Bespoke hydroxypropyl methylcellulose-based solid foams loaded with poorly soluble drugs by tunable modular design
Abstract
A tunable modular design (TMD) as a new approach was proposed to tailor the dose and drug release profile of poorly water-soluble drugs from hydroxypropyl methylcellulose (HPMC)-based solid foams by combining two manufacturing principles:
(1) freeze-drying aqueous HPMC-based gels to yield porous sturdy modules with specific doses of an active pharmaceutical ingredient (API) with the step size of 3 mg, and
(2) fine-tuning the desired dose of the API with the step size of 0.1 mg by inkjet printing of the API-loaded ink onto the modules.
Carvedilol (CAR) was used as a model poorly water-soluble API that requires frequent dose adjustment. The limitation of poor CAR solubility was overcome by designing pharmaceutically approved co-solvent systems. This approach ensured printable inks of a high drug content, and sturdy and flexible modules with uniform distribution of CAR to achieve effective and accurate doses of CAR.
The tailored release rate of CAR from TMD products was succeeded by varying the composition, particularly, the content and grade of HPMC, and physical dimensions of modules. The TMD approach holds potential for designing bespoke high-quality products, containing hydrophilic cellulose ethers such as HPMC and poorly water-soluble APIs.
Introduction
Traditional drug manufacturing, based on the mass production of fixed doses, poses a challenge to the treatment of patients with chronic diseases as they respond differently to medications due to various factors such as different physiology, genetics, and lifestyle (Goetz & Schork, 2018; Pirmohamed, 2014; Spear et al., 2001). To optimize the treatment outcome, these patients often need to manipulate doses themselves at home by splitting, crushing, and/or dispersing in water the commercial drug products as they are only available in a limited number of strengths. This can easily result in dosing errors that can lead to hospitalization and even death (Hodges et al., 2018). Such a challenge underscores the importance of personalized medicine in the modern era, particularly in developing patient-tailored drug products with accurate doses and desirable release profiles to avoid situations where patients are forced to self-manipulate commercially available tablets and capsules.
Additive manufacturing, encompassing various two-dimensional (2D) and three-dimensional (3D) printing techniques, has been explored to provide personalized drug products with customized appearance, dose, and drug release profile on demand (Lind et al., 2017; Norman et al., 2017). Among these techniques, 2D inkjet printing is a versatile, precise, and cost-effective method, offering accuracy and repeatability in dose deposition (Azizi Machekposhti et al., 2019). It has been used to produce solid oral dosage forms containing flexible and accurate doses of active pharmaceutical ingredients (API) (Alomari et al., 2015; Kolakovic et al., 2013). Briefly, the API-containing ink is jetted onto the API-free edible solid substrates (also later referred to as foams and modules) in a predefined pattern. The imprinted dose and drug release kinetics can be tuned by digitally adjusting either the printing area, density, and/or the number of subsequent printing layers (Raijada et al., 2021). The main limitation of inkjet printing is that it is alone primarily suitable only for delivering low-dose drug products. This is due to two main reasons: (1) the limited solubility of the API in the ink base, which mainly consists of the solvent mixtures approved for oral administration (Jouyban, 2008; Raijada et al., 2013), and (2) the limited ink absorption capacity of solid foams, which cannot hold higher volumes of printed inks when higher doses are desired (Scoutaris et al., 2016). To overcome this challenge, a new approach, known as tunable modular design (TMD), was proposed as a flexible dosing platform enabling sub-milligram dose adjustment of an antidepressant citalopram hydrobromide while reaching clinically relevant doses (Ahola et al., 2024). TMD combines two manufacturing principles to produce a wide range of accurate and tailored doses: (1) freeze-drying aqueous API-containing polymer-based gels to create porous solid foams (referred to as modules) loaded with predefined doses of API, and (2) fine-tuning the desired dose by inkjet printing API-containing ink onto these modules. TMD represents a new, customizable advancement compared to conventional drug manufacturing technologies that are based on batch production or extemporaneous production of patient-specific doses in compounding settings. The former is rigid, whereas the latter is an expensive and laborious manufacturing method. Therefore, TMD has the potential to enhance drug efficacy and meet the diverse needs of patients by providing precise dosage control, flexibility in ingredient adjustments, and tunable drug release. Freeze-dried hydroxypropyl methylcellulose (HPMC)-based solid foams with open-cell structures have been considered the most favorable modules for inkjet printing of pharmaceuticals due to their superior ink absorption, mechanical, and stability characteristics (Iftimi et al., 2019). Such foams are versatile and can be utilized for various routes of administration (Ayensu et al., 2012; Iftimi et al., 2019; Korelc et al., 2023). In the previous study by Ahola et al. (Ahola et al., 2024), the TMD approach was showcased with citalopram hydrobromide, a freely water-soluble biopharmaceutics classification system (BCS) class I drug that does not possess challenges regarding the API solubility in the pharmaceutically approved solvents for oral use.Therefore, this sufficient solubility of the studied API allows fast ink and module formulation to produce final drug products with accurate doses and immediate-release profiles. Formulation of continuously printable API-loaded ink with homogeneous distribution of API within the porous HPMC modules is extensive, expensive, and technologically challenging if the API is poorly soluble.
For inkjet printing poorly water-soluble pharmaceuticals, it is possible to use the suspension-type inks to increase the concentration of the API in the ink, and consequently, the printed dose. However, suspension-type inks tend to clog the jetting nozzles, resulting in fluctuations in the produced doses (Kollamaram et al., 2018; Palo et al., 2015). Furthermore, ensuring the homogeneous distribution of API particles within the ink during continuous printing and within the foam after freeze-drying is challenging. The solution-type inks also face challenges in formulating a printable ink containing poorly soluble APIs as their solubility in the solvents approved for oral use (e.g., water and ethanol) is limited (Raijada et al., 2013). For the same reason, it is challenging to produce edible foams with a homogeneous distribution of poorly soluble APIs within the modules when applying TMD. Furthermore, poorly water-soluble drugs have a limited dissolution rate, which frequently results in reduced bioavailability when administered orally (Kawabata et al., 2011). Inclusion of a surfactant or adjusting pH are the common methods to improve the dissolution characteristics of poorly water-soluble APIs (Edinger et al., 2018; Pardeike et al., 2011).
Carvedilol (CAR) is a poorly water-soluble API that belongs to the BCS class II category, with a water solubility of 11 μg/mL (Fernandes et al., 2018; Yuvaraja & Khanam, 2014). CAR is indicated for treating heart failure, hypertension, and left ventricular dysfunction (FDA, 2017). It requires frequent dose adjustments (BMA, 2020), especially for pediatric and geriatric patients. However, it is only commercially available in fixed strengths of 25 mg, 12.5 mg, 6.25 mg, and 3.125 mg, forcing patients and their caregivers to self-adjust doses. Incorrectly high CAR doses can cause severe adverse effects such as hypotension, cardiac insufficiency, and cardiac arrest, while too low doses can compromise the therapeutic effect. The availability of marketed immediate-release tablets (COREG) and extended-release capsules (COREG CR) (WaylisTherapeutics, 2024) highlights the need for drug products with different CAR release profiles.
The present study aimed to propose, for the first time, a roadmap for developing bespoke HPMC-based drug products using the TMD approach to enable flexible doses and tailored release profiles of poorly soluble APIs like CAR. We expect to develop a solution-type ink formulation with the highest CAR content within the printable range, based on the specific criteria of viscosity and surface tension. We hypothesize that different (immediate and extended) release profiles of CAR from printed and unprinted TMD modules can be achieved by varying the composition and physical dimensions of the porous HPMC-based modules loaded with poorly water-soluble API.
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Materials
Carvedilol (Cipla Ltd., Mumbai, India) was used as the model poorly water-soluble API. Propylene glycol (PG) (Sigma-Aldrich, USA), poloxamer 188 (Lutrol® F68, abbreviated to F68) (Sigma-Aldrich, Steinheim, Germany), glycerol (≥99.0 %) (Sigma-Aldrich, Malaysia), and ethanol absolute (Merck, Germany) were used as solvents. Hydroxypropyl methylcellulose (HPMC) (Metolose® 60SH-50 (HPMC M50) and Pharmacoat® 615 (HPMC P615) (Shin-Etsu Chemical, Tokyo, Japan) with a nominal viscosity of 50 mPa·s (Shin-Etsu, 2023b) and 15 mPa·s (Shin-Etsu, 2023a) for 2 wt% aqueous solution at 20 °C using Ubbelohde tube, respectively, were used. For both HPMC grades (Metolose® 60SH-50 and Pharmacoat® 615), the substitution type is 2910; the methoxy content is 28.0–30.0 %; the hydroxypropoxy content is 7.0–12.0 %; the molar substitution of hydroxypropoxy group (the average number of substituents in the anhydrous glucose unit) is 0.25; and the degree of substitution of methoxy group (the average number of substituted hydroxyl groups in the anhydrous glucose unit) is 1.9) (Shin-Etsu, 2006b, Shin-Etsu, 2023b). According to the size-exclusion chromatography with multi-angle light scattering (SEC-MALLS) performed by Shin-Etsu Chemical Co., Ltd., the weight-average molecular weights (Mw) are 60,000 g/mol and 76,800 g/mol; the weight-average degrees of polymerization (DPw) are 296 and 378; and the molecular weight distributions (Mw/Mn) are 1.89 and 2.64 for Metolose® 60SH-50 and Pharmacoat® 615, respectively (Shin-Etsu, 2006a). The following excipients were used for both ink formulation and module preparation: MilliQ water (18.2 MΩ) freshly prepared by ELGA LabWater system (High Wycombe, U.K.), polysorbate 20 (Tween 20) (Fluka Analytical, Switzerland) and lactic acid (LA) (88–92 %) (Fluka Analytical, Switzerland). The composition of the original inks (Primera Technology, USA) was the following: the yellow ink contains purified water, propylene glycol, glycerine, Yellow #5, polysorbate 80 (Tween 80), mono- and di-glycerides, Yellow #6 and NaOH; the cyan ink contains purified water, propylene glycol, glycerine, Blue #1, polysorbate 80 (Tween 80), NaOH, mono- and di-glycerides, and the magenta ink contains purified water, propylene glycol, carmoisine (dye), glycerine, polysorbate 80 (Tween 80), NaOH, mono- and di-glycerides and potassium citrate. 37 % hydrochloric acid (HCl) (Sigma-Aldrich, USA) was diluted with MilliQ water to prepare 0.1 M HCl for release experiments and 0.7 % HCl + 0.5 % (w/v) sodium dodecyl sulfate (SDS) (Merck, Germany) in water for the quantification of printed CAR amount.
Wuzhong He, Huiling Mu, Natalja Genina, Bespoke hydroxypropyl methylcellulose-based solid foams loaded with poorly soluble drugs by tunable modular design, Carbohydrate Polymers, Volume 357, 2025, 123397, ISSN 0144-8617, https://doi.org/10.1016/j.carbpol.2025.123397.
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