Oral Gels as an Alternative to Liquid Pediatric Suspensions Compounded from Commercial Tablets

Abstract

The aim of the study was to propose pharmacy-compounded oral gels as a new and alternative dosage form that is attractive to children as having a better masking taste than syrups and reducing the risk of spilling. The application and physical properties of the gels prepared with cellulose derivatives (hydroxyethylcellulose and carmellose sodium) or carbomers were evaluated. The results of the study showed the most suitable consistency, viscosity, and organoleptic properties for gels prepared with carbomer and cellulose derivatives at concentrations of 0.75% and 2.0%, respectively. The microbial stability of the gels was guaranteed by the use of methylparaben and potassium sorbate. VAL (valsartan) and CC (candesartan cilexetil) tablets, often used off-label in children, were pulverized and suspended in the hydrogel bases, resulting in final drug concentrations of 4 mg/g and 1 mg/g, respectively. There was no significant change in viscosity and consistency parameters when the pulverized tablets were added, and only small changes in viscosity and consistency were observed during 35 days of storage, especially in the gels with sodium carmellose and candesartan. On the basis of the drug assay, an expiry date of 25 °C was recommended: 35 days for valsartan and 14 days for candesartan preparations.

Introduction

The lack of age-appropriate dosage forms with a dose easily adjustable is still a highlighted problem in pediatric therapy [1,2,3,4,5]. The common practice is to prescribe medicinal products that are in tablet or capsule form and have a license for use only in adults [6,7]. Preparation of pediatric dosage forms from such products is an off-label use that is often practiced clinically. To adjust the dose in such situations, pharmacists compound powders in capsules (gelatine or starch), or in paper sachets, or prepare syrups. Powders, before administration to small children, are sprinkled and mixed with soft food, milk, or another beverage. Such manipulation brings the risk of drug–food interaction or administration of an incomplete dose (loss of powder) while emptying the capsule [8,9,10,11,12]. Oral liquid extemporaneous dosage forms (syrups, suspensions, and solutions) eliminate this kind of problem; however, palatability is still a challenge [12,13,14,15,16,17,18,19,20]. Although liquids are a popular alternative to powders in the USA, they are less frequently or rarely compounded in European countries [11,12,13,14,15,16,17,18,19,20,21].
Whereas pediatric topical oral gels (for example, to treat inflammation or infection in the oral cavity) are widely available, oral gels are less common as alternatives to tablets or syrups [22,23,24]. Commercial oral pediatric hydrogel dosage forms registered as medicinal products have already been introduced as attractive alternatives for dietary supplements with vitamins. Like any soft food, semisolid oral hydrogels may assess ease of swallowing without mixing powders with food, which always creates the risk of incompatibility. Thus, oral administration of hydrogels is a new trend in pediatric therapy and brings positive recommendations with respect to safety, good palatability, and flexibility of dosage by measured volume. Hydrogels could be an attractive dosage form because of their smooth structure, which improves the child’s feelings during administration, better taste masking, and less risk of liquid spilling from the spoon. They may be easily packed into single-dose sachets or in tubes. A dose from the latter may be measured using spoons or oral syringes.

If the active substance is suspended in the gel, the homogeneity during the whole time of storage should be assured by the proper viscosity of the carrier because, in contrast to liquid suspensions, the sediment cannot be restored by shaking. There is some risk that the high viscosity of the formulation may reduce the bioavailability of the drug or delay its absorption, but the same risk exists when mixing a child’s medicine with food. Although there is a lack of research on this topic, it is definitely possible to consider it, especially when drug absorption is rapid. On the other hand, absorption from a tablet is determined by its disintegration, while in a gel, the medicinal substance is in the form of already small particles.

Valsartan (VAL) and candesartan cilexetil (CC) are used in the treatment of hypertension and belong to the therapeutic category of angiotensin II receptor blockers. Commercially available are tablets with CC (4, 8, 16, and 32 mg—Atacand and generic products). CC is slowly absorbed from the gastrointestinal tract, with a tmax of 3–4 h [25,26]. The activity, safety, and pharmacokinetics data of CC were studied in children from 1 to 17 years of age, with a dose for children between 1 and 6 years of 0.2 mg/kg/day (the usual dose ranges from 0.05 to 0.4 mg/kg/day) and from 6 years of age and older (weight < 50 kg) of 4–8 mg once daily (the usual dose ranges from 2 to 16 mg/day) [25,26,27,28,29,30,31]. According to the Atacand FDA leaflet, preparation of oral suspension by dispersing tablets in commercially available suspending media (Ora-Sweet SF, Ora-Plus, or Ora-Blend) is recommended [25]. The physicochemical properties of CC and VAL are presented in Table 1.

Table 1. Physicochemical characteristics of candesartan cilexetil (CC) and valsartan (VAL) [32,33,34,35].

 

Tablets with VAL (40, 80, 160, and 320 mg—Diovan and generic products) are indicated for adults and children 6–16 years old [36,37,38,39]. For younger children from 1 year old, the Diovan solution is recommended with a starting dose of 1 mg/kg up to a maximum dose of 4 mg/kg once daily (with dose adjustment based on blood pressure response and tolerability). For children older than 6 years of age and < 35 kg weight, 20 mg once daily (7 mL solution) is recommended, and for > 35 kg weight, 40 mg (14 mL solution) is advised [40]. Absorption from the solution is faster than from tablets (tmax is 1–2 h for a solution and 2–4 h for tablets). The systemic exposure to valsartan (AUC) is 60% higher with the suspension or solution compared to tablets, and when switching between forms, the dose of VAL may need to be adjusted [40,41]. Unfortunately, the availability of this product in the form of a solution is very limited in many European countries, and the off-label use of VAL in tablets is very common.

Suspension-type syrups compounded from Diovan tablets (VAL concentration 4 mg/mL) and Ora-type media can be stored in a glass bottle for either up to 90 days at temperatures below 30 °C or up to 75 days at refrigerated conditions [41]. Syrups prepared with Atacand tablets, with CC concentrations of 1 mg/mL or 2 mg/mL, should be used within 30 days (up to 100 days when unopened) when stored at room temperature [25,42,43,44]. For simpler suspending media, based on sucrose, stability of the suspensions for 3 or 4 weeks at room temperature was declared [21].

The aim of the current study was to develop hydrogels as alternative formulations to VAL and CC liquid suspensions. The new compounded formulations are proposed for easier drug administration, as described above. The chemical stability of the drugs in the gel vehicles was evaluated by using a HPLC method. Physical stability and the rheological properties of the final formulations were investigated at different temperatures during the time. The results obtained should allow gel vehicles to be considered a new dispersing medium for active substances, including when the drugs are obtained by manipulating tablets or capsules. The proposed extemporaneous formulations could also represent a valuable alternative to Ora® products when they are not available on the market.

The study did not include the impact on the bioavailability of the drug in terms of both crushing tablets and incorporation in a viscous medium. The tested active substances belong to BCS class II and are sparingly soluble in water, and the risk of changing bioavailability should be taken into consideration. However, a similar risk occurs when combining medicines with food, which is a common practice in administering drugs to children.

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Materials

Hydroxyethylcellulose (HEC) (Natrosol 250 HR was purchased from A.C.E.F., Piacenza, Italy), sodium salt of carmellose (high-viscosity carboxymethylcellulose, CMC) (Sigma Aldrich, St. Louis, MO, USA), and carbomer (CAR) dedicated to oral use (Carbopol 974 P NF, Noveon, Cleveland, OH, USA) were used as gelling agents. Other chemical substances and solvents used in hydrogels were of pharmacopoeial quality: methylparaben (Fluka, Steinheim, Germany), glycerol (Amara, Krakow, Poland), potassium sorbate, and sorbitol (POCH, Avantor Performance Materials Poland, Gliwice, Poland).

Oral pediatric hydrogels were prepared with tablets obtained from a local pharmacy. For VAL hydrogels, Diovan® (Novartis, Nürnberg, Germany) coated tablets were used at a strength of 160 mg. The tablets contain the following excipients: microcrystalline cellulose, polyvinylpyrrolidone, colloidal silica, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 8000, and iron oxides. For CC preparation, Atacand® (Astra Zeneca, Södertälje, Sweden) uncoated tablets with a strength of 16 mg were used, composed of the following excipients: calcium carboxymethylcellulose, hydroxypropylcellulose, lactose monohydrate, magnesium stearate, corn starch, polyethylene glycol 8000, and iron oxides.

Reagents used for high-performed liquid chromatography (HPLC) analysis, that is, acetonitrile (POCH, Gliwice, Poland), methanol (J.T.Baker, Deventer, Netherlands), and ortho-phosphoric acid (Fluka, Steinheim, Switzerland), were of HPLC grade. The VAL and CC substances used for the calibration curve were donated by Polpharma (Starogard, Poland).

Trofimiuk, M.; Sznitowska, M.; Winnicka, K. Oral Gels as an Alternative to Liquid Pediatric Suspensions Compounded from Commercial Tablets. Pharmaceutics 2024, 16, 1229. https://doi.org/10.3390/pharmaceutics16091229