DE202023102185U1 - Printable wording - Google Patents

Abstract

Printable formulation, comprehensive
- 2 - 30% by weight of one or more gelling agents,
- 1 - 10% by weight of one or more thickeners,
- 1-40% by weight, preferably 10-35% by weight, of one or more lipid-based adjuvants, and
- 40-70% by weight of one or more solvents.

Description

AREA

The present disclosure relates to formulations suitable for 3D printing, in particular formulations comprising one or more lipid-based excipients.

BACKGROUND

Three-dimensional printing (3D printing) is a technology that offers the possibility of creating personalized dosage forms of medicines. The main benefit of using 3D printing technology for personalized medicines is the ability to produce small batches with carefully tailored dosages, shapes, sizes and release characteristics. It is also possible that flavorings can be incorporated into a tablet without the need for a film coating, thereby completely masking the taste of the chemical compounds. 3D printers can be installed in pharmacies, hospitals, clinics and anywhere, enabling the on-demand production of medicines, especially those that have poor stability or that require a cold chain for their storage. For pharmaceutical companies, 3D printing can significantly reduce costs, waste and environmental impact because the printers only dispense the exact amount of raw materials needed.

The biggest challenge in the 3D printing process is the development of the ink itself, as its physiochemical properties can greatly affect printability. The ink should be printable at moderate temperatures while being solid at ambient temperature.

Accordingly, there is still a need for additional printable drug formulations.

SUMMARY

It was observed that 3D printability of a formulation could be improved when part of a formulation's thickening agents were replaced by one or more lipid-based excipients.

• - 2 - 30 Gew.-% eines oder mehrerer Geliermittel,
• - 1 - 10 Gew.-% eines oder mehrerer Verdickungsmittel,
• - 1 - 40 Gew.-%, vorzugsweise 10 - 35 Gew.-% eines oder mehrerer Hilfsstoffe auf Lipidbasis, und
• - 40 - 70 Gew.-% eines oder mehrerer Lösungsmittel.

Accordingly, it is an object of the present invention to provide a printable formulation comprising

• - 2 - 30% by weight of one or more gelling agents,
• - 1 - 10% by weight of one or more thickeners,
• - 1-40% by weight, preferably 10-35% by weight, of one or more lipid-based adjuvants, and
• - 40-70% by weight of one or more solvents.

A number of exemplary and non-limiting embodiments of the invention are described in the appended dependent claims.

Various exemplary and non-limiting embodiments of the invention and for working methods, together with additional purposes and advantages thereof, can be gathered from the following description of specific exemplary embodiments when read in connection with the attached figures.

The verbs "comprise" and "include" are used in this document as non-exhaustive limitations that neither exclude nor require the presence of other features not mentioned. The features listed in the dependent claims can be freely combined with one another, unless expressly stated otherwise. In addition, it is to be understood that the use of "a" or "an" i. H. a singular form, in this document does not exclude a multiplicity.

DESCRIPTION

The specific examples provided in the following description should not be construed as limiting the scope and/or applicability of the appended claims. The lists and groups of examples given in the description below are not exhaustive unless expressly stated otherwise.

• - 2 - 30 Gew.-% eines oder mehrerer Geliermittel,
• - 1 - 10 Gew.-% eines oder mehrerer Verdickungsmittel,
• - 1 - 40 Gew.-%, vorzugsweise 10 - 35 Gew.-% eines oder mehrerer Hilfsstoffe auf Lipidbasis,
• - 40 - 70 Gew.-% eines oder mehrerer Lösungsmittel, und gegebenenfalls
• - ein oder mehrere Konservierungsmittel, Mittel zur Einstellung des pH-Werts und/oder Aromastoffe.

In one aspect, the present disclosure relates to a formulation comprising

• - 2 - 30% by weight of one or more gelling agents,
• - 1 - 10% by weight of one or more thickeners,
• - 1 - 40% by weight, preferably 10 - 35% by weight of one or more lipid-based excipients,
• - 40-70% by weight of one or more solvents, and optionally
• - one or more preservatives, pH adjusters and/or flavourings.

The gelling agents are preferably selected from a group consisting of gelatin, pullulan, carrageenan and agar. According to one embodiment, the gelling agent is gelatin and the formulation comprises 5-30% by weight of gelatin. According to another embodiment the gelling agent is agar and the formulation comprises 5-10% agar such as e.g. B. 6% by weight agar.

The thickening agents are preferably selected from a group consisting of mannitol, cellulose and silica. The cellulose can be microcrystalline cellulose (MCC).

The formulation includes one or more lipid-based excipients. Exemplary lipid-based excipients suitable for formulation are cocoa butter, coconut oil, glycerol gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. Preferred lipid-based excipients are cocoa butter and coconut oil. Mixtures of one or more lipid-based adjuvants can also be used.

The formulation includes one or more solvents. The preferred solvents are water and glycerin. According to an exemplary embodiment, the formulation comprises 40-50% by weight water and 5-6% by weight glycerin. Higher amounts of solvent such. B. 50% by weight or more may be preferred if high solubilization of API in the formulation is to be achieved. The presence of excessively high proportions of solvent, particularly water, but also one or more other near-infrared (NIR)-absorbing elements such as e.g. However, additives such as thickeners, other solvents and fillers should be avoided when NIR is used for formulation quality control.

The formulation may also comprise one or more preservatives, one or more pH adjusters and one or more flavoring agents. Exemplary pH adjusters are citric acid, sodium citrate and malic acid. Exemplary preservatives are sorbic acid, potassium sorbate and parabens. Exemplary flavorings are selected from beef flavor, bacon flavor, lamb flavor, chicken flavor, chicken liver flavor, cheese flavor, cod liver oil, marshmallow flavor, molasses flavor, vanilla flavor, peanut butter flavor, fruit flavor and berry flavor.

Typically the formulation may comprise up to 1% preservatives, up to 1% pH adjusters and up to 5% flavoring agents by weight based on the total weight of the formulation.

According to a preferred embodiment, the formulation comprises one or more sweeteners selected from the group of polyol sugars, which are not metabolized in the same way as normal carbohydrates and have fewer calories than sugar. An exemplary polyol sugar is erythritol.

It is essential that the printing formulation is thermoreversible. Their viscosity at printing temperature must allow printing at moderate temperature, such as B. at 40 - 50 ° C, while it must be solid at room temperature. The viscosity of the formulation of the present disclosure at 50°C (shear rate 150-800) is preferably 2-4 Pa·s.

According to a particular embodiment, the formulation comprises one or more active pharmaceutical ingredients (APIs). Exemplary APIs are selected from the group consisting of sildenafil, caffeine, prednisolone, gabapentin, ursodeoxycholic acid, atenolol, theophylline, diltiazem, hydrochlorothiazide, propranolol, metoprolol, metronidazole, captopril, furosemide, and pharmaceutically acceptable salts thereof. The formulation typically comprises from 0.1% to 10% by weight of one or more APIs, where the wt% is the total wt% of the APIs in the formulation.

The formulation used has a significant impact on the release of the active ingredient it contains. The proportion of the lipid-based excipient is preferably 10-35% by weight in order to more precisely control the viscoelastic behavior and to facilitate processing. With a lower ratio, the consistency is less favorable due to the low viscosity at optimal processing temperatures. At higher wt%, oil and water phase separation is more likely to occur. Due to the higher viscosity, higher temperatures may also be required. In addition, if the weight percent of a lipid-based excipient in the oral preparation is too high, the greasy consistency and taste can be objectionable.

• - Bereitstellung einer Formulierung, umfassend
  • - 2 - 30 Gew.-% eines oder mehrerer Geliermittel,
  • - 1 - 10 Gew.-% eines oder mehrerer Verdickungsmittel,
  • - 1 - 40 Gew.-%, vorzugsweise 10 - 35 Gew.-% eines oder mehrerer Hilfsstoffe auf Lipidbasis,
  • - 40 - 70 Gew.-% eines oder mehrerer Lösungsmittel, und
  • - 0,1 - 10 Gew.-% eines oder mehrerer aktiver pharmazeutischer Wirkstoffe (API),
• - Erhitzen der Formulierung auf eine Temperatur von mindestens 37 °C,
• - Drucken der Formulierung unter Verwendung eines 3D-Druckers bei mindestens 37 °C auf ein Drucksubstrat,
• - Abkühlen der Formulierung auf 30 °C oder darunter und
• - Lösen der Formulierung von dem Drucksubstrat, wodurch die feste Dosierungsformulierung bereitgestellt wird.

The solid dosage formulation can be manufactured by a process comprising:

• - Providing a formulation comprising
  • - 2 - 30% by weight of one or more gelling agents,
  • - 1 - 10% by weight of one or more thickeners,
  • - 1 - 40% by weight, preferably 10 - 35% by weight of one or more lipid-based excipients,
  • - 40-70% by weight of one or more solvents, and
  • - 0.1 - 10% by weight of one or more active pharmaceutical ingredients (API),
• - heating the formulation to a temperature of at least 37 °C,
• - Printing the formulation using a 3D printer at a minimum of 37 °C onto a print substrate,
• - cooling the formulation to 30°C or below and
• - releasing the formulation from the print substrate, thereby providing the solid dosage formulation.

According to one embodiment, the one or more APIs are added to the formulation during the manufacturing process of the formulation. According to another embodiment, the one or more APIs are admixed in a pre-formulated formulation. Exemplary, non-limiting APIs suitable for the present disclosure are sildenafil, caffeine, prednisolone, gabapentin, ursodeoxycholic acid, atenolol, theophylline, diltiazem, hydrochlorothiazide, propranolol, metoprolol, metronidazole, captopril, furosemide, and pharmaceutically acceptable salts thereof.

When the API is added to the formulation, its effect on viscosity depends on what phase it goes into, ie. H. lipophilic drugs in the lipid phase and hydrophilic in the water/hydrophilic phase. The properties of the API can also decrease or increase the viscosity. The effects depend on the solubility of the drugs in the matrix and hydrogen bonding. Substances that are able to form hydrogen bonds tend to have a higher viscosity than substances that do not form hydrogen bonds. In general, substances that can form multiple hydrogen bonds have an even higher viscosity. The hydrogen bonding potential is higher at higher concentrations and vice versa.

It is essential that the admixture is heated to 37°C or higher to ensure proper printing. The printing temperature is preferably between 37°C and 55°C. An example printing temperature is 40°C. Another example is a printing temperature of 45°C.

The mixture is printed onto a print substrate, which is preferably inside the 3D printer. After the printing process is complete, the mixture solidifies on cooling, e.g. B. by lowering the temperature to 30 °C or below.

test arrangement

3D printing

• Düsengröße 1,5 mm
• Druckgeschwindigkeit 1500 - 4000 mm/min
• Durchflussgeschwindigkeit Inhaltsstoffe 2 m/min
• Fließtemperatur Inhaltsstoffe 40 - 50 °C
• Vorheiztemperatur 40 - 50 °C
• Haltedicke der Inhaltsstoffe 0,2 - 2,5 mm
• Vorheizzeit 30 - 60 s
• Höhe der ersten Schichtdüse 10 mm
• Abstand zwischen den Schichten 1,4 mm

Printing was performed using a commercial 3D printer (Foodini by Natural Machines) equipped with ink cartridges, heaters, nozzles, control software and a print base. The typical printing parameters were as follows:

• Nozzle size 1.5mm
• Printing speed 1500 - 4000 mm/min
• Flow rate of ingredients 2 m/min
• Flow temperature ingredients 40 - 50 °C
• Preheating temperature 40 - 50 °C
• Holding thickness of the ingredients 0.2 - 2.5 mm
• Preheating time 30 - 60 s
• Height of the first layer nozzle 10 mm
• Distance between layers 1.4 mm

An exemplary printable formulation according to the present disclosure is presented in Table 1. The comparative formulation was as shown in Table 1, but mannitol was substituted for the cocoa butter. Table 1 Ingredients : Amount (g) % g/g gelatin 12:42 12:42 0.1242 Purified water 42.39 42.39 0.4239 glycerin 5.59 5.59 0.0559 potassium sorbate 0.15 0.15 0.0015 citric acid 0.47 0.47 0.0047 sucralose 0.048 0.05 0.0005 xylitol 20.38 20.38 0.2038 maltodextrin 4:23 4:23 0.0423 cocoa butter 12:23 12:23 0.1223 silica 1.23 1.23 0.0123 raspberry flavor 0.15 0.15 0.0015 vanilla flavor 0.23 0.23 0.0023 In total 100.00 100.00 1.00

observations

• • The printable formulation containing a lipid-based excipient produced a more consistent print from tablet to tablet. The extrusion was more controllable and the flow of material exiting the die was cut off in a controlled/uniform manner, with no undesirable dripping, resulting in a seamless deposition of the formulation. In addition, significantly less of the formulation was extruded into the waste bin before the start of each print job.
• • The addition of lipid-based excipients does not affect the solubility of water-soluble APIs. The formulation is homogeneous and does not separate for up to a month at room temperature. The mechanical properties are also favorable, making handling easier and the formulation less sticky.
• • Mass change, physical appearance and mouthfeel have also been improved.
• • The water retention capacity (water/solvent evaporation from the formulation is much less) of the final formulation has been significantly improved. Compared to the comparative formulations, the formulations are able to maintain their physical integrity and mechanical properties for a longer period of time when exposed to air.

Claims (13)

Printable formulation, comprehensive - 2 - 30% by weight of one or more gelling agents, - 1 - 10% by weight of one or more thickeners, - 1-40% by weight, preferably 10-35% by weight, of one or more lipid-based adjuvants, and - 40-70% by weight of one or more solvents. Printable wording after claim 1 wherein the one or more lipid-based excipients are selected from a group consisting of cocoa butter, coconut oil, glycerated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, fatty acid esters of polyethylene glycol and mixtures thereof, preferably cocoa butter and coconut oil and mixtures thereof . Printable wording after claim 1 or 2 , wherein the one or more gelling agents are selected from a group consisting of gelatin, pullulan, carrageenan and agar, preferably gelatin. Printable formulation according to any of the Claims 1 until 3 wherein the one or more thickeners are selected from a group consisting of mannitol, cellulose and silica. Printable formulation according to any of the Claims 1 until 4 , wherein the one or more solvents are selected from water and glycerin. Printable formulation according to any of the Claims 1 until 5 comprising one or more preservatives, one or more pH adjusters and/or one or more flavoring agents. Printable wording after claim 6 wherein the one or more preservatives are selected from sorbic acid, potassium sorbate and parabens. Printable wording after claim 6 or 7 wherein the one or more pH adjusting agents are selected from citric acid, sodium citrate and malic acid. Printable formulation according to any of the Claims 6 until 8th wherein the one or more flavorings are selected from a group consisting of beef flavor, bacon flavor, lamb flavor, chicken flavor, chicken liver flavor, cheese flavor, cod liver oil, marshmallow flavor, molasses flavor, vanilla flavor, peanut butter flavor and cherry flavor. Printable formulation according to any of the Claims 6 until 9 wherein the one or more flavoring agents comprise one or more polyol sugars. Printable formulation according to any of the Claims 1 until 10 , which comprises 0.1 - 10% by weight of one or more active pharmaceutical ingredients (API). Printable formulation according to any of the Claims 1 until 11 , where the viscosity of the printable formulation is 1-2 Pa s at 50 °C. formulation according to claim 12 , wherein the one or more APIs are selected from a group consisting of sildenafil, caffeine, prednisolone, gabapentin, ursodeoxycholic acid, atenolol, theophylline, diltiazem, hydrochlorothiazide, propranolol, metoprolol, metronidazole, captopril, furosemide and pharmaceutically acceptable salts thereof.