GB2614129A - Chewable semi-solid milk-based drug delivery platform and method for the preparation of milk-based drug compositions and its use - Google Patents

Abstract

A drug delivery platform is disclosed for sensitive patient populations, notably paediatric and geriatric population groups, subjects with swallowing difficulties and low treatment compliance groups. The composition is remarkable in that it is chewable, semi-solid and dairy-based. The composition is preferably in a form that is able to be 3D-printed. The dairy base of the composition may be milk and or yoghurt powder. A method is disclosed for the preparation thereof and its use.

Description

Chewable semi-solid milk-based drug delivery platform and method for the preparation of milk-based drug compositions and its use

Technical field of the invention

The present invention relates to a chewable semi-solid dairy-based drug delivery platform intended for use in sensitive patient populations, such as pediatric and geriatric, having swallowing difficulties and low treatment compliance.

Background of the invention

The development of age-appropriate formulations for the pediatric population is the fundamental cornerstone of medication adherence and an unmet need for health-care provision. The current availability of dosage forms designed specifically for children is limited, since adult medicines monopolize pharmaceutical manufacturing. The developmental and physical heterogenicity encountered within the pediatric population is a main challenge in developing pediatric medicines, as well as the inadequate information available on excipient safety and patient acceptability on diverse dosage forms, the ethical issues arising from clinical testing on children and the smaller size of the pediatrics market, in comparison with the adults one. It is therefore a common practice to use unlicensed or off-labeled medicines and extemporaneous preparations to complement the scarcity of commercially available child-appropriate dosage forms. However, this type of empirical interventions, considering children as "small adults", may have a negative impact on dose accuracy, stability and bioavailability of a drug product, thus exposing children to unpredictable safety risks.' The development of pediatric-appropriate dosage forms should thus fulfill certain qualitative and safety requirements. The variation in the physiological and biological characteristics of the pediatric patient population necessitates a breadth of dosage strengths, which are not sufficiently covered by the commercially available pharmaceutical products. The high acceptability and ease of administration of liquid dosage forms, such as syrups, may be counterbalanced by dose inaccuracy, stability, transportation and storage concerns, while the more conventional tablets and capsules might be difficult to swallow, especially by younger children. As such, powders, multiparticulate preparations comprised of granules, pellets or beads, orodispersible and effervescent tablets, lyophilisates, orally disintegration dosage forms, such as tablets and films, and chewable tablets have been introduced as a means to overcome swallowing difficulties posed by the conventional oral solid dosage forms.2 However, most of them require reconstitution or co-administration with an aqueous phase.

Chewable dosage forms have been added to the armamentarium against low compliance and adherence. The mastication might increase the bioavailability of APIs administered as chewable dosage forms by assisting their oral transmucosal absorption. Additionally, rapid and high bioavailability might occur since, after chewing and dissolution in physiological fluids, the drug is readily available for absorption through the gastrointestinal tract. Semi-solid dosage forms have been introduced as a means to overcome the gritty and chalky mouthfeel of chewable tablets, further affording to improved swallowability, allowing the patient to consume all ingredients including the API without having large solid dosage forms.

Therefore, flexibility in dose adjustment and dose titration based on the weight, age and severity of the patient's health would be beneficial for dose accuracy, while at the same time facilitating its administration or ease thereof.3 The "one size fits all" approach seems to have been overcome in pharmaceutical manufacturing since the demand for personalized drug products is steadily growing. Additive manufacturing has introduced pharmaco-printing in the landscape of patient-centric dosage forms, enabling customization on individual patient's health requirements.4 Moreover, it may provide the opportunity to involve sensitive patient groups, such as the pediatric population, in the process of custom design and therefore improve the healthcare experience and the overall acceptability of the final product.5 The acceptability of 3D printed chewable tablets of isoleucine prepared at a hospital setting by semi-solid extrusion 3DP has been recently investigated among four pediatric patients aged between 3-16 years old. The printlets, which varied in color and flavor, were well accepted by the children, who also showed specific color and flavor preferences.6 Formulations that appeal to children's preferences in terms of appearance, taste, texture, and smell can impact beneficial efforts to treatment compliance, quality of care and even therapeutic response.' Therefore, implementation of pediatric-friendly dosage forms not as a promotional trick, but rather as a supportive tool to overcome cases of force-feeding medicine and to change children's attitude to their care and health condition may contribute to improving the emotional state of the pediatric patient and their overall healthcare experience, especially in severe medical conditions.

At the same time, caution should be exercised in the selection of acceptable excipients to avoid exposure of children to potentially harmful materials. Milk is a natural, safe, abundant and cost-effective carrier, widely accepted and consumed by the general population, specifically by children for whom it is part of their daily routine. It has been reported to increase the solubility° and dissolution rate9 of lipophilic drugs, as well as the extend of drug absorption, compared to conventional capsule formulations.1° In addition, milk has gastroprotective effects" and is indicated to be administered with non-steroidal anti-inflammatory drugs to prevent stomach irritation caused by them.

Prior art

A publication of Cheng Pau Lee et al. in 2020 discloses a method to perform 3D printing of milk-based products consisting of milk powder and water via cold extrusion at room temperature using a direct ink writing (DIW) 3D printer with potential applications in formulating food. Milk inks were prepared by adding milk powder into deionized water at 70-75 w/w% weight concentrations and the samples were then mixed thoroughly and degassed at 25°C. 70 w/w% milk inks successfully fabricated complex 3D structures. Yet, there is no reference in this document to the use of the milk inks for pharmaceutical products. In addition, the milk powder used from Fernleaf Family Milk, Fonterra, Malaysia is not specific for consumption by children. Moreover, there is no information on whether a specific particle fraction of the milk powder was selected for the preparation of the milk inks. Previous studies have shown increased grittiness perception with increased size of multiparticulates, suggesting that smaller particles would be more appropriate than larger particles in terms of mouthfeel and overall product palatability in either children or adults.12 As reported in the publication, successful fabrication of complex 3D structures was achieved with formulations containing 70 w/w% milk powder and 30 % water, with no information included, however, on the final water content of the 3D printed structure. It is known from the literature that the water of milk powder commonly ranges between 2,5 % and 5 %, and no microbial growth occurs at such a low water content's Therefore, the lower the water content, the longer the shelf life of the 3D printed milk product will be. In addition, the fact that the 3D printing is performed via cold extrusion at room temperature does not favor the reduction of the water content of the 3D printed structure.

A publication of Karavasili C. et al in 2020 discloses the development of pediatric friendly chocolate-based oral drug dosage forms using extrusion-based 3D printing. The composition of the printable chocolate links consisted of bitter chocolate and corn syrup at a 1:1 wt ratio. The blank inks were prepared by first melting the bitter chocolate in a water bath at 38°C and adding the corn syrup preheated at the same temperature. The materials were then mixed gently with a rubber spatula until homogenization. For the drug loaded printable chocolate inks, the hydrophilic drug (paracetamol) was dissolved in the corn syrup, while the lipophilic drug (ibuprofen) was melted in the heated corn syrup at the drug's melting temperature which is 79°C. The chocolate inks were immediately loaded in the cartridge of the 3D printer and were left at room temperature overnight. Yet, there is no reference in this document to the use of milk powder. This document describes a method for the incorporation of lipophilic compounds which involves melting of the lipophilic drug in corn syrup after heating the latter at a temperature equal to the melting point of the drug and then mixing with chocolate. Given that the melting point of almost 80 % of all approved drugs fall within the temperature range of 80-240°C,14 this significantly reduces the number of lipophilic drugs that can be used with this specific drug delivery system, since heating of corn syrup above 100°C will result to alteration of its composition, due to water evaporation, and possibly degradation byproducts. The preparation process involves more than one raw material. It involves heating at high temperatures, the 3D printing resolution is not very high and no method to ensure precise printing of individualized dosages is provided. In addition, the use of chocolate has been associated with obesity and tooth decay in children.

The publication of Chatzitaki AT et al (2021) describes the development of soft semi-solid formulations as age-appropriate formulations for paediatric patients using extrusion-based 3D printing. The developed formulations consist of starch and water. The starch is sieved and the mean particle size of corn starch used for the preparation of the ink was calculated to be 75 pm. The 3D printed formulations enable dose personalization. However, there is no reference in this document to the use of milk powder or to the final water content of the 3D printed structure. The document describes a method for the incorporation of hydrophilic compounds only in the starch ink and there is no method provided for the incorporation of lipophilic compounds.

The document of Kytariolos et al 2013 explores the physicochemical characteristics of milk-based formulations. Specifically, the changes in colloidal stability of the emulsion and the size of the particles of the ingredients of milk, after the addition of alkaline regulatory or ethanol-containing drugs were assessed. The aim of the study of Kytariolos et al 2013 is to develop a formulation to be mixed with long-lasting milk prior use. However, there is no reference in of Kytariolos et al 2013 in regard to the use of the milk inks for pharmaceutical products or to the use of the 3D printing technique. In the present invention the use of 3D printing is necessary for the preparation of personalized dosage forms for pediatric patients.

The document W02021105051A1 describes the pharmaceutical composition and the method followed for the preparation of semi-solid formulations utilizing the 3D printing technique. The excipients used for ink preparation are polysaccharides (iota-carrageenan, xanthan gum, gelatin), sweeteners, flavor enhancers (strawberry flavor), binders or disintegrants (corn starch), water and colors, as well as active ingredients. There is no reference in this document in regard to the use of milk as excipient neither to a method that would enable dose accuracy in the formulations. At the same time, differences in both documents are found in the process of The document of Orubus S.E.F., et al 2016, describes the preparation of a milk-based dispersible tablet that is re-dispersed in water to form a suspension with similar organoleptic properties to milk in order to be a useful drug delivery platform to improve compliance in young children. The milk-based tablets referred to the document of Orubus S.E.F., et al 2016 are made by direct compression. However, it is stated that the platform cannot be used to incorporate high doses of active pharmaceutical ingredients. At the same time, the technique used for the preparation of dispersible tablets is a method for the manufacturing of large-scale commercially available medicines, so the platform and method used are not consistent with personalized doses. The document of Orubus S.E.F., et al 2016, describes that the milk-based dispersible tablets should be re-dispersed in water prior to administration. The additional manipulation of the formulations prior to administration may result in risks related to dose accuracy.

The publication of Binte Abu Bakar, et al 2019, mentions a method for the manufacturing of tablets by direct compression containing milk powder (children's milk powder or lyophilized milk) as an excipient, which are designed to be dispersed in 10-20 mL of water and administered according to the needs of each patient. However, the additional manipulations carried out to achieve the desired dose result in potential risks related to the dose accuracy. At the same time, the dispersible tablet consists of milk powder and of a dispersant (30 % w/w) which achieves disintegration in less than 20 minutes. The present invention does not mention the use of dispersants, in particular the paste described in the study consists of milk powder and water. At the same time, the manufacture of tablets with the technique of direct compression is a method of manufacturing dosage forms in a large-scale, enables no personalization in the administered drug dose. However, the similarities presented in the two documents are the use of milk powder for the manufacturing of pharmaceutical products and the sieving of milk powder to achieve uniformity of grains after lyophilization of milk and before compression.

Document CN108740284 discloses the preparation of instant milk protein gelatin and its applications in 3D printing, belonging to the technical feed of preparing 3D printing food material.

The method comprises the steps of firstly preparing the protein suspending liquid of casein sodium, then add concentrated milk protein (MPC) at concentrations of 15%-30% w/v into protein suspending liquid, then mixing occurs followed by refrigeration at 4°C for 7-10 h to form a uniform gelatinous mass. Yet, there is no reference in this document to the use of the inks for pharmaceutical products. The preparation process involves more than one raw material. It involves an additional refrigeration step for gelation to occur prior 3D printing. The final formulation is a gel consisting of a high-water content, of at least 85%-70%, which is associated with a low stability, the possibility of a microbial growth and shorter shelf life.

Aim of the invention The present invention aims at remedying the shortcomings of the prior art documents referred to above by providing a suitable solution to the problems stated above in connection with the difficulties encountered by specific population groups in particular, such as children and elder people, especially when having difficulties to swallow, including medication.

Summary of the invention

With this goal, it is proposed according to the present invention a drug composition delivery platform for targeted sensitive patient populations such as pediatric and geriatric population groups having swallowing difficulties and low treatment compliance, as defined in main claim 1. The invention is remarkable by appropriate features defined as a drug composition dosage form that is chewable, semi-solid and dairy-based, in particular milk and/or yoghurt based.

According to a particular embodiment of the drug delivery platform according to the invention, said dairy-base of said drug composition dosage form consists of milk, lactose free milk, fortified soy milk or yogurt powder, more particularly wherein said milk powder is an infant or toddler milk formula powder.

According to a more particular embodiment of the invention, the semi-solid drug dosage form comprises a mixture of milk powder and water for a 3D printed edible dosage form loaded with therapeutics.

According to a further embodiment of a product according to the invention, there is provided a 3D printed edible dosage from loaded with therapeutics in complex shapes, esp. a selectable fantasy shape, as appealing means, such as a cartoon character, according to child's preference, so that it is visually appealing to the child. This will encourage a pediatric patient in a hospital setting to consume the 3D printed dosage form, therefore increasing the possibility that the child takes their medication as prescribed.

According to an even more particular embodiment of the invention, the said shape consists of a specially featured character selected from animals to cartoon characters or oneiric figures that are visually appealing to the user or patient, notably wherein the said semi-solid drug dosage form contains tasting additives rendering it tastefully appealing to the user or patient.

The present invention also relates to a method for the preparation of a milk-based drug composition, particularly of a chewable semi-solid milk-based drug delivery platform as defined in the main method claim. The present invention particularly relates to a method for the preparation of a semi-solid drug dosage from consisting of milk powder and water. The invention further relates to a process for an extrusion-based 3D printing of the milk-based drug compositions in complex structures.

According to a main embodiment of a method according to the invention, for the preparation of a milk-based drug composition, particularly of a chewable semi-solid milk-based drug delivery platform as defined above, the semi-solid drug dosage form is obtained from mixing milk powder and water for a 3D printed edible dosage form which is loaded with therapeutics.

According to a particular embodiment of said method according to the invention, it is remarkable by the following steps: the milk or yogurt powder or yogurt is placed on the uppermost sieve of a sieve stack with a set of apertures with decreasing diameter and is shaken for a preset duration in a sieve shaker, after which the milk powder fraction with a particle size in a preselected range is collected and incorporated in the further preparation of the semi-solid drug dosage forms; Alternatively the milk or yogurt powder is micronized using known to the art milling processed (e.g., cutter mill, jet mill, pin mill, or hammer mill) (ii) hydrophilic therapeutic compounds are incorporated, wherein an appropriate amount of the therapeutic compound is first dissolved in an x fraction of water, after which the aqueous drug solution is then mixed with an (1-x) fraction of milk powder until a homogeneous milk paste is obtained, wherein the drug loaded milk paste is referred to as milk ink, resp. or (iii) lipophilic therapeutic compounds are incorporated, wherein an appropriate amount of therapeutic compound is first dissolved in an appropriate volume of absolute ethanol, the ethanolic drug solution is mixed with an appropriate amount of the milk powder and the dispersion is left in an oven as heating means, particularly at about 35°C for a certain duration, particularly of about 24 h until the complete evaporation of the organic solvent by means whereof a solid dispersion is obtained, after which the solid dispersion is then grinded in a mortar with a pestle as grinding means.

According to a more particular embodiment of said method according to the invention, there is the following additional step wherein appealing means consisting of food colorants or/and flavorings are dissolved in the said aqueous or ethanolic phase.

According to a still more particular embodiment of the invention, the process for the fabrication of complex 3D structures using an extrusion-based 3D printing. Milk-based drug compositions in complex structures particularly as defined above, is remarkable in that the drug loaded milk paste referred to as milk ink is loaded in a container means consisting of a cartridge of printing means, particularly an extrusion-based 3D printer, having a nozzle, wherein the cartridge is then assembled in the printing means. It may be possibly left under heating at a certain temperature for a certain time, particularly of 40°C, resp. 30 min prior the initiation of the 3D printing process, so as to facilitate the extrusion process.

According to a yet more particular embodiment of said method according to the invention, said milk paste referred to as milk ink is 3D printed with good resolution in 3D structures resembling a variety of pediatric, resp. geriatric or disabled friendly designs which is customizable for the following lists of selection parameters, ranging from animals to cartoon characters, particularly wherein patients get actively involved in the selection of the design to be 3D printed.

According to an even more particular embodiment of said method according to the invention, the 3D printed milk-based dosage forms are produced with a soft and/or smooth texture, which may be similar to that of a red bean paste like substance, and they are chewable and easy to process orally by the consumer, e.g. in a way similar to that of a smooth cream substance oral processing.

According to a preferred embodiment of the method according to the invention, said milk paste is 3D printed with a high drug dose accuracy, wherein a defined mass of the printed milk paste contains the required drug dose with high accuracy providing the required reliability and safety.

According to a specific embodiment of said method according to the invention, for the incorporation in the milk ink of a therapeutical compound with relatively low aqueous solubility, such as the antiepileptic drug carbamazepine, the concentration of the drug in the milk ink ranges from 60% w/w to 0,1 % w/w, and/or whereas for the incorporation in the milk ink of a therapeutic compound with high aqueous solubility, such as the antiepileptic drug sodium valproate, the concentration of the drug in the milk ink might ranges from 60 % w/w to 0,1 w/w.

Additional features and properties of the invention are defined in further subclaims as appended herewith thereby notably including in particular, the said drug dosage form may have complex shapes that may be composed from a combination of regular shapes notably, more particularly wherein the said shape may form identification means for identifying said drug dosage form, thereby enabling the identification of said drug dosage form, yet more particularly wherein it may have an irregular and/or asymmetric shape, which is customizable and featuring for appealing purposes, still more particularly wherein said appealing means may consist of dying means, wherein said drug composition delivering platform is colored or dyed, thereby providing an appealing effect in addition to said identifying power, wherein said appealing means also act as identification means and vice versa.

Particularly as to the method: (i) powder means may be placed in sieving means which is further submitted to a shaking movement under the action of a shaking means, after which a certain fraction of powder having a particle size comprised in a preselected range is collected stream downward from said sieving means, wherein the collected fraction is incorporated in the further preparation of said semi-solid dosage form; and (ii) hydrophilic therapeutic compounds may be further incorporated, wherein a required amount of therapeutic compound is first dissolved in a fraction of water, thus forming an aqueous drug solution, which is in turn mixed with a corresponding suitable fraction of said powder until a homogeneous mixture paste is obtained.

More particularly, (i) powder means may be placed in sieving means which is further submitted to a shaking movement under the action of a shaking means, after which a certain fraction of powder having a particle size comprised in a preselected range is collected stream downward from said sieving means, wherein the collected fraction is incorporated in the further preparation of said semi-solid dosage form; (iii) lipophilic compounds are further incorporated wherein a requested amount of said lipophilic therapeutic compound is first dissolved in an appropriate volume of absolute ethanol, thus yielding an ethanolic drug solution, which is further mixed with a corresponding suitable amount of said powder, thus generating a dispersion product which is submitted to a subsequent evaporation step, wherein said organic solvent is completely evaporated by submitting said dispersion to a heating step by heating said dispersion in heating means at a certain temperature and duration until said dispersion becomes solid, after which the solid dispersion thus obtained is submitted to a grinding step by means of grinding means, wherein said first step (i) is then repeated and said parts of said solid dispersion are then mixed with said corresponding parts of water, until a homogeneous paste is obtained.

Specifically for the incorporation of carbamazepine in the milk ink at a final concentration of 1,7% w/w, the following procedure may be followed: -0,5 g carbamazepine is dissolved in 200 mL of absolute ethanol in a large glass beaker; -22,3 g of milk powder with particle size in the range of 25-125 pm is then added in the ethanolic solution of the drug and left under magnetic stirring for 5 minutes; - the glass beaker is then transferred in an oven at 40°C for at least 24h to enable complete evaporation of ethanol; - the resulting dry powder is grinded using a pestle and mortar and then sieved to collect the particle size range of 25-125 pm; Alternatively, the dry powder is milled using a Quadro hammer mill.

- the 22,8 g of the collected dry powder (carbamazepine)milk powder) is then mixed with 6,62 g deionized water in order to have a final solids content of 77,5 % w/w, - the dispersion is then mixed with a spatula until a homogenized paste consisting of drug loaded milk ink is obtained.

According to a further embodiment of a method according to the invention, the fabrication of complex 3D structures uses extrusion-based 3D printing.

According to a particular embodiment thereof, there is proposed a process for the extrusion-based 3D printing of the milk-based drug compositions in complex structures.

At last, the present invention also relates to the use of a chewable semi-solid milk-based drug delivery platform as set out above, which is remarkable by its use in sensitive patient populations, particularly pediatric and geriatric population groups having said swallowing difficulties and low treatment compliance.

Further details and particulars are set out in a detailed description of preferred embodiments of the invention below as also illustrated by the drawings appended herewith.

Brief description of the drawings

Fig.1 represents 3D printed milk-based constructs resembling pediatric-friendly designs showing the high resolution of a prepared milk paste composition under prescribed printing conditions. Fig. 2 shows the results of a texture profile analysis of the milk-based 3D printed dosage forms, reporting hardness, adhesiveness and cohesiveness values. highlighting the ease of chewing and oral processing of the 3D printed milk-based dosage form, compared to common semi-solid foods, with linear regression analysis in the 3D printed milk-based dosage forms with an increasing number of printed layers containing a poorly water-soluble (carbamazepine) drug.

Fig. 3A, resp. B show the results of the assessment of dose accuracy performed with linear regression analysis in the 3D printed milk-based dosage forms with an increasing number of printed layers containing a poorly water-soluble (carbamazepine) (A), resp. a water-soluble (sodium valproate) drug (B).

Fig. 4A, represents an amplitude sweep test to define the linear viscoelastic region of the milk inks as a function of strain (%)., resp. Fig. 4B represents a frequency sweep test of the milk inks in the frequency range between 0,1-100 Hz. Fig. 4C represents the viscosity profiles of the milk inks as a function of shear rate (s-1).

Fig. 5A, resp. B show the mean percentage of carbamazepine (A) resp. sodium valproate (B) dissolved (± S.D.) from the 3D printed milk-based dosage form in media simulating the gastric environment in the fasted state (FaSSGF) and the intestinal environment in the fasted state (FaSSIF), wherein dotted vertical lines represent the time of medium change.

Fig. 6 shows the dissolution profile of carbamazepine in 1% SLS distilled water from the marketed product (Tegretol® 200 mg, black line) and the 3D printed milk-based dosage form (red line) containing carbamazepine in the form of the commercial dosage form.

Description of the invention

In a first embodiment, Fig. 1 shows the 3D printed milk-based constructs resembling pediatric-friendly designs, such as animals and cartoon characters, showing the high resolution of the prepared milk paste composition under the described printing conditions, resp. by a method for the preparation of a semi-solid drug dosage from consisting of milk powder and water.

The fabrication of complex 3D structures uses extrusion-based 3D printing. The method may provide a 3D printed edible dosage from loaded with therapeutics in complex shapes, such as a cartoon character, according to child's preference, so that it is visually appealing to the child as shown in Fig. 1. This will encourage a pediatric patient in a hospital setting to consume the 3D printed dosage form, therefore increasing the possibility that the child takes their medication.

In particular, the present invention discloses a method for the incorporation of both hydrophilic and hydrophobic therapeutic compounds in the milk-based formulation. The milk powder used may be infant or toddler milk formula powder or any other type and origin of milk powder.

Said method is set out hereafter in its various steps.

In a first step, the milk powder is placed on the uppermost sieve of a sieve stack with decreasing apertures (0,212-0,025 mm) and shaken for 2 min in a sieve shaker. The milk powder fraction with particle size in the 25-125 pm range is collected and further used for the preparation of the semi-solid drug dosage forms. Alternatively, the dry powder is milled using a Quadro hammer mill (conical mill at 1000-2500 rpm).

Then for the incorporation of hydrophilic therapeutic compounds, the appropriate amount of the therapeutic compound is first dissolved in 5-50 parts of water, most preferably in 22,5 parts of water. The aqueous drug solution is then manually mixed with 50-95 parts of milk powder, most preferably with 77,5 parts of milk powder until a homogeneous milk paste is obtained.

Alternatively, the hydrophilic drug might be incorporated in the form of a marketed dosage form, in solid, semi-solid or liquid form. For example, a tablet that will be crushed, grinded and mixed with the milk powder and the water to obtain the milk paste.

For the incorporation of lipophilic therapeutic compounds, the appropriate amount of therapeutic compound is first dissolved in an appropriate volume of absolute ethanol or any other appropriate water-soluble organic solvent -e.g. polyethylene glycol 300, polyethylene glycol 400, propylene glycol, glycerin etc.-, non-ionic surfactant -e.g. Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-a-tocopherol, polyethylene glycol 1000 succinate etc.-or water-insoluble lipids --organic liquids/semi-solids (beeswax, d-a-tocopherol, oleic acid, medium-chain mono-and diglycerides), various cyclodextrins -e.g. a-cyclodextrin, p-cyclodextrin, hydroxypropyl-p-cyclodextrin, and sulfobutylether-p-cyclodextrin etc.-or phospholipids -e.g. hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol etc.-. The ethanolic drug solution is mixed with an appropriate amount of the milk powder and the dispersion is left in an oven at 35°C for 24 h until a solid dispersion is obtained after the complete evaporation of the organic solvent. The solid dispersion is then grinded in a mortar with a pestle. Said first step is then repeated and 50-95 parts of the solid dispersion, most preferably 77,5 parts of the solid dispersion are manually mixed with 5-50 parts of water, most preferably with 22,5 parts of water until a homogeneous milk paste is obtained. Alternatively, the lipophilic drug might be micronized at D90<50 pm, then homogeneously mixed with the milk powder and the water to obtain the milk paste. Alternatively, the lipophilic drug might be incorporated in the form of a marketed dosage form, in solid, semi-solid or liquid form. For example, a tablet that will be crushed, grinded and mixed with the milk powder and the water to obtain the milk paste.

Additionally, food colorants or/and flavors and/or taste masking agents may optionally be dissolved in the aqueous or ethanolic phase or mixed with the milk powder to enhance the palatability of the milk-based dosage forms and mask the bitter taste of certain drugs, but also constitute them more appealing to the eye of a child.

