WO2021110544A1

WO2021110544A1 - Method for manufacturing a solid administration form and solid administration form

Info

Publication number: WO2021110544A1
Application number: PCT/EP2020/083568
Authority: WO
Inventors: Dieter Lubda
Original assignee: Merck Patent Gmbh
Priority date: 2019-12-02
Filing date: 2020-11-27
Publication date: 2021-06-10

Abstract

According to a method for manufacturing a solid administration form (13) comprising at least one active pharmaceutical ingredient, a powder (11) of particles (2) made from a flowable but setting composite material comprising the at least one active pharmaceutical ingredient is manufactured in a particle manufacturing step, and subsequently the solid administration form (13) is prepared from the powder (11) of particles (2) in a formulation step. During the particle manufacturing step the flowable composite material is liquefied and delivered to a discharge unit, with which droplets (8) of the liquefied composite material are intermittently discharged through an outlet of the discharge unit at a distance towards each other to a setting unit where the setting of the droplets (8) into the particles (2) occurs. After the setting of the liquefied composite material the particles (2) are collected to make the powder (11) of particles (2) that is used for preparation of the solid administration form (13) within the formulation step.

Description

Method for manufacturing a solid administration form and solid administration form

Technical Field

The present invention relates to a method for manufacturing a solid administration form comprising at least one active pharmaceutical ingredient, wherein a powder of particles made from a flowable but setting composite material comprising the at least one active pharmaceutical ingredient is manufactured in a particle manufacturing step, and subsequently the solid administration form is prepared from the powder of particles in a formulation step.

Background

Many solid administration forms are manufactured from a powder of particles that comprise at least one active pharmaceutical ingredient. Common methods of manufacturing the solid administration forms include compressing or molding, whereby the powder of particles is mixed with suitable excipients and compressed or molded into the shape of a tablet.

Due to the increasing number of poorly water-soluble drug substances in the pipeline of research and development of pharmaceutical industry, there is a need to increase the oral bioavailability of those insoluble drug substances.

Based on the physicochemical properties of the particular drug substance, the mechanism of bioavailability enhancement is divided into at least three categories: formation of amorphous solid dispersions, formation of crystalline solid dispersions, and formation of co-crystals.

Formulation of amorphous solid dispersions is a viable approach for improving the dissolution performance of poorly water-soluble drug substances. It is especially suitable for non-ionizable drug substances that cannot form pharmaceutical salts. The amorphous drug substance is stabilized within the matrix in order to prevent any re-crystallization. Amorphous drug exists in a higher energy state than crystalline drugs, and this can result in higher kinetic solubility and a faster dissolution rate. This allows drug molecules present in amorphous solid dispersions to be more readily absorbed from the gastrointestinal tract.

In order to increase the rate of dissolution it is well known to prepare formulations of poorly soluble compounds in form of solid dispersions. Various processes can be used to create solid dispersions. In general, these systems can be produced by processes either utilizing solvents or which require the melting of one or more of the added substances. These solid dispersions can be created by a number of methods, including, but not limited to, spray-drying, melt extrusion and thermokinetic compounding. A recently applied technology to support solubility of poor soluble drugs is the deposition of the drug in amorphous phase onto a carrier, e.g. porous silica.

Both melt extrusion and spray drying processes are widely used to prepare amorphous solid dispersions to enhance bioavailability of biopharmaceutics classification system classes II and IV drugs.

To achieve an amorphous dispersion through spray drying, for example, the solvent or co-solvent system utilized must be suitable to dissolve both the polymeric carrier vehicle and the compound of interest. In summary, these methods require the use of a solvent system, often organic in nature, to dissolve an inert carrier and active drug substance (Serajuddin A. T. M.; Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. (1999), 88(10), 1058-1066). Once a solution is formed, the solvent is subsequently removed by a mass transfer mechanism dependent on the manufacturing technique chosen. Although solvent-based techniques such as spray drying are relatively common, they suffer from several disadvantages. Selection of a solvent system that is compatible with the active substance and carrier polymer may prove to be difficult or require very large amounts of organic solvent. This presents a safety hazard at the manufacturing facility as organic solvents must be collected and disposed of properly to limit the environmental impact. Contrary to spray drying, hot melt extrusion is an anhydrous and solvent free process. There is no need of solvents or of hydrolysis of the active pharmaceutical ingredients for preparing the particles that are used for the preparation of the solid administration forms. Furthermore, hot melt extrusion is a well-known method widely used in the plastic or food industry, and it is increasingly used for manufacturing solid administration forms, e.g. solid administration forms comprising active pharmaceutical ingredients with reduced solubility. Hot melt extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier resulting in a composite material with increased dissolution rates and bioavailability. Polymers that can be used to optimize the drug-release profiles are e.g. ethylcellulose, cellulose acetate butyrate, poly ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride, or polyethylene-co-vinyl acetate. Triacetin and diethyl phthalate are known to be useful as plasticizer. The type and amount of plasticizer used, drying time of the polymers, extrusion temperatures and plasticization times also vary with each formulation. The polymer to drug ration also affects the drug release profile. Additives such as pore former and hydrophilic polymers can be used to increase the drug release rate by increasing the porosity of the solid administration form during dissolution. Viscosity inducing agents can be included into the polymer matrix to limit the burst release that is often seen with such polymer matrix systems.

The process of hot melt extrusion involves the application of heat, pressure and agitation to mix materials together and to extrude them from an extruder. Extruders that are used for hot melt extrusion can also be used for mixing, melting and introducing chemical reactions of the composite materials that is extruded.

However, the extruded composite material must be crushed into small particles that can be used for the preparation of the solid administration form. Crushing the extrudate into a powder of small particles can be very complex and time consuming. Usually, at least one milling step is required after cutting or breaking up the extrudate into small parts, which reduces the size of the small parts into the desired smaller size of the powder particles. The milling of the extruded composite material depends among other things on the polymer material as well as on the active pharmaceutical ingredients that have been mixed into the composite material. Often, the milling has to be performed by cryogenic mills using liquid nitrogen, whereby the material is cooled or chilled before milling, which reduces the risk of unwanted softening, adhering in lumps and clogging of the small particles during the milling process.

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Accordingly, there is a need for a method for manufacturing a solid administration form that can be performed easily and cost-effectively from a composite material comprising at least one active pharmaceutical ingredient.

Description of the invention

10

The present invention relates to a method for manufacturing a solid administration form comprising at least one active pharmaceutical ingredient, wherein during the particle manufacturing step the flowable composite material is liquefied and delivered to a discharge unit, wherein the droplets of the liquefied composite _"Ί material are intermittently discharged through an outlet of the discharge unit at a distance towards each other into a setting unit where the setting of the droplets into the particles occurs, and wherein after the setting of the liquefied composite material the particles are collected to make the powder of particles that is used for preparation of the solid administration form within the formulation step. It is considered a main benefit of this method that even though the powder of particles

20 can be made from a setting composite material, no crushing and milling of the extrudate from a hot melt extrusion process is required in order to obtain the powder of particles. The small particles are manufactured from droplets whose size already equals the desired size of the particles that are used for the manufacturing of the solid administration form. The size of the particles within the powder can vary 25 according to requirements or desired aspects of the solid administration form. Usually, the size of the particles comprised within the powder is less than 1 mm and typically in the range of 50 pm up to 500 pm, preferably in the range of 100 pm up to 300 pm.

In order to facilitate the harvesting of the particles the droplets are discharged from 30 the discharge unit onto a flat surface of the setting unit. The discharge unit can be a commercially available 3D printing device that is able to discharge a large number of small droplets of suitable composite material. Currently available discharge units are capable of discharging up to 200 droplets with an average size between e.g. 150 pm and 250 pm, which is considered an advantageous size for the particles of the powder from which the solid administration form can be made. After the setting of small droplets the solidified particles can be removed from the flat surface by e.g. by scraping off the particles with help of a peel bar.

According to an embodiment of the present invention, the discharge unit comprises a nozzle that is driven by piezo actuators to open and close for discharging the droplets onto the setting unit. Making use of piezo actuators to open and close the nozzle of the discharge unit allows for very rapid changes of the nozzle opening, resulting in high discharge rates of droplets of e.g. more than 100 or more than 200 droplets per second. The resulting particle size mainly depends on the nozzle diameter, which can be designed for or adapted to the specific requirements of the solid administration form.

According to an advantageous aspect of the invention, the setting unit is displaced with respect to the fixed discharge unit between successive discharges of droplets. The setting unit may comprise a flat surface onto which the droplets are discharged for the required setting of the droplets made from the setting composite material. A controlled displacement of the setting unit is less demanding than a displacement of the discharge unit. The displacement of the setting unit can be performed e.g. by using an XY-table, or by using a rotating disc whereby the droplets can be discharged onto a flat surface of the disc. The rotational speed of the disc can be adapted to the discharge rate of the droplets from the discharge unit as well as to the setting time that is required for sufficient solidification of the droplets in order to be able to remove the solidified particles from the surface of the disc.

According to the present invention the term “flowable but setting composite material” mean a composition that is flowable in order to be transported before liquefying and that can be solidified after being molten.

In yet another embodiment of the invention the particles are removed from the setting unit by directing an airstream onto a region of the setting unit that is spaced apart from a droplet receiving region of the setting unit, whereby the airstream pushes the hardened particles from the setting unit into a particle reservoir. The droplets can be discharged onto a surface of the setting unit that is coated with a non-stick finish which reduces the adhesion of solidified particles onto the surface. By making use of an airstream that blasts the hardened particles from the surface, there is no need for a mechanical device that removes the particles from the surface, which may cause unwanted damaging of the particles or abrasion of the surface as well as increased time requirements for mechanically scraping off the particles.

A suitable binder agent my comprise pharmaceutically acceptable excipients known to those skilled in the art, which may be used to produce the composites and compositions disclosed herein. Examples of excipients for use with the present invention include, but are not limited to, e.g., a pharmaceutically acceptable polymer, a thermolabile polymeric excipient, or a non-polymeric excipient. Other non-limiting examples of excipients include, lactose, glucose, starch, calcium carbonate, kaoline, crystalline cellulose, silicic acid, water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, polyvinyl pyrrolidone, dried starch, sodium alginate, powdered agar, calcium carmelose, a mixture of starch and lactose, sucrose, butter, hydrogenated oil, a mixture of a quaternary ammonium base and sodium lauryl sulfate, glycerine and starch, lactose, bentonite, colloidal silicic acid, talc, stearates and polyethylene glycol, sorbitan esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, poloxamers (polyethylene-polypropylene glycol block copolymers), sucrose esters, sodium lauryl sulfate, oleic acid, lauric acid, polyoxyethylated glycolyzed glycerides, dipalmitoyl phosphadityl choline, glycolic acid and salts, deoxycholic acid and salts, sodium fusidate, cyclodextrins, polyethylene glycols, polyglycolyzed glycerides, polyvinyl alcohols, polyacrylates, polymethacrylates, polyvinylpyrrolidones, phosphatidyl choline derivatives, cellulose derivatives, biocompatible polymers selected from poly-(lactides), poly(glycolides), poly(lactide- co-glycolides ), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-coglycolic acid)s and blends, combinations, and copolymers thereof.

Selection of the polymer carrier system is considered important for the successful development of formulation and manufacturing processes. The physicochemical and mechanical properties of polymers and drug substances must be carefully evaluated.

Suitable thermal binder agents that may or may not require a plasticizer include, for example, Eudragit™ RS PO, Eudragit™ SIOO, Kollidon SR (poly(vinyl acetate)- copoly(vinylpyrrolidone) copolymer), Ethocel™ (ethylcellulose), HPC (hydroxypropylcellulose), cellulose acetate butyrate, poly(vinylpyrrolidone) (PVP), poly( ethylene glycol) (PEG), poly( ethylene oxide) (PEO), poly(vinyl alcohol) (PVA), hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), hydroxyethylcellulose (HEC), sodium carboxymethyl-cellulose (CMC), dimethylaminoethyl methacrylate - methacrylic acid ester copolymer, ethylacrylate - 5 methylmethacrylate copolymer (GA-MMA), C-5 or 60 SH-50 (Shin-Etsu Chemical Corp.), cellulose acetate phthalate (CAP), cellulose acetate trimelletate (CAT), poly(vinyl acetate) phthalate (PV AP), hydroxypropylmethylcellulose phthalate (HPMCP), poly(methacrylate ethylacrylate) (1 : 1) copolymer (MA-EA), poly(methacrylate methylmethacrylate) (1 :1) copolymer (MA-MMA), poly(methacrylate methylmethacrylate) (1:2) copolymer, Eudragit L-30-D™ (MA-EA, 1:1), 10 Eudragit L-100-55™ (MA-EA, 1 :1), hydroxypropylmethylcellulose acetate succinate (HPMCAS), Coateric™ (PV AP), Aquateric™ (CAP), and AQUACOAT™ (HPMCAS), polycaprolactone, starches, pectins; polysaccharides such as tragacanth, gum arabic, guar gum, and xanthan gum.

A preferred thermal binder is poly(vinyl alcohol) (PVA). Polyvinyl alcohol (PVA) is a synthetic water-soluble polymer that has the idealized formula [CH2CH(OH)]n. It possesses good film-forming, adhesive, and emulsifying properties. PVA is prepared from polyvinyl acetate, where the functional acetate groups are either partially or completely hydrolysed to alcohol functional groups. If not completely hydrolysed, PVA is a random copolymer consisting of vinyl alcohol repeat units -

[CH2CH(OH)]- and vinyl acetate repeat units -[CH2CH(OOCCH3)]-. The polarity of

PVA is closely linked to its molecular structure. The hydrolysis degree and the molecular weight determine the molecular properties of PVA. As the degree of hydrolysis of acetate groups increases, the solubility of the polymer in aqueous media and also crystallinity and melting temperature of the polymer increase. However, at high hydrolysis degrees over 88 %, the solubility of PVA decreases again. PVA is generally soluble in water, but almost insoluble in almost all organic solvents, excluding, in some cases, ethanol.

The typical PVA nomenclature indicates the viscosity of a 4 % solution at 20° C and the degree of hydrolysis of the polymer. For example, PVA 4-88 is a PVA grade with a viscosity of 4 mPas that is 88 % hydrolysed, i.e. having 88 % of vinyl alcohol repeat units and 12 % of vinyl acetate repeat units. A skilled person is aware that a hydrolysis grade of e.g. 88 % and a viscosity of 4 mPas encompasses calculated hydrolysis grades of 87.50 % to 87.49 % and calculated viscosities of 3.50 mPas to 4.49 mPas % according to common rounding methods. Viscosity according to the invention is measured as stated in USP 39 under Monograph “Polyvinyl Alcohol” with the method Viscosity-Rotational Method D912D. The degree of hydrolysis according to the invention is measured as stated in USP 39 under Monograph “Polyvinyl Alcohol” under “Degree of Hydrolysis”.

A thermal binder according to the present invention can comprise any PVA grade. Preferred PVA grades are selected from the group consisting of PVA 3-74, PVA 3- 80, PVA 3-81, PVA 3-82, PVA 3-83, PVA 3-84, PVA 3-85, PVA 3-88, PVA 3-98, PVA 4-74, PVA 4-85, PVA 4-88, PVA 4-98, PVA 5-72, PVA 5-74, PVA 5-82, PVA 5-88, PVA 6-88, PVA 6-98, PVA 8-88, PVA 10-98, PVA 13-88, PVA 15-79, PVA 15- 99, PVA 18-88, PVA 20-98, PVA 23-88, PVA 26-80, PVA 26-88, PVA 2-98, PVA 28- 99, PVA 30-75, PVA 30-92, PVA 30-98, PVA 32-80, PVA 32-88, PVA 40-88 or any PVA grades in between. More preferred PVA grades are polyvinyl alcohols having a hydrolysis degree of 72 % to 90 %, in particular 74 % to 88 %, and a viscosity of a 4 % solution at 20° C of 2 mPas to 5 mPas, in particular 3 mPas to 5 mPas.

Particularly preferred PVA grades are selected from the group consisting of PVA 3- 80, PVA 3-81 , PVA 3-82, PVA 3-83, PVA 3-84, PVA 3-85, PVA 3-88, PVA 4-88, and PVA 5-74, in particular PVA 4-88.

Further preferred PVA grades have a degree of hydrolysis in the range of greater than 72.2 % according to the requirements of the European Pharmacopoeia, or between 85 - 89 % according to the United States Pharmacopoeia, and a molecular weight in the range of 14 000 g/mol to 250 000 g/mol. With increasing molecular weight, the viscosity of an aqueous solution of the PVA increases.

A binary solid dispersion of an active pharmaceutical ingredient and a binder agent can produced by any method known to the skilled person. Preferred methods for producing the binary solid dispersion are hot melt extrusion (HME), dry compaction and Twin Screw Wet Granulation (TSG).

Preferably those methods are performed with PVA 4-88. Dependend on the method of producing of the solid dispersion, further exhibients known to the skilled person in the art might be necessary to yield a suitable granulate.

A binary dispersion of an active pharmaceutical ingredient and a binder agent can exist as a single phase system, or as a multi-phase system, depending on their miscibility. In general, a single-phase amorphous solid dispersion system is desired for the following reasons. First of all, a single phase system tends to have better stability compared to a multiphase system. Due to phase separation, multi-phase systems comprise a drug-rich domain and a polymer-rich domain. In most cases, the drug-rich domain has a relatively low glass transition temperature and the drug molecules are less protected. Therefore, the drug-rich domain is more susceptible to re-crystallization, raising a physical stability concern. Regarding the drug substance that has good physical stability in the amorphous state, phase separation may negatively impact the dissolution performance of the formulation. A water- soluble polymer matrix facilitates the dissolution process of a poorly-soluble drug substance.

Therefore, a reduced percent of polymer in the drug-rich domains may decrease the dissolution rate of the drug from the formulation. In order to minimize the risk of phase separation, the polymer carrier needs to have good miscibility with the drug substance. Differential scanning calorimetry (DSC) is predominantly used to characterize the drug-polymer miscibility.

Yet another embodiment of the present invention includes a method of preplasticizing one or more pharmaceutical polymers by blending the polymers with one or more plasticizer selected from the group consisting of oligomers, copolymers, oils, organic molecules, polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, polypropylene glycols), multi-block polymers, single block polymers, poly( ethylene oxides), phosphate esters; phthalate esters, amides, mineral oils, fatty acids and esters thereof with polyethylene-glycol, glycerin or sugars, fatty alcohols and ethers thereof with polyethylene glycol, glycerin or sugars, and vegetable oils by mixing prior to agglomeration, by processing the one or more polymers with the one or more plasticizers into a composite

Examples of active pharmaceutical ingredients either approved or new and under development include, but are not limited to, antibiotics, analgesics, vaccines, anticonvulsants; antidiabetic agents, antifungal agents, antineoplastic agents, antiparkinsonian agents, antirheumatic agents, appetite suppressants, biological response modifiers, cardiovascular agents, central nervous system stimulants, contraceptive agents, dietary supplements, vitamins, minerals, lipids, saccharides, metals, amino acids and precursors, nucleic acids and precursors, contrast agents, diagnostic agents, dopamine receptor agonists, erectile dysfunction agents, fertility agents, gastrointestinal agents, hormones, immunomodulators, anti-hypercalcemia agents, mast cell stabilizers, muscle relaxants, nutritional agents, ophthalmic agents, osteoporosis agents, psychotherapeutic agents, para-sympathomimetic agents, para-sympatholytic agents, respiratory agents, sedative hypnotic agents, skin and mucous membrane agents, smoking cessation agents, steroids, sympatholytic agents, urinary tract agents, uterine relaxants, vaginal agents, vasodilator, anti-hypertensive, hyperthyroids, anti-hyperthyroids, anti-asthmatics and vertigo agents. In certain embodiments, the active pharmaceutical ingredient is a poorly water-soluble drug or a drug with a high melting point. The active pharmaceutical ingredient may be found in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates thereof.

According to an aspect of the invention the flowable composite material comprises a polymer and at least one amorphous active pharmaceutical ingredient that is mechanically mixed, dispersed or dissolved with or within the polymer. For many pharmaceutical applications a poor solubility or bioavailability of active pharmaceutical ingredients is addressed with hot melt extrusion of the composite material, which allows for incorporation of the active pharmaceutical ingredients in its amorphous forms into the polymer. For crystalline forms of active pharmaceutical ingredients, the reduced thermal stress and the only once performed transfer into its amorphous form during melting until discharge of the small portions of the composite material significantly enhances the solubility and bioavailability of poorly soluble materials.

In yet another embodiment of the invention the flowable but setting composite material includes non-soluble porous or non-porous carrier particles for altering or enhancing the properties of the solid administration form. By adding carrier particles it is possible to improve the solubility of the active pharmaceutical ingredient applied e.g. to a porous carrier particle, to change release properties of toe stabilize the active pharmaceutical ingredient against thermal degradation during the manufacturing process.

According to an advantageous embodiment of the invention, the flowable composite material is fabricated during delivery to the discharge unit, i.e. very shortly or immediately before the intermittently discharge of liquefied small portions of the composite material with the discharge unit. Thus, there will be no degradation of the active pharmaceutical ingredients and/or of the composite material due to long term storage of the composite material or due to transport of the prefabricated composite material to the discharge unit. It is also possible to make use of granules that are heated and liquefied immediately before delivery to the discharge unit. Alternatively, a mixture of particles can be used to generate the composite material by heating and melting the mixture of particles and subsequently delivering the molten mixture of the particle generated composite material to the discharge unit.

For many applications, there is no need for addition of stabilizing materials into the composite material, as there is no need for long-term storage of the prefabricated composite material until final use of the composite material for additive manufacturing of a solid administration form. However, for some applications it might be advantageous to add stabilizer and/or plasticizer to the composite material in order to adapt the properties and in particular mechanical properties of the composite material and the resulting solid administration form to individual requirements of the respective applications.

According to an advantageous embodiment of the invention an average diameter of the droplets is less than 350 pm, preferably less than 250 pm, more preferably less than 200 pm. The smaller the size of a single droplet, the more complex shapes and structures of the solid administration form are possible, and can be additively generated with great precision. In order to be able to manufacture solid administration forms comprising a reasonable large volume of composite material within a reasonable small amount of time, the size of a single droplet should be larger than 20 pm and preferably larger than 50 pm. As it seems possible to discharge several 100 droplets per second through a single nozzle of the discharge unit, a fairly rapid generation of tablets and similar solid administration forms is possible. Furthermore, a small diameter of a single droplet enables the generation of tablets with an individual, but well-defined content of the active pharmaceutical ingredient or ingredients.

According to another aspect of the invention, before or after discharging a predetermined first amount of a composite material a predetermined second amount of a second material is discharged, whereby the material of the second material differs from the composite material. Thus, it is also possible to make use of two or more different composite materials within a single solid administration form. For example, a porous structure of a first composite material with a poorly or rapidly soluble active pharmaceutical ingredient may be encased with a surrounding layer of a binder agent without any active pharmaceutical ingredient in order to e.g. prepare solid administration forms with preset shielding properties, decorative or taste masking properties or with predefined enteric properties. The first and second composite material can be delivered to and discharged from the discharge unit one after another, making use of the same means for delivering and discharging the composite material.

However, in order to enhance manufacturing speed and to reduce undesired contamination of the respective composite material that is used to generate some part of a solid administration form it is considered advantageous to provide for separate delivering and discharging means for each different composite material that is used for the additive manufacturing of a single solid administration form. For example, the discharge unit may comprise separate delivery channels that feed into a dedicated nozzle of the discharge unit, whereby each delivery channel and corresponding nozzle can be activated and used separately.

The invention also relates to a device for manufacturing a power of particles of a composite material comprising at least one active pharmaceutical ingredient, whereby the device comprises a discharge unit with at least one nozzle that is arranged above a setting unit, whereby a droplet of the liquefied composite material can be discharged from the discharge unit through the nozzle into the setting unit, where the setting of the droplets into particles occurs, and whereby the device also comprises a particle harvesting unit for collecting and removing the particles from the setting unit. The discharge unit may comprise a dosing head with one or more nozzles. The liquefied composite material can be fed from a composite material reservoir to the dosing head by a feed line, preferable a flexible feed line. The liquefied composite material can be discharged as droplets through the one or more nozzles to the setting unit, where the setting of the droplets to hardened particles occurs.

According to an embodiment of the invention the setting unit comprises a displacement mechanism that displaces the setting unit with respect to the discharge unit. The displacement mechanism can be a XY-table that supports the setting unit. By displacing a movable top plate of the XY-table the setting unit on top of the top plate of the XY-table can be displaced along the X-axis and along the Y- axis with respect to the discharge unit, thus providing for a different droplet receiving region of the setting unit at different times during the discharge of a large number of droplets. Thus, the droplets can be discharged from the nozzle onto an always changing droplet receiving region of the setting unit in order to avoid an agglomeration of droplets during the setting process.

According to an embodiment of the invention the discharge unit comprises a displacement mechanism that displaces the discharge unit with respect to the setting unit. The displacement mechanism can be a movable nozzle providing for a different droplet receiving region of the setting unit at different times during the discharge of a large number of droplets. Thus, the droplets can be discharged from the nozzle onto an always changing droplet receiving region of the setting unit in order to avoid an agglomeration of droplets during the setting process.

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According to an advantageous embodiment of the invention, the setting unit comprises a flat surface onto which the droplets are discharged from the discharge unit. The flat surface may be covered or coated with a non-stick finish which reduces the adhesion of solidified particles onto the surface. This facilitates the removal of particles from the setting unit with the particle harvesting unit.

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According to an aspect of the invention, the particle harvesting unit comprises a scraper that scrapes the particles from the setting unit. The scraper preferably comprises a rubber lip that removes the particles from the flat surface of the setting unit. The scraper can be actuated to continually or intermittently scrape across the _"Ί flat surface in order to remove the hardened particles from the surface into a particle reservoir.

In yet another embodiment of the invention, the particle harvesting unit comprises an airstream unit that directs an airstream onto a region of the setting unit that is spaced apart from a droplet receiving region of the setting unit, whereby the

20 airstream pushes the hardened particles from the setting unit into a particle reservoir. It is also possible to combine a scraper with an airstream unit.

In yet another embodiment of the invention, the particle harvesting is done by manually removing the particles from the plate.

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The invention also relates to a solid administration form comprising at least one active pharmaceutical ingredient, whereby the solid administration form is manufactured by performing the above described method.

Brief description of the drawings 30 The present invention will be more fully understood, and further features will become apparent, when reference is made to the following detailed description and the accompanying drawings. The drawings are merely representative and are not intended to limit the scope of the claims. In fact, those of ordinary skill in the art may appreciate upon reading the following specification and viewing the present drawings that various modifications and variations can be made thereto without deviating from the innovative concepts of the invention. Like parts depicted in the drawings are referred to by the same reference numerals.

Figure 1 illustrates a schematic perspective view of a manufacturing device for manufacturing of a powder of particles made from a flowable but setting composite material,

Figure 2 illustrates a schematic view of the manufacturing of a solid administration form composed of the powder of particles of composite material, and

Figure 3 illustrates a schematic view of another embodiment of the device for manufacturing of the powder of particles.

Detailed description of the invention

Figure 1 illustrates a manufacturing device 1 for manufacturing a powder of particles

2, whereby the particles 2 are made from a flowable but setting composite material.

A liquefied material is fed through a feed line 3 to a dosing head 4. The dosing head

4 has four nozzles 5. The liquid material is applied through the four nozzles 5 onto a flat surface 6 of a slowly rotating disc 7. The surface 6 of the disc 7 is coated with a non-stick finish in order to reduce the adhesion of discharged droplets 8 at the surface 6. After the individual droplets have been applied, the setting of the composite material occurs and the droplets 8 harden and become hardened particles 2. During the setting process, the disc 7 rotates so that the particles 2 are moved towards a scraper 9 which extends from the center of the disc 7 radially outwards across the disc 7. Once the particles 8 arrive at the scraper 9 on the rotating disc 7, the scraper 9 scrapes the particles 8 from the surface 6 of the disc 7 and transports them radially outwards until the particles 2 fall from the edge of the disc 7 into a particle reservoir 10 in which a powder 11 of the particles 2 accumulates.

The rotating speed of the rotating disc 7 is adapted to the size of the disc 7 and to the duration of the setting process of the discharged droplets 8 into the hardened particles 2. It is also possible to discharge the droplets 8 through a dosing head 4 with a single nozzle 5 and to displace the dosing head 4 or at least the nozzle 5 of the dosing head 4 with respect to the rotating disc 7 in a manner as to distribute the discharged droplets 8 along the radius of the disc 7 and to avoid unwanted agglomeration of droplets 8 that are discharged close to each other.

With the device 1 shown in Figure 1, a particle manufacturing step according to the method described above can be performed. During the particle manufacturing step the flowable composite material is liquefied and delivered through the feed line 3 to the dosing head 4 of a discharge unit. Wth the nozzles 5 of the dosing head 4 a large number of droplets 8 of the liquefied composite material is intermittently discharged at a distance towards each other to a setting unit, i.e. onto the flat surface 6 of the rotating disc 7 of the setting unit, where the setting of the droplets 8 into the particles 2 occurs. After the setting of the liquefied composite material the particles 2 are collected to make the powder 11 of particles 2 that is used for preparation of a solid administration form.

Figure 2 illustrates the formulation step for manufacturing the solid administration form from the powder 11 of particles 2 that has been previously manufactured with the device 1 as described above. During the formulation step a predetermined amount of powder 11 is placed in a mould 12. The powder 11 is compressed in the mould 12 and a solid administration form 13 in tablet form is pressed with a displaceable press plunger 14. Afterwards, the solid administration form 13 can be removed from the mould 12.

Figure 3 illustrates another embodiment of the device 1 for the manufacture of the powder 11 of particles 8 of the composite material that can be used for the manufacture of solid administration forms 13. The dosing head 4 is movably arranged over the surface 6 of a tray 15 of the setting unit. The dosing head 4 can be moved along a serpentine path over the surface 6 of the tray 15 in order to discharge droplets 8 of the composite material onto the surface 6 of the tray 15. After placing the droplets 8 on the surface 6, the setting of the droplets 8 occurs and the droplets 8 become hardened particles 2.

The hardened particles 2 can be removed from the surface 6 by tilting the tray 15 and by directing an airstream from an airstream unit 16 onto the surface 6 of the tray 15 in order to blow all the particles 2 from the surface 6 of the tray 15 into the particle reservoir 10.

Examples

The present description enables the person skilled in the art to apply the invention comprehensively. Even without further comments, it is assumed that a person skilled in the art will be able to utilize the above description in the broadest scope.

Practitioners will be able, with routine laboratory work, using the teachings herein, to prepare active ingredients comprising formulations as defined above in the new process.

The invention described may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in anyway.

If anything is still unclear, it is understood that the publications and patent literature cited should be consulted. Accordingly, these documents are regarded as part of the disclosure content of the present description.

For better understanding and in order to illustrate the invention, examples are given below which are within the scope of protection of the present invention. These examples also serve to illustrate possible variants. Owing to the general validity of the inventive principle described, however, the examples are not suitable for reducing the scope of protection of the present application to these alone. Furthermore, it goes without saying to the person skilled in the art that, both in the examples given and also in the remainder of the description, the com-ponent amounts present in the compositions always only add up to 100% by weight, volume or mol-%, based on the composition as a whole, and cannot exceed this, even if higher values could arise from the per cent ranges indicated. Unless indicated otherwise, % data are % by weight, volume or mol-%, with the exception of ratios.

The temperatures given in the examples and the description as well as in the claims are always in °C.

Example 1

Preparation of a suitable thermal binder in form of granules, to be used in the 3D Printing process, by hot melt extrusion (HME)

Pre-treatment of the material For the preparation of a suitable thermal binder in form of granules for the 3D Printing process by HME 2.0 kg polyvinyl-alcohol = PVA (Parteck MXP, Cat No 141360 from Merck KGaA Germany) with optimized particle size distribute for HME was dried at 85°C in a vacuum oven.

Extrusion was started by adjusting the dosing rate of the dosing unit and the screw speed of the extruder in small increments until the target parameters of 0.35 kg / h and 350 rpm reached. This took from the start of the process to the first exit of extrudate from the nozzle about 5 minutes. The extrudate emerged as very homogeneous, transparent strand from the nozzle (2mm in diameter), having a yellow-orange color. Extruder conditions used: Pressure at the nozzle 14-15 bar. Melting temperature 192 °C and a torque of 41-42%, Heating zones HZ 1 = 80°C/ HZ 2 - HZ 7 = 200°C Nozzle temperature = 200°C

The extrudate strand was discarded for about 10 minutes until it emerged homogeneously from the die. Thereafter, the strand was started to be conveyed to the pelletizer by means of a conveyor belt, which gave the extrudate a short cooling phase at room temperature and then to be cut to 1.5 mm pellets in length. The material was finally dried under vacuum at 85°C before use in 3D printing device to a LOD <0.1%.

Example 2

5 Preparation of a binary dispersion of dipyridamole as active pharmaceutical ingredient (API) and PVA as suitable thermal binder in form of granules, to be used in the 3D Printing process, by hot melt extrusion (HME)

Preparing the mixture

The binary mixture of PVA polymer (dried at 85°C in a vacuum oven) and 10% API was prepared by mixing 1.8 kg of PVA 4-88 (Parteck MXP, Cat No 141360 from Merck KGaA Germany) with 0.2 kg Dipyridamole Ph.Eur (LGM Pharma) as model API with yellow colour in a 10 L drum using a Rohnradmischer for 15 minutes.

Extrusion was started by adjusting the dosing rate of the dosing unit and the screw _"Ί speed of the extruder in small increments until the target parameters of 0.35 kg / h and 350 rpm reached. This took from the start of the process to the first exit of extrudate from the nozzle about 5 minutes. The extrudate emerged as very homogeneous, transparent strand from the nozzle (2mm in diameter), having a yellow-orange colour.

Extruder conditions used: Pressure at the nozzle 14-15 bar. Melting temperature ²⁰ 192 °C and a torque of 41-42%, Heating zones HZ 1 = 80°C/ HZ 2 - HZ 7 = 200°C

Nozzle temperature = 200°C

The extrudate strand was discarded for about 10 minutes until it emerged homogeneously from the die. Thereafter, the strand was started to be conveyed to the pelletizer by means of a conveyor belt, which gave the extrudate a short cooling 25 phase at room temperature and then to be cut to 1.5 mm pellets in length. The material was finally dried under vacuum at 85°C before use in 3D printing device to a LOD <0.1%.

Example 3

Preparation of a suitable thermal binder, to be used in the 3D Printing process, by

30 “Dry Compaction” For the preparation of a suitable thermal binder in form of dry compacted granules for the 3D Printing process 2.6 kg polyvinyl-alcohol = PVA (Parteck MXP, Cat No 141360 from Merck KGaA Germany) was compacted by physical dry compaction process.

For dry compaction a Powtec-Kompaktor RCC 100x20 (Powtec Maschinen und Engineering GmbH, Remscheid, Deutschland) was used, equipped with a sieve of 2.24mm mesh size. Product introduction of PVA powder with 30 rpm. For compaction, lumbers provided with lines and a lumber speed of 3 rpm a hydraulic pressure of 125 bars with a lumber slit of 2.1mm as well as a sieving mill speed of 50 rpm was used.

Dry compacted PVA 4-88 granules with a yield of 2.28 kg (>710pm) were prepared using conditions described before. The material was finally dried under vacuum at 85°C before use in 3D printing device to a LOD <0.1%.

Example 4

Preparation of a binary dispersion of an API and PVA as suitable thermal binder in form of granules, to be used in the 3D Printing process, by “Dry compaction”

Preparing the mixture

The binary mixture of PVA polymer and 10% API was prepared by mixing 1.8 kg of PVA 4-88 (Parteck MXP, Art No 141360 from Merck KGaA Germany) with 0.2 kg Caffeine (from Shandong Xinhua Pharmaceuticals China) as model API in a 12 L drum using a Rohnradmischer Elte 650, (Engelsmann AG, Ludwigshafen, Deutschland) for 5 minutes (36 rpm). After the first mixing time the mixture of PVA polymer and caffeine was homogenized by using a 710pm sieve following by another 5 minutes of mixing time.

For dry compaction 1.9 kg of the resulting mixture was dry compacted using a Powtec-Kompaktor RCC 100x20 (Powtec Maschinen und Engineering GmbH, Remscheid, Deutschland), equipped with a sieve of 2.24mm mesh size.. Product introduction of PVA powder with 30 rpm. For compaction, lumbers provided with lines and a lumber speed of 3 rpm a hydraulic pressure of 125 bars with a lumber slit of 1.5 mm as well as a sieving mill speed of 50 rpm was used. Resulting dry compacted mixture with a yield of 1.66 kg of PVA 4-88/caffeine granules (>710pm) prepared using conditions described before. The material was finally dried under vacuum at 85°C before use in 3D printing device to a LOD <0.1%.

Example 5

Preparation of a suitable thermal binder, to be used in the 3D Printing process, by Twin Screw Wet Granulation (TSG)

Granulation

1.6 kg of PVA 4-88 (Parteck MXP, Cat. No 141360 from Merck KGaA Germany) were weighed into a stainless-steel bowl and sieved through a 1 mm sieve into a 5 L stainless-steel barrel and mixed for 10 min in a drum hoop mixer.

For the granulation a Pharma 11 hot melt extruder modified with a TSG conversion kit (ThermoFisher Scientific) was used. The powder mixture was added with a _"Ί gravimetric feeder (Brabender Congrav OP1T) Dl-water was added with a peristaltic pump (Cole-Parmer Masterflex US). Each screw consisted of 4 Long Helix Feed Screws 3/2 L/D, 4 Feed Screws 1 L/D, 7 mixing elements 60° offset, 26 Feed Screws 1 L/D, 1 Distributive Feed Screw (front to end).

Before granulation, the barrel temperature was set to 30°C. Then the barrel was flooded with water at slow screw speed (10 rpm) and a water addition of -200 mL/h.

20

To prepare the granules the water addition was reduced to 30.1 mL/h (corresponds to the L/S ratio of 0.086). Screw speed was increased to 50 rpm and powder addition started with 0.1 kg/h. Screw speed and powder feed-rate were increased stepwise till the desired screw speed of 500 rpm (50-, then 100 rpm steps) and the powder feed-rate of 0.35 kg/h (0.05 kg/h steps) were reached.

25 First material was discarded. When the torque reached a constant level (after approx. 5 min) the resulting granules were collected in a stainless-steel bowl. To get the desired amount of 1 kg granules, granulation run for almost 3 hours. Resulting granules were tray dried in a vacuum oven for 24 h at 50°C / 0.1 bar to a LOD <0.1%.

Before use in the 3D printing process material was additionally sieved through a 5 30 mm sieve in order not to block the dosing of granules into the 3D printer by coarse particles Example 6

Preparation of a binary dispersion of an API and PVA as suitable thermal binder, to be used in the 3D Printing process, by Twin Screw Wet Granulation

5

Preparing the mixture

1.6 kg of PVA 4-88 (Parteck MXP, Cat. No 141360 from Merck KGaA Germany) and 0.4 kg of Caffeine (from Shandong Xinhua Pharmaceuticals China) were weighed into a stainless-steel bowl. Then both components were sieved through a 1 mm sieve into a 5 L stainless-steel barrel and mixed for 10 min in a drum hoop 0 mixer.

Granulation

20

Before use in the 3D printing process material was additionally sieved through a 5 30 mm sieve in order not to block the dosing of granules into the 3D printer by coarse particles Example 7

3 D printing process using a flowable material with and without addition of API.

Process of printing was performed whereby the flowable material is liquefied and delivered to a discharge unit, and whereby small portions of the liquefied material are intermittently discharged through an outlet of the discharge unit into a setting unit where the setting of small portions occurs, thereby gradually generating the solid administration form. This manufacturing method of additive manufacturing does not require the tedious prefabrication of a filament that is fed to the 3D printing device.

Evaluation of printing parameter and printing of solid administration form:

Determination of processing parameters & discharge properties Granulated material prepared by using different granulation technologies Examples 1-6 formed well separable droplets, homogeneously dropping out from the printing nozzle. At a nozzle temperature of 200°C the material shows translucent droplets. The required drop height of 200 pm +/- 10-20% was achieved with 65% discharge.

The suitable thermal binder as pure polymer or mixtures of polymer and API additives prepared in examples 1-6 were used for the printing of solid administration forms by additive manufacturing process (3D Printing) with a “Freeformer” from ARBURG GmbH + Co KG, Lossburg, Germany.

Conditions used for the printing process:

Temperature discharge unit: 190 °C

Temperature zone 2: 180 °C

T emperature zone 1 : 170 °C

Temperature printing room: 80 °C

Dynamic pressure: 80 bar

Metering stroke: 5 mm

Decompression speed: 2 mm/s Decompression space: 5 m

Discharge: 65 %

In order to find the suitable aspect ratio, test printing with different sheer volume 5 (ratio of width and layer thickness) were adjusted. Best properties could be achieved with an aspect ratio of 1.36 using material prepared in Example 1-6.

By using conditions describe before, optimize 3D printing process was performed with suitable binder of Example1-6 to generate the solid administration particles projected and depicted in Figure 1.

The discharge unit can be a commercially available 3D printing device that is able to discharge a large number of small droplets of suitable composite material. Currently available discharge units are capable of discharging up to 200 droplets with an average size between e.g. 150 pm and 250 pm, which is considered an advantageous size for the particles of the powder from which the solid administration _"Ί form can be made. After the setting of small droplets, the solidified particles can be removed from the flat surface by e.g. by scraping off the particles with help of a peel bar.

Resulting particles used in the 3D Printing process conditions are described in table 1.

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Table 1

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30

Claims

1. A method for manufacturing a solid administration form (13) comprising at least one active pharmaceutical ingredient, wherein a powder (11) of particles (2) made from a flowable but setting composite material comprising the at least one active pharmaceutical ingredient is manufactured in a particle manufacturing step, and subsequently the solid administration form (13) is prepared from the powder (11) of particles (2) in a formulation step, characterized in that during the particle manufacturing step the flowable composite material is liquefied and delivered to a discharge unit, and that droplets (8) of the liquefied composite material are intermittently discharged through an outlet of the discharge unit at a distance towards each other to a setting unit where the setting of the droplets (8) into the particles (2) occurs, and in that after the setting of the liquefied composite material the particles (2) are collected to make the powder (11) of particles (2) that is used for preparation of the solid administration form (13) within the formulation step.

2. The method of claim 1, characterized in that the discharge unit comprises a nozzle (5) that is driven by piezo actuators to open and close for discharging the droplets (8) to the setting unit.

3. The method of claim 1 , characterized in that between successive discharges of droplets (8) the setting unit is displaced with respect to the fixed discharge unit.

4. The method of claim 1, characterized in that the flowable composite material comprises a polymer and at least one amorphous active pharmaceutical ingredient that is dispersed or dissolved within the polymer.

5. The method of claim 1, characterized in that the flowable but setting composite material includes non-soluble porous or non-porous carrier particles for altering or enhancing the properties of the solid administration form (13).

6. The method of claim 1, characterized in that the flowable composite material is fabricated during delivery to the discharge unit.

7. The method of claim 1 , characterized in that the flowable composite material is made of or comprises granules prepared by known methods like e.g. hot melt extrusion, wet granulating, dry compaction or twin screw granulation.

8. The method of claim 7, characterized in that an average diameter of the droplets (8) is less than 350 pm, preferably less than 200 pm, and in that the average diameter of the droplets (8) is larger than 20 pm and preferably larger than 50 pm.

9- Device (1) for manufacturing a power (11) of particles (2) of a composite material comprising at least one active pharmaceutical ingredient, whereby the device (1) comprises a discharge unit with at least one nozzle (5) that is arranged above a setting unit, whereby a droplet (8) of the liquefied composite material can be discharged from the discharge unit through the nozzle (5) to the setting unit, where the setting of the droplets (8) into particles (2) occurs, and whereby the device (1) also comprises a particle harvesting unit for collecting and removing the particles (2) from the setting unit.

10. Device (1) according to claim 9, characterized in that the setting unit comprises a displacement mechanism that displaces the setting unit with respect to the discharge unit.

11. Device (1) according to claim 9 or claim 10, characterized in that the setting unit comprises a flat surface (6) onto which the droplets (8) are discharged from the discharge unit.

12. Device (1) according to one of the claims 9 to 11 , characterized in that the setting unit comprises a rotating disc (7) with a flat disc surface (6).

13. Device (1) according to one of the claims 9 to 12, characterized in that the particle harvesting unit comprises a scraper (9) that scrapes the particles (2) from the setting unit.

14. Device (1 ) according to one of the claims 9 to 13, characterized in that the particle harvesting unit comprises an airstream unit (16) that directs an airstream onto a region of the setting unit that is spaced apart from a droplet receiving region of the setting unit, whereby the airstream pushes the hardened particles (2) from the setting unit into a particle reservoir (10).

15. Solid administration form (13) comprising at least one active pharmaceutical ingredient, whereby the solid administration form (13) is manufactured by performing the method of claims 1 to 8.