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 Table of Contents  
Year : 2020  |  Volume : 5  |  Issue : 4  |  Page : 194-200

Availability of oral liquid formulations: Dilemmas in managing children with nephrotic syndrome

1 Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Paediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission11-Apr-2020
Date of Decision13-Apr-2020
Date of Acceptance20-Jul-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Prof. Nusrat Shafiq
Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Research Block B, Chandigarh - 160 012
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jncd.jncd_7_20

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Conditions such as nephrotic syndrome (NS), which require administration of drugs for a protracted period, present a difficult situation for pediatricians to treat due to lack of appropriate formulations. In the present study, we explored the issue of availability of pediatric oral formulations and suggested solutions with NS as an example. We searched PubMed, Embase and Ovid, Google, Google Scholar, Current Index of Medical Specialties-Monthly Index of Medical Specialties, and standard textbooks for data acquisition. We found that many drugs used in NS are either not available in suitable pediatric formulation or are not specifically approved for use in pediatric population. Most of these drugs have high pharmacokinetic variability, which further necessitates the availability of proper formulation. Standardized compounding vehicles are also not available in our country. Manipulation of existing adult dosage forms for administering to pediatric patients is often arbitrary and may be associated with either underdosing or overdosing. There is an urgent need for development and standardization of compounding vehicles so that required dose delivery can be ensured in children with NS.

Keywords: Extemporaneous preparations, nephrotic syndrome, oral liquid formulations, pediatric

How to cite this article:
Mothsara C, Tiewsoh K, Pandey AK, Malhotra S, Shafiq N. Availability of oral liquid formulations: Dilemmas in managing children with nephrotic syndrome. Int J Non-Commun Dis 2020;5:194-200

How to cite this URL:
Mothsara C, Tiewsoh K, Pandey AK, Malhotra S, Shafiq N. Availability of oral liquid formulations: Dilemmas in managing children with nephrotic syndrome. Int J Non-Commun Dis [serial online] 2020 [cited 2023 Feb 4];5:194-200. Available from: https://www.ijncd.org/text.asp?2020/5/4/194/306001

  Introduction Top

Nephrotic syndrome (NS) is a common glomerular disease in children with an estimated annual incidence of two to seven in 100,000 in children <18 years of age.[1] The management of NS is largely conservative and requires the administration of different types of drugs, which require precise dosing that may be affected by lack of appropriate pediatric formulations. About 80% of children are steroid sensitive and show remission with prednisolone or prednisone. Among the 20% of patients who do not respond to corticosteroids, alternatives are levamisole, cyclophosphamide, calcineurin inhibitors (cyclosporine and tacrolimus), and mycophenolate mofetil.[2] These drugs are also needed when adverse drug reactions of corticosteroids appear.[2] In addition to immunomodulators, the other drugs that are commonly used in these patients are diuretics, antihypertensives, and antimicrobials.[2]

Doses of these drugs need to be adjusted according to body weight or body surface area. Dose adjustment for children is difficult using tablet and capsule dosage forms. The oral route is the most favorable and convenient for all age groups. However, oral solid dosage forms are available in fixed doses, which is a challenge for pediatric population.[3] Unfortunately, most of the drugs used in pediatric population are not available in suitable dosage form.[3] Health-care professionals manipulate available adult oral dosage forms to dispense an adequate quantity of drugs by either splitting or crushing the tablet or by taking out the contents of the capsule. This leads to high variability and may cause overdosing or underdosing, which, in turn, leads to toxicity or subtherapeutic levels, respectively.[4] Many drugs exhibit high intersubject and intrasubject variabilities that can further be exaggerated in glomerular diseases such as NS, and this may require dose modifications.[5] This would be of greater concern with drugs having narrow therapeutic index.[4]

In the present study, the literature is explored for availability of pediatric formulations, understanding the need, existing practice gaps, and the ways these can be overcome by making appropriate pediatric formulations of drugs for NS.

  Methods Top

Search strategy

We searched PubMed, Embase, and Ovid using search terms “nephrotic syndrome,” “pediatric glomerular disease,” “idiopathic nephrotic syndrome,” “extemporaneous preparation,” “oral liquid preparations,” “oral liquid formulations,” “pediatric suitable preparations,” “tacrolimus,” “cyclophosphamide,” “levamisole,” “cloxacillin,” “clindamycin,” “spironolactone,” “hydrochlorothiazide,” “metolazone,” “enalapril,” “amlodipine,” “labetalol,” “prazosin,” “minoxidil,” “clonidine,” “nephrotic syndrome OR pediatric glomerular disease OR idiopathic nephrotic syndrome,” “tacrolimus OR cyclophosphamide OR levamisole OR cloxacillin OR clindamycin OR spironolactone OR hydrochlorothiazide OR metolazone OR enalapril OR amlodipine OR labetalol OR prazosin OR minoxidil OR clonidine,” AND “[nephrotic syndrome OR pediatric glomerular disease OR idiopathic nephrotic syndrome]” AND “[tacrolimus OR cyclophosphamide OR levamisole OR cloxacillin OR clindamycin OR spironolactone OR hydrochlorothiazide OR metolazone OR enalapril OR amlodipine OR labetalol OR prazosin OR minoxidil OR clonidine]” AND “[extemporaneous preparation].”

We also searched Google, Google Scholar, CIMS-MIMS India (Current Index of Medical Specialties and Monthly Index of Medical Specialties), and standard textbooks.[6],[7]

The drugs taken into consideration in the study are given in [Table 1].
Table 1: Drugs taken into consideration in the study

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For each of the drugs, we attempted to extract status of USFDA/Drug Controller General of India approval for pediatric use and/or evidence for use as mentioned in standard treatment guidelines, formulations available in the market with specific search for oral liquid formulations, and description of methods for preparation of liquid formulation by compounding on official websites of health care and research institutes.[8],[9],[10] We also searched for pharmacokinetic studies done to address interindividual variability, consistency of levels to justify the need for formulation, and pharmacokinetic studies in children with the developed formulation, if any.

  Results Top

Immunosuppressants used in nephrotic syndrome


Cyclophosphamide is an alkylating immunosuppressant agent, approved by the USFDA for childhood NS.[7],[11] It is indicated to maintain remission when prednisolone threshold becomes higher or steroid toxicity appears or in case of severe relapses with episodes of hypovolemia, thrombosis, or poor compliance.[2]

A significant variability has been seen with half-life, clearance, volume of distribution, and area under the curve of cyclophosphamide and its metabolites.[12],[13] It is available as either tablet or powder for injection. No oral liquid formulation is available in our country.[14] Extemporaneous preparation of oral liquid dose suspension of cyclophosphamide has been done in simple syrup and Ora-Plus from intravenous formulation, which was stable for 56 days at 4°C.[15] Ora-Plus is an oral suspending vehicle from Perrigo (Australia), which contains carboxymethylcellulose sodium, carrageenan, microcrystalline cellulose, xanthan gum, calcium sulfate, citric acid, sodium phosphate, dimethicone, potassium sorbate, trisodium phosphate, and methylparaben.[16]

Nationwide Children's Hospital, Columbus, USA, and College of Pharmacy, University of Michigan, and Gateway Pediatric Pharmacy Group (GPPG) have given formulae for reconstitutions of cyclophosphamide powder for injection into the oral suspension by Ora-Plus or simple syrup.[8],[9],[10]

There is a need for standardizing methodology for compounding and dispensing a pediatric formulation for cyclophosphamide to ensure correct dose administration.


Calcineurin inhibitors are recommended when patients show steroid resistance or when they continue to show steroid dependence or frequent relapses while on other steroid-sparing drugs.[2]

Many studies have shown wide interindividual variability in pharmacokinetics of tacrolimus.[17],[18] Because of intersubject variability in pharmacokinetics, individualized dosing is required for optimal therapy.[7]

Tacrolimus is available as an ointment, capsule, tablet, and cream in our country.[14] Oral suspension of tacrolimus 0.5 mg/ml and 1 mg/ml for use in pediatric patients has been prepared using both Ora-Plus and Ora-Sweet and shown stability of 56 days and 4 months, respectively, at room temperature.[19],[20] Tacrolimus capsule efficacy and pharmacokinetics were compared with tacrolimus oral suspension (prepared by the method previously described)[19] in pediatric liver transplant recipients.[21] Although extemporaneous formulation was not found bioequivalent, it was concluded that it could be an alternate for tacrolimus administration in small pediatric liver transplant recipients. It was found in a comparison that formulation prepared using the simple syrup and sterile water (1:1) can be a viable alternative to Ora-Plus when stored under refrigeration.[22]

Nationwide Children's Hospital (Columbus), College of Pharmacy, University of Michigan, and GPPG have also given the formula for the compounding of tacrolimus as oral suspension based on earlier reports.[8],[9],[10],[19]

The need for tacrolimus pediatric formulation is strong, and such compounding systems as mentioned above must also be established in most health-care setups dealing with these patients.


Levamisole is an immunomodulator and is used as an alternative to calcineurin inhibitors.[2],[7] Moderate interindividual variability with apparent clearance rate and distribution volume has been reported.[23]

Levamisole is available as an oral suspension in combination with albendazole or mebendazole but not as a single agent.[14] Oral liquid solution of levamisole strength 25 mg/mL prepared from tablets or pure powder in sterile water showed chemical stability for 90 days under refrigeration.[24] Not only is there a need to establish a method for compounding a pediatric formulation for levamisole, but also it should be available as single-drug preparation as well.

Drugs for infections in nephrotic syndrome

Infections are the most common cause of morbidity and mortality in children with NS.[25] Their susceptibility to infections is multifactorial. The commonly seen infections are peritonitis, respiratory tract infections, urinary tract infections, cellulitis, and meningitis.[25],[26] Infections are managed with antibiotics including parenteral cefotaxime, ceftriaxone, ampicillin, aminoglycosides and oral amoxicillin, amoxicillin-clavulanic acid, erythromycin, and cloxacillin. Whenever necessary, antifungals such as fluconazole and amphotericin B are also used. Viral infections such as varicella require acyclovir.[2] Most of the antibiotics and antivirals used in NS are available in the desired dosage form. Amoxicillin is available as oral suspension in combination with clavulanic acid. Many of these antibiotics are available as dry syrup or powder for suspension. However, cloxacillin and clindamycin are not available as oral liquid formulation in our country.[14]


Cloxacillin is a penicillinase and acid-resistant penicillin.[2],[7] It is used empirically for cellulitis when distinction between staphylococcal and streptococcal infections is not clear, and deeper tissue involvement is not ruled out. Significant interindividual variability in plasma concentrations of cloxacillin has been seen when high doses are used in critically ill patients, especially with renal failure,[27] patients on dialysis as well as healthy volunteers.[28]

It is available as dry syrup along with ampicillin, amoxicillin, ampicillin and Lactobacillus (60 million cells) or amoxicillin, Lactobacillus (60 million cells), and serratiopeptidase but not as a single agent.[14] Cloxacillin oral solution or suspension is not available in our country. Any study or pharmacy exercise for extemporaneous preparation of oral liquid of cloxacillin from other available forms could not be found. It is, therefore, of utmost importance that a method to compound cloxacillin formulation is developed and standardized.


Clindamycin is a protein synthesis inhibitor, indicated in NS for skin and soft-tissue infections, especially if the patient is allergic to penicillin.[7] Interindividual variability has been reported in the pharmacokinetic of clindamycin,[29] and it is closely associated with body weight. For varying weight groups in pediatric population as well as in patients with NS, a liquid oral formulation is needed.

Clindamycin is available as vaginal suppositories, topical gel, cream, ointment, injection, capsules, and tablets but not as any liquid formulation in our country.[14] We did not found any study or pharmacy exercise for extemporaneous preparation of clindamycin.

Drugs for edema in nephrotic syndrome

One of the major complications of NS is edema. The severity may vary from mild periorbital puffiness to anasarca. The management of edema in NS depends on the severity. For mild edema with steroid-sensitive NS, diuretics are not used because corticosteroids lead to diuresis within 5–20 days.[2] Diuretics that are used in severe edema or in patients with steroid-resistant NS include furosemide, spironolactone, hydrochlorothiazide (HCTZ), and metolazone.[2] Only furosemide is available as an oral solution. Spironolactone, metolazone, and HCTZ are not available as a liquid formulation in our country.[14]


Spironolactone is available as tablets alone or in combination with other drugs.[14] Spironolactone showed stability for 164 days at 24°C when prepared in simple syrup containing alcohol 10% and preservatives and for 28 days at 5°C and 30°C when compounded in cherry syrup with preservatives.[30],[31] Stability of spironolactone suspension prepared using spironolactone tablet, simple syrup, carboxymethylcellulose, and purified water was reported for 3 months when stored at 22°C and 4°C.[32] Pramar et al. developed a more stable oral liquid dosage form of spironolactone and showed stability for 93 days at 40°C.[33] However, this has not been translated into practical use although it has potential. Nationwide Children's Hospital (Columbus), College of Pharmacy, University of Michigan, and GPPG have also given the formulae for the compounding of spironolactone/HCTZ as an oral suspension using either Ora-Blend or cherry syrup.[8],[9],[10],[34]


HCTZ is available as tablets and capsules in combination with other drugs.[14] Formulation prepared using 20% glycerol and methylcellulose was found stable for 3 weeks when kept at 5°C and light protected.[35] Spironolactone (5 mg/ml)-plus-HCTZ (5 mg/ml) combination has been prepared in Ora-Sweet/Ora-Plus and cherry syrup-sweetened vehicles which were found stable for up to 60 days when stored light protected at 5°C and 25°C.[36] Nationwide Children's Hospital (Columbus) (5 mg/ml), College of Pharmacy, University of Michigan (10 mg/ml), and GPPG (5 mg/ml) have given the compounding formulae using Ora-Blend or Ora-Plus/Ora-Sweet.[8],[9],[10]


Metolazone is commercially available as a tablet dosage form only.[14] Metolazone retained >90% of initial concentration after 60 days at 5 and 25°C when stored without light.[37] It was suspended in Ora-Blend and cherry syrup as different formulations. Metolazone is also listed in the compounding list of Nationwide Children's Hospital (Columbus), College of Pharmacy, University of Michigan, and GPPG.[8],[9],[10]

Drugs used for hypertension in nephrotic syndrome

Hypertension may be detected at the onset of NS or later due to steroid toxicity. For managing hypertension in NS, ACE inhibitors, calcium channel blockers, or beta-adrenergic blockers are used.[2] Commonly used drugs are enalapril, amlodipine, and labetalol, whereas prazosin, minoxidil, and clonidine are less commonly used options. These are not available in pediatric suitable liquid forms.[14]


It is available as a tablet, capsule, and injection.[14] Three extemporaneous oral liquid preparations using deionized water, citrate buffer solution, and Ora-Plus and Ora-Sweet from enalapril maleate tablets were prepared. Deionized water preparation was stable for 56 days at 25°C, and the other two were stable for 91 days at 4°C and 25°C.[38] Enalapril suspension preparation using Ora-Blend SF is mentioned by GPPG.[10] Enalapril maleate suspension prepared using Oral Mix (MEDISCA Pharmaceuticals) from bulk powder or tablet was found stable for 90 days when stored in glass bottles or syringes at 5°C or 25°C.[39] In another study, two enalapril maleate suspensions were prepared using hydroxyethylcellulose 0.5% solution and 1:10 mixture of raspberry syrup and hydroxyethylcellulose 0.5% solution. Both formulations were found stable for 30 days at 4°C and 25°C.[40] The available methods or any new method has not been explored in health-care systems in our country.


Amlodipine is currently available as tablets only.[14] In a study, two amlodipine besylate suspensions were prepared using amlodipine tablets in Ora-Plus/Ora-Sweet (1:1) and another in 1% methylcellulose and syrup (1:1).[41] It was stored in plastic bottles and found stable for 91 and 56 days at 4°C and 25°C, respectively. In another study, suspensions prepared from tablets using the commercially available suspending vehicle Oral Mix were found stable for 90 days at 5°C, but at 25°C these showed stability for 60 and 40 days in bottles and syringes, respectively.[42]

Amlodipine is also listed by Nationwide Children's Hospital (Columbus), College of Pharmacy, University of Michigan, and GPPG for compounding as an oral suspension using commercially available Ora-Blend.[8],[9],[10]


It is available as a tablet and injection form.[14] High interindividual and intraindividual variability has been observed in pharmacokinetics of labetalol.[43]

Labetalol hydrochloride solution was found stable for 4 weeks under refrigeration and room temperature when prepared in simple syrup, distilled water, and fruit juices.[44] In another study, labetalol hydrochloride 40 mg/mL was found to be stable in three extemporaneous suspensions for up to 60 days when stored light protected at 5°C and 25°C which were prepared using Ora-Sweet/Ora-Plus (1:1) and Ora-Sweet SF/Ora-Plus and cherry syrup (1:1).[36] Nationwide Children's Hospital (Columbus), College of Pharmacy, University of Michigan, and GPPG have provided the formula and procedure for compounding as an oral suspension using Ora-Blend, simple syrup, and Ora-Plus/Ora-Sweet, respectively.[8],[9],[10]


Prazosin is available as a tablet only.[14] Wide interindividual variability in pharmacokinetics of prazosin has been observed.[45] No study or published literature could be found describing preparation, use, or stability of oral liquid formulation.


Minoxidil/diaminopyridine oxide combination is available as a topical solution. It is also available as a lotion, topical oil, topical spray, and tablet.[14] Extemporaneous oral suspension of minoxidil prepared using Ora-Plus/Ora-Sweet was reported to be stable for 3 weeks and 24 weeks when stored at room temperature and refrigerator, respectively.[46]


Clonidine is available in tablet and injection form.[14] Clonidine was found stable for 28 days as an oral liquid in simple syrup,[47] while another study described 35-day stability of 20 μg/mL clonidine oral solution when prepared in simple syrup.[48] Nationwide Children's Hospital (Columbus) and GPPG have provided the formula and procedure for compounding of clonidine as oral suspension.[8],[10]

  Discussion Top

Pediatric population is not the same as adult population. Pediatric patients handle drugs differently because of varying pharmacokinetics, the routes of drug administration, therapeutic dose, excipients in formulations, and taste acceptability.[3] The drugs described in this study have a significant intersubject or intrasubject pharmacokinetic variability and are not available in suitable dosage form for pediatric age group. Manipulations in available dosage forms do not guarantee required dose delivery.[4] For the pediatric population, oral route and liquid formulations are most convenient.[3] Most of the drugs are not available in oral liquid form, and many of those, which are available in oral liquid form, are not specifically labeled for pediatric use. Pharmaceutical companies do not find investing in pediatric formulation commercially profitable.[49],[50]

Compounding of suitable formulations is a common practice in developed countries. It is a fact that commercial agents such as Ora-Plus and Ora-Sweet are readily available for compounding in many countries, albeit not in our country. A few readily available suspending agents may be developed, taking into consideration permissible agents with their defined concentrations, and these may be used for compounding various drugs after the process is standardized by the pharmacists. However, extemporaneous preparation also can have issues such as stability under long-term storage and temperature conditions. Nonetheless, these are better options when no suitable marketed formulation is available or the alternative is manipulations by crushing or splitting tablets or capsules.

Although we have highlighted the problem of NS, the issue has much wider implications. If the pharmaceutical companies are not willing to provide such preparations, it is left to the health-care facilities to do it. In order to provide this service, facilities must strengthen their pharmaceutical departments to cater to the needs of the pediatric population that requires liquid oral formulations. The American Society of Health-System Pharmacists (ASHP) has taken an initiative called “Standardize 4 Safety Initiative” which plans to develop the standards for compounded oral liquid medication concentrations and doses.[51] ASHP and the Pediatric Pharmacy Advocacy Group (PPAG) has also published guidelines to provide pediatric pharmacy service in health-care systems. Both of the aforementioned documents will be useful in providing a pathway for strengthening the local initiatives for development of pediatric formulations.[52]

  Conclusion Top

Most drugs that are used in NS are not available in a suitable dosage form for pediatric population. There is an urgent need for development and standardization of easily accessible compounding vehicles so that required dose delivery can be ensured in children.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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