Solid dosage form production
The present invention utilizes 3D printing technology, specifically fused filament fabrication (FFF) 3D printing, to produce solid dosage forms, such as pharmaceutical tablets. The production process utilizes novel printing filaments, typically on a spool, which contain the active ingredient. Such active-containing filaments have proved to be extremely robust and the principles outlined in the present disclosure provide access to a variety of viable formulations directly from a 3D printer. This, for the first time, affords a viable means for the in situ (e.g. within a pharmacy) 3D printing of personalized medicines tailored to a patient's needs. The invention also relates to purpose-built software for operating the printing apparatus, as well as local, national and global systems for monitoring the real time operation of a plurality of printing apparati to enable facile detection of malfunctions, thereby making regulatory approval viable and facilitating regulatory compliance.
1. A solid dosage form, which is an orally-administrable immediate release tablet comprising a pharmaceutical active ingredient, obtainable by a method of printing a solid dosage form comprising:
a) providing a solid dosage form printing apparatus comprising:
a fused filament fabrication (FFF) 3D printer;
a build platform upon which the solid dosage form is printable;
an active ingredient-containing printing filament, wherein the active ingredient-containing printing filament comprises an active ingredient-containing filament composition comprising: the pharmaceutical active ingredient and an active ingredient carrier, wherein the active ingredient-containing filament is solid at standard ambient temperature and pressure (SATP);
optionally one or more further printing filaments, each suitably independently comprising a further filament composition;
at least one heated extrusion nozzle through and from which the active ingredient-containing printing filament and optionally one or more further printing filaments can be extruded; and
a computer for controlling the FFF 3D printer and optionally also the build platform;
b) operating the FFF 3D printer to print the orally-administrable, immediate release solid dosage form upon the build platform via a process comprising:
i) printing the active ingredient-containing printing filament through the at least one heated extrusion nozzle; and
ii) optionally printing one or more further printing filaments; and
c) optionally performing one or more further processing steps;
wherein the active ingredient-containing printing filament is formed via hotmelt extrusion of a hotmelt mixture prepared by mixing together at least the pharmaceutical active ingredient and the active ingredient carrier; wherein the mixing together is performed at a mixing temperature (T1) that is between 7° and 150° C. and the hotmelt extrusion is performed at a hotmelt extrusion temperature (T2) that is 10 to 50° C. lower than the mixing temperature;
wherein the operating temperature (T3) of the at least one heated extrusion nozzle through which the active ingredient-containing printing filament passes is between 9° and 220° C.;
wherein the hotmelt extrusion temperature (T2) is between 30 and 90° C. lower than the operating temperature (T3) of the at least one heated extrusion nozzle through which the active ingredient-containing printing filament passes; and
the active ingredient carrier is a polymer having a glass transition temperature at least 50° C. lower than the melting point of the pharmaceutical active ingredient.
2. The solid dosage form as claimed in claim 1 , wherein the solid dosage form comprises a plurality of active ingredients.
3. The solid dosage form as claimed in claim 2 , wherein operating the FFD 3D printer comprises printing one or more further printing filaments, wherein at least one further printing filament comprises an active ingredient such that the method provides an orally-administrable immediate release solid dosage form comprising more than one active ingredient.
4. The solid dosage form as claimed in claim 2 , wherein the active ingredient-containing printing filament comprises a plurality of active ingredients such that the method provides an orally-administrable immediate release solid dosage form comprising more than one active ingredient.
5. The solid dosage form as claimed in claim 1 , wherein the active ingredient-containing printing filament further comprises a disintegrant.
6. The solid dosage form as claimed in claim 1 , wherein the orally-administrable solid dosage form is a disintegrating tablet.
7. The solid dosage form as claimed in claim 1 , wherein the active ingredient carrier is selected from the group consisting of:
an (optionally alkyl-, suitably methyl-or ethyl-) acrylate, methacrylate and/or ethacrylate polymer or copolymer;
a cellulose or cellulose derivative;
polyvinyl alcohol (PVA);
poly (lactic-co-glycolic acid) (PLGA);
a PVP or PVP-based carrier; and
a PEG or PEG-based carrier;
and any combination thereof.
8. The solid dosage form as claimed in claim 1 , wherein the active ingredient carrier comprises at least one polymer or co-polymer selected from the group consisting of:
an acrylate, methacrylate and/or ethacrylate copolymer comprising amine-containing monomeric units;
an alkyl-acrylate, alkyl-methacrylate and/or alkyl-ethacrylate copolymer comprising amine-containing monomeric units;
an methyl-acrylate, methyl-methacrylate and/or methyl-ethacrylate copolymer comprising amine-containing monomeric units;
an ethyl-acrylate, ethyl-methacrylate and/or ethyl-ethacrylate copolymer comprising amine-containing monomeric units;
an acrylate, methacrylate and/or ethacrylate polymer or copolymer free of any amine-containing monomeric units;
an alkyl-acrylate, alkyl-methacrylate and/or alkyl-ethacrylate polymer or copolymer free of any amine-containing monomeric units;
an methyl-acrylate, methyl-methacrylate and/or methyl-ethacrylate polymer or copolymer free of any amine-containing monomeric units;
an ethyl-acrylate, ethyl-methacrylate and/or ethyl-ethacrylate polymer or copolymer free of any amine-containing monomeric units;
a cellulose or cellulose derivative;
a polyvinyl alcohol (PVA); and
a poly (lactic-co-glycolic acid) (PLGA).
9. The solid dosage form as claimed in claim 1 , wherein the active ingredient carrier serves as a solid matrix for retaining the active ingredient within the active-ingredient-containing printing filament prior to printing therewith.
10. The solid dosage form as claimed in claim 1 , wherein the active ingredient is dispersed or dissolved within the active ingredient carrier of the active-ingredient-containing printing filament.
11. The solid dosage form as claimed in claim 1 , wherein the active ingredient-containing printing filament is free of plasticizer.
12. The solid dosage form as claimed in claim 1 , wherein the active ingredient-containing printing filament further comprises a plasticizer.
13. The solid dosage form as claimed in claim 12 , wherein the plasticizer is selected from the group consisting of one or more of triethylcitrate (TEC), glycerol, castor oil, oleic acid, glycerol, tryacetin and a polyalkylene glycol.
14. The solid dosage form as claimed in claim 1 , wherein the active ingredient-containing printing filament further comprises one or more fillers, where the filler is different from the active ingredient carrier, and wherein the filler has a melting point of at least 200° C.
15. The solid dosage form as claimed in claim 1 , wherein the active ingredient-containing printing filament comprises greater than or equal to 5 wt % active ingredient.
16. The solid dosage form as claimed in claim 1 , wherein the active ingredient-containing printing filament has a diameter or maximum thickness of between 0.1 mm and 5 mm.