Development of a Hydrocortisone Orodispersible Thin Film Containing Its Succinate Prodrug

Abstract

Orodispersible thin film (ODF) is an innovative dosage form that allows for adjustable dosing and improved patient compliance. It is administered by mouth, where it dissolves, making it suitable for children.

Objectives: The aim of the study was to develop and characterize an optimal ODF formulation containing equivalent hydrocortisone at 0.5 mg/cm² using the solvent-casting method. A stability-indicating assay for the simultaneous quantification of hydrocortisone and hydrocortisone 21-hemissucinate (HMS) was developed. ODFs were characterized by organoleptic properties and by testing for uniformity of mass, content, stability, thickness, and dissolution.

Results: When optimized, ODF is thin, flexible, and transparent, making it suitable for production in hospital pharmacies using standard equipment. In contrast to the water-insoluble hydrocortisone, the HMS-loaded cast gel successfully satisfied the tests, including content uniformity. Disintegration appeared acceptable as compared to the commercial grade ondansetron ODF (Setofilm^®). The physicochemical stability of the active ingredients (i.e., HMS, hydrocortisone) contained in the ODF at 0.5 mg/cm² is demonstrated for at least 84 days at 23 °C.

Conclusion: The ODF formulated with the water-soluble hydrocortisone prodrug HMS allows accurate drug level to be achieved, thus opening up new opportunities for use in pediatric patients.

Introduction

Hydrocortisone (HCT) is a glucocorticoid that is mainly used as a replacement therapy for children with adrenal insufficiency and also in a variety of autoimmune and inflammatory diseases. Adrenal insufficiency is a group of autosomal recessive genetic disorders that result in a total or partial deficiency of an enzyme involved in adrenal steroidogenesis. A mutation found in over 95% of cases results in a congenital deficiency of 21-hydroxylase, which at least impairs cortisol biosynthesis [1,2]. Hormone replacement therapy with glucocorticoids and/or mineralocorticoids is the standard of care. To mimic the physiological hormonal peak, an HCT formulation with immediate drug release is administered in three doses per day at 10 to 15 mg/m2/day, corresponding to ~1 to 2 mg per dose for a child [3]. In addition, dose adjustment is regularly necessary due to growth of the child. Therefore, a dosage form allowing for safe dose adjustment is necessary. Only one licensed HCT treatment, in the form of granules for oral suspension, has been developed for children under the trade name Alkindy® (Diurnal, Cardiff, United Kingdom) [4]. However, this treatment is unavailable in many countries, and the only approved oral products containing HCT are only suitable to be used in the adult population. Consequently, dose adjustments are required for the pediatric population, which could be achieved by crushing adult tablets and suspending them extemporaneously in liquid by the family or caregiver.

However, this practice is associated with a high risk of inaccurate dosage [5]. In this context, a safer alternative is the production of hard capsules, which are prepared mainly by hospitals or community pharmacies. However, the quality of these HCT pharmaceutical preparations is highly variable, which can have important consequences in the therapeutic management [6].

There is a growing interest in orodispersible thin film (ODF) formulations, as they allow for better compliance in populations with swallowing difficulties, such as elderly patients and children [7]. Indeed, recent studies have shown an improvement in the acceptability and palatability of ODFs in young children in comparison with oral liquid formulations [7,8]. The European Pharmacopeia provides the following definition for ODFs: “single- or multilayer sheets of suitable materials, to be placed in the mouth where they disperse rapidly” [9]. ODFs are designed to dissolve directly in the oral cavity, allowing the incorporated active pharmaceutical ingredient (API) to be swallowed with saliva. However, ODFs also have their limitations, particularly in terms of production and the need for a homogeneous and reproducible film [10].

While the production of ODFs can be automated, it can also be performed using a manual process, making it feasible for production in hospital or community pharmacies. Recently, various methods for ODF production have been explored, including 3D printing and solvent-casting. The most suitable method for community or hospital pharmacies is solvent-casting, due to its ease of implementation and significantly lower cost compared to 3D printing [11].

Briefly, to produce an ODF, the API and excipients are dissolved in water to form a gel, which is then poured and dried to form a large film which is cut into individual units of the desired size and dose. The main components of an ODF include the API, a polymeric agent such as maltodextrin or cellulose derivatives, a plasticizer such as glycerol, and other excipients to improve disintegration and mouth feel [12,13]. The low water content of ODFs provides superior microbiological and chemical stability comparable to that of solid oral dosage forms [14]. In addition, the pharmaceutical preparation process ensures uniform distribution of the API, the large-cast gel can be cut into multiple fragments whose surface area corresponds to the dose to be administered, enabling pharmacists to pre-prepare customized doses tailored to individual patient needs [15].

One of the major advantages of ODFs is their ability to disintegrate quickly. Among the parameters that influence disintegration, the solubility of the API plays a crucial role in the properties of ODFs. In particular, the water solubility of the API promotes the disintegration process, as well as ensuring uniformity and that each individual ODF unit will deliver the intended dose [11]. A water-insoluble API must be homogeneously and stably dissolved in the casting solution to ensure uniformity of the ODF API content. The low solubility of HCT in water is a critical issue when formulating ODF with HCT. Therefore, several strategies are possible, such as the use of lipid complexes or cyclodextrins to make HCT more water-soluble. However, an intravenous water-soluble form of HCT, hydrocortisone hemisuccinate (HMS), was chosen for our study. This ester HCT prodrug also has the advantage of releasing HCT by spontaneous hydrolysis.

The aim of this study is to develop an appropriate casting solution and production method for producing ODFs with a reproducible dose of HCT/HMS. A variety of excipients and conditions, with or without the incorporation of HMS into the casting gel, will be investigated to achieve this goal.

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Materials

Pure micronized pharmaceutical-grade powdered hydrocortisone (HCT), GF-grade hydroxypropylcellulose (HPC) (Klucel GF® 300 mPa.s), sucralose, and povidone K25 were purchased from Inresa Pharmaceutical (Bartheim, France). Hydrocortisone 21-hemisuccinate sodium salt (HMS) was obtained from SERB Pharmaceutical (Hydrocortisone Upjohn®; Paris, France). Ondansetron ODF at 4 mg (Setofilm®) was purchased from Norgine (Rueil-Malmaison, France). Pharmaceutical-grade polysorbate 80 (tween 80) and glycerol were obtained from Cooper (Melun, France). Pharmaceutical-grade glyceryl monolinoleate (Maisine®) was kindly provided by Gattefosse (Saint-Priest, France), and cola flavor was obtained from IFF (Tillburg, The Netherlands). Acetonitrile and orthophosphoric acid were of analytical grade and purchased from VWR chemicals (Fontenay-sous-Bois, France). Distilled sterile water was purchased from Aguettant (Lyon, France).

Boisseillier, C.; Demange-Labriet, L.; Kariyawasam, D.; Marchadour, P.; Fauqueur, A.-S.; Annereau, M.; Denis, L.; Cotteret, C.; Cisternino, S.; Schweitzer-Chaput, A. Development of a Hydrocortisone Orodispersible Thin Film Containing Its Succinate Prodrug. Pharmaceuticals 2025, 18, 86. https://doi.org/10.3390/ph18010086

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