Formulation of a 3-months Stability Oral Viscous Budesonide Gel and Development of an Indicating Stability HPLC Method
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Mathilde Bonnet
Mathilde Bonnet is a French PharmD candidate. She started studying pharmacy at the University of Lyon and is currently a resident in Paris. She worked in the sector of manufacturing and control at Robert Debré pediatric hospital in Paris, and is especially interested in drug formulation and correct drug usage.
,
Marine Dermu
Marine Dermu is a French Hospital Pharmacist, trained at Lille University and successively in Poitiers, La Rochelle and Rennes in France for her internship. After completion of her PharmD in November 2014, she specialized in pharmaceutical compounding working at Robert Debré pediatric hospital in Paris. There she supervised aseptic manufacturing of injectable drugs (parenteral nutrition and production for clinical trials unit) and non sterile products. Her involvement in the quality control lab enabled her to develop new analytical methods and stability studies. She also took part in the in situ production design of experimental products.
Clara Roessle is a French Hospital Pharmacist. She received her PharmD in November 2017. She trained at Montpellier University and completed her internship in Paris. She is currently working at Robert Debré pediatric hospital. There she is supervising aseptic manufacturing of injectable drugs (parenteral nutrition and production for clinical trials unit) and non sterile products.
Marc Bellaiche, MD, is a French Hospital paediatrician since 1991, and is responsible of the endoscopy unit at Robert Debre Hospital (Largest French paediatric hospital, in Paris Area). 1200 endoscopy procedures were done last year. He is the president of the French Society of paediatric GI and nutrition. He is focus in the area of dymotility and functional GI disorders.
Tarik Abarou is a laboratory technician in the pharmacy of Robert Debré Hospital.
Véronique vasseur is a laboratory technician in the pharmacy of Robert Debré Hospital.
Samira Benakouche is a laboratory technician in the pharmacy of Robert Debré Hospital.
Thomas Storme, PhD, is a French Hospital Pharmacist since 2007, and is responsible of the compounding facility at Robert Debré Hospital (Largest French paediatric hospital, in Paris Area). The Robert Debré compounding facility consists in 3 units:– a Quality Control Lab’– a non sterile compounding (capsules, oral liquids, suppositories, oral gel, cream … )– a Sterile compounding facility, divided into: chemotherapy + CIVAS and TPN compounding
He was resident in pharmacy at Paris area hospital, during his residency; he specialized in compounding, Quality control and oncology care. He studied pharmacy at Paris-Descartes University. In parallel with his residency, he completed in 2007 a PhD in Medicinal Chemistry and Experimental Pharmacology on the development and the Evaluation of Ifosamide analogs designed to lower side effects.
Abstract
Background
Eosinophilic Esophagitis is an increasing pathology which can cause stomach symptom like dysphagia, vomiting, food blockage. The treatment consists in dietary therapy and topical corticosteroid therapy to avoid the important number of side effects of the oral corticosteroids. There is presently no available topical form adapted for treating esophageal pathology.
Methods
The aim of this work was to develop an oral viscous budesonide gel (OVBG). A focus on palatability was made in order to use OVBG in children. A stability indicating HLPC method able to quantify budesonide contained in our OVBG has been developed.
Results
Previous work of Hefner and Al. showed that xanthan gum had a longer esophageal mucosal contact time than sucralose. This encouraged the development of a xanthan gum-based formulation. This OVBG has also the advantage to facilitate compliance thanks to its taste and pleasant texture. The stability length of the preparation can be extended over a 3-months period, stored in a refrigerator at 2–8 °C.
Conclusions
An adapted pediatric formulation with a 3-months stability was developed. Furthermore, the formulation can be easily reproduced in community pharmacy. Regarding the increasing number of patients concerned OVBG is a good answer to a real clinical need.
Introduction
Eosinophilic Esophagitis (EoE) is a recent and increasing pathology characterized by eosinophilic infiltration of the esophagus. EoE affects both children and adults, with a male predominance. Symptoms vary according to age but generally patient presents dysphagia, vomiting, abdominal pain, or even a food blockage [1, 2, 3]. Diagnosis must be confirmed by a esophagogastroduodenal endoscopy, and with esophageal biopsy showing at least 15 eosinophils per High-Power-Field (eos/hpf). Current treatment options are limited, mainly with dietary therapy and corticosteroids [4]. However, elimination diets are very binding and not always sufficient to improve symptoms. In addition, given the important number of side effects of the oral corticosteroid therapy, topical corticosteroid therapy is widely used. Unfortunately, there is presently no available topical form adapted for treating esophageal pathology. Several comparisons of different topical forms of steroids have been achieved and all of them showing the superiority of oral viscous versus nebulized and swallowed corticosteroid therapy for patients with EoE [5, 6]. This is the reason why it is a common practice to mix extemporaneously liquid budesonide intended for nebulized administration with sucralose (Splenda™)[7]. According to Hefner and Al. xanthan gum shows longer esophageal mucosal contact time compared to sucralose [8]. This led to develop an oral viscous budesonide gel (OVBG), based on xanthan gum and adapted for the pediatric population. In order to improve compliance, special attention is paid to palatability and ease of use, especially thanks to a suitable measuring spoon. Furthermore, the formulation can be easily reproduced in community pharmacy. As the method described in the European Pharmacopoeia 9th edition (Eur. Ph. 9) isn’t specifically adapted for viscous form, a stability indicating HLPC method able to quantify budesonide contained in the OVBG has been developed. Besides, considering the increasing number of patients concerned, it seemed important to extend the stability length of the preparation over a 3-months period, stored in a refrigerator at 2–8 °C.
Materials and Methods
OVBG formulation
Components
Budesonide suspension for nebulisation 1 mg/2ml=budesonide respules 1 mg/2ml (BUDARROW) was supplied by Arrow génériques™. Xanthan gum (ref: 161208A) and glycerol (CE N°200–289–5) were bought to Cooper™ (Melun, France). EDTA (ref: 63,819–25), sodium benzoate (ref: 53,232–1), sodium saccharin (ref: 82,385–100) and raspberry aroma (ref: 7046–25) were purchased from Inresa™ (Bartenheim, France). Sterile water was supplied by Fresenius™ (Sevres, France).
Preparation of oral viscous gel
Several formulations with different amounts of budesonide or xanthan gum were prepared. Appropriate amounts of glycerin were added to xanthan gum and then dispersed in water containing budesonide to ease the preparation. The formulations underwent macroscopic and microscopic studies, as well as pH determination.
pH determinations
The determination of the pH was performed on compounding day and each month (T0, T1, T2, T3) using a HI-1131 pH meter (Hanna instruments™, Tannerie, France). The measurement has been performed on the three batches (n=3). A variation of one unit in the pH value was considered significant enough to indicate a modification compared to the initial pH of prepared solution [9].
Visual examination
A visual examination was performed the day of the compounding and each month (T0, T1, T2, T3) on three separate batches. Each tube was opened, observed in front of white and black background by a single trained examiner in its entirety in order to detect a color change or a texture modification.
Evaluation of palatability and ease of use
The formulation was tested by 15 people who completed a satisfaction survey to assess the OVBG. The note breaks down as follows: 4 points on taste, 4 points on back-taste, 2 points for odour and 2 points for texture. Moreover, several measuring spoons have been tested in order to select a reproducible spoon compatible with pediatric dosage. An information and instruction manual has also been prepared for parents.
Stability indicating HPLC method and microbiology
Chemicals and reagents
Budesonide powder (BUDSIGMA) with a purity ≥ 99 % was purchased from Sigma-Aldrich™ (Saint-Quentin-Fallavier, France) (batch number: BCBQ8374V). All reagents and chemicals were analytical grade and included potassium dihydrogen phosphate (VWR™, Leuven, Belgium), acetonitrile for HPLC (Sigma-Aldrich™, Saint-Louis, USA), hydrochloric acid (HCl) solution 1 M and sodium hydroxide (NaOH) (VWR™, Leuven, Belgium), absolute ethanol (VWR™, Fontenay-sous-bois, France).
Development
HPLC apparatus
The HPLC system consisted of an Ultimate 3000 (Thermo scientific™, Waltham, USA) with a diode array detector operating between 190 and 800 nm. The separation was performed with a C-18 reverse phase column (accucore C18, 100 mm x 2.1 mm, 2.6 µm particule size, batch: 11,610, Thermo scientific™, Waltham, USA). The mobile phase was composed of acetonitrile (68 %) and a 23 mM potassium dihydrogen phosphate pH 3.2 buffer (32 %). The flow rate was 0.6 ml/min. The column temperature was maintained at 20 °C, and the injection volume was 10µL. The wavelength of detection was 247 nm.
Sample preparation
Stock solution of budesonide was prepared by dissolving 20 mg of budesonide (BUDSIGMA) in 20 mL of ethanol creating a 1 mg/mL solution of budesonide. Calibration standards were prepared by adding budesonide working stock solution into mobile phase to achieve the required concentrations (10, 15, 20, 25, 30 µg/mL). Quality control samples were prepared by adding budesonide (BUDARROW) into mobile phase to achieve the following concentration of 20 µg/mL. All solutions were prepared in amber glass vials.
OVBG samples were prepared by weighing accurately about 2 g of OVBG into 10 ml brown volumetric flask, then bringing up to volume with ethanol. Thereafter, the flask is placed in an ultrasounds bath for 10 minutes. The sample is then centrifuged for 5 min at 3500 rpm. Finally, the supernatant is diluted to 2/5th with the mobile phase.
Chromatographic conditions
The HPLC method was validated according to the International Conference on Harmonization (ICH Q2, R1)[10] in terms of:
- Linearity of the response function, defined as the ability (within a range from 10 to 30 µg/mL) of the method to obtain test results directly proportional to the amount of budesonide in the sample. Demonstration of its linearity has been performed with triplicates of the five concentrations levels (10, 15, 20, 25, 30 µg/mL) and considered admissible if the response was adjusted to linear model according to Fisher test (p-value>0.05).
The same 15 samples have been prepared with a reconstituted solution of excipients in order to assess the possible existence of a matrix effect. Non significant Student tests comparing y-intercepts and slopes of budesonide and budesonide + matrix samples would be in favour for a lack of matrix effect.
- Accuracy, defined as the closeness of agreement between the value found and the value accepted as true. The procedure would be declared adequate if 95 % confidence interval of the average recovery includes the value of 100 %.
- Precision, defined as repeatability evaluated by preparing and analyzing 6 low (10 µg/mL), 6 middle (20 µg/mL) and 6 high (30 µg/mL) replicates within a day and intermediate fidelity, analyzing these same samples prepared on six different days. Analyte concentration variations were expressed as a relative bias compared to the theory concentration. The method was considered acceptable if all the sample are in a range of +/− 15 %.
- Detection limit and quantitation limit defined with an approach based on maximum amplitude of background noise. The maximum amplitude of background noise is determined over a distance equal to 20 times the width at mid-height of the assayed analyte. hmax corresponds to this maximum amplitude [9]. The limit of detection (LOD) was determined by the formula: LOD=3.3 * hmax * (injected quantity/recorded signal), and the limit of quantitation (LOQ)=10 * hmax * (injected quantity/recorded signal).
- Specificity, defined as the ability of this stability-indicating method to discriminate between compounds of closely related structures which are likely to be resent, e. g. degradation products [9]. Hence, budesonide was exposed to different degradative conditions (acidic, alkaline, UV). The acidic degradation was performed by adding a HCl (1.0 M) solution in the budesonide suspension (0.5 mg/ml) (1:1 v/v) and neutralized after one hour with a NaOH (1.0 M) solution. The alkaline degradation was carried out by adding a NaOH (0.1 M) solution in the budesonide suspension (0.5 mg/ml) (1:1 v/v) and neutralized after different times (10 min, 20 min, 30 min, 40 min) with a HCl (0.1 M) solution. The light degradation was realized with an UV exposure for 15 minutes. (λ=253.7nm, 4.9W, Sankyo denki G15T8)
OVBG stability experiments
A batch corresponds to 240 grams of gel distributed in 4 tubes of approximately 60 grams each. Analyte concentration variations were expressed as a relative bias compared to the initial concentration measured at T0. Analyses were performed in triplicate. According to EMA guidelines [11], the preparation was considered stable if less than 15 % loss of the initial concentration occurs.
Microbiology quality testing of non sterile products
This preparation is not produced by aseptic processes and, therefore, is not expected to be totally free from microbial contaminations. As it is specified in General Chapter 5.1.4 (Microbiological quality of pharmaceutical preparations) in Eur. Ph. 9, for aqueous oral formulations, enumeration of total aerobic counts (ETAC) was established and had to be less than 102 CFU/g. Moreover, mold count/total yeast (MC/TY) should not exceed 101. Lastly, the preparation should also demonstrate the absence of Escherichia coli among at least 1 g of product. The microbiological test was performed the day of fabrication and one month after the first tube opening, and it was opened every day to reflect the use of the patient. Moreover, a microbiological test was realized three months after the fabrication.
Results and Discussion
OVBG formulation
Characteristic of gel
We choose to develop an OVBG in xanthan gum, to improve esophageal contact time. The active substance is the budesonide suspension for nebulisation 1 mg/2ml (BUDARROW). Sodium benzoate is used here as an antimicrobial preservative because the OVBG is packaged in a multi-dose tube. Glycerol is a moistening agent. EDTA acts as a stabilizer, and we add a sweetener, sodium saccharin. This formulation also allows the addition of aroma to improve palatability of the product. Based on taste test results, raspberry aroma was elected. As we know from previously reported result [12], rapid degradation of budesonide after light exposure made photoprotection mandatory. Taking it into account and the need to have a multidose package, we chose an aluminum pharmaceutical cream tube as primary packaging. The final formulation is presented in Table 1.
Formulation for 100 g of OVBG.
| Component | Quantity |
|---|---|
| Budesonide (BUDARROW) | 25 mg |
| Xanthan Gum | 2 g |
| Sodium Benzoate | 189 mg |
| Glycerol | 12.4 g |
| EDTA | 100 mg |
| Sodium Saccharin | 75 mg |
| Aroma | 6 drops |
| Water | qsp 100 g |
Xanthan gum is a non-toxic suspending agent and stabilizing agent, compatible with most other pharmaceutical ingredients, with good stability and viscosity properties [13]. The gel contains also excipients known to have a recognised action but there are mentioned on the label. The sodium benzoate (E 211), antimicrobial preservative (multidose tube), may lead to skin and mucous membranes irritations; it is contraindicated in infant of less of 56 days but it does not correspond to the population targeted with this treatment [13]. Glycerol could cause digestive troubles, nevertheless, the risk remains low in this case because the ingested amount is lower than 1 g per dose [13]. The main notorious effect linked to this preparation is oral candida which can easily be avoided by systematic mouth rinsing-without swallowing the water after each use.
One of study limitations is the lack of measurement of rheological properties due to the unavailability of the equipment in the hospital. However, the texture of the preparation remained the same over the three months.
pH determinations
The pH was measured at four different times and presented in Table 2. The pH of the oral gel of budesonide remained stable during the three months of conservation.
pH values of the OVBG in its final packaging, stored at 2–8 °C.
| Batch number 1 | Batch number 2 | Batch number 3 | Mean ± standard deviation | |
|---|---|---|---|---|
| T0 | 5,37 | 5,38 | 5,28 | 5,34 ± 0,06 |
| T1 | 5,32 | 5,39 | 5,34 | 5,35 ± 0,04 |
| T2 | 5,33 | 5,34 | 5,30 | 5,32 ± 0,02 |
| T3 | 5,29 | 5,32 | 5,30 | 5,30 ± 0,02 |
Visual examination
No color change was noticed during the three months. Moreover, the texture was still the same along the study.
