Homogeneity and mechanical properties of orodispersible films loaded with pellets

Introduction

Orodispersible film (ODF) is a dosage form for patients with special needs such as geriatric and paediatric patients as well as patients with dysphagia [1], [20], [2]. Orodispersible films (ODFs) have a form of a polymeric strips with wide range of thickness: from 10 to 350 µm (usually up to 100 µm) and a surface from 2 to 8 cm2. The ODF mass depends on formulation method and film size (surface) and is usually in the range from 10 to even 100 mg. The drug load can be up to 25–30 % of the film mass, therefore, this dosage form is only suitable for high potency drugs [3], [4], [5].

This drug form may display different biopharmaceutical characteristics depending on designed properties such as single or multiple-layer polymer sheets, fast-dissolving or sustained-release matrix [6], [7], [8], [12], [9], [1]. If the active pharmaceutical ingredient (API) is absorbed via the oral mucosa it may lead to increased bioavailability thanks to circumventing the first pass metabolism [7], [10], [11].

ODFs have been reported to increase patients compliance by improving ease of swallowing without requiring water [1]. The films are usually placed on tongue however they may also be applied to cheeks, palate or sublingually [2], [12]. Films may adhere to oral mucosa and/or dissolve in the saliva and therefore cannot be spat out what also prevents chocking [1], [13].

Approximately 30 % of the paediatric medication used globally is off-label what potentially lead to dossing errors and adverse effects [14], [15]. Currently in youngest children group: infants, toddlers and preschool (< 6 years), still the most acceptable form are liquids such as syrups, suspensions drops and solutions [16], [17], however Alessandrini et al. [16] reported that the percentage of children with a chronic condition selecting liquid as the most acceptable form was less than 40 % in comparison to 93 % with healthy status.

The European Medicines Agency’s (EMA) and World Health Organization (WHO) recommended the use of solid drug formulations in children any time when it is possible [18], [19]. The lack of proper system for adjustment the dosage in relation to children body mass is a main, next to swallowing, problem limiting factor for the use of adequate solid dosage oral forms in preschool pediatric population. The ODFs choice as a new solid drug form may solve this problems due to the possibility to assure accurate dosing and convenient way of application [20], [21], [22]. The film sheet can be cut during production process into suitable size allowing high dose flexibility appropriate to paediatric patient age or body mass. According to Klingman et al. (2020) it is possible to adjust the dose by dividing single dose ODFs in an accurate half dose. An example of a recently registered market product with a size-controlled dose is Sympazan in which clobazam doses of 5, 10 and 20 mg are obtained in a 12.8 x 22 mm, 22 x 25.6 mm, 22×32 mm film sheets, respectively (Otter Pharmaceuticals, product information) [42].

Lately the acceptability of ODF was reported in infants and preschool children in published studies by Kean et al. (2023), Wargenau et al. [13], Klingman et al. [21], Orlu et al. [23] and Visser et al. [24].

Kean and Adeleke [25] reported that in children < 6 years ODFs increased patients compliance and oral administration was possible also without requiring water. In a group of between 2 days and 6 years old 70 % of patients completely swallowed and 25.3 % partially swallowed ODF drug form, and no one spat it out (0 %) [13]. These results were better than in a group receiving a syrup (13.3 % patients spat it out). Also Klingman et al. [21] reported overall superior swallowability of the ODF film (2 x 3 cm2) compared to 0.5 – 3 mL glucose syrup in neonates and infants. In a group of preschool children 72 % patients reported a willingness to take an ODF again what was confirmed by caregivers − 86 % of them positively rated child’s ODF acceptance [23].

APIs are usually dissolved in the film matrix with respect to achieve proper homogeneity and mechanical properties (flexibility). Therefore, the solubility of the API significantly limits the dose of the drug in the single-dose film sheet [26]. Recently it has been shown that in order to obtain high loadings of up to 50 % w/w of nanoparticles could be realized while maintaining good mechanical film properties as well as reasonable disintegration times [27].

In contrast to ODFs with dissolved API, less research was focused on the suspending poorly water soluble drugs in film formulations or to incorporate solid particles to achieve modification of the drug release rate or to achieve taste masking. Lately, researchers have demonstrated that the inclusion of nanocrystal dispersions or microparticles in ODFs can lead to improved drug dissolution rates or enable extended drug delivery [27], [28], [29], [30], [31], [32]. The suspension type ODFs are still a challenge to ensure homogeneity in production process and product development [33], [34].

This study is aimed to evaluate possibility to incorporate in ODF matrix spherical granules − pellets. Pellets are considered to be a promising pediatric formulation approach allowing many different formulation variations and dosage strengths with one single multiparticulate formulation [35]. According to our knowledge there is until now only one published work [33]demonstrating that prolonged release ODFs can be obtained by incorporation of diclofenac loaded pellets. Moreover, the authors showed that it was possible to achieve satisfying dose uniformity in the 6 cm2 films loaded with relatively big diclofenac pellets (< 620 µm). There is a need to determine the influence of pellets on ODF physicochemical properties in dependence on their size and concentration in the matrix as well as to establish the procedures for their quality control.

We aimed to develop ODFs with a high load of pellets that were examined in two different particle sizes and in different concentrations. The possibility to achieve the homogenous distribution of spherical granules in ODF matrix was evaluated. The incorporation of pellets with the active substance into ODF is a technological challenge due to the expected greater difficulty in uniformly distributing them than in the case of much smaller and more numerous particles of the active substance introduced as a simple suspension. Success in this matter makes it possible to easily mask the taste of the active substance and modify its release rate by using pellets coated with functional coatings. Although high particle loads were aimed, a major focus was to achieve films with a good quality to enable appropriate handling by the patient. Thus, it was necessary to analyze whether an embedding the pellets into the film structure would affect its mechanical properties and disintegration time.

Download the full article as PDF here Homogeneity and mechanical properties of orodispersible films loaded with pellets

or read more here

Materials

Pellets in two different sizes: Cellets® 100 and Cellets® 200 (CL100 and CL200) (Harke Pharma GmbH, Mülheim an der Ruhr, Germany), composed of microcrystalline cellulose, were used as model spherical granules. Hypromellose (HPMC, Pharmacoat 606, Shin‐Etsu Chemical, Tokyo, Japan) with glycerol 86 % (GL, Fagron, Nazareth, Belgium) employed as a plasticizer were used to prepare ODF matrix. Purified pharmaceutical‐grade water was used as a solvent.

Katarzyna Centkowska, Martyna Szadkowska, Marta Basztura, Małgorzata Sznitowska, Homogeneity and mechanical properties of orodispersible films loaded with pellets, European Journal of Pharmaceutics and Biopharmaceutics, Volume 205, 2024, 114537, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2024.114537.

Visit our Excipient Landscape 2024 here:

Get more information on different excipients and their manufacturers