WO2017134418A1 - Produits et procédés pour administration orale - Google Patents

Produits et procédés pour administration orale Download PDF

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Publication number
WO2017134418A1
WO2017134418A1 PCT/GB2017/050178 GB2017050178W WO2017134418A1 WO 2017134418 A1 WO2017134418 A1 WO 2017134418A1 GB 2017050178 W GB2017050178 W GB 2017050178W WO 2017134418 A1 WO2017134418 A1 WO 2017134418A1
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WIPO (PCT)
Prior art keywords
drug
polymer
mixture
filament
plasticizer
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PCT/GB2017/050178
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English (en)
Inventor
Abdul Basit
Alvaro GOYANES
Simon GAISFORD
Fabrizio FINA
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Ucl Business Plc
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Publication of WO2017134418A1 publication Critical patent/WO2017134418A1/fr

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    • 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
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/06—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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 present invention relates to solid pharmaceutical oral dosage formulations and pharmaceutical filaments for the manufacture of such dosage formulations.
  • the invention further relates to methods for the manufacture of pharmaceutical filaments by means of hot melt extrusion and methods to manufacture solid pharmaceutical oral dosage formulations by means of hot melt extrusion to provide a pharmaceutical filament and subsequent fused- deposition modelling 3-dimensional printing from such a filament.
  • Oral administration of drugs is the most popular route for systemic effects due to its ease of ingestion, pain-avoidance, versatility and patient compliance. Patient compliance, high- precision dosing, and manufacturing efficiency have made tablets and caplets the solid dosage form of choice.
  • caplet etc its enteric coating is disrupted and loses the properties for which it was developed and applied.
  • Such methods and the formulations produced thereby would be of great value for production of medicines on a large scale or at the point of dispensing.
  • Immediate-release, sustained-release and controlled-release or modified- release such as time-delayed-release and pH-triggered-release oral dosage formulations are all needed.
  • 3-Dimensional Printing (3DP) is beginning to be explored as technology for the production of personalized dose medicines and various commercially available 3D printing approaches have been reported to print medicines.
  • the first system used to manufacture 3D printed medicines was based on powder bed-liquid 3D printing technology in the late 1990s, see for example Katstra et al "Oral dosage forms fabricated by three dimensional printing", J.
  • FDM fused-deposition modelling
  • FDM 3DP was first used in pharmaceutics in 2014 to print tablets with a polyvinyl alcohol (PVA) filament loaded with fluorescein as a model drug and has recently been expanded to other drugs. See, for example, Goyanes, A., Buanz, A.B., Basit, A.W., Gaisford, S., 2014, "Fused-filament 3D printing (3DP) for fabrication of tablets", Int. J. Pharm., vol. 476, pp.
  • PVA polyvinyl alcohol
  • the filaments were loaded with drug via passive diffusion, by incubation of the PVA strand within an alcoholic solution of the drug.
  • the drug loading was less than 2% by weight.
  • cellulosic enteric polymers provide filaments which are unprintable and very poor quality.
  • One approach currently used to achieve site specific drug delivery for FDM 3DP formulations is to apply the more conventional approach of coating a 3D printed formulation with enteric polymers, such as Eudragit ® L. This approach does not solve the problem of providing a dosage which is tailored to an individual patient without disruption of an enteric coating by splitting tablets or caplets into smaller fractions.
  • the current invention provides a process for producing a solid pharmaceutical oral dosage formulation comprising:
  • the process may have one or all of the following features, or a mixture thereof: the hot melt extrusion is performed using a filament extruder; the extruding temperature of the hot melt extrusion is in the range from 50°C to 150°C; the mixture that is hot melt extruded comprises said at least one lubricant selected from stearic acid, stearin, magnesium stearate, calcium stearate, colloidal silica, talc, zinc stearate, sodium stearyl fumarate, polyethylene glycol, or mixtures thereof; the mixture that is hot melt extruded comprises from 0.01 wt.% to 80 wt.% of the said at least one drug by total weight of the mixture; the said at least one drug is orally administrable and is selected from the group consisting of poorly water-soluble drugs, immunosuppressants, central nervous system drugs, circulatory system drugs, respiratory system drugs, digestive system drugs, antibiotics, antitussive and expectorant drugs, antihistamine drugs, antipyretic
  • the said mixture is ground before undergoing hot melt extrusion.
  • the print temperature of the fused-deposition modelling 3-dimensional printing is lower than 250°C.
  • the fused-deposition modelling 3-dimensional printing is performed using an extruding print speed in the range from 50 mm/s to 200 mm/s.
  • the fused-deposition modelling 3-dimensional printing is performed with a layer height setting in the range of 0.01 mm to 0.5 mm.
  • the fused-deposition modelling 3-dimensional printing is performed with an infill setting in the range of 1 % to 100%.
  • the invention provides a solid pharmaceutical oral dosage formulation produced by the processes according to the invention.
  • the invention provides a pharmaceutical filament for use in fused deposition modelling 3-dimensional printing, comprising:
  • said matrix comprises:
  • said pharmaceutical filament is produced by step (i) of the process as defined herein.
  • the invention provides a process for producing a pharmaceutical filament as previously defined, said process comprising step (i) of the process defined herein.
  • the invention provides a process for producing a solid pharmaceutical oral dosage formulation comprising fused deposition modelling 3-dimensional printing from a pharmaceutical filament as defined herein.
  • the invention provides a solid pharmaceutical oral dosage formulation having a laminated core comprising multiple layers,
  • each layer comprising:
  • said matrix comprises:
  • the average thickness of each layer in the laminated core is in the range from 0.01 mm to 0.5mm.
  • the invention provides the use of hot melt extrusion in combination with fused deposition modelling 3-dimensional printing for the production of a solid
  • each layer comprising:
  • said matrix comprises:
  • the invention provides the use of a lubricant in the hot melt extrusion of a mixture comprising at least one drug, at least one polymer and optionally at least one plasticizer, to provide a pharmaceutical filament for fusion-deposition modelling 3- dimensional printing, said use comprising addition of said lubricant to said mixture prior to undergoing hot melt extrusion.
  • the invention provides the use of a pharmaceutical filament comprising:
  • said matrix comprises:
  • the invention provides apparatus for carrying out the process of the invention, said apparatus comprising:
  • the said filament extruder produces a pharmaceutical filament as defined herein, and/or in use the said fused-deposition modelling 3-dimensional printer produces a solid pharmaceutical oral dosage formulation according to the invention.
  • the fused-deposition modelling 3-dimensional printer may comprise multiple nozzles.
  • the invention provides a kit for producing a solid pharmaceutical oral dosage formulation, comprising:
  • kits may preferably be as defined herein.
  • the fused- deposition modelling 3-dimensional printer may comprise multiple nozzles.
  • the invention provides a process for producing a solid pharmaceutical oral dosage formulation comprising
  • components (a) to (d) and steps (i) and (ii) may be as defined herein.
  • the invention provides a solid pharmaceutical oral dosage formulation having a laminated core comprising multiple layers,
  • each layer comprising a mixture of:
  • said matrix comprises: (b) at least one polymer
  • the invention provides a process for producing a solid pharmaceutical oral dosage formulation comprising
  • components (a) to (d) and steps (i) and (ii) may be as defined herein.
  • the invention provides a solid pharmaceutical oral dosage formulation having a laminated core comprising multiple layers, each layer comprising a mixture of:
  • said matrix comprises:
  • At least when used in connection with a number has its standard meaning, i.e. means that number is the minimum value for the specified parameter/component.
  • at least one polymer means there is one or more polymer and discloses the options of one polymer or more than one polymer being present.
  • excipient means a pharmacologically inactive component such as a diluent, disintegrant, carrier, etc of a pharmaceutical product.
  • the excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient.
  • composition or “pharmaceutical composition” or “solid oral composition” or “dosage form” as used herein synonymously include solid dosage forms such as tablets, capsules, granules, mini-tablets and the like meant for oral administration.
  • not greater than or “no more than” when used in connection with a number has its standard meaning, i.e. means that the specified parameter has a maximum value equal to the specified number.
  • the term "in the range from X to Y” has its standard meaning, i.e. the value of the parameter is a minimum of X and a maximum of Y.
  • multiple has its standard meaning, i.e. at least 2, more preferably at least 3.
  • no less than or not less than when used in connection with a number has its standard meaning, i.e. means that the specified parameter has a minimum value equal to the specified number.
  • the term “performed using” as for example in “hot melt extrusion is performed using” has its standard meaning, i.e. when the claimed process is carried out, the specified feature applies.