Palatability and ease of use
The measuring spoon delivers 2 grams of OVGB, corresponding to 0.5 mg of budesonide. Considering dosage, which is either 1 or 2 mg daily [14], this spoon allows reproducible and easy administration, with a maximum of four spoons per day. The taste, back-taste, odour and texture tests obtained an average result of 9.3 out of 12.
Stability indicating HLPC method
HPLC method parameters
Budesonide is a mixture of two epimers (22R and 22S) (Figure 1) which is sparingly soluble in ethanol (1 gram in 30 to 100 mL). The retention time of the B-epimer (22-R) was 4 min and 4.5 min for the A-epimer (22-S). The resolution between the two peaks was 1.58 which means that they were correctly separated. The asymmetry corresponding to the B-epimer was 1.19 (for a superior limit at 1.5). Also, the number of plates for the B-epimer was 4265 meaning that the chromatography column had a good efficiency (>4000).
![Figure 1: Chemical structure of budesonide, 16α,17α-[Butylidenebis(oxy)]-11ß, 21-dihydroxypregna-1,4-diene-3,20-dione.](/document/doi/10.1515/pthp-2018-0005/asset/graphic/j_pthp-2018-0005_fig_001.jpg)
Chemical structure of budesonide, 16α,17α-[Butylidenebis(oxy)]-11ß, 21-dihydroxypregna-1,4-diene-3,20-dione.
Both epimers appear to have similar pharmacological effects and it was possible to add the surface of the two peaks to obtain total active budesonide concentration.
Linearity and matrix effect
The function response is linear from 10 to 30 µg/mL (Fisher test p-value=0.965), and the response variance is a constant (homoscedasticity, Cochran test with 5 series of 3 determinations). There was no significant matrix effect, Student comparison tests of y-intercepts and slopes were both not significant (respective p-values of 0.987 and 0.603).
Accuracy
The value of 100 % recovery was included in the 95 % confidence interval [90.04 – 103.20], response variances at each concentration levels were constant (homoscedasticity, Cochran test), average recoveries at each concentration level were not significantly different (Fisher test, p-value=0.973).
Precision
Repeatability and intermediate fidelity determined with 3 controls are presented in Table 3. The levels of control sample were selected to reflect low, medium and high concentration levels. The repeatability of the target compound varied from −2,48 % to 4,57 % (Relative Bias) while the reproducibility ranged from −9,87 % to 10,84 %.
Measured concentrations at low, medium and high level for precision. Repeatability assessed by intra-day assay (n=6) and intermediate fidelity assessed by inter-day assay (n=6, 6 different days). SD: Standard Deviation. CV: Coefficient of Variation.
| Intra-day assay (n=6) | Inter-day assay (n=6, 6 days) | |||
|---|---|---|---|---|
| Nominal concentration (µg/mL) | Measured concentration (µg/mL) (mean +/- SD) | CV (%) | Measured concentration (µg/mL) (mean +/- SD) | CV (%) |
| 10 | 10,33 +/- 0,06 | 0,6 | 10,27 +/- 0,41 | 2,2 |
| 20 | 20,57 +/- 0,11 | 0,5 | 20,49 +/- 0,78 | 3,2 |
| 30 | 29,13 +/- 0,10 | 0,3 | 30,61 +/- 1,02 | 2,7 |
Detection limit and quantitation limit
The LOD and LOQ for budesonide were 0.17 µg/mL and 0.5 µg/mL respectively (hmax=0.07 mAu) . These limits were good enough for determination of the budesonide containing in the OVBG.
Specificity
Figure 2 is the typical chromatogram of budesonide. The method proved to be both selective as well as stability indicating. There was no degradation of budesonide exposed to an acidic solution. Budesonide was degraded when submitted to alkaline conditions and peaks of the degradation products were separated from the drug peak. Figure 3 shows chromatogram of budesonide samples subjected to NaOH stress conditions. Also, budesonide did totally degrade by an UV exposition after 15 minutes. Oxidation and heat were not tested as degradation conditions because it has already been demonstrated that budesonide was not sensitive to both parameters [15].
Representative typical HPLC-chromatogram of budesonide at a concentration of 20 µg/mL.
Superimposition of HPLC-chromatograms of budesonide exposed to NaOH 0,1 M for different durations (A: 10 min, B: 20 min, C: 30 min, D: 40 min); E denotes degradation products.
OVBG stability experiments
Three separates batch were dosed at T0 and T3-months. Analyse were performed in triplicate. No significant change in budesonide gel concentration occurred after 3 months at 2–8 °C. In Figure 4, the 3-months chromatograms did not show any degradation products as described in budesonide monograph Ph. Eur. 9 and found in the forced degradation tests. All batch results are presented in Table 4.
Stability study of OVBG: comparative chromatogram of the same batch at T0 (top figure) and T3-months (bottom figure), showing no difference in budesonide area and no degradation products.
Stability data (n=3). Results expressed as relative biases compared to T0 for each separate three batchs.
| Nominal concentration (µg/mL) | Relative bias (%) 3 months, 2–8 °C | |
|---|---|---|
| Batch number 1 | 20 | −4,41 |
| Batch number 2 | 20 | −1,05 |
| Batch number 3 | 20 | −2,37 |
Microbiology quality testing of non sterile products
Microbial assays which were performed the day of the fabrication, after one month of a daily use and after a 3-months period stored at 2–8 °C, were all negative. ETAC was<102 CFU/g, MC/TY was<101 CFU/g. Besides, No E. coli was detected in any tube.
Conclusion
Given the rising incidence of EoE, patients who need medication are more and more numerous. This oral gel of budesonide made with xanthan gum is a good answer to a real clinical need. Concerning gel efficacy, it should be compared to a medication with budesonide mixed with sucralose but it would require a clinical trials recruiting several patients. In our hospital, the first patient who received the OVBG with xanthan gum showed a clear clinical and endoscopical improvement. Indeed, the number of eos/hpf went from over 25 to 2 after 5 months of daily medication with oral budesonide gel. This patient had already followed an exclusion diet as well as a budesonide mixed with Gaviscon™ medication but despite that, previous treatments had not given positive results. Actually, our cohort includes 5 patients receiving well tolerated new formulation with promising results.
This gel presents the advantage of being easy to produce, to use and also palatable. Therefore, extended shelf life is needed to settle production campaigns. Furthermore, the relative ease of preparation and access to the pharmaceutical ingredients allows it realization in community pharmacy.
Statistical tests have shown that U-HLPC dosage method was linear and without any matrix effect, accurate, precise. Moreover, forced degradation tests showed that the method is stability indicating and allows the separation of budesonide from degradation products. The U-HPLC method enables to have reliable and fast results, about 4 times faster than the method exposed in the budesonide monograph from the Eur. Ph. 9.
Stability study demonstrated that budesonide oral gel was stable for 3 months if it is stored in a refrigerator between 2 and 8 °C. For conservation practicality matter at the patient’s home and at the hospital, it would have been interesting to study this gel stability at room temperature. However, fridge conservation presents the advantage of improving the gel taste.
European Medicines Agency very recently adopted a positive opinion about an orphan medicinal product with budesonide for the treatment of EoE. However, the drug is only licensed for adults [16].
About the authors
Mathilde Bonnet is a French PharmD candidate. She started studying pharmacy at the University of Lyon and is currently a resident in Paris. She worked in the sector of manufacturing and control at Robert Debré pediatric hospital in Paris, and is especially interested in drug formulation and correct drug usage.
Marine Dermu is a French Hospital Pharmacist, trained at Lille University and successively in Poitiers, La Rochelle and Rennes in France for her internship. After completion of her PharmD in November 2014, she specialized in pharmaceutical compounding working at Robert Debré pediatric hospital in Paris. There she supervised aseptic manufacturing of injectable drugs (parenteral nutrition and production for clinical trials unit) and non sterile products. Her involvement in the quality control lab enabled her to develop new analytical methods and stability studies. She also took part in the in situ production design of experimental products.
Clara Roessle is a French Hospital Pharmacist. She received her PharmD in November 2017. She trained at Montpellier University and completed her internship in Paris. She is currently working at Robert Debré pediatric hospital. There she is supervising aseptic manufacturing of injectable drugs (parenteral nutrition and production for clinical trials unit) and non sterile products.
Marc Bellaiche, MD, is a French Hospital paediatrician since 1991, and is responsible of the endoscopy unit at Robert Debre Hospital (Largest French paediatric hospital, in Paris Area). 1200 endoscopy procedures were done last year. He is the president of the French Society of paediatric GI and nutrition. He is focus in the area of dymotility and functional GI disorders.
Tarik Abarou is a laboratory technician in the pharmacy of Robert Debré Hospital.
Véronique vasseur is a laboratory technician in the pharmacy of Robert Debré Hospital.
Samira Benakouche is a laboratory technician in the pharmacy of Robert Debré Hospital.
Thomas Storme, PhD, is a French Hospital Pharmacist since 2007, and is responsible of the compounding facility at Robert Debré Hospital (Largest French paediatric hospital, in Paris Area). The Robert Debré compounding facility consists in 3 units:– a Quality Control Lab’– a non sterile compounding (capsules, oral liquids, suppositories, oral gel, cream … )– a Sterile compounding facility, divided into: chemotherapy + CIVAS and TPN compounding
He was resident in pharmacy at Paris area hospital, during his residency; he specialized in compounding, Quality control and oncology care. He studied pharmacy at Paris-Descartes University. In parallel with his residency, he completed in 2007 a PhD in Medicinal Chemistry and Experimental Pharmacology on the development and the Evaluation of Ifosamide analogs designed to lower side effects.
Conflicts of interest: The authors state no conflict of interest. The authors have read the journal’s Publication ethics and publication malpractice statement available at the journal’s website and hereby confirm that they comply with all its parts applicable to the present scientific work.
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Articles in the same Issue
- Frontmatter
- graphical-abstract
- Editorial
- Paediatric Needs: Challenge and Opportunities for Hospital Pharmacists
- Research Articles
- Physicochemical Stability of 5 mg/mL Pediatric Prednisone Oral Suspension in Syrspend® SF PH4
- Safe use of Dexamethasone in pediatrics: design and evaluation of a novel stable oral suspension
- Paediatric formulation: budesonide 0.1 mg/mL viscous oral solution for eosinophilic esophagitis using cyclodextrins
- Physicochemical and Microbiological Stability of a New Oral Clonidine Solution for Paediatric Use
- Formulation of a 3-months Stability Oral Viscous Budesonide Gel and Development of an Indicating Stability HPLC Method
- Physicochemical Stability of Extemporaneously Prepared Oral Suspension of Fluconazole 50 mg/mL in SuspendIt™
- Opinion Paper
- Development and Preparation of Oral Suspensions for Paediatric Patients – a Challenge for Pharmacists
Articles in the same Issue
- Frontmatter
- graphical-abstract
- Editorial
- Paediatric Needs: Challenge and Opportunities for Hospital Pharmacists
- Research Articles
- Physicochemical Stability of 5 mg/mL Pediatric Prednisone Oral Suspension in Syrspend® SF PH4
- Safe use of Dexamethasone in pediatrics: design and evaluation of a novel stable oral suspension
- Paediatric formulation: budesonide 0.1 mg/mL viscous oral solution for eosinophilic esophagitis using cyclodextrins
- Physicochemical and Microbiological Stability of a New Oral Clonidine Solution for Paediatric Use
- Formulation of a 3-months Stability Oral Viscous Budesonide Gel and Development of an Indicating Stability HPLC Method
- Physicochemical Stability of Extemporaneously Prepared Oral Suspension of Fluconazole 50 mg/mL in SuspendIt™
- Opinion Paper
- Development and Preparation of Oral Suspensions for Paediatric Patients – a Challenge for Pharmacists
