WO2020201319A1

WO2020201319A1 - 3d printing compositions for modified-release pharmaceutical applications

Info

Publication number: WO2020201319A1
Application number: PCT/EP2020/059198
Authority: WO
Inventors: Jonathan Eleuthère Maurice GOOLE; Giuseppe Jonathan Anthony MANINI; Christoph Jonathan NOBER
Original assignee: Universite Libre de Bruxelles ULB
Current assignee: Universite Libre de Bruxelles ULB
Priority date: 2019-04-01
Filing date: 2020-04-01
Publication date: 2020-10-08
Anticipated expiration: 2021-10-01

Abstract

The present invention relates to the field of 3D printing objects for modified-release pharmaceutical applications. In particular, the present invention concerns 3D printing compositions and methods of preparing them. Further, the present invention concerns 3D printed capsules and methods for producing them. Further, the present invention concerns the use of 3D printed capsules comprising at least one active pharmaceutical ingredient as medicament.

Description

3D PRINTING COMPOSITIONS FOR MODIFIED-RELEASE PHARMACEUTICAL APPLICATIONS

FIELD OF THE INVENTION

BACKGROUND TO THE INVENTION

A large number of orally administered active pharmaceutical ingredients (API) or compounds can only achieve maximal pharmacological effect or limit unwanted side effects when they are released from the pharmaceutical composition in the intestine. In particular, many API, such as antibiotics or proton pump inhibitors, are susceptible to degradation prior to reaching the enteric region where they can be absorbed in the systemic circulation. Other oral-delivered drugs may provoke irritation of the gastric mucosa and should therefore be shielded from the gastric environments until their release in the intestine (e.g. non-steroidal anti-inflammatory drugs). In addition, some API need to specifically target a section of the intestine, such as chemotherapeutic agents for (colon) cancer treatment or for the treatment of intestinal bowl diseases such as ulcerative colitis or Crohn's disease (e.g. anti-inflammatory drugs; oral corticosteroids).

The use of delayed-release coating materials such as enteric coating has been proposed to target intestinal release of oral-delivered drugs. Enteric coating must be able to resist to acidic pH (e.g. gastric conditions), but it should dissolve towards intestinal fluids. Flowever, the process of enteric coating of magistral preparations realised in community pharmacies or hospitals is an erratic and time-consuming process. Moreover, the most commonly used enteric coating polymer is cellulose acetate phthalate (CAP), which is dissolved in an organic solvent to be used as a coating solution by dipping standard capsules. Flowever, the use of organic solvents is anything but free of risk as they are easily flammable, toxic, harmful to the environment and residual traces can remain in the final product. Moreover, the efficacy of this coating method is considered to be erratic and may lead to potential therapeutic failure.

In recent years, three-dimensional (3D) printing technology has gained much interest in the healthcare industry, especially for the production of oral dosage forms and drug delivery systems. 3D printing also referred to as solid freeform fabrication (SFF) process, is a manufacturing technique for creating a 3D object layer-by-layer following a software-generated digital model. 3D printing has major advantages over traditional rapid prototyping processes, as the materials used are typically less expensive and easily adjustable. Moreover, it is very useful for creating medicine that is tailored to patient-specific needs.

Fused Deposition Modelling (FDM) is currently regarded as the most low cost and easily accessible 3D printing technology. In a typical FDM process, a molten thermoplastic polymer filament is carried on by two rollers, molten in a high temperature heating block, extruded through a nozzle and finally deposited onto a build plate where the molten matter solidifies quickly. The printing head can move within the x- and y-axes whereas the platform, which can be thermostatically controlled, can move vertically on the z-axis, creating 3D structures layer-by-layer by fusing the layers together.

Flot-Melt Extrusion (FIME) technology can be used to produce the filaments that are required for printing using FDM 3D printers. Drug loaded filaments which are suitable for 3D printing have been produced using HME. In the HME process, active pharmaceutical ingredients (APIs) are blended with a thermoplastic polymer and then extruded as filaments. This technique was shown to have been used for manufacturing 3D printed tablets containing API in their matrix. However, these types of tablets still needed to be coated with a layer of enteric polymer to achieve delayed- release properties. Moreover, the techniques commonly used to administer coated capsules to small animals (e.g. rodents) tend to break the coating layer, which will then result in an early release of the drug within the animal. As such, it is very difficult to adapt properties of coated tablets during pre-clinical studies.

Accordingly, it is an aim of the invention to overcome the problems of the art. In particular, there is a need for a composition allowing 3D printing of objects suitable for delayed-release pharmaceutical applications. There is also a need for a method for improving the same.

Summary of the Invention

The present application generally relates in a first aspect to a 3D printing composition comprising:

(a) at least one thermoplastic polymer,

(b) at least one modified-release polymer,

(c) at least one plasticizer; and,

wherein the modified-release polymer is either an enteric polymer having a pH-dependent dissolution threshold of at least pH 5.0, preferably at least pH 5.3, more preferably at least pH 5.5, even more preferably at least pH 5.6, or is a sustained-release polymer. In some embodiments the at least one thermoplastic polymer is selected from polylactic acid (PLA), hypromellose acetate succinate (HPMCAS), poly(lactic-co-glycolic acid) (PLGA), Acrylonitrile butadiene styrene (ABS), polyethylenimine (PEI), polycaprolactone (PCL), and/or their derivatives, and/or mixture thereof.

In some preferred embodiments the at least one thermoplastic polymer is polylactic acid (PLA) or polyvinyl alcohol (PVA), or is a thermoplastic polymer mixture comprising PLA and/or PVA.

In some more preferred embodiments the at least one thermoplastic polymer is polylactic acid (PLA) or is a thermoplastic polymer mixture comprising PLA. In some embodiments wherein the modified-release polymer is a delayed-release preferably enteric polymer, the enteric polymer has a pH-dependent dissolution threshold of at least pH 5.1, preferably at least pH 5.2, more preferably at least pH 5.3, even more preferably at least pH 5.4, even more preferably at least pH 5.5, even more preferably at least pH 5.6, even more preferably at least pH 5.7, even more preferably at least pH 5.8, even more preferably at least pH 5.9, even more preferably at least pH 6.0.

In some embodiments the modified-release polymer is present in an amount of at least 60 wt.% of the total weight of composition (w/w), preferably 65 wt.%, more preferably 70 wt.%. In a particular embodiment the enteric polymer is present in an amount of at least 60 wt.% of the total weight of composition (w/w), preferably 65 wt.%, more preferably 70 wt.%. In another particular embodiment the sustained-release polymer is present in an amount of at least 60 wt.% of the total weight of composition (w/w), preferably 65 wt.%, more preferably 70 wt.%.

In some embodiments the enteric polymer is a poly(meth)acrylate derivative, preferably poly(methacylic acid-co-ethyl acrylate) 1:1, poly(methacylic acid-co-methyl methacrylate) 1:1, poly(butyl methacylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, and/or mixtures thereof. In some embodiments the enteric polymer is a cellulose derivative such as hypromellose acetophtalate and hypromellose acetate succinate (HPMCAS), polyvinyl acetate phthalate, shellac derivatives, and/or mixtures thereof. More preferably the enteric polymer is poly(methacylic acid-co-ethyl acrylate).

In some embodiments, the sustained-release polymer is a (semi)permeable polymer allowing the diffusion of water and dissolved API. Preferably, the sustained -release polymer is poorly soluble to insoluble in water.

In some embodiments the sustained-release polymer is a poorly water soluble polymer, preferably poly(meth)acrylate derivatives such as poly(ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.1 or 1:2:0.2, and/or mixtures thereof. In some embodiments the sustained-release polymer is a water insoluble polymer, preferably poly(ethyl acrylate-co-methyl methacrylate) 2:1, or polymethacrylate ester derivatives or insoluble cellulose derivatives such as ethylcellulose, and/or mixtures thereof.

In some embodiments the thermoplastic polymer is present in an amount of at least 5.0 wt.% of the total weight of composition (w/w). Preferably, PLA is present in an amount of at least 5.0 wt.% of the total weight of composition (w/w).

In some embodiments the plasticizer is present in an amount of at least 5.0 wt.% of the total weight of composition (w/w), preferably 18.0 wt.%. Preferably polyethylene glycol 400 (PEG400) and/or triethyl citrate (TEC) is present in an amount of at least 5.0 wt.% of the total weight of composition (w/w), preferably 18.0 wt.%.

According to a further aspect, the present application relates to the use of the composition as disclosed herein for 3D printing, preferably for 3D printing a modified-release capsule.

In some embodiments the use is for 3D printing a delayed-release preferably enteric capsule or for 3D printing a sustained-release capsule.

According to a further aspect, the present application relates to a 3D printed modified-release capsule made from the composition as disclosed herein.

In some embodiments the 3D printed modified-release capsule is a delayed-release preferably enteric capsule, or is a sustained-release capsule.

In some embodiments wherein the capsule is a delayed-release preferably enteric capsule, the capsule has a pH-dependent dissolution threshold of at least pH 5.5, preferably at least pH 6.0, more preferably at least pH 6.5, more preferably about pH 6.8.

In some embodiments wherein the capsule is a modified-release preferably enteric capsule, the capsule has a dissolution time (as oral dosage form) of at least 2 hours to at most 8 hours, preferably at least 4 hours to at most 8 hours.

In some embodiments wherein the capsule is a sustained-release capsule, the capsule is (semi)permeable allowing the diffusion of water and dissolved API. Preferably, the sustained- release capsule is poorly soluble to insoluble in water.

In some embodiments the modified-release capsule comprises a capsule body and a capsule cap connected by means of a sealing system.

In some embodiments the modified-release capsule comprises at least one active pharmaceutical ingredient (API) contained within the capsule.

According to a further aspect, the present application relates to the 3D printed modified-release capsule as disclosed herein comprising at least one API for use as a medicament.

In some embodiments the present application relates to the 3D printed delayed-release preferably enteric capsule as disclosed herein comprising at least API for use as a medicament. In some embodiments the present application relates to the 3D printed sustained-release capsule as disclosed herein comprising at least one API for use as a medicament.

According to a further aspect, the present application relates to a method for producing a 3D printed modified-release capsule, comprising at least the steps of:

(i) providing a composition as disclosed herein; and,

(ii) 3D printing a modified-release capsule from said composition.

In some embodiments the step of 3D printing is for 3D printing a delayed-release preferably enteric capsule or for 3D printing a sustained-release capsule.

In some embodiments the 3D printing is fused-deposition modelling (FDM) 3D printing, the method comprising the steps of:

(ii.a) producing printable filament from said composition, preferably by means of hot melt extrusion (HME); and,

(ii.b) FDM 3D printing a modified-release capsule with the printable filament.

In some embodiments the step of FDM 3D printing is for FDM 3D printing a delayed-release preferably enteric capsule or for FDM 3D printing a sustained-release capsule.

In some embodiments the (FDM) 3D printing comprises the steps of: (FDM) 3D printing a capsule body, (FDM) 3D printing a capsule cap, and connecting the capsule body and the capsule cap to form a modified-release capsule, preferably connecting and/or sealing by means of a sealing system.

In some embodiments the method comprises the step of filling the modified-release capsule with at least one API, preferably by means of a filling device. Preferably the filling of API is performed after 3D printing of the modified-release capsule.

In some embodiments wherein the modified-release capsule comprises a capsule body and a capsule cap, the connecting of the capsule body and the capsule cap is performed after the filling of API.

Brief description of the figures

The following description of the figures of specific embodiments as described herein is only given by way of example and is not intended to limit the present explanation, its application or use. In the drawings, identical reference numerals refer to the same or similar parts and features.

FIG.l illustrates three hollow 3D printed capsules of various dimensions (A)-(C).

FIG.2 illustrates four exemplary sealing systems suitable for use in the present invention 2A-2D. FIG.3 presents the results of a dissolution test to verify the influence of the capsule's layer height 100 pm (■), 200 pm (·), 300 pm ( A ) on the release profile of model-API, compared to the reference (D).

FIG.4 presents the results of a dissolution profile of a model-API from 3D printed enteric capsules (A) (■), (B) (·), (C) ( A ) characterized by a layer height of 200 pm.

Detailed description of the invention

Before the present systems and processes of the invention are described, it is to be understood that this is not limited to particular systems and methods or combinations described, since such systems and methods and combinations may, of course, vary. It is also to be understood that the terminology used herein is not intended to be limiting, since the scope will be limited only by the appended claims.

As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. It will be appreciated that the terms "comprising", "comprises" and "comprised of" as used herein comprise the terms "consisting of", "consists" and "consists of".

The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

The term "about" or "approximately" as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of +/-10% or less, particularly +/-S% or less, more in particular +/-!% or less, and still more in particular +/-0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed aspects and embodiments. It is to be understood that the value to which the modifier "about" or "approximately" refers is itself also specifically, and particularly, disclosed.

Whereas the terms "one or more" or "at least one", such as one or more or at least one member(s) of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of the members, or to any two or more of the members, such as, e.g., any >3, >4, >5, >6 or >7 etc. of the members, and up to all the members. All references cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings of all references herein specifically referred to are incorporated by reference.

Unless otherwise defined, all terms used herein, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art. By means of further guidance, term definitions are included to better appreciate the teaching as described herein.

In the following passages, different aspects are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred, particular or advantageous may be combined with any other feature or features indicated as being preferred, particular or advantageous.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment as described herein. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those skilled in the art. For example, in the claims and/or numbered statements specified herein, any of the specified embodiments can be used in any combination.

In the present description, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration only of specific embodiments in which the invention may be practiced. Parenthesized or emboldened reference numerals affixed to respective elements merely exemplify the elements by way of example, with which it is not intended to limit the respective elements. It is to be understood that other embodiments may be utilised and structural or logical changes may be made without departing from the scope of the present invention. The following detailed description, therefore, is not to be taken in a limiting sense, and the scope of the present invention is defined by the appended claims.

The present invention generally relates to 3D printed objects suitable for use in modified-release pharmaceutical applications. In particular, the objects are 3D printed capsules which can be loaded or filled with one or more pharmaceutically active compounds. The 3D printed capsule may then ensure that the one or more pharmaceutically active compounds are released in the desired target location, such as the intestine. The present invention also provides for compositions which may be used for producing the 3D printed capsules; in particular the composition may be used to produce 3D printing materials such as filaments which may then be used for producing the 3D printed capsules. The present invention also provides for 3D printing methods for producing the 3D printed capsules. The present invention also provides for a use of the 3D printed capsule in pharmaceutical applications as medicament.

Taking into consideration the problems involved in the conventional production methods (e.g. coating of a pharmaceutical composition) the present invention thus provides an alternative and/or improvement for achieving delayed release of orally administered pharmaceutically active compounds. The invention is suitable for use in combination with any pharmaceutically active compounds requiring modified-release when orally administered, preferably enteric (intestinal or colon) release. The 3D-printed capsules described herein could be particularly efficient for use in smaller-scale production such as community pharmacies, hospitals or research facilities. The present methods may allow for easier adaptation of the volume of the capsules (e.g. dedicated to young patients; pre-clinical studies on small animals) and the subsequent dose of the drug.

The present inventors have been able to print 3D hollow enteric standard-shape capsules capable of meeting the European Pharmacopoeia 9^th Edition requirements for enteric-release oral dosage forms. The expected dissolution time in the case of sustained release was evaluated in accordance with the pharmacopeia recommendation for sustained release oral dosage forms using dissolution assays in HCI 0,1M. In particular, using sodium riboflavin-5'-phosphate (RF5'PNa) as a model drug, no release into acidic medium at pH 1.2 for 2 hours and at least 80% of dissolution within 45 minutes in phosphate buffer pH 6.8 could be observed from 3D-printed enteric capsules. Further details thereof are provided in Example 3.

The active pharmaceutical ingredient (API) as used herein refers to a substance or compound in a pharmaceutical formulation that is biologically active and is meant to produce a desired therapeutic effect in the body. Other terms such as active compound, active substance, or active constituent and active ingredient indicate a similar meaning and purpose and may therefore be used interchangeably herein. The APIs may be categorized into different classes according to various classification systems which differentiate APIs based on their intended purpose, mechanism of action and/or physical parameters such as solubility. The present application is by no means limited to a particular API type of class. However, in view of the intended effect of providing modified-release pharmaceutical applications targeting a specific region (such as the enteric region), the API will preferably be an API that benefits from such a modified release (such as in the enteric region). Modified-release pharmaceutical application as used herein refers to a form of solid dosage wherein release of the API within the gastrointestinal tract is modified; it is a non-immediate- release form. Release of the API may be delayed to reach a specific timing and/or target; this may also be referred to as a delayed-release application. Release of the API may also be extended over a prolonged period of time to prolong and/or maintain a specific concentration of available API; this may also be referred to as a sustained-release application. Additionally, the modified-release may be a combination of delayed, timed, targeted, prolonged, extended and/or sustained release. The modified-release polymer as used herein then refers to a polymer enabling an orally administered API in solid dosage form to unfold its full therapeutic potential (i.e. achieving maximal pharmacological effect and/or reducing possible side effects) by modifying release of the API within the gastrointestinal tract. Combination of at least one modified-release polymer and at least one API may thus be regarded as a modified-release pharmaceutical application. In view of the foreseen pharmaceutical application the modified-release polymer should also be non-toxic for the target.

The delayed-release polymer as used herein refers to a polymer enabling an orally administered API in solid dosage form to unfold its full therapeutic potential by delaying release of the API within the digestive system. The enteric polymer as used herein refers to a delayed-release polymer enabling an orally administered API in solid dosage form to unfold its full therapeutic potential by targeting release of the API in the enteric region (usually the upper tract of the intestine) after passing through the gastric region. Typically, release of the API will be delayed by preventing dissolution or disintegration of the API in the gastric environment. The enteric polymer may protect the API from the acidity of the stomach or it may protect the stomach from the detrimental effects of the API. The enteric polymer should resist the acidic pH (i.e. below pH 4.5), but should dissolve towards intestinal fluids (i.e. above pH 4.5, but below pH 7.0); the enteric polymer is a pH-dependently soluble polymer.

Exemplary API which may be used in combination with a delayed-release preferably enteric polymer in the present invention may include (1) (gastric) acid-liable compounds which include antibiotics such as erythromycin, or proton pump inhibitors (PPI) such as omeprazole, lansoprazole, tenatoprazole, esomeprazole, rabeprazole, pantoprazole; (2) compounds that may provoke irritation of the gastric mucosa, which include non-steroidal inflammatory pharmaceutically active compounds (e.g. diclofenac, aceclofenac, ibuprofen, ketoprofen, oxaprozine, indomethacin, meloxicam, piroxicam, tenoxicam, celecoxib, etoricoxib, nabumetone, naproxen or aspirin); (3) compounds that need to target a specific section of the gastrointestinal tract, which include chemotherapeutic agents for (colon) cancer treatment (e.g. fluorinated pyrimidines such as hexycarbamoyl-5-fuorouracil (carmofur), uracil/tegafur, uracil/tegafur/leucovorin, capecitabine etc.) or agents for the treatment of intestinal bowl diseases such as ulcerative colitis or Crohn's disease such as anti-inflammatory drugs (e.g. mesalazine, sulfasalazine), or oral corticosteroids (e.g. budesonide, beclometasone); (4) compounds that have an improved or prolonged therapeutic efficacy by using a modified-release pharmaceutical application, such as antibiotics (e.g. amoxicilline, cefadroxil, cefazoline, cefuroxime, cefotaxime, meropenem, aztreonam, eruthromycin, azithromycin, clarithromycin, roxithromycin, spiramycine, doxycycline, minocycline, clindamycin, lincomycin, ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, sulfamethazole & trimethroprim, isoniazide, rifampicine, ethambutol, gentamicine), antihypertensive (e.g. nifedipine, amlodipine, barnidipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nimodipine, nisoldipine, nitrendipine, verapamil, diltiazem), antiarrhythmic (e.g. flecainide, amiodarone, cibenzoline, disopyramide, sotalol), beta-blocker (e.g. metoprolol, atenolol, bisoprolol, carvedilol, celiprolol, esmolol, labetalol, nebivolol, propranolol), diuretics (e.g. furosemide, torasemide, spironolactone), anti inflammatory drugs (e.g. ibuprofen, diclofenac), analgesics (e.g. tramadol, oxycodone, morphine) and/or vitamins (e.g. riboflavin-5'-phosphate). It is understood that the provided list is to be regarded as non-exhaustive; any API benefitting from delayed- release and especially enteric release is to be regarded as suitable for the present invention.

The sustained-release polymer as used herein refers to a polymer enabling an orally administered API in solid dosage form to unfold its full therapeutic potential by controlling the rate of release of the API within the gastrointestinal tract. Typically the sustained release will maintain the concentration of API at a (near) constant level for a specific period of time. Typically, release of the API will be extended by preventing dissolution or disintegration of the API within the gastrointestinal tract.

Exemplary APIs which may be used in the present invention in combination with a sustained- release polymer may include antibiotics (e.g. amoxicilline, cefadroxil, cefazoline, cefuroxime, cefotaxime, meropenem, aztreonam, eruthromycin, azithromycin, clarithromycin, roxithromycin, spiramycine, doxycycline, minocycline, clindamycin, lincomycin, ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, sulfamethazole and trimethroprim, isoniazide, rifampicine, ethambutol, gentamicine), antihypertensive (e.g. nifedipine, amlodipine, barnidipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nimodipine, nisoldipine, nitrendipine, verapamil, diltiazem), antiarrhythmic (e.g. flecainide, amiodarone, cibenzoline, disopyramide, sotalol), beta- blockers (e.g. metoprolol, atenolol, bisoprolol, carvedilol, celiprolol, esmolol, labetalol, nebivolol, propranolol), diuretics (e.g. furosemide, torasemide, spironolactone), anti-inflammatory drugs (e.g. ibuprofen, diclofenac) and/or analgesics (e.g. tramadol, oxycodone, morphine). It is understood that the provided list is to be regarded as non-exhaustive; any API benefiting from sustained-release in the gastrointestinal tract is to be regarded as suitable for the present invention.

3D printing as used herein may refer to any printing technology in which material is joined or solidified under computer control to create a 3D object or structure, usually by successively adding material layer by layer. A particularly suitable example of 3D printing technology for use with the present invention is fused deposit modelling (FDM) which is described further below. However, other 3D printing methods and devices are available on the market or are in development. As such, it is understood that the skilled person will be capable of adjusting the herein described invention to be compatible with any 3D printing technology by means of general routine work normal in the field of 3D printing technology.

(a) at least one thermoplastic polymer,

(b) at least one plasticizer;

(c) at least one modified-release polymer, wherein the modified-release polymer is either an enteric polymer having a pH-dependent dissolution threshold of at least pH 5.0, preferably at least pH 5.3, more preferably at least pH 5.5, even more preferably at least pH 5.6, or is a sustained-release polymer.

The 3D printing composition is a composition suitable for 3D printing a modified-release capsule. The composition comprises at least one thermoplastic polymer, at least one plasticizer and at least one modified-release polymer. Since the composition relates to a capsule, the composition preferably does not comprise and/or contain the primary API; it contains less than 1.0% of weight of the primary API, preferably less than 0.10%, more preferably less than 0.010%. The primary API is understood to refer to a pharmaceutically active compound to which the intended therapeutic effect of the orally administered solid dosage form is attributed. Typically the primary API will be the API requiring modified-release. The composition may comprise one or more secondary APIs. The secondary API is understood to refer to a pharmaceutically active compound which may produce one or more therapeutic side-effects which are not the primary intended therapeutic effect of the orally administered solid dosage. For instance, they may benefit the target, promote the effect or intake of the primary API, or have any other effect. Typically the secondary API will be the API not requiring modified-release.

Preferably the 3D printing composition comprises:

(a) at least one thermoplastic polymer, (b) at least one plasticizer;

(c) at least one enteric polymer, wherein the modified-release polymer is either an enteric polymer having a pH-dependent dissolution threshold of at least pH 5.0, preferably at least pH 5.3, more preferably at least pH 5.5, even more preferably at least pH 5.6, or is a sustained- release polymer.

Preferably the 3D printing composition comprises:

(a) at least one thermoplastic polymer,

(b) at least one plasticizer;

(c) at least one sustained-release polymer, wherein the modified-release polymer is either an enteric polymer having a pH-dependent dissolution threshold of at least pH 5.0, preferably at least pH 5.3, more preferably at least pH 5.5, even more preferably at least pH 5.6, or is a sustained-release polymer.

The thermoplastic polymer is a biodegradable and/or bioactive printable polymer having temperature-specific mechanical properties, preferably being solid at room temperature and becoming viscous liquid at increased temperature. There may be more than one thermoplastic polymer comprised in the composition, such as two, three, four or more thermoplastic polymers. The thermoplastic polymer may be polylactic acid (PLA), Hypromellose Acetate Succinate (HPMCAS), poly(lactic-co-glycolic acid) (PLGA), Acrylonitrile butadiene styrene (ABS), Polyethylenimine (PEI), Polycaprolactone (PCL), and/or their derivatives, and/or mixture thereof; preferably is PLA or a polymer mixture comprising PLA.

PLA is a biodegradable high-performance thermoplastic suitable for use in medical 3D printing technologies. It has been found that the combination of PLA with at least one modified-release polymer provides for a very stable and durable 3D printing composition. PLA may also be mixed with other thermoplastic polymers in any concentration and/or proportion, preferably with one or more thermoplastic polymers as listed above.

PLA may be present in an amount of at least 50.0 wt.% (weight) to at most 100.0 wt.% of the total amount of thermoplastic polymers present in the composition (w/w), preferably 75.0 to 100.0 wt.%, more preferably 90.0 to 100.0 wt.%. A higher or exclusive amount of PLA vis-a-vis the total thermoplastic polymer amount was observed to provide for a particularly stable and durable 3D printing composition. Moreover, typically the other thermoplastic polymer may be less degradable than PLA.

PLA may be present in an amount of at least 5.0 wt.% (weight) of the total weight of composition (w/w). Preferably PLA is present in an amount of at least 5.0 to at most 15.0 wt.% of the total weight of composition (w/w), more preferably 6.0 to 14.0 wt.%, even more preferably 7.0 to 13.0 wt.%, even more preferably 8.0 to 12.0 wt.%, even more preferably 9.0 to 11.0 wt.%, even more preferably about 10.0 wt.%. The PLA percentage may also be increased above 15.0 wt.%, but doing so may slow down the diffusion of water and in turn the dissolution rate of the polymer in the intestine. Accordingly, higher PLA wt.% may then require the addition of other compounds which promote the dissolution rate.

The at least one other thermoplastic polymer(s) may be present in an amount of at least 5.0 wt.% (weight) of the total weight of composition (w/w). Preferably the thermoplastic polymer(s) is present in an amount of at least 5.0 to at most 15.0 wt.% of the total weight of composition (w/w), more preferably 6.0 to 14.0 wt.%, even more preferably 7.0 to 13.0 wt.%, even more preferably 8.0 to 12.0 wt.%, even more preferably 9.0 to 11.0 wt.%, even more preferably about 10.0 wt.%.

In a particular embodiment wherein the modified-release polymer is an enteric polymer, the at least one thermoplastic polymer may be selected from polylactic acid (PLA), polyvinyl alcohol (PVA), Hypromellose Acetate Succinate (HPMCAS), poly(lactic-co-glycolic acid) (PLGA), Acrylonitrile butadiene styrene (ABS), Polyethylenimine (PEI), Polycaprolactone (PCL), and/or their derivatives, and/or mixture thereof; preferably is PLA or PVA, or is a polymer mixture comprising PLA and/or PVA; most preferably is PLA or is a polymer mixture comprising PLA.

In a particular embodiment wherein the modified-release polymer is a sustained-release polymer, the at least one thermoplastic polymer may be selected from polylactic acid (PLA), polyvinyl alcohol (PVA), Hypromellose Acetate Succinate (HPMCAS), poly(lactic-co-glycolic acid) (PLGA), Acrylonitrile butadiene styrene (ABS), Polyethylenimine (PEI), Polycaprolactone (PCL), and/or their derivatives, and/or mixture thereof; preferably is PLA or PVA, or is a polymer mixture comprising PLA and/or PVA; most preferably is PLA or is a polymer mixture comprising PLA.

The plasticizer also referred to as dispersant is an additive that can increase the plasticity or decrease the viscosity of the composition. There may be more than one plasticizer comprised in the composition, such as two, three, four or more plasticizers.

The at least one plasticizer may be present in an amount of at least 5.0 wt.% of the total weight of composition (w/w), preferably at least 7.5 wt.%, more preferably at least 10.0 wt.%, even more preferably at least 12.5 wt.%, even more preferably at least 15.0 wt.%, even more preferably at least 17.5 wt.%. When the plasticizer amount is below 5.0 wt.% the polymer may become too brittle, which may require the addition of other additives. Preferably the at least one plasticizer is present in an amount of at most 25.0 wt.% of the total weight of composition (w/w), preferably at most 22.5 wt.%, more preferably at most 20.0 wt.%, even more preferably at most 18.0 wt.%. When the plasticizer amount is above 25 wt.% the polymer may become too soft, which may require the addition of other additives. Preferably the at least one plasticizer is present in an amount of at least 5.0 to at most 25.0 wt.% of the total weight of composition (w/w), preferably

7.5 to 22.5 wt.%, more preferably 10.0 to 20.0 wt.%, even more preferably about 12.5 wt.% to 20 wt.%, even more preferably about 15.0 wt.% to 20.0 wt.%, even more preferably about 16.0 wt.% to 19.0 wt.%, for example 17.0 wt.%, for example 17.5 wt.%, for example 18.0 wt.%, for example

18.5 wt.%.

The plasticizer may be selected from polyethylene glycol (PEG), triethyl citrate (TEC), ethanol, isopropanol, cetyl alcohol and stearyl alcohol, sorbitol, glycerine, beeswax, triethyl citrate, polyethylene glycol, propylene glycol, triacetin, dibutyl sebacate, glycerin monostearate, 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, polyethylene glycol polymethacrylate compatible, propylene glycol, pyrrolidone, stearic acid, triethanolamine, and/or mixtures thereof. Preferably the plasticizer is polyethylene glycol 400 (PEG400) and/or triethyl citrate (TEC).

The modified-release polymer may be a delayed-release polymer, preferably an enteric-release polymer. The enteric-release polymer or simply enteric polymer is a pH-dependently soluble polymer with a pH-dependent dissolution threshold. The pH-dependent dissolution threshold refers to a value or a range of values wherein the solubility of the pH-dependently soluble polymer changes from insoluble to soluble, or vice versa. The polymer will also be regarded as insoluble when it is (very) poorly soluble; as used herein insoluble will refer to a solubility of less than 0.1 g of polymer per 100 mL of solvent. The polymer will also regarded as soluble when it is sparingly or freely soluble; as used herein soluble will refer to a solubility of at least 0.1 g of polymer per 100 mL of solvent. The reference solvent will typically refer to (secreted) fluids which may be contacted as a result of oral administration; these may include saliva gastric fluid, enteric fluid, and others. Accordingly, the enteric polymer will be insoluble below pH 5.0 such as pH 4.5 or pH 4.0, but will become soluble at and above pH 5.0, such as pH 5.1 or 5.5.

A pH threshold below pH 5.0 may result in a partial release of API before reaching the desired enteric region, such as the gastric region; therefore the enteric polymer has a pH-dependent dissolution threshold of at least pH 5.0. Preferably the enteric polymer has a pH-dependent dissolution threshold of at least pH 5.1, more preferably at least pH 5.2, even more preferably at least pH 5.3, even more preferably at least pH 5.4, even more preferably at least pH 5.5; for example pH 5.6, for example pH 5.7, for example pH 5.8, for example pH 5.9, for example pH 6.0. Preferably the enteric polymer has a pH-dependent dissolution threshold of at most pH 7.0, more preferably at most pH 6.5, even more preferably at most pH 6.4, even more preferably at most pH 6.3, even more preferably at most pH 6.2, even more preferably at most pH 6.1; for example pH 6.0. A pH threshold above pH 7.0 may result in a release of API in the colonic region. Preferably the enteric polymer has a pH-dependent dissolution threshold of at least pH 5.0 to at most pH 7.0, more preferably from pH 5.0 to pH 7.0, even more preferably from pH 5.5 to pH 6.5, even more preferably from pH 5.5 to pH 6.0; even more preferably pH 5.6 to pH 5.9, for example pH 5.6 to pH 5.8, for example pH 5.7 to pH 5.9, for example pH 5.6 to pH 5.7.

The enteric polymer may be present in an amount of at least 60.0 wt.% of the total weight of composition (w/w), preferably 65.0 wt.%, more preferably 70.0 wt.%. More in particular, the enteric polymer is present in an amount of at least 60.0 to at most 80.0 wt.% of the total weight of composition (w/w), preferably 65.0 to 75.0 wt.%, more preferably about 70.0 wt.%, for example 72.0 wt.%.

The enteric polymer may be selected from poly(meth)acrylate derivatives such as poly(methacylic acid-co-ethyl acrylate) 1:1 (commercially available as EUDRAGIT L100-55), poly(methacylic acid- co-methyl methacrylate) 1:1 (commercially available as EUDRAGIT L100), poly(butyl methacylate- co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1 (commercially available as EUDRAGIT L12.5), cellulose derivatives such as hypromellose acetophtalate and hypromellose acetate succinate (HPMCAS), polyvinyl acetate phthalate, shellac derivatives, and/or mixtures thereof. Preferably the enteric polymer is poly(methacylic acid-co-ethyl acrylate) (commercially available as EUDRAGIT L100-55).

Poly(methacylic acid-co-ethyl acrylate) may be present in an amount of at least 60.0 wt.% of the total weight of composition (w/w), preferably 65.0 wt.%, more preferably 70.0 wt.%. More in particular, the enteric polymer is present in an amount of at least 60.0 to at most 80.0 wt.% of the total weight of composition (w/w), preferably 65.0 to 75.0 wt.%, more preferably about 70.0 wt.%, for example 72.0 wt.%.

The modified-release polymer may be a sustained-release polymer. The sustained-release polymer is a (semi)permeable polymer which allows the diffusion of water (inwards) and dissolved API (outwards), but is itself typically poorly soluble to insoluble in water; as used herein insoluble will refer to a solubility of less than 0.1 g of polymer per 100 mL of solvent. The reduced polymer solubility may delay or prevent its dissolution in the gastrointestinal tract, allowing for a longer and greater control over the sustained-release properties. The sustained-release polymer does not have a pH-dependent dissolution threshold; the solubility is pH-independent.

The sustained-release polymer may be selected from poorly water soluble poly(meth)acrylate derivatives such as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (commercially available as Eudragit RS) or 1:2:0.2 (commercially available as Eudragit RL). The sustained-release polymer may also be selected from water insoluble poly(ethyl acrylate-co-methyl methacrylate) 2:1 (commercially available as Eudragit NE 30D), or polymethacrylate ester derivatives or insoluble cellulose derivatives such as ethylcellulose. The sustained-release polymer may also be a mixture of poorly water soluble and insoluble polymers.

The 3D printing composition as disclosed may further comprise various additives such as lubricants, stabilizers, hydrophobic excipients and/or other additives. The lubricants refer to additives that reduce friction. The lubricants may be chosen from talc, magnesium stearate or mixtures thereof. The stabilizers refer to additives that help formulators maintain the desirable properties of the product until oral administration. The stabilizers are preferably tension-active agents. The hydrophobic excipients refer to a hydrophobic substances formulated alongside the active ingredient. The hydrophobic excipients may be lipids.

The present application generally relates in a further aspect to a use of a composition for 3D printing, the composition comprising:

(a) at least one thermoplastic polymer, preferably PLA,

(b) at least one plasticizer;

(c) at least one modified-release polymer,

wherein the modified-release polymer is either an enteric polymer having a pH-dependent dissolution threshold of at least pH 5.0, preferably at least pH 5.3, more preferably at least pH

5.5, even more preferably at least pH 5.6, or is a sustained-release polymer.

The same embodiments described above for the composition are foreseen for the use of the composition for 3D printing; the use of the composition for 3D printing is according to one or more embodiments of the composition as described herein. The use is preferably for 3D printing a modified-release capsule; more preferably a modified-release capsule for an orally administered solid dosage form. Accordingly, the composition may be for use as a medicament.

The composition may be adapted to the requirements of the 3D printing technology. In case the 3D printing technology is a 3D printing technology that used printable filaments, the composition is preferably used for producing a 3D printable filament comprising the composition. The 3D printable filament may be for instance produced using hot melt extrusion (HME). In case the 3D printing technology is fused-deposition modelling (FDM) 3D printing, the composition is preferably used for producing an FDM compatible 3D printable filament comprising the composition. The present application generally relates in a further aspect to a 3D printed modified-release capsule made from a composition comprising:

(a) at least one thermoplastic polymer, preferably PLA,

(b) at least one plasticizer;

(c) at least one modified-release polymer,

5.5, even more preferably at least pH 5.6, or is a sustained-release polymer.

The same embodiments described above for the composition are foreseen for the capsule made from the composition; the composition for making the 3D printed modified-release capsule is according to one or more embodiments of the composition as described herein. The capsule may contain or comprise at least one (API) contained within or filled into the capsule; the capsule is therefore suitable for containing or filling an API.

In a particular embodiment wherein the modified-release capsule is made from a composition comprising an enteric polymer, the capsule may be referred to as an enteric-release capsule or simply enteric capsule. The enteric capsule may have a pH-dependent dissolution depending on the concentration, processing and pH-dependent dissolution threshold of modified-release polymer. Preferably the modified-release capsule has a pH-dependent dissolution threshold of at least pH 5.1, more preferably at least pH 5.2, even more preferably at least pH 5.3, even more preferably at least pH 5.4, even more preferably at least pH 5.5, even more preferably at least pH

5.6, even more preferably at least pH 5.7, even more preferably at least pH 5.8, even more preferably at least pH 5.9, even more preferably at least pH 6.0, even more preferably at least pH 6.1, even more preferably at least pH 6.2, even more preferably at least pH 6.3, even more preferably at least pH 6.4, even more preferably at least pH 6.5, even more preferably at least pH

6.6, even more preferably at least pH 6.7, even more preferably at least pH 6.8, even more preferably at least pH 6.9, even more preferably at least pH 7.0. Preferably the modified-release capsule has a pH-dependent dissolution threshold of at least pH 5.0 to at most pH 7.0, more preferably from pH 5.5 to pH 7.0, even more preferably from pH 6.0 to pH 7.0, even more preferably from pH 6.5 to pH 7.0; for example pH 6.6 to pH 6.9, for example pH 6.7 to pH 6.8.

The dissolution time for oral dosage of the 3D printed modified-release capsule comprising at least one modified-release polymer may range from at least 2 hours to at most 8 hours, preferably at least 4 hours to at most 8 hours. For example, 5 hours, 6 hours or 7 hours. The dissolution time was evaluated in accordance with the pharmacopeia recommendation for sustained release oral dosage forms. Further details are provided in Example 3. In a particular embodiment wherein the modified-release capsule is made from a composition comprising a sustained-release polymer, the capsule may be referred to as a sustained-release capsule. The sustained-release capsule will allow the diffusion of water (inwards) and dissolved API (outwards), but will itself be poorly soluble to insoluble in water.

The capsule may be a single-piece capsule. In such a case the capsule may be filled with one or more API during the 3D printing of the capsule, or the 3D printing may be (temporarily) interrupted to allow for filling the capsule with the API; the API will preferably be contained within the capsule during and after 3D printing.

The capsule may be a multi-piece capsule; the capsule may comprise a capsule body and a capsule cap. In such a case the capsule may be filled with one or more API after 3D printing of the capsule and subsequently sealed inside the capsule by connecting the capsule body with the capsule cap; the API will preferably be contained within the capsule after 3D printing. The capsule body and the capsule cap may be connected or connectable by means of a sealing system; the sealing system seals the capsule body and the capsule cap. The sealing is preferably permanent; the sealed capsule is not intended to be unsealed or opened. The sealing system may be one of many sealing systems available in the art. Examples include a screw thread sealing system, an overlapping sealing system, a click-on sealing system, an adhesive sealing system, and so on. It is understood that the skilled person will be capable of adjusting the herein described capsule and methods for producing said capsule to be compatible with any sealing system by means of general routine work normal in the field of 3D printing technology.

The main zone of weakness of capsules, which can create a non-sealing system, is typically the point of contact between the capsule body and the capsule cap. Accordingly, the present disclosure provides for a sealing system which was found to be particularly effective in decreasing permeability (i.e. reducing water diffusion) prior the dissolution of the capsule. Examples of suitable sealing systems may be found illustrated in FIG. 2. It is noted that FIG. 2D presents a particularly preferred embodiment of a sealing system. Preferably the sealing system will be as short as possible. Preferably the walls of the sealing system are limited to a single layer of 3D printing material.

The capsule may have a geometric shape consisting of a cylinder with hemispherical ends (spherocylinder). The capsule may have a total length (i.e. measured from one end to the other opposite end) of at least 21.0 mm to at most 27.0 mm, preferably 22.0 to 26.0 mm, more preferably 22.0 to 2.05 mm; for example 23.0 mm, for example 24.0 mm. The capsule may have a (average) wall thickness (i.e. measured from the inside of the capsule wall to the outside of the wall) of at least 400 miti to at most 700 miti, preferably 425 miti to 675 miti, more preferably 450 pm to 650 pm; for example 475 pm, for example 500 pm, for example 525 pm, for example 550 pm, for example 575 pm, for example 600 pm, for example 625 pm.

In case of a multi-piece capsule comprising a capsule body and a capsule cap, the capsule body to capsule cap ratio may range from 1.60 to 1.75, preferably 1.62 to 1.73 , even more preferably 1.65 to 1.71; for example 1.66, for example 1.67, for example 1.68, for example 1.69, for example 1.70. The capsule body may be defined by a body length of at least 18.0 mm to at most 23.0 mm such as for example 18.4 mm, preferably 18.5 to 22.5 mm such as for example 22.2 mm, more preferably 19.0 to 22.0 mm, even more preferably 19.5 to 21.5 mm, even more preferably 20.0 to 21.0 mm; for example 20.2 mm, for example 20.5 mm, for example 21.2 mm. The capsule body may be defined by a body diameter of at least 7.0 mm to at most 10.0 mm, preferably 7.5 to 9.5 mm, more preferably 8.0 to 9.0 mm; for example 8.2, for example 8.5, for example 9.0, for example 9.5. Further, the capsule cap may be defined by a cap length of at least 10.0 mm to at most 13.0 mm such as for example 12.9 mm, preferably 10.5 to 12.5 mm such as for example 10.7 mm, more preferably 11.0 to 12.0 mm; for example 11.7 mm. The capsule cap may be defined by a cap diameter of at least 7.0 mm to at most 10.0 mm such as for example 9.9 mm, preferably 7.5 to 9.5 mm such as for example 7.6 mm, more preferably 8.0 to 9.0 mm; for example 8.5 mm.

The present application generally relates in a further aspect to the use of a 3D printed enteric capsule for delaying the release of an API contained in the capsule, the capsule being made from a composition comprising:

(a) at least one thermoplastic polymer, preferably PLA,

(b) at least one plasticizer;

(c) at least one modified-release polymer,

5.5, even more preferably at least pH 5.6, or is a sustained-release polymer.

The capsule may be filled with at least one API; the API being contained by the boundaries of the inner capsule walls. The same embodiments described above for the capsule are foreseen for the use of the capsule in modifying the release of an API contained within the capsule; the use of the capsule is according to one or more embodiments of the capsule as described herein. The use is therefore for modifying the release of an orally administered API contained within the modified- release capsule. Accordingly, the 3D printed modified-release capsule may be for use as a medicament. In a particular embodiment wherein the modified-release capsule is made from a composition comprising an enteric polymer, the use is for delaying the release of an orally administered API contained within the modified-release capsule as a solid dosage form; preferably by delaying release of the API until the intestinal tract.

In a particular embodiment wherein the modified-release capsule is made from a composition comprising a sustained-release polymer, the use is for sustaining the release of an orally administered API contained within the sustained-release capsule as a solid dosage form; preferably by controlling the rate of release of the API within the gastrointestinal tract.

The use as medicament may be understood to refer to a method of treatment of a subject in need of an API comprising the steps of administering to a subject a 3D printed modified-release capsule according to one or more embodiments as described herein, said capsule being filled with said API and/or containing said API.

The dissolution time for oral dosage of the 3D printed enteric capsule comprising at least one modified-release polymer may range from at least 2 hours to at most 8 hours, preferably at least 4 hours to at most 8 hours. For example, 5 hours, 6 hours or 7 hours. The dissolution time was evaluated in accordance with the pharmacopeia recommendation for sustained release oral dosage forms. Further details are provided in Example 3.

The present application generally relates in a further aspect to a method for producing a 3D printed modified-release capsule, comprising at least the steps of:

(i) providing a composition comprising:

(a) at least one thermoplastic polymer, preferably PLA,

(b) at least one plasticizer;

(c) at least one modified-release polymer,

wherein the modified-release polymer is either an enteric polymer having a pFI-dependent dissolution threshold of at least pH 5.0, preferably at least pH 5.3, more preferably at least pH 5.5, even more preferably at least pH 5.6, or is a sustained-release polymer,

(ii) 3D printing a modified-release capsule from said composition.

In a particular embodiment wherein the modified-release capsule is 3D printed from a composition comprising an enteric polymer, the enteric capsule may have a pH-dependent dissolution threshold of at least pH 5.0, preferably at least pH 5.3, more preferably at least pH 5.5, even more preferably at least pH 5.6.

In a particular embodiment wherein the modified-release capsule is 3D printed from a composition comprising a sustained-release polymer, the sustained-release capsule may allow the diffusion of water (inwards) and dissolved API (outwards), but will itself be poorly soluble to insoluble in water.

The same embodiments described above for the composition are foreseen for the step of providing the composition in the method for producing the 3D printed modified-release capsule; the composition is according to one or more embodiments of the composition as described herein. Similarly, the same embodiments described above for the capsule are foreseen for the step of 3D printing the capsule in the method for producing 3D printed modified-release capsule; the capsule is according to one or more embodiments of the composition as described herein.

As discussed above, the capsule may be produced as a single-piece or as a multi-piece capsule comprising a capsule body and cap that are connected or are connectable to form the capsule. In case of the latter (multi-piece capsule), the method may comprise the steps of: 3D printing a capsule body, 3D printing a capsule cap, and connecting the capsule body and the capsule cap to form a modified-release capsule. Preferably the connecting is performed by means of a sealing system; the sealing system sealing the capsule body to the capsule cap.

As discussed above, the capsule may contain or be filled with at least one API; the API being contained by the boundaries of the inner capsule walls. Accordingly, the method may comprise the step of: step of filling the modified-release capsule with at least one API. Preferably the step of filling is performed by means of a filling device. Additionally the modified-release capsule may encapsulate the at least one API. Preferably the step of encapsulating is performed by means of an encapsulation device.

After 3D printing of the modified-release capsule, the 3D printed modified-release capsule may be immersed in acetone and/or phosphate buffer. After 3D printing of the modified-release capsule, the 3D printed modified-release capsule may be heat treated, preferably at a temperature of 45°C for 10 sec.

The 3D printing may be performed by means of any 3D printing technology known in the art. It is understood that the skilled person will be capable of adjusting the provided composition to the requirements of the 3D printing technology by means of general routine work normal in the field of 3D printing technology. The 3D printing process may be software controlled.

A particularly suitable example of 3D printing technology for use with the present invention is fused deposit modelling (FDM). FDM is typically regarded as the most low cost and easily accessible 3D printing technology. In FDM 3D printers, thermoplastic filaments are typically used as the starting material. The filaments are melted or softened, and then extruded from a printer head that is able to move in the x- and y-direction. Further, the printer head or the platform is able to move in the z-direction. The 3D object is formed by stacking several layers of filament. Each layer fuses and bonds to the layers below. The layers of melted filament solidify after being extruded from the print head. As one layer cools down and solidifies, another layer of the melted filament will be deposited on top of it until the 3D printing of the object is completed. Accordingly, if the 3D printing is FDM 3D printing, the method may comprise the steps of:

(i) producing 3D printable filament from the composition as described herein; and,

(ii) FDM 3D printing a modified-release capsule from the printable filament from step (i).

The FDM print resolution (i.e. layer height) may be in the range of 50 pm to 300 pm, more preferably 75 pm to 275 pm, even more preferably 75 pm to 250 pm, even more preferably 100 pm to 250 pm, even more preferably 100 pm to 225 pm; even more preferably 100 pm to 200 pm; for example 125 pm, for example 150 pm, for example 175 pm. The FDM printing temperature may be in the range from 160°C to 180°C, preferably 165°C to 175°C, more preferably about 170°C; for example 167°C, for example 172°C. An increase of temperature may cause a slumping down of the build as well as the emersion of air pocket. A decrease of temperature may cause viscoelastic contraction and reduce the adhesion between layers. The most preferred temperature for a layer of 100, 200 and 300 pm was found to be 167°C, 172°C and 175°C, respectively. The preferred temperature also depends on the layer height as an increase of the layer height may entail a higher flow of matter which may require a higher temperature for the printing process. The FDM printing speed may be in the range from 1.0 mm/s to 5.0 mm/s, preferably 2.0 mm/s to 4.0 mm/s, more preferably 2.0 mm/s to 3.0 mm/s; for example 2.5 mm/s. The flow rate of an FDM drying fan may be in the range of 1.0 I/s to 6.0 I/s, preferably 1.5 I/s to 5.5 I/s, more preferably 2.0 I/s to 5.0 I/s, even more preferably 2.5 I/s to 4.5 I/s, even more preferably 3.0 to 4.0 I/s, even more preferably about 3.5 I/s; for example 3.4 I/s, for example 3.5 I/s.

Flot-Melt Extrusion (FIM E) technology can be used to produce the filaments required for 3D printing using an FDM 3D printer. HM E is a continuous process where heat and pressure are applied to melt or soften materials through an orifice to produce thermoplastic filaments of uniform shape and density. The extruder may contain heaters that provide heat for the melting or softening of the materials. The screws in the extruder can provide shear stress and intense mixing of the materials. The friction created by the screws in the barrel and the heat provided cause the polymeric material to melt. The screw then conveys the melted material down the barrel for extrusion. Accordingly, if the 3D printing is FDM 3D printing, the method may comprise the steps of producing 3D printable filament from said composition filament by means of HM E; in particular when referring to step (i). The HM E printable filament may have a diameter of at least 1.5 mm to at most 3.1 mm, preferably 1.6 mm to 3.0 mm, more preferably 1.7 to 2.9 mm. In a particular embodiment, the HME printable filament may have a diameter of 1.50 mm to 1.90 mm, preferably 1.60 mm to at most 1.80 mm, more preferably 1.65 to 1.75 mm, even more preferably about 1.70 mm. In a particular embodiment, the HME printable filament may have a diameter of at least 2.65 mm to at most 3.05 mm, preferably 2.75 mm to at most 2.95 mm, more preferably 2.80 mm to at most 2.90 mm, even more preferably about 2.85 mm. The HME extruding temperature may be in the range from at least 140°C to at most 190°C, preferably 140°C to at most 180°C, more preferably 140°C to at most 170°C, even more preferably 140°C to at most 160°C, even more preferably 142°C to at most 158°C, even more preferably 144°C to at most 156°C, even more preferably 146°C to at most 154°C, even more preferably 148°C to at most 152°C, even more preferably about 150°C. The HME extrusion speed may be in the range from at least 5 to at most 15 rpm, preferably 6 to 14 rpm, more preferably 7 to 13 rpm, more preferably 8 to 12 rpm, even more preferably 9 to 11 rpm, even more preferably about 10 rpm.

EXAMPLES

The present invention is further illustrated by the following examples and illustrative embodiments. The provided embodiments may be regarded as preferred embodiments non- limitative to the scope of the invention.

Example 1

Reference is made to FIG.l which illustrates three hollow 3D printed capsules of various dimensions. The respective dimensions for the first capsule (A), the second capsule (B), and the third capsule (C) are presented below in Table 1. The selected sizes of the capsules correspond with those commonly used in community pharmacies, hospitals and research facilities.

Table 1

The listed capsules were 3D printed using an FDM 3D printing apparatus according to the following procedures:

HME preparation of filaments: PLA was purchased as extruded filaments from Makerbot^® (1.75 mm diameter, print temperature 220-240 °C, p = 1300 kg/m3 MakerBot^® Inc., USA) and NatureWorks LLC (p = 1240 kg/m3, MFI = 6 g/10 min, 4.3 wt % D-isomer content). The enteric methacrylic acid copolymer Eudragit^® L100-55 (EL) was purchased from Evonik™ (Darmstadt, Germany) and CAP was obtained from Sigma- Aldrich^® (USA). Both polyethylene glycol 400 (PEG400) (Merck^®, Germany) and diethyl phthalate (DEP) (Sigma-Aldrich^®, USA) were used as plasticizers. Coscarmellose sodium (Ac-Di-Sol^®, FMC, USA) was employed as the superdisintegrant and lactose 80 mesh (DMV International^®, Netherlands) was used as a diluent.

PLA purchased in the form of a filament was cut into small pieces. Thereafter, EL100-55 was added and, eventually, the required amount of PEG400 was also dispersed in a mortar and then processed with a pestle. Then, liquid nitrogen was poured over the viscous mass, which became very brittle. After crushing with a pestle, the fragments were passed through a sieve with a mesh of 2.00 mm until reaching a coarse-grained "powder", which enabled an easy and continuous extruder feeding.

The filaments were prepared by means of HME using a parallel twin-screw extruder (Thermo Scientific^® Process 11, Thermo Fisher Scientific Inc.^®, USA) with 7 separate heating zones, excluding the die (ø = 1.70 mm). Temperature, die pressure, torque and speed of rotation of the screws were constantly monitored. The speed of the screws was fixed at 10 rotations per minute (rpm) and each heating zone, including the die was set at 150 °C, except for the first heating zone, which was heated up to only 140°C. Extruded filaments were manually pulled. To ensure that the extruded filaments were homogenous, a couple of runs were conducted. The first extrudate was cut into small pieces before being reextruded. After production, the diameter of the filament was checked every 5 cm in length with an electronic measuring calliper and portions that had not a diameter in the acceptable range of 1.70 ± 0.1 mm were discarded.

FDM 3D printing:

FDM was performed by a MakerBot^® Replicator 2 equipped with a 0.4 mm nozzle (MakerBot^® Industries, USA). The MakerBot^® Desktop Beta Version 3.10.0.1364 Software was used as the slicer program with modified settings. At least 15 cm of the developed enteric filaments were employed. Three layer heights were evaluated: 100, 200 and 300 pm. The optimal printing temperature was set at 167°C, 172°C and 175°C for a layer height of 100 pm, 200 pm and 300 pm, respectively.

The launching of the active cooling was set at layer 3 or at layer 7 when a raft was needed. The fan power was fixed at 100%, 70% and 10% for a layer height of 100, 200 and 300 pm, respectively. The print speed specifies the speed of the nozzle during the printing process. It was set at 5.0 mm/s for a layer height of 100 and 200 miti. It was reduced to 3.0 mm/s for the 300 miti setting. The print speed of the dome was reduced to 2.0 mm/s for a layer height of 200 pm and to 1.0 mm/s at 300 pm. The infill density was fixed at 0%, which allowed the printing of a hollow capsule, where the border is only one sheet thick. The thickness was set at 0.40 mm and is the height of filled layers of the dome.

A raft was used for the head of the capsule. The air humidity and the temperature in the operating room were equilibrated at 30± 2 % and at 20± 2 °C, respectively. Some printed capsules were put into a climate chamber at 45 °C or 60 °C for 10 to 15 seconds to evaluate the impact of post-proceeding heat treatment on the final release profiles. Blue tape was used on the building plate to increase the adhesion of the first printed layer.

When changing the filament before a new printing process, the printer was cleaned and levelling of the build plate was performed following assembly of the heating block. To clean the heating block, its temperature was increased to 250°C for 5 minutes; the material remaining at the surface of the nozzle was removed by means of a brass brush; then, the nozzle was unscrewed and any residue inside was manually removed; finally, it was immersed in acetone for 5 minutes and phosphate buffer pH 6.0 for another 5 minutes before being dried under a hot air stream.

Example 2

Reference is made to FIG.2 which illustrates four sealing systems which may be used for sealing the capsule body to the capsule cap.

FIG.2A presents a screw thread design of a capsule body, the capsule cap would be provided with a fitting corresponding to the thread of the body.

FIG.2B presents a complete capsule design wherein the capsule body comprises two circumferentially spaced circles, the first circle being located near the edge of the capsule body opening and the second circle located nearer to the capsule body centre. Both circles extend outwards over of the capsule body outer wall; the circle diameter is larger than the average capsule diameter. The capsule cap on the other hand comprises one circumferentially spaced circle which can extend over the circumferentially spaced circles of the capsule body by telescoping the open ends of the outer cap parts over the open ends of the inner body.

FIG.2C presents a second complete capsule design wherein the capsule body also comprises two circumferentially spaced circles with the difference (compared to FIG.2B) that the circles are spaced further apart. The capsule cap comprises two circumferentially spaced circles going inwards; the circle diameter is smaller than the average capsule diameter. The cap can be pushed over the circumferentially spaced circles of the capsule body by means of a click-on mechanism. FIG.2D presents a third preferred complete capsule design wherein the capsule body also comprises two circumferentially spaced circles with the difference (compared to FIG.2C) that the capsule neck comprising said circles has a smaller diameter than the average capsule diameter. The capsule cap also comprises two circumferentially spaced circles going inwards; the circle diameter is lower than the average capsule diameter. The cap can be pushed over the circumferentially spaced circles of the capsule body by means of a click-on mechanism.

Example 3

The dissolution profiles of the three hollow 3D printed capsules discussed in Example 1 were compared to that of conventional enteric-coated capsules. RF5'PNa (Certa^®, Belgium) was selected as a coloured model drug for ease of visualisation and quantification and quick of potential leaks from the capsule. The capsules were filled with 1% w/w of RF5'PNa, 30 % w/w of crosscarmellose sodium and 69 % w/w of lactose 80 mesh. Dissolution was carried out on an equivalent of 9.0 mg of RF5'PNa.

A Distek 2100C USP 29 dissolution apparatus (Distek Inc., North Brunswick, NJ, USA), according to Type II (paddle) method was used for the dissolution tests (37.0 ± 0.2°C; 100 rpm). A metal lattice with a fine mesh was bent to enclose the capsule and kept it at the bottom of the holder. Release testing was carried out in 900 ml of HCI 0.1 M (pH 1.2) for 2 hours; then, the acidic medium was replaced by 900 mL of phosphate buffer 0.05 M (pH 6.8) for the next 45 minutes. As RF5'PNa is a photosensitive substance, the dissolution tests were conducted in a dark room. Dissolution was carried out on an equivalent of 13.0, 9.0 and 6.5 mg of RF5'PNa, from capsules (a), (b) and (c), respectively. The amount of RF5'PNa released was detected spectrophotometrically with a Nanophotometer^® NP80 (Implen^®, Germany) at a wavelength of 445 nm. The percentages of drug release were measured at preselected time intervals and averaged (n=3).

First dissolution tests:

The influence of the capsule layer height on the dissolution of the 3D printed enteric capsules was evaluated. The test results are presented in FIG 3, which shows the release profile of the model drug (RF5'PNa) from 3D printed enteric capsules having a layer height of 100 pm (■), 200 pm (·), 300 pm ( A ), and compared to coated capsules reference (A).The capsules were placed in HCI 0.1N medium for 2 hours, which was then replaced by a phosphate buffer pH 6.8 for 45 minutes (37°C, lOOrpm).

After 2 hours in acidic medium (pH 1.2), no RF5'PNa was released from the coated capsules. 3D- printed hollow enteric capsules released 5±1 % w/w of RF5'PNa, when the layer height was set at 100 or 200 pm. Moreover, more than 80% w/w of RF5'PNa were released within 45 min in phosphate buffer pH 6.8. Flowever, it could be observed that the percentage of release was lower from 3D-printed enteric capsules characterized by a layer height of 100 pm (87±1 % w/w) that that from those with a layer height of 200 pm (100±1 % w/w). In contrast, 3D printed hollow enteric capsules with 300 pm layer height already released 23±3% w/w after 2 hours in HCI 0.1N (pH 1.2).

Second dissolution tests:

The influence of the capsule size on the dissolution of the 3D printed enteric capsules was evaluated with a fixed layer height of 200 pm. The test results are presented in FIG 4, which shows the dissolution profile of the model drug (RF5'PNa) from 3D printed enteric capsules (A) (■), (B) (·), and (C) (▲).

As it can be seen, the 3D-printed enteric capsules satisfy the requirements for the dissolution of enteric oral dosage form, regardless of their size. After 2 hours in acidic medium pH 1.2, 3D- printed enteric capsules (A), (B) and (C) characterized by a layer height of 200 pm released 7±2% w/w, 5±2% w/w and 5±1% w/w of RF5'PNa, respectively. Moreover, they were all able to release the entire amount of RF25'PNa within 45 min at pH 6.8.

Claims

1. A 3D printing composition comprising:

(a) at least one thermoplastic polymer,

(b) at least one plasticizer, and,

(c) at least one modified-release polymer;

characterised in that the modified-release polymer is either an enteric polymer having a pH-dependent dissolution threshold of at least 5.0 pH, preferably at least 5.3 pH, more preferably at least 5.5 pH, even more preferably at least 5.6 pH, or is a sustained-release polymer.

2. The composition according to claim 1, wherein the modified-release polymer is present in an amount of at least 60.0 wt.% of the total weight of composition (w/w), preferably 65.0 wt.%, more preferably 70.0 wt.%.

3. The composition according to any either one of claims 1 or 2, wherein the thermoplastic polymer is polylactic acid (PLA).

4. The composition according to any one of claims 1 to 3, wherein the thermoplastic polymer, preferably PLA, is present in an amount of at least 5.0 wt.% of the total weight of composition (w/w); preferably in an amount of at least 5.0 wt. % to at most 15.0 wt.% of the total weight of composition (w/w).

5. The composition according to any one of claims 1 to 4, wherein the plasticizer is present in an amount of at least 5.0 wt.% of the total weight of composition (w/w); preferably in an amount of at least 5.0 wt. % to at most 25.0 wt.% of the total weight of composition (w/w).

6. Use of the composition according to any one of claims 1 to 5 for 3D printing, preferably for 3D printing a modified-release capsule.

7. A 3D printed modified-release capsule (100) made from the composition of any one of claims 1 to 5.

8. The capsule (100) according to claim 7, wherein the capsule has a pH-dependent dissolution threshold of at least pH 5.0, preferably at least pH 5.3, more preferably at least pH 5.5, more preferably about pH 5.6.

9. The capsule (100) according to either one of claims 7 or 8, wherein the capsule comprises a capsule body and a capsule cap connected by means of a sealing system (200).

10. The capsule (100) according to any one of claims 7 to 9, comprising at least one active pharmaceutical ingredient (API) contained within the capsule.

11. The 3D printed modified-release capsule (100) according to claim 10 for use as a medicament.

12. A method for producing a 3D printed modified-release capsule (100), comprising at least the steps of:

(i) providing a composition according to any one of claims 1 to 5; and,

(ii) 3D printing a modified-release capsule from said composition.

13. The method according to claim 12, wherein the 3D printing is fused-deposition modelling (FDM) 3D printing, the method comprising the steps of:

(ii.b) FDM 3D printing a modified-release capsule (100) with the printable filament.

14. The method according to either one of claims 12 or 13, wherein the 3D printing comprises the steps of: 3D printing a capsule body, 3D printing a capsule cap, and connecting the capsule body and the capsule cap to form a modified-release capsule, preferably connecting by means of a sealing system (200).

15. The method according to any one of claims 12 to 14, comprising the step of

(iii) filling the 3D printed modified-release capsule (100) with at least one active pharmaceutical ingredient (API), preferably by means of a filling device.