Pediatric Oral Formulations: An Updated Review of Commercially Available Pediatric Oral Formulations Since 2007.

Oral pediatric formulations are either ready-to-use or require manipulation and multiuse or single-use. Strong encouragement for preservative-free pediatric formulations has resulted in fewer multiuse solutions or suspensions in favor of single-use solid oral dosage forms. This updated review covering new pediatric formulations marketed in the United States of America, Europe, and Japan spanning the years 2007 to mid-2018 identified 16 types of pediatric oral formulations of which 7 are ready-to-use and 9 require manipulation, and 51 total new pediatric oral formulations of which 21 are ready-to-use and 30 require manipulation. Ready-to-use formulations include oral solution, oral suspension, oral soluble film, tablet, scored tablets, orally disintegrating tablet, chewable tablet, and mini-tablets. Formulations requiring manipulation include sprinkle capsule, powder for oral solution, powder for oral suspension, granules for oral suspension, oral powder, oral granules, tablet, dispersible tablet, dispersible scored tablet, tablet for oral suspension, and mini-tablets (oral granules). Significant advances in packaging technology include filling mini-tablets, granules, or powders into sachets, stick packets, blisters, and 2-piece capsules. The future of pediatric oral formulations will increasingly be with user-friendly, preservative-free, taste-masked formulations including multiparticulate single-use solid dosage forms including mini-tablets, orally disintegrating tablets, and sprinkle capsules with or without a specialized package configuration.

Quality assessment of fluconazole capsules and oral suspensions compounded by pharmacies located in the United States.

OBJECTIVE To evaluate pharmaceutical characteristics (strength or concentration, accuracy, and precision), physical properties, and bacterial contamination of fluconazole compounded products. SAMPLE Fluconazole compounded products (30- and 240-mg capsules; 30- and 100-mg/mL oral suspensions) from 4 US veterinary compounding pharmacies. PROCEDURES Fluconazole compounded products were ordered 3 times from each of 4 pharmacies at 7- or 10-day intervals. Generic fluconazole products (50- and 200-mg tablets; 10- and 40-mg/mL oral suspensions) served as references. Compounded products were evaluated at the time of receipt; suspensions also were evaluated 3 months later and at beyond-use dates. Evaluations included assessments of strength (concentration), accuracy, precision, physical properties, and bacterial contamination. Acceptable accuracy was defined as within ± 10% of the labeled strength (concentration) and acceptable precision as within ± 10%. Fluconazole was quantified by use of high-performance liquid chromatography. RESULTS Physical characteristics of compounded products differed among pharmacies. Aerobic bacterial cultures yielded negative results. Capsules (30 and 240 mg) had acceptable accuracy (median, 96.3%; range, 87.3% to 135.2%) and precision (mean ± SD, 7.4 ± 6.0%). Suspensions (30 and 100 mg/mL) had poor accuracy (median, 73.8%; range, 53.9% to 95.2%) and precision (mean ± SD, 15.0 ± 6.9%). Accuracy and precision were significantly better for capsules than for suspensions. CONCLUSIONS AND CLINICAL RELEVANCE Fluconazole compounded products, particularly suspensions, differed in pharmaceutical and physical qualities. Studies to evaluate the impact of inconsistent quality on bioavailability or clinical efficacy of compounded fluconazole products are indicated, and each study should include data on the quality of the compounded product evaluated.

Feasibility of amlodipine besylate, chloroquine phosphate, dapsone, phenytoin, pyridoxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in SyrSpend(®) SF PH4 oral suspensions.

The objective of this study was to evaluate the feasibility of 10 commonly used active pharmaceutical ingredients (APIs) compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend(®) SF PH4 liquid): (i) amlodipine, (as besylate) 1.0mg/mL; (ii) chloroquine phosphate,15.0 mg/mL; (iii) dapsone, 2.0 mg/mL; (iv) phenytoin, 15.0 mg/mL; (v) pyridoxine hydrochloride, 50.0 mg/mL; (vi) sulfadiazine, 100.0 mg/mL; (vii) sulfasalazine, 100.0 mg/mL; (viii) tetracycline hydrochloride, 25.0 mg/mL; (ix) trimethoprim, 10.0 mg/mL; and (x) zonisamide, 10.0 mg/mL. All suspensions were stored both at controlled refrigeration (2-8 °C) and controlled room temperature (20-25 °C). Feasibility was assessed by measuring the percent recovery at varying time points throughout a 90-day period. API quantification was performed by high-performance liquid chromatography (HPLC-UV), via a stability-indicating method. Given the percentage of recovery of the APIs within the suspensions, the expiration date of the final products (API+vehicle) was at least 90 days for all suspensions with regard to both the controlled temperatures. This suggests that the vehicle is stable for compounding APIs from different pharmacological classes.

Reference material development for calibration and verification of image-based particle analyzers.

The need is well recognized for suitable reference populations for calibrating and verifying the size and concentration accuracy of particle analysis instruments for use in the measurement of suspended protein particles in biopharmaceuticals. Polystyrene bead standards are normally used as a reference material for calibrating and validating particle analyzers. However, these standards, unlike protein particles, are easily detected and do not challenge the sensitivity of optical instruments. Groups of instruments verified only with beads can still exhibit significant differences in measuring concentrations of more challenging protein particles. To minimize these and obtain consistent concentration measurements between instruments, reference populations must closely resemble protein aggregates in possessing high transparency and a refractive index close to typical protein matrix fluids. This paper describes work on evaluating a promising reference candidate and the use of this to harmonize the performance of Micro-Flow Imaging instruments. Results show that use of a suitable reference population can significantly increase measurement consistency when multiple instruments are used to characterize the same protein particle suspension.

Effect of grewia gum as a suspending agent on ibuprofen pediatric formulation.

The purpose of this work was to evaluate the potential of grewia gum (GG) as a suspending agent in pharmaceutical oral formulation using ibuprofen as model drug. Ibuprofen pediatric suspension (25 mg/5 mL) was formulated with grewia gum (0.5% w/v) as the suspending agent. Similar suspensions of Ibuprofen containing either sodium carboxymethylcellulose (Na-CMC) or hydroxymethylpropylcellulose (HPMC) were also produced. The suspensions were evaluated for ease of redispersion, sedimentation, rheological properties, and the effect of aging on the rheological properties at 25°C. The particle size and particle size distributions of the dispersed solute were determined. The redispersion time was 19, 11, and 0.5 min, respectively, for formulation containing Na-CMC, HPMC, and GG .The sedimentation volumes were 0.05, 0.05, and 0.125 mL, respectively, for Na-CMC, HPMC, and GG . Viscosities of suspensions at spindle speed of 25 rpm were of the order: GG > HPMC > Na-CMC when freshly prepared and of the order: HPMC > GG > Na-CMC within 6 months of storage. The particles size was 72.72, 73.82, 81.93, and 83.41 µm, respectively, for suspensions containing Na-CMC, ibuprofen alone, HPMC, and GG. Greatest hysteresis was observed in formulation containing HPMC. All the formulations were stable. It was our conclusion that the difference in the physicochemical properties of ibuprofen pediatric formulations was influenced more by the suspending agent used in the formulations than the drug. GG combined better redispersion with minimal changes in viscosity on storage compared to Na-CMC and HPMC as suspending agent. Thus GG may serve as a good suspending agent requiring no further aid in suspension redispersibility.

Evaluation of supercritical fluid engineered budesonide powder for respiratory delivery using nebulisers.

OBJECTIVES: Currently, suspensions prepared from micronised drug substances are the only delivery system marketed for nebulisation of steroids, and reported inconsistent or low bioavailability arising from their use provides a rationale for researching alternative formulations. Supercritical fluid processing of drug substances to obtain respirable-sized particles has been used over the last decade to formulate dry powder inhalers. We aimed thus to process budesonide powder to improve its deposition characteristics. METHODS: In an attempt to overcome the limitations of nebuliser suspensions when prepared from micronised drug particles, budesonide powder was processed using a supercritical fluid based process and suspended using Tween 80 as a surfactant to provide an aqueous nebuliser formulation. The in-vitro characteristics of the emitted dose on nebulisation for the prepared suspension were then compared to a commercially available suspension formulation of budesonide using a jet and a vibrating mesh nebuliser. KEY FINDINGS: The results showed a significant improvement of the in-vitro deposition properties of the suspension containing supercritical fluid engineered budesonide particles. CONCLUSIONS: The results indicated the benefit of such materials compared with traditionally micronised drug powders.

[Standard prescriptions for the formulation of medicinal preparations in pharmacies. I. Suspensions for dermal administration]. / Standardní receptura pro prípravu lécivých prípravku v lékárnách. I. Suspenze k aplikaci na kuzi.

The paper summarizes the present state of standard prescriptions for the formulation of suspensions for dermal administration in the Czech Republic and compares it with the NRF (Neues Rezeptur-Formularium in Deuscher Arzneimittel-Codex) standard prescriptions. The analysis of medical prescriptions for suspensions for dermal administration dispensed in the pharmacies of the Czech Republic has revealed that 18.8 % of the prescriptions were for 50% suspension of zinc(II) oxide in sunflower oil. This preparation should therefore become a candidate for standardization as a monograph in the national part of the Czech Pharmacopoeia.

Evaluation of nebulised hay dust suspensions (HDS) for the diagnosis and investigation of heaves. 1: Preparation and composition of HDS.

Currently, heaves is investigated by exposing susceptible horses to dusty hay. Consequently, the response will be dependent on the organic dust content and composition of the hay. It was hypothesised that the use of a hay dust suspension (HDS) would reduce the variability of the challenge and therefore standardise experimental protocols. Furthermore, analysis of HDS would also permit further investigation of the organic dust components responsible for the response. Three hay dust suspensions (HDS-1, 2 and 3) were prepared for use in the diagnosis and investigation of heaves. HDS were produced from fine dust particles, comprising mostly fungal spores, collected from 3 batches of dusty hay. HDS-1 and 3 were analysed for endotoxin, beta-D-glucan and protein concentrations, general protease activity and enumeration and size distribution of particulates. Protease activity was mainly attributable to a 28 kDa serine protease and to 85 kDa and 160 kDa metalloproteases. The particulate and soluble components of HDS could be aerosolised by jet nebulisation. We therefore conclude that detailed analysis of HDS is possible, that such a challenge system provides a method of standardising experimental protocols and that all components of HDS (both soluble and particulate) can be delivered to the lung using standard nebulisation techniques. For the above reasons, nebulised HDS offers considerable advantages over conventional hay/straw challenge for the diagnosis and investigation of heaves.

Heavy metal contamination of nanosuspensions produced by high-pressure homogenisation.

High pressure homogenisation is a method for the production of nanosuspensions. In this process crystalline drug particles are pressed with high pressure through a narrow homogenisation gap. Due to the conditions in the gap it seems possible that metal erosion can occur. In this study the heavy metal (Fe) contamination of nanosuspensions produced by high pressure homogenisation was determined. Therefore nanosuspensions were analysed by atom absorption spectroscopy concerning their load of iron which is chosen as reference metal. The results show that the erosion of metal is below 1 ppm and will not cause any toxicological problems.

Particulate matter determination in LVPs produced in Dutch hospital pharmacies, Part 1: Particle-counting accuracy.

Reproducible particle counting using the light-obscuration technique is often troublesome because no absolute standard is available. Therefore, at the Laboratory of Dutch Pharmacists the "calibration-in-time" method was developed. This method enables checking of the amount of particles counted from a diluted latex suspension as a function of time. A particularity of the method is the one-step dilution procedure. The calibration-in-time method is compared with the particle-counting accuracy test according to the USP < 788 >. Advantages and disadvantages of both methods are discussed.

Factors in the preparation of biological indicators that affect the decimal reduction time.

The ISO 11138 series on biological indicators (BIs) lacks concrete specifications of the suspension, carrier material, and culture medium optimal for the preparation of the microorganisms. The suspension and culture medium used are thought to influence the accuracy of decimal reduction time (D) values. Their combined effects have not been elucidated, but some individual effects of particular suspensions, carrier materials, and culture media have been reported. Contrary to these reports, however, the author did not find such individual effects in a study of D values obtained using distilled water or saline as the suspension solution, paper or cotton yarn as the carrier material, and soybean casein digest (SCD) broth or agar as the culture medium. The study demonstrated that the combined effect of salt in the suspension during drying and the entrapment of microorganisms in salt crystal by pores in the cotton yarn carrier material increased microorganism resistance. D values also differed depending on the culture medium. Further investigation is needed to establish the optimal culture medium for BI microorganisms.

Minimal water requirements for suspending powdered antidotal charcoals.

The minimal amounts of water needed to assure complete suspension of 50 g of 4 different antidotal charcoals were determined. The water volumes ranged from 170-192 ml. The total suspension volumes (water + charcoal) ranged from 201-221 ml. Since manufacturers package 50 g charcoal formulations with a total volume of 8 fluid ounces (237 ml) there is only 16-36 ml of water beyond the minimal amounts needed for suspension. It is recommended that water in an amount of 10% or more of the total volume (ie 24 ml or more) be added by manufacturers to help prevent compaction during storage, or be added by users to aid in resuspension and to increase the suspension flow rate during delivery through tubes.

Container residue after the administration of aqueous activated charcoal products.

Commercial aqueous activated charcoal (AC) products may sit in emergency departments, pharmacies, and homes for prolonged periods resulting in the inability to resuspend the AC for patient administration. The potential risk to the patient from not receiving an adequate amount of AC, especially when AC may be the sole means of gastric decontamination, is obvious. To simulate this potential problem, samples of five different aqueous AC products (ActaChar, Actidose, InstaChar, LiquiChar, and SuperChar) were placed into storage for periods of 3 and 12 months. At the end of each study period, samples were agitated and the effluent and container residue were collected, oven-dried, and weighed. With the exception of Actidose, all products retained substantial amounts of AC in the container at both time intervals. These data stress the negative impact of dormant storage on the resuspendability of aqueous activated charcoal products. Furthermore, they suggest the importance of thorough container agitation and rinsing to insure that the patient receives sufficient AC. This is especially important when AC is the sole means of decontamination.

Bioluminescence for USP sterility testing of pharmaceutical suspension products.

Bioluminescence measurement significantly improved the accuracy, sensitivity, precision, and reliability of the current visual endpoint determination for the USP sterility test and eliminated the day 7 transfer/dilution step required for testing suspension products. Thirteen strains of bacteria and fungi (representing potential contaminants in sterile products), three pharmaceutical suspension products, and four media were used in the experiment. No interference from suspension products was encountered in the detection of microbial growth by the bioluminescence measurement. The poor fungal growth encountered was attributed to insufficient diffusion of oxygen into the medium and was circumvented by use of a large tube size (38 by 200 mm) or by vortexing the medium once during the 2-week incubation period. Bioluminescence measurement would facilitate automated handling of the sterility test endpoint readout operation. The optimum parameters of bioluminescence measurement for application in sterility testing were determined.