  • pharmaceutical grade has its standard meaning of being suitable for use in pharmaceutical products.
  • the product may be in excess of 80% purity, preferably 90% purity, more preferably 95% purity, even more preferably 99% purity.
  • pharmaceutical grade products may be products that are more than 99% pure and without binders, fillers, excipients. dyes, or unknown substances.
  • solid throughout this application is used to refer to the state of matter, i.e. to distinguish from liquids and gels.
  • weight % or “percent by weight” has its standard meaning throughout this application, i.e. percentage by weight based on the total weight of the relevant mixture. In other words the total weight of the mixture is 100%.
  • the component materials used are pharmaceutical-grade, in order to provide end products which are suitable for oral administration of drugs.
  • the drug is not particularly limited insofar as it is orally administrable.
  • examples of such a drug include poorly water-soluble drugs, immunosuppressants, central nervous system drugs, circulatory system drugs, respiratory system drugs, digestive system drugs, antibiotics, antitussive and expectorant drugs, antihistamine drugs, antipyretic, analgesic and anti-inflammatory drugs, diuretic drugs, autonomic drugs, antimalarial drugs, anti-diarrheal drugs, steroids, antineoplastic drugs, psychotropic drugs, proteins, peptides, biological drugs, and vitamins and derivatives thereof.
  • the drug is selected from anti-inflammatory drugs, immunosuppressants, steroids, and antineoplastic drugs. More preferably, from anti-inflammatory drugs, steroids, and antineoplastic drugs
  • poorly water-soluble drugs examples include azole-based compounds such as
  • nifedipine such as nifedipine, nitrendipine, amlodipine, nicardipine, nilvadipine, felodipine and efonidipine; propionic acid-based compounds such as ibuprofen, ketoprofen and naproxen; and indoleacetic acid-based compounds such as indomethacin and acemetacin. Additional examples include griseofulvin, phenytoin, carbamazepine and dipypridamole. Examples of immunosuppressants include azathioprine; cyclosporin; and methotrexate.
  • central nervous system drugs examples include diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam, diclofenac, indomethacin, sunlindac, lorazepam, nitrazepam, phenytoin, acetaminophen, ethenzamide, ketoprofen and chlordiazepoxide.
  • Examples of the circulatory system drugs include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide nitrate, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, etilefrine hydrochloride, digitoxin, propranolol hydrochloride and alprenolol hydrochloride.
  • respiratory system drugs examples include amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol and guaifenesin.
  • Examples of the digestive system drugs include benzimidazole-based drugs having an antiulcer action such as 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2- pyridyl)methylsulfinyl]benzimidazole; cimetidine; ranitidine; pirenzepine hydrochloride; pancreatin; bisacodyl; and 5-aminosalicyclic acid.
  • benzimidazole-based drugs having an antiulcer action such as 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2- pyridyl)methylsulfinyl]benzimidazo
  • antibiotics examples include talampicillin hydrochloride, bacampicillin hydrochloride, cefaclor and erythromycin.
  • antitussive and expectorant drugs examples include noscapine hydrochloride, carbetapentane citrate, dextromethorphan hydrobromide, isoaminile citrate and dimemorfan phosphate.
  • antihistamine drugs examples include chlorpheniramine maleate, diphenhydramine hydrochloride and promethazine hydrochloride.
  • antipyretic, analgesic and anti-inflammatory drugs examples include ibuprofen, diclofenac sodium, flufenamic acid, sulpyrine, aspirin, ketoprofen, 5ASA (otherwise known as mesalazine or mesalamine), 4ASA, sulphasalazine, and balsalazide.
  • diuretic drugs examples include caffeine.
  • autonomic drugs include dihydrocodeine phosphate, dl-methylephedrine hydrochloride, propranolol hydrochloride, atropine sulfate, acetylcholine chloride and neostigmine.
  • antimalarial drugs examples include quinine hydrochloride.
  • Examples of the anti-diarrheal drugs include loperamide hydrochloride.
  • Examples of the steroid drugs include prednisolone, budesonide and fluticasone.
  • antineoplastic drugs examples include fluorouracil; methotrexate; dactinomycin;
  • bleomycin etoposide
  • taxol vincristine
  • doxorubicin cisplatin
  • daunorubicin VP-16
  • Examples of the psychotropic drugs include chlorpromazine.
  • Vitamin A examples include Vitamin A, Vitamin B1 ,
  • Vitamin B2 Vitamin B6, Vitamin B12, Vitamin C, Vitamin D, Vitamin E, Vitamin K, calcium pantothenate and tranexamic acid.
  • proteins and peptides include erythropoietin, a glycosylated protein hormone and haematopoietic growth factor, which is considered useful in the management of anaemia in chronic renal failure among other conditions and has been investigated in the treatment of anaemia of inflammatory bowel disease as well as other normocytic- normochromic anaemias.
  • Erythropoietin is conventionally administered subcutaneously or intravenously, although a tabletted form of erythropoietin has been disclosed (RU-A- 2152206).
  • interferons include interferons, TNF antagonists and specific protein and polypeptide agonists and antagonists of the immune system, hormones, such as human growth hormone and cytokines and cytokine antagonists.
  • hormones such as human growth hormone and cytokines and cytokine antagonists.
  • high molecular weight compounds that might be used include vaccines.
  • biological drugs include: blood factors, such as Factor VIII and Factor IX;
  • thrombolytic agents such as tissue plasminogen activator; hormones such as insulin, glucagon, growth hormone and gonadotrophins; haematopoietic growth factors such as erythropoietin, colony stimulating factors; interferons such as - ⁇ . - ⁇ , and - ⁇ ; interleukin- based products such as interleukin-2; vaccines such as hepatitis B surface antigen;
  • Preferred proteins, peptides and biological drugs include: abatacept, adalimumab, alefacept, erythropoietin, etanercept, infliximab, trastuzumab, ustekinumab, denileukin difitox, and golimumab.
  • Pharmacologically acceptable derivatives and/or salts of the drugs may also be used in the formulation.
  • An example of a suitable salt of prednisolone is methyl prednisolone sodium succinate.
  • a further example is fluticasone propionate.
  • the drug is selected from the group of anti-inflammatory drugs,
  • immunosuppressants consisting of:
  • ibuprofen diclofenac sodium
  • 5ASA otherwise known as mesalazine or mesalamine
  • 4ASA sulphasalazine
  • balsalazide azathioprine, cyclosporin, and methotrexate
  • prednisolone, budesonide and fluticasone fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof.
  • the drug is selected from anti-inflammatory drugs, steroids, and
  • antineoplastic drugs selected from the group consisting of: ibuprofen, diclofenac sodium, 5ASA (otherwise known as mesalazine or mesalamine), 4ASA, sulphasalazine, and balsalazide; prednisolone, budesonide and fluticasone; fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof.
  • the at least one drug does not include theophylline, prednisolone, fluorescein or nifedipine. In another embodiment, applicable to all aspects of the invention, the at least one drug does not include 5ASA (otherwise known as mesalazine or mesalamine) or 4ASA.
  • the formulation will typically comprise a therapeutically effective amount of the or each drug which may be from about 0.01 wt,% to about 99 wt,%, based on the total weight of the formulation.
  • the actual dosage would be determined by the skilled person using their common general knowledge.
  • "low" dose formulations typically comprise no more than about 20 wt.% of the drug, and preferably comprise from about 1 wt.% to about 10 wt.%, e.g. about 5 wt.%, of the drug.
  • "High” dose formulations typically comprise at least 40 wt.% of the drug, and preferably from about 45 wt.% to about 85 wt.%, e.g. about 50 wt.% or about 80 wt.%.
  • the solid pharmaceutical oral dosage formulation is a "low" dose formulation.
  • the drug may be present in an amount which may be from about 0.01 wt,% to about 99 wt,%, based on the total weight of the mixture.
  • the actual dosage would be determined by the skilled person using his common general knowledge.
  • initial mixtures typically comprise no more than about 25 wt.% of the drug, and preferably comprise from about 1 wt.% to about 15 wt.%, e.g. about 5 wt.%, of the drug.
  • initial mixtures typically comprise at least 45 wt.% of the drug, and preferably from about 45 wt.% to about 85 wt.%, e.g. about 50 wt.% or about 80 wt.%.
  • the amount of drug in the initial mixture corresponds to the amount of drug in the final solid pharmaceutical oral dosage formulation, in terms of wt.%.
  • the amount of drug in the initial mixture corresponds to the amount of drug in the final solid pharmaceutical oral dosage formulation, in terms of wt.%.
  • the drug may preferably be present in the initial mixture in an amount in the range of 0.01 wt.% to 80 wt.%, for example 0.1 wt% to 60 wt.%. More preferably the drug is present in the mixture in an amount in the range of 1 wt.% to 49 wt.%, typical ranges include 2 wt.% to 35 wt.%, 3 wt.% to 25 wt.%. Even more preferred is a range of 1 wt.% to 15 wt.%, e.g. about 5 wt.% or about 10 wt.%.
  • a preferred combination, applicable to all aspects of the invention is 1 wt.% to 15 wt.%, more preferably 3 wt.% to 10 wt.% of at least one drug selected from the group of antiinflammatory drugs, immunosuppressants, steroids, and antineoplastic drugs consisting of: ibuprofen, diclofenac sodium, 5ASA (otherwise known as mesalazine or mesalamine), 4ASA, sulphasalazine, and balsalazide; azathioprine, cyclosporin, and methotrexate;
  • prednisolone, budesonide and fluticasone fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof.
  • Polymers (Polymeric Materials) A wide range of polymers used to manufacture solid pharmaceutical oral dosage forms is already on the market. These include, for example, polymethacrylate polymers, cellulosic polymers and polyvinyl-based polymers. The terms “polymer” and “polymeric materials” are used herein interchangeably.
  • the polymer which has the greatest impact upon release of the drug in the digestive system, specifically, its dissolution properties under the conditions found in the stomach and intestine. Selection of the polymer is therefore influenced by the drug used and the release-behaviour desired in the end-product solid pharmaceutical oral dosage formulations.
  • Immediate-release is the term generally applied to solid pharmaceutical oral dosage formulations, such as tablets and caplets, which disintegrate rapidly and get dissolved to release the drug. Immediate-release may be provided for by way of an appropriately pharmaceutically acceptable diluent or carrier which does not prolong, to an appreciable extent, the rate of drug-release and/or absorption. This term excludes formulations which are adapted to provide for "modified”, “controlled”, “sustained”, “prolonged”, “extended” or “delayed” release of drug.
  • Immediate-release formulations may release at least 70%, preferably 80%, of the drug within 4 hours, such as within 3 hours, preferably 2 hours, more preferably within 1.5 hours, and especially within an hour (such as within 30 minutes) of oral administration.
  • immediate-release formulations typically may be described as having a "burst effect", i.e. the majority, for example 90-100%, of the drug is released within the first hour after application.
  • Controlled-release also referred to as “modified-release” is a term used to describe drug- release where the release does not occur immediately, i.e. is not “immediate-release” as set out above. Throughout this application the terms “controlled-release” and “modified-release” are used synonymously.
  • Controlled-release formulations include formulations which exhibit sustained-release (also referred to as extended-release), delayed- release such as time-delayed-release and pH-triggered-release, or site-specific-release such as enteric release i.e. intestinal-specific-release, properties.
  • sustained-release also referred to as extended-release
  • delayed-release such as time-delayed-release and pH-triggered-release
  • site-specific-release such as enteric release i.e. intestinal-specific-release, properties.
  • enteric release i.e. intestinal-specific-release
  • polymers such as PVP may be effective.
  • the present invention preferably involves the use of a polymeric material that dissolves in a pH dependent manner.
  • a polymer is pH sensitive, i.e. has a "pH threshold" which is the pH below which it is insoluble in aqueous media and at or above which it is soluble in aqueous media.
  • pH threshold is the pH below which it is insoluble in aqueous media and at or above which it is soluble in aqueous media.
  • the term “insoluble” is used to mean that 1 g of a polymeric material requires more than 10,000 ml of solvent or “surrounding medium” to dissolve at a given pH.
  • the term “soluble” is used to mean that 1 g of a polymeric material requires less than 10,000 ml, preferably less than 5,000 ml, more preferably less than 1000 ml, even more preferably less than 100 ml or 10 ml of solvent or surrounding medium to dissolve at a given pH.
  • surrounding medium the Inventors mean gastric fluid and intestinal fluid, or an aqueous solution designed to recreate in vitro gastric fluid or intestinal fluid.
  • the normal pH of gastric juice is usually in the range of pH 1 to 3.
  • the polymer used according to the invention is insoluble below pH 5 and soluble at about pH 5 or above and, thus, is usually insoluble in gastric juice.
  • Such a material may be referred to as a gastro-resistant material or an "enteric" material.
  • the polymer thus preferably has a pH threshold of pH 5 or above, e.g. about pH 5.5 or above, preferably about pH 6 or above and more preferably about pH 6.5 or above.
  • the polymer typically has a pH threshold of no more than about pH 8, e.g. no more than about pH 7.5 and preferably no more than about pH 7.2.
  • the polymer has a pH threshold within the range of pH found in intestinal fluid.
  • the pH of intestinal fluid may vary from one person to the next, but in healthy humans is generally from about pH 5 to 6 in the duodenum, from about 6 to 8 in the jejunum, from about 7 to 8 in the ileum, and from about 6 to 8 in the colon.
  • the polymeric material preferably has a pH threshold of about 6.5, i.e. is insoluble below pH 6.5 and soluble at about pH 6.5 or above, and more preferably has a pH threshold of about 7, i.e. is insoluble below pH 7 and soluble at about pH 7 or above.
  • the pH threshold at which a material becomes soluble may be determined by a simple titration technique which would be part of the common general knowledge to the person skilled in the art.
  • the polymer is typically a material such as a polymethacrylate polymer, a cellulose polymer or a polyvinyl-based polymer.
  • suitable cellulose polymers include cellulose acetate phthalate (CAP); cellulose acetate trimellitate (CAT); and hydroxypropylmethylcellulose acetate succinate (HPMC-AS).
  • suitable polyvinyl-based polymers include polyvinyl acetate phthalate (PVAP).
  • the polymer is preferably an "anionic" polymeric material, i.e. a polymeric material containing groups that are ionisable in aqueous media to form anions (see below), and more preferably a co-polymer of a (meth)acrylic acid and a (meth)acrylic acid Ci_ 4 alkyl ester, for example, a copolymer of methacrylic acid and methacrylic acid methyl ester.
  • a polymer is known as a poly(methacrylic acid/methyl methacrylate) co-polymer.
  • Suitable examples of such co-polymers are usually anionic and not sustained release polymethacrylates.
  • the ratio of carboxylic acid groups to methyl ester groups (the "acid:ester ratio") in these co-polymers determines the pH at which the co-polymer is soluble.
  • the acid:ester ratio may be from about 2: 1 to about 1 :3, e.g. about 1 : 1 or, preferably, about 1 :2.
  • the molecular weight ("MW") of preferred anionic co-polymers is usually from about 120,000 to 150,000 g/mol, preferably about 125,000 g/mol or about 135,000 g/mol.
  • Preferred anionic poly(methacrylic acid/methyl methacrylate) co-polymers have a molecular weight of about 125,000 g/mol.
  • Suitable examples of such polymers have an acid:ester ratio of about 1 : 1 and a pH threshold of about pH 6, or have an acid:ester ratio of about 1 :2 and a pH threshold of about pH 7.
  • a specific example of a suitable anionic poly(methacrylic acid/methyl methacrylate) copolymer having a molecular weight of about 125,000 g/mol, an acid:ester ratio of about 1 : 1 and a pH threshold of about pH 6 is sold under the trade mark Eudragit ® L. This polymer is available in the form of a powder (Eudragit L 100), or as an organic solution (12.5%) (Eudragit ® L 12.5).
  • a specific example of a suitable anionic poly(methacrylic acid/methyl methacrylate) co- polymer having a molecular weight of about 125,000 g/mol, an acid:ester ratio of about 1 :2 and a pH threshold of about pH 7 is sold under the trade mark Eudragit ® S.
  • This polymer is available in the form of a powder (Eudragit ® S 100) or as an organic solution (12.5%) (Eudragit ® S 12.5).
  • the polymer may be a co-polymer of methacrylic acid and ethyl acrylate.
  • Preferred poly(methacrylic acid/ethyl acrylate) co-polymers have a molecular weight from about 300,000 to 350,000 g/mol, e.g. about 320,000 g/mol. Suitable examples of such copolymers have an acid:ester ratio of about 1 : 1 and a pH threshold of about pH 5.5.
  • a specific example of a suitable anionic poly(methacrylic acid/ethyl acrylate) co-polymer is available in the form of a powder and sold under the trade mark Eudragit ® L 100-55, or in the form of an aqueous dispersion (30%) and sold under the trade mark Eudragit ® L 30 D-55.
  • the polymeric material may be a co-polymer of methyl acrylate, methyl methacrylate and methacrylic acid.
  • Preferred poly(methyl acrylate/methyl methacrylate/methacrylic acid) copolymers have a molecular weight from about 250,000 to about 300,000 g/mol, e.g. about 280,000 g/mol.
  • Suitable examples of such co-polymers have a methyl acrylate:methyl methacrylate:methacrylic acid ratio of about 7:3: 1 thereby providing an acid:ester ratio of about 1 : 10 and a pH threshold of about pH 7.
  • a specific example of a suitable anionic poly(methyl acrylate/methyl methacrylate/ethyl acrylate) co-polymer is available in the form of an aqueous dispersion (30%) and is sold under the trade mark Eudragit ® FS 30 D.
  • the Eudragit ® co-polymers are manufactured and/or distributed by Evonik GmbH, Darmstadt, Germany.
  • the polymeric material may be a blend of at least two different polymers having a pH threshold of about pH 5 and above.
  • the polymers in the blend are different polymethacrylate polymers.
  • the polymers may be present in the blend in a polymer weight ratio from about 1 :99 to about 99: 1 , .e.g. from about 10:90 to about 90: 10, or from 25:75 to about 75:25, or from about 40:60 to about 60:40, for example about 50:50.
  • An example of a suitable mixture would include a mixture, e.g. a 1 : 1 mixture, of Eudragit ® L and Eudragit ® S.
  • a further example would include a blend, e.g. a 50:50 blend, of Eudragit S and Eudragit FS.
  • At least one polymer will be enteric, exhibiting pH-dependent-release and having a pH threshold in the range from 5.5 to 7, especially cellulosic enteric polymers.
  • Suitable particularly preferred polymers include hydroxypropylmethylcellulose acetate succinate (HPMC AS). Suitable polymers are available commercially, for instance, hypromellose acetate succinate (HPMC AS), AQOAT ® , is available from Shin-Etsu Chemical Co. Ltd. Japan. This is marketed in three different grades depending on the ratio between acetyl and succinoyl groups - L, M and H - with pH thresholds of 5.5, 6.0 and 6.5 respectively.
  • HPMC AS hypromellose acetate succinate
  • AQOAT ® is available from Shin-Etsu Chemical Co. Ltd. Japan. This is marketed in three different grades depending on the ratio between acetyl and succinoyl groups - L, M and H - with pH thresholds of 5.5, 6.0 and 6.5 respectively.
  • At least one polymeric material is selected from the group consisting of methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, Shellac, Cellulose acetate trimellitate, Sodium alginate, and Zein.
  • the amount of polymer present is typically in the range of 15 wt.% to 85 wt.% by total weight of the mixture or formulation.
  • the mixture may be preferable for the mixture to contain no more than 80 wt.% polymer, such as no more than 75 wt.%, no more than 60 wt.%, no more than 50 wt.%, no more than 40 wt.%, no more than 30 wt.% or no more than 20 wt.% polymer.
  • the mixture may contain no less than 70 wt.%, no less than 60 wt.%, no less than 50 wt.%, no less than 40 wt.%, no less than 30 wt.%, no less than 20 wt.%, no less than 10 wt.%, no less than 5 wt.% or no less than 1 wt.% of polymer, by total weight of the mixture or formulation.
  • Typical ranges of polymer content include, for example, 1-40 wt.%, such as 5-30 wt.% or 10- 20 wt.%, and 50-80 wt.% such as 60-75 wt.% or 70-80 wt.%.
  • the mixture or formulation may comprise 1 wt.% to 15 wt.%, more preferably 3 wt.% to 10 wt.%, of at least one drug selected from the group of anti-inflammatory drugs, immunosuppressants, steroids, and antineoplastic drugs consisting of ibuprofen, diclofenac sodium, 5ASA (otherwise known as mesalazine or mesalamine), 4ASA, sulphasalazine, and balsalazide; azathioprine, cyclosporin, and methotrexate; prednisolone, budesonide and fluticasone; fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and
  • the mixture or formulation may comprise 3 wt.% to 10 wt.% of drug selected from ibuprofen, diclofenac sodium, 5ASA (otherwise known as mesalazine or mesalamine), 4ASA, sulphasalazine, and balsalazide; azathioprine, cyclosporin, and methotrexate; prednisolone, budesonide and fluticasone; fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof, and 20 wt.% to 80 wt.% of at least one cellulosic enteric polymer such as hydroxypropy
  • lubricant in the mixture being hot melt extruded provides the necessary properties in the pharmaceutical filament so that this is suitable for 3-dimensional printing by fused-deposition modelling.
  • properties may include, for example, flexibility and hardness in the filament.
  • lubricants are sometimes used in the step of forming the tablet from granules or powder.
  • the lubricant is added at this stage in order to aid in the tablet formation, for example by preventing the granulated or powdered material from sticking to the tablet forming equipment.
  • the lubricant is added to the initial mixture prior to hot melt extrusion and as such forms part of the polymeric matrix in which the drug is dispersed.
  • Suitable lubricants for all aspects and embodiments of the invention include, for example, stearic acid, stearin, talc, magnesium stearate, calcium stearate, colloidal silica, zinc stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, canola oil, cottonseed oil, vegetable oil, castor oil, ethylene glycol stearates, octyldodecanol, fumaric acid, iauric acid, palmitic acid, myristic acid, stearic Acid, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, polyoxyethylene stearates, polyvinyl alcohol, potassium benzoate, sodium benzoate, sodium hyaluronate, starch, isopropyl myristate, leucine, medium-chain triglycerides, mineral Oil,
  • preferred lubricants for all aspects and embodiments of the current invention include stearic acid, stearin, talc, magnesium stearate, calcium stearate, colloidal silica, zinc stearate, sodium stearyl fumarate, polyethylene glycol, or mixtures thereof, or co-processed excipients incorporating a lubricant.
  • the lubricant may be selected from stearic acid, stearin and stearates eg calcium stearate, magnesium stearate and zinc stearate.
  • the lubricant comprises or consists of magnesium stearate.
  • the lubricant may be used in amounts from 0.1 wt.% to 50 wt.% by total weight of the mixture or formulation. It is preferable to use relatively low amounts of lubricant, for example 0.1 wt.% to 25 wt.% by total weight of the mixture or formulation. Preferably the lubricant is present in an amount in the range of 0.5-20 wt.%, more preferably 3-12 wt.% e.g. about 5 wt.%.
  • the lubricant may typically amount to 1 wt.% to 10 wt.% lubricant, by total weight of the mixture or formulation.
  • the mixture or formulation comprises 0.1 wt.% to 15 wt.% of a lubricant selected from stearic acid, stearin, calcium stearate, magnesium stearate and zinc stearate, especially 0.1 wt.% to 15 wt.% of calcium stearate, magnesium stearate and zinc stearate, and most especially 0.1 wt.% to 15 wt.% of magnesium stearate, by total weight of the mixture or formulation.
  • a lubricant selected from stearic acid, stearin, calcium stearate, magnesium stearate and zinc stearate, especially 0.1 wt.% to 15 wt.% of calcium stearate, magnesium stearate and zinc stearate, and most especially 0.1 wt.% to 15 wt.% of magnesium stearate, by total weight of the mixture or formulation.
  • wt.% to 25 wt.% of at least one drug in combination with 20 wt.% to 80 wt.% of polymeric material, and 0.1 to 15 wt.% of lubricant, by total weight of the mixture or formulation.
  • the mixture or formulation may comprise 1 wt.% to 15 wt.%, more preferably 3 wt.% to 10 wt.%, of at least one drug selected from the group of anti-inflammatory drugs, immunosuppressants, steroids, and antineoplastic drugs consisting of ibuprofen, diclofenac sodium, 5ASA (otherwise known as mesalazine or mesalamine), 4ASA, sulphasalazine, and balsalazide; azathioprine, cyclosporin, and methotrexate; prednisolone, budesonide and fluticasone; fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and
  • the mixture or formulation may comprise 3 wt.% to 10 wt.% of drug selected from ibuprofen, diclofenac sodium, 5ASA (otherwise known as mesalazine or mesalamine), 4ASA, sulphasalazine, and balsalazide; azathioprine, cyclosporin, and methotrexate; prednisolone, budesonide and fluticasone; fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof; and 20 wt.% to 80 wt.% of at least one cellulosic enteric polymer such as hydroxypropy
  • the plasticizer is used to influence the melting temperature of the polymer for hot melt extrusion.
  • Suitable plasticizers include: higher alcohols, polyols, beeswax, triethyl citrate, alkylene glycols, triacetin, dibutyl sebacate, glycerin monostearate, methylparaben and monoglycerin acetate, esters of citric acid, esters of phthalic acid, esters of fatty acids, vegetable and mineral oils, or mixtures thereof.
  • citrate esters examples include: tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate.
  • Suitable fatty acid esters include: butyl stearate, glyceryl monostearate, stearyl alcohol.
  • Suitable phthalate esters include: diethyl phthalate, dibutyl phthalate, dioctyl phosphate, dimethyl phthalate.
  • suitable glycol derivatives include: polyethylene glycol, propylene glycol.
  • suitable other plasticizers include: mineral oil, castor oil, benzyl benzoate, chlorbutanol, dextrin, mineral oil and lanolin alcohols, palmitic acid, petrolatum and lanolin alcohols, polyethylene glycol, poiymethacry!ate compatible, propylene glycol, pyrroiidone, stearic acid, triethanolamine, and Vitamin E TPGS.
  • the plasticizer is selected from the group consisting of acetone, methanol, ethanol, isopropanol, cetyl alcohol and stearyl alcohol, mannitol, sorbitol, glycerine, beeswax, triethyl citrate, polyethylene glycol, propylene glycol, triacetin, dibutyl sebacate, glycerin monostearate, methylparaben, and monoglycerin acetate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, butyl stearate, glyceryl monostearate, stearyl alcohol, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, dimethyl phthalate, mineral oil, castor oil, benzyl benzoate, chlorbuianol, dextrin, mineral oil and lanolin alcohols, palmitic acid
  • the plasticizer is selected from the group consisting of acetone, methanol, ethanol, isopropanol, cetyl alcohol and stearyl alcohol, mannitol, sorbitol, glycerine, beeswax, triethyl citrate, polyethylene glycol, propylene glycol, triacetin, dibutyl sebacate, glycerin monostearate, methylparaben, and monoglycerin acetate or mixtures thereof.
  • the plasticizer comprises or is selected from methylparaben, mannitol, triethyl citrate or mixtures thereof.
  • the plasticizer can be present in a wide range of amounts, depending on the amount of other components and the desired properties of the filament, for example, flexibility.
  • the plasticizer will be present in the mixture in an amount in the range of 1 wt.% to 80 wt.%, preferably 1 wt.% to 65 wt.% by total weight of the mixture. It may be preferred to use at least 10 wt.% plasticizer, more preferably at least 15 wt.% plasticizer. It may be preferred to use no more than 50 wt.% plasticizer, more preferably no more than 45 wt.% plasticizer. For example there may be 12 wt.% to 42 wt.% plasticizer present, by total weight of the mixture.
  • More than one plasticizer may be used, for example two plasticizers.
  • the total amount of plasticizer may preferably be as set out hereinbefore.
  • formulations i.e. 1 wt.% to 25 wt.% drug, and 1 wt.% to 10 wt.% lubricant, there may be 12 wt.% to 42 wt.% of plasticizer, by total weight of the mixture or formulation.
  • the mixture or formulation comprises 10 wt.% to 50 wt.% of a plasticizer comprising or selected from methylparaben, mannitol, triethyl citrate or mixtures thereof.
  • wt.% to 25 wt.% of at least one drug in combination with 20 wt.% to 80 wt.% of polymeric material, 0.1 to 15 wt.% of lubricant, and 10 to 50 wt.% plasticizer by total weight of the mixture or formulation.
  • the mixture or formulation may comprise 1 wt.% to 15 wt.%, more preferably 3 wt.% to 10 wt.%, of at least one drug selected from the group of anti-inflammatory drugs, immunosuppressants, steroids, and antineoplastic drugs consisting of ibuprofen, diclofenac sodium, 5ASA (otherwise known as mesalazine or mesalamine), 4ASA, sulphasalazine, and balsalazide; azathioprine, cyclosporin, and methotrexate; prednisolone, budesonide and fluticasone; fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and
  • the mixture or formulation may comprise 3 wt.% to 10 wt.% of drug selected from ibuprofen, diclofenac sodium, 5ASA (otherwise known as mesalazine or mesalamine), 4ASA, sulphasalazine, and balsalazide; azathioprine, cyclosporin, and methotrexate; prednisolone, budesonide and fluticasone; fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof; and 20 wt.% to 80 wt.% of at least one cellulosic enteric polymer such as hydroxypropy
  • Conventional pharmaceutical excipients such as diluents may be included in amounts up to 30 wt % of the mixture or formulation. Preferably less than 10 wt%, more preferably less than 5 wt.% of such additives are present.
  • the mixture to be hot melt extruded comprises or consists of:
  • prednisolone, budesonide and fluticasone fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof;
  • a plasticizer selected from methylparaben, mannitol, triethyl citrate or mixtures thereof.
  • the mixture includes:
  • prednisolone, budesonide and fluticasone fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof;
  • the mixture includes:
  • prednisolone, budesonide and fluticasone fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof;
  • prednisolone, budesonide and fluticasone fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof;
  • suitable mixtures may comprise 3 wt.% to 10 wt.%, such as about 5 wt.%, of at least one drug selected from ibuprofen, diclofenac sodium, 5ASA (otherwise known as mesalazine or mesalamine), 4ASA, sulphasalazine, and balsalazide; azathioprine, cyclosporin, and methotrexate;
  • prednisolone, budesonide and fluticasone fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin; and pharmacologically acceptable derivatives and salts thereof, with the other excipients as listed in table 1.
  • Extrusion is a process of converting raw material into a product of uniform shape and density by forcing it through a die under controlled conditions.
  • the extrusion process can be operated in continuous manner and is capable of consistent product flow at relatively high throughput rates.
  • the extrusion process comprises (i) mixing, for example sifting and blending, component materals, for example a drug and one or more pharmaceutically acceptable excipients such as lubricant, polymer and plasticizer, and (ii) passing the material through the extruder.
  • HME hot melt extrusion
  • Suitable extruders include filament extruders such as single-screw extruder, twin screw extruder, intermeshing screw extruder, and multiscrew extruder.
  • the particle sizes of the polymer, lubricant and optional plasticizer are similar to that of the drug, for example, within a tolerance of 10%, more preferably 5%, most preferably 2%. Without being bound by theory, this is believed to assist in providing a homogeneous starting mixture leading to final drug-loading in the filament to reflect the theoretical drug-loading. Grinding the materials may also contribute to the same effect.
  • the components can be mixed together and ground either manually or using a mixer, prior to hot melt extrusion.
  • the temperature of the extruder is approximately uniform so that the component materials are mixed in the extruder at the same temperature as the extruding temperature. It is preferred for the feed temperature also to be approximately the same as the extruding and mixing temperatures.
  • the extruding temperature in the hot melt extrusion is in the range from 50 °C to 200 °C.
  • the extruding temperature is 150 °C or less, for example 50 °C to 120
  • the extruding temperature is less than 110 °C, for example from 60°C to 105°C, preferably 70°C to 100°C, more preferably 75°C to 98°C e.g. 80-95 such as about 85°C
  • the rate of extrusion or extrusion speed is sometimes defined as the amount of material produced per unit time during the hot melt extrusion process. This is typically indicated by the screw speed of the extruder, for example in the range of 5 rpm to 300 rpm, for example 5 rpm to 25 rpm, such as about 15 rpm.
  • the die nozzle of the extruder may be of any shape and dimensions suitable for producing a filament that is compatible with fused-deposition modelling 3-dimensional printers.
  • the die will have a nozzle that produces an essentially cylindrical filament, having a diameter in the range of 0.5 mm to 5 mm.
  • the type of polymer being used will influence the choice of diameter for the die nozzle. For example, to obtain a 3 mm diameter pharmaceutical filament, a die nozzle having a diameter in the range of 1.5 mm to 3.7 mm would be typical, or to obtain a pharmaceutical filament having a diameter of about 1.5 mm to 2 mm, for example 1.75 mm., a die nozzle having a diameter of 1 mm to 2 mm would be typical.
  • the polymer melts with other excipients such as lubricant and optionally plasticizer. Together these components form a molten mixture in which the drug is molecularly dispersed/dissolved.
  • the molten polymer mixture is referred to herein as a "matrix”.
  • matrix applies to the mixture of polymer and other excipients such as lubricant and plasticizer, if present, and may also be applied to the cooled and solidified mixture as well as the molten mixture.
  • matrix does not require a chemical reaction or change in the chemical structure of the polymer, such as might be found upon curing, for example.
  • the polymer matrix is uncured.
  • the extruded product, the pharmaceutical filament may be viewed as a solid dispersion/dissolution wherein at least one drug is dispersed in a matrix, the matrix comprising at least one polymer and other excipients if present.
