Formulation and Evaluation of Polysaccharide Microparticles for the Controlled Release of Propranolol Hydrochloride

Introduction

It is well established that pediatric patients are not small adults. They have different body compositions and physiological and biochemical processes that govern the pharmacokinetics and pharmacodynamics of drugs [1,2,3]. However, due to the ethical and financial challenges that clinical trials in children bring [4], most of the medicines prescribed for pediatric patients are designed for adults. The pediatric doses are achieved by dilution of liquid formulations, opening of capsules, or fine grinding of tablets, administered as suspensions [5]. This practice is known as off-label drug use, which brings certain risks, such as dosing inaccuracy, unpredictable and variable bioavailability, unknown preparation stability, use of excipients that may be toxic, and a low overall acceptability of the medicine for both children and caregivers [6,7,8]. In order to avoid these risks, pediatric patients must be treated with medications that are developed and approved exclusively for them. The development of pediatric, age-appropriate formulations is a complex process due to numerous factors that must be considered, i.e., taste masking, the heterogeneity of the pediatric population, the requirement to use excipients safe for children, cultural/religious preferences, and the need for dose flexibility [9]. Liquid formulations are the most preferred dosage forms for pediatric patients since they are easy to swallow. However, liquid dosage forms have some serious disadvantages, such as poor stability, which requires the employment of different excipients, such as preservatives, taste-masking problems, and the high cost of storage and transportation [10]. Therefore, there is an agreement to shift from liquid to solid dosage forms, and multi-particulates are considered to be one of the most suitable formulation platforms for oral drug delivery to pediatric patients [8,9,10]. Multi-particulates are small, discrete, multiple-unit dosage forms, including nanoparticles, microparticles, pellets or beads, microcapsules, spheroids, minitablets, etc. These systems are suitable for taste masking by using film-coating technologies [11]. Additionally, dose flexibility, which is often required for pediatric drugs, can be ensured by varying the number or quantity of multi-particulate units administered [9]. It was also reported that multi-particulate formulations were well-accepted and preferred over oral liquids by children from three months of age [12].

Depending on the polymer(s) used in their fabrication, multi-particulates can be programmed for pulsatile, delayed, controlled, or targeted drug release [13]. Pediatric patients with chronic conditions may benefit from controlled-release systems to reduce the frequency of administration [8]. The most utilized polymers in pharmaceutical technology for the preparation of controlled-release drug delivery systems, such as microparticles and nanoparticles, are polysaccharides. This large group of biopolymers are used as encapsulating agents due to their numerous advantages, such as biodegradability, biocompatibility, low toxicity, and swelling properties. Sodium alginate is widely used for the encapsulation of active substances because it has the ability to form a gel structure, such as the “egg-box”, as a result of cross-linking with calcium ions (ionotropic gelation process) [14]. In previous studies, sodium alginate was combined with different polymers, such as hydroxypropyl methylcellulose, polyvinyl alcohol, and gelatin, to formulate dosage forms for pediatric use [15,16].

In this study, sodium alginate was used along with hydroxypropyl methylcellulose and hydroxypropyl guar gum as drug-release modifiers, as well as chitosan as a coating agent, in order to achieve controlled release of propranolol hydrochloride from microparticles formulated for pediatric use. Hydroxypropyl methylcellulose is a water-soluble derivative of cellulose commonly used in drug delivery systems for controlled release [17]. Hydroxypropyl guar gum is the most commonly used derivative of guar gum due to the significantly improved characteristics achieved by the controlled process of etherification of naturally occurring polymer with propylene oxide [18]. Chitosan, as a polycationic polysaccharide and the most important derivative of chitin, has found wide pharmaceutical and drug delivery applications because of its non-toxicity, biodegradability, biocompatibility, non-antigenic nature, and low cost [19]. The thickness of the shell depends on the chitosan molecular weight. Low-molecular-weight chitosan was chosen because it forms a thick shell with a better anti-swelling ability compared to high-molecular-weight chitosan [20].
Propranolol hydrochloride is a non-cardio-selective beta blocker used to treat different conditions in children, such as hypertension, arrhythmias, hyperthyroidism, phaeochromocytoma, hemangiomas, and tetralogy of Fallot, as well as prophylaxis of migraine [21]. Currently, a commercial liquid formulation of propranolol for pediatric patients is authorized in Europe (Hemangiol® 3.75 mg/mL oral solution, Pierre Fabre Medicament Production, Gien, France) and the United States (Hemangeol® 4.28 mg/mL oral solution, Pierre Fabre Pharmaceuticals, Inc., Parsippany, NJ, USA), available on prescription. After first opening, the medicine should be used within two months. Propranolol is rapidly decomposed at alkaline pH and its maximum stability in solution is at pH 3. The commercially available oral solution of propranolol contains citric acid as a stabilizer (pH around 3), sodium saccharin as a sweetener, strawberry and vanilla as flavoring agents to mask the drug’s bitter taste, and propylene glycol (2.6 mg/mL) as a solvent. Daily intake should be limited since they are all labeled as potentially harmful in children and have been associated with toxicity, principally in neonates [22]. According to the provisional pediatric biopharmaceutics classification system (pBCS), propranolol hydrochloride has been reported as one of the drugs with no changes between pBCS and adult BCS. Thus, it is a class I (high permeability and high solubility) compound [23] and is almost completely absorbed after oral administration [24]. However, propranolol is extensively metabolized by the liver and only about 25% of the drug reaches the systemic circulation. It also has a fairly short half-life (3–4 h), which means that, for an optimum effect, the administration of propranolol hydrochloride as an oral solution must be carried out several times a day [24]. Considering all the presented drawbacks of commercially available oral solutions of propranolol, the formulation of a controlled-release solid system, such as microparticles, might be a better solution for the use of this drug in the pediatric population.

Microparticle systems based on polysaccharides, which regulate drug release via diffusion-controlled mechanisms, are described in the literature [25,26,27], but no study has been reported on the encapsulation of propranolol hydrochloride into microparticles intended for the pediatric population. The main objective of this study was to formulate an encapsulation system for propranolol hydrochloride, based on sodium alginate and various other polysaccharide polymers, to control and prolong its release. The method used to develop this system was ionotropic gelation in the presence of calcium chloride as a cross-linking agent. The obtained microparticles were then subjected to different physicochemical characterization, such as particle size measurement, swelling, and dissolution rates in simulated gastric and intestinal media under conditions appropriate for the pediatric population.

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Materials

Sodium alginate (Na-ag), the polymer used for the preparation of microparticles, was obtained from Sigma-Aldrich (Oslo, Norway). Hydroxypropyl methylcellulose (HPMC) 4000 mPa·s was procured from Fagron (Nazareth, Belgium). Hydroxypropyl guar gum with molar substitution 0.4 (HPGG) was purchased from Ashland Inc. (Wilmington, DE, USA). Low-molecular-weight chitosan (LCW) with a high degree of deacetylation (DDA = 95%) was purchased from Sigma-Aldrich Chemie GmbH (Taufkirchen, Germany). Propranolol hydrochloride (PCH; manufactured by TCI EUROPE, Zwijndrecht, Belgium) was used as the model drug. Freshly obtained purified water (GenPure apparatus, Thermo Fisher GmbH, Dreieich, Germany) was used for the preparation of polymer dispersions and during the tests. All other reagents and chemicals used were of analytical grade and correspond to the requirements of valid pharmacopoeias (Ph. Eur. and USP).

Stojmenovski, A.; Gatarić, B.; Vučen, S.; Railić, M.; Krstonošić, V.; Kukobat, R.; Mirjanić, M.; Škrbić, R.; Račić, A. Formulation and Evaluation of Polysaccharide Microparticles for the Controlled Release of Propranolol Hydrochloride. Pharmaceutics 2024, 16, 788. https://doi.org/10.3390/pharmaceutics16060788

Read also our introduction article on Chitosan here: