Application of Hydrophilic Polymers to the Preparation of Prolonged-Release Minitablets with Bromhexine Hydrochloride and Bisoprolol Fumarate

Abstract

Introduction

The oral route remains the most common method of drug administration due to the ease of self-administration by patients or caregivers, the highest acceptability, and the possibility of controlling and modifying the release of the active pharmaceutical ingredient (API) [1,2]. Solid oral dosage forms, particularly tablets, are the most popular kind of formulation. Their advantages include dosage accuracy, stability during storage, resistance to handling and transportation, and many more. The major drawback of tablet administration is the frequent problem of swallowing, especially encountered in pediatric and geriatric populations [3]. One of the solutions to this problem is formulation of minitablets [4]. They are a solid dosage form with a typical diameter of 1–3 mm and a weight of approximately 5–25 mg. Due to their small size, they can be swallowed much easier or administered with liquid or soft foods [5,6,7,8].
One of the most popular trends in the development of dosage forms, intended to improve patient compliance, is the reduction in the frequency of dosing by modification of the rate of drug substance release. Prolonged- or sustained-release preparations by definition have a reduced rate of API release and allow the possibility of maintaining a constant blood level of the drug substance for 8–12 h or even longer (e.g., 24 h) [9]. These dosage forms also offer fewer fluctuations in the plasma level of a drug and a lower maximum concentration directly after administration, which can lead to fewer adverse effects [10]. The technological development of extended-release drug forms focuses particularly on substances with a short half-life, ranging from 1 to 6 h [11,12]. It is not recommended to prepare a prolonged-release drug form for substances that are absorbed only in the upper gastrointestinal tract or require a washout period during standard therapy and for those drugs that are used in doses greater than 500 mg. Also excluded are APIs, whose absorption cannot be limited by their dissolution rate [12]. There are numerous technologies used to slow down the release of the drug substance, e.g., coating the semi-finished or finished product with a functional polymer, incorporation of drug substances into matrices that slowly dissolve or erode, complexation with substances that modify solubility, bonding with ion exchangers, modification of the crystallization process, and chemical modification of the drug substance to change its solubility (esterification or salt formation) [12].

The great possibilities in modifying API release come from its incorporation into a functional matrix. The simplest way is to directly compress bulk or granulated API with a mixture of excipients using a tablet press. The tablet matrix may be hydrophilic, lipophilic, or insoluble in the digestive tract. Tablets made of a hydrophilic matrix are produced mainly for APIs that are poorly soluble in water. In this case, water-soluble polymers are used, which swell in the gastrointestinal tract, creating a high-viscosity hydrogel. These compounds may differ in parameters such as molecular weight, degree of swelling, or viscosity of the hydrogel that forms [13]. The hydrogel layer controls the release rate of the drug substance from the matrix. Water gradually wets the tablet and penetrates into its core, and the dissolved active substance diffuses through a layer of viscous gel that limits its release. This wetted tablet also erodes, and its surface gradually decreases, resulting in a smaller release surface and a slower release process as the tablet moves through the gastrointestinal tract. The balance between erosion rate and changes in the thickness of the gel layer allow stabilization of the API release within a particular time and release with a constant speed. An example of a hydrophilic polymer is hydroxypropylmethylcellulose (HPMC), which is a biodegradable ester derivative of cellulose [14,15]. It is compatible with most APIs and excipients and is odorless, flavorless, transparent, relatively inexpensive, and readily available. HPMC has a linear structure of glucose molecules and is non-ionic [15,16]. Aqueous solutions of HPMC exhibit a sol–gel transition during heating and a reversible gel–sol transition during cooling [17]. Another derivative of cellulose is methylcellulose (MC), available in the form of white powder and insoluble in hot water but forming a colloid in the temperature range 50–70 °C [18,19]. Another example of a hydrophilic polymer is sodium alginate (SA), a natural polysaccharide formed in the cell wall of various species of algae and bacteria. It is nontoxic, biodegradable, and biocompatible. Structurally, alginates are a combination of β-D-mannuronic and α-L-glucuronic acid fractions linked to each other by one to four glycosidic bonds. SA is a white or slightly yellowish powder that is easily soluble in water. In cold water, it can form very viscous solutions and gels when combined with divalent ions [20].

Bisoprolol fumarate (BFM) belongs to a class of medications called beta-blockers [21]. It selectively blocks β1-receptors, preventing their stimulation and limiting the effects of adrenaline or norepinephrine. It has no ability to stabilize cell membranes or intrinsic sympathomimetic activity. Bisoprolol fumarate works by relaxing blood vessels and slowing the heart rate to improve and decrease blood pressure. It is used to treat hypertension, stable angina pectoris, and stable chronic heart failure with impaired left ventricular systolic function (in combination with other drugs) [21]. Bisoprolol fumarate is available on the European market only in the form of immediate-release preparations, and there is no pediatric form available [22]. It is dosed once a day due to a long half-life (approximately 10–12 h).

Bromhexine hydrochloride (BHX) is a well-known expectorant from the group of mucolytics [23]. It is metabolized in the liver to the active compound ambroxol. Bromhexine is indicated in acute and chronic bronchial diseases with excessive mucus secretion. It reduces the content of mucopolysaccharides in mucus, which has an expectorant effect. In addition, it stimulates the synthesis and secretion of surfactant. In this way, it improves the function of the cilia of the respiratory epithelium. It does not disturb the natural cough reflex. The biological half-life of bromhexine is approximately 12 h. Multiple dosage forms with bromhexine are registered, including conventional tablets, orodispersible tablets, syrups, and oral drops. The pediatric dosing regimen requires drug administration three times a day, which can cause problems with acceptability, compliance, and effective therapy. Unfortunately, there is no modified release dosage form containing bromhexine [24].

The chemical structures of bisoprolol fumarate and bromhexine hydrochloride are presented in Figure 1. BFM is highly soluble in water and highly permeable, thus belonging to a class I of the Biopharmaceutical Classification System (BCS). BHX is poorly soluble in water and neutral media, but its solubility in the acidic conditions is much higher. It belongs to BCS class II.

The aim of our study was to assess the possibility of development of extended-release minitablets based on hydrophilic polymers and with selected model drugs used in pediatric therapies. The minitablet formulation is intended to facilitate easy swallowing due to its small size, while the extended form can make administration less frequent, leading to better compliance. Furthermore, the great advantage of prolonged-release minitablets is the lack of risk of releasing the entire dose of the active substance in the event of damage to the coating of a single tablet as well as the fact that the release is independent of the frequency of gastric emptying [25]. The incorporation of a small dose into a single minitablet also allows easy and precise dose adjustment in pediatric patients according to their body weight.

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Materials

Two active pharmaceutical ingredients (API) were used for the study: bromhexine hydrochloride (99.4% purity) (BHX) (VenPetrochem, Mumbai, India) and bisoprolol fumarate (99.5% purity) (BFM) (Wuhan ChemNorm Biotech Co., Ltd., Wuhan, China). The other excipients included Metolose 90SH-400 and Metolose 90SH-4000 cP—hydroxypropyl methylcellulose (Shin-Etsu Chemical, Tokyo, Japan); Metolose SM 4000 cP—methylcellulose (Shin-Etsu Chemical, Tokyo, Japan); sodium alginate (Sigma-Aldrich, St. Louis, MO, USA); Parteck SRP 80—polyvinyl alcohol (Merck, Darmstadt, Germany); Flowlac 100—spray-dried lactose (Meggle Pharma, Wasserburg am Inn, Germany); Pearlitol 100SD—D-mannitol (Roquette, Lestrem, France); Vivapur 101—microcrystalline cellulose (JRS Pharma, Holzmühle, Germany); Cab-O-Sil—silicon dioxide (Cabot, Rheinfelden, Germany); and Pruv—sodium stearyl fumarate (JRS Pharma, Holzmühle, Germany). All other ingredients were of analytical grade. The water for the preparation of solutions was purified with the reversed-osmosis Elix Essential 15 UV system (Merck Millipore, Molsheim, France).

Grzejdziak, A.; Brniak, W.; Lengier, O.; Żarek, J.A.; Hliabovich, D.; Mendyk, A. Application of Hydrophilic Polymers to the Preparation of Prolonged-Release Minitablets with Bromhexine Hydrochloride and Bisoprolol Fumarate. Pharmaceutics 2024, 16, 1153. https://doi.org/10.3390/pharmaceutics16091153

Read also our introduction article on Alginates here: