WO2021156607A1 - Formulations de médicaments - Google Patents

Formulations de médicaments Download PDF

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Publication number
WO2021156607A1
WO2021156607A1 PCT/GB2021/050227 GB2021050227W WO2021156607A1 WO 2021156607 A1 WO2021156607 A1 WO 2021156607A1 GB 2021050227 W GB2021050227 W GB 2021050227W WO 2021156607 A1 WO2021156607 A1 WO 2021156607A1
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WO
WIPO (PCT)
Prior art keywords
groups
group
photo
bonds
monomer
Prior art date
Application number
PCT/GB2021/050227
Other languages
English (en)
Inventor
Yinfeng HE
Ricky Wildman
Clive Roberts
Derek Irvine
Giuseppe Mantovani
Richard HAGUE
Christopher Tuck
Vincenzo TARESCO
Original Assignee
The University Of Nottingham
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Application filed by The University Of Nottingham filed Critical The University Of Nottingham
Priority to CN202180027100.1A priority Critical patent/CN115666530A/zh
Publication of WO2021156607A1 publication Critical patent/WO2021156607A1/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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6943—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a pill, a tablet, a lozenge or a capsule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • B33Y80/00—Products made by additive manufacturing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs

Definitions

  • the present invention relates to methods of producing solid drug formulations and to solid drug formulations as made by the methods.
  • the invention uses a monomeric photo-reactive material that is suitable for use in advanced manufacturing techniques, such as 3D printing, where there is a requirement for low viscosity.
  • the solid drug formulations can be made in a tailored manner, including the ability to control and personalise the dose of the drug and the release rate of the drug.
  • polymers when providing active ingredients in prodrug form.
  • US 5032572A uses polymers containing cross-linked azo bonds for releasing therapeutic agents into the lower gastrointestinal tract.
  • US 5851546A uses a polymer for the controlled release of a pendent chain linked active ingredient; the polymeric prodrug material is obtained by polymerization that is initiated thermally or by gamma irradiation and the active ingredient is released in response to pH.
  • WO 2017/015703 describes a polymer useful in biomedical applications; the polymer may be made by free radical polymerisation of: an initiator; an antiseptic/analgesic/anti- inflammatory monomeric unit; and at least three of: a water-soluble monomeric unit; a mechanical strength-conferring monomeric unit; a protein-reactive monomeric unit; and a thermosetting monomeric unit.
  • A additive manufacturing
  • 3DP 3D printing
  • IJ3DP inkjet-based 3D printing
  • printable ink solutions need to exhibit relatively low viscosities (1-30 mPa.s) and fast curing speeds. This applies for 3DP in general and in particular for inkjet-based 3D printing; stereolithography (single photon or multi-photon); extrusion additive manufacturing; reactive extrusion additive manufacturing; and reactive binder jetting.
  • UV inkjet 3D printing has also been used as a manufacturing approach to produce ropinirole HC1 tablets using an aqueous photo curable ink solution, as described in Clark E A, et al., International Journal of Pharmaceutics, 2017, 529(1-2): 523-530.
  • API active pharmaceutical ingredient
  • the invention provides, in a first aspect, a cartridge that contains a photo-reactive material in liquid form which is suitable for making personalised solid dosage formulations, the photo- reactive material comprising: (a) prodrug monomer that comprises an active pharmaceutical ingredient in a prodrug form, in which the active pharmaceutical ingredient is releasably attached to a polymerisable group via a releasable covalent bond, and, optionally, (b) diluent monomer that comprises a polymerisable group.
  • the photo-reactive material exhibits a viscosity of 1-100 mPa.s (e.g. 1-30 mPa.s) at 25°C measured using a Brookfield viscometer.
  • This cartridge provides a ready-to-use photo-reactive material which is suitable for use in 3D printing and other advanced manufacturing techniques where there is a requirement for low viscosity liquids as the reactive material or “ink”.
  • the cartridge is a container that provides the photo-reactive material in ready-to-use form, such that it can be provided directly to the manufacturing apparatus (e.g. 3DP apparatus; electrospinning apparatus; microfluidic jetting apparatus; microfluidic-based emulsification or polymerization apparatus; or reactive injection moulding apparatus).
  • the photo-reactive material does not need to be decanted.
  • the cartridge thus allows the photo-reactive material to be used directly in the manufacturing apparatus, for example the cartridge may be directly inserted into the manufacturing apparatus.
  • the cartridge may be configured to fit into, or engage with, the manufacturing apparatus.
  • the cartridge is sealed.
  • the ready-to-use photo-reactive material can be stored and/or transported, and then used when needed in an advanced manufacturing technique such as 3DP (additive manufacturing); electrospinning; microfluidic jetting; microfluidic-based emulsification or polymerization; or reactive injection moulding.
  • the photo-reactive material used in the present invention is in monomeric form. This contrasts with the traditional polymeric prodrug form.
  • the photo-reactive material used in the present invention comprises monomer (a), and preferably comprises two different monomers, (a) and (b).
  • the photo-reactive material of the present invention can be considered as a liquid mixture of two different monomers, each of which comprises a photo-polymerisable group.
  • the photo-reactive material is “tuneable”; by controlling the overall hydrophilicity of the material, hydrolysis can be facilitated or hindered, which in turn can control drug release.
  • the invention provides a cartridge that contains a reactive material in liquid form, the reactive material comprising: (a) prodrug monomer that comprises an active pharmaceutical ingredient in a prodrug form, in which the active pharmaceutical ingredient is releasably attached to a photo-polymerisable group via a releasable covalent bond, and (b) diluent monomer that comprises a photo-polymerisable group.
  • This reactive material is beneficial for use in manufacturing personalised solid dosage formulations of the active pharmaceutical ingredient, e.g. via 3DP techniques such as IJ3DP.
  • the reactive material can be used to form a solid dosage formulation by triggering polymerisation of the photo- polymerisable groups, such that a polymer is formed that includes the active pharmaceutical ingredient in a prodrug form, and thus the reactive material is photo-reactive.
  • the invention provides a cartridge that contains a photo- reactive material in liquid form which is suitable for making personalised solid dosage formulations, the photo-reactive material comprising: (a) prodrug monomer that comprises an active pharmaceutical ingredient in a prodrug form, in which the active pharmaceutical ingredient is releasably attached to a polymerisable group via a releasable covalent bond, and (b) diluent monomer that comprises a polymerisable group.
  • diluent monomer (b) in the photo-reactive material. This allows control of the overall hydrophilicity/hydrophobicity and/or allows control of the viscosity of the material.
  • the diluent monomer (b) has a different hydrophilicity to the prodrug monomer (a) and so by altering the ratio of the prodrug monomer (a) to the diluent monomer (b), the overall hydrophilicity/hydrophobicity of the solid dosage formulation can be controlled. This in turn allows the release rate of the API to be controlled.
  • the diluent monomer (b) is more hydrophilic than the prodrug monomer (a).
  • the diluent monomer includes one or more hydrophilic moiety selected from hydroxyl moieties, carbonyl moieties, carboxyl moieties, and amino moieties.
  • the diluent monomer (b) is more hydrophobic than the prodrug monomer (a); this may be useful if the prodrug monomer is very hydrophilic already and there is a desire to limit the hydrolysis process that causes the drug release.
  • the viscosity can be controlled, as well as (or instead of) the hydrophilic/hydrophobic balance.
  • the diluent monomer (b) has a different viscosity than the prodrug monomer (a) and so by altering the ratio of the prodrug monomer (a) to the diluent monomer (b), the overall viscosity of the photo-reactive material can be controlled.
  • the diluent monomer (b) has a lower viscosity than the prodrug monomer (a).
  • the diluent monomer has a molecular weight of 900g/mol or less, such as 850g/mol or less or 800g/mol or less, e.g. 750g/mol or less or 700g/mol or less.
  • a monomer with little or no branching/substituent groups may be useful to lower the viscosity.
  • the photo-reactive material is provided in a cartridge, in particular in a sealed cartridge, which can then be used to form a solid dosage formulation when required, by using an advanced manufacturing technique such as 3DP.
  • 3DP advanced manufacturing technique
  • a pharmacy or hospital or other medical facility could have a supply of cartridges containing the photo-reactive material and could use a technique such as 3DP, e.g. I3DJP, to form a solid dosage formulation when required.
  • the solid dosage formulation can be manufactured to provide a personalised solid dosage formulation, e.g. to provide a personalised dose of the API that is tailored to the patient’s needs.
  • This photo-reactive material is beneficial for use in manufacturing personalised solid dosage formulations of the active pharmaceutical ingredient, e.g. via 3DP techniques such as IJ3DP.
  • the photo-reactive material can be used to form a solid dosage formulation by triggering photo-polymerisation of the polymerisable groups, such that a polymer is formed that includes the active pharmaceutical ingredient in a prodrug form.
  • the polymerisable groups as polymerised form a polymeric backbone.
  • the active pharmaceutical ingredient is in a prodrug form whereby the active pharmaceutical ingredient is releasably attached to the polymeric backbone via the releasable covalent bond.
  • the releasable covalent bond can then be broken to release the active pharmaceutical ingredient in its active form.
  • ester bonds and acetal bonds can both decompose in the presence of water (by hydrolysis). The hydrolysis of ester bonds is accelerated in alkaline environments, whilst the hydrolysis of acetal bonds is accelerated in acidic environments. Therefore in one embodiment the releasable covalent bond can preferentially release the active pharmaceutical ingredient in a desired location, e.g. in the acidic environment of the stomach.
  • the active pharmaceutical ingredient may be releasably attached by a releasable covalent bond that breaks in response to a stimulus; for example a stimulus selected from: the presence of water, a change in pH, the presence of an enzyme and/or the presence of a peptide.
  • a stimulus selected from: the presence of water, a change in pH, the presence of an enzyme and/or the presence of a peptide.
  • the releasable covalent bond has been formed by reacting a first reactive functional group that is present on the active pharmaceutical ingredient when it is in its active form with a second reactive functional group.
  • This second reactive functional group may be provided on a reactive carrier monomer that also comprises the polymerisable group. Therefore in the prodrug monomer the active pharmaceutical ingredient is in a prodrug form.
  • the active pharmaceutical ingredient is present in a form in which one of its reactive functional groups has been reacted to form a bonding group comprising the releasable covalent bond.
  • the active pharmaceutical ingredient is also in a prodrug form.
  • the active pharmaceutical ingredient is provided in its active form.
  • polymer-based solid dosage formulations can be prepared having much higher drug loadings than can be achieved when the API is dissolved or dispersed in a printable ink.
  • drug loadings of as high as 50-60% have been achieved.
  • the solid dosage formulations may be solid products, e.g. in the form of a tablet or implant, or may be in the form of a solid that is suspended or dispersed in a pharmaceutically acceptable carrier.
  • polymer-based solid dosage formulations can be prepared where the API is uniformly dispersed throughout the solid dosage formulation. This is particularly beneficial in terms of providing accurate dosing when the solid dosage formulation is intended to deliver the API in a controlled release manner over time.
  • the overall hydrophilicity/hydrophobicity of the solid dosage formulation can be controlled. This in turn allows the release rate of the API to be controlled. This ability to readily “tune” the characteristics of the solid dosage formulation is advantageous.
  • the shape of the solid dosage formulation can also be used to influence the release rate of the API, e.g. by increasing or decreasing the surface area of the solid dosage formulation.
  • the invention provides, in a second aspect, a method of making a solid dosage formulation suitable for delivering an active pharmaceutical ingredient to a patient, the method comprising: a) providing a photo-reactive material as defined in the first aspect, optionally by providing a cartridge according to the first aspect; b) depositing the photo-reactive material; and c) photo-polymerising the deposited photo-reactive material; so as to obtain a solid dosage formulation comprising the active pharmaceutical ingredient in a prodrug form.
  • the depositing step may, for example, comprise depositing the material on a surface or in a shaped mold. Steps b) and c) may be repeated as required. Therefore, it may be that successive layers of photo-reactive material are deposited and polymerised, with each subsequent layer being placed on the previously polymerised layer(s). This is of course standard and well known in 3D printing techniques.
  • steps b) and c) can be repeated as many times as necessary to obtain the solid dosage formulation in the desired shape and size.
  • the skilled person will appreciate that it is possible to sequentially deposit and photo-polymerise multiple layers of photo-reactive material (as known in the art when using a printable ink solution). Computerised control of the steps may be used to achieve the desired shape and size.
  • the steps b) and c) can, in one embodiment, be carried out by using 3D printing techniques.
  • the invention is not limited to 3D printing techniques.
  • the present invention is beneficial for use in any techniques where the printable ink solution needs to exhibit relatively low viscosity and fast curing speeds.
  • 3DP techniques such as IJ3DP, vat polymerisation (e.g. stereolithography), extrusion additive manufacturing, reactive extrusion additive manufacturing, and reactive binder jetting, and also for techniques such as electrospinning, microfluidic jetting, microfluidic-based emulsification and polymerization and reactive injection moulding.
  • two or more photo-reactive materials according to the invention are used, with each photo-reactive material including a different API.
  • the steps a) to c) may be carried out for each photo-reactive material, so as to provide a solid dosage formulation that includes two or more regions, each containing a different API.
  • the invention permits a solid dosage formulation to be prepared that is personalised in terms of a combination of two or more APIs that are tailored to the patient’s needs and is personalised in terms of the doses of the APIs that are also tailored to the patient’s needs.
