Expandable multi-excipient structured dosage forms for extended drug release

Abstract

To provide an expandable multi-excipient structured dosage form for extended drug release.SOLUTION: Many drug therapies can be greatly improved by dosage forms that reside in the stomach for an extended period of time and release the drug slowly. Accordingly, disclosed herein is an expandable structured dosage form for extended release. Dosage forms generally comprise a three dimensional structural framework of thin, solid elements. The elements comprise at least one drug, at least one physiological fluid-absorbing excipient, and at least one strength-enhancing excipient. Upon ingestion, the three dimensional structural framework expands in at least one dimension to form an expanded semi-solid mass that can be retained in the stomach for an extended period of time and release the drug.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] Cross-reference to related inventions This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 991,052, filed March 17, 2020, U.S. Provisional Application No. 63 / 085,893, filed September 30, 2020, and U.S. Provisional Application No. 63 / 158,870, filed March 9, 2021, each of which is incorporated by reference in its entirety. This application further claims priority to and the benefit of U.S. Application No. 16 / 860,911, filed April 28, 2020, entitled "Expandable structured dosage form for immediate drug delivery," and U.S. Application No. 16 / 916,208, filed June 30, 2020, entitled "Dosage form comprising structural framework of two-dimensional elements," each of which is incorporated by reference in its entirety.

[0002] This application is related to U.S. Application No. 15 / 482,776, filed April 9, 2017, entitled "Fibrous dosage form," U.S. Application No. 15 / 964,058, filed April 26, 2018, entitled "Method and apparatus for the manufacture of fibrous dosage forms," ​​International Application No. PCT / US19 / 19004, filed February 21, 2019, entitled "Expanding structured dosage form," and International Application No. PCT / US19 / 52030, filed September 19, 2019, entitled "Dosage form comprising structured solid-solution framework of sparingly-soluble drug and method for manufacture thereof," all of which are incorporated herein by reference in their entireties. [Background technology]

[0003] Background of the Invention Tablets and capsules, which are popular oral delivery dosage forms, are porous solids of compacted drug and excipient particles. As shown in Figure 1a, a typical ingested dosage form may fragment into its granular components in the stomach, releasing drug molecules. The drug particles and molecules then travel along the gastrointestinal tract, where the particles continue to dissolve and the drug molecules can be absorbed by the bloodstream. The drug that reaches the end of the gastrointestinal tract can be excreted.

[0004] However, many kinds of drugs cannot be optimally delivered by conventional solid dosage forms.For example, drugs that are soluble at very low pH but insoluble at higher pH can only be absorbed in the upper gastrointestinal tract.The residence time in the upper part is generally short; this can limit the amount of drug that can be absorbed and can make extended drug delivery impossible.As a result, the efficacy, safety and convenience of drug treatment can be impaired.

[0005] Drug absorption can be prolonged by a dosage form that resides in the stomach for an extended period of time and slowly releases the drug. Indeed, several gastroretentive devices have been proposed over the years. Floating and swellable dosage forms are the most common.

[0006] Floating dosage forms are designed to float on top of the stomach contents in the upper stomach, thus preventing passage into the small intestine. However, this concept generally requires that the stomach be frequently filled with food and drink and that the patient be in an upright position. Due to these requirements being difficult to implement, such dosage forms may not be preferred.

[0007] Swellable dosage forms must be smaller than the diameter of the esophagus (approximately 15-20 mm) to facilitate ingestion. Figure 1b. However, in the stomach, they must expand to a size much larger than the diameter of the pylorus (approximately 13-20 mm) to preclude immediate passage into the small intestine. However, current granular dosage forms typically do not expand quickly enough; their pores may not be well connected, and therefore the diffusion distance for water absorption may be too long.

[0008] The diffusion distance can be reduced by a fibrous dosage form having continuous void spaces through which water penetrates upon immersion. Thus, in International Application No. PCT / US19 / 19004, the present inventors (Blaesi and Saka) present a fibrous dosage form that rapidly swells due to fast water absorption by thin fibers. The swellable fibers can coalesce to form a viscous gel, from which drug molecules can be slowly released.

[0009] In a previous disclosure, a non-limiting experimental dosage form that expanded to twice its initial length in 15 minutes released 80% of the drug in approximately 2 hours. However, in some cases, the therapeutic benefit of an expandable gastroretentive dosage form may be greater if the drug release time can be controlled over even longer periods of time. Therefore, in this disclosure, new formulations and dosage form microstructures are presented to stabilize and strengthen the swollen dosage form without compromising its rapid expansion. Also disclosed are concepts to control and extend the rate and time range of drug release from stabilized swollen structured dosage forms. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Application No. PCT / US19 / 19004 Summary of the Invention [Means for solving the problem]

[0011] Summary of the Invention In one aspect, the invention herein includes fibers for the manufacture or construction of pharmaceutical dosage forms, the fibers comprising at least one active ingredient and at least two excipients forming the fibers; the at least two excipients comprising one or more fluid-absorbing polymeric components and one or more strength-enhancing polymeric components; upon exposure to physiological fluids, the one or more strength-enhancing excipients form a fluid-permeable semi-solid network that provides mechanical support to the fiber; and the one or more fluid-absorbing excipients transition, upon absorption of the physiological fluids, into a viscous mass or viscous solution that swells the fiber along at least one dimension.

[0012] In another aspect, the invention herein includes a fiber for manufacturing a pharmaceutical dosage form, the fiber comprising at least one active ingredient and at least two excipients forming the fiber; the at least two excipients comprising one or more fluid-absorbing polymeric components, wherein the solubility of physiological fluid (e.g., gastric fluid) in the fluid-absorbing polymeric components is greater than 600 mg / ml; the at least two excipients further comprising one or more strength-enhancing polymeric components; the one or more strength-enhancing polymeric components having a modulus of elasticity in the range of between 0.2 MPa and 500 MPa and a strain at break greater than 0.2 after immersion in physiological fluid (e.g., gastric fluid) under physiological conditions; upon exposure to physiological fluid, the one or more strength-enhancing excipients form a fluid-permeable, semi-solid network that mechanically supports the fiber; and the one or more fluid-absorbing excipients transition, upon absorption of the physiological fluid, to a viscous mass or viscous solution that swells the fiber along at least one dimension.

[0013] In some embodiments, the solubility of physiological fluids in the absorbable excipient is greater than 750 mg / ml.

[0014] In some embodiments, the rate of penetration of physiological / body fluids into the absorbent excipient under physiological conditions is greater than the average thickness of the element divided by 3600 seconds.

[0015] In some embodiments, the at least one absorbent excipient comprises hydroxypropyl methylcellulose.

[0016] In some embodiments, the molecular weight of the hydroxypropyl methylcellulose excipient is within the range between 30 kg / mol and 1000 kg / mol (eg, between 50 kg / mol and 300 kg / mol).

[0017] In some embodiments, the at least one absorbent excipient is hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, hydroxypropyl methyl ether cellulose, starch, chitosan, pectin, polymethacrylate (e.g., poly(methacrylic acid, ethyl acrylate) 1:1 or butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmethacrylat-copolymer), polyethylene oxide, or vinylpyrrolidone-acetic acid. The polymer is selected from the group comprising vinyl acid copolymers.

[0018] In some embodiments, the molecular weight of the at least one absorbent excipient is in the range of 30 kg / mol to 100,000 kg / mol (eg, between 50 kg / mol and 100,000 kg / mol).

[0019] In some embodiments, the solubility in the at least one strength-enhancing excipient in the relevant physiological fluid is 750 mg / ml or less (eg, 600 mg / ml or less) under physiological conditions.

[0020] In some embodiments, the at least one strength-enhancing excipient comprises an elastic modulus in the range of 0.3 MPa to 150 MPa (eg, 0.5 MPa to 100 MPa) after immersion in physiological fluids under physiological conditions.

[0021] In some embodiments, the at least one strength-enhancing excipient comprises a tensile strength in the range of 0.05 MPa to 200 MPa (eg, 0.1 MPa to 100 MPa) after immersion in physiological fluids under physiological conditions.

[0022] In some embodiments, the at least one strength-enhancing excipient comprises a strain at break greater than 0.3 (e.g., greater than 0.4, or greater than 0.5, or greater than 0.6) after immersion in physiological fluids under physiological conditions.

[0023] In some embodiments, the volume or weight fraction of one or more absorbent excipients in the fiber is in the range of between 0.1 and 0.85 (e.g., between 0.15 and 0.8 or between 0.15 and 0.75).

[0024] In some embodiments, the volume or weight fraction of one or more strength-enhancing excipients in the fiber is in the range between 0.15 and 0.9 (eg, 0.2-0.9, 0.25-0.9, 0.3-0.9).

[0025] In some embodiments, the at least one strength-enhancing excipient comprises an enteric polymer.

[0026] In some embodiments, the at least one strength-enhancing excipient comprises an enteric polymer that has at least 10 times greater solubility in a basic solution having a pH value greater than 7 than in an acidic solution having a pH value of 5 or less.

[0027] In some embodiments, the at least one strength-enhancing excipient comprises a methacrylic acid-ethyl acrylate copolymer.

[0028] In some embodiments, the at least one strength-enhancing excipient is selected from the group comprising hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate, ethyl acrylate polymers (e.g., polymers comprising ethyl acrylate), methacrylate polymers (e.g., polymers comprising methacrylate), ethyl acrylate-methyl methacrylate copolymer, poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], and ethyl cellulose.

[0029] In some embodiments, the at least two excipients form a solid solution across the thickness of the fiber.

[0030] In some embodiments, the phase or phases comprising the strength-enhancing excipients are substantially connected or substantially continuous along the length of the fiber.

[0031] In some embodiments, the fiber comprises a plurality of segments having substantially the same weight fraction of physiological fluid-absorbing excipient distributed therein.

[0032] In some embodiments, the fiber comprises multiple segments having substantially the same weight fraction of strength-enhancing excipient distributed therein.

[0033] In some embodiments, upon exposure to physiological fluids under physiological conditions, the diffusivity of the absorbent polymeric excipient in the fiber is greater than or equal to 10 -12 m 2 / s or less (e.g., 0.5 × 10 -12 m 2 / s or less or 0.2 × 10 -12 m 2 / s or less).

[0034] In some embodiments, upon exposure to physiological fluid under physiological conditions, the diffusivity of the physiological fluid in the fiber is greater than or equal to 0.2×10 -12 m 2 / s (e.g., 0.5 × 10 -12 m 2 / s greater than or equal to 10 -12 m 2 / s).

[0035] In some embodiments, upon exposure to physiological fluid, the fiber expands to a length between 1.3 and 4 times its length prior to exposure to the physiological fluid.

[0036] In some embodiments, upon exposure to physiological fluids, the fibers expand in all dimensions.

[0037] In some embodiments, upon exposure to physiological fluids, the fibers transition into a semi-solid mass.

[0038] In some embodiments, upon exposure to physiological fluids, the fibers transition into a semi-solid mass and the one or more strength-enhancing excipients form a connected network throughout the semi-solid mass.

[0039] In some embodiments, the expanded fiber or semi-solid mass maintains its length between 1.3 and 4 times its initial length for an extended period of time.

[0040] In some embodiments, the expanded semi-solid mass comprises a modulus of elasticity in the range of 0.005 MPa to 30 MPa (eg, between 0.005 MPa and 20 MPa or between 0.02 MPa and 20 MPa).

[0041] In some embodiments, the expanded semi-solid mass comprises a tensile strength in the range between 0.002 MPa and 20 MPa (eg, between 0.005 MPa and 15 MPa).

[0042] In another aspect, the invention herein includes a pharmaceutical dosage form comprising a drug-containing solid comprising an outer surface and an inner three-dimensional structural framework of one or more thin structural elements, said framework being adjacent to and terminating at said outer surface; said elements having segments spaced apart from their bordering segments, thereby defining one or more interconnected free spaces throughout the drug-containing solid; said elements further comprising at least one active ingredient and at least two excipients; said at least two excipients comprising at least one physiological fluid-absorbing polymeric component and at least one strength-enhancing polymeric component; upon immersion in physiological fluid, said fluid penetrates at least one interconnected free space and diffuses into one or more of said elements, resulting in the framework expanding in at least one dimension and transitioning into a semi-solid mass; and said semi-solid mass releasing drug over an extended period of time.

[0043] In some embodiments, upon exposure to physiological fluids, the strength-enhancing excipients form a fluid-permeable, semi-solid network to provide mechanical support to the scaffold; and the fluid-absorbing excipients transition, upon absorption of the physiological fluids, to a semi-solid or viscous mass that expands the scaffold along at least one dimension.

[0044] In a further aspect, the pharmaceutical dosage form comprises a drug-containing solid comprising an outer surface and an inner three-dimensional structural framework of one or more thin structural elements, said framework being adjacent to and terminating at said outer surface; said elements having segments spaced apart from bordering segments, thereby defining one or more interconnected free spaces throughout the drug-containing solid; said elements further comprising at least one active ingredient and at least two excipients; said at least two excipients comprising at least one physiological fluid-absorbing polymeric component and at least one strength-enhancing polymeric component; upon exposure to physiological fluid, said strength-enhancing excipients form a fluid-permeable semi-solid network that mechanically supports said framework; and said fluid-absorbing excipients transition, upon absorption of said physiological fluid, into a viscous mass or viscous solution that expands said framework along at least one dimension.

[0045] In a further aspect, the pharmaceutical dosage form herein comprises a drug-containing solid comprising an outer surface and an inner three-dimensional structural framework of one or more thin structural elements, said framework being contiguous with and terminating at said outer surface; said elements having segments spaced apart from bounding segments thereby defining one or more interconnected free spaces throughout the drug-containing solid; said elements further comprising at least one active ingredient and at least two excipients; said at least two excipients comprising one or more fluid-absorbing polymeric components, wherein the solubility of physiological fluid (e.g., gastric fluid) in the fluid-absorbing polymeric components is greater than 600 mg / ml; the at least two excipients further comprise one or more strength-enhancing polymeric components; the one or more strength-enhancing polymeric components have an elastic modulus in the range between 0.1 MPa and 500 MPa and a strain at break greater than 0.2 after immersion in physiological fluid (e.g., gastric fluid) under physiological conditions; upon exposure to physiological fluid, the one or more strength-enhancing excipients form a fluid-permeable semi-solid network that provides mechanical support to the fibers; and the one or more fluid-absorbing excipients, upon absorption of the physiological fluid, transition to a viscous mass or viscous solution that swells the fibers along at least one dimension.

[0046] In some embodiments, one or more phases comprising the strength-enhancing excipients form a substantially continuous or connected structure along the length of one or more structural elements.

[0047] In some embodiments, one or more phases comprising the strength-enhancing excipients form a substantially continuous or connected structure throughout the three-dimensional structural framework.

[0048] In some embodiments, upon ingestion by a human or animal subject, physiological fluids permeate at least one interconnected free space and diffuse into one or more of said elements, thereby expanding the scaffold in all dimensions and transitioning the scaffold into a semi-solid mass that releases the drug over time.

[0049] In some embodiments, upon exposure to physiological fluid, the scaffold expands to a length between 1.3 and 4 times its length prior to exposure to the physiological fluid.

[0050] In some embodiments, upon extended exposure to physiological fluids, the expanded scaffold or semi-solid mass maintains its length between 1.3 and 4 times its initial length for an extended period of time.

[0051] In some embodiments, the semi-solid mass comprises a substantially continuous or connected network of one or more strength-enhancing excipients.

[0052] In some embodiments, the semi-solid mass comprises a substantially continuous or connected network of strength-enhancing excipients that extends across the length, width and thickness of said semi-solid mass.

[0053] In some embodiments, one or more phases comprising the strength-enhancing excipients extend along the length of the structural element.

[0054] In some embodiments, the average thickness of the one or more structural elements is in the range of 1 μm to 1.5 mm.

[0055] In some embodiments, the one or more interconnected free spaces form an open pore network that extends over a length at least equal to the thickness of the drug-containing solid.

[0056] In some embodiments, the one or more interconnected free spaces terminate at the outer surface of the drug-containing solid.

[0057] In some embodiments, the free space is contiguous.

[0058] In some embodiments, the effective free spacing between segments across one or more interconnected free spaces is, on average, in the range of 1 μm to 2.5 mm.

[0059] In some embodiments, the free spacing between segments of one or more structural elements is precisely controlled across the drug-containing solid.

[0060] In some embodiments, the three-dimensional structural framework comprises a single, continuous structure throughout the drug-containing solid.

[0061] In some embodiments, the volume fraction of the structural elements within the drug-containing solid is within a range between 0.2 and 0.98 (eg, 0.25-0.98 or 0.3-0.98).

[0062] In some embodiments, the three-dimensional structural scaffold comprises crisscross stacked layers of fibers.

[0063] In some embodiments, the solubility in physiological fluids in the at least one absorbable excipient is greater than 700 mg / ml (eg, greater than 775 mg / ml or greater than 825 mg / ml).

[0064] In some embodiments, the rate of penetration of physiological / body fluids into the absorbent excipient under physiological conditions is greater than the average thickness of the element divided by 3600 seconds.

[0065] In some embodiments, the at least one absorbent excipient comprises hydroxypropyl methylcellulose.

[0066] In some embodiments, the molecular weight of the hydroxypropyl methylcellulose excipient is in the range between 45 kg / mol and 500 kg / mol.

[0067] In some embodiments, the at least one absorbent excipient is selected from the group comprising hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, hydroxyethyl 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), polyethylene oxide, or vinylpyrrolidone-vinyl acetate copolymer.

[0068] In some embodiments, the molecular weight of the at least one absorbent excipient is in the range of 50 kg / mol to 10,000 kg / mol.

[0069] In some embodiments, the solubility in the at least one strength-enhancing excipient in the relevant physiological fluid is 750 mg / ml or less under physiological conditions.

[0070] In some embodiments, the at least one strength-enhancing excipient comprises an elastic modulus in the range of 0.5 MPa to 100 MPa after immersion in physiological fluids under physiological conditions.

[0071] In some embodiments, the at least one strength-enhancing excipient comprises a tensile strength in the range of 0.05 MPa to 100 MPa after immersion in physiological fluids under physiological conditions.

[0072] In some embodiments, the at least one strength-enhancing excipient comprises a strain at break of greater than 0.5 after immersion in physiological fluid under physiological conditions.

[0073] In some embodiments, the volume or weight fraction of one or more absorbent excipients in the fiber is in the range between 0.15 and 0.8.

[0074] In some embodiments, the volume or weight fraction of one or more strength-enhancing excipients in the fiber is in the range of between 0.25 and 0.9.

[0075] In some embodiments, the at least one strength-enhancing excipient comprises an enteric polymer.

[0076] In some embodiments, the at least one strength-enhancing excipient comprises an enteric polymer that has at least 10 times greater solubility in a basic solution having a pH value greater than 7 than in an acidic solution having a pH value of 5 or less.

[0077] In some embodiments, the at least one strength-enhancing excipient comprises a methacrylic acid-ethyl acrylate copolymer.

[0078] In some embodiments, the at least one strength-enhancing excipient is selected from the group comprising hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate, ethyl acrylate polymers (e.g., polymers comprising ethyl acrylate), methacrylate polymers (e.g., polymers comprising methacrylate), ethyl acrylate-methyl methacrylate copolymer, poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], and ethyl cellulose.

[0079] In some embodiments, the at least two excipients form a solid solution across the thickness of the fiber.

[0080] In some embodiments, the phase or phases comprising the strength-enhancing excipients are substantially connected or substantially continuous along the length of the fiber.

[0081] In some embodiments, the element or framework comprises a plurality of segments having substantially the same weight fraction of physiological fluid-absorbing excipient distributed therein.

[0082] In some embodiments, the element or scaffold comprises multiple segments having substantially the same weight fraction of strength-enhancing excipients distributed therein.

[0083] In some embodiments, upon exposure to physiological fluids under physiological conditions, the diffusivity of the absorbent polymeric excipient in the fiber is greater than or equal to 10 -12 m 2 / s or less (e.g., 0.5 × 10 -12 m 2 / s or less or 0.2 × 10 -12 m 2 / s or less).

[0084] In some embodiments, upon exposure to physiological fluid under physiological conditions, the diffusivity of the physiological fluid in the fiber is greater than or equal to 0.2×10 -12 m 2 / s (e.g., 0.5 × 10 -12 m 2 / s greater than or equal to 10 -12 m 2 / s).

[0085] In some embodiments, at least one free space is filled with a substance that is removable by physiological fluids under physiological conditions.

[0086] In some embodiments, upon immersion in physiological fluid, the drug-containing solid transitions into a semi-solid mass comprising a length within a range of between 1.3 and 3.5 times its length prior to exposure to said physiological fluid within 300 minutes of immersion in said physiological fluid.

[0087] In some embodiments, upon immersion in physiological fluid, the drug-containing solid transitions into a semi-solid mass comprising a length within a range of between 1.3 and 3.5 times its length prior to exposure to said physiological fluid within 100 minutes of immersion in said physiological fluid.

[0088] In some embodiments, the expanded fiber or semi-solid mass maintains its length between 1.3 and 4 times its initial length for an extended period of time.

[0089] In some embodiments, the expanded semi-solid mass comprises a modulus of elasticity in the range of 0.002 MPa to 10 MPa.

[0090] In some embodiments, the expanded semi-solid mass comprises a tensile strength in the range between 0.001 MPa and 10 MPa.

[0091] In some embodiments, 80 percent of the drug content is released from the drug-containing solid into the physiological fluid within 1 hour to 30 days after immersion of the drug-containing solid in the physiological fluid under physiological conditions.

[0092] In some embodiments, 80 percent of the drug content is released from the drug-containing solid into physiological fluid within 2 to 150 hours after immersion of the drug-containing solid in said physiological fluid under physiological conditions.

[0093] In some embodiments, upon ingestion by a human or animal subject, the dosage form is gastroretentive.

[0094] Elements of embodiments described with respect to one aspect of the invention may be applied with respect to another aspect. By way of example and not limitation, certain embodiments of a claim described with respect to the first aspect may include features of a claim described with respect to the second or third aspect, and vice versa.

[0095] 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 explanation of the drawings]

[0096] [Figure 1] Figure 1 presents a schematic representation of the gastrointestinal transit of dosage forms: (a) conventional dosage form and (b) expandable fibrous dosage form. t: time; t0: initial time; tdis: disintegration time.

[0097] [Figure 2]FIG. 2 shows a non-limiting example of elements disclosed herein for dosage form construction or fabrication.

[0098] [Figure 3] FIG. 3 illustrates a non-limiting example of a pharmaceutical dosage form according to the present invention herein and its swelling and drug release process upon immersion in a dissolution medium.

[0099] [Figure 4] FIG. 4 illustrates another non-limiting example of a pharmaceutical dosage form according to the present invention herein and its swelling and drug release process upon immersion in a dissolution medium.

[0100] [Figure 5] FIG. 5 illustrates a non-limiting course of a dosage form herein after ingestion by a human or animal subject.

[0101] [Figure 6] FIG. 6 illustrates another non-limiting example of a pharmaceutical dosage form according to the invention herein and its swelling and drug release process upon immersion in a dissolution medium.

[0102] [Figure 7] Figure 7 presents a non-limiting schematic of water absorption and water concentration in fibers: (a) an initial solid fiber containing a solid solution of a drug, an absorbent excipient (HPMC), and a strength-enhancing excipient (enteric excipient), and (b) a viscous fiber at time t after immersion in acidic water. Because the solubility of acidic water is high for HPMC, low for the enteric excipient, and extremely low for the drug, the HPMC-enteric excipient-drug-water solution can be separated into three phases: (1) a highly viscous solution of water, HPMC, and dissolved drug molecules, (2) water-plasticized enteric excipient, and (3) drug particles.

[0103] [Figure 8] FIG. 8 shows non-limiting schematic microstructures of an expanding dosage form: (a) the initial structure and (b) the structure at time t after expansion.

[0104] [Figure 9] Figure 9 provides non-limiting schematics of drug release through expanded fibrous dosage forms: (a) φ~0, (b) 0<φ<1, and (c) φ~1. φ is the volume fraction of fibers in the dosage form.

[0105] [Figure 10] Figure 10 is a non-limiting schematic illustrating drug release from an swollen fiber containing both drug particles and drug molecules: (a) an swollen fiber in a stirred solution, (b) drug concentration versus radius r, assuming quasi-steady concentration profiles in the infinitesimally thin interfacial and particle-depleted regions. The particle-dispersed region (A), interfacial region (B), particle-depleted region (C), and solution outside the fiber (D) are also shown.

[0106] [Figure 11] Figure 11 shows a non-limiting schematic of drug release from an expanded semi-solid dosage form with 2R / λ~1: (a) the dosage form in a stirred solution, (b) drug concentration versus distance x, assuming a quasi-steady concentration profile in the particle-depleted region. A: particle-dispersed region, B: interfacial region, C: particle-depleted region, and D: solution.

[0107] [Figure 12] FIG. 12 shows a non-limiting schematic diagram of an expanded semi-solid dosage form exposed to cyclic loading.

[0108] [Figure 13] FIG. 13 presents a non-limiting dosage form according to the invention herein along with its microstructure.

[0109] [Figure 14] FIG. 14 presents non-limiting microstructural parameters of the dosage forms herein.

[0110] [Figure 15]FIG. 15 shows another non-limiting example of microstructural parameters of the dosage forms herein.

[0111] [Figure 16] FIG. 16 provides a non-limiting example of point contact between elements or segments.

[0112] [Figure 17] FIG. 17 is a non-limiting example of line contact between elements or segments.

[0113] [Figure 18] FIG. 18 presents non-limiting microstructures of elements herein before and after exposure to physiological fluids: (a) a solid solution of drug molecules, absorbent excipients, and strength-enhancing excipients; (b) a core-shell structure comprising a core of drug and absorbent excipients and a shell of strength-enhancing excipients; (c) dispersed particles of absorbent excipients and drug in a matrix of strength-enhancing excipients; and (d) dispersed particles of strength-enhancing excipients in a matrix of drug and absorbent excipients.

[0114] [Figure 19] FIG. 19 shows a non-limiting example of a dosage form disclosed herein and its swelling and drug release after exposure to physiological fluids.

[0115] [Figure 20] Figure 20 shows an image of a single fiber after immersion in the solution. The fiber transitioned from solid to viscous and swelled both radially and axially.

[0116] [Figure 21] Figure 21 presents experimental results of the expansion of a single fiber: (a) normalized radial expansion ΔR / R0 versus time t, (b) normalized axial expansion ΔL / L0 versus t, (c) ΔR / R0 versus t1 / 2, and (d) ΔL / L0 versus t1 / 2.

[0117] [Figure 22]Figure 22 presents images obtained from experiments of fibrous dosage forms after immersion in dissolution solutions. The volume fraction of fibers in the solid dosage forms, φ, was as follows: (a) φ = 0.16, (b) φ = 0.39, and (c) φ = 0.56.

[0118] [Figure 23] FIG. 23 plots the experimental results of normalized expansion of fibrous dosage forms: (a) ΔL / L0 versus time t and (b) ΔL / L0 versus t1 / 2 / R0.

[0119] [Figure 24] Figure 24 displays the experimental results of drug release by a single fiber: (a) fraction of released drug md / M0 versus time t and (b) md / M0 versus t1 / 2 / R0.

[0120] [Figure 25] FIG. 25 presents experimental results of drug release from fibrous dosage forms: (a) log-log plot of fraction of drug released md / M0 versus time t and (b) log-log plot of md / M0 versus t.

[0121] [Figure 26] Figure 26 shows a semi-logarithmic plot of t0.8 versus φ. The line is t0.8 = 0.58 × exp(7.35φ0).

[0122] [Figure 27] Scanning electron microscope images of uncoated and coated dosage forms: (a) top and (b) front views of the uncoated dosage form, (c) top and (d) front views of the coated dosage form, and (f) cross section of the coated fiber.

[0123] [Figure 28] Top view images of dosage forms after immersion in dissolution medium: (a) uncoated dosage form, and (b) enteric coated dosage form.

[0124] [Figure 29]Normalized radial expansion of the dosage form ΔRdf / Rdf,0 versus time t.

[0125] [Figure 30] Images of dosage forms during diametral compression: (a) uncoated and (b) coated dosage forms.

[0126] [Figure 31] (a) Load P vs. displacement δ per unit length for uncoated and coated dosage forms, and (b) dP / dδ vs. δ in diametral compression. The inset in Figure 6a shows a schematic of the load applied to a uniform, isotropic, linear elastic cylinder compressed by diametrally opposed flat platens. P is the load intensity or force per unit thickness. Rdf is the radius of the cylinder (or expanded dosage form). The small arrows represent the Hertzian contact pressure distributed over the contact width 2a.

[0127] [Figure 32] Images of the expanded coated dosage form before (left) and after (right) diametric compression. The compression-tested coated dosage form had visible cracks within the axis of symmetry.

[0128] [Figure 33] Location and structure of an uncoated dosage form after administration to fasted dogs. Dry food was offered 4-6 hours after administration; this is visible in the bottom row of images. Images were obtained by biplane fluoroscopy. Images show the ventral side in a lateral view (cranial left, caudal right).

[0129] [Figure 34] Location and structure of coated dosage forms after administration to fasted dogs. Dry food was given 4-6 and 30 hours after administration. Images were obtained by biplane fluoroscopy. Images show the ventral side in a lateral view (cranial left, caudal right).

[0130] [Figure 35] Expansion of dosage form radius in vivo and comparison with in vitro data: (a) Uncoated and coated dosage forms in vivo, and (b) In vivo / in vitro comparison of uncoated and coated dosage forms.

[0131] [Figure 36] Short-time fluoroscopic image series during a contraction pulse by the stomach wall: (a) uncoated dosage form, 2 hours after administration and (b) coated dosage form, 7 hours after administration.

[0132] [Figure 37] FIG. 37 presents experimental results of physiological fluid sorption by the viscosity-enhancing excipients herein.

[0133] [Figure 38] Nominal tensile stress σ versus engineering strain ε in thin, acidic water-soaked tensile specimen films of Eudragit L100-55. Stress was derived as follows: σ = F / Wh, where F is the force applied by the grips, W is the width of the thin section of specimen film, and h is its thickness. Engineering strain ε = ΔL / L0, where ΔL is the distance traveled by the grips and L0 is the initial distance between the grips.

[0134] [Figure 39] Figure 39 presents a non-limiting schematic of the gastrointestinal transit of a drug and the drug concentration in the blood versus time. Top row: granular dosage form. Bottom row: expandable fibrous dosage form. DETAILED DESCRIPTION OF THE INVENTION

[0135] definition In order that this disclosure may be more readily understood, certain terms are first defined below. Additional definitions for these and other terms are set forth throughout the specification.

[0136] In this application, the use of "or" means "and / or" unless otherwise specified. As used in this application, the term "comprise" and variations of this term, 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 cover any normal variations understood by one of ordinary skill in the art.

[0137] Furthermore, in this disclosure, the terms "one or more active ingredients" and "drug" are used interchangeably. As used herein, "active ingredient" or "active agent" or "drug" refers to an agent whose presence or level correlates with an elevated target level or activity compared to that observed in the absence of the agent (or a different level of the agent). In some embodiments, the active ingredient is an active ingredient whose presence or level correlates with a target level or activity that is comparable to or greater than a particular reference level or activity (e.g., that observed under appropriate reference conditions, e.g., in the presence of a known active agent, e.g., a positive control).

[0138] Furthermore, in the context of some embodiments herein, a three-dimensional structural framework (or network) of one or more elements includes a drug-containing structure (e.g., an assembly or assemblage or arrangement or skeleton or skeletal structure or three-dimensional lattice structure of one or more drug-containing elements) that extends across a length, width, and thickness of greater than 100 μm, including, but not limited to, a drug-containing structure that extends across 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.

[0139] In other embodiments, the three-dimensional structural framework (or network) of drug-containing elements may include drug-containing structures (e.g., an assembly or assemblage of one or more elements or a backbone or skeletal structure) that extend over a length, width, and thickness that is greater than the average thickness of at least one element (or at least one segment) in the three-dimensional structural framework (or network) of elements, including, but not limited to, drug-containing structures 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 the average thickness of at least one element (or at least one segment) in the three-dimensional structural framework (or network) of elements.

[0140] In some embodiments, the three-dimensional structural framework (or network) of the drug-containing elements is continuous. Further, in some embodiments, the drug-containing elements are linked to one another or interpenetrating.

[0141] It may be noted that the terms "three-dimensional structural network," "three-dimensional structural framework," and "three-dimensional lattice structure" are used interchangeably herein. Also, the terms "three-dimensional structural framework of drug-containing elements," "three-dimensional structural framework of elements," "three-dimensional structural framework of one or more elements," "three-dimensional structural framework of one or more drug-containing elements," "three-dimensional framework of elements," "three-dimensional structural framework of fibers," "three-dimensional framework," "structural framework," etc. are used interchangeably herein.

[0142] As used herein, a "structural element" or "element" refers to a two-dimensional element (or two-dimensional structural element), or a one-dimensional element (or one-dimensional structural element), or a zero-dimensional element (or zero-dimensional structural element).

[0143] As used herein, a two-dimensional structural element is said to have a length and width that are significantly greater than its thickness. In the present disclosure, the length and width of a two-dimensional structural element are more than twice its thickness. An example of such an element is a "sheet." A one-dimensional structural element is said to have a length that is significantly greater than its width or thickness. In the present disclosure, the length of a one-dimensional structural element is more than twice its width and thickness. An example of such an element is a "fiber." A zero-dimensional structural element is said to have a length and width on the order of its thickness. In the present disclosure, the length and width of a zero-dimensional structural element are no more than twice its thickness. Furthermore, the thickness of a zero-dimensional element is less than 2.5 mm. An example of such a zero-dimensional element is a "particle" or "bead," which includes a polyhedron, a sphere, an ellipsoid, or a cluster thereof.

[0144] Furthermore, for purposes of the invention herein, a segment of a one-dimensional element is a portion of said element along its length. A segment of a two-dimensional element is a portion of said element along its length and / or width. A segment of a zero-dimensional element is a portion of said element along its length and / or width and / or thickness. The terms "segment of a one-dimensional element," "fiber segment," "segment of a fiber," and "segment" are used interchangeably herein. Also, the terms "segment of a two-dimensional element" and "segment" are used interchangeably herein. Also, the terms "segment of a zero-dimensional element" and "segment" are used interchangeably herein.

[0145] As used herein, the terms "fiber," "fibers," "one or more fibers," "one or more drug-containing fibers," and "drug-containing fiber" are used interchangeably. They are understood to refer to solid drug-containing structural elements (or building blocks) that constitute part or all of a three-dimensional structural network (e.g., part or all of a dosage form structure, or part or all of a drug-containing solid structure, etc.). A fiber has a length that is significantly greater than its width and thickness. In the present disclosure, a fiber is said to have a length that is greater than twice its width and thickness (e.g., the length is greater than twice the fiber width, the length is greater than twice the fiber thickness). This includes, but is not limited to, fiber lengths that 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 fiber width and thickness. In other embodiments included but not limited to within this disclosure, the length of the fibers may be greater than 0.3 mm, or greater than 0.5 mm, or greater than 1 mm, or greater than 2.5 mm.

[0146] Furthermore, as used herein, the term "fiber segment" or "segment" refers to a portion of a fiber along the length of said fiber.

[0147] In the invention herein, fibers (or fiber segments) can be joined so that they can serve as building blocks of "assembled structural elements" having geometries different from that of the original fibers. Such assembled structural elements include two-dimensional, one-dimensional, or zero-dimensional elements.

[0148] For purposes of the 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 (e.g., one or more drug particles or drug molecules, or clusters thereof, etc.) embedded in or attached to the solid element (or solid dosage form, or solid matrix, or three-dimensional structural framework, or drug-containing solid) to drug in the dissolution medium.

[0149] A poorly soluble drug herein includes an active ingredient or drug having a solubility in physiological or body fluids (or dissolution media or aqueous solutions) under physiological conditions of less than 1 mg / ml. This includes, but is not limited to, a solubility in physiological or body fluids under physiological conditions of less than 0.5 mg / ml, or less than 0.2 mg / ml, or less than 0.1 mg / ml, or less than 0.05 mg / ml, or even less. It may be noted that the terms "sparingly soluble drug," "poorly water-soluble drug," and "poorly soluble drug" are used interchangeably herein.

[0150] As used herein, the terms "dissolution medium," "physiological fluid," "body fluid," "dissolution solution," "medium," "fluid," "aqueous solution," and "osmotic agent" are used interchangeably. They are understood to refer to any fluid produced by or contained within the human body under physiological conditions, or any fluid resembling a fluid produced by or contained within the human body under physiological conditions. Generally, dissolution fluids contain water and may therefore be aqueous. Examples include, but are not limited to, water, saliva, gastric fluid, gastrointestinal fluid, saline, etc., at a temperature of 37° C. and with pH adjusted to appropriate physiological conditions.

[0151] Furthermore, for purposes of the invention herein, an "absorbable excipient" is considered to be an excipient that "absorbs" gastric fluid or related physiological fluid under physiological conditions. Generally, the absorbable excipient is a solid, semi-solid, or viscoelastic material in its dry state at room temperature. However, upon contact with (e.g., immersion in) gastric fluid or related physiological fluid under physiological conditions, the absorbable excipient can absorb the fluid and form a solution or mixture with the fluid having a weight fraction of gastric fluid or related physiological fluid greater than 0.4. This includes, but is not limited to, forming a solution or mixture with a weight fraction of gastric fluid or related physiological fluid greater than 0.5, greater than 0.6, greater than 0.7, greater than 0.75, greater than 0.8, greater than 0.85, greater than 0.9, or greater than 0.95. In other words, the solubility of gastric fluid or related physiological fluid in the absorbable excipient under physiological conditions is generally greater than about 400 mg / ml. This includes, but is not limited to, a solubility in gastric or related physiological fluids in the absorbable excipient of greater than 500 mg / ml, or greater than 600 mg / ml, or greater than 700 mg / ml, or greater than 750 mg / ml, or greater than 800 mg / ml, or greater than 850 mg / ml, or greater than 900 mg / ml, or greater than 950 mg / ml. Preferably, the absorbable excipient is mutually soluble with the relevant physiological fluid. In the present invention, "relevant physiological fluid" is understood to mean the relevant physiological fluid surrounding the dosage form in the relevant physiological application. For example, if the dosage form is a gastroretentive dosage form, the relevant physiological fluid is gastric fluid. Non-limiting examples of preferred absorbable high molecular weight excipients may include, but are not limited to, water-soluble polymers with large molecular weights and amorphous molecular structures, such as hydroxypropyl methylcellulose having a molecular weight greater than 50 kg / mol or hydroxypropyl methylcellulose having a molecular weight in the range between 50 kg / mol and 300 kg / mol. The terms "physiological fluid-absorbing excipient," "absorbent excipient," "fluid-absorbing excipient," and "water-absorbing excipient" are used interchangeably herein.

[0152] Furthermore, in the invention herein, a "strength-enhancing excipient" is also generally a solid, semi-solid, or viscoelastic material in a dry state at room temperature. However, upon contact with (e.g., immersion in) gastric fluid or related physiological fluids under physiological conditions, the strength-enhancing excipient absorbs the fluid much less, and therefore remains a semi-solid, viscoelastic, or highly viscous material. Generally, the solubility of gastric fluid or related physiological fluids in the strength-enhancing excipient under physiological conditions is 800 mg / ml or less. This includes, but is not limited to, a solubility of gastric fluid or related physiological fluids in the strength-enhancing excipient under physiological conditions of 750 mg / ml or less, or 700 mg / ml or less, or 650 mg / ml or less, or 600 mg / ml or less, or 550 mg / ml or less, or 500 mg / ml or less, or 450 mg / ml or less, or 400 mg / ml or less. In a non-limiting extreme example, the relevant physiological fluids may be insoluble or virtually insoluble in the strength-enhancing excipient.

[0153] However, the relevant physiological fluid typically has poor solubility in the strength-enhancing excipient. Thus, upon immersion of the strength-enhancing excipient in the relevant physiological fluid, the stiffness (e.g., modulus) or viscosity of the strength-enhancing excipient may decrease somewhat compared to the stiffness or viscosity of the dry strength-enhancing excipient. Similarly, upon immersion of the strength-enhancing excipient in the relevant physiological fluid, the strain at failure of the strength-enhancing excipient may increase compared to the strain at failure of the dry strength-enhancing excipient. Because the strength-enhancing excipient may be a semi-solid, viscoelastic, or highly viscous material even after prolonged immersion in the relevant physiological fluid, it is also referred to herein as a "stabilizing excipient," "viscoelastic excipient," or "semi-solid excipient."

[0154] Furthermore, for purposes of the invention herein, a "solid solution" of at least two components (e.g., at least two excipients) is considered a solid having at least two components partially or completely dissolved (e.g., molecularly dispersed or molecularly intermixed) with one another. This includes, but is not limited to, a first component (e.g., a first excipient) dissolved, dispersed, or intermixed with a second component (e.g., a second excipient), or a second component dissolved, dispersed, or intermixed with the first component. The solid solution may have a molecular configuration or crystalline structure that is the same as or similar to that of the first component, or the same as or similar to that of the second component, or a molecular configuration or crystalline structure that is different from that of the first component and different from that of the second component. However, often, at least two components are amorphous polymers, and the resulting solid solution is also an amorphous polymer. Furthermore, often in preferred embodiments, the concentrations of the at least two molecularly dispersed components forming the solid solution are substantially uniform throughout the solid solution. By way of example and not limitation, in solid materials, solid solutions can be experimentally detected or demonstrated by methods such as differential scanning calorimetry, X-ray spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, and the like. For more information regarding solid solutions, see, for example, International Application No. PCT / US19 / 52030, filed September 19, 2019, entitled "Dosage form comprising a structured solid-solution framework of a sparingly soluble drug and method for manufacture thereof," and any references therein.

[0155] Further information regarding the definitions, characteristics, features, composition, analysis, etc. of the disclosed dosage forms and elements for making or constructing them is provided throughout this specification. Scope of the invention

[0156] It is contemplated that particular features described individually or as part of an embodiment in this disclosure may be combined with other individually described features or parts of other embodiments, even if the other features and embodiments do not mention the particular feature. Thus, 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, not limitation. Therefore, it should be understood that the invention herein is not limited to these precise embodiments. Other embodiments apparent to those skilled in the art are within the scope of the claimed invention.

[0157] By way of example, and not limitation, the compositions, systems, devices, methods, and processes of the claimed inventions are intended to 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 practiced by those skilled in the art.

[0158] Furthermore, when compositions, articles and devices are described as having, including or comprising particular components, or processes and methods are described as having, including or comprising particular steps, it is also contemplated that there are compositions, articles and devices of the invention that consist essentially of or consist of the recited components, and that there are processes and methods according to the invention that consist essentially of or consist of the recited processing steps.

[0159] Similarly, when compositions, articles, and devices are described as having, including, or comprising particular compounds and / or materials, it is further contemplated that there are compositions, articles, and devices of the invention that consist essentially of, or consist of, the listed compounds and / or materials.

[0160] 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.

[0161] The citation of any publication herein 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. Detailed Description of the Invention Aspects of the elements

[0162] As shown schematically in Figure 2a, dosage forms 200 disclosed herein generally comprise a drug-containing solid 201 having an outer surface 202 and an inner structure 204 comprising one or more elements 210. A non-limiting example of a single element 210, e.g., fiber 210, for construction or manufacture of a pharmaceutical dosage form is illustrated in the inset of Figure 2a. The fiber or element 210 comprises at least one active ingredient 220 and at least two excipients 230, 240 that form the element or fiber 210. The at least two excipients 230, 240 comprise one or more fluid-absorbing polymeric components 230 and one or more strength-enhancing polymeric components 240.

[0163] Upon exposure to physiological fluid 260, such as saliva, gastric fluid, or physiological-like fluid, one or more strength-enhancing excipients 240 form a fluid-permeable, semi-solid network 242 that provides mechanical support to elements or fibers 210 (FIGS. 2b-2e). Additionally, one or more fluid-absorbing excipients 230, upon absorption of the physiological fluid 260, transition to a viscous mass or viscous solution 232 that swells the elements or fibers 210 along at least one dimension.

[0164] 2a shows a further non-limiting example of a single element 210, e.g., fiber 210, for the construction or manufacture of a pharmaceutical dosage form. The element or fiber 210 includes at least one active ingredient 220 and at least two excipients 230, 240 that form the element or fiber 210. The at least two excipients 230, 240 include one or more fluid-absorbing polymeric components 230, in which the solubility of physiological fluid is greater than 750 mg / ml. The at least two excipients 230, 240 further include one or more strength-enhancing polymeric components 240. The one or more strength-enhancing polymeric components 240 have a modulus of elasticity in the range of between 0.1 MPa and 200 MPa and a strain at break greater than 0.5 after immersion in said physiological fluid under physiological conditions. Preferably, further, the one or more strength-enhancing polymeric components 240 form one or more phases that are substantially connected and / or substantially continuous along the length of the element or fiber 210. Generally, a "phase" is understood herein as a region or space within the element or fiber 210 in which many or all physical properties are substantially uniform or constant throughout. By way of example and not limitation, a solid solution including strength-enhancing excipients 240 includes a "phase comprising one or more strength-enhancing excipients."

[0165] Upon exposure to the physiological fluid 260, the fluid 260 diffuses into the element or fiber 210, thereby causing the element or fiber 210 to expand in at least one dimension to a length between 1.3 and 4 times its length prior to exposure to the physiological fluid 260. Figures 2b and 2c. By way of example and not limitation, the initial thickness h0 of the element or fiber 210 (also referred to herein as "thickness prior to exposure to the physiological fluid") may expand to a length h(t1) = 1.3-4x h0 upon exposure to the physiological fluid 260.

[0166] Also, upon exposure to the physiological fluid 260, the elements or fibers 210 transition into a semi-solid mass 212. The semi-solid mass 212 may maintain its length between 1.3 and 4 times its initial length for an extended period of time. FIGS. 2c-2e. The term "semi-solid mass maintaining its length between 1.3 and 4 times its initial length for an extended period of time" refers herein to a semi-solid mass immersed in unstirred or lightly stirred dissolving solution (e.g., acidic water), wherein the immersed semi-solid mass maintains its length between 1.3 and 4 times its initial length for an extended period of time, e.g., for more than 1 hour, or more than 2 hours, or more than 5 hours, or even longer.

[0167] Additionally, within or throughout the elements or fibers 210 or semi-solid mass 212, the one or more strength-enhancing excipients 240 form a fluid-permeable semi-solid network 242 that mechanically supports the elements or fibers or semi-solid mass 210, 212. Additionally, the one or more fluid-absorbing excipients 230, upon absorption of the physiological fluid 260, transition into a viscous mass or viscous solution 232 that swells the elements or fibers 210 in at least one dimension.

[0168] In general, one or more strength-enhancing excipients may be noted to "form a fluid-permeable, semi-solid network to mechanically support the element or fiber or semi-solid mass" within or throughout an element if the mechanical strength or stiffness (e.g., modulus, tensile strength, etc.) of the element after exposure to physiological fluid is substantially greater than the mechanical strength or stiffness of the element comprising the fluid-absorbent excipient alone (e.g., without the strength-enhancing excipient) after exposure to physiological fluid. By way of example and not limitation, one or more strength-enhancing excipients "form a fluid-permeable, semi-solid network to mechanically support the element or fiber or semi-solid mass" within or throughout an element if the tensile strength or modulus of the element after exposure to physiological fluid is at least two times greater than the tensile strength or modulus of the corresponding element comprising the fluid-absorbent excipient alone (e.g., without the strength-enhancing excipient) after exposure to physiological fluid. This includes, but is not limited to, a tensile strength or modulus of an element comprising one or more strength-enhancing excipients that form a "fluid-permeable semi-solid network to provide mechanical support for the element or fiber or semi-solid mass" after exposure to physiological fluid that is at least three times greater, or at least four times greater, or at least five times greater, or at least six times greater, or at least seven times greater than the tensile strength or modulus of a corresponding element comprising the fluid-absorbent excipient alone (e.g., without the strength-enhancing excipient) after exposure to said physiological fluid. Dosage form

[0169] Figure 3a shows a non-limiting example of a pharmaceutical dosage form disclosed herein. Dosage form 300 comprises a drug-containing solid 201 having an outer surface 302 and an inner three-dimensional structural framework 304 (e.g., a lattice structure, network, skeleton, etc.) of one or more thin structural elements 310. For purposes of 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. Thin structural elements 310 are also referred to herein as "elements" or "structural elements." Structural elements 310 may comprise fibers, beads, sheets, or combinations thereof.

[0170] The scaffold 304 is adjacent to and terminates at the outer surface 302. In preferred embodiments, the structural scaffold 304 forms a single continuous or connected structure throughout the drug-containing solid 301 (e.g., where every element 310 may be bonded to at least another element 310 to form a single continuous structure). Furthermore, in preferred embodiments, the one or more thin structural elements 310 are arranged in an orderly or substantially orderly manner.

[0171] The elements 310 may further include segments spaced apart from segments of the bounding elements or segments, thereby defining one or more interconnected free spaces 315 throughout or across the drug-containing solid 301. For purposes of the invention herein, a free space 315 is considered "interconnected throughout or across the drug-containing solid" if it extends across at least half the thickness of the drug-containing solid 301 (e.g., if the free space 315 is continuous or connected). This includes, but is not limited to, a free space 315 extending across at least two-thirds the thickness of the drug-containing solid 301, or a free space 315 extending across a length at least equal to the thickness of the drug-containing solid 301. Furthermore, in preferred embodiments, the one or more interconnected free spaces 315 are connected to the outer surface 302. Thus, it is not necessary to rupture a wall (e.g., a wall comprising the three-dimensional structural framework 304 of element 310) to obtain an interconnected free space 315 (e.g., an open channel of free space 315) from the outer surface 302 of drug-containing solid 301 to a point or location (or any point) in said interconnected free space 315. Furthermore, typically, at least one of said one or more interconnected free spaces 315 is filled with a substance (e.g., a gas, a solid highly soluble in said physiological fluid, etc.) that is removable by physiological fluid under physiological conditions.

[0172] A non-limiting example of a preferred inner three-dimensional structural framework 304 includes multiple crisscross stacked layers of fibrous elements 310. Herein, the crisscross stacked layers of fibrous elements 310 are referred to as plies (e.g., "layers" or "planes") of fibers 310 or fiber segments stacked in a cross-ply arrangement. In a cross-ply arrangement, the fibers 310 (or fiber segments) in a ply (or "layer" or "plane") are oriented transversely or at an angle relative to the fibers 310 in the plies above or below. Furthermore, in a cross-ply structure, the free space 315 typically extends throughout the length, width, and thickness of the drug-containing solid 301. Furthermore, the free space 315 is continuous with and terminates at the outer surface 302 of the drug-containing solid 301. Further details regarding how interconnected free spaces 315 are defined herein, what they may consist of, and how their lengths may be measured are provided in FIG. 13 and the section "Dosage Form Embodiments" herein.

[0173] Further, in the invention herein, the structural element 310 comprises at least one active ingredient 320, 325 (e.g., at least one drug) and at least two excipients 330, 340 (also referred to herein as "dual excipients"). Typically, the at least one active ingredient 320, 325 is dispersed in at least one of the at least two excipients 330, 340, either as active ingredient molecules 320 or as particles 325 comprising the at least one active ingredient. Thus, the at least two excipients 330, 340 (or all of the excipients, or the excipient as a whole) may form a continuous or connected structure throughout one or more elements 310 (e.g., throughout the thickness of one or more elements, and / or throughout the length of one or more elements, and / or throughout the width of one or more elements) or throughout the three-dimensional structural framework 304. Additionally, in some preferred embodiments, the at least two excipients 330, 340 may form a solid solution.

[0174] The at least two excipients 330, 340 further include at least one physiological fluid-absorbing polymeric component 340 (eg, a water-absorbing polymeric component) and at least one strength-enhancing polymeric component 340.

[0175] As shown schematically in non-limiting FIG. 3b, upon immersion of dosage form 300 or drug-containing solid 301 in dissolution fluid 260 (e.g., acidic water, gastric fluid, relevant physiological fluid, relevant physiological-like fluid, etc.), fluid 360 may penetrate or access interconnected free spaces 315 and wet structural framework 304, 310. For purposes of the invention herein, a surface (e.g., a surface of three-dimensional structural framework 304, 310) is "wetted by a fluid" if the fluid is in contact with (e.g., in direct contact with) the surface. Furthermore, a surface is generally understood herein to be "uniformly wetted" by a fluid if at least 20-70 percent of the area of ​​the surface is in contact with (e.g., in direct contact with) the fluid. In a preferred embodiment herein, upon immersion of the drug-containing solid 301 in physiological fluid 360, at least 60 to 70 percent of the surface of the three-dimensional structural framework 304, 310 (or coating of the three-dimensional structural framework 304, 310) is wetted by (e.g., contacted by) the fluid at a time within a range between the time of immersion and 600 seconds after the time of immersion.

[0176] The fluid 360 may then diffuse or infiltrate into the three-dimensional structural framework 304 or elements 310 or segments that it surrounds. Furthermore, as water or dissolved fluid or physiological fluid 360 diffuses into the elements 310, they may expand as the mass and volume of the fluid 360 in the elements 310 increases. Thus, in some embodiments, the drug-containing solid 301 or the three-dimensional structural framework 304, 310 expands due to the infiltration (e.g., diffusion or influx) of physiological fluid or bodily fluid 360 into the three-dimensional structural framework 304, 310 of the elements.

[0177] It may be noted that within or throughout one or more elements or scaffolds 210, 304, 310, one or more strength-enhancing excipients 240 may form a fluid-permeable semi-solid network 242 that mechanically supports the elements or scaffolds 210, 304, 310, as shown schematically in Figures 2c-2e. Also, one or more fluid-absorbing excipients 230, 330 may transition, upon absorption of said physiological fluids 260, 360, into a viscous mass or viscous solution 232 that swells said elements or scaffolds 210, 304, 310 in at least one dimension.

[0178] Furthermore, if the three-dimensional structural framework 304, 310 is uniformly wetted and the composition and geometry (e.g., element thickness, etc.) are substantially uniform throughout the three-dimensional structural framework 304, 310, the drug-containing solid 301 or the three-dimensional structural framework 304, 310 may expand uniformly in all dimensions, as shown diagrammatically in the non-limiting Figure 3c. The terms "expanding in all dimensions," "expand in all dimensions," or "expansion in all dimensions" are understood as an increase in the length of the sample (e.g., the length and / or width and / or thickness of the sample) and an increase in the volume of the sample. Thus, pure shear deformation is not considered "expansion in all dimensions" herein.

[0179] The expansion of dosage form 300 or drug-containing solid 301 can be substantial, as shown schematically in Figures 3b and 3c. Thus, in some embodiments, at least one dimension of drug-containing solid 301, 304 (e.g., side length of drug-containing solid or scaffold 301, 304, thickness of drug-containing solid or scaffold 301, 304, etc.) expands upon immersion in said physiological fluid 360 to at least 1.3 times its initial value (e.g., initial length, or length prior to exposure to said physiological fluid 360). This includes, but is not limited to, at least one dimension of the drug-containing solid expanding upon immersion in or exposure to dissolution solution 360 to at least 1.35 times, or at least 1.4 times, or at least 1.45 times, or at least 1.5 times, or at least 1.55 times, or at least 1.6 times, or at least 1.65 times, or at least 1.7 times, or at least 1.75 times, or at least 1.8 times, or at least 1.85 times, or at least 1.9 times its initial value.

[0180] Additionally, in some embodiments, the dosage form 300 or drug-containing solid or scaffold 301, 304 expands to at least twice its initial volume upon immersion in or exposure to physiological fluid 360 under physiological conditions. This includes, but is not limited to, a drug-containing solid or scaffold 301, 304 that expands to at least 2.5 times its initial volume, or at least 3 times, or at least 3.5 times, or at least 4 times, or at least 4.5 times, or at least 5 times, or at least 5.5 times its initial volume upon immersion in or exposure to physiological fluid 360.

[0181] The rate of expansion generally depends on the rate at which the physiological fluid 360 is absorbed by the structural scaffold 304, 310 (e.g., by one or more absorbent polymeric excipients 330, etc.), as well as the presence and stringency of constraints to expansion. The rate at which physiological fluid 360 is absorbed by the scaffold 304, 310 typically increases when the specific surface area (e.g., the ratio of surface area to volume) of the scaffold 304, 310 increases. Thus, if the element 310 is thin, the surface area to volume ratio is typically large, and the rate at which physiological fluid 360 is absorbed by the scaffold 304, 310 can be faster.

[0182] Constraints on expansion may originate, for example, from non-uniformity in physiological fluid 360 concentration across the three-dimensional structural framework 304, 310. By way of example and not limitation, a wetted element or segment may absorb physiological fluid, but the expansion of the wetted element or segment may be constrained if it is connected (e.g., attached) to a dry, solid element or segment that does not expand. Therefore, to minimize constraints on expansion, uniform wetting of the elements in the structural framework may be crucial. Uniform wetting is made possible, among other things, by interconnected free spaces (e.g., continuous free spaces through which physiological fluid can permeate) and by the hydrophilic surface composition of the three-dimensional structural framework of the elements.

[0183] The expansion of one or more elements 310, or the expansion of the scaffold 304, or the expansion of the drug-containing solid 301 may also be constrained if the stiffness or elastic modulus or plastic modulus of the strength-enhancing excipient 340 network within the elements or fibers 310 is too large. Thus, after exposure to physiological fluid 360, the stiffness or elastic modulus or plastic modulus of the one or more strength-enhancing excipients 340 generally should not be too large so that the expansion of the dosage form (or of the drug-containing solid 301, or of the scaffold 304, or of one or more elements 310) is not overly constrained. However, the stiffness or elastic modulus or plastic modulus of the one or more strength-enhancing excipients 340 must also be large enough to ensure that the strength-enhancing excipient 340 network provides sufficient mechanical support or stabilization of the one or more elements or scaffolds 304, 310 after exposure to physiological fluid 360. Thus, preferably, after immersion in physiological fluid 360 under physiological conditions, the strength-enhancing polymeric component(s) 340 have a modulus of elasticity in the range of between 0.1 MPa and 200 MPa.

[0184] Similarly, to ensure that the semi-solid strength-enhancing excipient network does not break upon expansion and remains highly connected within the expanded element or semi-solid mass, one or more strength-enhancing polymeric components 340 may have a strain at break greater than 0.5 or even greater.

[0185] As the fluid 360 concentration in the structural framework or elements 304, 310 or segments increases, they may further transition from a solid to a semi-solid or viscoelastic state. Thus, upon diffusion or penetration of physiological fluid 360 into the three-dimensional structural framework, or into one or more elements, or into one or more segments 304, 310, the drug-containing solid 301 (or three-dimensional structural framework 304, or one or more elements 310, or one or more segments) may transition from a solid to a semi-solid or viscoelastic mass 312.

[0186] Because the concentration of excipients in semi-solid or viscoelastic mass 312 decreases as it absorbs water or physiological fluid, the stiffness of semi-solid or viscoelastic mass 312 generally decreases as it swells. Accordingly, in the invention herein, the normalized swelling of drug-containing solid 301 (or of scaffold 304 or semi-solid or viscoelastic mass 312) may be limited to ensure that the stiffness and strength of semi-solid or viscoelastic mass 312 remain great enough that the (mechanical or geometric) integrity of semi-solid or viscoelastic mass 312 is substantially maintained over an extended period of time under appropriate physiological conditions. More specifically, in some embodiments, the length, width, thickness, diameter, etc. of drug-containing solid 301 (or of scaffold 304 or semi-solid or viscoelastic mass 312) may swell upon immersion in physiological fluid to no more than five times its initial value (e.g., the initial length of the drug-containing solid or scaffold prior to exposure to said physiological fluid). This includes, but is not limited to, the length, width, thickness, diameter, etc. of a drug-containing solid (or skeletal or semi-solid or viscous mass) that swells to no more than 4.5 times, or no more than 4 times, or no more than 3.5 times, or no more than 3 times, or no more than 2.5 times its initial value prior to exposure to said physiological fluid.

[0187] Concomitant with the ingress or penetration of fluid 360 into element 310, drug molecules 320 may be released from drug-containing solid 301 or semi-solid or viscoelastic mass 312 into physiological fluid 360. By way of example and not limitation, drug molecules may diffuse from drug-containing solid 301 or semi-solid or viscoelastic dosage form 312 into physiological fluid 360. Figures 3c-3f. If the amount of drug per unit volume of the semi-solid or viscoelastic mass is much greater than the solubility, and if semi-solid or viscoelastic mass 312 is several millimeters thick and stabilized or maintained for an extended period of time, the drug release time may be extended.

[0188] As a result, upon immersion of the drug-containing solid or dosage form in physiological fluid, the fluid may penetrate at least the interconnected free spaces and diffuse into one or more elements (e.g., fibers), causing the framework to expand in at least one dimension and transition into a semi-solid mass. The swollen semi-solid mass may have a length between 1.3 and 4 times the initial length of the drug-containing solid prior to exposure to the physiological fluid. The semi-solid mass may further release drug over an extended period of time (e.g., over a period of more than 1 hour, or over a period of more than 2 hours, or over a period of more than 5 hours, etc.).

[0189] 4a schematically illustrates a further non-limiting example of a pharmaceutical dosage form disclosed herein. Dosage form 400 comprises a drug-containing solid 401 having an outer surface 402 and an inner three-dimensional structural framework 404 of one or more thin structural elements 410. (It may be noted that in some preferred embodiments, framework 404 comprises crisscrossed stacked layers of one or more fibers 410.) Framework 404 is adjacent to and terminates at said outer surface 402. Elements 410 have segments spaced apart from bordering segments, thereby defining one or more interconnected free spaces 415 throughout drug-containing solid 401. Elements 410 further comprise at least one active ingredient 420 and at least two excipients 430, 440. The at least two excipients 430 , 440 include one or more physiological fluid-absorbing polymeric excipients or components 430 and one or more strength-enhancing polymeric excipients or components 440 .

[0190] Upon exposure to physiological fluid 460, the one or more fluid-absorbing excipients 430 transition into a viscous mass or viscous solution 432. Figures 4b-4c. The one or more fluid-absorbing excipients or viscous mass or solution 430, 432 further expand the scaffold 404 along at least one dimension upon absorption of the physiological fluid 460. Figures 4b-4f. Additionally, upon exposure to physiological fluid 460, the one or more strength-enhancing excipients 440 form a fluid-permeable semi-solid network 442 that mechanically supports the scaffold 404, as illustrated schematically in non-limiting Figures 4c-4f.

[0191] 4a also illustrates another non-limiting example of a pharmaceutical dosage form disclosed herein. Dosage form 400 comprises a drug-containing solid 401 having an outer surface 402 and an inner three-dimensional structural framework 404 of one or more thin structural elements 410. (It may be noted that in some preferred embodiments, framework 404 comprises crisscrossed stacked layers of one or more fibers 410.) Framework 404 is adjacent to and terminates at said outer surface 402. Elements 410 have segments spaced apart from bordering segments, thereby defining one or more interconnected free spaces 415 throughout drug-containing solid 401. Elements 410 further comprise at least one active ingredient 420 and at least two excipients 430, 440.

[0192] The at least two excipients 430, 440 include one or more fluid-absorbing polymeric components or excipients 430, in which the solubility of physiological fluid is greater than 750 mg / ml. The at least two excipients 430, 440 further include one or more strength-enhancing polymeric components or excipients 440. After immersion in said physiological fluid under physiological conditions, the one or more strength-enhancing polymeric components 440 have a modulus of elasticity in the range between 0.1 MPa and 200 MPa and a strain at break greater than 0.5. Preferably, further, the one or more strength-enhancing polymeric components 440 form one or more phases that are substantially connected and / or substantially continuous along the length of the one or more structural elements 410.

[0193] 4b-4f, upon immersion in or exposure to the physiological fluid 460, the fluid 460 permeates at least one interconnected free space 415 and diffuses into one or more elements 410, thereby causing the scaffold 404 to expand in at least one dimension to a length between 1.3 and 4 times its length prior to exposure to the physiological fluid 460. By way of example and not limitation, the initial thickness H of the scaffold 404 (also referred to herein as "thickness prior to exposure to the physiological fluid") may expand to a thickness H = 1.3-4x H upon exposure of the scaffold 404 to the physiological fluid 460. Similarly, the initial length L of the scaffold 404 may expand to a length L = 1.3-4x L upon exposure of the scaffold 404 to the physiological fluid 460.

[0194] Also, upon exposure to the physiological fluid 460, the scaffold 404 or drug-containing solid 401 transitions into a semi-solid mass 412. The semi-solid mass 412 can maintain its length between 1.3 and 4 times the initial length of the scaffold 404 or drug-containing solid 401 over an extended period of time. FIGS. 4c-4f. The term "semi-solid mass maintaining its length between 1.3 and 4 times its initial length over an extended period of time" refers herein to a semi-solid mass immersed in unstirred or lightly stirred dissolution fluid (e.g., acidic water), wherein the immersed semi-solid mass maintains its length between 1.3 and 4 times its initial length over an extended period of time, for example, for more than 1 hour, or for more than 2 hours, or for more than 5 hours, or even longer. Generally, the semi-solid mass 412 may also release the drug 420 into the physiological fluid 460 over time (e.g., over a period of time greater than 1 hour, or greater than 2 hours, or greater than 5 hours, etc.).

[0195] Additionally, within one or more elements 410 or semi-solid mass 412, one or more strength-enhancing excipients 440 form a fluid-permeable semi-solid network 442 that provides mechanical support to one or more elements 410, scaffold 404, or semi-solid mass 412. (FIGS. 4c-4f) Additionally, one or more fluid-absorbing excipients 430, upon absorption of the physiological fluid 460, transition into a viscous mass or viscous solution 432 that expands the one or more elements 410 or scaffold 404 in at least one dimension.

[0196] A non-limiting progression of dosage form structure after ingestion by a human or animal subject (e.g., dog, pig, etc.) is shown in FIG. 5. Initially, dosage form 500 is solid and has a swallowable size and geometry. Upon ingestion, the dosage form enters the stomach, and the interconnected free spaces 515 are permeated with gastric fluids (and / or saliva, esophageal fluids, etc.) (FIG. 5a). Gastric fluids (and / or saliva, esophageal fluids, etc.) then diffuse into the three-dimensional structural framework and / or elements 510 (e.g., fibers) that it surrounds. As a result, the drug-containing solid expands, forming a semi-solid mass 512 having a size (e.g., width, diameter, etc.) greater than the diameter or width of the pylorus and a strength or rigidity such that it is substantially non-fragmentable in the gastric environment (e.g., under normal gastric conditions) for an extended period of time (FIG. 5b).

[0197] Furthermore, as the drug-containing solid absorbs gastric fluid and transitions into a semi-solid mass, drug molecules may be released from the drug-containing solid or semi-solid mass into the gastric fluid over an extended period of time (see Figures 5b and 5c). Thus, the size and strength or rigidity of the semi-solid mass 512 may remain large enough to prevent its passage into the intestine through the pylorus for an extended period of time, thereby prolonging and / or controlling drug release into the stomach. However, ultimately, the rigidity or strength of the semi-solid mass 512, 513 may be so low that it disintegrates, or becomes excessively deformed, or crumbles, or fragments, or dissolves, etc., in the stomach and passes into the intestine (see Figure 5d). It may be noted that the terms "disintegrate" or "disintegrate" are used as equivalents of "fragment," "fragmentation," "deform," "excessive deformation," "dissolve," "dissolution," "erode," "erode," "mechanically weaken," "soften," "fracture," "fracture," and the like. Modeling the swelling, drug release, and disintegration of dosage forms

[0198] The following examples provide non-limiting ways in which the swelling and drug release behavior of the disclosed dosage forms can be modeled, so that those skilled in the art can more readily understand the details and advantages of the present invention. The models and examples are for illustrative purposes only and are not meant to be limiting in any way. (a) Microstructure and formulation of dosage form

[0199] The non-limiting model refers to a dosage form as shown schematically in non-limiting Figure 6a. Dosage form 600 includes a drug-containing solid 601 having an outer surface 602 and an inner three-dimensional structural framework 604 comprising a plurality of crisscrossed stacked layers of one or more fibrous elements 610 adjacent to and terminating at (e.g., defining) said outer surface 602. Fibrous elements 610 have segments spaced apart from like segments of bordering elements, thereby defining free spaces 615, where multiple adjacent free spaces of successive layers combine to define one or more interconnected free spaces 615 throughout drug-containing solid 601. At least one of said one or more interconnected free spaces 615 terminates at said outer surface 602 and is filled with a substance removable by physiological fluids under physiological conditions. The fibrous elements 610 further comprise at least one active ingredient 620 and at least two excipients 630, 640 across their thickness. The at least two excipients 630, 640 include one or more physiological fluid-absorbing polymeric components 630 having a molecular weight greater than 50 kg / mol and one or more strength-enhancing components 640. Furthermore, in the specific non-limiting dosage forms considered in these models, the at least two excipients 630, 640 form at least a solid solution. Also, the phase(s) including the one or more strength-enhancing excipients 640 are substantially connected or continuous along the length of the one or more fibers or structural scaffolds. Similarly, the phase(s) including the one or more strength-enhancing excipients 640 are substantially connected or continuous across the thickness of the one or more fibers or structural scaffolds.

[0200] Further, in a specific, non-limiting example herein, the physiological fluid-absorbent polymeric excipient 630 generally comprises hydroxypropylmethylcellulose (HPMC) with a molecular weight of 120 kg / mol. HPMC is mutually soluble with typical physiological fluids. Thus, the solubility of physiological fluids in the absorbent excipient (e.g., HPMC) may be greater than about 1000 mg / ml, or even 750 mg / ml. The strength-enhancing excipient 640 generally comprises methacrylic acid-ethyl acrylate copolymer (also referred to herein as "Eudragit L100-55"). The mechanical properties of Eudragit L100-55 after exposure to physiological fluids are shown in Example 2.7 and Table 5 of the present disclosure. Briefly, after immersion in physiological fluid, the strength-enhancing excipient 640 (e.g., Eudragit L100-55) comprises an elastic modulus of about 5.7 MPa (e.g., between 0.2 MPa and 200 MPa), a tensile strength of about 1.8 MPa (e.g., between 0.2 MPa and 200 MPa), and a strain at break of about 3.5 (e.g., greater than 0.5, or between 0.5 and 20). Furthermore, the strength-enhancing excipient 640 (e.g., Eudragit L100-55) is an enteric excipient that is poorly soluble or virtually insoluble in aqueous media having pH values ​​below about 5.5, but soluble in aqueous media having pH values ​​above about 5.5-6. The drug 620 in the non-limiting dosage form modeled herein generally comprises ibuprofen. (b) Concept of dosage form swelling, drug release, and disintegration

[0201] As shown schematically in non-limiting Figure 6b, upon immersion of dosage form 600 or drug-containing solid 401 in an agitated dissolution liquid 660, for example, deionized (DI) water containing 0.1 M hydrochloric acid (HCl), the liquid may permeate at least one interconnected free space 615 and wet the structural scaffold 604, 610. This may allow liquid 660 to diffuse into one or more of the fibrous elements 610, causing scaffold 604, 610 to expand along all dimensions and transition into a semi-solid or viscoelastic or viscous mass 650.

[0202] Without wishing to be bound by any particular theory, furthermore, within the elements or fibers, the solubility of the acidic fluid may be high in the absorbent excipient (e.g., HPMC, etc.) but low in the strength-enhancing excipient (e.g., Eudragit L100-55, etc.). Thus, as the water concentration in the fibers increases, the excipient may separate into two phases: a highly viscous solution of water and absorbent excipient (e.g., within the polyhedral cells, cavities, etc. of the fibrous elements), and a semi-solid network of the strength-enhancing excipient (e.g., within the fibrous elements, a semi-solid membrane, a semi-solid polyhedral network of membranes, a semi-solid framework, a semi-solid network of cell walls, a semi-solid network of fibers, etc.). Figure 6c. Water molecules may easily pass into the cells through the cell walls or membrane of the strength-enhancing excipient (or semi-solid network), but the passage of absorbent excipient molecules out of the cells may be hindered. As a result, due to the inward osmotic flow of water, internal pressure may develop in the cells, and the cells, fibers, and dosage form may swell. However, the concentration of absorbent excipient molecules and the internal pressure in the cells may decrease as they swell. Thus, eventually, the swelling may stop, and an expanded complex semi-solid, viscoelastic, or viscous mass may be formed that may have a substantially stable (e.g., substantially constant or unchanged) geometry over an extended period of time.

[0203] Furthermore, as the dissolution medium (such as water) enters the fiber, the fiber may become supersaturated with drug, and the drug molecules may aggregate as particles until solubility is reached (Figures 6c and 6d). Alternatively, remaining drug molecules may diffuse out of the semisolid dosage form or semisolid or viscous mass into the dissolution medium. As the drug molecules are released, the drug particles in the fiber may dissolve back down until they are depleted (Figures 6d-6e). If the amount of drug per unit volume of the semisolid or viscous mass is much greater than the solubility and the semisolid or viscous mass is several millimeters thick, the drug release time may be extended.

[0204] Furthermore, it may be noted that water-soluble components, such as absorbent excipients, may slowly dissolve from the semi-solid or viscous mass, and the semi-solid or viscous mass may disintegrate over time. However, the manner in which the semi-solid or viscous mass disintegrates may depend on the conditions to which it is exposed. By way of example and not limitation, in a gently stirred solution, the semi-solid or viscous mass may not be substantially deformed (e.g., sheared) or may not crumble. However, when the semi-solid or viscous mass is exposed to repeated compression or impact, such as in the stomach of a human or animal subject, the semi-solid or viscous mass may deform somewhat due to the forces acting on it, and may eventually crumble or rupture. (c) Swelling of a single fiber

[0205] Upon immersion of the fiber in the solution, the rate of fiber expansion can be determined by the inward diffusion flow of water, as shown in non-limiting Figure 7. The governing diffusion equation in cylindrical coordinates can be written as:

number

[0206] The water concentration in the fiber at the liquid-fiber interface is c b The initial and boundary conditions can then be written as follows, as shown in Figure 7: c w =0 t=0, 0≦r <R0(1b) c w =c b t ≥ 0, r = R(t) (1c) where R0 is the initial fiber radius, which increases as the mass of water in the fiber increases.

[0207] An analytical solution to equation (1a) subject to the initial condition (1b) and moving boundary condition (1c) may not be available at this point. However, under the highly approximate assumptions that the water diffusion coefficient in the fiber is constant and the concentration of water in the fiber is very small, the water concentration profile shown schematically in non-limiting FIG. 7 can be approximated by the following (see, e.g., J. Crank, "The Mathematics of Diffusion", second edition, Oxford University Press, 1975):

number

[0208] By integrating equation (2) over the fiber volume, the ratio of the mass of water in the fiber per unit length at time t, M w (t), and the ratio of the mass of water in the fiber per unit length at infinite time M w,∞ can be obtained. For small times (e.g., t< <R0 2 / D w ) for

number

[0209] The mass of water per unit length of the fiber is the volume of water per unit length at time t, V w (t), and can be written in terms of fiber volume per unit length as t → ∞. Under the very approximate assumption of small fiber expansion, M w (t)=p w V w (t) (5a) M w,∞ =c b V0(5b) where V is the initial fiber volume per unit length.

[0210] From equations (4) and (5), the normalized volume expansion of the fiber can be expressed as:

number

[0211] If we further assume that the fiber expands isotropically, the normalized radial and axial expansion can be one-third of the volume expansion. Thus, for small times and small expansions,

number

[0212] For more information on the diffusion of solutions into fibers or other geometries, see, for example, J. Crank, "The Mathematics of Diffusion", second edition, Oxford University Press, 1975. Additional models for estimating fiber expansion rates will be apparent to those skilled in the art. are all within the spirit and scope of the present disclosure. (d) Swelling of the dosage form

[0213] Upon immersion of the fibrous dosage form in the dissolution liquid, the dissolution liquid may penetrate into one or more free spaces and diffuse into one or more fibers. As a result, the one or more fibers may swell, as shown schematically in the non-limiting Figure 8.

[0214] Since the dosage form can expand due to water diffusion into the fibers, the normalized longitudinal expansion of the dosage form ΔL / L0| DF is the normalized longitudinal and axial expansion of a single fiber, ΔL / L0| SF and ΔR / R0| SF May be related to:

number

[0215] Therefore, for some dosage forms where fiber expansion is isotropic, k LL and k RL is in the range of about 0.25 to 4 (including but not limited to the range of 0.5 to 2).

[0216] Any additional models for estimating the rate of expansion of a dosage form that are apparent to one of ordinary skill in the art are within the spirit and scope of this disclosure. (e) Drug release by dosage form

[0217] Because the drug in the non-limiting examples herein is poorly soluble (e.g., the mass of drug in the swollen fiber per unit volume of the swollen fiber is initially greater than the drug solubility in the swollen fiber), as water diffuses into the fiber, the drug molecules in the fiber may precipitate as particles. The fiber may then be a "homogeneous" semi-solid or viscous mass of water, drug molecules, and drug particles. From this semi-solid or viscous fiber mass, the drug molecules may diffuse into the fluid-filled voids or free spaces of the dosage form and subsequently be transported into the dissolution fluid. Furthermore, as the drug molecules diffuse out of the fiber, the drug particles in the fiber may dissolve back down until they can be depleted.

[0218] Three cases can be distinguished. Figure 9. If the fiber volume fraction in the dosage form is very small, as in Figure 9a, the rate-limiting diffusion distance may be the radius of a thin single fiber, and the drug release rate may be fast. However, if the fiber volume fraction is very large, as in Figure 9c, the rate-limiting diffusion distance may be half the thickness of the corresponding thick monolithic slab, and the drug release rate may be very slow. If the fiber volume fraction is intermediate, as in Figure 9b, the drug release rate may be between these two extremes. The two extremes are modeled as follows: (e1) Case 1: Drug release limited by diffusion in the fiber (2R / λ ≈ 0)

[0219] In the first case, the fibers are separated by a large distance and the fluid velocity around the fibers is such that the rate of drug release from the fibrous dosage form is limited by the rate of diffusion within the fibers. In this fiber, two regions can be distinguished as shown in the non-limiting Figure 10: a region with dispersed drug particles and a drug particle-depleted region containing only dissolved drug molecules. These two regions can be delineated by a thin, inward-moving boundary with a thickness on the order of the interparticle distance.

[0220] In particle-dispersed regions, the total drug mass per unit volume (drug particles plus drug molecules) can be an initial value, much greater than the drug solubility (Figure 7b). In particle-free regions, the drug concentration can be governed by the following diffusion equation, subject to the initial, interfacial, and boundary conditions:

number

[0221] Condition (9c) can be made to require that the mass of drug particles depleted from the moving boundary can be equal to the mass of drug that diffuses out as molecules. Thus, by conservation of mass in differential volume at the interface, the following condition can be written: (c d,0 -c s )ΔR * =D d (dc d / dr)Δt r=R * (t) (9e) In the formula, ΔR * is the change in radius of the interface over the time interval Δt. Rearranging and rewriting the differential form, we get

number

[0222] An analytical solution to equation (9a) that obeys conditions (9b)-(9f) may not be available at this point. However, as in the non-limiting case herein, c d,0 >>c s (For further details on quasi-steady state, see, e.g., J. Crank, "The Mathematics of Diffusion", second edition, Oxford University Press, 1975.) That is, the drug concentration in the particle-free region can be expressed as:

number

number

number

number

number

number

[0223] From the geometry, the fraction of drug released by the fiber in time t can be written as:

number

[0224] Combining equations (15) and (16) yields the following implicit equation for the fraction of drug released, based on appropriate geometric and physicochemical parameters:

number

number

[0225] Furthermore, in equation (18), m d Substituting / M0=0.8 and rearranging, the time to release 80 percent of the drug content can be estimated by:

number

[0226] Therefore, by equation (19), the drug release time can increase if the concentration of drug in the fiber divided by the solubility and the fiber radius increase and the diffusivity of the drug in the fiber decreases.

[0227] For more information on the diffusion of drugs out of fibers or other geometries, see, for example, J. Crank, "The Mathematics of Diffusion", second edition, Oxford University Press, 1975. It is clear to one skilled in the art that a single All additional models for estimating the rate and time of drug release by the fibers are within the spirit and scope of the present disclosure. (e2) Case 2: Diffusion-limited drug release in a monolithic semi-solid dosage form (2R / λ ≈ 1)

[0228] In the second case, the fibers are packed so closely together that the expanded semi-solid or viscous dosage form is essentially a monolithic slab, as illustrated in the non-limiting Figure 10. When the solution is stirred and the dosage form is several millimeters thick, drug release is limited by diffusion in the slab. Similar to diffusion in a single fiber, particle-dispersed and particle-depleted regions are delineated by inwardly moving interfaces (Figure 11). At the moving interface, the mass of depleted drug particles should be the same as the mass of drug diffusing outward. Therefore, (c d,0 -c s )ΔX=D d (dc d / dx)Δt x=HX(t) (20) where c d,0 is the initial drug mass per unit volume of the slab, H is the half-thickness of the slab, X(t) is the advance of the interface position at time t, and ΔX is the incremental advance of the interface position during the time interval Δt. Rearranging and rewriting in differential form gives

number

[0229] According to the quasi-steady-state assumption, the concentration profile can then be linear (Figure 10b). Therefore, the velocity of the interface toward the origin, dX / dt, can be expressed as:

number

number

[0230] Fraction of drug released m d / M0 can be approximately equal to X / H, where H is the half-thickness of the mass of the semi-solid or viscous dosage form. Thus, the fraction of drug released can be approximated by:

number

number

[0231] Additional models for estimating the rate and time of drug release from monolithic slabs will be apparent to those skilled in the art, all within the spirit and scope of the present disclosure. (f) Disintegration of dosage form

[0232] The rate of disintegration of a semi-solid or viscous dosage form generally depends greatly on the force to which it is exposed. Since the preferred application of the dosage form herein is extended drug release to the stomach, a highly approximate model is developed herein to estimate the disintegration time of the dosage form in the stomach.

[0233] In the stomach, dosage forms are generally exposed to cyclic compressive forces by the stomach wall. A non-limiting force field acting on an expanded semi-solid or viscous dosage form includes opposing cyclic loads P per unit length, with a maximum load per unit length P, as shown schematically in FIG. max The corresponding maximum cyclic stress (tension) along the axis of symmetry can be estimated as follows (for further details, see e.g., A. H. Blaesi and N. Saka, Int. J. Pharm. 509 (2016) 444-453):

number

[0234] To avoid immediate destruction of the dosage form, the tensile strength of the swollen semi-solid or viscous dosage form should be less than σ max The tensile strength of the expanded semi-solid or viscous dosage form must be greater than σ max If the dosage form is larger than several compression pulses N f After this, fatigue failure may be observed.

[0235] Dosage form P max σ max , and assuming that stiffness, strength, geometry, etc. are time-invariant, the fatigue life N of the dosage form can be calculated similarly to the Basquin equation: f A power function for can be proposed as follows:

number

[0236] In general, the tensile strength of an swollen semi-solid or viscous dosage form can be determined primarily by the characteristics of the strength-enhancing excipient network. Under the highly approximate assumption that the strength-enhancing excipient network in or around fibers or elements can be considered a cellular material, the tensile strength of the dosage form can be expressed as follows (for further details, see, e.g., M.F.A. Shby, Metall. Trans. A 14A (1983) 1755-1769):

number

[0237] Substituting equation (28) into equation (27) and rearranging, we get

number

[0238] Gastric residence time t r is approximately N f ×t パルス Therefore, from equation (29),

number

[0239] Combining equation (30) with equation (26), we get

number

[0240] According to equation (31), the parameters that can be varied to modify the gastric residence time are the radius of the dosage form, R df , the breaking strength σ of excipients immersed in acidic water under monotonic loading f,se , and the volume fraction of the strength-enhancing excipient in the dosage form, φ se However, the radius of the dosage form cannot be varied over a wide range. Similarly, for a given formulation, σ f,se is generally given. Therefore, the main variable that can be adjusted to control gastric residence time is φ se From the non-limiting experimental results shown later, a φ of about 0.2 to 0.5 se For example, the gastric residence time of the fibrous dosage form can be extended to greater than about 1 day, sufficient to extend the delivery of the drug into the upper gastrointestinal tract and improve the efficacy, safety, and convenience of numerous drug treatments. Dosage Form Embodiments

[0241] In light of the above theoretical model and non-limiting examples, which are suggestive and approximations rather than exact, as well as other considerations, the dosage forms disclosed herein may further include the following embodiments. a) The external geometry of the drug-containing solid and the three-dimensional structural framework of the element

[0242] In some embodiments, the average length and / or average width and / or average thickness of the drug-containing solid (e.g., the three-dimensional structural framework of one or more elements) is greater than 1 mm, including, but not limited to, greater than 1.5 mm, or greater than 2 mm, or greater than 3 mm, or within the ranges of 1 mm to 30 mm, 1.5 mm to 30 mm, 2 mm to 30 mm, 5 mm to 20 mm, 5 mm to 18 mm, 6 mm to 20 mm, 7 mm to 20 mm, 7 mm to 19 mm, 7 mm to 18 mm, 7 mm to 17 mm, 7 mm to 16 mm, 8 mm to 20 mm, 8 mm to 18 mm, 8 mm to 16 mm, 8 mm to 15 mm, 8 mm to 14 mm, 8 mm to 13 mm, or 8 mm to 12 mm. For purposes of the invention herein, length generally refers to a measure of distance in the direction of greatest distance, thickness generally refers to a measure of distance in the direction of smallest distance, and width is less than length but greater than thickness. Furthermore, in some embodiments, the "width" direction may be orthogonal to the length direction and / or the thickness direction.

[0243] Additionally, in some embodiments, the width perpendicular to the longest dimension of the dosage form or drug-containing solid herein is greater than 6 mm, including, but not limited to, greater than 7 mm, or greater than 8 mm, or greater than 9 mm, or within the ranges of 6 mm to 18 mm, 6 mm to 16 mm, 6 mm to 15 mm, 7 mm to 18 mm, 7 mm to 16 mm, 7 mm to 15 mm, or 8 mm to 18 mm, 8 mm to 16 mm, or 8 mm to 15 mm.

[0244] The dosage forms or drug-containing solids or three-dimensional structural frameworks herein can have any common or unusual external shape of drug-containing solids. For non-limiting examples of common tablet shapes, see, e.g., K. Alexander, "Dosage forms and their routes of Administration," in M. Hacker, W. Messer, and K. Bachmann, "Pharmacology: Principles and Practice," Academic Press, 1999. Press, 2009. Any other geometries, external shapes or dimensions of the dosage form, drug-containing solid or three-dimensional structural framework of the element that are apparent to one skilled in the art are all within the spirit and scope of the present invention. b) Surface composition of the elements and segments

[0245] In some embodiments, the surface composition of at least one element is hydrophilic to allow rapid penetration of dissolution fluid into the interior of the dosage form structure (e.g., into the interconnected free spaces of a drug-containing solid). Such embodiments include, but are not limited to, embodiments in which the surface composition of one or more structural elements and / or the surface composition of one or more segments and / or the surface composition of the three-dimensional structural framework of an 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 droplet of physiological fluid on said 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 of 80 degrees or less, or 70 degrees or less, or 60 degrees or less, or 50 degrees or less, or 40 degrees or less, or 30 degrees or less. It may be noted that in some embodiments, the contact angle need not be fixed. In this case, a solid surface may be considered "hydrophilic" if the contact angle of a droplet of physiological fluid in air on the solid surface is 90 degrees or less (including, but not limited to, 80 degrees or less, or 70 degrees or less, or 60 degrees or less, or 50 degrees or less, or 40 degrees or less) after at least 20 to 360 seconds of the droplet being placed on the surface. A non-limiting schematic diagram of a droplet on a surface is shown in U.S. Application Serial No. 15 / 482,776, entitled "Fibrous dosage form."

[0246] Generally, when the contact angle between the liquid and the surface of the three-dimensional structural framework of one or more elements decreases, the penetration rate of physiological fluid into the interconnected free space increases. Thus, in some embodiments, at least one element, or at least one segment of the element, or the three-dimensional structural framework of the element, comprises a hydrophilic or highly hydrophilic coating to enhance the penetration rate of fluid 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 considered "highly hydrophilic" if the contact angle of a droplet of physiological fluid on the solid surface in air is 45 degrees or less. This includes, but is not limited to, a contact angle of a droplet of the liquid on the solid surface in air of 35 degrees or less, or 30 degrees or less, or 25 degrees or less, or 20 degrees or less, or 15 degrees or less.

[0247] Non-limiting examples of hydrophilic (or highly hydrophilic) compounds that can serve as coatings for elements (or segments of elements, or the three-dimensional structural framework of elements) include polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone, silicon dioxide, sugars or polyols (e.g., mannitol, maltitol, xylitol, maltitol, isomalt, lactitol, sucrose, glucose, fructose, galactose, erythritol, maltodextrin, etc.), and the like.

[0248] In a preferred embodiment, the coating of one or more components comprises at least one polyol. In another preferred embodiment, the coating of one or more components comprises at least one sugar, such as sucrose, fructose, glucose, or galactose. In another preferred embodiment, the coating of one or more components comprises at least silicon dioxide.

[0249] Any other compositions or coatings on the surface of one or more elements or three-dimensional structural frameworks that are apparent to one skilled in the art are all encompassed by the present invention. c) Microstructure of drug-containing solids and three-dimensional structural scaffolds

[0250] In some embodiments, when the drug-containing solid contains at least one continuous channel or free space having at least two openings in contact with the dissolution liquid, the dissolution liquid can penetrate into the interior of the structure (e.g., into at least one free space or into multiple free spaces). The more such channels with at least two ends in contact with the dissolution liquid there are, the more uniform the penetration into the structure can be. Also, the larger the space spanned by the continuous channel with at least two ends in contact with the dissolution liquid, the more uniform the penetration into the structure can be. Uniform penetration is desirable in the invention herein.

[0251] Thus, in the invention herein, a plurality of adjacent free spaces combine to define one or more interconnected free spaces (e.g., free spaces that are "contiguous," "in direct contact," "fused," or "without any walls between them") that form an open pore network extending across at least half the thickness of the drug-containing solid. This includes, but is not limited to, a plurality of adjacent free spaces that combine to define one or more interconnected free spaces that form an open pore network extending across at least two-thirds the thickness of the drug-containing solid, or across a length at least equal to the thickness of the drug-containing solid, or across a length at least equal to a side length of the drug-containing solid, or across a length and width at least equal to half the thickness of the drug-containing solid, or across a length and width at least equal to the thickness of the drug-containing solid, or across a length, width, and thickness at least equal to half the thickness of the drug-containing solid, or across a length, width, and thickness at least equal to two-thirds the thickness of the drug-containing solid, or across a length, width, and thickness at least equal to the thickness of the drug-containing solid, or across the entire length, width, and thickness of the drug-containing solid.

[0252] Also, in some embodiments, the open pore network constitutes or occupies at least 30 percent (e.g., at least 40 percent, or at least 50 percent, or at least 60 percent, or at least 70 percent, or at least 80 percent, or 100 percent) of the free space of the drug-containing solid (e.g., at least 30 percent, or at least 40 percent, or at least 50 percent, or at least 60 percent, or at least 70 percent, or at least 80 percent, or at least 85 percent, or at least 90 percent, or at least 95 percent, or at least 98 percent, or 100 percent of the free space of the drug-containing solid is part of the same open pore network).

[0253] In a preferred embodiment, all free spaces are interconnected to form a single continuous open pore network. In the invention herein, when all free spaces of a drug-containing solid are interconnected, the free spaces of the drug-containing solid are also referred to as "contiguous." An element or three-dimensional structural framework may essentially form a three-dimensional lattice structure surrounded by contiguous or interconnected free spaces. Furthermore, in a preferred embodiment, one or more interconnected free spaces terminate at the outer surface of the drug-containing solid.

[0254] In a drug-containing solid having a continuous free space that terminates at the outer surface of the drug-containing solid, it is not necessary to disrupt walls (e.g., walls comprising the three-dimensional structural framework of the element) to obtain interconnected clusters of free space (e.g., open channels of free space) from the outer surface of the drug-containing solid (or from any point within the free space) to a point (or any point) in the free space within the internal structure. The entire or essentially all free space is connected and accessible from (e.g., connected to) the outer surface of the drug-containing solid.

[0255] 13 schematically illustrates a pharmaceutical dosage form 1300 comprising a drug-containing solid 1301 having an outer surface 1302 and an inner three-dimensional structural framework 1304 comprising multiple crisscross stacked layers of one or more fibrous elements 1310. The framework 1304 is adjacent to and terminates at the outer surface 1102. The fibrous elements 1310 further have segments spaced apart from similar segments of the bordering elements, thereby defining free spaces 1320. A plurality of adjacent free spaces 1325 combine to define one or more interconnected free spaces that form an open pore network 1330.

[0256] As shown in the non-limiting schematic view of cross section AA, free spaces 1320 are interconnected throughout drug-containing solid 1301, and said open pore network 1330 extends throughout the length and thickness of drug-containing solid 1301 or dosage form 1300. In other words, the length L across which open pore network 1330 extends is 細孔 is the same as the length or diameter D of the dosage form 1300 or drug-containing solid 1301; and the thickness H across which the open pore network 1330 extends. 細孔 is the same as the thickness H of dosage form 1300 or drug-containing solid 1301. It may be noted that the term "cross section" is understood herein as a "plane" or a "surface." Thus, a "cross section" is not a "projection" or a "projected view."

[0257] 13, the microstructure is rotationally symmetric. If the plane or cross-section AA is rotated 90 degrees about the central axis, the microstructure (e.g., microstructural details) is the same. Thus, the open pore network 1330 also extends across the entire width of the drug-containing solid 1301 or dosage form 1300. In other words, the width across which the open pore network 1330 extends is the same as the width or diameter D of the dosage form 1100 or drug-containing solid 1101.

[0258] 13 , as shown in cross section AA, the open pore network 1330 or free space(s) 1320 or free spaces 1325 are continuous, with the free space 1320 terminating at the outer surface 1302 of the drug-containing solid 1301. It is not necessary to disrupt a wall (e.g., a wall comprising the three-dimensional structural framework 1304 of the element) to obtain an interconnected cluster of free spaces (e.g., open channels of free space) from the outer surface 1302 of the drug-containing solid 1301 to a point (or any point or location) in the free spaces 1320, 1325, 1330. The entire free spaces 1320, 1325, 1330 are accessible from the outer surface 1302 of the drug-containing solid 1301. Also, it is not necessary to disrupt walls (e.g., walls comprising the three-dimensional structural framework 1304 of the elements) to obtain interconnected clusters of free spaces (e.g., open channels of free space) from any point or location within the free spaces 1320, 1325, 1330 to any other point or location in the free spaces 1320, 1325, 1330. The entire free spaces 1320, 1325, 1330 are accessible from any point, location, or location within the free spaces 1320, 1325, 1330.

[0259] Additionally, the structure shown in FIG. 13 includes fibers (or fiber segments) in a layer that are unidirectionally aligned (e.g., parallel). The fibers (or fiber segments) in layers above and below the layer are also unidirectionally aligned and perpendicular to the fibers in the layer (e.g., the fibers in the layers above and below the layer are perpendicular to the fibers in the layer, and vice versa). The fibers in the layers above and below the layer also touch or "fuse with" the fibers in the layer at fiber-to-fiber point contacts. Thus, a structural framework, network, or 3D lattice structure can be considered a network that includes nodes or nodes at fiber-to-fiber point contacts and edges defined by fiber segments between adjacent nodes or nodes. In the specific example of FIG. 13, the distance λ of fiber segments between adjacent point contacts is uniform or constant throughout the network.

[0260] Thus, in some embodiments, the three-dimensional structural scaffolds herein comprise a fibrous network having fiber-to-fiber point contacts and fiber segments between adjacent contact points, wherein the length of the fiber segments between adjacent point contacts is uniform across the fibrous network. In some embodiments of the invention herein, a variable (e.g., length, distance, width, angle, concentration, etc.) may be noted to be uniform across the structural scaffold (e.g., across the fibrous network) if the standard deviation of a plurality (e.g., a plurality of randomly selected, e.g., at least 3, or at least 4, or at least 5, or at least 6, or at least 10, or at least 20 randomly selected) counts of said variable across the structural scaffold is less than the mean value. This includes, but is not limited to, a standard deviation of a plurality (e.g., a plurality of randomly selected, e.g., at least 3 or at least 4 or at least 5 or at least 6 or at least 10 or at least 20 randomly selected) counts of said variable across the structural framework that is less than half the mean value, 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, or less than one-eighth the mean value, or less than one-tenth the mean value, or less than one-fifteenth the mean value. The term "uniform" is also referred to herein as "constant" or "nearly constant" or "approximately constant."

[0261] The graph in Figure 14 is a non-limiting plot of the number of fiber segments between adjacent point contacts versus the distance λ of the fiber segments between adjacent point contacts. In this non-limiting example, the λ value is the average λ avg It is distributed in a very narrow window or zone around it, so the standard deviation of the λ value is very small; λ is precisely controlled; and the structure is regular, deterministic, and ordered.

[0262] Thus, in some embodiments, the three-dimensional structural network herein comprises a fibrous network having interfiber point contacts 1475 and fiber segments 1410, 1411 between adjacent contact points, and the length of the fiber segments between adjacent point contacts is precisely controlled. It may be noted that when microstructural parameters are precisely controlled, dosage form properties (e.g., uniformity of fluid penetration into a drug-containing solid, swelling rate, drug release rate, etc.) can be optimized. In the invention herein, the term "precisely controlled" is also referred to as "ordered" or "well-arranged." A variable or parameter (e.g., fiber segment spacing between point contacts, contact width, fiber thickness, interfiber spacing, etc.) is precisely controlled if it is deterministic and not stochastic (or random). A variable or parameter may be deterministic if the standard deviation of the variable's values ​​is less than the mean value during multiple repetitions of a step involving the variable (e.g., when multiple dosage forms are produced under identical or nearly identical conditions). This includes, but is not limited to, a standard deviation of the values ​​of said variable that is less than half the mean value, 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, or less than one-seventh, or less than one-eighth, or less than one-ninth, or less than one-tenth, or less than one-twelfth, or less than one-fifteenth, or less than one-twentieth, or less than one-twentieth of the mean value of said variable, or less than one-thirtieth of the mean value of said variable.

[0263] Furthermore, in some embodiments, the three-dimensional structural networks or scaffolds herein comprise fibrous networks having fiber-to-fiber point contacts and fiber segments between adjacent contact points, wherein the average length of the fiber segments between adjacent contact points is between 1 and 15 times the average thickness of one or more fibers, including, but not limited to, fibrous networks having fiber-to-fiber point contacts and fiber segments between adjacent contact points, wherein the average length of the fiber segments between adjacent contact points is between 1 and 12 times, or between 1 and 10 times, or between 1 and 9 times, or between 1 and 8 times, or between 1 and 7 times, or between 1 and 6 times, or between 1 and 5 times, or between 1 and 4.5 times, or between 1 and 4 times the average thickness of one or more fibers.

[0264] More generally, in some embodiments, the volume fraction of an element (e.g., fiber) in the drug-containing solid (e.g., the volume of the element (e.g., fiber) divided by the volume of the drug-containing solid) is in the range of 0.1 to 0.95, including, but not limited to, volume fractions of elements in the drug-containing solid in the ranges of 0.15 to 0.95, 0.15 to 0.9, 0.15 to 0.85, 0.2 to 0.95, 0.2 to 0.9, 0.2 to 0.85, 0.25 to 0.95, 0.25 to 0.9, or 0.25 to 0.85.

[0265] Furthermore, in the structure shown in FIG. 15, at the inter-fiber point contact 1575, the two tangents 1580 of the two contacting fibers or fiber segments form an angle α. Because the fiber segment distance λ between the point contacts is uniform or constant throughout the network, the angle α formed by the two tangents of the contacting fiber segments at the contact point (e.g., the angle of intersection) is approximately 90°. However, it may be noted that the angle formed by the two tangents of the contacting fiber segments (e.g., the angle of intersection) can also take on other values, including, but not limited to, an average value greater than 0 degrees. This includes, but is not limited to, angles formed by the two tangents of the contacting fiber segments (e.g., the angle of intersection) between 20 and 90 degrees, or within the ranges of 30-90, 40-90, 50-90, 60-90, or 70-90 degrees. Furthermore, the angle formed by the two tangents of the contacting fiber segments (e.g., the angle of intersection) can also be precisely controlled. Thus, in some embodiments herein, a three-dimensional structural network of fibers comprises a fibrous network having inter-fiber point contacts defined by intersecting fibers or fiber segments, and the angles of intersection at said point contacts are precisely controlled across said fibrous network.

[0266] Further examples of fibrous structures in accordance with the invention herein will be apparent to those skilled in the art, all of which are within the scope of this disclosure.

[0267] However, it may be further noted that in some embodiments, the three-dimensional structural framework comprises stacked layers (or plies) of particles, fibers, or sheets, or any combination thereof. Furthermore, in some embodiments, one or more layers or plies are bonded to layers above or below said one or more layers.

[0268] Furthermore, many of the above features and characteristics may also be applied to three-dimensional structural frameworks of stacked layers of sheets or beads (e.g., particles), e.g., as shown in co-pending International Application No. PCT / US2019 / 52030, filed September 19, 2019, entitled "Dosage form comprising structured solid-solution framework of sparingly soluble drug and method for manufacture thereof" (e.g., these features or characteristics may be similar to the features or characteristics of such three-dimensional structural frameworks). Such features or characteristics would be apparent to one of ordinary skill in the art given all the information disclosed herein. The application of such features or characteristics to three-dimensional structural frameworks of stacked layers of beads (e.g., particles) or even sheets (e.g., two-dimensional elements), or any combination of fibers, beads, and / or sheets, is encompassed by the invention herein.

[0269] Further non-limiting embodiments of dosage form structures are described 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 / 964,058 entitled "Dosage form comprising two-dimensional structural No. 15 / 964,063, entitled "Expanding Structured Dosage Forms," ​​and International Application No. PCT / US19 / 19004, entitled "Expanding Structured Dosage Forms." Further examples of how elements can be structured or arranged in a three-dimensional structural framework of one or more solid elements will be apparent to those skilled in the art, all of which are within the spirit and scope of the present invention. (g) Contact and bonding between elements or fibers

[0270] Because the individual elements (e.g., fibers, beads, sheets, etc.) are generally thin and elongated, they may bend or deform due to the application of mechanical loads. Thus, in some embodiments, the three-dimensional structural framework of the elements may include contact points between elements or segments to provide mechanical support to the structure. Such inter-element contacts include, but are not limited to, point contacts or line contacts.

[0271] For purposes of the invention herein, a point contact is said to have a contact area or zone (e.g., the common surface of two elements or segments in contact) extending over a length and width of 2.5 mm or less. This includes, but is not limited to, a contact width between two elements (or two segments) of 2 mm or less, or 1.75 mm or less, or 1.5 mm or less. In another non-limiting example, the contact width 2a between two elements (or two segments) in a point contact can be 1.1 times or less the thickness of the contacting elements (or segments) at the point of contact. This includes, but is not limited to, a contact width 2a between two elements (or two segments) of 1 time or less, or 0.8 times or less, or 0.6 times or less the thickness of the contacting fibers (or segments) at the point of contact. A line contact is said to have a contact area or zone extending over a contact length that is much greater than the contact width. The contact width is typically 2.5 mm or less. Furthermore, at the point of contact (e.g., at the contact zone of a point contact or at the contact zone of a line contact), the elements or segments may be deformed. The geometry of the element or segment at or near the contact point (e.g., at or near a point contact, or at or near a line contact) is then different from its geometry elsewhere. In some embodiments, at the contact point, the element is "flat" or "flattened."

[0272] FIG. 16 is a non-limiting example of a point contact 1480 between two orthogonally aligned fiber segments 1610. FIG. 16a is a front view of the two segments, and FIG. 16b is a top view. The contact area is circular. The diameter of the circle or "contact width" 2a is designated in the figure. FIG. 17 is a non-limiting example of a line contact 1780 between two unidirectionally aligned fiber segments 1710. FIG. 17a is a front view, and FIG. 17b is a top view. As shown in the figure, the contact width 2a is significantly smaller than the contact length λ. In general, point contacts may allow for better connectivity of free space, so they may be preferred in some embodiments herein. For more information regarding point and line contacts, see, for example, K.L. Johnson, "Contact Mechanics," Cambridge University Press, 1985.

[0273] In some embodiments, the number of point contacts in the three-dimensional structural network is at least 10. This includes, but is not limited to, at least 20, or at least 50, or at least 75, or at least 100, or at least 125, or at least 150, or at least 175, or at least 200, or at least 250, or at least 300 point contacts in the three-dimensional structural network. Furthermore, in some embodiments, the number of point contacts in the three-dimensional structural network is precisely controlled. Furthermore, in some embodiments, the number of line contacts in the three-dimensional structural network is at least 10. However, in some embodiments, the number of line contacts in the three-dimensional structural network is 10 or fewer. Furthermore, in some embodiments, the number of line contacts in the three-dimensional structural network is precisely controlled.

[0274] At the contact zone (e.g., at one or more point contacts, or at one or more line contacts, etc.), two elements or segments may be bonded, which is understood herein as "fixed," "joined," "attached," "welded," etc. (e.g., by interdiffusion of molecules at the contact points, such as interdiffusion of an absorbent excipient from one element or segment to another contacting element or segment, or interdiffusion of a viscosity-enhancing excipient from one element or segment to another contacting element or segment, etc.). Generally, the bond strength is a fraction of the bulk strength of the contacting elements or segments. The fraction is typically 1 or less. This includes, but is not limited to, bond strengths of 0.8 times or less, or 0.6 times or less, or 0.4 times or less the strength of the bulk of the elements or segments. However, to provide mechanical support to the dosage form structure, the bond strength should generally be greater than 0.01 times, or greater than 0.02 times, or greater than 0.05 times, or greater than 0.1 times, or greater than 0.2 times, or greater than 0.3 times, or greater than 0.4 times, or greater than 0.5 times the bulk strength of the element or segment. Further, in some embodiments, the bond strength is within the range of 0.001 to 1, 0.01 to 1, 0.02 to 1, 0.05 to 1, 0.1 to 1, 0.2 to 1, 0.3 to 1, 0.4 to 1, 0.5 to 1, 0.001 to 0.95, 0.001 to 0.9, 0.005 to 1, 0.005 to 0.95, or 0.01 to 0.9 times the strength of the bulk of the element or segment.For further information on determining and measuring the strength of solid materials, see, for example, J. M Gere, S. Timoshenko, "Mechanics of materials", fourth edition, PWS Publishing Company, 1997; M. F. Ashby, "Materials selection in mechanical design", fourth edition, Butterworth-Heinemann, 2011; K. L. Johnson, "Contact mechanics", Cambridge University Press, 1985.

[0275] Thus, in some embodiments, the three-dimensional structural framework is a solid body in which at least one element (e.g., at least one fiber, etc.) or at least one segment of an element is connected to another element or segment, forming a continuous structure, including, but not limited to, a three-dimensional structural framework of elements forming a continuous solid structure in which at least two elements or at least two segments, or at least three elements or at least three segments, or at least four elements or at least four segments, or at least five elements or at least five segments are connected to another element or segment of an element.

[0276] Furthermore, if the contact width between elements or segments is sufficiently large, the inter-element contacts may provide adequate or improved mechanical support to the three-dimensional structural framework of the elements or to the viscous mass formed after immersion of the framework in a dissolution solution. Thus, in some embodiments, the contact width 2a between two elements (or two segments) is greater than 1 μm. This includes, but is not limited to, contact widths between two elements or two segments greater than 2 μm, or greater than 5 μm, or greater than 10 μm. Furthermore, in some embodiments, the average contact width between elements or segments across the three-dimensional structural framework of the elements is greater than 0.02 times the average thickness of the elements. This includes, but is not limited to, average contact widths between elements or segments across the three-dimensional structural framework of the elements greater than 0.05 times, or greater than 0.1 times, or greater than 0.2 times, or greater than 0.3 times, or greater than 0.4 times, or greater than 0.5 times the average thickness of the elements or segments across the three-dimensional structural framework of the elements. Furthermore, in some embodiments, the average contact width between elements (or segments) across the three-dimensional structural framework is in the range of 1 μm to 1 mm, 1 μm to 2 mm, 2 μm to 2 mm, 2 μm to 1 mm, 5 μm to 1.5 mm, 5 μm to 1 mm, 10 μm to 1.5 mm, 10 μm to 1 mm, 15 μm to 1 mm, 20 μm to 1 mm, or 25 μm to 1 mm.

[0277] Furthermore, it may be noted that in some embodiments, the contact width of contacts between elements or segments in the three-dimensional structural framework of the dosage form or drug-containing solid or element is precisely controlled. Furthermore, in some embodiments, the number of contacts between elements (e.g., fibers, fiber segments, beads, sheets, etc.) or segments in the dosage form or drug-containing solid or three-dimensional structural network is precisely controlled.

[0278] Any other feature or characteristic of contact or bonding between elements that would be apparent to one skilled in the art is encompassed by the present invention.

[0279] d) Free spacing between fibers or elements

[0280] Furthermore, typically, the size or diameter of the channels (e.g., channel width, or pore size, or free spacing, or effective free spacing) must be on the microscale or macroscale to allow dissolution fluid to penetrate the interior of the structure. Thus, in some embodiments, the effective free spacing λ between elements or segments across one or more interconnected free spaces throughout the drug-containing solid or across one or more open pore networks. f,e (or average effective free spacing) (e.g., the pore size or pore diameter at any point in the open pore network, or the pore size or pore diameter everywhere in the open pore network) is greater than 1 μm, including λ greater than 1.25 μm, or greater than 1.5 μm, or greater than 1.75 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 (or mean effective free interval), but are not limited to:

[0281] However, since the volume of a dosage form is generally limited, if the effective free spacing is too large, the mass of drug and excipients that can be loaded into the dosage form may become too small. Furthermore, the free spacing between elements (and the volume fraction of the elements) should not be too small to ensure that the viscosity of the viscous mass formed after immersion in physiological fluid is sufficiently high. For these and / or other reasons, in some embodiments, the effective free spacing (or average effective free spacing) across the interconnected free space across the drug-containing solid or open pore network may be in the range of 1 μm to 5 mm, 1 μm to 3 mm, 1 μm to 2 mm, 1 μm to 1.5 mm, 2 μm to 4 mm, 2 μm to 3 mm, 2 μm to 2 mm, 5 μm to 2.5 mm, 5 μm to 2 mm, 5 μm to 1.5 mm, 10 μm to 2 mm, 10 μm to 1.5 mm, 10 μm to 3 mm, 15 μm to 3 mm, 15 μm to 1.5 mm, 20 μm to 3 mm, 30 μm to 3 mm, 40 μm to 3 mm, or 40 μm to 2 mm.

[0282] Furthermore, in some embodiments, the average effective free spacing between segments or elements across one or more free spaces (e.g., across all free spaces in the dosage form) is within the range of 1 μm to 3 mm. This includes, but is not limited to, average effective free spacing between segments or elements across one or more free spaces within the range of 1 μm to 2.5 mm, or 1 μm to 2 mm, or 2 μm to 3 mm, or 2 μm to 2.5 mm, or 5 μm to 3 mm, or 5 μm to 2.5 mm, or 10 μm to 3 mm, or 10 μm to 2.5 mm, or 15 μm to 3 mm, or 15 μm to 2.5 mm, or 20 μm to 3 mm, or 20 μm to 2.5 mm. The effective free spacing can be determined experimentally from microstructural images (e.g., scanning electron micrographs, micro-computed tomography, etc.) of the drug-containing solid. A non-limiting example describing and illustrating how the effective free spacing can be determined from microstructural images is described and illustrated in U.S. Application No. 15 / 482,776, entitled "Fibrous dosage form."

[0283] Furthermore, it may be noted that in some embodiments herein, the free or effective free spacing between elements or segments across a drug-containing solid, or across one or more interconnected free spaces, or across one or more open pore networks, is precisely controlled.

[0284] Furthermore, the free spacing between the elements and the surface composition of the elements is generally designed to allow physiological, bodily, or dissolved fluids to penetrate into the dosage form structure upon immersion of the dosage form in a liquid. Thus, in some embodiments, the free spacing between the segments and the composition on the surface of one or more elements is such that the penetration time of physiological / bodily fluids into one or more interconnected free spaces of the drug-containing solid is 300 seconds or less under physiological conditions. This includes, but is not limited to, a penetration time of physiological / bodily fluids into one or more interconnected free spaces of the drug-containing solid of 200 seconds or less, or 100 seconds or less, or 50 seconds or less, or 20 seconds or less, or 10 seconds or less under physiological conditions.

[0285] Furthermore, in some embodiments, upon immersion of the drug-containing solid in physiological fluid, the fluid penetrates greater than 40 percent of the free space of the drug-containing solid within 600 seconds of immersion.

[0286] Furthermore, in some embodiments, upon immersion of the drug-containing solid in physiological fluid, the fluid penetrates greater than 60 percent of the free space of the drug-containing solid within 400 seconds of immersion.

[0287] Furthermore, in some embodiments, upon immersion of the drug-containing solid in physiological fluid, the fluid penetrates greater than 50 percent of the free space of the drug-containing solid within 200 seconds of immersion.

[0288] Furthermore, in some embodiments, upon immersion of the drug-containing solid in physiological fluid, the fluid penetrates greater than 40 percent (e.g., greater than 50 percent, or greater than 60 percent, or greater than 70 percent, or greater than 80 percent, or greater than 90 percent, or greater than 95 percent, or 100 percent) of the free space of the drug-containing solid within 100 seconds of immersion.

[0289] It should be apparent to one skilled in the art that the free space, free interval, or effective free interval herein can include many additional dimensions, features, and characteristics, all of which are included in this disclosure and the present invention. (e) Composition of free space

[0290] Typically, one or more interconnected free spaces 215 are filled with a substance that is removable by physiological fluid under physiological conditions. Such a substance that is removable by physiological fluid under physiological conditions can be, for example, a gas that escapes from the free space upon penetration by said physiological fluid. However, such a substance that is removable by physiological fluid under physiological conditions can also be a solid that is highly soluble in said physiological fluid and therefore rapidly dissolves upon contact with or immersion in said physiological fluid.

[0291] Non-limiting examples of biocompatible gases that may fill the free space include air, nitrogen, CO2, argon, oxygen, and nitric oxide, among others.

[0292] Non-limiting examples of solids that are removed or dissolved after contact with physiological / body fluids include, among others, sugars or polyols, such as sucrose, fructose, galactose, lactose, maltose, glucose, maltodextrin, mannitol, maltitol, isomalt, lactitol, xylitol, and sorbitol. Other examples of solids include, among others, polymers, such as polyethylene glycol, polyvinylpyrrolidone, and polyvinyl alcohol. Typically, a solid material should have a solubility in physiological / body fluids (e.g., aqueous physiological or body fluids) under physiological conditions of greater than 50 g / L to be rapidly removed or dissolved after contact with the dissolution medium. This includes, but is not limited to, a solubility of greater than 75 g / L, or greater than 100 g / L, or greater than 150 g / L, or greater than 200 g / L. When a solid material needs to be dissolved rapidly after contact with the dissolution medium, the diffusion rate of the solid material (such as a molecule dissolved in physiological / body fluids under physiological conditions) is typically 4 x 10 -12 m 2 / s, which must be greater than 6 × 10 -12 m 2 / s or greater than 8 × 10 -12 m 2 / s or greater than 1 × 10 -11 m 2 / s or greater than 2 × 10 -11 m 2 / s or greater than 5 × 10 -11 m 2 Diffusion rates in physiological fluids under physiological conditions greater than 1 / s include, but are not limited to, diffusivities in physiological fluids greater than 1 / s.

[0293] Furthermore, in some embodiments, the solid that can fill the free space has a molecular weight (e.g., average molecular weight, e.g., number average molecular weight or weight average molecular weight) of 80 kg / mol or less, including but not limited to, a molecular weight (e.g., average molecular weight, e.g., number average molecular weight or weight average molecular weight) of 70 kg / mol or less, or 60 kg / mol or less, or 50 kg / mol or less, or 45 kg / mol or less, or 40 kg / mol or less, or 35 kg / mol or less, or 30 kg / mol or less.

[0294] All further compositions of free space that would be apparent to one skilled in the art given all the information herein are encompassed by the present invention. (f) Geometry of elements or fibers

[0295] After permeating the free space or one or more interconnected free spaces, the dissolution or physiological fluid can surround one or more elements or segments (e.g., fibers, fiber segments, etc.). To achieve a high specific surface area (i.e., a high surface area to volume ratio) of the solid in contact with the dissolution fluid, in some embodiments, one or more elements (e.g., fibers, etc.) have an average thickness h0 of 2.5 mm or less, including, but not limited to, h0 of 2 mm or less, or 1.75 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, or 700 μm or less, or 650 μm or less, or 600 μm or less, or 550 μm or less, or 500 μm or less, or 450 μm or less.

[0296] However, it can be noted that when elements are very thin and tightly packed, the spacing and free space between elements may be so small that the rate at which the dissolution fluid can penetrate or flow into the free space is limited. Furthermore, dosage forms with very thin elements may be difficult to manufacture, for example, by 3D-micropatterning or 3D-printing. Thus, in some embodiments, one or more elements may be larger than 1 μm, or larger than 2 μm, or larger than 5 μm, or larger than 10 μm, or larger than 20 μm, or 5 μm to 2 mm, 5 μm to 1.5 mm, 5 μm to 1.25 mm, 5 μm to 1 mm, 5 μm to 750 μm, 5 μm to 500 μm, 10 μm to 2 mm, or 10 μm to 1.5 mm. , 10 μm to 1.25 mm, 10 μm to 1 mm, 15 μm to 1 mm, 20 μm to 1 mm, 25 μm to 1 mm, 30 μm to 1 mm, 20 μm to 1.5 mm, 25 μm to 1.5 mm, 25 μm to 1.25 mm, 25 μm to 1 mm, 30 μm to 1.5 mm, 30 μm to 1.25 mm, 30 μm to 1 μm, 40 μm to 1.5 mm or 40 μm to 1 mm.

[0297] In some embodiments, the average thickness (e.g., the average thickness of the elements (e.g., fibers, etc.) in the three-dimensional network) of one or more elements (e.g., fibers, etc.) that make up (e.g., produce, fabricate, etc.) the three-dimensional network is precisely controlled. Furthermore, to ensure unconstrained expansion, in some embodiments, the thickness of one or more elements (e.g., wet or wettable elements, fibers, wet or wettable fibers, etc.) is uniform throughout the one or more elements. This includes, but is not limited to, a uniform element thickness throughout the three-dimensional structural framework of the element or a uniform element thickness throughout the drug-containing solid.

[0298] The element thickness, h, can be considered the smallest dimension of the element (i.e., h≦w and h≦l, where h, w, and l are the thickness, width, and length of the element, respectively). The average element thickness, h0, is the average of the element thicknesses along the length and / or width of one or more elements. Non-limiting examples illustrating how the average element thickness can be derived are provided in U.S. Application No. 15 / 482,776, entitled "Fibrous dosage form."

[0299] Generally, one or more elements (e.g., fibers, etc.) or segments (e.g., fiber segments, etc.) can further comprise a continuous (e.g., single or internally connected) solid matrix through its thickness. In other words, an element can comprise an outer element surface and an internal, continuous solid matrix adjacent to, terminating at, and / or defining said outer element surface.

[0300] In some embodiments, at least one outer surface of an element (e.g., the outer surface of one or more fibers or the outer surface of a fiber segment) further comprises a coating. The coating can cover part or all of the outer surface of one or more elements or segments. The coating can further have a composition that is different or distinct from the composition of one or more elements or segments. The coating can be solid and may or may not contain or include a drug. (f) Micro- and nanostructure and composition of drug-containing elements or fibers

[0301] In the invention herein, at least two excipients can have complementary functions or functionalities that may be desired or necessary to produce the expandable gastroretentive dosage forms disclosed herein. The micro- or nanostructure of the elements greatly influences their properties.

[0302] 18a presents a non-limiting example of an element 1810 (e.g., a fiber) that includes a solid solution 1812 of a drug 1815, one or more physiological fluid-absorbing excipients 1816, and one or more strength-enhancing excipients 1818. The solid solution 1812 is a phase that includes the strength-enhancing excipients 1818; this 1812 is connected along the length L0 of the element 1810. Thus, the phase 1812 that includes the strength-enhancing excipients 1818 is connected along the length of the element 1810.

[0303] Upon exposure to physiological fluid 1890, such as saliva, gastric fluid, or physiologically-like fluid, one or more strength-enhancing excipients 1818 form a fluid-permeable semi-solid network 1819 to mechanically support elements 1811, FIG. 18b. Also, upon absorption of the physiological fluid 1890, one or more fluid-absorbing excipients 1816 transition into a viscous mass or solution 1817, swelling elements 1810, 1811 along at least one dimension (or in all dimensions).

[0304] Because phase 1812 containing strength-enhancing excipient 1818 is connected along the length of element 1810 prior to exposure to said physiological fluid 1890, a semi-solid network 1819 of strength-enhancing excipient 1818 is connected along the length L of expanded element 1811. The connected semi-solid network 1819 of strength-enhancing excipient 1818 mechanically supports or strengthens expanded element 1811.

[0305] 18c presents a non-limiting example of an element 1820 (e.g., a fiber) comprising a core 1823 of drug 1825 and absorbent excipient 1826 (without any dissolved molecules of strength-enhancing excipient), said core 1823 being surrounded by a layer or shell 1824 of strength-enhancing excipient 1828. The layer or shell 1824 of strength-enhancing excipient 1828 is connected along the length L0 of element 1820. Thus, the layer 1824 comprising strength-enhancing excipient 1828 is connected along the length of element 1820.

[0306] Upon exposure to physiological fluid 1892, such as saliva, gastric fluid, or physiologically-like fluid, one or more strength-enhancing excipients 1828 form a fluid-permeable semi-solid network 1829 to mechanically support elements 1821, FIG. 18d. Also, upon absorption of the physiological fluid 1892, one or more fluid-absorbing excipients 1826 transition into a viscous mass or solution 1827, swelling elements 1820, 1821 along at least one dimension (or in all dimensions).

[0307] Because phase 1824 including strength-enhancing excipient 1828 is connected along the length of element 1820 prior to exposure to said physiological fluid 1892, a semi-solid network 1829 of strength-enhancing excipient 1828 is connected along length L of expanded element 1821. The connected semi-solid network 1829 of strength-enhancing excipient 1828 mechanically supports or strengthens expanded element 1821.

[0308] 18e presents a non-limiting example of an element 1830 (e.g., a fiber) comprising dispersed particles 1833 (without any dissolved molecules of the strength-enhancing excipient) of drug 1835 and absorbent excipient 1836 in a matrix 1834 of strength-enhancing excipient 1838. The matrix 1834 of strength-enhancing excipient 1838 is connected along the length of the element 1830. Thus, the phase 1834 comprising the strength-enhancing excipient 1838 is connected along the length of the element 1830.

[0309] Upon exposure to physiological fluid 1894, such as saliva, gastric fluid, or physiologically-like fluid, one or more strength-enhancing excipients 1838 form a fluid-permeable semi-solid network 1839 to mechanically support elements 1831, FIG. 18f. Also, upon absorption of the physiological fluid 1894, one or more fluid-absorbing excipients 1836 transition into a viscous mass or solution 1837, swelling elements 1830, 1831 along at least one dimension (or in all dimensions).

[0310] Because phase 1834 including strength-enhancing excipient 1838 is connected along the length of element 1830 prior to exposure to said physiological fluid 1894, a semi-solid network 1839 of strength-enhancing excipient 1838 is connected along length L of expanded element 1831. The connected semi-solid network 1839 of strength-enhancing excipient 1838 mechanically supports or strengthens expanded element 1831.

[0311] 18g presents a non-limiting example of an element 1840 (e.g., a fiber) that includes a matrix 1843 of drug 1845 and absorbent excipient 1846 (without any dissolved molecules of strength-enhancing excipient), and dispersed particles 1844 of strength-enhancing excipient 1848. The dispersed particles 1844 of strength-enhancing excipient 1848 are not connected along the length L0 of the element 1840. Thus, the element or fiber 1840 does not include a phase that includes the strength-enhancing excipient 1848 connected along the length of the element 1840.

[0312] Upon exposure to physiological fluid 1896, such as saliva, gastric fluid, or a physiologically-like fluid, absorption of said physiological fluid 1896 causes one or more fluid-absorbing excipients 1846 to transition into a viscous mass or viscous solution 1847, swelling said elements 1840, 1841 along at least one dimension (or in all dimensions), FIG. 18h.

[0313] However, because phase 1844 including strength-enhancing excipient 1848 is not connected along the length of element 1840 prior to exposure to said physiological fluid 1896, a semi-solid network of strength-enhancing excipient 1848 cannot form along length L of expanded element 1841. (Strength-enhancing excipient 1848 can constitute dispersed particles 1849 in expanded element 1841.) The semi-solid network of strength-enhancing excipient 1848 cannot substantially mechanically support or strengthen expanded element 1841. Such embodiments are generally not preferred by the inventions herein. In some embodiments, therefore, one or more phases including strength-enhancing excipient form a connected or continuous or contiguous (or substantially connected or substantially continuous or substantially contiguous) network, structure, or matrix within one or more elements or within the three-dimensional structural framework of the elements. In some embodiments, the one or more phases comprising the strength-enhancing excipients are further substantially connected or substantially continuous along the length of one or more structural elements or throughout the three-dimensional structural framework.

[0314] Generally, a phase or phases comprising a strength-enhancing excipient can be said to be substantially connected along the length of an element or element or through a structural scaffold if the mechanical strength or stiffness (e.g., modulus) of the element or scaffold after exposure to physiological fluid is substantially greater than the mechanical strength or stiffness of an element or scaffold comprising the fluid-absorbing excipient alone (e.g., without the strength-enhancing excipient) after exposure to said physiological fluid. By way of example, but not limitation, one or more phases comprising a strength-enhancing excipient are connected along the length of an element if the tensile strength or modulus of the element after exposure to physiological fluid is at least two times greater than that of a corresponding element comprising the fluid-absorbing excipient alone (e.g., without the strength-enhancing excipient) after exposure to said physiological fluid. This includes, but is not limited to, a tensile strength or modulus of the element after exposure to physiological fluid that is at least 3 times greater, or at least 4 times greater, or at least 5 times greater, or at least 6 times greater, or at least 7 times greater than that of a corresponding element comprising the fluid-absorbing excipient alone (e.g., without the strength-enhancing excipient) after exposure to said physiological fluid.

[0315] In some embodiments, the one or more phases comprising the strength-enhancing excipients further form a single continuous (e.g., connected) structure or a single continuous (e.g., connected) network structure along or through the elements of the three-dimensional structural framework.

[0316] In some embodiments, furthermore, the concentration of the at least one strength-enhancing excipient is substantially homogeneous within or through or across one or more elements or the three-dimensional structural framework of an element.

[0317] In some embodiments, the concentration of at least one absorbent excipient is substantially homogeneous within or through or across one or more elements or the three-dimensional structural framework of an element.

[0318] In some embodiments, one or more elements further comprise multiple (e.g., two or more) segments having substantially the same weight fraction of physiological fluid-absorbing excipient distributed within the segments (e.g., the standard deviation of the weight fraction of the absorbent excipient within the elements is less than or equal to the mean value).

[0319] In some embodiments, one or more elements further comprise multiple (e.g., two or more) segments having substantially the same weight fraction of strength-enhancing excipient distributed within the segments (e.g., the standard deviation of the weight fraction of strength-enhancing excipient within the elements is less than or equal to the mean value).

[0320] In some embodiments, at least two excipients (eg, at least one absorbent excipient and at least one strength-enhancing excipient) further form a solid solution.

[0321] The properties of the at least two excipients combined together can further depend on the weight fraction of the individual components. More specifically, by varying the weight fraction of the absorption and consistency enhancing excipients in the three-dimensional structural scaffold, related properties such as the rate of swelling, the degree of swelling, the rate of disintegration of the three-dimensional structural scaffold, and the dissolution rate of the drug can be varied, adjusted, or controlled.

[0322] In some embodiments, the weight fraction of absorbable polymeric excipient 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 absorbable polymeric excipient in an 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.

[0323] Similarly, in some embodiments, the weight fraction of absorbable polymeric excipients in the three-dimensional structural scaffold of one or more elements relative to the total weight of said scaffold is greater than 0.1, including but not limited to, a weight fraction of absorbable polymeric excipients in the structural scaffold relative to the total weight of said scaffold of 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.

[0324] In some embodiments, the weight fraction of absorbent polymeric excipients in at least one element relative to the total weight of absorbent excipients and viscosity enhancing excipients in said element is greater than 0.3, including but not limited to, a weight fraction of absorbent polymeric excipients in an element relative to the total weight of absorbent excipients and viscosity enhancing excipients in said element greater than 0.4, or greater than 0.5, or greater than 0.6, or greater than 0.65, or greater than 0.7.

[0325] Similarly, in some embodiments, the weight fraction of absorbable polymeric excipients in the three-dimensional structural scaffold of one or more elements relative to the total weight of absorbable excipients and consistency-enhancing excipients in said scaffold is greater than 0.1, including, but not limited to, a weight fraction of absorbable polymeric excipients in the structural scaffold relative to the total weight of absorbable excipients and strength-enhancing excipients in said scaffold of greater than 0.2, or greater than 0.3, or greater than 0.4, or greater than 0.5, or greater than 0.55.

[0326] In some embodiments, the weight fraction of the strength-enhancing excipient relative to the total weight of the functional excipients (e.g., strength-enhancing excipients and absorbency excipients) is 0.9 or less, including, but not limited to, a weight fraction of the strength-enhancing excipient relative to the total weight of the functional excipients of 0.85 or less, or 0.8 or less, or 0.75 or less, or 0.7 or less, or in the ranges of 0.1-0.9, 0.1-0.85, 0.15-0.85, 0.15-0.9, 0.2-0.85, 0.2-0.9, 0.25-0.9, 0.25-0.85, 0.3-0.9, 0.3-0.85, 0.15-0.8, or 0.15-0.7.

[0327] In some embodiments, the volume of strength-enhancing excipient per unit volume of dosage form or drug-containing solid (e.g., the volume fraction of strength-enhancing excipient in a dosage form or drug-containing solid relative to the volume of said dosage form or said drug-containing solid) is greater than 0.05, including, but not limited to, a volume of strength-enhancing excipient per unit volume of dosage form or drug-containing solid (e.g., the volume fraction of strength-enhancing excipient in a dosage form or drug-containing solid relative to the volume of said dosage form or said drug-containing solid) that is greater than 0.1, or greater than 0.15, or greater than 0.2, or greater than 0.25.

[0328] In some embodiments, the weight of the strength-enhancing excipient per unit volume of the dosage form or drug-containing solid (e.g., the density of the strength-enhancing excipient in the dosage form or drug-containing solid relative to the volume of the dosage form or drug-containing solid) is 50 kg / m 3 This is greater than 100 kg / m 3 or greater than 150kg / m 3 or greater than 200kg / m 3 These include, but are not limited to, a weight of strength-enhancing excipient per unit volume of a dosage form or drug-containing solid (e.g., density of a strength-enhancing excipient in a dosage form or drug-containing solid relative to the volume of said dosage form or said drug-containing solid) that is greater than

[0329] Any further microstructure of the elements will be apparent to those skilled in the art, all of which are within the spirit and scope of the present invention. (f) Properties and composition of absorbent excipients

[0330] The drug-containing element herein comprises at least one or more physiological fluid-absorbing excipients. In some specific embodiments, the absorbing excipients may be mutually soluble with the relevant physiological fluid under physiological conditions, and thus "absorb" or "mix with" the physiological fluid until their concentration is homogenous throughout the fluid. Thus, the absorbing excipients can facilitate the swelling and dissolution and / or disintegration of the drug-containing solid or viscous mass.

[0331] In some embodiments, the absorbent excipient (and / or element or segment) further has an effective diffusivity of physiological / body fluids of 0.05×10 or less under physiological conditions. -11 m 2 / s, which is greater than 0.1 × 10 -11 m 2 / s or 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, effective diffusivities of physiological / body fluids in the absorbent excipient (and / or element or segment) that are greater than 1 / s.

[0332] Alternatively, for absorbent excipients into which physiological / body fluid diffusion may or may not be Fickian, the rate of permeation can be specified. In some embodiments, the rate of permeation of physiological / body fluid into the solid absorbent excipient (and / or elements or segments) is greater than the average thickness of one or more drug-containing elements divided by 3600 seconds (i.e., h / 3600 μm / s). In other non-limiting examples, the rate of permeation may be greater than h / 1800 μm / s, greater than h / 1200 μm / s, greater than h / 800 μm / s, greater than h / 600 μm / s, greater than h / 500 μm / s, greater than h / 400 μm / s, or greater than h / 300 μm / s.

[0333] To determine the effective diffusion rate (and / or rate of penetration) of a dissolution medium in a solid absorbent excipient (and / or element or segment), the following procedure can be applied: An element (e.g., an element or segment of a dosage form structure, or preferably, an element or segment consisting solely of an absorbent excipient) can be placed in a static dissolution medium at 37°C. The time t1 at which the element substantially disintegrates or deforms can be recorded. (By way of example, but not limitation, deformation of an element can generally be considered substantial if either the length, width, or thickness of the element differs from its initial value by at least 20-80 percent (e.g., at least 20 percent, or at least 30 percent, or at least 40 percent, or at least 50 percent, or at least 60 percent, or at least 70 percent, or at least 80 percent, etc.). Then, D eff =h init 2 / 4t1(in the formula, h init is the initial element or segment thickness (e.g., the thickness of the dry element or segment) according to the effective diffusivity D eff Similarly, the rate of physiological / body fluid penetration into an element or segment can be determined as h init / 2t1. Further non-limiting examples for deriving the effective diffusivity or rate of penetration are provided in U.S. Application No. 15 / 482,776, entitled "Fibrous dosage form."

[0334] To ensure that the drug-containing solid expands substantially and that the integrity of the expanded semi-solid mass is preserved for extended periods in physiological fluids under physiological conditions, the molecular weight of the one or more physiological fluid-absorbing excipients must be substantial. Thus, in some embodiments, the molecular weight of at least one absorbable polymeric excipient is greater than 30 kg / mol. This includes, but is not limited to, absorbable polymeric excipient molecular weights greater than 40 kg / mol, greater than 50 kg / mol, greater than 60 kg / mol, greater than 70 kg / mol, or greater than 80 kg / mol.

[0335] To ensure that the dosage form can be fabricated by patterning the viscous drug-excipient paste, and for other reasons, the molecular weight of at least one absorbent excipient (or the absorbent polymeric excipient as a whole) can be limited.

[0336] By way of example, but not limitation, the molecular weight of the at least one absorbent excipient (or the average molecular weight of the absorbent excipient as a whole) can be within the ranges of 30 kg / mol to 10,000,000 kg / mol, 50 kg / mol to 10,000,000 kg / mol, 70 kg / mol to 10,000,000 kg / mol, 80 kg / mol to 10,000,000 kg / mol, 70 kg / mol to 5,000,000 kg / mol, or 70 kg / mol to 2,000,000 kg / mol. Preferably, the physiological fluid-absorbing excipient comprises hydroxypropyl methylcellulose having a molecular weight within the range of between about 50 kg / mol and 500 kg / mol (e.g., 70 kg / mol to 300,000 kg / mol).

[0337] Thus, in some embodiments, at least one absorbent excipient (or the absorbent excipient as a whole) can comprise multiple individual chains or molecules that dissolve or unravel upon immersion in physiological fluid.

[0338] In some embodiments, at least one absorbent excipient further has a solubility of greater than 20 g / L in relevant physiological / body fluids under physiological conditions. This includes, but is not limited to, at least one absorbent excipient (or the absorbent excipient as a whole) having a solubility in relevant physiological / body fluids under physiological conditions of greater than 50 g / L, or greater than 75 g / L, or greater than 100 g / L, or greater than 150 g / L, or greater than 175 g / L, or greater than 200 g / L, or greater than 250 g / L, or greater than 300 g / L, or greater than 350 g / L. In extreme cases, the absorbent excipient (e.g., at least one absorbent excipient or the absorbent excipient as a whole) is mutually soluble with relevant physiological fluids under physiological conditions. The solubility of a material is referred to herein as the maximum amount or mass of the material that can be dissolved at equilibrium in a given volume of physiological fluid under physiological conditions, divided by the volume of the fluid or formed solution. By way of example, but not limitation, the solubility of a solute in a solvent can be determined by optical methods.

[0339] Preferably, furthermore, at least one absorbable polymeric excipient (or the absorbable polymeric excipient as a whole) comprises an amorphous molecular structure in the solid state (e.g., an amorphous arrangement of molecules, or an arrangement of molecules without long-range order). A non-limiting method for determining the molecular structure of a solid (e.g., distinguishing amorphous molecular structure from crystalline molecular structure) is differential scanning calorimetry.

[0340] Non-limiting examples of excipients that meet some or all of the requirements of an absorbable polymeric 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. (f) Characteristics and Composition of Strength-Enhancing Excipients

[0341] The drug-containing element herein further comprises at least one or more strength-enhancing excipients. Generally, the at least one strength-enhancing excipient (or the strength-enhancing excipient as a whole) is also slightly permeable to relevant physiological fluids under physiological conditions, which can facilitate rapid expansion of the dosage form or drug-containing solid or scaffold upon immersion. In some embodiments, therefore, the diffusion coefficient of relevant physiological fluids under physiological conditions in the at least one strength-enhancing excipient (or the strength-enhancing excipient as a whole) is greater than 1×10 -13 m 2 / s, which is greater than 2 × 10 -13 m 2 / s or greater than 5 × 10 -13 m 2 / s or greater than 7 × 10 -13 m 2 / s or greater than 1 × 10 -12 m 2 / s or greater than 2 × 10 -12 m 2 / s or greater than 3 × 10 -12 m 2 / s or greater than 4 × 10 -12 m 2 / s or greater than 5 × 10 -12m 2 / s or greater than 6 × 10 -12 m 2 This includes, but is not limited to, a diffusion rate in the relevant physiological fluid under physiological conditions in at least one strength-enhancing excipient (or the strength-enhancing excipient as a whole) that is greater than 1 / s.

[0342] In some embodiments, the strength-enhancing excipient further reduces or decreases or slows down the rate at which physiological fluid-absorbing excipient is removed, eroded, or dissolved from an element, three-dimensional structural scaffold, or dosage form, or semi-solid mass, upon immersion of the element, three-dimensional structural scaffold, or dosage form, or semi-solid mass, in a relevant physiological fluid under physiological conditions. By way of example, but not by way of limitation, in some embodiments, upon immersion of an element (e.g., fiber, etc.), in a relevant physiological fluid under physiological conditions, the rate at which physiological fluid-absorbing excipient is removed, eroded, or dissolved from the element, due to the presence of strength-enhancing excipient in the element at a relevant content, may be substantially limited by the rate of diffusion of the absorbent excipient through the element.

[0343] In some embodiments, therefore, upon immersion of the element in a relevant physiological fluid under physiological conditions, the diffusion rate of at least one physiological fluid-absorbing excipient in or through said element is greater than or equal to 5×10 -12 m 2 / s or less. This is 2×10 -12 m 2 / s or less or 1×10 -12 m 2 / s or less or 5×10 -13 m 2 / s or less or 2×10 -13 m 2 / s or less or 1×10 -13 m 2 / s or less or 5×10 -14 m 2 / s or less or 2×10 -14 m 2 This includes, but is not limited to, a diffusion rate of at least one physiological fluid-absorbing excipient in or through the element of 1 / s or less.

[0344] In some embodiments, furthermore, upon immersion of the element in the relevant physiological fluid under physiological conditions, the diffusivity of the at least one physiological fluid-absorbing excipient through an element (e.g., through a semi-solid element or through a physiological fluid-permeable element) is no more than 0.3 times the self-diffusivity of said at least one absorbent excipient in the relevant physiological fluid under physiological conditions, including, but not limited to, a diffusivity of the at least one absorbent excipient through an element (e.g., through a viscous element or through a water-permeable element) that is no more than 0.2 times, or no more than 0.1 times, or no more than 0.05 times, or no more than 0.02 times, or no more than 0.01 times, or no more than 0.005 times, or no more than 0.002 times, or no more than 0.001 times the self-diffusivity of said at least one absorbent excipient in the relevant physiological fluid under physiological conditions.

[0345] Generally, the strength-enhancing excipient's solubility in physiological fluids (e.g., gastric fluids, etc.) can be limited to ensure that the excipient remains a semi-solid or viscoelastic material after exposure to the physiological fluid and stabilizes or mechanically supports or reinforces one or more components. In some embodiments, therefore, at least one strength-enhancing excipient has a solubility of 1 g / L or less in relevant physiological / body fluids under physiological conditions. This includes, but is not limited to, at least one strength-enhancing excipient (or one or more strength-enhancing excipients, or the strength-enhancing excipient as a whole) having a solubility in relevant physiological / body fluids under physiological conditions of 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, or 0.05 g / L or less, or 0.02 g / L or less, or 0.01 g / L or less, or 0.005 g / L or less, or 0.002 g / L or less, or 0.001 g / L or less. In extreme cases, the strength-enhancing excipient (e.g., at least one strength-enhancing excipient or the strength-enhancing excipient as a whole) may be insoluble or at least practically insoluble in relevant physiological fluids under physiological conditions.

[0346] It can be noted that even if the strength-enhancing excipient has low solubility in the relevant physiological fluid, the strength-enhancing excipient may soften or plasticize slightly upon contact with or immersion in the physiological fluid under physiological conditions. As a result, at least one strength-enhancing excipient may be solid in the dry state, but may transition to a semi-solid or viscoelastic material upon immersion in or exposure to the relevant physiological fluid (e.g., gastric juice, etc.) under physiological conditions.

[0347] In general, the mechanical properties (e.g., stiffness, yield strength, tensile strength, etc.) of a strength-enhancing excipient immersed in physiological fluid should be great enough to stabilize or mechanically support the dosage form or drug-containing solid or scaffold. However, the stiffness, yield strength, tensile strength, etc. of a strength-enhancing excipient immersed in physiological fluid should not be too great, so that the expansion of the dosage form or drug-containing solid or scaffold after exposure to said physiological fluid is not excessively impaired or restricted. Thus, strength-enhancing excipients that constitute or form a semi-solid material upon exposure to the relevant physiological fluid are typically preferred herein.

[0348] In some embodiments, the strength-enhancing excipient immersed in a physiological fluid (e.g., a film immersed in a relevant physiological fluid (e.g., acidic water) for a period of time long enough for the water concentration in the film to approximately equilibrate) comprises an elastic modulus or elastic-plastic modulus or plastic modulus greater than 0.02 MPa. This includes, but is not limited to, strength-enhancing excipients immersed in a physiological fluid (e.g., a film immersed in a relevant physiological fluid (e.g., acidic water) for a period of time long enough for the water concentration in the film to approximately equilibrate) that comprise an elastic modulus or elastic-plastic modulus or plastic modulus greater than 0.05 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa, or greater than 0.3 MPa, or greater than 0.4 MPa, or greater than 0.5 MPa, or greater than 0.6 MPa, or greater than 0.7 MPa, or greater than 0.8 MPa, or greater than 0.9 MPa, or greater than 1 MPa. In some embodiments, the strength-enhancing excipient immersed in physiological fluid (e.g., a film immersed in a relevant physiological fluid (e.g., acidic water) for a period of time long enough for the water concentration in the film to roughly equilibrate) further comprises an elastic or elastoplastic or plastic modulus of about 1000 MPa or less (e.g., 500 MPa or less, or 200 MPa or less, or 100 MPa or less, or 50 MPa or less, or 20 MPa or less, or 10 MPa or less). Preferably, the elastic modulus of the strength-enhancing excipient immersed in physiological fluid should be greater than about 0.1 MPa and about 500 MPa or less.

[0349] In some embodiments, furthermore, the strength-enhancing excipients immersed in physiological fluids (e.g., acidic water) (e.g., films immersed in the relevant physiological fluid (e.g., acidic water) for a period of time long enough for the water concentration in the film to approximately equilibrate) comprise a yield strength of greater than 0.005 MPa. This includes, but is not limited to, strength-enhancing excipients immersed in physiological fluids (e.g., films immersed in the relevant physiological fluid (e.g., acidic water) for a period of time long enough for the water concentration in the film to approximately equilibrate) that comprise a yield strength of greater than 0.0075 MPa, or greater than 0.01 MPa, or greater than 0.02 MPa, or greater than 0.05 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa. In some embodiments, the strength-enhancing excipient, when immersed in physiological fluid (e.g., a film immersed in physiological fluid (e.g., acidic water) for a period of time long enough that the water concentration in the film is approximately at equilibrium), further comprises a yield strength of 500 MPa or less (e.g., 200 MPa or less, or 100 MPa or less, or 75 MPa or less, or 50 MPa or less, or 20 MPa or less, or 10 MPa or less, or 5 MPa or less).

[0350] In some embodiments, furthermore, the strength-enhancing excipient immersed in a physiological fluid (e.g., a film immersed in a relevant physiological fluid (e.g., acidic water) for a period of time long enough for the water concentration in the film to approximately equilibrate) comprises a tensile strength greater than 0.02 MPa. This includes, but is not limited to, strength-enhancing excipients immersed in a physiological fluid (e.g., a film immersed in a relevant physiological fluid (e.g., acidic water) for a period of time long enough for the water concentration in the film to approximately equilibrate) comprising a tensile strength greater than 0.05 MPa, or greater than 0.08 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa, or greater than 0.3 MPa, or greater than 0.4 MPa, or greater than 0.5 MPa, or greater than 0.6 MPa. In some embodiments, the strength-enhancing excipient further comprises a tensile strength of 500 MPa or less (e.g., 200 MPa or less, or 100 MPa or less, or 75 MPa or less, or 50 MPa or less, or 20 MPa or less, or 10 MPa or less) when immersed in a physiological fluid (e.g., a film immersed in a relevant physiological fluid (e.g., acidic water) for a period of time long enough for the water concentration in the film to approximately equilibrate).

[0351] In some embodiments, furthermore, strength-enhancing excipients immersed in physiological fluids (e.g., films immersed in relevant physiological fluids (e.g., acidic water) for a time long enough that the water concentration in the film is approximately at equilibrium) comprise a strain at break greater than 0.2. This includes, but is not limited to, strength-enhancing excipients immersed in physiological fluids (e.g., films immersed in relevant physiological fluids (e.g., acidic water) for a time long enough that the water concentration in the film is approximately at equilibrium) that comprise a strain at break greater than 0.5, or greater than 0.75, or greater than 1, or greater than 1.25, or greater than 1.5, or greater than 1.75, or greater than 2, or greater than 2.25, or greater than 2.5. Preferably, the strain at break of a strength-enhancing excipient immersed in physiological fluids should be greater than about 1.

[0352] Furthermore, in some embodiments, the solubility of at least one strength-enhancing excipient (or the solubility of the strength-enhancing excipient as a whole) may vary in different physiological fluids under physiological conditions. By way of example, but not limitation, in some embodiments, the solubility of at least one strength-enhancing excipient in an aqueous physiological fluid may depend on the pH value of said physiological fluid. More specifically, in some embodiments, at least one strength-enhancing excipient may be poorly soluble, insoluble, or practically insoluble in aqueous physiological fluids that are acidic (e.g., gastric fluid, or fluids having a pH value less than about 5), but may be soluble in aqueous physiological fluids having higher pH values, such as intestinal fluids (e.g., fluids having a pH value greater than about 6, or greater than about 6.5, or greater than about 7). Strength-enhancing excipients that have a lower solubility in acidic solutions than in basic solutions are also referred to herein as "enteric excipients."

[0353] In some embodiments, therefore, at least one strength-enhancing excipient has a solubility in aqueous fluids having a pH value of 4 or less that is 10 times less (e.g., 20 times less, or 50 times less, or 100 times less, or 200 times less, or 500 times less) than the solubility of said strength-enhancing excipient in aqueous fluids having a pH value greater than 7.

[0354] A non-limiting example of such a strength-enhancing excipient that is poorly soluble in gastric or acidic fluids but soluble in intestinal fluids (e.g., aqueous fluids having a pH value greater than about 5.5) is methacrylic acid-ethyl acrylate copolymer.

[0355] Other non-limiting examples of strength-enhancing excipients herein can include hydroxypropyl methylcellulose acetate succinate, methacrylic acid-ethyl acrylate copolymers, methacrylate copolymers (e.g., poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2, poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, poly(ethyl acrylate-co-methyl methacrylate) 2:1, etc.), and the like. (h) Swelling of the drug-containing solid and formation of a semi-solid mass

[0356] 19 presents a non-limiting example of a pharmaceutical dosage form 1900 comprising a drug-containing solid 1901 having an outer surface 1902 and an inner three-dimensional structural framework 1904 of one or more substantially regularly arranged thin structural elements 1910. Framework 1904 is adjacent to and terminates at said outer surface 1902. The structural elements comprise a hydrophilic surface composition. The structural elements 1910 further comprise segments spaced apart from the bounding segments 1910, thereby defining free spaces 1915. A plurality of adjacent free spaces 1915 combine to define one or more interconnected free spaces 1915 and form an open pore network extending across at least half the thickness of the drug-containing solid 1901 (e.g., spanning the entire length, width, and thickness of the drug-containing solid and terminating at its outer surface 1902). The structural element 1910 further comprises at least one active ingredient (e.g., at least one drug) dissolved as drug molecules 1920 or dispersed as particles in the excipient matrix 1930, 1950. Thus, the drug forms a solid solution or solid dispersion with the excipient matrix 1930, 1950. The excipient matrix 1930, 1950 comprises at least one absorbent polymeric excipient 1930 and at least one strength-enhancing polymeric excipient.

[0357] Upon immersion in a relevant physiological fluid, the fluid penetrates the interconnected free spaces and diffuses into one or more of the elements, such that the framework expands in all dimensions. Because the dosage forms (or drug-containing solids) herein can comprise a structural framework of thin elements having a hydrophilic surface composition surrounded by interconnected free spaces that can terminate at the outer surface of the drug-containing solid, the rate of fluid penetration and diffusion, and consequently, the rate of expansion of the three-dimensional structural framework of the drug-containing solid or element, can be substantial.

[0358] In some embodiments of the invention herein, therefore, at least one dimension (e.g., lateral length or thickness) of the drug-containing solid expands upon transition to a fluid or viscous medium within 300 minutes of immersion in physiological or bodily fluids under physiological conditions to at least 1.3 times its initial value (e.g., its initial length prior to exposure to said physiological fluid), including, but not limited to, at least one dimension of the drug-containing solid reaching a length of at least 1.3 times its initial length within 250 minutes, or within 200 minutes, or within 150 minutes, or within 100 minutes, or within 50 minutes, or within 40 minutes, or within 30 minutes, or within 20 minutes of immersion in said physiological or bodily fluids under physiological conditions. This may include, but is not limited to, at least one dimension of the drug-containing solid or scaffold expanding to a length of at least 1.35 times its initial length, or at least 1.4 times its initial length, or at least 1.45 times its initial length, or at least 1.5 times its initial length, or at least 1.55 times its initial length, or at least 1.6 times its initial length, or at least 1.65 times its initial length within 300 minutes of immersion in or exposure to physiological or bodily fluids under physiological conditions.

[0359] Furthermore, in some embodiments, the drug-containing solid expands to at least twice its initial volume within about 300 minutes of immersion in physiological or bodily fluids under physiological conditions, including, but not limited to, a drug-containing solid that expands to at least 3 times, or at least 4 times, or at least 4.5 times, or at least 5 times, or at least 5.5 times, or at least 6 times, or at least 6.5 times its initial volume within about 300 minutes of immersion in physiological or bodily fluids under physiological conditions.

[0360] In some embodiments, the drug-containing solid (or three-dimensional structural scaffold) expands isotropically (e.g., uniformly in all directions) while transitioning to a semi-solid mass. For purposes of the invention herein, a solid mass is generally understood to expand isotropically if the normalized expansion (e.g., length difference and initial length ratio, such as (L(t)-L0) / L0, (H(t)-H0) / H0, etc.) deviates from its maximum value by less than about 50-75 percent with changes in direction or orientation. Thus, in isotropically expanding solids, semi-solid masses, or scaffolds, the normalized expansion is roughly the same in all directions. Figure 19 shows a non-limiting schematic illustration of an isotropically expanding drug-containing solid. For more information regarding isotropic expansion of drug-containing solids, see, e.g., International Application No. PCT / US19 / 19004, filed February 21, 2019, entitled "Expanding structured dosage forms."

[0361] In some embodiments, upon extended exposure to physiological fluids (e.g., greater than 2, 4, 6, 8, or 10 hours in a gently stirred solution such as acidic water), the swollen scaffold or semi-solid mass maintains its length between 1.3 and 4 times its initial length for an extended period of time.

[0362] In some embodiments, the semi-solid mass comprises a substantially continuous or connected network of one or more strength-enhancing excipients.

[0363] In some embodiments, the semi-solid mass comprises a substantially continuous or connected network of strength-enhancing excipients that extends across the length, width and thickness of said semi-solid mass. j) Mechanical properties of the expanded semi-solid mass

[0364] In some embodiments, the semi-solid mass (e.g., swollen drug-containing solid or dosage form) formed after immersion of the drug-containing solid in physiological fluid under physiological conditions further comprises a modulus of elasticity greater than 0.005 MPa, including, but not limited to, a viscous or semi-solid mass (e.g., swollen drug-containing solid or dosage form) formed after immersion of the drug-containing solid in a dissolution fluid comprising a modulus of elasticity greater than 0.007 MPa, or greater than 0.01 MPa, or greater than 0.015 MPa, or greater than 0.02 MPa, or greater than 0.025 MPa, or greater than 0.03 MPa, or greater than 0.035 MPa, or greater than 0.04 MPa, or greater than 0.045 MPa, or greater than 0.05 MPa, or greater than 0.055 MPa, or greater than 0.06 MPa, or greater than 0.065 MPa, or greater than 0.07 MPa, or greater than 0.075 MPa. In some embodiments, the viscous or semi-solid mass (e.g., the expanded drug-containing solid or dosage form) formed after immersion of the drug-containing solid in the dissolution liquid is thus a highly elastic mass or semi-solid or structure that cannot be broken or permanently deformed for extended periods of time within the stomach (e.g., under the compressive force of the stomach wall).

[0365] In some embodiments, the viscous or semi-solid mass (e.g., swollen drug-containing solid or dosage form) formed after immersion of the drug-containing solid in the dissolution liquid further comprises an elastic modulus of 50 MPa or less (e.g., 40 MPa or less, or 30 MPa or less, or 20 MPa or less, or 10 MPa or less, or 5 MPa or less).

[0366] In some embodiments, the semi-solid mass formed after immersion of the drug-containing solid in the dissolution liquid further comprises a yield strength or breaking strength of greater than 0.002 MPa, including, but not limited to, a viscous or semi-solid mass formed after immersion of the drug-containing solid in the dissolution liquid comprising a yield strength or breaking strength of greater than 0.005 MPa, or greater than 0.007 MPa, or greater than 0.01 MPa, or greater than 0.02 MPa, or greater than 0.025 MPa, or greater than 0.03 MPa, or greater than 0.035 MPa, or greater than 0.04 MPa, or greater than 0.045 MPa, or greater than 0.05 MPa, or greater than 0.055 MPa, or greater than 0.06 MPa, or greater than 0.065 MPa, or greater than 0.07 MPa, or greater than 0.075 MPa, or greater than 0.8 MPa.

[0367] In some embodiments, the semi-solid mass (e.g., swollen drug-containing solid or dosage form) formed after immersion of the drug-containing solid in the dissolution liquid further comprises a yield strength or breaking strength of 50 MPa or less (e.g., 20 MPa or less, or 10 MPa or less, or 5 MPa or less, or 2 MPa or less, or 1 MPa or less).

[0368] In some embodiments, therefore, upon ingestion, the dosage form is retained in the stomach for an extended period of time and delivers the drug into the bloodstream at a precisely controlled rate over an extended period of time (e.g., 80 percent of the drug is released in 30 minutes to 200 hours, 1 hour to 200 hours; 1 hour to 150 hours; 3 hours to 200 hours; 5 hours to 200 hours; 3 hours to 60 hours; 5 hours to 60 hours; 2 hours to 30 hours; 5 hours to 24 hours; 30 minutes to 96 hours, 30 minutes to 72 hours, 30 minutes to 48 hours, 30 minutes to 36 hours, 30 minutes to 24 hours, 1 to 10 hours, 45 minutes to 10 hours, 30 minutes to 10 hours, 45 minutes to 8 hours, 45 minutes to 6 hours, 30 minutes to 8 hours, 30 minutes to 6 hours, 30 minutes to 5 hours, 30 minutes to 4 hours, etc.). This allows for improved control of drug concentrations in the bloodstream and improved effectiveness or reduced side effects of many drug therapies. j) Drug release characteristics of drug-containing solid dosage forms and viscous masses

[0369] Thus, in some embodiments, 80 percent of the drug content in the drug-containing solid is released in more than 30 minutes after immersion in physiological fluid or body fluid under physiological conditions, including, but not limited to, drug-containing solids that release 80 percent of the drug content in more than 40 minutes, or more than 50 minutes, or more than 60 minutes, or more than 100 minutes, or in 30 minutes to 150 hours, 30 minutes to 48 hours, 30 minutes to 36 hours, or 45 minutes to 24 hours after immersion in physiological fluid under physiological conditions. k) Mechanical properties of drug-containing solids and solid dosage forms

[0370] In some embodiments, the tensile strength of the drug-containing solid or the three-dimensional structural framework of one or more elements is between 0.01 MPa and 100 MPa (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).

[0371] Finally, in some embodiments, the tensile strength of the drug-containing solid or the three-dimensional structural framework of one or more elements is between 0.01 MPa and 100 MPa (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). [Example]

[0372] Experimental Example Part 1 The following examples present how fibrous dosage forms can be prepared and analyzed, and will allow those skilled in the art to more easily understand the principles. The examples are presented for illustrative purposes and are not intended to be limiting in any way. Example 1.1 Preparation of fibrous dosage forms

[0373] Non-limiting Examples 1-7 refer to a fibrous dosage form consisting of a single fiber and 20 wt% ibuprofen drug, 60 wt% hydroxypropylmethylcellulose (HPMC) having a molecular weight of 120 kg / mol (absorbent excipient), and 20 wt% methacrylic acid-ethyl acrylate copolymer (1:1) having a molecular weight of approximately 250 kg / mol (strength-enhancing and enteric excipient, also referred to herein as "Eudragit L100-55").

[0374] To prepare the dosage form, ibuprofen drug particles were first dissolved in dimethyl sulfoxide (DMSO) solvent to form a homogeneous solution with a drug concentration of 60 mg / ml DMSO. The ibuprofen-DMSO solution was then mixed with excipients (75 wt% hydroxypropylmethylcellulose (HPMC) with a molecular weight of 120 kg / mol and 25 wt% Eudragit L100-55) at a ratio of 240 mg excipient / ml DMSO.

[0375] The mixture was extruded through a laboratory extruder to form a homogeneous viscous paste. The viscous paste was then extruded into a tube with an inner radius R n The paste was placed in a syringe equipped with a 76 μm hypodermic needle. The paste was extruded through the needle to form wet fibers that were deposited as single fibers or as a fibrous dosage form having a cross-ply structure as previously disclosed (see, for further details, e.g., U.S. Application No. 15 / 482,776, filed April 9, 2017, entitled "Fibrous dosage form"; U.S. Application No. 15 / 482,776, filed April 26, 2018, entitled "Method and apparatus for the manufacture of No. 15 / 964,058, entitled "Dosage form comprising structured solid-solution framework of sparingly-soluble drug and method," filed September 19, 2019. (See International Application No. PCT / US19 / 52030, entitled "For manufacture thereof"). The nominal interfiber spacing λ in the dosage form n were 1250 μm (formulation A), 500 μm (formulation B), and 350 μm (formulation C), as listed in Table 3.

[0376] After deposition or patterning of the fibers and dosage forms, they were subjected to hot air at approximately 40-60°C and 1 m / s for approximately 1 day to evaporate the solvent and solidify the structure. After that, the solvent concentration in the solid fibers and dosage forms was below the 0.005 wt% limit specified by regulatory agencies. The solid dosage forms were finally trimmed with a microtome blade into square disks with nominal dimensions of approximately 7.5 mm x 7.5 mm x 2 mm. Example 1.2 Estimation of microstructural parameters

[0377] A non-limiting example for estimating some microstructural parameters of a dosage form is as follows: Under the broad assumption that the fibers and dosage forms shrink isotropically during solvent evaporation, the radius R and length or interfiber spacing λ of solid fibers and fibrous dosage forms can be derived from nominal values ​​as follows:

number

[0378] The volume fraction of fibers in the solid cross-ply structure of the dosage form can be expressed as follows (for further details, see, e.g., AH Blaesi, N. Saka, Mater. Sci. Eng. C (2021) 110211 and references therein):

number

number

[0379] Table 1 below lists the nominal and estimated microstructural parameters of various dosage forms prepared as described in non-limiting Example 1.1. [Table 1] Example 1.3 Measurement of microstructural parameters

[0380] The fibers and formulation were prepared using a Zeiss Merlin High Performance column equipped with a GEMINI column. The images were taken using a High Resolution SEM. Images were taken without any sample preparation. Imaging was performed using an in-lens secondary electron detector. The microscope was operated with an applied accelerating voltage of 5 kV and a probe current of 95 pA.

[0381] Figure 5a is a scanning electron microscope image of a single fiber. The average fiber radius was approximately 49.5 μm. Figure 5b presents a top view of the microstructure of fibrous dosage form B. The fiber radius R0 = 45.2 ± 6 μm and the interfiber distance λ0 = 390.3 ± 18 μm. Both values ​​are in rough agreement with the estimates presented in Table 1.

[0382] It may further be noted that cross-sectional images of the fibers or dosage forms may be taken to further characterize the microstructure (for non-limiting examples of cross-sectional images of fibrous cross-ply structures, see, e.g., U.S. Application No. 15 / 482,776, filed April 9, 2017, entitled "Fibrous dosage form," U.S. Application No. 15 / 964,058, filed April 26, 2018, entitled "Method and apparatus for the manufacture of fibrous dosage forms," ​​or U.S. Application No. 15 / 964,058, filed September 19, 2019, entitled "Dosage form"). (See International Application No. PCT / US19 / 52030, "Comprising a structured solid-solution framework of a sparingly-soluble drug and method for manufacture thereof"). Example 1.4 Single fiber expansion

[0383] To determine the swelling rate of a single fiber, the fiber was immersed in a beaker filled with 400 ml dissolution solution (0.1 M hydrogen chloride (HCl) in deionized water at a temperature of 37°C). The solution was stirred with a rotating paddle at 50 rpm. The immersed sample was continuously imaged with a Nikon DX camera.

[0384] Images of a single fiber at various time points after immersion in the dissolution solution are shown in Figure 20. The fiber transitioned from a solid to a semi-solid or viscous state and swelled both radially and axially. The integrity of the swelled fiber was preserved for more than an hour.

[0385] Figures 21a and 21b present plots of the normalized radial and axial expansion, ΔR / R0 and ΔL / L0, of a single fiber versus time. Both ΔR / R0 and ΔL / L0 steadily increased with time, but at a decreasing rate. The radial expansion was slightly greater than the axial expansion. After 8 minutes of immersion, ΔR / R0 was 0.8 and ΔL / L0 was approximately 0.63.

[0386] Figures 21c and 21d show the 1 / 2 1 is a plot of the normalized radial and longitudinal expansion of a single fiber versus / R0. In agreement with model equation (7), for short periods (e.g., t≦5 min), it is:

number

number

[0387] From equations (34) and (7), the diffusivity of the solute in the fiber can be estimated as:

number

number

[0388] ρ w / c b Approximately 1 and k from Figure 27 R and k L Using the value, D w Approximately 1.76×10 -11 m 2 / s and by equation (35b), D w Approximately 1.05×10-11 m 2 / s. Example 1.5 Swelling of fibrous dosage forms

[0389] To determine the swelling rate of the fibrous dosage forms, the dosage forms were immersed in a beaker filled with 400 ml dissolution solution (0.1 M HCl in deionized water at 37° C.). The solution was stirred with a rotating paddle at 50 rpm. The immersed samples were continuously imaged with a Nikon DX camera.

[0390] For all dosage forms A, B, and C, upon immersion of the dosage form in the dissolution solution, the liquid rapidly penetrated the interfiber void spaces. The solid dosage form then expanded isotropically and transformed into a highly viscous mass, Figure 22. The geometry of the expanded viscous mass (or expanded viscous dosage form) A, B, and C was stabilized by the enteric excipients and stored or maintained for more than 2, 10, and 50 hours, respectively.

[0391] Figure 23a is a plot of normalized longitudinal expansion ΔL / L0 versus time. The ratio ΔL / L0 increased with time at a decreasing rate. The ratio of the dosage form length after 15 minutes to the initial length, L 15 / L0 was about 2, Table 2. After about 20 minutes, the dosage form had not swelled any further.

[0392] Figure 23b shows the relationship between ΔL / L0 and t 1 / 2 / R0. Consistent with equations (7) and (8), ΔL / L0 is initially 1 / 2 It was proportional to / R0.

number

[0393] From Figures 21 and 23, k ex is the k of a single fiber L and k R The constant k LL =k ex / k L Approximately 1.2 and k RL =k ex / k R Approximately 0.92. Example 1.6 Drug release from a single fiber

[0394] Drug release from a single fiber was monitored under the same conditions using the same setup as in Section 1.4. At regular time intervals, aliquots of the dissolution solution were sampled, and their UV absorbance spectra were obtained using a Perkin Elmer Lambda 950 UV / Vis spectrophotometer. The fraction of drug released was determined by subtracting the UV absorbance at 235 nm from the UV absorbance at 230 nm and dividing the resulting value by the value obtained at "infinite" time (i.e., when all the drug had dissolved).

[0395] In Figure 24a, the fraction of drug released by a single fiber, m d / M0 is plotted against time t. The time to release 80 percent of the initial amount of drug is t 0.8 was 42 min. Furthermore, as predicted in the modeling section, the fraction of drug released followed an equation of the form (Figure 30b):

number

[0396] From equations (24) and (37), the diffusivity of the drug through the expanded fiber can be written as:

number

[0397] A non-limiting parameter, c d,0 Approximately 37.9mg / ml, c s Approximately 0.05 mg / ml and k dApproximately 1.27×10 -6 m / s 1 / 2 (Figure 24) Diffusion rate D d Approximately 3×10 -10 m 2 / s, which is about half the number of drug molecules in water. Thus, neither the absorption excipients nor the strength-enhancing excipients substantially blocked drug diffusion. [Table 2] Example 1.7 Drug release from fibrous dosage forms

[0398] Drug release from the fibrous dosage forms was monitored under the same conditions using the same setup as in Section 1.5. At regular time intervals, aliquots of the dissolution solution were sampled, and their UV absorbance spectra were obtained using a Perkin Elmer Lambda 950 UV / Vis spectrophotometer. The fraction of drug released was determined by subtracting the UV absorbance at 235 nm from the UV absorbance at 230 nm and dividing the resulting value by the value obtained at "infinite" time (i.e., when all the drug had dissolved).

[0399] Figure 25a is a plot of the fraction of drug released by the dosage form versus time. 0.8 The times were 2, 10, and 38 hours, respectively, Table 2. Therefore, t 0.8 Time increased greatly with φ.

[0400] Fiber dosage form 0.8 Although analytical equations for calculating the time are not currently available, an empirical equation can be derived as shown below. From the drug release model shown in the section "Model for Dosage Form Swelling, Drug Release, and Disintegration", c d,0 ≫c s In this case, the fraction of drug released by a single fiber can be written as:

number

number

[0401] Both equations (39a) and (39b) are of the same form. Thus, the fraction of drug released by the fibrous dosage form can be assumed to follow the equation:

number

[0402] Figure 25b shows the m for all dosage forms. d / M0 vs t 1 / 2 The data are in reasonable agreement with the values ​​calculated by equation (12), provided that κ(φ) and ζ(φ) are the weighted geometric means of the corresponding values ​​for a single fiber (φ=0, equation (39a)) and a consolidated slab (φ=1, equation (39b)):

number

[0403] Substituting equations (41) and (42) in equation (40) yields:

number

[0404] m in equation (43) d Substituting / M0=0.8 and rearranging the time to release 80 percent of the drug content can be written as follows:

number

[0405] By taking the logarithm of both sides of equation (44) and rearranging, we obtain

number

[0406] By exponentiation and rearranging again, equation (45) can be rewritten in exponential form as follows: t 0.8 =αexp(βφ) (46a) (In the formula,

number

[0407] Figure 26 shows the experimental 0.8 A semi-logarithmic plot comparing the data with the calculated values, which show broad agreement.

[0408] Thus, by varying φ, the t 0.8 The time increased exponentially from thin single fibers to thick monolithic slabs. Example 1.8 Diffusion rate of absorbent excipient (e.g., HPMC 120k) through a single disintegrating fiber

[0409] A single fiber with a radius of approximately 80 μm was immersed in a dissolution solution (deionized water with 0.1 M HCl at 37 degrees Celsius) stirred with a paddle at 50 rpm. At specific time points, the fiber was removed from the dissolution bath and the weight of the disintegrating fiber was determined by a Mettler Toledo analytical balance.

[0410] In this experiment, the time to remove 63 percent of the initial weight of HPMC excipient in the fiber was greater than 8 hours.

[0411] For an approximate order of magnitude analysis of the diffusivity of the absorbent excipient through the swollen fiber, the diffusivity D of the absorbent excipient molecules through the fiber ae is assumed to be a constant. Then, the absorbent excipient concentration in the swollen fiber, c ae (t) can be defined by the following formula:

number

[0412] According to Crank, the analytical solution of equation (46) can be written as:

number

[0413] The ratio of the mass of absorbent excipient in the fiber at time t, M(t), to the mass at t=0, M, can then be approximated by an adapted form of the equation presented by Crank:

number

number

[0414] From equation (49b), a rough estimate of the time constant for removing absorbent excipients from swollen fibers can be written as:

number

[0415] In a non-limiting experiment, the time constant τ f Approximately R f 2 / 5.76D HPMC was greater than about 8 hours. f Using approximately 80 μm, the diffusivity D ae Approximately R f 2 / 5.76τ f is about 4 x 10 -14 m 2 It was smaller than / s.

[0416] Furthermore, the self-diffusivity D of the absorbent excipient in water or physiological fluid self It can be pointed out that can be estimated by an adapted form of the Stokes-Einstein equation:

number

number

[0417] The above results and calculations suggest that the diffusivity of HPMC 120k through the fibers was at least about three orders of magnitude less than the self-diffusivity of HPMC 120k in water at 37 degrees Celsius. Experimental Example Part 2

[0418] The following examples present additional ways in which the disclosed dosage forms can be prepared and analyzed, and will enable those skilled in the art to more readily understand the principles of the invention herein. The examples are presented for illustrative purposes and are not intended to be limiting in any way. Example 2.1 Preparation of fibrous dosage forms

[0419] Barium sulfate particles (gastrointestinal contrast agent), ibuprofen (non-limiting model drug), and Eudragit L100-55 (strength-enhancing enteric excipient) were first dispersed or dissolved in liquid dimethyl sulfoxide (DMSO) solvent to form homogeneous suspensions with concentrations of 137, 64, and 64 mg / ml DMSO. The suspensions were then mixed with hydroxypropyl methylcellulose (HPMC 120k) having a molecular weight of 120 kg / mol at a ratio of 192 mg / ml DMSO.

[0420] The mixture was extruded through a laboratory extruder to form a homogeneous viscous paste. The viscous paste was then extruded into a tube with an inner radius R nThe paste was placed in a syringe equipped with a hypodermic needle of 84 μm. The paste was extruded through the needle to form wet fibers patterned layer by layer as a fibrous formulation with a cross-ply structure. The nominal interfiber spacing in the layers, λ n was 650 or 450 μm.

[0421] After patterning, the sample was placed in a vacuum chamber at a pressure of 100 Pa and a temperature of 20°C for approximately 1 day, and then exposed to an airflow at 60°C and a velocity of 1 m / s for 60 minutes to evaporate the solvent and solidify the structure. The dried dosage form consisted of 42% HPMC 120k, 30% barium sulfate, 14% ibuprofen, and 14% Eudragit L100-55 by weight. The dosage form had a diameter of 13 mm and a thickness (λ) of 5 mm. n = 650 μm) and a diameter of 14 mm and a thickness of 5 mm (λ n The discs were trimmed to a nominal size of 0.05 mm (0.05 mm = 450 μm).

[0422] λ n = 650 μm was coated with a hydrophilic coating. The coating solution consisted of ethanol saturated with sucrose; it was kept at -20°C. The dosage form was dipped into the coating solution and immediately exposed to a pressure of 200 Pa for about 1 hour to evaporate the ethanol. The dipping-evaporation process was repeated three times. Because the hydrophilic coating dissolves rapidly upon contact with water, this dosage form is referred to as "uncoated" in the non-limiting experimental examples herein.

[0423] λ n= 450 μm were coated with an enteric coating. Two coating solutions were used: (I) 1.33 mg Eudragit L100-55 in 40 ml acetone, and (II) 2 ml Kollicoat SR in 20 ml deionized water. Both coating solutions were kept at room temperature. The dosage form was dipped into the coating solution and immediately exposed to a pressure of 200 Pa for approximately 1 hour to evaporate the solvent. The dipping-evaporation process was repeated six times for solution I and three times for solution II. Because the enteric coating does not dissolve in acidic water, this dosage form is referred to as "coated" in the non-limiting experimental examples herein. Example 2.2 Scanning electron microscope image

[0424] The microstructure of the fibrous dosage forms was imaged using a Zeiss Merlin High Resolution SEM equipped with a GEMINI column. Uncoated dosage forms were imaged before the sugar coating was applied; coated dosage forms were imaged after enteric coating. The top surface was imaged after coating the samples with a 10 nm thick layer of gold. The samples were cut with a thin blade (MX35 Ultra, Thermo Scientific, Waltham, MA) and coated with gold as described above, after which the cross section was imaged. Specimens were imaged with either an in-lens secondary electron or backscattered electron detector at an accelerating voltage of 5 kV and a probe current of 95 pA.

[0425] Figures 27a and 27b present scanning electron microscope images of the top and front views of a 3D-printed, uncoated dosage form. The dosage form consisted of a cross-ply structure with continuous void spaces. The dry fiber radius R was 59 μm, and the interfiber spacing λ was 365 μm (Table 1).

[0426] The top and front views of the microstructure of a dosage form dip-coated with enteric excipients are shown in Figures 27c-27d. The top surface was mostly covered with the coating, but voids of approximately 100-300 μm were also present (Figure 2c). In the main body, the voids between horizontally aligned fibers in the layers were preserved (Figure 27d). However, the spaces between vertically aligned fibers in different layers were mostly filled with the coating (Figures 2d and 2e). The dry fiber radius R0 was approximately 55 μm, and the interfiber spacing λ0 was 294 μm (Table 3). [Table 3]

[0427] From previous studies, if the wet 3D printed structure shrinks isotropically during drying, the microstructural parameters of the dried cross-ply structure can be calculated from the nominal parameters of the wet 3D printing process as follows:

number

[0428] Furthermore, from previous studies, the volume fraction of fiber in the dosage form, φ f can be calculated by the following formula:

number

[0429] where n layers is the number of stacked layers and H0 is the half thickness of the dry dosage form. For the relevant parameters listed in Table 3, φ is the thickness of the uncoated and coated dosage forms, respectively. f =0.34 and 0.4.

[0430] Further, considering the coated dosage form, a honeycomb structure having square voids of side length λ−2R surrounded by walls with a distance λ between the walls, the volume fraction of void space can be written as:

number

number

number

[0431] For the relevant parameters, as listed in Table 1, φ c = 0.21. Thus, the volume fraction of the coating in the dosage form was substantial. However, this could be increased further if desired. Example 2.3 Expansion of the dosage form due to water diffusion

[0432] To characterize the swelling of the dosage forms in vitro, the dosage forms were immersed in a beaker filled with 800 ml dissolution solution (0.1 M hydrochloric acid (HCl) in deionized (DI) water at 37°C). The solution was stirred with a rotating paddle at 50 rpm. The samples were imaged at different time points with a Nikon DX camera.

[0433] Images of the dosage form at various time points after immersion in the dissolution solution are shown in Figure 28. The normalized radial expansion ΔR of the dosage form obtained from these images is shown in Figure 29. df / R df,0 is plotted against time.

[0434] The uncoated dosage form rapidly swelled and transformed into a highly viscous mass, Figure 29a. The normalized swelling was 0.56 by 5 minutes and 0.76 by 20 minutes. The viscous mass stabilized for more than 10 hours, although the normalized swelling decreased slightly from 0.77 at 200 minutes to 0.6 at 800 minutes, Figures 28a and 29.

[0435] The enteric coated dosage form expanded more slowly; ΔR df / R df,0 was approximately 0.08 at 50 minutes, then gradually increased to 0.53 by 200 minutes, and plateaued to 0.7 by 500 minutes, Figures 28b and 29. The dimensions of the expanded dosage form then remained essentially unchanged for more than one day. Example 2.4 Diameter compression test

[0436] To determine the mechanical properties of the expanded semi-solid mass (or dosage form), the dosage form was first immersed in the above-mentioned dissolution solution (0.1 M HCl in DI water at 37°C) for 30 minutes (uncoated dosage form) and 6 hours (coated dosage form). Diametric compression testing was then performed using a Zwick Roell mechanical testing machine equipped with a 10 kN load cell and compression platens. The relative speed of the platens was 2 mm / s. The test was stopped as soon as the specimen visibly fractured.

[0437] Figure 30 is a series of images of diametric compression of an expanded semi-solid mass or dosage form. The expanded uncoated dosage form barely supported its own weight, Figure 30a. Upon compression, the dosage form further deformed and fractured. When the load was released, the dosage form did not recover its original shape.

[0438] The expanded coated dosage form, in contrast, was much firmer, Figure 30b. Upon compression, the dosage form deformed and, when the load was released, rebounded, regaining a shape and size similar to its original form. Nevertheless, as shown in Figure 32, the dosage form exhibited cracks along the axis of symmetry after compression.

[0439] Figure 31a presents the results of the load per unit length P versus displacement δ during diametral compression of two types of expanded dosage forms. The corresponding slope of the load, dP / dδ, is plotted against δ in Figure 31b. For all dosage forms, the load and its slope steadily increased with displacement up to a displacement of approximately 10-13 mm. However, thereafter, the P-δ curves showed a turning point, and the slope decreased. The load of the expanded coated dosage forms was approximately 20-30 times that of the expanded uncoated forms.

[0440] For data analysis, the expanded dosage form was subjected to diametric compression by two rigid flat platens with a radius R df From the equations of elasticity, for small displacements, the relative displacement of the platens can be approximated by (for further details, see, for example, A.H.Blaesi, N. Saka, Int. J. Pharm. 509 (2016) 444-453; or K.L.Johnson, "Contact Mechanics", Cambridge University Press, Cambridge, UK, 1985):

number

[0441] For expanded uncoated dosage forms, E df =0.0075MPa (7.5kPa or approximately 10 -5 GPa), Table 4. This modulus is comparable to that of gelatin (e.g., Jello); it is so low that the dosage form can be considered a viscous gel or viscous mass rather than an elastic solid or semi-solid (for further details on material classification, see, e.g., M.F.A. Shby, Materials selection in mechanical design, Third ed., Butterworth-Heinemann, Oxford, UK, 2005). For coated dosage forms, E df =0.098MPa (approx. 10 -4 GPa). This value is comparable to the modulus of low stiffness, highly flexible polymer foams, such as natural rubber or silicone foams (for further details on material classification, see e.g., MFAshby, (See Materials Selection in Mechanical Design, Third ed., Butterworth-Heinemann, Oxford, UK, 2005).

[0442] When equation (51) is significantly violated, i.e., when dP / dδ is at its maximum value or P is at the turning point, excessive plastic deformation or failure of the dosage form is observed. From Figure 31, it can be seen that the turning point or load at failure is P for uncoated dosage forms. f,df =0.18N / mm, and for coated dosage forms, P f,df =4.66N / mm, Table 4.

[0443] From the load at break, the tensile strength of the dosage form can be estimated:

number

[0444] Thus, the stiffness and strength of the expanded dosage form are substantially increased by the enteric coating (e.g., by coating the fibers with a strength-enhancing excipient). In other words, by increasing the weight fraction of the strength-enhancing excipient in the dosage form or by increasing the density of the strength-enhancing excipient in the dosage form (e.g., by increasing the mass of the strength-enhancing excipient in the dosage form per unit volume of the dosage form), the stiffness and strength of the expanded dosage form are greatly increased.

[0445] Furthermore, it should be noted that both the expanded uncoated dosage form and the expanded coated dosage form were soft materials that were unlikely to injure the gastrointestinal mucosa. [Table 4] Example 2.5 Gastric residence time of dosage forms in dogs

[0446] Two healthy beagle dogs (13–15 kg; 3 years old; female; non-gonadectomized) were randomly assigned to five experimental groups containing either coated or uncoated dosage forms. The animals were fasted for 18 hours prior to the experiment. The coated or uncoated dosage forms were then administered to the awake dogs with 30 ml of water. The location of the dosage forms was monitored by fluoroscopic imaging (using a Philips Allura Clarity 2-plane fluoroscopy system) at the time points indicated in Figures 33–35. Between imaging sessions, the dogs were allowed to ambulate freely. At 4–6 and 30 hours after ingestion, the dogs were offered 180 grams of basal dry food (Sensinesse 25 / 13, Petzeba AG, Alberswil, Switzerland). No sedatives, anesthesia, or other supplements were administered before, during, or after the experiment. The study was designed with the goal of replacing animal testing with non-sensitive alternatives, reducing animal testing, minimizing the number of animals used, and improving animal testing to cause minimal pain and suffering. All procedures were performed in compliance with the Swiss Animal Welfare Act and approved by government authorities.

[0447] Figures 33 and 34 present fluoroscopic images of the dosage form at various time points after administration to dogs.

[0448] As shown in Figure 33, the uncoated dosage form passed from the mouth to the stomach in less than 1 minute. In the stomach, this was due to a normalized radial expansion ΔR df / R fd,0 = 0.63, and then ΔR df / R df,0=0.67, Figure 35a and Table 5. Thus, the in vivo swelling rate was approximately one-tenth of the rate measured in vitro, Figure 35b. After approximately 300 minutes, when the dogs were fed, the dosage form exhibited visible cracks. The cracks grew rapidly, resulting in fracture at approximately 350 minutes. The fragments then passed into the intestine, where they dissolved. By approximately 380 minutes (6.3 hours), the entire dosage form was essentially dissolved.

[0449] The coated dosage form also passed from the mouth to the stomach in less than 1 minute, as shown in Figure 34. Similar to the in vitro results, this was followed by a moderate rate of normalized radial expansion ΔR up to 200 minutes. df / R df,0 = 0.5 at 2200 min and 0.6 by 500 min (Figure 35b and Table 5). The integrity of the dosage form was largely preserved until 2200-2700 min (37-45 h) after ingestion. At 2700 min, fragments were visible in the intestine. The fragments rapidly dissolved; after 3 h, by 2900 min, the fragments were essentially invisible. [Table 5]

[0450] Thus, swelling was comparable to in vitro results, but in dogs, both uncoated and coated dosage forms eventually fragmented. Fragmentation was attributed to contraction pulses by the stomach wall, which repeatedly squeezed and bent the dosage form. Pulses occurred approximately every 10 to 30 seconds.

[0451] Figure 36a shows a series of fluoroscopic images of an uncoated dosage form during a contraction pulse by the stomach wall approximately 2 hours after ingestion. The (expanded) dosage form was initially circular and 23 mm in diameter. At 2.6 seconds, the dosage form was compressed approximately 11 mm to a width of roughly 12 mm. At 5 seconds, the dosage form had regained its circular shape to roughly its initial diameter. However, although the expanded uncoated dosage form withstood the initial compression pulse, it fractured shortly after the images were taken.

[0452] Figure 36b shows a series of fluoroscopic images of the coated dosage form during a contraction pulse approximately 7 hours after ingestion. Initially, the (expanded) dosage form was circular and 23 mm in diameter. At 1 second, the dosage form collapsed diametrically, and at 2.3 seconds, it had compressed diametrically by approximately 6.5 mm to a width of approximately 16.5 mm. The dosage form regained its original shape after approximately 5 seconds. The compression-rebound cycle was repeated for several more hours as the coated dosage form was retained in the stomach.

[0453] For the analysis of the forces applied to the dosage form and its gastric retention, Applicants define the diametrically opposed cyclic load per unit length, P, and the maximum load per unit length, P, acting on the expanded semi-solid or viscous dosage form. max The non-limiting force field shown in Figure 12 can be considered, including: max was approximately 6.5 mm in vivo, Figure 36b and Table 5. In the in vitro experiment, at δ = 6.5 mm, P was approximately 1 N / mm, Figure 31a. Therefore, in the in vivo experiment, the maximum cyclic load intensity imposed by the stomach wall, P max Approximately 1N / mm.

[0454] The corresponding cyclic stress (tension) along the axis of symmetry can be approximated as:

number

[0455] According to equation (31), if the dosage form disintegrates by fatigue fracture, the gastric residence time can be estimated as follows:

number

[0456] Therefore, t パルス = 20 seconds, P max =1N / mm, R df =11.5mm, σ f,se =1.8N / mm 2 , C8=0.65 and φ se = 0.21, so by equation (54) the constant b = -0.151. Example 2.6 Solubility and Sorption of Deionized Water with 0.1M HCl in Strength-Enhancing Excipients

[0457] A strength-enhancing excipient (methacrylic acid-ethyl acrylate copolymer (1:1) having a molecular weight of approximately 250 kg / mol, also referred to herein as "Eudragit L100-55") was received from Evonik, Essen, Germany.

[0458] Solid films of the strength-enhancing excipient were prepared by dissolving Eudragit L100-55 in DMSO to form a viscous solution, pouring the solution into a metal dish to form a film, and evaporating the DMSO in a vacuum chamber at a pressure of approximately 1 mbar and a temperature of approximately 50°C for approximately 1 day. The thickness of the solid frozen film, h0, was approximately 250 μm.

[0459] To determine the properties of the solid films, the solid films were first immersed in the relevant dissolution solution (water with 0.1 M HCl at 37°C). Then, the weight of the film at a specific time point was measured using a Mettler Toledo analytical balance. The weight fraction of water (or dissolution solution) in the film, w w was determined by the following formula:

number

[0460] Figure 37a is a plot of the weight fraction of water (or dissolving liquid) in the film versus time after immersion. The weight fraction of water increased with time at a gradually decreasing rate, reaching a plateau at about 2000 seconds to a value of about 0.39. Thus, the "solubility" of dissolving liquid in the strength-enhancing Eudragit L100-55 excipient film was about 39 weight percent, or roughly 390 mg / ml.