  • hot melt extrusion preferably may provide a pharmaceutical filament comprising at least one drug dispersed in a matrix, wherein the matrix comprises at least one polymer, at least one lubricant and optionally at least one plasticizer, as hereinbefore defined and discussed.
  • the pharmaceutical filament prepared by hot melt extrusion according to one aspect of the invention, may be viewed as a solid dispersion wherein at least one drug is dispersed in a matrix, the matrix comprising at least one polymer and other excipients if present.
  • the pharmaceutical filament comprises at least one drug dispersed in a matrix, wherein the matrix comprises at least one polymer, at least one lubricant and optionally at least one plasticizer, as hereinbefore defined and discussed.
  • the pharmaceutical filament according to the invention is preferably suitable for printing using fused-deposition modelling 3-dimensional printing.
  • the pharmaceutical filament according to the invention has a flexibility and hardness performance compatible with FDM 3DP.
  • Typical pharmaceutical filaments may be of any length compatible with the printer being used, for example at least 10 cm, and/or less than 5 m. The skilled worker can determine the necessary minimum and maximum lengths of filament, depending on the choice of printer.
  • the filament cross-section is typically essentially circular, such that the filaments are typically essentially cylindrical.
  • Different 3-dimensional printers use different diameters of filament, for example 1.75 mm, or 3 mm.
  • the diameter of the filament will be in the range from about 1 mm to about 10 mm, for example 1.5 mm to 3.5 mm.
  • the pharmaceutical filament comprises at least one drug dispersed in a matrix, wherein the matrix comprises at least one polymer, at least one lubricant and optionally at least one plasticizer, as hereinbefore defined and discussed.
  • Pharmaceutical filaments according to all aspects of the invention will typically contain a therapeutically effective amount of the or each drug which may be from about 0.01 wt,% to about 99 wt,%, based on the total weight of the filament.
  • filaments typically comprise no more than about 25 wt.% of the drug, and preferably comprise from about 1 wt.% to about 15 wt.%, e.g. about 5 wt.%, of the drug.
  • filaments typically comprise at least 45 wt.% of the drug, and preferably from about 45 wt.% to about 85 wt.%, e.g. about 50 wt.% or about 80 wt.%.
  • the amount of drug in the filament corresponds to the amount of drug in the corresponding final solid pharmaceutical oral dosage formulation, in terms of wt.%.
  • the drug may preferably be present in the filament in an amount in the range of 1 wt.% to 60 wt.%. More preferably the drug is present in the filament in an amount in the range of 1 wt.% to 49 wt.%, typical ranges include 2 wt.% to 35 wt.%, 3 wt.% to 25 wt.%. Even more preferred is a range of 1 wt.% to 15 wt.%, e.g. about 5 wt.% or about 10 wt.%, based on the total weight of the filament.
  • the pharmaceutical filament comprises at least one drug, at least one polymer, at least one lubricant and optionally at least one plasticizer as hereinbefore discussed and defined.
  • the pharmaceutical filament is produced by hot melt extrusion as hereinbefore discussed and defined.
  • Alternative methods of producing suitable pharmaceutical filaments include passive diffusion according to the art.
  • Fused-Deposition Modelling 3-Dimensional Printing 3-dimensional printing generally relates to processes used for manufacturing solid objects of almost any shape starting from computer aided design (CAD) files and based on the addition of materials layer by layer (additive manufacturing). Each layer represents a cross-section of the object derived from the virtual model and is in turn printed on the previous one so that the final product will constitute an approximation of that model, the resolution of which increases with the reduction of the layer thickness.
  • the process occurs automatically, under computer control, in principle avoiding any Manual task (automated fabrication), and the time and costs of manufacturing do not depend on the complexity of the product geometry.
  • Fused-deposition modelling involves the use of a filament that is extruded through a tip under defined pressure conditions and progressively layered in the melted/softened state to build up the final product.
  • the principle underpinning FDM technology is the deposition of thin strands of melted polymer from a filament, creating layers until the desired object is printed.
  • Suitable printers for FDM 3DP include MakerBot Replicator 2 (MakerBot (RTM) industries, LLC, US).
  • Parameters that can be varied in FDM 3DP typically include extruding print speed, initial position of the building platform and its lowering speed, tip diameter, print resolution (layer height), and infill %.
  • a layer height in the range of 0.01 mm to 10 mm, preferably 0.01 mm to 0.5 mm, more preferably 0.05 to 0.25 mm, such as 0.1 mm. It is believed that reduction in the layer thickness provides better i.e. increased print resolution of the object printed.
  • the infill % used is 100%.
  • an infill % of 0-1 % allows for hollow forms to be printed, while infill % of higher than 80% will provide a dosage form that is essentially monolithic and an infill % of essentially 100% will provide a non-hollow, monolithic dosage form, for example a tablet which is not hollow.
  • This can be considered in terms of void space in the dosage form.
  • the void space in the dosage form is less than 5% by volume.
  • FDM 3-dimensional printers can provide oral dosage forms having a range of geometries. For example, cylindrical, prismatic, oval, elongated, capsule-shaped, diamond-shaped. This is typically controlled by the CAD software.
  • the extruding print speed also referred to as “print speed” or “rate of extrusion” for FDM 3DP is the speed at which the nozzle of the printer moves while printing. A higher speed means a lower print time. Suitable print speeds for the current invention range from about 50 mm/s to about 200 mm/s.
  • the print speed may be in the range from 50 mm/s to 150 mm/s, preferably 80-100 mm/s e.g. 90 mm/s. Without being bound by theory, it is believed that a faster print speed leads to less adhesion between layers in the printed product. This could impact on the drug-release behaviour in the products of the current invention.
  • the platform temperature is the temperature of the platform onto which the filment is extruded and printed. In theory a higher temperature than room temperature, for example 60-90 °C assists the printed objects in attaching to the surface of the platform. Typically room temperature may be used as the platform temperature, for example 20-25 °C.
  • the print temperature or extrusion print temperature is the temperature at which the filament is forced through the printer tip. In all aspects and embodiments of the current invention it is preferred that the print temperature is as low as possible, in order to avoid or reduce degradation of the polymer.
  • Typical print temperatures may be lower than 250 °C, preferably 150-220°C.
  • the print temperature may be greater than 170 °C, such as in the range from greater than 170-210°C, more preferably 180-200°C, for example about 190°C. Without being bound by theory, it is believed that a lower print temperature also leads to less adhesion between layers in the printed product.
  • the print temperature should ideally be low enough to avoid degradation of the drug and not chemically affect the pharmaceutical filament.
  • the solid pharmaceutical oral dosage form produced by 3DP is hence a laminated structure, comprising multiple layers, for example at least 2, more preferably at least 3 layers, wherein each layer comprises at least one drug dispersed in a matrix including at least one polymer, at least one lubricant and optionally at least one plasticizer.
  • solid should be construed to distinguish from liquid and gels in terms of the state of matter.
  • the solid oral pharmaceutical dosage formulations according to the current invention are essentially monolithic as well as solid (i.e. not liquid or gel). More preferably these are also laminated i.e. consist of multiple layers superimposed on each other.
  • the solid oral pharmaceutical dosage formulations have a laminated core comprising multiple layers, wherein each layer comprises:
  • the matrix comprises:
  • the drug, polymer, lubricant and plasticizer may be as hereinbefore discussed and defined.
  • the laminated core comprises at least 2, more preferably at least 3 layers. In one embodiment, applicable to all aspects of the invention the laminated core comprises not more than 500 layers, more preferably not more than 300 layers. Preferably the laminated core comprises from 3 to 200 layers, more preferably from 10 to 100 layers, for example 20 to 80 layers, such as about 50 layers.
  • each layer in the laminated core may be within the range from 0.01 mm to 10 mm, more preferably 0.01 mm to 0.5mm.
  • pharmaceutical oral dosage formulation means a dosage form or unit dose, such as a tablet or caplet, containing a drug, which is to be orally administered, i.e. taken through the mouth. Oral administration can include buccal, sublabial and sublingual administration but the current invention preferably relates to oral administration by swallowing.
  • the dosage forms may be cylindrical, spherical, prismatic, oval, capsule-shape, or elongate, or diamond shaped.
  • the solid pharmaceutical oral dosage forms according to the invention may preferably be provided by a process comprising hot melt extrusion and/or fused-deposition modelling as previously discussed and defined. Most preferably the process includes both hot melt extrusion and fused-deposition modelling as previously discussed and defined.
  • the solid pharmaceutical oral dosage forms according to the invention may provide at least one of immediate-release, sustained-release or controlled-release drug delivery
  • controlled-release is provided, specifically enteric-release that is pH-dependent, for example having a pH-threshold of at least 5, for example 5.5-7.
  • the invention provides the use of hot melt extrusion in combination with fused deposition modelling 3-dimensional printing for the production of a solid
  • each layer comprising:
  • said matrix comprises:
  • the invention provides the use of a lubricant in the hot melt extrusion of a mixture comprising at least one drug, at least one polymer and optionally at least one plasticizer, to provide a pharmaceutical filament for fusion-deposition modelling 3- dimensional printing, said use comprising addition of said lubricant to said mixture prior to undergoing hot melt extrusion.
  • a pharmaceutical filament comprising:
  • the components (a) to (d), i.e. the drug, polymer, lubricant, and optional plasticizer, and the hot melt extrusion and fusion-deposition modelling 3-dimensional printing are as defined hereinbefore.
  • the invention provides apparatus for carrying out the processes according to the invention.
  • Said apparatus comprises or consists of:
  • a fused-deposition modelling 3-dimensional printer (ii) a fused-deposition modelling 3-dimensional printer.
  • Suitable FDM 3-dimensional printers include standard fused-deposition modelling 3D printers such as the MakerBot Replicator 2X, MakerBot Inc, USA.
  • Suitable filament extruders include single-screw extruder, twin screw extruder, intermeshing screw extruder, and multiscrew extruder.
  • the apparatus of the invention uses a mixture comprising components (a) to (d) as defined hereinbefore and produces pharmaceutical filaments and subsequently the corresponding solid pharmaceutical oral dosage formulations as previously defined hereinbefore.
  • kits for producing a solid pharmaceutical oral dosage, formulation comprising:
  • Suitable FDM 3-dimensional printers include standard fused-deposition modelling 3D printers such as the MakerBot Replicator 2X, MakerBot Inc, USA. Components (a) to (d) and said solid pharmaceutical oral dosage formulation are as previously defined hereinbefore.
  • Suitable filament extruders include single-screw extruder, twin screw extruder, intermeshing screw extruder, and multiscrew extruder.
  • Figure 1 SEM photographs of pharmaceutical filaments (a) LG; (b) MG; (c) HG.
  • Figure 2 TGA results of (a) starting materials and (b) pharmaceutical filaments.
  • Figure 3 DSC thermograms for pure polymers AQOAT ® and pharmaceutical filaments.
  • Figure 4 X-ray powder diffraction patterns for starting materials and pharmaceutical formulations.
  • Figure 5 3D printed tablets, (A) 20% infill and (B) 100% Infill; left to right AQ LG100, AQ MG100 and AQ HG100 in each row.
  • Figure 6 3-Dimensionally Printed tablets AQ HG 20% infill after 24h dissolution.
  • Figure 8 Drug-release profile for example 2.
  • Example 1 preparation and printing of control led-release enteric formulations
  • Paracetamol USP grade was used as a model drug (MW 151.16, solubility at 37°C: 21.80 g/L) and was purchased from Sigma-Aldrich, UK.
  • Hydroxypropylmethylcellulose acetate succinate HPMC AS: AQOAT ® AS-LG, AQOAT ® AS-MG and AQOAT ® AS-HG
  • HPMC AS Hydroxypropylmethylcellulose acetate succinate
  • AQOAT ® AS-LG AQOAT ® AS-MG and AQOAT ® AS-HG
  • Methylparaben NF grade (Amresco, USA) was used as a plasticizer and magnesium stearate (Sigma-Aldrich Co. Ltd., UK) as a lubricant.
  • the salts (listed below) for preparing the buffer dissolution media were purchased from VWR International Ltd., Poole, UK.
  • the mixture of drug and excipients was then extruded using a single-screw filament extruder (Noztec Pro hot melt extruder, Noztec, UK) in order to obtain the drug-loaded filament (extrusion temperature 80°C, nozzle diameter 1.75 mm, screw speed 15 rpm).
  • the extruded filaments obtained were protected from light and kept in a vacuum desiccator until printing.
  • the drug-loading of the filaments was determined by HPLC analysis.
  • Oral dosage pharmaceutical formulations were printed from the drug-loaded filaments using a standard fused-deposition modelling 3D printer (MakerBot Replicator 2X, MakerBot Inc, USA).
  • the filament is pushed through a metallic nozzle that is heated to melt the filament, the softened mass is deposited onto a movable platform forming layers until the desired object (a solid dosage form) is obtained.
  • AutoCAD 2014 Autodesk Inc., USA
  • the . stl format contains only the object surface data, and all the other parameter need to be set up from the MakerBot software.
  • the printer settings were as follows: High resolution without raft and an extrusion temperature of 190°C, speed while extruding (90 mm/s), speed while travelling (150 mm/s), number of shells (2) and layer height (0.10 mm). Two infill percentages was 20 and 100% where evaluated in order to produce tablets of low and high density.
  • the selected 3D geometry was a cylindrical tablet (10mm diameter x 3.6mm height).
  • TZero aluminium pans and lids were used with an average sample mass of 8-10 mg.
  • samples were heated at 10 °C/min in open aluminium pans with a Discovery TGA (TA instruments, Waters, USA). Nitrogen was used as a purge gas with a flow rate of 25 mL/min. Data collection and analysis were performed using TA Instruments Trios software and percentage mass loss and/or onset temperature were calculated.
  • Discs of 23mm diameter x 1 mm height made from PVA filament or drug-loaded PVA filament were 3D printed and analysed. A sample of pure budesonide was also analysed.
  • the angular range of data acquisition was 3-60° 2 ⁇ , with a stepwise size of 0.02° at a speed of 5 min.
  • the physical dimensions of the tablets were measured using a digital caliper. Pictures of the tablets were taken with a smartphone camera (iPhone 5, Apple, USA).
  • the filaments required a basic pH medium in order to dissolve (two drops of 5M NaOH were added before making to the top to increase the pH).
  • Samples of solutions were then filtered through 0.45 ⁇ filters (Millipore Ltd., Ireland) and the concentration of drug determined with HPLC (Hewlett Packard 1050 Series HPLC system, Agilent Technologies, UK).
  • the validated high performance liquid chromatographic assay entailed injecting 20 ⁇ _ samples for analysis using a mobile phase, consisting of 85% of water and 15% of methanol, through a Luna 5 mm C8 column, 25 x 4.6 cm (Phenomenex, UK) maintained at 40°C.
  • the mobile phase was pumped at a flow rate of 1 mL/min and the eluent was screened at a wavelength of 247 nm. All measurements were made in duplicate.
  • Drug dissolution profiles for the formulations were obtained with a USP-II apparatus (Model PTWS, Pharmatest, Germany): 1) the formulations were placed in 750 mL of 0.1 M HCI for 2 h to simulate gastric residence time, and then 2) transferred into 950 mL of modified Hanks (mHanks) bicarbonate physiological medium for 35 min (pH 5.6 to 7); 3) and then in modified Krebs buffer (1000ml) (pH 7 to 7.4 and then to 6.5).
  • the modified Hanks buffer based dissolution medium (136.9 mM NaCI, 5.37 mM KCI, 0.812 mM MgS0 4 .7H 2 0, 1.26 mM CaCI 2 , 0.337 mM Na 2 HP0 4 .2H 2 0, 0.441 mM KH 2 P0 4 , 4.17 mM NaHC0 3 ) forms an in-situ modified Kreb's buffer by addition of 50 mL of pre-Krebs solution (400.7 mM NaHC0 3 and 6.9 mM KH 2 P0 4 ) to each dissolution vessel.
  • the formulations were tested in the small intestinal environment for 3.5 h (pH 5.6 to 7.4), followed by pH 6.5 representing the colonic environment. These parameters were selected to simulate typical conditions for intestinal transit of pharmaceutical formulations and pH values in different segments of the Gl tract in fasted individuals.
  • the buffer capacity and ionic composition of the physiological bicarbonate buffers also closely match the buffer capacities of the intestinal fluids collected from different parts of the gut in humans.
  • the medium is primarily a bicarbonate buffer in which bicarbonate (HC0 3 " ) and carbonic acid (H 2 C0 3 ) co-exist in an equilibrium, along with C0 2 (aq) resulting from dissociation of the carbonic acid.
  • the pH of the buffer system can be decreased by purging C0 2 (g) in the solution, which promotes the formation of carbonic acid.
  • an inert gas such as helium, which removes the dissolved C0 2 from the solution, increases the pH of the medium.
  • the purging of gases is controlled by an Auto pH SystemTM, which consists of a pH probe connected to a source of carbon dioxide gas (pH-reducing gas), as well as to a supply of helium (pH-increasing gas), controlled by a control unit.