  • the solid dosage formulation as made in accordance with the invention may be a tablet or other solid formulation for oral, buccal, sublingual, vaginal or rectal administration. It may alternatively be an implant, e.g. for providing a controlled extended or delayed release of an API. It may, yet further alternatively, be a solid product for topical administration of an API, such as a patch or bandage. Another option is that the photo-polymerisation results in the formation of a solid material (e.g. solid particles) that is then suspended or dispersed in a pharmaceutically acceptable carrier (e.g. water or an aqueous-based carrier), such that the solid dosage formulation is in the form of a solid that is suspended or dispersed in a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g. water or an aqueous-based carrier
  • the invention provides, in a third aspect, a solid dosage formulation comprising an active pharmaceutical ingredient in a prodrug form as obtainable by (e.g. as produced by) the method of the second aspect.
  • the invention provides, in a fourth aspect, a solid dosage formulation as defined in the third aspect for use in medicine, and in particular for use in the treatment of a patient using a personalised therapy.
  • the therapy may, for example, be personalised in terms of the dose of the API being tailored for the patient.
  • the prodrug monomer used in the present invention comprises an active pharmaceutical ingredient (API) in a prodrug form, in which the active pharmaceutical ingredient is releasably covalently bonded to a polymerisable group.
  • API active pharmaceutical ingredient
  • the prodrug monomer is photo-reactive.
  • its polymerisable group is photo- polymerisable, i.e. it is triggered to polymerise by light, e.g. UV light or NIR light.
  • the releasable covalent bond is formed by a reactive functional group that is present on the API in its active form reacting with a second reactive functional group.
  • This second reactive functional group may be provided on a reactive carrier monomer that also comprises the polymerisable group.
  • the API is present in prodrug form.
  • the resulting polymer also comprises the API in prodrug form.
  • the API is released from the polymer by the releasable covalent bond being broken, to provide the API in active form.
  • a range of different active pharmaceutical ingredients can be manufactured in a solid dosage formulation using the present invention.
  • any drug that in its active form has a reactive functional group which can be used to form a releasable covalent bond, and thus can be releasably covalently bonded to a polymerisable group, can be utilised in the present invention.
  • this reactive functional group is not present, because it has reacted to form the releasable covalent bond.
  • the active pharmaceutical ingredient is present in a form in which one of its reactive functional groups has been reacted to form a bonding group comprising the releasable covalent bond.
  • Part of the bonding group may be comprised within the active pharmaceutical ingredient structure; for example, for an API that has a carboxyl group when in its active form, an ester prodrug may be formed where the releasable covalent bond is the C-O part of the ester and where the carbonyl part of the ester is present within the active pharmaceutical ingredient structure (and will form part of the carboxyl group in the API when the releasable covalent bond is broken and the API returns to its active form).
  • an ester prodrug may be formed where the releasable covalent bond is the C-O part of the ester and where the carbonyl part of the ester is present within the active pharmaceutical ingredient structure (and will form part of the carboxyl group in the API when the releasable covalent bond is broken and the API returns to its active form).
  • the active pharmaceutical ingredient is a drug that in its active form has one or more functional group selected from hydroxyl groups, carboxyl groups, aldehyde groups, ketone groups, thiol groups and amine groups. It may be that the active pharmaceutical ingredient is a drug that in its active form has a hydroxyl group, carboxyl group, ketone group, thiol group or amine group. In one non-limiting embodiment, the active pharmaceutical ingredient is a drug that in its active form has a carboxyl group.
  • the covalent bond is C-O, C-N, or C-S
  • the releasable covalent bond is selected from: ester bonds, acetal bonds, disulfide bonds, azo bonds, imine bonds, peptide bonds, anhydride bonds, hemithioacetal bonds, hydrazine bonds, oxime bonds, carbamate bonds and carbonate bonds.
  • Specific but non-limiting examples of releasable covalent bonds that can be used in the present invention are: ester bonds, acetal bonds, disulfide bonds, azo bonds, imine bonds, peptide bonds, anhydride bonds and hemithioacetal bonds.
  • the releasable covalent bond is selected from: ester bonds, acetal bonds, imine bonds, peptide bonds, anhydride bonds, hemithioacetal bonds, hydrazine bonds, oxime bonds, carbamate bonds and carbonate bonds.
  • the active pharmaceutical ingredient is present in a form in which one of its reactive functional groups has been reacted to form a bonding group comprising the releasable covalent bond.
  • the bonding group may be selected from: ester groups, acetal groups, disulfide groups, azo groups, imine groups, peptide groups, anhydride groups, hemithioacetal groups, hydrazine groups, oxime groups, carbamate groups and carbonate groups.
  • the bonding group may be selected from: ester groups, acetal groups, disulfide groups, azo groups, imine groups, peptide groups, anhydride groups and hemithioacetal groups.
  • Part of the bonding group may be comprised within the active pharmaceutical ingredient structure that is present in the prodrug monomer.
  • the active pharmaceutical ingredient may be releasably bonded by a covalent bond that breaks in response to a stimulus; for example a stimulus selected from: the presence of water, a change in pH, the presence of an enzyme and/or the presence of a peptide.
  • a stimulus selected from: the presence of water, a change in pH, the presence of an enzyme and/or the presence of a peptide.
  • the active pharmaceutical ingredient may be releasably bonded by a covalent bond that breaks in response to the presence of water.
  • the photo-reactive material is “tuneable”. By controlling the overall hydrophilicity of the material, hydrolysis can be facilitated or hindered, which in turn can control drug release when the stimulus is the presence of water.
  • Table 1 provides details of exemplary releasable covalent bonds and the associated reactive functional group that is required on the API to enable such a bond to be formed in the prodrug monomer, as well as setting out non-limiting examples of drugs that include such groups (which could therefore be used to form prodrug monomers having such a releasable covalent bond).
  • Table 1 also sets out details of the conditions under which each releasable covalent bond breaks, thereby releasing the drug in active form, i.e. the “releasing condition” for the API.
  • reaction schemes for the formation of each releasable covalent bond type are set out in Table 2, below. Where reagents are given these are exemplary and not limiting on the reaction scheme. These reaction schemes are also not limiting, but show how a range of prodrug monomers according to the invention could be formed.
  • the API in active form, is reacted with a compound that comprises: (1) a second reactive functional group, which is able to react with the first reactive functional group that is on the API and form a bonding group comprising the releasable covalent bond, and (2) a polymerisable group (in the exemplary reaction schemes below, this is shown as a methacrylate group, but it will be appreciated that other polymerisable groups can be used).
  • a polymerisable group in the exemplary reaction schemes below, this is shown as a methacrylate group, but it will be appreciated that other polymerisable groups can be used.
  • a Cl or C 2 alkyl spacer group between the bonding group and the polymerisable group; this is optional and alternative spacer groups can also be used.
  • the monomers used should be pharmaceutically acceptable. Therefore the prodrug monomer as formed should be purified as necessary to ensure that it is pharmaceutically acceptable. Methods for purification to pharmaceutically acceptable standards are well known in the art, e.g. crystallization, liquid-liquid extraction, and flash chromatography.
  • the active pharmaceutical ingredient is a drug which in its active form has a carboxyl group (COO ), especially a carboxylic acid group (-COOH).
  • COO carboxyl group
  • -COOH carboxylic acid group
  • the active pharmaceutical ingredient is a drug which in its active form has a carboxylic acid group and the releasable covalent bond in the prodrug form is an ester or an anhydride bond.
  • the prodrug monomer comprises a spacer group.
  • the spacer group is located in the prodrug monomer between the bonding group that provides the releasable covalent bond and the polymerisable group.
  • a spacer group may be beneficial to space the polymerisable group from the releasable covalent bond. This then means that when the polymer is formed, the spacer group spaces the releasable covalent bond from the polymeric backbone. This may assist with the release of the API from the polymer.
  • the spacer group may in one embodiment have a C 1 -C 8 , preferably C 1 -C 6 , backbone which is optionally substituted.
  • the backbone may optionally include one or more ester or ether or thioether linkage.
  • the backbone may, for example, be a C 1 -C 8 , preferably C 1 -C 6 , alkyl group or a C 2 -C 8 , preferably C 2 -C 6 , alkene group or a C 2 -C 8 , preferably C 2 -C 6 , alkyne group, each of which may optionally include one or more ester or ether or thioether linkage and each of which is optionally substituted.
  • the backbone is a C 1 -C 4 , preferably C 1 -C 3 , alkyl group or a C 2 -C 4 , preferably C 2 -C 3 , alkene group or a C 2 -C 4 , preferably C 2 -C 3 , alkyne group, each of which may optionally include one or more ester or ether or thioether linkage and each of which is optionally substituted.
  • a C1, C2, C3 or C4 alkyl may be preferred.
  • the backbone is suitably straight chain, but if provided with an alkyl side chain then the spacer group can overall be seen as branched.
  • a straight chain backbone may assist with achieving a desirably low viscosity.
  • the optional substitution is with one or more substituent groups (e.g. 1, 2 or 3 substituent groups) selected from hydroxyl, halo (e.g. F or C1) and NR), where each R' is independently selected from hydrogen, methyl and ethyl.
  • substituent groups e.g. 1, 2 or 3 substituent groups
  • halo e.g. F or C1
  • NR e.g. N-(2-amino)
  • any substituent groups present are selected from hydroxyl, and NR), where each R' is independently selected from hydrogen and methyl.
  • the spacer group is unsubstituted.
  • the spacer group is a straight chain, unsubstituted C1, C2, C3 or C4 alkyl group, such as a straight chain, unsubstituted C1, C2, C3 alkyl group.
  • the bonding group (comprising the releasable covalent bond) together with the spacer group, when present, can together be considered as a linking group that connects the API (in prodrug form) with the polymerisable group.
  • the polymerisable group may suitably include one or more functional group selected from: acrylate, methacrylate, acrylamide, methacrylamide, and epoxy. In one embodiment it includes one or more functional group selected from: acrylate, methacrylate, acrylamide, and epoxy, e.g. one or more functional group selected from: acrylate and methacrylate.
  • the prodrug monomer may optionally include more than one polymerisable group.
  • the prodrug monomer may comprise the bonding group (which provides the releasable covalent bond), a spacer group, and two (or more than two) polymerisable groups attached to the spacer group. When there are two or more polymerisable groups they may be the same or different.
  • the prodrug monomer includes only one polymerisable group.
  • the prodrug monomer preferably has a molecular weight of 1000g/mol or less, such as 950g/mol or less or 900g/mol or less, e.g. 850g/mol or less or 800g/mol or less. This assists with achieving a viscosity compatible with the reactive material being an ink for 3DP, e.g. IJ3DP.
  • the prodrug monomer has a molecular weight of from 100 to 1000g/mol, e.g. from 150 to 950g/mol or from 175 to 900g/mol, such as from 200 to 850g/mol, or from 250 to 800g/mol.
  • active pharmaceutical ingredient in its active form can have the formula:
  • A-Rg wherein Rg is a reactive functional group as defined above and A is the remainder of the active pharmaceutical ingredient, and the prodrug monomer may have the formula:
  • Rb is a bonding group (comprising a releasable covalent bond) as defined above
  • X is an optionally present spacer group
  • Y is a polymerisable group
  • n is an integer representing the number of polymerisable groups attached to the spacer group, e.g. 1, 2 or 3.
  • the releasable covalent bond, API, spacer group and polymerisable group may all be as defined above.
  • n 1, i.e. the prodrug monomer has the formula:
  • the active pharmaceutical ingredient in its active form has the formula: and the prodrug monomer has formula: Diluent monomer
  • the diluent monomer is different to the prodrug monomer.
  • the diluent monomer comprises a polymerisable group.
  • the diluent monomer is photo- reactive.
  • its polymerisable group is photo-polymerisable, i.e. it is triggered to polymerise by light, e.g. UV light or NIR light.
  • the polymerisable group may suitably include one or more functional group selected from: acrylate, methacrylate, acrylamide, methacrylamide and epoxy. In one embodiment it includes one or more functional group selected from: acrylate, methacrylate, acrylamide, and epoxy, e.g. one or more functional group selected from: acrylate and methacrylate.
  • the diluent monomer may optionally include more than one polymerisable group, for example the diluent monomer may comprise two (or more than two) polymerisable groups. When there are two or more polymerisable groups they may be the same or different.
  • the diluent monomer includes only one polymerisable group.
  • the diluent monomer includes a polymerisable group that is the same as a polymerisable group present in the prodrug monomer. In one embodiment the diluent monomer includes one or more hydrophilic moiety selected from hydroxyl moieties, carbonyl moieties, carboxyl moieties, and amino moieties.
  • the diluent monomer includes one or more pH adjusting groups, such as: an anhydride group, -COOH, or -COO-Na + .
  • pH adjusting groups such as: an anhydride group, -COOH, or -COO-Na + .
  • Such groups may assist in controlling the drug release speed by affecting the pH in the local environment.
  • the release condition is pH dependent and therefore affecting the pH will have an impact on the release of the drug.
  • the diluent monomer may be of the following formula:
  • X’ is a spacer group
  • Z is a polymerisable group and m is an integer representing the number of polymerisable groups attached to the spacer group, e.g. 1, 2 or 3.
  • n 1 + diluent monomer
  • the spacer group X’ may be the same as or different to the spacer group in the prodrug monomer, when present.
  • the spacer group X’ preferably includes one or more hydrophilic moiety, e.g. selected from hydroxyl moieties, carbonyl moieties, carboxyl moieties, and amino moieties.
  • the spacer group X’ may, in one embodiment, have a C 1 -C 12 , preferably C 1 -C 8 , backbone which is optionally substituted.
  • the backbone may optionally include one or more ester or ether or thioether linkage.
  • the backbone may, for example, be a C 1 -C 12 , preferably C 1 -C 8 , alkyl group or a C 2 -C 12 , preferably C 2 -C 8 , alkene group or a C 2 -C 12 , preferably C 2 -C 8 , alkyene group, each of which may optionally include one or more ester or ether or thioether linkage and each of which is optionally substituted.
  • the backbone is a C 1 -C 4 , preferably C1-C 3 , alkyl group or a C 2 -C 4 , preferably C 2 -C 3 , alkene group or a C 2 -C 4 , preferably C 2 -C 3 , alkyene group, each of which may optionally include one or more ester or ether or thioether linkage and each of which is optionally substituted.
  • a C1, C2, C3 or C4 alkyl may be preferred.
  • the backbone is suitably straight chain, but if provided with an alkyl side chain then the spacer group X’ can overall be seen as branched.
  • a straight chain backbone may assist with achieving a desirably low viscosity.
  • the optional substitution is with one or more substituent groups (e.g. 1, 2 or 3 substituent groups) selected from hydroxyl, halo (e.g. F or C1) and NR' 2 , where each R' is independently selected from hydrogen, methyl and ethyl.
  • substituent groups e.g. 1, 2 or 3 substituent groups
  • halo e.g. F or C1
  • NR' 2 e.g. 1 and NR' 2
  • each R' is independently selected from hydrogen, methyl and ethyl.
  • any substituent groups present are selected from hydroxyl and NR), where each R' is independently selected from hydrogen and methyl.
  • there are only one or two substituent groups e.g. only one substituent group, e.g. a hydroxyl substituent group.
  • the spacer group X’ is unsubstituted. In another embodiment, the spacer group X’ has a -OH substituent group.
  • the spacer group X’ is a C1, C2, C3 or C4 alkyl group (such as a C2 or C3 alkyl group) which may optionally have one or two substituent groups, e.g. only one substituent group, e.g. a hydroxyl substituent group.
  • the diluent monomer is suitably low viscosity, for example it may have a viscosity of 80mPa.s or less, especially 50 mPa.s or less, e.g. from 1 to 50mPa.s, at 25°C (e.g. measured using a Brookfield viscometer).
  • the diluent monomer preferably has a molecular weight of 900g/mol or less, such as 850g/mol or less or 800g/mol or less, e.g. 750g/mol or less or 700g/mol or less. This assists with achieving a viscosity compatible with the reactive material being an ink for 3DP, e.g. IJ3DP.
  • the diluent monomer has a molecular weight of from 50 to 900g/mol, e.g. from 75 to 850g/mol or from 100 to 800g/mol, such as from 100 to 750g/mol or from 100 to 700g/mol.
  • the diluent monomer includes one or more (e.g. one or two) polymerisable group selected from acrylate, methacrylate, acrylamide and epoxy and has a viscosity of from 1 to 50 mPa.s at 25°C (e.g. measured using a Brookfield viscometer).
  • it also includes one or more (e.g. one or two) hydrophilic moiety selected from hydroxyl moieties, carbonyl moieties, carboxyl moieties, and amino moieties.
  • the diluent monomer is selected from hydroxyethyl acrylate, hydroxyethyl methacrylate, 2-ethylhexyl acrylate, poly(ethylene glycol) diacrylate (PEGDA) with an average molecular weight Mn of 575 or less, e.g. Mn 250 or 575, and hydroxyethyl acrylamide.
  • PEGDA poly(ethylene glycol) diacrylate
  • the diluent monomer does not need to include any API.
  • One role of the diluent monomer is to provide the ability to tune the hydrophilic/hydrophobic balance of the resulting polymer.
  • Another role is to allow control of the viscosity of the reactive material.
  • the monomers used should be pharmaceutically acceptable. Therefore the diluent monomer as formed should be purified as necessary to ensure that it is pharmaceutically acceptable. Methods for purification to pharmaceutically acceptable standards are well known in the art, e.g. crystallization, liquid-liquid extraction, and flash chromatography.
  • the prodrug monomer and the diluent monomer may be included in any respective ratio to one another.
  • a benefit is that by changing the ratio of the two respective monomer types, the overall hydrophilicity/hydrophobicity of the solid dosage formulation can be controlled. This in turn allows the release rate of the API to be controlled. As can be seen from the examples, by including a greater proportion of hydrophilic monomer, the release rate for the API can be increased.
  • the overall hydrophilicity of the co- polymerized final product can be tuned. This, in turn, allows control of the rate of hydrolysis and therefore drug release.
  • the ratio of prodrug monomer: diluent monomer is from 5 :95 to 95:5 or from 10:90 to 90: 10, such as from 20:80 to 80:20 or from 25:75 to 75:25.
  • the photo-reactive material includes a quantity of prodrug monomer and, optionally, a quantity of diluent monomer.
  • prodrug monomer plus diluent monomer makes up 80wt% or more, or 85wt% or more, or 90wt% or more (such as 95wt% or more or 99wt% or more) of the reactive material.
  • the photo-reactive material may, in one embodiment, solely consist of prodrug monomer and diluent monomer.
  • photo-reactive material may optionally be included in the photo-reactive material provided that they are not detrimental to the ability of the photo-reactive material to exhibit a low viscosity (preferably 1-30 mPa.s at 25°C measured using a Brookfield viscometer) and to be photo-polymerisable.
  • optional components may, for example, include diluents, colours, flavours, stabilizers, fillers or the like.
  • the photo-reactive material may optionally further comprise a photoinitiator. It will be appreciated that a photoinitiator can usefully be included because the polymerisation is intended to be triggered by light, e.g. by UV light.
  • photoinitiators examples include 2,2-dimethoxy-2-phenylacetophenone (DMPA), benzophenone (BP), and (2,4,6-trimethylbenzoyl) diphenylphosphine oxide (TMDPO).
  • DMPA 2,2-dimethoxy-2-phenylacetophenone
  • BP benzophenone
  • TMDPO 2,4,6-trimethylbenzoyl diphenylphosphine oxide
  • the photoinitiator may be included at any suitable concentration in the reactive material, e.g. in an amount of from 0.5 to 5wt%.
  • the photo-reactive material is deposited and then photo-polymerised.
  • the depositing step can involve forming a layer of the material or placing the material in a mold or carrying out any step that means that when polymerisation occurs the material solidifies into a desired shape.
  • the polymerisation is triggered by light (e.g. UV light or NIR light).
  • light e.g. UV light or NIR light.
  • the skilled reader will be aware of polymerisation techniques and in particular polymerisation as used in 3DP techniques.
  • the photo-reactive material is used to form a solid dosage formulation by a 3DP technique, e.g. a technique selected from inkjet-based 3D printing; vat polymerisation (e.g. stereolithography, which may be single photon or multi-photon); extrusion additive manufacturing; reactive extrusion additive manufacturing; and reactive binder jetting.
  • a 3DP technique e.g. a technique selected from inkjet-based 3D printing; vat polymerisation (e.g. stereolithography, which may be single photon or multi-photon); extrusion additive manufacturing; reactive extrusion additive manufacturing; and reactive binder jetting.
  • the solid dosage formulation as made in accordance with the invention may be a tablet or other solid formulation for oral, buccal, sublingual, vaginal or rectal administration. It may alternatively be an implant, e.g. for providing a controlled extended or delayed release of an API. It may, yet further alternatively, be a solid product for topical administration of an API, such as a patch or bandage.
  • polymerisation results in the formation of a solid material (e.g. solid particles) that is then suspended or dispersed in a pharmaceutically acceptable carrier (e.g. water or an aqueous-based carrier), such that the solid dosage formulation is in the form of a solid that is suspended or dispersed in a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g. water or an aqueous-based carrier
  • a key benefit of the present invention is the versatility of the reactive material in terms of the range of solid dosage formulations that it can be used to manufacture, with the ability to provide a tailored dose, and the ability to tune the release profile.
  • the solid dosage formulations can be prepared using a range of APIs, including but not limited to drugs having a carboxylic acid group, and can be prepared having much higher drug loadings than can be achieved when the API is dissolved or dispersed in a printable ink.
  • Ibuprofen was selected as an exemplary API in relation to which it would be beneficial to be able to manufacture personalised solid dosage formulations.
  • Prodrug monomers were prepared from ibuprofen attached via an ester bonding group (with an ester bond as the releasable covalent bond) to a number of different polymerisable groups. An ethyl spacer group was included between the bonding group and the polymerisable group. The prodrug monomers were combined with diluent monomers to form reactive materials in liquid form and their properties were assessed.
  • prodrug monomer plus diluent monomer with the best properties was then used in a number of different ratios and these reactive materials were used as the ink in an inkjet printing process to produce tablets.
  • Figure 1 is a schematic of the approach used.
  • Figure la illustrates how the selected drug candidate (with a first reactive functional group) is attached to a reactive carrier molecule (with a second reactive functional group, a spacer group and a polymerisable group).
  • the first reactive functional group and second reactive functional group form a temporary releasable (degradable) covalent bond.
  • the resulting prodrug monomer is prepared into a reactive material in liquid form which can be used as the ink in inkjet printing; the ink was inkjet printed and polymerized in-situ by UV photo-polymerization to form a solid 3D structure;
  • Figure lb) illustrates the molecular structures of ibuprofen, hydroxyethyl acrylate and the resulting prodrug monomer.
  • Figure lc) illustrates a bespoke tablet made according to the invention, with multi-material IJ3DP, having a spatially varying drug distribution.
  • IBHEMA Ibuprofen attached hydroxy ethyl methacrylate
  • Ibuprofen attached hydroxyethyl acrylamide (IBHAAm) Ibuprofen (3.00 g, 15.6 mmol, 1 eq.) was dissolved in DCM (50 mL), together with N- hydroxyethyl acrylamide (2.34 g, 20.3 mmol, 1.3 q.) and DMAP (0.21 g, 2.40 mmol, 0.15 eq.). The stirring solution was cooled in an ice bath. EDC-HC1 (3.60 g, 18.8 mmol, 1.2 eq.) was slowly added to the stirring mixture. The reaction was left stirring overnight at room temperature. The crude was washed twice with brine and twice with HC1 2M. The organic phase was then dried over MgSO 4 , filtered, and the solvent was removed under reduced pressure. The resulting oil was used without any further purification. Yield: 67%
  • IBHEA Ibuprofen attached hydroxyethyl acrylate
  • prodrug monomer For each prodrug monomer, a number of ink formulations were prepared, with three different loadings of prodrug monomer (30%, 50% and 70% by molecular ratio) in diluent monomer. Hydroxyethyl acrylate (HEA), hydroxyethyl methacrylate (HEMA) and hydroxyethyl acrylamide (HAAm) were used as the hydrophilic diluent monomers.
  • DMPA 2,2-dimethoxy-2-phenylacetophenone
  • the inks were then purged with nitrogen for 15 minutes, after which they were each filtered by using a 5 ⁇ m PTFE syringe filter.
  • inks in terms of miscibility and curability were those based on the IBHEA prodrug monomer and with HEA as the diluent monomer. This was followed by IBHEA with HEMA and IBHEMA with HEA, and then IBHEMA with HEMA.
  • the formulations were printed using a Dimatix Materials printer (DMP-2830 Fujifilm).
  • the printer was enclosed in a metallic environment box and filled with nitrogen gas.
  • the oxygen level was kept between 0.25 ⁇ 0.05 % during the printing process to minimize the inhibition effect caused by oxygen during the free radical photo-polymerization curing procedure.
  • a lOpL disposable printhead, Dimatix Materials Cartridge (DMC-11610, Fujifilm) was used for printing.
  • In-line UV curing was applied at the cartridge height immediate after each swath of ink droplets are deposited, by using a LED UV unit (365nm, 800mW/cm2, Printed Electronics Limited, Tam worth, UK) attached and moving with the printhead unit.
  • the printing temperature was set to 28°C.
  • the sample was printed at 30 ⁇ m for the first layer and reduced to 20 ⁇ m for all the following layers.
  • the height of the printhead was set to 700 ⁇ m with an increment of 9 ⁇ m after each layer printed.
  • the tested inks based on the IBHEA prodrug monomer and with HEA as the diluent monomer exhibited reliable droplet formation and were able to cure within a short period of UV exposure. There was good suitability for 3DIJP because the droplets were able to support any subsequent ink layers placed upon them, as required during the formation of 3D structures.
  • IBHEA-HEA The best results being seen with IBHEA-HEA is consistent with the fact that free radical polymerization propagation kinetics are known to be higher with acrylate monomers when compared to methacrylates that contain similar pendant groups. 4. Testing
  • HEA is hydrophilic due to the pendant hydroxyl group, and thus both HEA and poly-HEA are water soluble. Conversely, the attachment of ibuprofen on to HEA consumes the hydroxyl and converts it into an ester bond. Thus, the esterification process makes both the ibuprofen (loss of carboxylic acid) and HEA (hydroxyl loss) more hydrophobic. Consequently, the synthesized IBHEA acts as a hydrophobic component and so varying the ratio of the hydrophobic IBHEA and hydrophilic HEA allows the overall hydrophilicity of the co-polymerized final product to be tuned. This, in turn, allows control of the rate of hydrolysis and therefore drug release.
  • PBS Phosphate-Buffered Saline
  • in vitro drug release test was carried out in PBS solution at pH 2.0, pH 7.3 and pH 12.0 and three samples were tested for each condition.
  • One printed dosage was immersed in lOmL of dissolution media and kept at 37.5°C. lmL of media was sampled at 6, 25, 49, 120, 216, 316, 384, 480 hours and filtered through 0.45 ⁇ m pore size syringe filter. After each sampling, the dissolution media was replaced with fresh ones.
  • HPLC machine MSQ plus and U3000 Liquid Chromatography - Mass Spectrometry System
  • ACE 3 Cl 8 analytical column 150 mm x 4.6 mm
  • UV detection wavelength 265 nm
  • the mobile phase was 65% acetonitrile and 35% PBS solution tuned to pH 2.5 ⁇ 0.2 by phosphate acid. Both parts of the mobile phase were degassed and filtered through a 0.45 ⁇ m syringe filter.
  • Figure 2 shows the results for the ibuprofen release as measured over 20 days for 30:70, 50:50 and 70:30 IBHEA: HEA. It can be seen that the printed products show different release behaviours in different pH environments. Overall, the more hydrophilic molecules (more HEA) display a faster release speed. In this regard, under all pH environments, the products that contain higher concentrations of HEA exhibit faster ibuprofen release, suggesting that the HEA allowed for greater intimate contact between the ester bonds and the water molecules that drive hydrolysis. In an alkaline environment, the release was considerably increased, indicating a base catalysed release mechanism.
  • the specimens were printed using a formulation that contained 30 mol% of IBHEA released 87.6 wt% of the loaded ibuprofen in a pH 12 environment, whilst the specimens in pH 2 and pH 7 released 20.1 wt% and 21.2 wt% respectively.
  • the poly-IBHEA-HEA copolymer decomposes to poly-HEA homopolymer, a water-soluble polymer. Once decomposition occurred the release profile test could not be continued after that time point; in this regard it was not possible to replace media for the following time points because removing media also would remove polymer debris from then on.
  • Figure 3 is a set of images that illustrates the change in the products as the drug is released.
  • the set of pictures on the left, from top to bottom, show the change of the physical state of the products after the specified percentage of drug release (8%, 31% and 87% released).
  • the whole device becomes soluble in water and can be washed away after delivery is complete.
  • the set of pictures on the right, from top to bottom, show schematics of the molecular state of the products after the specified percentage of drug release (8%, 31% and 87% released).
  • BJ6 fibroblasts were grown in Dulbecco’s modified eagle medium (DMEM) supplemented with 10 % (v/v) foetal calf serum, 1% MEM non-essential amino acids solution (Sigma- Aldrich), and 1% antibiotics/antimycotics (100 units/mL penicillin, 100 mg/mL streptomycin, and 0.25 mg/mL amphotericin B; Life Technologies). Cells were cultured until they reached 80% confluency. Then, the cells were detached using trypsin EDTA, centrifuged at 200 x g for 5 min and re-suspended in medium. Cells were seeded in a 96 well plate at a density of 5,000 cells per well and left to attach for 24 hours before the cytotoxicity experiments. A new seeded well plate was used for each time point.
  • DMEM Dulbecco’s modified eagle medium
  • MEM non-essential amino acids solution Sigma- Aldrich
  • Samples of the inkjet printed products as produced above were sterilised under UV light for 50 minutes and transferred onto a 48-well plate. Each well containing a sample was filled with 2 ml of culture medium. Samples were incubated in the medium for a total of three days. After day 1 and 3 of incubation, 200 m ⁇ of medium were transferred on triplicates to the cells seeded on the 96-well plates. Cells were incubated for 24 hours on the medium to test if any of the leached substances from the printed samples were cytotoxic. Cells cultured in fresh medium were used as negative control. Cytotoxicity was measured using Presto BlueTM (Invitrogen) following the manufacturer’s instructions. The fluorescent signal was measured with an automated microplate reader (Tecan) using an excitation wavelength of 560 nm and an emission wavelength of 590 nm.
  • a cytotoxicity test (following ISO 10993) was also carried out with samples of all the inkjet printed products.
  • Table 1 Therefore a 58% loading of the drug in the formulation was able to be achieved.
  • Figure 4 shows the FTIR spectra before and after printing. It was found that all the characteristic peaks related to unreacted acrylates disappeared in the final product. This indicates high conversion.
  • FTIR-ATR is a surface based technique (ca. tens of microns)
  • FTIR-ATR is a surface based technique (ca. tens of microns)
  • specimens from each formulation were dissolved and characterized by H’NMR. No characteristic peak for the acrylate groups in either HEA or IBHEA were observed.
  • a more complex multi material core shell structure was also printed, in which the same drug loaded ink formulation (30 mol% ibuprofen loading) was embedded into an inkjet printed poly-HEA (0 mol% Ibuprofen loading) shell by co-printing both formulations.
  • Tof-SIMS (with depth analysis) was used to further investigate the state of the ibuprofen drug. This showed that no chemical or physical changes were observed to the loaded drug molecules through the inkjet print process.
  • Figure 6 shows the results of the Tof-SIMS analysis.
  • Figure 6a) shows the Tof- SIMS characterization of the printed 30 mol%-70 mol% IBHEA-HEA) tablet.
  • Figure 6b) shows the Tof-SIMS characterization of the printed 70 mol%-30 mol% (IBHEA-HEA) tablet.
  • Figure 6c) shows the Tof-SIMS characterization of the printed 50mol%-50mol% (IBHEA-HEA) tablet.
  • the drug molecules were observed to be homogeneously distributed.
  • these drug-releasing inks that were successfully tested using inkjet-based 3D printing can also be used in other techniques where the printable ink solution needs to exhibit relatively low viscosity and fast curing speeds.
  • 3DP techniques e.g. stereolithography; extrusion additive manufacturing; reactive extrusion additive manufacturing; and reactive binder jetting
  • electrospinning microfluidic jetting; microfluidic-based emulsification and polymerization; and reactive injection moulding.
  • the loaded drug was shown to be homogeneously distributed throughout both the reactive material (ink) and the solid printed product without recrystallization or precipitation, indicating physical stability.
  • the solid printed product was able to achieve zero order drug release in an alkaline environment that hydrolyses the ester bond.
  • the release period could be extended by increasing the drug loading.
  • prodrug monomers can each be successfully used to prepare ink formulations in the same manner as described above, and these ink formulations can be 3D printed, as described above.
  • the invention provides a range of photo-reactive materials that can be used as drug- releasing inks. These monomeric materials have relatively low viscosity, making them suitable for use in advanced manufacturing techniques. They can in particular be used with 3DP, and especially IJ3DP.
  • Tested API dopamine 0.1M (15.3g) of dopamine and 0.1M (12.8g) of 2-oxoethyl methacrylate were added into a flask. 0.1M B(OCH2CF3)3 was added as the catalyst. THF (200mL) was used as reaction solvent and added into the flask at last. The reactants were allowed to react at room temperature for 2 hours with stirring at 600r ⁇ m
  • 0.1M (18g) aspirin and 0.1M (13g) 2-aminoethyl methacrylate were added into a flask and connected to a reflux apparatus.
  • the reactor was heated up to 140°C and the progress of the conversion was tracked by TLC with 1 : 1 hexane and EtoAc. Once the reaction was complete, the reactant was extracted by adding AcOEt and then recrystallized.
  • tiopronin Tiopronin 0.075M (12.3g) and anhydrous 2-oxoethyl methacrylate 0.05M (6.4g) were added into a flask.
  • Anhydrous toluene (40mL) containing 0.05M triethylamine was then added into the reactor.
  • the reaction was carried out at room temperature for 13 days with flushed nitrogen atmosphere.
  • the product was then washed with ammonium chloride solution.
  • the organic layer wascollected and then dried with magnesium sulphate.
  • Methacrylohydrazide (30 mg) was dissolved in lmL dry methanol in a glass vial equipped with a stirrer bar. 4-(4-hydroxylphenthyl)butan-2-one (1.2x excess) was added and the reaction stirred overnight at 35 °C. The reaction was purified by column chromatography.
  • DSC N,N'-Disuccinimidyl carbonate
  • HEMA Hydroxyethyl-methacrylate
  • Methyl salicylate (0.494 g, 3.25 mmol) and DMAP (1.19 g, 9.75 mmol) were dissolved in 50 mL of dichloromethane (DCM), and then triphosgene (0.24 g, 0.81 mmol, dissolved in 5 mL of DCM) was slowly introduced under a N 2 atmosphere. After stirring for 30 min at room temperature, 2-(3-(hydroxymethyl)-4-nitrophenoxy)ethyl methacrylate (HNEMA) (1.0 g, 3.56 mmol, dissolved in 10 mL of DCM) was added dropwise. The reaction mixture was stirred in the dark for 12 h and a precipitate formed during this period.
  • DCM dichloromethane
  • HNEMA 2-(3-(hydroxymethyl)-4-nitrophenoxy)ethyl methacrylate

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Abstract

La présente invention concerne des procédés de production de formulations de médicaments solides à l'aide de techniques de fabrication de pointe, telles que l'impression 3D, qui impliquent une exigence de faible viscosité. L'invention utilise un matériau photo-réactif sous forme liquide, le matériau photo-réactif comprenant : (a) un monomère de promédicament comprenant un ingrédient pharmaceutique actif sous forme de promédicament, dans lequel l'ingrédient pharmaceutique actif est fixé de manière libérable à un groupe polymérisable par l'intermédiaire d'une liaison covalente libérable, et, éventuellement, (b) un monomère de diluant qui comprend un groupe polymérisable.
PCT/GB2021/050227 2020-02-03 2021-02-02 Formulations de médicaments WO2021156607A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3290270A (en) 1963-05-23 1966-12-06 Nat Starch Chem Corp Salicylic acid derivatives and polymers thereof
US5032572A (en) 1984-07-18 1991-07-16 Medical College Of Ohio Polymers containing cross-linked azo bonds, which polymers are useful for releasing therapeutic agents into the lower gastrointestinal tract
US5851546A (en) 1995-06-14 1998-12-22 Council Of Scientific & Industrial Research Polymer composition for controlled release of active ingredients in response to pH, and a process of preparing the same
US20110243884A1 (en) * 2008-10-10 2011-10-06 O'shea Michael Shane Biodegradable polymer - bioactive moiety conjugates
WO2017015703A1 (fr) 2015-07-24 2017-02-02 The University Of Sydney Polymère antiseptique et leur synthèse
WO2018225073A1 (fr) * 2017-06-08 2018-12-13 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Impression 3d de doses unitaires médicinales
WO2019185725A1 (fr) * 2018-03-29 2019-10-03 Universität Rostock Dispositif servant à fabriquer des systèmes de libération de principes actifs à impression 3d comprenant des dépôts de principes actifs, ainsi que procédé servant à fabriquer des systèmes de libération de principes actifs à impression 3d

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7968085B2 (en) * 2004-07-05 2011-06-28 Ascendis Pharma A/S Hydrogel formulations
EP2262845A1 (fr) * 2008-02-15 2010-12-22 University of Southern Mississippi Monomères et polymères avec des ingrédients actifs attachés de façon covalente
GB0810359D0 (en) * 2008-06-06 2008-07-09 Univ Belfast Composition
CN102159251B (zh) * 2008-09-18 2014-06-04 克里斯特递送有限公司 制备控释系统的方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3290270A (en) 1963-05-23 1966-12-06 Nat Starch Chem Corp Salicylic acid derivatives and polymers thereof
US5032572A (en) 1984-07-18 1991-07-16 Medical College Of Ohio Polymers containing cross-linked azo bonds, which polymers are useful for releasing therapeutic agents into the lower gastrointestinal tract
US5851546A (en) 1995-06-14 1998-12-22 Council Of Scientific & Industrial Research Polymer composition for controlled release of active ingredients in response to pH, and a process of preparing the same
US20110243884A1 (en) * 2008-10-10 2011-10-06 O'shea Michael Shane Biodegradable polymer - bioactive moiety conjugates
WO2017015703A1 (fr) 2015-07-24 2017-02-02 The University Of Sydney Polymère antiseptique et leur synthèse
WO2018225073A1 (fr) * 2017-06-08 2018-12-13 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Impression 3d de doses unitaires médicinales
WO2019185725A1 (fr) * 2018-03-29 2019-10-03 Universität Rostock Dispositif servant à fabriquer des systèmes de libération de principes actifs à impression 3d comprenant des dépôts de principes actifs, ainsi que procédé servant à fabriquer des systèmes de libération de principes actifs à impression 3d

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ACOSTA-VELEZ ET AL., BIOENGINEERING, vol. 4, no. 1, 2017, pages 11
CLARK E A ET AL., INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 529, no. 1-2, 2017, pages 523 - 530
CLARK ELIZABETH A ET AL: "3D printing of tablets using inkjet with UV photoinitiation", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 529, no. 1, 30 June 2017 (2017-06-30), pages 523 - 530, XP085156676, ISSN: 0378-5173, DOI: 10.1016/J.IJPHARM.2017.06.085 *
KYOBULA M ET AL., JOURNAL OF CONTROLLED RELEASE, vol. 261, 2017, pages 207 - 215
S. DAVARAN ET AL., JOURNAL OF CONTROLLED RELEASE, vol. 58, no. 3, 1999, pages 279 - 287

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