The drug loaded milk paste (milk ink) resulting from step (ii) or step (iii) or after the addition of food colorings or/and flavorings is loaded within the cartridge of an extrusion-based 3D printer.

The cartridge may have a volume capacity of 50 mL or less. The cartridge is then assembled in the 3D printer and left under heating at 40°C for 30 min prior the initiation of the 3D printing process in order to facilitate the extrusion process or the printing process may start at room temperature without the need for preheating or heating during the 3D printing process. It has a nozzle with a diameter of 2 mm or less, most preferably 0,6 mm, to enable a high printing accuracy and resolution. The printing speed may be adjusted to 100 mm/s, most preferably to 25 mm/s so that the printing resolution is not compromised.

The milk paste (milk ink) prepared following the steps described above can be 3D printed under the conditions also described above with a good resolution in 3D structures resembling a variety of pediatric friendly designs, ranging from animals to cartoon characters as shown in Fig. 1. Patients may also be involved in the selection of the design to be 3D printed according to their preference, which may prove beneficial in improving the healthcare experience and the overall acceptability of the final product by this patient, even if reluctant. Formulations that appeal to children's preferences in terms of appearance, taste, texture, and smell can impart beneficial effects to treatment compliance, quality of care and even therapeutic response.

is The 3D printed milk-based dosage forms are chewable with a soft and smooth texture, similar to that of red bean paste and are easy to process orally in a way similar to that of mayonnaise and whipped cream oral processing being referred to Fig. 2. Swallowing difficulties and taste aversion are the primary reasons for medicine rejection. This is highly relevant for geriatric and pediatric patients who need to chew or crush the tablets prior to swallowing due to their large size, e.g. in case diameter >8 mm, resulting to low compliance rates.

The milk paste or milk ink can be also 3D printed with high drug dose accuracy, in the meaning that a defined mass of the printed milk paste (milk ink) will contain the claimed drug dose with high accuracy as visible in Fig. 3A, B. This is extremely important for pediatric patients for whom the current availability in a variety of dosage strengths is limited, and especially for hospitalized pediatric patients for whom frequent adjustment of dosage strength is required during hospitalization. Until now there is no other means to adjust dosage strength in a hospital pharmacy other than manual compounding. Yet, as with any process that involves human intervention, the possibility of drug or dosage errors during manual compounding is relatively high, posing significant dangers for patients' lives.

A main embodiment consists in that, for the incorporation in the milk ink of a therapeutical compound with relatively low aqueous solubility, such as the antiepileptic drug carbamazepine, the concentration of the drug in the milk ink might range from 60% w/w to 0,1 % w/w. For the incorporation of carbamazepine in the milk ink at a final concentration of 1,7 % w/w the following procedure was followed. 0,5 carbamazepine was dissolved in 200 mL of absolute ethanol in a large glass beaker. 22,3g of milk powder -with particle size in the range of 25-125 pm-were then added in the ethanolic solution of the drug and left under magnetic stirring for 5 minutes. The glass beaker was then transferred in an oven at 40°C for at least 24h to enable complete evaporation of ethanol. The resulting dry powder was grinded using a pestle and mortar and then sieved to collect the particle size range of 25-125 pm. The 22,8 g of the collected dry powder -carbamazepine-milk powder-were then mixed with 6,62 g deionized water in order to have a final solids content of 77,5 % w/w. The dispersion was then manually mixed with a spatula until a homogenized paste -drug loaded milk ink-was obtained.

For the incorporation in the milk ink of a therapeutic compound with high aqueous solubility, such as the antiepileptic drug sodium valproate, the concentration of the drug in the milk ink might range from 60 % w/w to 0,1 % w/w. For the incorporation of sodium valproate in the milk ink at a final concentration of 4,3 % w/w the following procedure was followed. 0,970 g sodium valproate was dissolved in 5,0625 mL of deionized water in a glass beaker. 17,43 g of milk powder with particle size in the range of 25-125 pm were then added in the aqueous solution of the drug in order to have a final solids content of 77,5 % w/w. The dispersion was then manually mixed with a spatula until a homogenized paste was obtained, herein consisting of said drug loaded milk ink.

Alternatively, marketed dosage forms could be used instead of the pure actives, in order to avoid the potential risk of patent infringement. In that case, the commercial dosage form would be crushed (if it is a solid dosage form) and mixed with the milk powder resulting from step (i), followed by the addition of water to obtain the milk paste (milk ink) or if it is in liquid form, it would substitute water in whole or in part.

The drug loaded milk ink could be prepared in a certified manufacturing facility and appropriately reconstituted with water before use within the 3D printing unit or even extemporaneously prepared by the pharmacist by mixing the appropriate amounts of milk powder, pure drug or crushed commercial dosage form and water.

The rheological properties of the milk paste (milk ink) were assessed on an Anton Paar MCR92 rheometer (Antoon Paar, Ostfildern, Germany) using a stainless-steel parallel plate configuration with a diameter of 25 mm and the geometry gap was set at 1 mm. The temperature was controlled through a Peltier plate (P-PTD 200/AIR/18P). In order to investigate the effect of temperature on the rheological behavior of the milk ink, the same thermal history as during the extrusion printing experiment was applied to the sample (40°C). After sample loading and trimming, the sample was allowed to equilibrate for 30 min at 40°C in order to simulate the printing procedure before starting the measurement. The temperature-dependent viscosity curves were evaluated (n 3) on freshly prepared pastes/inks made from different milk powder to water weight ratios -e.g. 80 g milk powder and 20 mL distilled water for F80 formulation-. The rheological properties of the optimum for the 3D printing application milk ink composition -containing 77,5% w/w milk powder-were also assessed in the presence of carbamazepine and valproic acid sodium salt. The apparent viscosity (Pa s) was measured at a shear rate of 200 s-1 with a sample volume of 500 pL. An initial viscosity flow curve test was carried out while heating the sample up to 40°C. Each test was repeated three times. Oscillatory tests (n 3) were carried out at 40°C after sample equilibration at 40°C for 30 min. In order to determine the linear viscoelastic region, amplitude sweeps were run at 1 Hz, ranging the strain from 0,00001 to 1%. The mechanical spectra were evaluated by means of frequency sweeps performed over the range 0,1-100 Hz, at a constant strain of 0,0001% which was within the linear viscoelastic region of the strain sweeps. Amplitude sweeps were conducted to determine the linear viscoelastic region (LVR) of the different inks (Fig. 14A). All experiments thereafter were conducted at a strain (%) value of 0,001 %. The storage modulus G' and the loss modulus G" were determined as a function of frequency at a constant amplitude during the oscillation frequency sweep test. G" indicates the viscous properties of the material at a certain frequency, while G' is a measure of the material's elasticity. As a result, a paste or paste-like material has a mechanical spectrum in which G' values are larger than G" in the frequency range tested, and the moduli have low frequency dependency (Fig. 4A, 8). Increase in the milk powder content resulted in an increase in the G' of the respective milk inks, indicating the higher mechanical strength of the inks. The printing inks appear exceptionally high consistency at low shear stresses, showing solid-like behavior, before yielding and after that shear thinning as the shear stress increased. These are precisely the rheological properties required for successful printing inks that must have shear-thinning behavior under pressure in order to pass effectively through the printing nozzle but hold the printed shape when pressure is released. The viscosity flow curves (Fig. 4C) reflected the shear thinning behavior of all the ink compositions, which is highly desirable for paste-like inks used in extrusion-based 3D printing applications. Higher viscosity values were observed for the inks containing higher milk powder content, whereas the addition of either carbamazepine or valproic acid in the optimum for the extrusion-based 3D printing ink composition (77,5% w/w) did not significantly affect the viscosity of the ink.

The drug compounds that may be used to prepare the drug loaded milk inks may belong but not restricted to any of the following drug classes: antiepileptics, antivirals, corticosteroids, anabolic steroids, antihypertensive, allergenics, alternative medicines, amebicides, antibiotics, analgesics, anorectal preparations, anorexiants, antacids, anthelmintics, anti-infectives, antianginal and antiarrhythmic agents, antineoplastics, antiemetics, antiparkinson agents, antispasmodics, antidepressants, antidiabetics, antidiuretic, antidotes, antifungals, antihistamines, antihyperlipidemics, antimalarials, antipsoriatics, antipsychotics, antirheumatics, antithyroid, antituberculosis, antivirals, anxiolytics, sedatives and hypnotics, barbiturates, biologicals, bisphosphonates, cardiovascular agents, central nervous system agents, diuretics, expectorants, gastrointestinal agents, herbal products, hormones, immunologic agents, insulin, iron products, laxatives, metabolic agents, minerals and electrolytes, antidepressants, nutraceutical products, nutritional products, probiotics and vitamins among others.

In a last phase 3D printing dependent use of the preparation for 3D printing is proposed. The drug loaded milk ink was then loaded into a plastic luer lock dispensing syringe with a volume capacity that may range from 0,5 to 100 mL or higher. In the present example the drug loaded milk ink was loaded in a 50 mL dispensing syringe. The syringe was fitted with a nozzle having a diameter that may range from 0,2 to 2 mm. In the present example a nozzle having a diameter of 0,6 mm was used.

The syringe was then placed onto the metallic heated holder of any type of an extrusion-based 3D printer. In the present example, a food 3D printer consisting of a Food Bot Food 3D Chocolate Printer was used. Prior to 3D printing, the syringe was allowed to equilibrate for 30 min at 40°C in the metallic heated holder in order to both facilitate the printing process and to decrease the final water content of the 3D printed dosage forms, therefore contributing to the extension of their shelf life.

The designs to be 3D printed using the drug loaded milk ink are derived from stereolithography templates that may be obtained from any open-source database and are then imported in any slicing software, such as Cura 15.02.1. After selecting the design of choice, its dimensions may be adjusted so as to accommodate the desired drug dose. The printing speed may be set at 0,5 mm/s up to 50 mm/s. In the present example, the printing speed was set at 15 mm/s and representative 3D printed milk-based constructs resembling pediatric-friendly designs, such as animals and cartoon characters, showing the high resolution of the prepared milk paste composition under the described printing conditions are shown in Fig. 1.

In order to confirm the soft texture of the 3D printed dosage forms and their suitability for consumption from patients with swallowing difficulties, such as the pediatric and geriatric patients, texture profile analysis (TPA) was conducted on rectangular shaped 3D printed constructs (1 cm x 1 cm) using a TA.Xtplus Texture Analyzer (Stable Mycro Systems, Godalming, UK) with a cylindrical probe (50 mm). Samples were compressed twice at a speed of 1 mm/s and deformation level was set at 40 % of the initial tablet height. The TPA parameters consist of the hardness being the first force peak height; resp. the cohesiveness being the ratio of the area of the first peak over the area of the second peak; the springiness being the time value of the detected height during the second compression to the respective value during the first compression; the gumminess being the hardness x cohesiveness and adhesiveness: the negative area between two compressions. Said TPA parameters were calculated from the respective TPA curves as shown in Fig. 2, which shows the results of the texture profile analysis of the milk-based 3D printed dosage forms, which reported hardness values (9,2 ± 0,8 N) similar to that of red bean paste (6,95 ± 0,28 N), adhesiveness (3,16 ± 0,88 mJ) similar to that of mayonnaise (2,80 ± 0,10 mJ) and cohesiveness (0,36 ± 0,02) similar to that of whipped cream (0,61 ± 0,04).15 These findings highlight the ease of chewing and oral processing of the 3D printed milk-based dosage form, compared to common semi-solid foods, with linear regression analysis in the 3D printed milk-based dosage forms with an increasing number of printed layers containing a poorly water-soluble (carbamazepine) drug. That asset is highly desirable especially for pediatric and geriatric patients with swallowing difficulties.

Dose accuracy in the 3D printed milk dosage forms was assessed as follows. The drug loaded milk links were 3D printed in cubes of 15 mm x 15 mm x y mm height having increasing number of layers ranging from 1 to 9. Immediately the cubes were weighted and dissolved in 9:1 mixture of methanol: water until completely dissolved. The samples were centrifuged for 10 minutes at 4,000 rpm. The supernatant was analyzed for the drug content (mg) with high-pressure liquid chromatography (HPLC) analysis and results were plotted against the number of layers.

Carbamazepine quantification was performed with a Discovery® HS C18 column (15 cm x 4,6 mm, 5 mm, Supelco/SigmaAldrich). The mobile phases consisted of a mixture of acetonitrile (A) and water (B), at a ratio of (A:B) 50:50 v/v and the flow rate was set at 0,7 mL/min. The operating UV wavelength was set at 285 nm the injection volume was 20 pL. Sodium valproate quantification was performed using a Discovery® HS C18 column (15 cm x 4,6 mm, 5 mm, Supelco/SigmaAldrich). The mobile phase consisted of acetonitrile and 25 mH NaH2PO4 aqueous solution (pH 2,3) at a 70:30 (v/v) ratio. The flow rate was set at 0,8 mL/min, the injection volume at 35 pL and detection was performed at 210 nm. The obtained drug content was then plotted against the number of printed layers. Linear regression was used to predict the relationship between the two variables. The closer the value of R2 to 1 the better the dose accuracy achieved.

This is clearly exemplified in Fig. 3A, resp B. where R2 for both carbamazepine (0,9993) and sodium valproate (0,9995) fulfils this requirement. Fig. 3A, B each show the results of the assessment of dose accuracy with linear regression analysis in the 3D printed milk-based dosage forms with increasing number of printed layers (n=4 ± S.D.) containing either a poorly water-soluble (carbamazepine) or water-soluble (sodium valproate) drug.

Ideally, an algorithm designed to operate in the computer interface, that might also be used to operate the 3D printer, would enable the pharmacist or clinical staff to adjust the dose for each individual patient based on their physiological, such as body weight, age, etc., or pathological parameters -e.g. renal function-related to their condition by simply adding the desired dosage strength in the computer interface.

The dissolution profile of carbamazepine from the 3D printed milk dosage form that was prepared using the commercial drug product (Tegretol® 200 mg) crushed and mixed with the milk powder and water, was generated in the dissolution conditions for carbamazepine as described in the U.S. Pharmacopeia (USP) 42nd edition. In particular in 900 mL of water containing 1% of sodium lauryl sulfate (SLS 1%) as the dissolution medium, in USP type II apparatus (paddle) at a rotational speed of 75 rpm (Fig. 6). The dissolution profile of carbamazepine from the 3D printed milk dosage form was identical to the one obtained from the commercial dosage form (Tegretol® 200 mg).

EXAMPLES

Example: Preparation of the composition with yoghurt powder In various embodiments of the present invention, the term milk powder as used herein and in the appended claims refers to an infant or toddler milk formula powder or freeze-drying yoghurt powder or thermal-drying yoghurt powder, or commercially available yoghurt powder. In other words, the milk powder, which the milk paste or milk ink is directly obtained from, can be toddler milk formula powder or yoghurt powder and water.

Yoghurt powder was purchased from local supermarkets and stored at 25 °C till used.

The commercially available yoghurt powder is placed on the uppermost sieve of a sieve stack with decreasing apertures (0,212-0,025 mm) and shaken for 2 min in a sieve shaker. The yoghurt powder fraction with particle size in the 25-125 pm range is collected and further used for the preparation of the semi-solid drug dosage forms. Alternatively, the dry powder is milled using a Quadro hammer mill (conical mill at 1500-3500 rpm).

For preparing both formulas, 7.75 g of type yoghurt powder were weighed in a vessel and 2.25 g of purified water at room temperature were added.

In the case of formula A, the hydrophilic compound was weighed and was dissolved in a fraction of water, thus forming an aqueous drug solution, which is in turn mixed with a corresponding suitable fraction of said yoghurt powder until a homogeneous mixture paste is obtained.

For preparing formula B, the method was identical to the one used for formula A, but with an extra step prior to mixing step. The lipophilic compound is first dissolved in an appropriate volume of absolute ethanol, thus yielding an ethanolic drug solution, which is further mixed with a corresponding suitable amount of said yoghurt powder, thus generating a dispersion product which is submitted to a subsequent evaporation step, wherein said organic solvent is completely evaporated by submitting said dispersion to a heating step by heating said dispersion in heating means at a certain temperature and duration until said dispersion becomes solid, after which the solid dispersion thus obtained is submitted to a grinding step by means of grinding means, wherein said preparation of formula A is then repeated and said parts of said solid dispersion are then mixed with said corresponding parts of water, until a homogeneous paste is obtained.

Preferably, the mass ratio of yoghurt powder to water in these milk pastes will be 90:10 to 10:90, more preferably 80:20 to 20:80, still more preferably 80:20 to 50:50, most preferably 77.5:22.5.

References ' Zajicek A, Fussier M.I, Barrett.IS, et al. A report from the pediatric formulations task force: perspectives on the state of child-friendly oral dosage forms. Aaps J. 2013;4:1072-81.

Lopez, F.L., Ernest, T.B., Orlu, M., Tuleu, C., 2018. The effect of administration media on palatability and ease of swallowing of multiparticulate formulations. Int. J. Pharm. 551, 67-75.

3 WHO Expert Committee on Specifications for Pharmaceutical Preparations, 2012. Development of paediatric medicines: points to consider in formulation. httipliaDr)S.

whaint/medicinedocs/documents/s19833en/s19833en.pdf (accessed 8 June 2021).

4 Goyanes, A., Madla, CM., Umerji, A., Duran Pipeiro, G., Giraldez Montero, J.M., Lamas Diaz, Mt, Gonzalez Barcia, M., Taherali, F., Sanchez-Pintos, P., Couce, M.-.L., Gaisford, S., Basit, A.W., 2019. Automated therapy preparation of isoleucine formulations using 3D printing for the treatment of MSUD: first single-centre, prospective, crossover study in patients. Int. J. Pharm. 567, 118497 Gioumouxouzis, C.I., Karavasili, C., Fatouros, D.G., 2019. Recent advances in pharmaceutical dosage forms and devices using additive manufacturing technologies. Drug Discov. Today. 24, 636-643.

6 Goyanes, A., Madla, CM., Umerji, A., Duran Pipeiro, G., Giraldez Montero, J.M., Lamas Diaz, M.J., Gonzalez Barcia, M., Taherali, F., Sanchez-Pintos, P., Couce, M.-.L., Gaisford, S., Basit, A.W., 2019. Automated therapy preparation of isoleucine formulations using 3D printing for the treatment of MSUD: first single-centre, prospective, crossover study in patients. Int. J. Pharm. 567, 118497.

7 Greca, A.M.L, 1990. Issues in adherence with pediatric regimens. J. Pediatr. Psychol. 15, 423-436.

8 Macheras, P., Ismailos, G., Reppas, C., 1991. Bioavailability study of a freeze-dried sodium phenytoinmilk formulation. Biophania. Drug Dispos. 12, 687-695 eGalia, F., Nicolaides, F., Herter, D., Uibenberg, R., Reppas, C., Dressman, 1998.Evaluation of various dissolution media for predicting in vivo performance ofclass I and II drugs. Pharm. Res. 15, 698-705.

Macheras, P., Reppas, C., 1986a. Studies on drug-milk freeze dried formulations. I:Bioavailability of sulfamethizole and dicumarol formulations. J. Phanat Sci. 75,692-696.

11 Dial, E.J., Romero, D., Lichtenberger, L.M., 1995. Gastroprotection by dairy foodsagainst stress-induced ulcerogenesis in rats. Dig Dis. Sci. 11, 2295-2299 42 Lopez, 11.L., Mistry, P., Batchelor, El. K. et at Acceptability of placebo multiparticulate formulations in children and adults. Sci Rep 8, 9210 (2018). https://doi.org/10.1038/s41598-018-27446-6 Bylund G. 2003. Dairy Processing Handbook. Lund, Sweden: 'tetra Pak Processing Systems AB, pp. 361-374 14 Mao, F., Kong, Q., Ni, W., Xu, X., Ling, D., Lu, Z., & Li, J. (2016). Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery. ChernistryOpen, 5(4), 357-368. https://doi.org/I0.1002/open.201600015 Effects of texture properties of semi-solid food on the sensory test for pharyngeal swallowing effort in the older adults

Claims (18)

1. CLAIMS1. Drug composition delivery platform for sensitive patient populations, notably for pediatric and geriatric population groups with swallowing difficulties and low treatment compliance, characterized in that the drug composition dosage form is chewable, semi-solid and dairy based resp., in particular milk-based or yoghurt-based.
2. 2. Drug delivery platform according to claim 1, characterized in that said dairy-base of said drug composition dosage form consists of milk and/or yoghurt powder.
3. 3. Drug delivery platform according to claim 2, characterized in that said milk powder is an infant or toddler milk formula powder.
4. 4. Drug delivery platform according to one of the preceding claims 2 or 3, characterized in that the semi-solid drug dosage form comprises a mixture of milk or yoghurt powder and water for a 3D printed edible dosage form (1) loaded with therapeutics in the field of pharmaceutical 20 compounding.
5. 5. Drug delivery platform according to the preceding claim 4, characterized in that the said semi-solid drug dosage form (1) comprises a mixture of milk and/or yoghurt powder and water in a 3D printed edible dosage form with a shape that is featured with appealing means for the user or patient.
6. 6. Drug delivery platform according to any of the preceding claims 1 to 5, characterized in that the said shape consists of a specially featured character selected from animals to cartoon characters or oneiric figures that are visually appealing to the user or patient.
7. 7. Drug delivery platform according to one of the preceding claims, characterized in that the said semi-solid drug dosage form contains additives rendering its (1) taste and smell appealing to the user or patient.
8. 8. Method for the preparation of a dairy-based drug composition, particularly of a chewable semi-solid dairy-based drug delivery platform, more particularly milk-based or yoghourt-based, as defined in any of the preceding claims 1 to 7, characterized in that the semi-solid drug dosage form is obtained from mixing milk powder and water for a 3D printed edible dosage form which is loaded with therapeutics.
9. 9. Method according to claim 8, characterized by the following steps: the milk powder is sieved, after which the milk powder fraction with a particle size in a preselected range is collected and incorporated in the further preparation of the semi-solid drug dosage forms; Alternatively, the milk or yogurt powder is micronized using known to the art milling processed (e.g., cutter mill, jet mill, pin mill, or hammer mill) hydrophilic therapeutic compounds are incorporated, wherein an appropriate amount of the therapeutic compound is first dissolved in an x fraction of water, after which the aqueous drug solution is then mixed with an (1-x) fraction of milk powder until a homogeneous milk paste is obtained, wherein the drug loaded milk paste is referred to as milk ink, resp. or incorporated in the form of a marketed dosage form, in solid, semi-solid or liquid form, or (iii) lipophilic therapeutic compounds are incorporated, wherein an appropriate amount of therapeutic compound is first dissolved in an appropriate volume of /absolute ethanol/ appropriate solvent, the drug solution is mixed with an appropriate amount of the milk powder and the dispersion is left in an oven as heating means by means whereof a solid dispersion is obtained, after which the solid dispersion is then grinded in a mortar with a pestle as grinding means or the lipophilic drugs are mixed with the milk powder in a micronized form or the lipophilic drugs are incorporated in the form of a marketed dosage form, in said solid, semi-solid or liquid form.
10. 10. Method according to claim 8 or 9, characterized by the following additional step wherein appealing means consisting of food colorants and/or flavors mixed with the milk powder or the aqueous phase by means whereof the palatability of the milk-based dosage forms is enhanced. 25
11. 11. Process for the fabrication of complex 3D structures using an extrusion-based 3D printing milk-based drug compositions in complex structures particularly as defined in any of the preceding claims, characterized in that the drug loaded milk paste referred to as milk ink is loaded in a container means consisting of a cartridge of printing means, particularly an extrusion-based 3D printer, having a nozzle, wherein the cartridge is then assembled in the printing means.
12. 12. Method according to any of the claims 8 to 11, characterized in that said milk paste referred to as milk ink is 3D printed with good resolution in 3D structures resembling a variety of pediatric, resp. geriatric or disabled friendly designs which is customizable for the following lists of selection parameters, ranging from animals to cartoon characters, particularly wherein patients get actively involved in the selection of the design to be 3D printed.
13. 13. Method according to any of the claims 8 to 12, characterized in that the 3D printed milk-based dosage forms are produced with a soft and/or smooth texture, and are chewable and easy to process orally.
14. 14. Method according to any of the claims 8 to 13, characterized in that the said milk paste is 3D printed with a high drug dose accuracy, wherein a defined mass of the printed milk paste contains the required drug dose with high accuracy providing the required reliability and safety.
15. 15. Method according to one of the claims 8 to 14, characterized in that for the incorporation in the milk ink of a therapeutical compound with relatively low aqueous solubility, such as the antiepileptic drug carbamazepine, the concentration of the drug in the milk ink ranges from 60 °A w/w to 0,1 % w/w.
16. 16. Method according to one of the claims 8 to 14, characterized in that for the incorporation in the milk ink of a therapeutic compound with high aqueous solubility, such as the antiepileptic drug sodium valproate, the concentration of the drug in the milk ink might range from 60 % w/w to 0,1 w/w.
17. 17. Method according to one of the claims 8 to 16, characterized in that the drug compounds used to prepare the drug loaded milk and/or yoghurt inks belong to any of the following drug classes: antiepileptics, antivirals, corticosteroids, anabolic steroids, antihypertensive, allergenics, alternative medicines, amebicides, antibiotics, analgesics, anorectal preparations, anorexiants, antacids, anthelmintics, anti-infectives, antianginal and antiarrhythmic agents, antineoplastics, antiemetics, antiparkinson agents, antispasmodics, antidepressants, antidiabetics, antidiuretic, antidotes, antifungals, antihistamines, antihyperlipidemics, antimalarials, antipsoriatics, antipsychotics, antirheumatics, antithyroid, antituberculosis, antivirals, anxiolytics, sedatives and hypnotics, barbiturates, biologicals, bisphosphonates, cardiovascular agents, central nervous system agents, diuretics, expectorants, gastrointestinal agents, herbal products, hormones, immunologic agents, insulin, iron products, laxatives, metabolic agents, minerals and electrolytes, antidepressants, nutraceutical products, nutritional products, probiotics and vitamins.
18. 18. Use of a chewable semi-solid dairy -based drug delivery platform particularly as defined in any of the claims 1 to 7, for sensitive patient populations such as pediatric, geriatric population groups or disabled and vulnerable, with swallowing difficulties and low treatment compliance.