  • the control unit is able to provide a dynamically adjustable pH during testing (dynamic conditions) and to maintain a uniform pH value over the otherwise unstable bicarbonate buffer pH.
  • the percentage drug released from the formulations was determined using an in-line UV spectrophotometer (Cecil 2020, Cecil Instruments Ltd., Cambridge, UK) at 244 nm.
  • HME technology was successfully employed to extrude pharmaceutical grade excipients into filaments of appropriate physical characteristics and diameter for 3D printing ( Figure 1). All the mixtures were initially prepared with 5% paracetamol (Table 2). The use of pharmaceutical grade excipients of similar particle size to that of the drug helped to obtain a homogeneous mixture that led to final drug loadings of the filaments to be similar to the theoretical drug loading. In previous studies where a commercial PVA filament was used as starting material for HME and 3D printing, these were cut into small fragments (using a pelletizer) and mixed with the drug before HME.
  • Methylparaben was selected as a main plasticizer due to its superior plasticization efficiency and delayed drug-release profile compared with other plasticizers (TEC, PEG 8000, citric acid monohydrate and acetyltributyl citrate) as reported in a recent study with polymethacrylathe matrix pellets obtained by HME. All the formulations were prepared with 5% w/w magnesium stearate, which was found to be essential in facilitating the extrusion process due to its lubricant properties.
  • plasticizers TEC, PEG 8000, citric acid monohydrate and acetyltributyl citrate
  • TGA data of drug loaded filaments also showed no sign of drug degradation at the printing temperature (190°C) ( Figure 2).
  • the weight loss up to 190 °C was between 4 and 5.5% w/w for all the filaments.
  • TGA data of the three pure AQOAT polymers ( Figure 2) shows a weight loss of at least 2.9% due to water evaporation, hence storing the filaments in a desiccator before printing is useful.
  • a further weight loss of 0.59% for AQ LG was the effective value for the degradation of the polymer at printing temperature that demonstrated the stability of AQOAT polymers and their suitability for 3D printing tablets.
  • the average weight loss for the pure polymer AQOAT ® was 5 ⁇ 2%; as the decomposition of PVA is reported to start above 250 °C, this mass loss could be attributed to the evaporation of water.
  • the mass loss noticeable for the active compounds alone could be related to the first stage of decomposition.
  • TGA data for magnesium stearate showed an excellent stability at the printing temperature, weight loss seen before 100°C is due to loss of absorbed water.
  • methylparaben which has a relatively low boiling point, showed an evaporation process starting at about 100°C and completed at above 200°C. DSC and TGA analyses of the pure substances and extruded filament were performed to study how the drug was incorporated in the polymers ( Figure 3).
  • Paracetamol raw material melts around 168°C indicative of form I, while AQOAT polymers show a glass transition around 135°C and melting between 175 and 200°C (Figure 5).
  • the DSC data of the paracetamol-loaded filaments shows no evidence of melting around 168°C, indicating that the drug is molecularly dispersed within the polymer matrix as a solid solution/dispersion.
  • DSC of the mixture of AQOAT LG showed a the glass transition (Tg) at 74°C while the TG for the filament containing paracetamol was shifted about 8°C ahead (the drug was not acting as a plasticizer).
  • AQ LG20 showed 100% release after 7h and AQ MG20 100% after 10h, comparatively AQ LG100 and AQ MG100 showed respectively a 96% and 85% of drug released after 10 hours. All AQOAT LG and MG formulations were completely dissolved after 12 hours.
  • the dissolution data from the different dosage forms do show that it is very feasible to design devices with controlled-drug-release profiles by careful selection of the composition of the filaments.
  • the drug dissolution is driven by erosion-mediated process.
  • the printer software enabled easy fabrication of oral drug delivery devices with different inner structures (multilayer device and DuoCaplet), which would be challenging to manufacture by powder compaction, demonstrating the potential of 3DP as a novel manufacturing technology in pharmaceutics.
  • enteric (carboxylic acid containing) polymer dissolution in aqueous solutions is complex and influenced by a multitude of factors not merely limited to pH, and differs considerably from that of non-ionic polymer dissolution by virtue of an additional ionization step that stabilises the polymer chains.
  • the rank order in the dissolution of these products can be explained by the determining factors for enteric coating dissolution; that is, polymer pKa and chemical structure. Polymers with higher pKa values have higher dissolution pH thresholds and include the Eudragit ® S100 coated product, Octasa ® 800, which had slower drug-release.
  • FDM appears to be a versatile approach suitable for manufacturing delayed-release control- release formulations using different polymers.
  • the use of 3D printers with multiple nozzles would allow in the future the fabrication of formulations made with polymers providing different drug-release profiles, with different geometries and combining layers incorporating different drugs (even incompatible) with different doses for a personalized treatment.
  • Hot melt extrusion produced a range of paracetamol-loaded filaments made with pharmaceutical grade excipients, based on polymers that provide control or sustained drug- release.
  • Filaments comprising magnesium stearate lubricant presented the right physical characteristics to be loaded and be used to print within a FDM 3D printer.
  • the pH dependent polymers AQOAT LG, AQOAT MG and AQOAT HG were easy to extrude and easy to 3D print with resulting tablets very robust and well-shaped and showed good dissolution profiles of those tablets.
  • Drug-release test in biorelevant media showed distinctive controlled-release drug-release profiles from the different 3D printed tablets depending on the properties of the polymers.
  • Tablets were prepared according to the processes outlined in Example 1 , with the formulation in table 3.
  • Tablets were prepared according to the processes outlined in Example 1 , with the formulation in table 4.
  • Example 4 preparation and printing of controlled-release formulations incorporating Table 5: tablets composition for example 4
  • Tablets were prepared according to the processes outlined in Example 1 , with the formulations in table 5.
  • Tablets were prepared according to the processes outlined in Example 1 , with the formulations in table 6.

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Abstract

L'invention concerne un procédé de production de compositions pharmaceutiques solides pour administration par voie orale comprenant : (i) l'extrusion à chaud d'un mélange comprenant : (a) au moins un médicament, (b) au moins un polymère, (c) au moins un lubrifiant et (d) éventuellement au moins un plastifiant, pour obtenir un filament de médicament ; et (ii) l'impression 3D du modèle par dépôt à l'état fondu dudit filament de médicament.
PCT/GB2017/050178 2016-02-02 2017-01-25 Produits et procédés pour administration orale WO2017134418A1 (fr)

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WO2019240700A3 (fr) * 2017-12-29 2020-02-13 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions pharmaceutiques orales de mésalazine
WO2019240700A2 (fr) 2017-12-29 2019-12-19 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions pharmaceutiques orales de mésalazine
CN112839637A (zh) * 2018-08-13 2021-05-25 中央兰开夏大学 固体剂型生产
WO2020035680A1 (fr) * 2018-08-13 2020-02-20 University Of Central Lancashire Production de formes posologiques solides
JP2021535199A (ja) * 2018-08-13 2021-12-16 ユニバーシティ・オブ・セントラル・ランカシャーUniversity of Central Lancashire 固形製剤の製造方法
CN113301888A (zh) * 2019-01-18 2021-08-24 默克专利股份有限公司 制造固体施用形式的方法和固体施用形式
WO2020148442A1 (fr) * 2019-01-18 2020-07-23 Merck Patent Gmbh Procédé de fabrication d'une forme d'administration solide, et forme d'administration solide
WO2020201319A1 (fr) * 2019-04-01 2020-10-08 Université Libre de Bruxelles Compositions d'impression 3d pour des applications pharmaceutiques à libération modifiée
WO2022117512A1 (fr) * 2020-12-01 2022-06-09 UCB Biopharma SRL Formulations
WO2022178279A1 (fr) * 2021-02-19 2022-08-25 Nova Thin Film Pharmaceuticals Llc Procédé et système de fabrication de films solubles oraux, compositions de films solubles oraux, films solubles oraux préparer par ce procédé, et leurs méthodes d'utilisation
WO2022195008A1 (fr) * 2021-03-18 2022-09-22 UCB Biopharma SRL Formulations comprenant une protéine thérapeutique et au moins un stabilisant
WO2023126970A1 (fr) * 2021-12-30 2023-07-06 Laurus Labs Limited Films oraux de médicaments anti-inflammatoires non stéroïdiens
WO2024092237A1 (fr) * 2022-10-28 2024-05-02 Board Of Regents, The University Of Texas System Impression tridimensionnelle moyenne en air continu pour formes posologiques pharmaceutiques

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