Formulation of minitablets with personalised dissolution profile by fluid-bed granulation of drug nanosuspensions

Abstract

Transforming poorly soluble active pharmaceutical ingredients (APIs) into a nanoparticulate form is a proven way of improving their dissolution characteristics. The preparation of API nanosuspensions is commonly achieved by wet-stirred media milling. The challenge lies in converting the nanosuspension into a solid dosage form without compromising its re-dispersibility. In the present work, an API nanosuspension was combined with additional excipients and used as a binder in fluid-bed granulation to obtain granules with systematically varying dissolution properties. Specifically, polymeric excipients (hydroxypropyl methylcellulose grade E5 and polyvinylpyrrolidone grade K30) were used in the nanosuspension binder to granulate microcrystalline cellulose or Pearlitol CR-H substrate. The resulting granules were used as feed material to prepare minitablets whose combination enabled the formation of multi-unit dosage form (MUDF) capsules with tuneable drug release profiles, paving the way to rational design and manufacturing of precision medicines.

Introduction

An increasing number of drugs, both in development and on the market, belong to a low aqueous solubility class (Benet et al., 2011, Benet, 2013). Low solubility is one of the most common causes of low oral bioavailability. When such drugs occur in a co-prescription, the problem can be further exacerbated by poor adherence to prescription medication often reported among polypharmacy patients (Sutherland et al., 2015, Brown and Bussell, 2011, Garner, 2010). Cardiovascular diseases, for example, frequently require treatment with multiple drugs in combination therapy and it has been shown that fixed dose combinations (FDC) measurably improve the treatment outcomes (Huffman et al., 2017, Poulter et al., 2020, Parati et al., 2021, Gupta et al., 2010). While FDCs are typically used for combining two or more different Active Pharmaceutical Ingredients (API) into a single dosage form, they can also be used for combining the same API in two different compositions that provide different drug release characteristics. Examples of such formulations include analgesics in the so-called immediate release/extended release (IR/ER) tablets, which have the benefit of providing a rapid onset of action with a more durable effect on the patient (Legg et al., 2017, Devarakonda et al., 2015).FDCs often have the form of layered tablets, but other technical approaches such as multi-unit dosage forms (MUDF) or various complex polypills have also been reported (Poulter et al., 2020, Parati et al., 2021, Gupta et al., 2010, Kavanagh et al., 2018, Jacob et al., 2020, Rahim et al., 2020, Šoltys et al., 2019, Taupitz et al., 2013). MUDFs offer the benefit of dose flexibility and potential personalisation by adjusting the nature and count of individual subunits specifically to the needs of individual patients or small patient cohorts.

The present work is concerned with the fabrication of MUDFs that enable the personalisation of drug release profiles by combining subunits with the same API but different dissolution characteristics to achieve the desired overall drug release profile.The manufacturing of MUDFs consists of two fundamental steps: the fabrication of subunits such as pellets and minitablets, and their combination into a sachet, capsule or a larger tablet to achieve the desired effect. When using a nanosuspension as a means of improving the drug dissolution characteristics (Aghrbi et al., 2021, Sheng et al., 2020, Li et al., 2016, Li et al., 2016, Wu et al., 2011), the challenge lies in converting the nanosuspension into a solid form that preserves the high specific surface of the individual particles after redispersion and at the same time enables good powder flow properties and handling in the solid state (Rahim et al., 2020, Singhal et al., 2022, Sahnen et al., 2020, Fülöp et al., 2018, Steiner et al., 2017, Parmentier et al., 2017). The nanosuspension itself can be manufactured by an established wet stirred medial milling process (Li et al., 2016, Wu et al., 2011, Hládek et al., 2022, Prajapati and Serajuddin, 2019) and followed by spray drying, spray coating, and wet granulation as the most common solidification approaches (Sahnen et al., 2020, Azad et al., 2016, Sievens-Figueroa et al., 2012).

Drug content uniformity is a particularly important quality attribute when manufacturing MUDFs. Using nanosuspension as a binder in fluid-bed granulation makes it possible to achieve a uniform dispersion of API particles throughout the product and across granule size classes. The use of suitable excipients directly in the nanosuspension or as additional components in the fluid-bed process can achieve immediate, sustained, or pH-dependent drug release (Lecomte et al., 2005, Han et al., 2018). Other advantages of fluid-bed granulation are robustness and scalability, as well as the ability to control the final granule size and density via process parameters such as nozzle arrangement, binder spray rate or drying temperature (Thapa et al., 2019, Kemp et al., 2019, Müller et al., 2019, Liu et al., 2013, Chaudhury et al., 2013, Närvänen et al., 2008, Cryer and Scherer, 2003, Hemati et al., 2003).

In the present work, a laboratory-scale fluid-bed granulation process with a top-spray nozzle arrangement was used to produce several grades of granules with systematically varying dissolution properties, utilizing a drug nanosuspension as a binder. These granules were then pressed into minitablets with “fast” and “slow” release profiles. By combining such minitablets at predetermined ratios, MUDFs with a tuneable dissolution profile were achieved, which could be reliably predicted by the superposition of the dissolution profiles of individual minitablets. This approach highlights the potential to utilize BCS II compounds by processing them in nanosuspension form for enhanced solubility, followed by conversion into a dry formulation that allows for full redispersibility. The choice of excipients used as substrates further modulates the release profiles, supporting the rational design and manufacture of precision medicines where drug release profiles can be tailored to meet the needs of specific patient populations based on individual physiological factors, such as gastrointestinal transit time (Asnicar et al., 2021, Procházková et al., 2023). The minitablets can be filled into capsules or packaged in sachets or other suitable containers to enhance handling and dosing convenience for patients.

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Chemicals

Ezetimibe as a model poorly soluble API (pKa 9.48, Mw 409 g∙mol−1), microcrystalline cellulose (Avicel PH-101), hydroxypropyl methylcellulose (HPMC) grades E5 and K4M, polyvinylpyrrolidone (PVP K30), and sodium dodecyl sulphate (SDS) were kindly donated by Zentiva, k.s. Pearlitol CR H (coprocessed D-mannitol and HPMC K4M in ratio 1:3) and Pearlitol 160 C (pure D-mannitol) were purchased from Roquette, France. Magnesium stearate was purchased from Rettenmaier & Soehne GmbH Co (Rosenberg, Germany). Buffer salts were purchased from Lachner, Czechia and Sigma-Aldrich, Germany.

Elizaveta Mutylo, Ondřej Navrátil, Adam Waněk, Filip Šembera, František Štěpánek, Formulation of minitablets with personalised dissolution profile by fluid-bed granulation ofdrug nanosuspensions, International Journal of Pharmaceutics, 2024, 125013, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125013.

Read also our introduction article on Mannitol here: