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 within the housing; heating the injected granular solid or solids to form a plasticized matrix or injecting a solvent to solvate at least one injected granular solid, such that the injected granular solid or solids form a plasticized matrix; conveying the plasticized matrix towards the outlet of the extrusion channel by applying a mechanical action to the plasticized matrix; extruding the plasticized matrix through an outlet to form at least one plasticized fiber; and Structuring at least one plasticized fiber into a three-dimensional structural scaffold of one or more drug-containing fibers. Including, A method in which, upon immersion in a physiological fluid, the three-dimensional scaffold is uniformly wetted and transitions to a viscous medium, thereby expanding in all dimensions. (Item 53) 53. The method of claim 52, wherein the step of structuring at least one plasticized fiber into a three-dimensional structured network of one or more drug-containing fibers is carried out by 3D patterning of the at least one plasticized fiber on a substrate. (Item 54) 53. The method of claim 52, wherein the three-dimensional structural scaffold of one or more drug-containing fibers comprises a plurality of crisscross stacks of fiber-like structural elements. (Item 55) 1. An apparatus for producing a pharmaceutical solid dosage form, comprising: an interior hollow housing having an interior surface enclosing and defining an extrusion channel having a first end, a second end, and a cross-section extending axially along its length from said first end to said second end and terminating at an outlet at said second end, the interior hollow housing having at least a first feed inlet between said first end and said second end for injecting at least one solid component into said extrusion channel, and at least a second feed inlet between said first feed inlet and said outlet for injecting at least one solvent into said extrusion channel to solvate the at least one injected solid component to form a plasticized matrix; at least one conveying element for extruding the plasticized matrix in the extrusion channel through an outlet to form at least one plasticized fiber; and A fiber structuring unit for structuring one or more plasticized fibers into a three-dimensional structured network of one or more drug-containing fibers. wherein, when immersed in a physiological fluid, the three-dimensional scaffold is uniformly wetted and transitions to a viscous medium, thereby expanding in all dimensions. (Item 56) Item 57. The apparatus of item 55, wherein the fiber structuring unit includes a translation or rotation stage. 57. The apparatus of claim 56, wherein the one or more plasticized fibers are structured into a three-dimensional structured network of one or more drug-containing fibers by 3D patterning the one or more plasticized fibers on a substrate defined by or attached to a translation or rotation stage. (Item 58) 56. The device of item 55, wherein the three-dimensional structural scaffold of one or more drug-containing fibers comprises a plurality of crisscross stacks of fiber-like structural elements. (Item 59) 1. An apparatus for producing a pharmaceutical solid dosage form, comprising: an interior hollow housing having an interior surface enclosing and defining an extrusion channel having a first end, a second end, and a cross-section extending axially along its length from said first end to said second end and terminating at an outlet at said second end, the interior hollow housing having at least a first feed port between said first end and said second end for injecting at least one solid component into said extrusion channel; at least one heating element for fluidizing the at least one injected solid component so that the injected solid component or components form a plasticized matrix in said extrusion channel; at least one conveying element for extruding the plasticized matrix in the extrusion channel through an outlet to form at least one plasticized fiber; and A fiber structuring unit for structuring one or more plasticized fibers into a three-dimensional structured network of one or more drug-containing fibers. wherein, when immersed in a physiological fluid, the three-dimensional scaffold is uniformly wetted and transitions to a viscous medium, thereby expanding in all dimensions. (Item 60) Item 61. The apparatus of item 59, wherein the fiber structuring unit includes a translation or rotation stage. 61. The apparatus of claim 60, wherein the one or more plasticized fibers are structured into a three-dimensional structured network of one or more drug-containing fibers by 3D patterning the one or more plasticized fibers on a substrate defined or mounted by a translation or rotation stage. (Item 62) 60. The device of item 59, wherein the three-dimensional structural scaffold of one or more drug-containing fibers comprises a plurality of crisscross stacks of fiber-like structural elements.

Claims

[Claim 1] The invention as depicted in the drawings.

Images