Extemporaneous Furosemide Suspensions for Pediatrics Use Prepared from Commercially Available Tablets

Objective: Three furosemide aqueous suspensions for paediatric oral usage (2 mg/ml) were investigated to determinate its physicochemical stability under different storage conditions. Method: Formulations using sugar syrup and sugar-free vehicles were stored at 4 and 25 o C and the furosemide content was determined by spectrophotometer. Each sample was analyzed in triplicate at different time points (0, 7, 14, 28, 56, 72 and 90 days). Results: Liquid suspensions were successfully formulated from commercially available tablets. In both cases, samples showed suitable physical stability. Furosemide was chemically stable in aqueous suspension during the 90 days of the study at the two storage temperatures. Conclusions: All the tried oral liquid formulations can be conserved at 4 and 25 o C at least 56, 72 and 90 day period. HeyamAli 1 , Rasha Saad , Ahmed Ahmed 3 , and Babiker El-Haj 4 1 Department of Pharmaceutics and Pharmacy Practice, Dubai Pharmacy College Dubai, United Arab Emirates 2 Department of Pharmaceutical Chemistry, School of Pharmacy, Management & Science University, Malaysia 3General surgery-Colorectal department, Nottingham Hospital, United Kingdom, 4Ajman University of Science and Technology, Shāriqah, United Arab Emirates. Submission: 4 January 2016 Accepted: 10 January 2016 Published: 25 January 2016 www.ijppr.humanjournals.com Citation: Rasha Saad et al. Ijppr.Human, 2016; Vol. 5 (2): 116-138. 117 1:0 INTRODUCTION The lack of commercially available oral liquid dosage forms is an ongoing problem in many practice settings. A pharmacist is often challenged to provide an extemporaneous oral liquid for Pediatric patients; Patients who are unable to swallow solid dosage forms such as tablets or capsules; Patients who must receive medications via nasogastric or gastrostomy tubes; Patients who require non-standard doses that are more easily and accurately measured by using a liquid formulation 1 . For oral administration, furosemide is available in UAE as tablets 40mg. The oral liquid dosage form is not available, although it is manufactured in other countries. Pediatric demands for this product in clinical settings necessitate pharmacist involvement in retaining compounding skills to extemporaneously prepare such products in stable oral liquid forms 2 . The lack of paediatric liquid dosage forms represents a challenge for hospital and community pharmacists. Usually, children require smaller doses than adults which are adjusted by body weight. Thereby solid dosage forms must be fractionated in order to fit paediatric dosages. This practice represents a concern issue because correct dosing must be ensured 13 . Preparing extemporaneous liquid formulations using tablets is one of the most common practices employed to adjust doses for paediatric patients. Moreover, children under 7 years old are unable to swallow capsules or tablets. Liquid formulations which are flavored aqueous solutions, syrups, or suspensions, are administered directly into the child's mouth by drop, spoon, or oral dispenser or incorporated into the child's food14. General dose volumes are < 5 ml for children under 5 years and < 10 ml for those of 5 years and over15. Among paediatric pharmacy practice, traditional compounding techniques have become a useful tool in order to develop not commercially available liquid dosage forms 17 . In this context, liquid formulations facilitate oral administration and enhance children treatment adherence. An appropriate design of a liquid dosage form requires not only a comprehensive analysis of chemical and physical considerations of drugs and pharmaceutical excipients but also evaluation of drug stability in the mid-long term as well as drug effectiveness, tolerance and formulation safety 17 . www.ijppr.humanjournals.com Citation: Rasha Saad et al. Ijppr.Human, 2016; Vol. 5 (2): 116-138. 118 Studies (2, 7, 9, 11-14) have identified that the preparation of liquid formulations for paediatric patients is both a daily experience and challenge for the pharmacist and paediatric health care provider. Appropriate formulations for administration to children exist for only a minority of commercially available drugs and the need for extemporaneously compounded formulations is escalating due to the release of many new drugs formulated for adults but with expected use in children (7, 9, 11) . Children require titratable individualised doses in milligrams per kilogram of body weight and most children under six years of age cannot swallow tablets (15, 16) . A survey (14) into the informational needs of hospital compounding pharmacists providing pharmaceutical care to paediatric patients at 57 sites in the USA and Canada listed 76 extemporaneously prepared drug formulations as having adequate stability data, 109 formulations for which improved stability data were requested, and an additional 103 drug formulations prescribed by paediatricians that had no compounding or stability information available. There are many reasons for the lack of commercially available paediatric formulations. The overall size of the paediatric market is much smaller than for adults, especially for common diseases such as hypertension. The industry is thus reluctant to commit resources to seek labelling for infants and children (unless a disease occurs exclusively or frequently in the paediatric population) since the formulation has to have been adequately studied in paediatric patients. Therefore, additional costs, limited financial returns, delay in marketing for adults, and perceived greater legal liability and regulatory requirements are impediments to developing and marketing a paediatric drug formulation (7, 17) . Tablets are often cut into smaller segments (halves or quarters) in the pharmacy or on the ward to obtain appropriately sized dosage units for children, however, a major concern is that segments from tablets cannot be cut with great accuracy of dose (12, 19-21) . McDevitt et al (20) conducted an extensive analysis on the ability to split a 25-mg hydrochlorothiazide tablet accurately by 94 volunteers. Of 1752 manually split tablet portions, 41.3% deviated from ideal weight by more than 10% and 12.4% deviated by more than 20%. gender, age, education, and tablet-splitting experience were consistently found not to be predictive of accuracy. Most subjects (96.8%) stated a preference for commercially produced, lower-dose tablets, and 77.2% were willing to pay more for them. The issue of cost containment in the treatment of hypertension has seen many physicians prescribing larger dosages of drugs and then instructing patients to split the tablets to receive the correct dose, and some health www.ijppr.humanjournals.com Citation: Rasha Saad et al. Ijppr.Human, 2016; Vol. 5 (2): 116-138. 119 maintenance organisations are providing tablet splitters to patients while dispensing larger than prescribed doses (20) . Another practice seen in paediatric care is to use injectable solutions for oral administration (13, 26) . When a drug is formulated for paediatric use, several factors unique to paediatrics must be considered such as the immaturity of the intestinal tract and the subsequent influence on gastrointestinal absorption, seriously ill neonates are often fluid restricted, limiting the volume of medications that can be received. Additives, including preservatives and sugar must be chosen carefully. Patients who are fructose intolerant have had significant adverse effects from sorbitol and there is a link between chronic uses of sugar-sweetened medication and dental caries (11) . Formulations may also contain preservatives; an excipients considered to be largely inert in adults, however, may lead to life-threatening toxicity in paediatrics when multiple doses of medications with the same preservative are employed. This is particularly the case with benzyl alcohol and benzoic acid (11) . The physical, chemical, microbial and therapeutic stability of the above paediatric extemporaneous preparations may not have been undertaken at all. This coupled with the increased potential for calculation or dispensing errors may prove the practice of modifying commercially available products to be extremely unsafe. Although information (29-31) is available detailing extemporaneous formulations for parenteral and oral use, however, only some of the formulations have documented stability data.