[0461] Figure 37b shows the absorbed mass m w,∞ = m(t=2000s)-m0, the mass of solution absorbed by the film at time t, divided by w (t)=m(t)-m0, vs. t 1 / 2 / h0. For short times, the fit to the data was linear; thus, initially, the data followed a curve of the form

number

[0462] According to Crank, in Fickian diffusion, for short periods of time, the mass of water (or physiological fluid) adsorbed by a flat film in "infinite" time, m w,∞ The mass of water adsorbed at time t, m, divided by w (t) can be approximated by:

number

[0463] Therefore, D w can be estimated from the data plotted in Figure 33b as follows:

number

[0464] A solid film of Eudragit L100-55 was prepared by dissolving 3 g of Eudragit powder in 40 ml of acetone, pouring the solution into a polyethylene box measuring 100 mm x 60 mm to form a film, and allowing it to dry at room temperature for approximately 1 day. The solid frozen films were punched into tensile specimens according to 53504, type S 3A. The specimen thickness was 150-250 μm.

[0465] The tensile specimens were immersed in a dissolution solution (water with 0.1 M HCl at 37°C) for approximately 1 hour. The water-immersed specimens were then loaded in a Zwick Roell mechanical testing machine equipped with a 20-N load cell. The initial distance between the grips was 28 mm. During the tensile test, the grips were retracted at a relative speed of 2 mm / s, and the force and distance between the grips were recorded. If the specimen fractured, the test was stopped and the load was reduced to less than 80% of the maximum load.

[0466] From the force and distance records and the geometry of the tensile specimen, the nominal stress σ and strain ε in the specimen can be derived as follows:

number

[0467] Figure 38 plots the nominal stress σ versus the engineering strain ε for tensile specimen films immersed in acidified water containing the strength-enhancing Eudragit L100-55 excipient. Initially, the stress increased steeply and roughly linearly with strain. At strains between about 0.06 and 0.12, the slope decreased substantially. Then, the stress increased with strain at a nonlinear, progressive rate. Finally, the stress dropped sharply as the specimen fractured.

[0468] From the stress-strain curve, several properties of the film immersed in acidic water can be derived: elastic modulus,

number

[0469] As listed in Table 6, the average value of the measured properties, E = 5.7 MPa (5 × 10 -3 GPa), σ y = 0.26 MPa and σ f = 1.8 MPa. These values ​​are comparable to the properties of typical low strength elastomers or rubbers (for further details on material classification, see, e.g., M.F.A. Shby, Materials selection in mechanical design, Third ed., Butterworth-Heinemann, Oxford, UK, 2005). [Table 6] Application Examples

[0470] In some embodiments, the amount of active ingredient contained in the dosage forms disclosed herein is appropriate for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. By way of example, but not limitation, the active ingredient may be acetaminophen, aspirin, caffeine, ibuprofen, analgesics, anti-inflammatory agents, anthelmintics, antiarrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetics, antiepileptics, antihistamines, antihypertensives, antimuscarinics, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antivirals, anxiolytics and sedatives, beta-adrenergic receptor blocking agents, cardiac inotropic agents, corticosteroids, and the like. steroids, antitussives, diuretics, dopaminergic agents, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid, calcitonin and bisphosphonates The anti-inflammatory drug may be selected from the group consisting of a prostaglandin, a radiopharmaceutical, an anti-allergic agent, a sympathomimetic, a thyroid agent, a PDE IV inhibitor, a CSBP / RK / p38 inhibitor or a vasodilator.

[0471] Furthermore, although useful for improving nearly any drug therapy, the disclosed dosage forms may be particularly beneficial for therapies that require tight control of blood concentrations of drugs that are acid-soluble or reasonably soluble, but poorly soluble or practically insoluble in basic solutions.

[0472] More specifically, as shown schematically in non-limiting Figure 39a, upon ingestion of a traditional granular dosage form containing a drug that is soluble in acid but insoluble in basic solutions, the dosage form may fragment into its component microparticles in the stomach, releasing the drug as particles and molecules. Because the drug molecules can pass into the upper acidic portion of the intestine, they can enter the bloodstream, and the drug concentration in the blood may increase rapidly, as shown in non-limiting Figure 39b. However, because the drug molecules can enter the lower basic portion, they may precipitate as particles that cannot be absorbed (or are absorbed very slowly), and the drug concentration in the blood may decrease over time, as shown in Figure 39b. Furthermore, because the drug may be excreted, bioavailability, understood herein as the mass of drug absorbed by the blood after ingestion of the dosage form divided by the mass of drug in the initial dosage form, may be low. Because transit time through the stomach and upper intestine and the physicochemical environment therein may be variable, bioavailability may be even more variable. Consequently, drug concentrations in the blood may fluctuate beyond the optimal range, potentially compromising the efficacy and safety of drug therapy, FIG. 39b.

[0473] In contrast, the disclosed dosage forms allow for retention of the dosage form in the stomach and a slower drug delivery rate over an extended period of time. For example, the disclosed dosage form can be smaller than the diameter of the esophagus (approximately 15-20 mm) to facilitate ingestion, as shown in non-limiting Figure 39c. However, once in the stomach, it can rapidly expand to a size larger than the diameter of the pylorus (approximately 13-20 mm). Furthermore, as the dosage form expands, it transitions from a solid to a semi-solid or highly viscous state and remains in that state for an extended period of time, thereby preventing its immediate passage into the small intestine and eliminating any risk of mechanically damaging the gastric mucosa. Drug molecules are released slowly and over an extended period into the stomach and can be primarily absorbed in the upper portion of the gastrointestinal tract after release. As a result, the drug absorption rate can be fairly constant over an extended period of time, bioavailability can be high, and bioavailability variability can be low. As a result, as shown in the non-limiting Figure 39d, drug concentrations in the blood can be well controlled within an optimal range; the effectiveness of drug therapy can be increased and / or the side effects of therapy can be reduced.

[0474] In some embodiments, the dosage forms herein therefore comprise one or more active ingredients or drugs that are more soluble in acidic solutions (e.g., in the stomach or duodenum) than in basic solutions (e.g., in the intestinal tract or large intestine). Thus, in some embodiments, the dosage forms comprise at least one active pharmaceutical ingredient that has a pH-dependent solubility in physiological or bodily fluids.

[0475] Furthermore, in some embodiments, the dosage forms herein comprise at least one active pharmaceutical ingredient that has at least 5 times greater solubility in an acidic solution than in a basic solution. This includes, but is not limited to, at least one active ingredient that has 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 an acidic solution than in a basic solution. For purposes of the invention herein, a solution is considered "acidic" if its pH value is about 5.5 or less. A solution is considered "basic" if its pH value is greater than about 5.5.

[0476] Furthermore, in some embodiments, the dosage forms herein comprise at least one active pharmaceutical ingredient that is a basic compound. For purposes of the invention herein, a compound is considered to be "basic" if the acid dissociation constant (e.g., pKa value) of said compound is greater than about 5.5.

[0477] More generally, the disclosed dosage forms may also be beneficial for therapeutic methods requiring tight or fairly tight control of blood concentrations of drugs that are poorly soluble (e.g., poorly soluble) in aqueous physiological or gastrointestinal fluids.

[0478] Thus, in some embodiments, the dosage forms herein comprise at least one active pharmaceutical ingredient having a solubility of 5 g / L or less in aqueous physiological / body fluids under physiological conditions, including, but 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 aqueous physiological or body fluids under physiological conditions.

[0479] Furthermore, it can be noted that due to the greater bioavailability, with the disclosed dosage forms, the mass of drug that a patient is recommended or expected to ingest to achieve a therapeutic effect may be lower than with traditional dosage forms.

[0480] Furthermore, due to the ability to release drug in the upper gastrointestinal tract for an extended period of time, the disclosed dosage forms can reduce the dosing frequency for the treatment of specific diseases or medical conditions. "Dosing frequency" is understood herein as the number of times a patient can take or is recommended to take a drug dose at a given time (for example, by a medical professional such as a doctor or pharmacist). In other words, "dosing frequency" can be understood as the reciprocal of the recommended time interval between two drug doses to be taken by or administered to a patient. "Drug dose" can be understood as the specific drug mass to be taken by or administered to a patient at a specific time point. The specific drug mass may be contained in one or more dosage forms.

[0481] The disclosed dosage forms can therefore be useful for therapeutic methods involving drugs with short half-lives in the blood or human or animal body. "Half-life" is understood herein as the period required for the "maximum" concentration or "maximum" amount of a drug in the blood or body to decrease by half under conditions in which the drug is not delivered to the blood or body during that period. The concentration of a drug in blood can generally be estimated from measurements of the concentration of the drug in plasma.

[0482] In some embodiments, the dosage forms herein therefore comprise at least one active pharmaceutical ingredient that has a half-life in the human or animal body (e.g., physiological system) of one day or 24 hours or less, including, but not limited to, a half-life in the human or animal body of 22 hours or less, or 20 hours or less, or 18 hours or less, or 16 hours or less, or 14 hours or less, or 12 hours or less, or 10 hours or less, or 8 hours or less, or 6 hours or less, or 4 hours or less, or in the ranges of 0.5 to 24 hours, 0.5 to 20 hours, 0.5 to 16 hours, 0.5 to 12 hours, 0.5 to 10 hours, 0.5 to 8 hours, or 0.5 to 6 hours.

[0483] Finally, the disclosed dosage forms can be manufactured by economical processes that allow for more personalized medicine. The present invention provides, for example, the following items. (Item 1) A fiber for manufacturing a pharmaceutical dosage form, comprising: at least one active ingredient and at least two excipients forming said fiber; the at least two excipients include one or more fluid-absorbing polymeric components and one or more strength-enhancing polymeric components; upon exposure to physiological fluids, the one or more strength-enhancing excipients form a fluid-permeable, semi-solid network that provides mechanical support to the fibers; The one or more fluid-absorbent excipients, upon absorption of the physiological fluid, transition to a viscous mass or viscous solution that swells the fibers along at least one dimension. fiber. (Item 2) A fiber for manufacturing a pharmaceutical dosage form, comprising: at least one active ingredient and at least two excipients that form the fiber; the at least two excipients comprise one or more fluid-absorbing polymeric components, and the solubility of physiological fluids (e.g., gastric fluids) in the fluid-absorbing polymeric components is greater than 600 mg / ml; the at least two excipients further comprise one or more strength-enhancing polymeric components; the one or more strength-enhancing polymeric components have an elastic modulus in the range between 0.2 MPa and 200 MPa and a strain at break greater than 0.2 after immersion in physiological fluid (e.g., gastric fluid) under physiological conditions; upon exposure to physiological fluids, the one or more strength-enhancing excipients form a fluid-permeable, semi-solid network that provides mechanical support to the fibers; The one or more fluid-absorbent excipients, upon absorption of the physiological fluid, transition to a viscous mass or viscous solution that swells the fibers along at least one dimension. fiber. (Item 3) 10. The fiber of any preceding item, wherein the solubility of physiological fluid in the absorbent excipient is greater than 750 mg / ml. (Item 4) The fiber of any preceding item, wherein the rate of physiological / body fluid penetration into the absorbent excipient under physiological conditions is greater than the average thickness of the element divided by 3600 seconds. (Item 5) The fiber of any preceding item, wherein the at least one absorbent excipient includes hydroxypropyl methylcellulose. (Item 6) 10. The fiber of any preceding item, wherein the molecular weight of the hydroxypropyl methylcellulose excipient is in the range between 30 kg / mol and 1000 kg / mol. (Item 7) 2. The fiber of any preceding item, wherein the at least one absorbent excipient is selected from the group comprising hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, hydroxyethyl 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), polyethylene oxide, or vinylpyrrolidone-vinyl acetate copolymer. (Item 8) The fiber of any preceding item, wherein the molecular weight of the at least one absorbent excipient is in the range of 30 kg / mol to 100,000 kg / mol. (Item 9) The fiber of any preceding item, wherein the solubility in the at least one strength-enhancing excipient in the relevant physiological fluid is 750 mg / ml or less under physiological conditions. (Item 10) The fiber of any preceding item, wherein the at least one strength-enhancing excipient comprises a modulus of elasticity in the range of 0.5 MPa to 100 MPa after immersion in physiological fluid under physiological conditions. (Item 11) The fiber of any preceding item, wherein the at least one strength-enhancing excipient comprises a tensile strength in the range of 0.05 MPa to 200 MPa after immersion in physiological fluid under physiological conditions. (Item 12) The fiber of any preceding item, wherein the at least one strength-enhancing excipient comprises a strain at break of greater than 0.5 after immersion in physiological fluid under physiological conditions. (Item 13) 10. The fiber of any preceding item, wherein the volume or weight fraction of the one or more absorbent excipients in the fiber is in the range of between 0.1 and 0.85. (Item 14) 10. The fiber of any preceding item, wherein the volume or weight fraction of the one or more strength-enhancing excipients in the fiber is in the range of between 0.15 and 0.9. (Item 15) The fiber of any preceding item, wherein the at least one strength-enhancing excipient comprises an enteric polymer. (Item 16) 10. The fiber of any preceding item, wherein the at least one strength-enhancing excipient comprises an enteric polymer, the enteric polymer having at least 10 times greater solubility in a basic solution having a pH value greater than 7 than in an acidic solution having a pH value of 5 or less. (Item 17) The fiber of any preceding item, wherein the at least one strength-enhancing excipient comprises a methacrylic acid-ethyl acrylate copolymer. (Item 18) 2. The fiber of any preceding item, wherein the at least one strength-enhancing excipient is selected from the group comprising hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate, ethyl acrylate polymers (e.g., polymers comprising ethyl acrylate), methacrylate polymers (e.g., polymers comprising methacrylate), ethyl acrylate-methyl methacrylate copolymer, poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], and ethyl cellulose. (Item 19) 10. The fiber of any preceding item, wherein the at least two excipients form a solid solution across the thickness of the fiber. (Item 20) 10. The fiber of any preceding item, wherein one or more phases comprising the strength-enhancing excipient are substantially connected or substantially continuous along the length of the fiber. (Item 21) The fiber of any preceding item, comprising a plurality of segments having substantially the same weight fraction of physiological fluid-absorbing excipient distributed therein. (Item 22) The fiber of any preceding item, comprising a plurality of segments having substantially the same weight fraction of the strength-enhancing excipient distributed therein. (Item 23) Upon exposure to physiological fluids under physiological conditions, the diffusivity of the absorbent polymeric excipient in the fiber is greater than 10 -12 m 2 / s or less (e.g., 0.5 × 10 -12 m 2 / s or less or 0.2 × 10 -12 m 2 3. The fiber of any preceding item, wherein the fiber is 0.15 to 0.25 mm thick (1 / s or less). (Item 24) Upon exposure to physiological fluid under physiological conditions, the diffusion rate of the physiological fluid in the fiber is 0.2×10 -12 m 2 / s (e.g., 0.5 × 10 -12 m 2 / s greater than or equal to 10 -12 m 2 / s), fibers as described in any preceding item. (Item 25) 10. The fiber of any preceding item, which upon exposure to physiological fluid swells to a length between 1.3 and 4 times its length before exposure to said physiological fluid. (Item 26) The fiber of any preceding item, which expands in all dimensions upon exposure to physiological fluids. (Item 27) The fiber of any preceding item, which transitions into a semi-solid mass upon exposure to physiological fluids. (Item 28) The fiber of any preceding item, which upon exposure to physiological fluids transitions into a semi-solid mass, and the one or more strength-enhancing excipients form a connected network throughout the semi-solid mass. (Item 29) 10. The fiber of any preceding item, wherein the swollen fiber or semi-solid mass maintains its length between 1.3 and 4 times its initial length over an extended period of time. (Item 30) 10. The fiber of any preceding item, wherein the expanded semi-solid mass comprises a modulus of elasticity in the range of 0.005 MPa to 20 MPa. (Item 31) 10. The fiber of any preceding item, wherein the expanded semi-solid mass comprises a tensile strength in the range between 0.002 MPa and 20 MPa. (Item 32) 1. A pharmaceutical dosage form comprising a drug-containing solid comprising an outer surface and an inner three-dimensional structural framework of one or more thin structural elements, the framework is adjacent to and terminates at the outer surface; the elements have segments spaced apart from bounding segments, thereby defining one or more interconnected free spaces throughout the drug-containing solid; the element further comprises at least one active ingredient and at least two excipients; the at least two excipients include at least one physiological fluid-absorbing polymeric component and at least one strength-enhancing polymeric component; upon immersion in physiological fluid, the fluid penetrates at least one interconnected free space and diffuses into one or more of the elements, causing the scaffold to expand in at least one dimension and transition into a semi-solid mass; the semi-solid mass releasing the drug over an extended period of time; Pharmaceutical dosage forms. (Item 33) The dosage form of any preceding item, wherein upon exposure to physiological fluid, the strength-enhancing excipients form a fluid-permeable, semi-solid network to provide mechanical support to the scaffold; and the fluid-absorbing excipients transition, upon absorption of the physiological fluid, to a semi-solid or viscous mass that expands the scaffold along at least one dimension. (Item 34) 1. A pharmaceutical dosage form comprising a drug-containing solid comprising an outer surface and an inner three-dimensional structural framework of one or more thin structural elements, the framework is adjacent to and terminates at the outer surface; the elements have segments spaced apart from bounding segments, thereby defining one or more interconnected free spaces throughout the drug-containing solid; the element further comprises at least one active ingredient and at least two excipients; the at least two excipients include at least one physiological fluid-absorbing polymeric component and at least one strength-enhancing polymeric component; Upon exposure to physiological fluids, the strength-enhancing excipients form a fluid-permeable, semi-solid network that provides mechanical support to the scaffold; the fluid-absorbing excipient transitions upon absorption of the physiological fluid into a viscous mass or viscous solution that expands the scaffold along at least one dimension; Pharmaceutical dosage forms. (Item 35) 1. A pharmaceutical dosage form comprising a drug-containing solid comprising an outer surface and an inner three-dimensional structural framework of one or more thin structural elements, the framework is adjacent to and terminates at the outer surface; the elements have segments spaced apart from bounding segments, thereby defining one or more interconnected free spaces throughout the drug-containing solid; the element further comprises at least one active ingredient and at least two excipients; the at least two excipients comprise one or more fluid-absorbing polymeric components, and the solubility of physiological fluids (e.g., gastric fluids) in the fluid-absorbing polymeric components is greater than 600 mg / ml; the at least two excipients further comprise one or more strength-enhancing polymeric components; the one or more strength-enhancing polymeric components have an elastic modulus in the range between 0.2 MPa and 200 MPa and a strain at break greater than 0.2 after immersion in physiological fluid (e.g., gastric fluid) under physiological conditions; upon exposure to physiological fluids, the one or more strength-enhancing excipients form a fluid-permeable, semi-solid network that provides mechanical support to the fibers; The one or more fluid-absorbent excipients, upon absorption of the physiological fluid, transition to a viscous mass or viscous solution that swells the fibers along at least one dimension. Pharmaceutical dosage forms. (Item 36) The dosage form of any preceding item, wherein one or more phases comprising the strength-enhancing excipient form a substantially continuous or connected structure along the length of one or more structural elements. (Item 37) The dosage form of any preceding item, wherein one or more phases comprising strength-enhancing excipients form a substantially continuous or connected structure throughout the three-dimensional structural framework. (Item 38) The dosage form of any preceding item, wherein upon ingestion by a human or animal subject, physiological fluid permeates at least one interconnected free space and diffuses into one or more of said elements, thereby expanding said framework in all dimensions and transitioning said framework into a semi-solid mass that releases said drug over time. (Item 39) 10. The dosage form of any preceding item, wherein upon exposure to physiological fluid, the scaffold expands to a length between 1.3 and 4 times its length before exposure to said physiological fluid. (Item 40) 10. The dosage form of any preceding item, wherein upon extended exposure to physiological fluids, the swollen framework or semi-solid mass maintains its length between 1.3 and 4 times its initial length for an extended period of time. (Item 41) The dosage form of any preceding item, wherein the semi-solid mass comprises a substantially continuous or connected network of one or more strength-enhancing excipients. (Item 42) 10. The dosage form of any preceding item, wherein the semi-solid mass comprises a substantially continuous or connected network of strength-enhancing excipients extending across the length, width and thickness of the semi-solid mass. (Item 43) 10. The dosage form of any preceding item, wherein one or more phases comprising strength-enhancing excipients extend along the length of the structural element. (Item 44) 10. The dosage form of any preceding item, wherein the average thickness of the one or more structural elements is in the range of 1 μm to 1.5 mm. (Item 45) The dosage form of any preceding item, wherein the one or more interconnected free spaces form an open pore network extending over a length at least equal to the thickness of the drug-containing solid. (Item 46) 10. The dosage form of any preceding item, wherein one or more interconnected free spaces terminate at the outer surface of the drug-containing solid. (Item 47) 8. The dosage form of any preceding item, wherein the free space is continuous. (Item 48) 10. The dosage form of any preceding item, wherein the effective free spacing between segments across one or more interconnected free spaces is, on average, in the range of 1 μm to 2.5 mm. (Item 49) The dosage form of any preceding item, wherein the free spacing between segments of the one or more structural elements is precisely controlled across the drug-containing solid. (Item 50) The dosage form of any preceding item, wherein the three-dimensional structural framework comprises a single, continuous structure throughout the drug-containing solid. (Item 51) 10. The dosage form of any preceding item, wherein the volume fraction of structural elements within the drug-containing solid is within the range of between 0.2 and 0.98. (Item 52) 10. The dosage form of any preceding item, wherein the three-dimensional structural framework comprises crisscross stacked layers of fibers. (Item 53) 10. The dosage form of any preceding item, wherein the solubility in physiological fluids in the at least one absorbable excipient is greater than 700 mg / ml. (Item 54) 10. The dosage form of any preceding item, wherein the rate of physiological / body fluid penetration into the absorbent excipient under physiological conditions is greater than the average thickness of the element divided by 3600 seconds. (Item 55) The dosage form of any preceding item, wherein the at least one absorbent excipient comprises hydroxypropyl methylcellulose. (Item 56) 10. The dosage form of any preceding item, wherein the molecular weight of the hydroxypropyl methylcellulose excipient is in the range of between 30 kg / mol and 1000 kg / mol. (Item 57) The dosage form of any preceding item, wherein the at least one absorbable excipient is selected from the group comprising hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, hydroxyethyl 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), polyethylene oxide, or vinylpyrrolidone-vinyl acetate copolymer. (Item 58) The dosage form of any preceding item, wherein the molecular weight of the at least one absorbent excipient is in the range of 30 kg / mol to 100,000 kg / mol. (Item 59) The dosage form of any preceding item, wherein the solubility in the relevant physiological fluid in the at least one strength-enhancing excipient is 750 mg / ml or less under physiological conditions. (Item 60) 10. The dosage form of any preceding item, wherein the at least one strength-enhancing excipient comprises an elastic modulus in the range of 0.5 MPa to 100 MPa after immersion in physiological fluid under physiological conditions. (Item 61) 10. The dosage form of any preceding item, wherein the at least one strength-enhancing excipient comprises a tensile strength in the range of 0.05 MPa to 200 MPa after immersion in physiological fluid under physiological conditions. (Item 62) The dosage form of any preceding item, wherein the at least one strength-enhancing excipient comprises a strain at break of greater than 0.5 after immersion in physiological fluid under physiological conditions. (Item 63) 10. The dosage form of any preceding item, wherein the volume or weight fraction of the one or more absorbent excipients in the fiber is in the range of between 0.1 and 0.85. (Item 64) 10. The dosage form of any preceding item, wherein the volume or weight fraction of the one or more strength-enhancing excipients in the fiber is in the range of between 0.15 and 0.9. (Item 65) The dosage form of any preceding item, wherein the at least one strength-enhancing excipient comprises an enteric polymer. (Item 66) 10. The dosage form of any preceding item, wherein the at least one strength-enhancing excipient comprises an enteric polymer, the enteric polymer having at least 10 times greater solubility in a basic solution having a pH value greater than 7 than in an acidic solution having a pH value of 5 or less. (Item 67) The dosage form of any preceding item, wherein the at least one strength-enhancing excipient comprises a methacrylic acid-ethyl acrylate copolymer. (Item 68) The dosage form of any preceding item, wherein the at least one strength-enhancing excipient is selected from the group including hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate, ethyl acrylate polymers (e.g., polymers comprising ethyl acrylate), methacrylate polymers (e.g., polymers comprising methacrylate), ethyl acrylate-methyl methacrylate copolymer, poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], and ethyl cellulose. (Item 69) 10. The dosage form of any preceding item, wherein the at least two excipients form a solid solution through the thickness of the fiber. (Item 70) 10. The dosage form of any preceding item, wherein one or more phases comprising the strength-enhancing excipient are substantially connected or substantially continuous along the length of the fiber. (Item 71) 10. The dosage form of any preceding item, wherein the element or framework comprises a plurality of segments having substantially the same weight fraction of physiological fluid-absorbing excipient distributed therein. (Item 72) The dosage form of any preceding item, wherein the element or framework comprises a plurality of segments having substantially the same weight fraction of the strength-enhancing excipient distributed therein. (Item 73) Upon exposure to physiological fluids under physiological conditions, the diffusivity of the absorbent polymeric excipient in the fiber is greater than 10 -12 m 2 / s or less (e.g., 0.5 × 10 -12 m 2 / s or less or 0.2 × 10 -12 m 2 / s or less). (Item 74) Upon exposure to physiological fluid under physiological conditions, the diffusion rate of the physiological fluid in the fiber is 0.2×10 -12 m 2 / s (e.g., 0.5 × 10 -12 m 2 / s greater than or equal to 10 -12 m 2 / s), a dosage form described in any preceding item. (Item 75) 10. The dosage form of any preceding item, wherein at least one free space is filled with a substance removable by physiological fluids under physiological conditions. (Item 76) The dosage form of any preceding item, wherein upon immersion in physiological fluid, the drug-containing solid transitions to a semi-solid mass comprising a length within a range of between 1.3 and 3.5 times its length prior to exposure to the physiological fluid within 300 minutes of immersion in the physiological fluid. (Item 77) The dosage form of any preceding item, wherein upon immersion in physiological fluid, the drug-containing solid transitions to a semi-solid mass comprising a length within a range of between 1.3 and 3.5 times its length prior to exposure to the physiological fluid within 100 minutes of immersion in the physiological fluid. (Item 78) 10. The dosage form of any preceding item, wherein the swollen fiber or semi-solid mass maintains its length between 1.3 and 4 times its initial length over an extended period of time. (Item 79) 10. The dosage form of any preceding item, wherein the swollen semi-solid mass comprises an elastic modulus in the range of 0.005 MPa to 15 MPa. (Item 80) 10. The dosage form of any preceding item, wherein the expanded semi-solid mass comprises a tensile strength in the range of between 0.002 MPa and 15 MPa. (Item 81) 10. The dosage form of any preceding item, wherein 80 percent of the drug content is released from the drug-containing solid into the physiological fluid within 1 hour to 30 days after immersion of the drug-containing solid in the physiological fluid under physiological conditions. (Item 82) 10. The dosage form of any preceding item, wherein 80 percent of the drug content is released from the drug-containing solid into the physiological fluid within 2 to 150 hours after immersion of the drug-containing solid in the physiological fluid under physiological conditions. (Item 83) The dosage form of any preceding item, which upon ingestion by a human or animal subject is gastroretentive.

Claims

[Claim 1] The invention described in the specification.

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