Printable dose formulation

Abstract

The present disclosure concern printable dose formulations comprising an active pharmaceutical ingredient and excipients including one or more surfactants of hydrophilic-lipophilic balance (HLB) of at least 8. The disclosure also relates to a method for preparing medicament dosages using the printable dose formulations.

Description

[0001] Printable dose formulation

[0002] FIELD

[0003] The present disclosure relates to printable dose formulations comprising an active pharmaceutical ingredient and one or more solubilizers of hydrophilic-lipophilic balance (HLB) value of at least 8. The disclosure also relates to methods for preparing medicament dosages using the printable dose formulations using 3D printers.

[0004] BACKGROUND

[0005] 3D printing enables pharmacists to create precise and accurate patient-tailored pharmacy preparations. The 3D printing technology allows for the deposition of pharmaceutical materials very accurately, ensuring that each dose meets exact specifications. High level of precision minimizes the risk of dosing errors and enhances patient safety. 3D printing ensures consistent and reproducible results, eliminating batch-to-batch variations common in manual compounding. The technology also facilitates stringent quality control measures, reducing the likelihood of contamination or inconsistencies in the final product.

[0006] To fulfill the above-mentioned benefits is not straightforward. For example, a dose formulation to be printable by semisolid extrusion technology needs to be a homogenous paste, liquid or gel formed by solvents or heat and extrudable through a nozzle on a printing substrate such as on a blister package. This could be cumbersome in particular for formulations including active pharmaceutical ingredients (APIs) of low solubility. Also, the final pharmacy preparations must be easily removable from the printing substrate.

[0007] SUMMARY

[0008] It was observed that when solubilizers of hydrophilic-lipophilic balance (HLB) value of at least 8 were added to certain dose formulations, formulations suitable for 3D semisolid extrusion printing could be obtained.

[0009] Accordingly, it is an object of the present invention to provide a printable dose formulation comprising

[0010] 0.1 -10 wt.-% active pharmaceutical ingredient (API),

[0011] 48-59 wt.-% excipients, and at least 40 wt.-% water, wherein the excipients include one or more solubilizers of hydrophilic-lipophilic balance value of at least 8, and wherein the printable dose formulation includes 0.1 - 10 wt.-% of said one or more solubilizers.

[0012] It is also an object of the present invention to provide a method for preparing a medicament dosage, the method comprising providing a printable dose formulation according to claim 1 and a printing substrate; and printing using a 3D printer the printable dose formulation on the printing substrate.

[0013] A number of exemplifying and non-limiting embodiments of the invention are described in accompanied dependent claims.

[0014] Various exemplifying and non-limiting embodiments of the invention and to methods of operation, together with additional objects and advantages thereof, are best understood from the following description of specific exemplifying embodiments when read in connection with the accompanying figures.

[0015] The verbs “to comprise” and “to include” are used in this document as open limitations that neither exclude nor require the existence of also unrecited features. The features recited in depending claims are mutually freely combinable unless otherwise explicitly stated. Furthermore, it is to be understood that the use of "a" or "an", i.e., a singular form, throughout this document does not exclude a plurality.

[0016] BRIEF DESCRIPTION OF FIGURE

[0017] Figure 1 shows release (%) of an exemplary dose formulation including 2.5 wt-% prednisolone and 2.5 wt.-% polysorbate as a function of time. Dissolution was performed using USP II (paddle) apparatus. Media: 500 mL Milli Q water at 37 °C ± 0.5 °C; number of samples analyzed: 4 tablets; paddle rpm:50.

[0018] DESCRIPTION

[0019] The specific examples provided in the description given below should not be construed as limiting the scope and / or the applicability of the appended claims. Lists and groups of examples provided in the description given below are not exhaustive unless otherwise explicitly stated.

[0020] According to one aspect the present disclosure concerns a printable dose formulation comprising

[0021] 0.1-10 wt.-% active pharmaceutical ingredient (API),

[0022] 48-59 wt.-% excipients, and at least 40 wt.-% water, wherein the excipients include one or more solubilizers of HLB value at least 8, preferably 8-18, more preferably 11-18, and wherein the printable dose formulation includes 0.1-10 wt.-%, preferably 0.25-5 wt.-%, such as 2.5-3 wt.-% of said one or more solubilizers.

[0023] As defined herein a solubilizer is an excipient used in dose formulations to assist solubility of poorly soluble drugs.

[0024] Relatively high HLB value is required since the dose formulations of the present disclosure include at least 40 wt.-% water, such as 40-50 wt.-% water. Contents of the solubilizers exceeding 10 wt.-% of the total mass of the formulation should be avoided since too high content could deteriorate printing properties of the dose formulation by significantly changing viscosity and / or density of the formulation.

[0025] The one or more solubilizers are preferably selected from polyethylene glycols, polysorbates, and polyoxyl stearate, more preferably from polyoxyl stearate and polysorbates, most preferably polysorbates. Polysorbates are preferred since they have a well-defined safety limits for daily use.

[0026] Exemplary solubilizers suitable for the present disclosure are listed in table 1 .

[0027] Table 1 The API : solubilizer ratio (w / w) in the formulation is preferably from 1 :2 to 1.3:1 , such as is 1 :1. These ratios ensure the formation of homogeneous dose formulations.

[0028] For allowing direct printing into blisters the amount of the one or more solubilizers of HLB value of at least 8 in the dose formulation is preferably at least 0.5 wt.-%. This is to reduce the adherence of the formulation to the blister material, such as plastic. This in turn, avoids breakage of the formulation when it is removed from the blister material for administration.

[0029] According to one embodiment the API is of BCS Class II, and its content in the dose formulation is preferably from 0.1 wt.-% to 5 wt.-%, more preferably from 0.25 wt.- % to 2.5 wt.-%. Higher API contents, such as up to 10 wt.-% could be used, but homogenization of the dose formulation e.g., by preheating and sonification may be needed prior to printing. Exemplary APIs of BCS Class II suitable for the present disclosure are furosemide, hydrocortisone, spironolactone, hydrochlorothiazide, clopidogrel bisulfate, ramipril, quetiapine, tacrolimus, omeprazole, and prednisolone. When the API is of BCS Class I, higher API contents in the dose formulation can be used. An exemplary APIs of BCS Class I suitable for the present disclosure are metoprolol, propranolol, and captopril.

[0030] The API is preferably microsized or nanosized. Accordingly, the average particle size of the API from 1 m to few hundred pm, and less than 1 pm for microsized and nanosized API, respectively. Methods for reducing the API particle size to pm or sub pm level are well known in the art. Micronization and nanonization enhances API solubility by enlarging API surface area. However, obtaining a homogenous mixture of the micronized or nanosized API and excipients in a solid dose can be challenging because microsized or nanosized APIs are prone to exhibit agglomeration caused by high powder cohesion. It was observed that homogeneity of micronized and nanosized APIs and also bulk APIs in the dose formulations was considerably improved by the solubilizers of HLB value of at least 8.

[0031] In addition to solubilizers of HLB value of at least 8, the dose formulation includes one or more further excipients such as sweeteners, suspending agents, gelling agents, emulsifiers, moisturizers, taste masking agents, preservatives, and buffering agents. Exemplary sweeteners xylitol and sucralose. Exemplary preservative is sorbate, preferably potassium sorbate, and an exemplary gelling agent is gelatin. Overall content of the excipients, including the solubilizers of HLB value at least 8, in the dose formulation is 48-59 wt.-%.

[0032] According to a particular a printable dose formulation comprises water, xylitol, gelatin, cocoa butter, glycerol, maltodextrin, colloidal glycerol, citric acid, vanilla flavor, sodium citrate, raspberry flavor, potassium sorbate, sucralose, polysorbate, one of more solubilizers of HLB value of at least 8, and one or more APIs.

[0033] The present invention also concerns a method for preparing a medicament dosage, the method comprising providing a printable dosage formulation comprising

[0034] 0.1 -10 wt.-% active pharmaceutical ingredient,

[0035] 48-59 wt.-% excipients, and at least 40 wt.-% water, wherein the excipients include one or more solubilizers of HLB value at least 8, preferably 8-18, more preferably 11 -18, and wherein the printable dose formulation includes 0.1-10 wt.-% of said one or more solubilizers; and a printing substrate; and printing using a 3D printer the printable dose formulation on the printing substrate.

[0036] An exemplary 3D printer suitable for the method is a semisolid extrusion printer. An exemplary printing base is a blister package, preferably made of plastic.

[0037] Experimental

[0038] The formulations were printed using a commercial 3D printer equipped with ink supply cartridges, heating elements, printheads (nozzle size 1.5 mm), control software, and a printing platform. An exemplary base formulation used in the experiments (i.e. a formulation including water but excluding the solubilizers of HLB value of at least 8 and the API) is shown in Table 2. Table 2.

[0039] The following dosing parameters were applied

[0040] - dosing speed 1500-4000 mm / min - Ingredient flow speed 2 m / min

[0041] - Ingredient flow temp. 40-50 °C

[0042] - Pre-heat Temp 40-50 °C

[0043] - Ingredient hold 0.2-2.5 mm

[0044] - Pre-heat time 30-60 s - First layer nozzle height 10 mm

[0045] - Distance between layers 1 .4 mm

[0046] Manufacture of the dose formulations

[0047] Comparative example

[0048] Prednisolone (1 wt.-%) was added to the formulation of table 2 with continuous mixing at 45 °C for 30 min. Homogenous admixture could not be obtained. Then the admixture was sonicated for 15 min in 45°C and mixed until seemingly homogenous. The formulation was printed on a plastic blister using the printing parameters shown above. The dose sticked and adhered on the blister. Examples

[0049] API, a solubilizer of HLB value of at least 8, and the formulation of table 2 were mixed and the new formulation formed was printed on a blister package using the 3D printer and the printing parameters shown above. The dose was allowed to cool to ambient temperature. Mass of the dose was 400 mg. Properties of the formulations prepared are collected in table 3. Dissolution testes were performed as per monograph, in USP NF 21 (United States Pharmacopeia and National formulary 2021 ). An exemplary dissolution profile is shown in figure 1 .

[0050] Table 3

[0051] The formulations including solubilizers were homogenous, and when printed, the printed dose did not adhere to the blister package.

[0052] Content uniformity (CU) test Dose formulations including metoprolol tartrate and the formulation of table 2 in the presence and absence of polysorbate were prepared. Results are shown in table 4. Table 4

[0053] The test for content uniformity and the limits for acceptance value were in accordance with chapter 2.9.40 uniformity of dosage units, European Pharmacopoeia 11 .0.

Claims

What is claimed is1 . A printable dose formulation comprising:0.1 -10 wt.-% active pharmaceutical ingredient (API), 48-59 wt.-% excipients, and at least 40 wt.-% water characterized in that the excipients include one or more solubilizers of HLB value at least 8, preferably 8-18, more preferably 11 -18 and in that the printable dose formulation includes 0.1-10 wt.-%, preferably 0.25-5.0 wt.-% of said one or more solubilizers.

2. The printable dose formulation according to claim 1 wherein said one or more solubilizers are selected from polyethylene glycols, polysorbates, and polyoxyl stearate, preferably from polyoxyl stearate and polysorbates, more preferably polysorbates.

3. The printable dose formulation according to claim 1 or 2 wherein the API : solubilizer ratio (w / w) in the printable dose formulation is from 1 :2 to 2:1 , preferably from 1 :2 to 1 :1 .3, such as 1 :1 .

4. The printable dose formulation according to any one of claims 1 to 3 comprising 40-50 wt.-% water.

5. The printable dose formulation according to any one of claims 1 to 4 wherein the API is of BCS Class II, and the formulation comprises 0.1 - 5 wt.-% of said API.

6. The printable dose formulation according to any one of claims 1 to 5 wherein the API is selected from prednisolone, hydrocortisone, spironolactone, clopidogrel bisulphate, ramipril, quetiapine, tacrolimus, and omeprazole.

7. The printable dose formulation according to any one of claims 1 to 6 wherein the API is microsized or nanosized.

8. The printable dose formulation according to any one of claims 1 to 7 wherein the excipients include one or more sweeteners, gelling agents, buffering agents, preservatives, emulsifiers, suspending agents and / or co-solvents.

9. A method for preparing a medicament dosage, the method comprising providing a printable dose formulation according to any one of claims 1 to 8 anda printing substrate, and printing using a 3D printer the printable dose formulation on the printing substrate.

10. The method according to claim 9 wherein the 3D printer is a semisolid extrusion printer.

11. The method according to claim 9 or 10 wherein the printing substrate is a blister package.

12. The method according to claim 11 wherein the blister package is made of plastic.

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