WO2018225073A1 - Impression 3d de doses unitaires médicinales - Google Patents

Impression 3d de doses unitaires médicinales Download PDF

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Publication number
WO2018225073A1
WO2018225073A1 PCT/IL2018/050624 IL2018050624W WO2018225073A1 WO 2018225073 A1 WO2018225073 A1 WO 2018225073A1 IL 2018050624 W IL2018050624 W IL 2018050624W WO 2018225073 A1 WO2018225073 A1 WO 2018225073A1
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WO
WIPO (PCT)
Prior art keywords
hydrogel
active agent
formulation
unit dosage
monomers
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Application number
PCT/IL2018/050624
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English (en)
Inventor
Shlomo Magdassi
Ofra BENNY
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Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.
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Application filed by Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. filed Critical Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.
Publication of WO2018225073A1 publication Critical patent/WO2018225073A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
    • B29C64/10—Processes of additive manufacturing
    • B29C64/106—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material
    • B29C64/112—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material using individual droplets, e.g. from jetting heads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00—Processes of additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing

Definitions

  • the invention generally concerns methods of 3D printing medicinal unit doses and products obtained thereby.
  • Three-dimensional (3D) printing or additive manufacturing is a process of making a solid object from a digital model.
  • 3D printing is achieved using an additive process, where successive layers of materials are laid down in different shapes by a printing process.
  • 3D printing provokes a great interest and becomes a very useful method in a variety of fields such as tissue engineering, medical devices, pharmaceutics, dentistry, aerospace, construction and automotive. This is due to some clear advantages such as rapid manufacturing with unprecedented flexibility in material composition, special geometries, complex microstructure, surface texture, product performance (release kinetics) and capability of fabricating parts directly from Computer aided design (CAD) models.
  • CAD Computer aided design
  • the main 3D printing technologies are based on the following three approaches: Selective polymerization of photo-sensitive monomer by UV; Selective sintering or binding of particles in powder (binder jetting); and Selective deposition of filaments or cutting sheets of paper/nylon.
  • Each approach requires suitable materials and tailoring the printing composition ("ink”) for optimal performance according to the printing technology.
  • the first USFDA approved 3D printed tablet, SpritamTM demonstrates the use of 3D printing by binder jetting for making rapidly disintegrating structures for high- dose epileptic medications.
  • the current 3D printing of drugs is focused on powder- based and melt-based freeform fabrication methods. These have been used to prepare dosage forms with varying geometries and surface areas by the selective deposition method [6], multiple drug and multiple release kinetics by fused deposition modeling
  • Hydrogels are three dimensional cross linked network of hydrophilic polymers which can absorb large amount of water or biological fluids by swelling.
  • the hydrogels may respond to chemical and physical stimuli such as temperature, pressure, pH, ionic strength and magnetic or electric field [9]. Due to their biocompatibility and swelling capability in different stimuli, they can be used for drug delivery systems for control drug release [10-12].
  • chemical and physical stimuli such as temperature, pressure, pH, ionic strength and magnetic or electric field [9]. Due to their biocompatibility and swelling capability in different stimuli, they can be used for drug delivery systems for control drug release [10-12].
  • the enhancement of bioavailability is a central issue. Therefore, drugs that are sensitive to stomach conditions, i.e.
  • the high enzymatic activity and the low pH are often administered within an enteric coated tablet, which protect the drug and prevents premature drug release in the stomach, while enabling a maximal absorption in the small intestine. Therefore, by using smart hydrogels it is possible to minimize drug release in the stomach while enhancing its release in the intestinal pH [13].
  • the inventors of the technology disclosed herein have embarked on fabricating stimuli -responsive, e.g., pH responsive, hydrogel tablets, having internal complex structures, for controlled release of drugs.
  • stimuli -responsive e.g., pH responsive, hydrogel tablets
  • the printing can be performed by a variety of printing processes, such as direct write of polymers with dissolved or embedded drugs, and digital light processing (DLP).
  • DLP digital light processing
  • -3D printing e.g., by inkjet printing, laser induced forward transfer (LIFT) or any other 3D printing method:
  • a formulation comprising at least one carrier material or at least one precursor of a carrier material, e.g., photo-sensitive monomers, oligomers and/or polymers forming hydrogels; and
  • the 3D printing comprises polymerization of the at least one carrier material, e.g., photo-sensitive monomers, oligomers and/or polymers, and/or selective deposition by direct writing through extrusion;
  • the at least one carrier material e.g., photo-sensitive monomers, oligomers and/or polymers, and/or selective deposition by direct writing through extrusion;
  • formulation comprising the at least one carrier material or at least one precursor of the carrier material, and the formulation comprising the at least one active agent are 3D printed in combination (i.e., as a formulation containing both at least one carrier material and at least one active agent), simultaneously (e.g., at the same time through different nozzles), or one after the other (e.g., in separate steps).
  • the unit dosage form is formed by selective polymerization of photo-sensitive monomers, oligomers or polymers, i.e., being at least one carrier material or the hydrogel material itself, which are deposited, as defined, with at least one active agent.
  • the photo-sensitive monomers, oligomers or polymers are of at least one erodible hydrogel that acts as the matrix in which at least one active agent is contained.
  • the deposited material is subsequently photo-polymerized, e.g., by DLP, to achieve curing of the photo-reactive monomer s/oligomers/polymers.
  • the localized polymerization may be performed within a bath filled with at least one carrier material, e.g., polymerizable ink comprising photosensitive monomers and/or polymers, usually by proper focusing of UV light.
  • the unit dosage form is formed by selective material deposition by direct writing through extrusion.
  • the direct writing methodology involves deposition by extrusion of at least one carrier formulation and at least one formulation comprising the active agent, in combination, or simultaneously, or in separate steps, one after the other or in any other sequence, as defined herein, through a single nozzle or multiple nozzles, to form a material pattern of a controlled architecture, i.e., a desired predetermined shape and size.
  • the 3D printed hydrogels formed by extrusion can be printed with or without employing UV irradiation.
  • the formulation comprising the carrier material(s), e.g., monomers/oligomers/polymers ink composition may contain also at least one photoinitiator.
  • photoinitiators may be selected in a non-limiting fashion from diphenyl(2,4,6- trimethylbenzoyl)phosphine oxide (TPO), lithium TPO, Ig 2959 (l-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-l-propane-l-one), Ig 184 (1- hydroxy-cyclohexyl-phenyl-ketone), Ig 651 (2,2-dimethoxy-l,2-diphenylethan-l-one), Ig 907 (2-methyl-4'-(methylthio)-2-mo holinopropiophenone), ITX (2- isopropylthioxanthone), Ig 819 (bis(2,4,6-trimethylbenzoyl)-phenylphosphine
  • TPO diphenyl
  • the carrier material is a hydrogel material that is printed as indicated herein.
  • the hydrogel material may be cured, e.g., photocured, or allowed to form into a solid unit, e.g., by drying.
  • the formulation may also comprise additional agents, such as oxygen scavengers, photosensitizers, polymers, block or graft copolymers, surfactants and various medical excipients.
  • additional agents such as oxygen scavengers, photosensitizers, polymers, block or graft copolymers, surfactants and various medical excipients.
  • the 3D printing method is for producing a unit dosage form (a solid drug delivery system) composed (consists or comprises) of at least one pharmaceutically acceptable erodible hydrogel and at least one active agent, the dosage form having an internal structure responsive to at least one stimulus selected from a change in pH, temperature, pressure, humidity, an electric field, a magnetic field, ions, specific molecules or solvent compositions, and light and sound waves, such that at least one active agent has a release profile determined by, e.g., the geometric shape of the internal structure.
  • a unit dosage form a solid drug delivery system
  • the dosage form having an internal structure responsive to at least one stimulus selected from a change in pH, temperature, pressure, humidity, an electric field, a magnetic field, ions, specific molecules or solvent compositions, and light and sound waves, such that at least one active agent has a release profile determined by, e.g., the geometric shape of the internal structure.
  • the hydrogel may be selected amongst hydrogels sensitive to pH, and thus may swell in environments having a pH of the intestine (ranging for example from pH 6.8-7.4.
  • a pH of the intestine ranging for example from pH 6.8-7.4.
  • the unit dosage form When in contact with a different pH, or a pH that is outside of the programed pH value, e.g., a lower pH such as the pH of the stomach, the unit dosage form remains unaffected by the low pH, and starts swelling and releasing the active agent only at the appropriate pH, e.g., in the intestine.
  • the structure may affect the release of the active agent by controlling the geometric, surface area, porosity/concentrate of the printed structure and combination of them.
  • the "unit dosage form" that is manufactured or produced in accordance with the invention is a solid drug delivery system (which may be monolithic or multiparticulate, in a form of tablets, capsules or pills.
  • the unit dosage form is intended for delivery of at least one agent for pharmaceutical purposes, diagnostic purposes, imaging purposes, or for local treatment by irradiations.
  • the unit dosage form may be suitable for oral administration, rectal administration, vaginal administration, administration as depot inserts to be placed under the skin for prolonged release of an active agent, for use as contact lenses which may control release of active agent in to the eye, or may be administered as a unit dosage form suitable for placing inside a subject's body, e.g., post-surgery, for example, after excision of a tumor.
  • the solid unit dosage form consists or comprises at least one erodible hydrogel and at least one active agent and has an internal structure of a predetermined geometric shape that is responsive to at least one stimulus, as indicated herein.
  • the internal structure allows, following erosion of the hydrogel and stimulation of the structure, controlled, sustained or site-dependent release of the at least one active agent, and thus may be engineered based on the particular intended use or application.
  • erosion when in reference to the hydrogel, means any sorts of partial or full degradation, destruction, decomposition, disintegration or otherwise breakdown or solubilization or swelling of the hydrogel matrix, in the body, following contact with a body tissue or fluid, which exposes the internal structure to a stimulus, as defined.
  • the internal structure is an architectural element of a predetermined geometrical shape and size (millimeter-size, micron-size or nano-size) that is made of the hydrogel material and may or may not comprise an amount of the at least one active agent.
  • the element is formed by printing the monomers/oligomers/polymers (or the hydrogel) of the volume of the unit dosage to adopt a geometrical shape with specific external and inner structure, that may hold at least a portion of the at least one active agent.
  • the architectural element may have an initial geometrical shape and size which upon stimulation undergoes a structural change (in both or one of shape and size), enabling complete or partial release of the at least one active agent.
  • the release profile of the at least one active agent from the solid hydrogel is determined or controlled, to any extent, by the geometric shape of element.
  • the internal structure or element is contained within the unit dosage form, which has an external shape that may be a shape of a pill, a tablet or a capsule or of any other shape.
  • the shape or geometry of the element is not typically the same as the external shape of the unit dosage form as a whole.
  • the external shape is visible to the naked eye while the internal shape or element is a 3D printed feature that may be small enough to be noted by the naked eye.
  • the internal structure should not be limitedly considered a separable structure or element that can be removed from within the unit dosage.
  • the term "internal structure" is a mere depictive expression intended to indicate a complex structure that is formed in the unit dosage form by 3D printing, as detailed herein.
  • the internal structure may be of a size of at least 100 ⁇ , or of at least 110 ⁇ , or of at least 120 ⁇ , or of at least 130 ⁇ , or of at least 140 ⁇ , or of at least 150 ⁇ , or of at least 160 ⁇ , or of at least 170 ⁇ , or of at least 180 ⁇ , or of at least 190 ⁇ , or of at least 200 ⁇ , or of at least 210 ⁇ , or of at least 220 ⁇ , or of at least 230 ⁇ , or of at least 240 ⁇ , or of at least 250 ⁇ , or of at least 260 ⁇ , or of at least 270 ⁇ , or of at least 280 ⁇ , or of at least 290 ⁇ , or of at least 300 ⁇ , or of at least 350 ⁇ , or of at least 400 ⁇ , or of at least 450 ⁇ , or of at least 500 ⁇ , or of at least 550 ⁇ , or of at least 600 ⁇ , or of at least 650 ⁇ , or of at least 700 ⁇ , or
  • the element may be in form of a material void (areas free of any material and may comprise air or a gas) or material concentrate in any inner region of the unit dosage.
  • the element may be further covered by an external coating of the unit dosage and may thus be regarded as being fully internal.
  • the architectural element is a single element situated at the center of the unit dosage form.
  • the element may be a plurality of elements formed at different regions of the unit dosage form. In such cases, each element may be the same or may be different. Where a plurality of elements are present, they may be of the same material, size and shape, or may be of different materials, sizes and shapes. In some embodiments, the plurality of elements comprise or consist a plurality of material voids.
  • the architectural element may be in the form of a channel or multiple channels within the hydrogel material, each channel may be material-free, or may comprise an amount of the at least one active agent that, upon stimulation is released in a predesigned form.
  • the element may further be in the form of stacked layers, each layer comprising a different active agent or a different matrix material, e.g., hydrogel, or a combination of the two.
  • the element may additionally be in the form of material localities.
  • regions within the unit dosage wherein the at least one active agent is present at higher concentrations optionally surrounded or encapsulated or encased with a hydrogel material enabling controlled release or a releases profile different from a neighboring material locality.
  • the internal structure is homogenous, e.g., containing a single architectural element or a plurality of such elements that are the same or evenly distributed within the unit dosage.
  • the internal structure may be heterogeneous, e.g., containing a plurality of architectural elements that are different or positioned with preference to a particular region within the dosage unit.
  • unit dosage forms having complicated or unusual geometries or forms may be fabricated.
  • Such geometries or forms can enable programmed release of an active materials , and may be:
  • Porous unit dosages having one or more or a plurality of material voids for use as floating objects such as tablets for drug delivery of at least one active agent in the stomach and elongation of retention time.
  • Units comprising combinations of several drugs to be released in different kinetics governed by materials and inner structure of the 3D printed systems. This includes the ability to combine both biomolecules (hydrophilic) and hydrophobic drugs to be released in the intestine or any desired location in the body.
  • Units comprising combined responsive materials in the hydrogel matrix or in a material void, such as metal nanoparticles to be used for localization with external magnetic, or to cause local heating under magnetic field or light.
  • Units comprising combined compounds enabling real time imaging of the intestine.
  • pH responsive objects can be used in blocking parts of the intestine prior to surgeries or to substitute an intestinal shortening surgery.
  • pH responsive delivery systems that protect the drug in the stomach and release the drug in the intestine.
  • Objects containing drugs which have irregular external structure that enables increasing significantly surface area upon contact with body fluids, or can be used as physical and physico-chemical adhesion arms to specific locations in the body.
  • the release profile associated or predetermined for any active agent comprises in the unit dosage may depend, inter alia, on the presence of one or more hydrogels that control the rate at which the unit dosage decomposes or erodes or undergoes a chemical or physical change, the rate at which the internal element releases the active agent, the form of the element containing an active agent, the element position within the unit dosage and others.
  • the unit dosage may comprise a first hydrogel having a first geometrical shape and comprising at least one active agent, and a second or further hydrogel that surrounds, encapsulates or encases the first hydrogel to form an erodible element of a second geometrical shape, wherein the second hydrogel does not contain an amount of the at least one active agent.
  • the second hydrogel When the unit dosage is exposed to a stimuli, as defined, the second hydrogel erodes without causing the active agent from the first hydrogel to diffuse out.
  • hydrogels of different properties e.g., molecular weights, electrical charges, different degrees of cross-linking, different substituents, etc, can alter the period of time that the active agent is released.
  • the first geometrical shape may determine the release profile of the at least one active agent
  • the property of the second hydrogel can be used to control the speed at which the at least one active agent is released.
  • the unit dosage may comprise a first hydrogel in a first geometrical shape and having a first active agent, and a second hydrogel in a second geometrical shape and having a second active agent.
  • the unit dosage may comprise a first hydrogel in a first geometrical shape, holding a first active agent, coated or encapsulated or encased with a second hydrogel having the same geometrical shape or different shape holding a second active agent.
  • the use of the two different hydrogels, each containing or holding a different active agent provides a release profile whereby the active agents can be released one after the other, at different time points or at different locations, in response to different stimuli.
  • the at least one carrier acting as a matrix for holding the active agent, and further being selected amongst hydrogels, may be a hydrogel or a polymerizable precursor thereof.
  • the polymerizable form is a material that comprises one or more polymerizable moieties selected from an acrylate, a methacrylate, an acrylamide, a methacrylamide, a styrene group, a maleate, a fumarate, an itaconate, a vinyl ether, a vinyl ester, an allyl ether and an allyl ester.
  • Non-limiting examples of such polymerizable materials include acid containing monomers, acrylic monomers, amine containing monomers, crosslinking acrylic monomers, dual reactive acrylic monomers, epoxides/anhydrides/imides, fluorescent acrylic monomers, fluorinated acrylic monomers, high or low refractive index monomers, hydroxy containing monomers, mono and bifunctional glycol oligomeric monomers, styrenic monomers, acrylamides, vinyl and ethenyl monomers and many others.
  • the polymers used in the fabrication of the hydrogels are made by chemical polymerization or by two or more component polymerization or gel formation. Examples include bi component epoxy (catalyst and monomer), chitosan and alginate, sodium alginate and calcium ions, and other polyelectrolytes (e.g., water soluble polymers having dissociating groups in each repeating unit), such as charged polysaccharides.
  • Hydrogels are three-dimensional (3D) materials having the ability to absorb large amounts of water while maintaining their dimensional stability, softness and rubbery consistence, as well as low interfacial tension with water or biological fluids.
  • the hydrogels formed by methods of the invention and which constitute the unit dosage form are stimuli responsive hydrogels that may erode under physiological conditions and which are capable of changing at least one of their properties (such as volume, shape, charge, volume, formation of cracks, channel opening, etc) upon contact with a stimulus selected as herein.
  • the stimulus is a change in pH, or exposure to acidic pH.
  • Non-limited examples for hydrogels include poly(vinyl alcohol)/glycine hydrogels, gelatin gels and agar-agar gels, aery late based hydrogels, polysaccharides and others.
  • the at least one active agent may be any drug, pharmaceutical or agent used in the fields of medicine, including imaging, treatment or prophylaxis that are administered in the form of solid unit dosages. It may be selected amongst drugs, diagnostic agents, imaging agents, and others.
  • the invention further provides a printing formulation (in the form of a formulation or a dispersion) for use in a method of the invention.
  • the formulation comprises a first formulation of at least one carrier material in the form of a hydrogel or a precursor thereof and a second formulation of at least one active agent, each of the first and second formulation being formed in a liquid medium and may comprise at least one additive selected from agents for pharmaceutical purposes, diagnostic purposes, imaging purposes, or for local treatment by irradiations, photoinitiators, monomers, polymers, polyelectrolytes, crosslinking agents, viscosity agents and other additives.
  • the first and second formulations are formulated as separate formulations for simultaneous or stepwise use, or as a single combined formulation for combined use.
  • the at least one hydrogel, precursors thereof and active agent are as defined herein.
  • the liquid medium forming the formulations are selected from water or water solutions such as those containing surfactants or ethanol.
  • the invention further provides unit dosage forms formed according to methods of the invention. As indicated herein, the invention further provides the following aspect and embodiments of the invention:
  • a method for fabricating a unit dosage form comprising 3D printing: —a formulation comprising at least one hydrogel or at least one precursor thereof;
  • the 3D printing comprises polymerization of precursors of the at least one hydrogel, or selective deposition of the hydrogel by direct writing through extrusion;
  • the formulation comprising the at least one hydrogel or at least one precursor thereof, and the formulation comprising the at least one active agent are 3D printed in combination, simultaneously, or one formulation after the other; and wherein the unit dosage form comprises the at least one hydrogel and at least one active agent, and having an internal structure being responsive to at least one stimulus selected from a change in pH, temperature, pressure, humidity, an electric field, a magnetic field, ions, specific molecules or solvent compositions, light and sound waves, such that the at least one active agent has a release profile determined by the geometric shape of the internal structure.
  • the 3D printing comprises inkjet printing or laser induced forward transfer (LIFT).
  • LIFT laser induced forward transfer
  • the precursor of the at least one hydrogel is selected from a photo-sensitive monomer, oligomer and polymer forming hydrogels.
  • the unit dosage form is formed by selective polymerization of photo-sensitive monomers, oligomers or polymers
  • the unit dosage form is formed by selective material deposition by direct writing through extrusion.
  • photopolymerization is achieved in the presence of at least one photoinitiator.
  • the at least one photoinitiator is selected from diphenyl(2,4,6- trimethylbenzoyl)phosphine oxide (TPO), lithium TPO, Ig 2959 (l-[4- (2-hydroxyethoxy) -phenyl] -2-hydroxy-2-methy 1-1 -propane- 1 -one), Ig 184 (1-hydroxy- cyclohexyl-phenyl-ketone), Ig 651 (2,2-dimethoxy-l,2-diphenylethan-l-one), Ig 907 (2- ⁇ 1 ⁇ 1-4'-( ⁇ 6 ⁇ 1 ⁇ 111 ⁇ )-2- ⁇ 1 ⁇ 1 ⁇ 1 ⁇ 6 ⁇ 6), ITX (2-isopropylthioxanthone), Ig 819 (bis(2,4,6-trimethylbenzoyl)-phenylphosphineoxide), EDB (ethyl 4- (dimethylamino) benzoate), camphorquinone (CQ), ⁇ , ⁇ -di
  • TPO
  • the at least one hydrogel is pH sensitive.
  • the unit dosage form is in a form of a tablet, a capsule or a pill.
  • the unit dosage form is for oral administration, rectal administration, vaginal administration, administration as depot inserts to be placed under the skin for a prolonged release of the at least one active agent, or for placing inside a subject's body.
  • the internal structure being in a form of an element having a predetermined geometrical shape and size.
  • the element is a single element situated at the center of the unit dosage form.
  • the element is a plurality of elements at different regions of the unit dosage form.
  • each element of the plurality of elements is the same or different.
  • the element is homogenous or heterogeneous.
  • the element is in a form of a material void or a material concentrate.
  • the element is in a form of a channel or multiple channels within the hydrogel material, each channel may be material-free, or may comprise an amount of the at least one active agent.
  • the element is in a form of stacked layers, each layer comprising a different active agent or a different hydrogel.
  • the element is in a form of material localities.
  • the precursor of the at least one hydrogel is selected from an acrylate, a methacrylate, an acrylamide, a methacrylamide, a styrene group, a maleate, a fumarate, an itaconate, a vinyl ether, a vinyl ester, an allyl ether and an allyl ester.
  • the precursor of the at least one hydrogel is selected from polymerizable acid containing monomers, acrylic monomers, amine containing monomers, crosslinking acrylic monomers, dual reactive acrylic monomers, epoxides/anhydrides/imides, fluorescent acrylic monomers, fluorinated acrylic monomers, high or low refractive index monomers, hydroxy containing monomers, mono and bifunctional glycol oligomeric monomers, styrenic monomers, acrylamides, and vinyl and ethenyl monomers.
  • the at least one hydrogel is selected from a bi component epoxy, chitosan and alginate, sodium alginate and calcium ions, and polyelectrolytes.
  • the polyelectrolyte is a charged polysaccharide.
  • the at least one hydrogel is selected from poly(vinyl alcohol)/glycine hydrogels, gelatin gels, agar-agar gels, acrylate based hydrogels and polysaccharides.
  • the at least one active agent is a drug, a pharmaceutical, an imaging agent, a therapeutic drug or prophylactic drug.
  • the at least one active agent is selected amongst drugs, diagnostic agents, imaging agents, and therapeutic agents.
  • the invention further provides a printing formulation for use in a method of fabricating a unit dosage form by 3D printing, the formulation comprising a first formulation of at least one hydrogel or a precursor thereof and a second formulation of at least one active agent, each of the first and second formulations being formed in a liquid medium and optionally comprises at least one additive selected from pharmaceutical agents, diagnostic agents, imaging agents, irradiation agents, photoinitiators, monomers, polymers, polyelectrolytes, crosslinking agents and viscosity modifying agents.
  • the first and second formulations are formulated as separate formulations for simultaneous or stepwise use, or as a single combined formulation for combined use.
  • Fig. 1 provides chemical structures of the printed solution components: a) Monomer, b) Photo-initiator, c) dye.
  • Figs. 2A-F provide images of 3D printed hydrogel tablets using DLP technique.
  • Figs. 3A-D provide images of sulforhodamine B loaded 3D printed tablets with different shapes, before and after 24h swelling in phosphate buffer (pH 7.4); (A). Box;
  • Fig. 4 shows swelling index of different 3D printed tablets with different shapes; ( ⁇ ) hemisphere ( ⁇ ) 5X5 ( ⁇ ) hive and ( A) box.
  • 3D printed dosage forms made by photopolymerization process with the DLP method.
  • unit forms can be similarly prepared by other methods based on pre-formed polymer using a direct write process and other wet deposition processes.
  • a composition containing dissolved polymers and the active pharmaceutical material, which have a suitable viscosity suitable for the specific printing technology can be extruded through a nozzle by a direct write process, while the solidification of the printed structure results from full or partial drying, to yield a 3D structure.
  • the viscosity can range from 10 cPs to hundreds of thousands of cPs.
  • the required object can be made by printing different compositions, for example one containing a negatively charged molecule, such as alginate, and one containing a positively charged molecule, such as chitosan.
  • the solidification can be obtained by various means, such as induction of pH change, electrolytes changes, electrical or hydrogen bond interactions between various molecules, IR drying or UV or chemical crosslinking.
  • Acrylic acid was purchased from Acros.
  • TPO Photo-initiator (Diphenyl(2,4,6- trimethylbenzoyl)phosphine oxide, was obtained from BASF.
  • the surfactant Brij 58 and the dye Sulforhodamine B were purchased from Sigma.
  • PEGDA polyethylene glycol diacrylate
  • Sodium hydrogen phosphate (Merck), Sodium chloride (Bio-Lab), Potassium phosphate monobasic (Sigma Aldrich) and Hydrochloric acid (J.T Baker) were used for the dissolution medium.
  • Triple Distilled Water, (TDW) was obtained from NANOpure®-DIamondTM (TDW; 0.0055 uS.cm-l ; Barnsted system, Dubuque, IA, USA).
  • Aqueous inks containing Sulforhodamine B as drug model were prepared in three steps: A. dissolving of the following components by magnetic stirring: TDW, (58% w/w), acrylic acid, (38% w/w), PEGDA, (2% w/w) and TPO nanoparticles powder of, (2% w/w).
  • the TPO nanoparticles were prepared by lyophilizing clear solutions containing 23.75 % w/w Brij 58, 1.25 % w/w TPO, 25 % TDW and 50 % 2- propanol. Lyophilization was performed using laboratory-scale benchtop freeze-drying system (Labconco Freezone 2.5, Missouri, USA). The solution (30 mL sample in a 100 mL round bottom flask) was lyophilized at a temperature of -47 ⁇ 3°C and absolute pressure of -0.470 mbar. The samples were kept in these conditions for 24 hours.
  • a pre-designed hydrogel model was 3D printed using a 3D printer (Pico 2, Asiga, Australia). This printer operates by stereolithography system with digital mirror device and UV-LED light source (385 nm). 3D printing of the hydrogel was performed at a rate of 3 seconds per layer (100 ⁇ layer thickness with 3 seconds irradiation to each layer). Each structure (build size 16 x 16 x 5 mm / 24 x 24 x 10 mm) was printed within 20-40 minutes.
  • the 3D printed hydrogels were lyophilized for 24 h in order to remove all water and then the dry mass was recorded. The structures were then observed under an environmental scanning electron microscope (Quanta 200 FEG, Holland) to visualize gross morphology.
  • the 3D printed dried samples were first weighed (Wi) and then immersed in buffers of different pH at 37 ⁇ 0.5 C. After each predetermined time interval, the hydrogels were removed from the medium, blotted dry in order to gently remove excess water, and weighed again, (Wt). The swelling index of the printed hydrogel was determined from the ratio of the swollen mass and dr masses.
  • Drug release data from all shapes were fitted to various kinetic models to evaluate the release pattern.
  • the correlation of the release to each kinetic model was calculated and the coefficient of determination (R 2 ) were obtained.
  • the different kinetic models examined were zero order, Korsmeyer-Peppas and Higuchi model given by equations below.
  • Mt/Mco is the ratio between the cumulative amounts of drug released (up to 60% release only at Krosmeyer-Peppas model) at time t (Mt) and infinite time (M ⁇ )
  • Ko, Km and KH are the zero order
  • Krosmeyer-Peppas and Higuchi models release constants respectively
  • n is the release exponent indicative of the drug release mechanism.
  • An n value ⁇ 0.45 indicates Fickian, mechanism that mainly occur due to diffusion.
  • the release rate is independent of time and the mechanism controlled mainly by erosion.
  • Intermediate values i.e. 0.45 ⁇ n ⁇ 0.89) represent a non- Fickian or anomalous transport and suggest mechanism of release influenced from both erosion and drug diffusion.
  • the tablets were incubated for 72 hours in 50 ml of DDW under gentle stirring. The condition medium were collected, diluted and supplemented to the cell medium for 72 hours incubation. MTT (3-(4,5- Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) viability assay was performed according to manufacturer instruction and optical absorption was measured by plate reader (570 nm).
  • the swelling index of tablets with each of the shapes was measured under the same sink conditions.
  • the calculated surface areas of the four shapes are presented in ascending order; hemisphere, 5X5, box, and hive: 6.2 cm 2 , 9.1 cm 2, 22.4 cm 2 and 89.6 cm 2 respectively.
  • the tablets were weighted and the surface area was normalized according to the average weight of each shape. Normalized surface area of hive, 5X5, hemisphere and box were; 58.2 cm 2 /g, 20.1 cm 2 /g, 4.22 cm 2 /g and 4.15 cm 2 /g respectively.
  • Sulforhodamine B was selected as a drug model due to its high solubility in all pH range tested and its pH independent absorption over the range of pH between 3 to 10.
  • the release mechanism of Sulforhodamine B was found to be governed by the pH dependent swelling properties.
  • the effect of pH on release from the 3D tablets was evaluated by measuring the cumulative release at pH 1.2 and pH 7.4.
  • the results shown in Fig. 5 indicate a major difference in release from the hive and 5X5 shapes, compared to the hemisphere and box shapes.
  • Responsiveness index was calculated for each shape; 5X5 shape presented in Figure 5B has shown the largest RI of 2.4 after 24 hours. Hive shape has demonstrated a responsive index of 1.48. Both box and hemisphere shapes exhibit similar low RI of 1.4 and 1.3 respectively. Using such differences in the extent of drug release, could potentially facilitate the fine-tuning of drug release profile in vivo.
  • Such behavior is related to the response rate in which the polymer structure alters post absorption of the surrounding molecules.
  • Anomalous diffusion mechanism obtained here is in accordance with poly acrylic acid glassy character at 37C, extensive swelling of glassy polymers often abstained from following Fickian concentration dependent release. Instead, glassy polymer tends to react slowly to changes in their environment. System parameters such as stress, temperature, medium type and concentration are time-dependent resulting in an anomalous release.
  • Fig. 7 shows viability level after 72 hr of treatment normalized to the untreated cells.
  • Cells supplemented with DDW (control) reached values of 0.9 OD and served as reference for treated cells.
  • the tablets condition media and dilutions of 1 :2 and 1 :4 reached values of 0.87, 0.86 and 0.90 OD respectively.
  • Statistical tests were performed showing no significant difference between treated and untreated cells, suggesting that there is no cytotoxic effect (Fig. 7).
  • 3D printed drug-loaded hydrogels can be used for targeted and delayed drug release in the small intestine, as they can pass, intact, through the acidic environment of the stomach, with minimal drug release.
  • Hydrogels of polyacrylic acid exhibit very low solubility in acidic conditions due the carboxylic acid groups, which remain unionized at low pH. As the pH of the surrounding media increases, these groups in tablet matrix begin to ionize, thus resulting in increased hydrophilicity and solubility.
  • These structures can be used to protect drugs from the acidic conditions of the stomach, as well as to prevent gastric irritation that is caused by a variety of drugs.

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Abstract

La technologie de l'invention concerne des comprimés d'hydrogel sensible aux stimuli, ayant des structures complexes internes, pour une libération contrôlée de médicaments.
PCT/IL2018/050624 2017-06-08 2018-06-07 Impression 3d de doses unitaires médicinales WO2018225073A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111359550A (zh) * 2020-03-18 2020-07-03 江南大学 一种具有降血糖作用的蛋白功能化气凝胶及其制备方法
CN112175205A (zh) * 2019-07-01 2021-01-05 哈尔滨工业大学 一种磁性水凝胶及其制备方法和3d打印方法
ES2828509A1 (es) * 2019-11-26 2021-05-26 Fund Idonial Composicion para la impresion 3d de farmacos semisolidos
WO2021156607A1 (fr) * 2020-02-03 2021-08-12 The University Of Nottingham Formulations de médicaments
US20210339462A1 (en) * 2018-04-23 2021-11-04 Io Tech Group Ltd. Laser-based droplet array jetting of high viscous materials
CN114762680A (zh) * 2020-12-31 2022-07-19 中国人民解放军总医院 3d打印抗菌水凝胶微颗粒及其制备方法
GR1010614B (el) * 2023-01-27 2024-01-23 Εθνικο Μετσοβιο Πολυτεχνειο, Μεθοδος εκτυπωσης φαρμακων με λεϊζερ και συστημα εφαρμογης αυτης

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017072536A1 (fr) * 2015-10-29 2017-05-04 University Of Central Lancashire Formes solides et leurs procédés de préparation
US20170143831A1 (en) * 2015-11-24 2017-05-25 The Texas A&M University System In vivo live 3d printing of regenerative bone healing scaffolds for rapid fracture healing
WO2018020237A1 (fr) * 2016-07-25 2018-02-01 University Of Central Lancashire Production d'une forme posologique solide
WO2018104537A1 (fr) * 2016-12-09 2018-06-14 Biogelx Limited Impression 3d et administration de médicament

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017072536A1 (fr) * 2015-10-29 2017-05-04 University Of Central Lancashire Formes solides et leurs procédés de préparation
US20170143831A1 (en) * 2015-11-24 2017-05-25 The Texas A&M University System In vivo live 3d printing of regenerative bone healing scaffolds for rapid fracture healing
WO2018020237A1 (fr) * 2016-07-25 2018-02-01 University Of Central Lancashire Production d'une forme posologique solide
WO2018104537A1 (fr) * 2016-12-09 2018-06-14 Biogelx Limited Impression 3d et administration de médicament

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
AHMED EM: "Hydrogel: preparation, characterization and applications: a review", J. ADV. RES., vol. 6, 2015, pages 105 - 121
ALHNAN MA; OKWUOSA TC; SADIA M; WAN KW; AHMED W: "Emergence of 3D printed dosage forms: opportunities and challenges", PHARM. RES., 2016
ALOMARI M. ET AL.: "Personalised dosing: Printing a dose of one's own medicine", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 494, no. 2, 10 December 2014 (2014-12-10), pages 568 - 577, XP029294863, ISSN: 0378-5173, DOI: 10.1016/J.IJPHARM.2014.12.006 *
ALOMARI M; MOHAMED FH; BASIT AW; GAISFORD S: "Personalized dosing: printing a dose of one's own medicine", IJPHARM, vol. 494, 2015, pages 568 - 577, XP029294863, DOI: doi:10.1016/j.ijpharm.2014.12.006
GOYANES A. ET AL.: "Effect of geometry on drug release from 3D printed tablets", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 494, no. 2, 28 April 2015 (2015-04-28), pages 657 - 663, XP029294872, ISSN: 0378-5173, DOI: 10.1016/J.IJPHARM.2015.04.069 *
GOYANES A; ROBLES-MARTINEZ P; BUANZ A; BASIT AW: "Effect of geometry on drug release from 3D printed tablets", IJPHARM, vol. 494, 2015, pages 657 - 663, XP029294872, DOI: doi:10.1016/j.ijpharm.2015.04.069
GOYANES A; WANG J; BUANZ A ET AL.: "3D printing of medicines: engineering novel oral devices with unique design and drug release characteristics", AM. CHEM. SOC., vol. 12, 2015, pages 4077 - 4084
HOFFMAN AS: "Hydrogels for biomedical applications", ADV. DD REV., vol. 54, 2002, pages 3 - 12, XP002294912
KALEPU S; MANTHINA M; PADAVALA V: "Oral lipid-based drug-delivery systems: an overview", ACTA PHARM. SINICA B, vol. 3, no. 6, 2013, pages 361 - 372, XP055203441, DOI: doi:10.1016/j.apsb.2013.10.001
KRISHNA RAO KSV; HA CS: "pH sensitive hydrogels based on acryl amides and their swelling and diffusion characteristics with drug delivery behavior", POLYM. BULL., vol. 62, 2009, pages 167 - 181, XP019708528
MILLER DS; PARSONS AM; BRESLAND J ET AL.: "A simple and inexpensive enteric-coated capsule for delivery of acid-labile macromolecules to the small intestine", J. ZHEJIANG UNI-SCI B, vol. 16, no. 7, 2015, pages 586 - 592, XP035511699, DOI: doi:10.1631/jzus.B1400290
PEPPAS NA; BURES P; LEOBANDUNG W; ICHIKAWA H: "Hydrogels in pharmaceutical formulations", EURO. J. PHARM. BIO., vol. 50, 2000, pages 27 - 46, XP004257178, DOI: doi:10.1016/S0939-6411(00)00090-4
RIZWAN M; YAHYA R; HASSAN A ET AL.: "pH sensitive hydrogels in drug delivery: brief history, properties, swelling and release mechanism, material selection and applications", POLYM., vol. 9, 2017, pages 137
SANDEEP C; HARIKUMAR SL; KANUPRIYA: "Hydrogels: a smart drug delivery system", IJRPC, vol. 2, no. 3, 2012, pages 603 - 614
WEI Q. ET AL.: "Viscosity-controlled printing of supramolecular-polymeric hydrogels via dual-enzyme catalysis", JOURNAL OF MATERIALS CHEMISTRY B, vol. 4, no. 38, 1 January 2016 (2016-01-01), GB, pages 6302 - 6306, XP055459310, ISSN: 2050-750X, DOI: 10.1039/C6TB01792D *
ZHANG XF; YU DG; ZHU LM; BRANFORD-WHITE C; DOWDEN S; YANG XL: "Sustained-release floating drug delivery systems prepared using three-dimensional printing", 2009, IEEE

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210339462A1 (en) * 2018-04-23 2021-11-04 Io Tech Group Ltd. Laser-based droplet array jetting of high viscous materials
US11548212B2 (en) * 2018-04-23 2023-01-10 Io Tech Group Ltd. Laser-based droplet array jetting of high viscous materials
CN112175205A (zh) * 2019-07-01 2021-01-05 哈尔滨工业大学 一种磁性水凝胶及其制备方法和3d打印方法
CN112175205B (zh) * 2019-07-01 2022-05-06 哈尔滨工业大学 一种磁性水凝胶及其制备方法和3d打印方法
ES2828509A1 (es) * 2019-11-26 2021-05-26 Fund Idonial Composicion para la impresion 3d de farmacos semisolidos
WO2021156607A1 (fr) * 2020-02-03 2021-08-12 The University Of Nottingham Formulations de médicaments
CN111359550A (zh) * 2020-03-18 2020-07-03 江南大学 一种具有降血糖作用的蛋白功能化气凝胶及其制备方法
CN114762680A (zh) * 2020-12-31 2022-07-19 中国人民解放军总医院 3d打印抗菌水凝胶微颗粒及其制备方法
CN114762680B (zh) * 2020-12-31 2023-07-18 中国人民解放军总医院 3d打印抗菌水凝胶微颗粒及其制备方法
GR1010614B (el) * 2023-01-27 2024-01-23 Εθνικο Μετσοβιο Πολυτεχνειο, Μεθοδος εκτυπωσης φαρμακων με λεϊζερ και συστημα εφαρμογης αυτης

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