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Case Study: Hydrocortisone for paediatrics

Abstract

Hydrocortisone is found on the EMA unmet medical need priority list (2011) for the use in paediatric population for children suffering from all forms of adrenal insufficiency. Although there is a particular need in neonates and in infants, i.e. children younger than two years, there is a main issue. No licensed hydrocortisone preparation for paediatric use is available in Europe. Within the TAIN program (treatment of adrenal insufficiency in neonates and infants) supported by the European Commission [1], oral drug dosage research has been initiated.

Issues on Hydrocortisone

Hydrocortisone can be given orally, topically, or by injection [2]. After oral administration, free cortisol passes easily through cellular membranes which explains its 100% bioavailability [3]. Paediatrics key characteristics are taste masking (Figure 1) and the requirement of dedicated dosing units. Also the immediate drug release shell be comparable to crushed Hydrocortisone tablets.

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Taste masking increases customer compliance of bitter actives in paediatrics.

Transforming these requirements into a development strategy, following focus points need to be considered:

  1. Dosage change by multiparticulates
  2. Layering/coating of starter beads demands narrow size distribution and defined smooth surfaces.

These considerations exclude working on standard dry powder forms like rough granules, but recommend the usage of pellets. We will focus on pellets made of microcrystalline cellulose (MCC), which are Cellets® 350. The main advantage of these MCC pellets are narrow size distribution, smooth surface and chemical inertness. By spray coating, functional layers are coated onto the MCC pellet (Figure 2). Different drug loads can be achieved.

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Coated MCC pellet (green). Functional layers: hydrocortisone (blue), seal coat (orange), taste masking (grey).

A concept and selection of feasible excipients provide Cellets® as starter beads, cellulose derivates as binder, seal coating and taste masking.

The size distribution of Cellets® 350 is known to be highly narrow (Figure 3). Also critical parameters, such as sphericity and smoothness of the surface are almost perfect which is presented by an electron microscopy image in Figure 4. In turn, a subsequent precise layering of the active and adjustment of optimal time release profiles is possible.

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Size distribution of MCC pellets, type Cellets® 350.

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Electron microscopy image of a Cellets® 350 starter beads. A high degree of sphericity and a smooth surface are advantages of these starter beads.

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Finalized hydrocortisone pellets. Embedded pictures: electron microscopy image of a hydrocortisone pellet (top) and cross section (bottom).

After processing the hydrocortisone pellets are finalized and look – as the Cellets starter beads do – perfectly spherical with a smooth surface (Figure 5).

Summary

In this case study hydrocortisone by means of use in paediatric population for children suffering from all forms of adrenal insufficiency was investigated. Based on Cellets® 350 starter beads, multi-layering hydrocortisone pellets were manufactured with five dosage strengths between 0,5 mg and 10 mg. Extremely bitter API was successfully taste masked and a fast dissolution profile was obtained. Clinical trial material was produced for Phase I study.

Acknowledgement

We acknowledge Fraunhofer IFAM (Dresden, Germany) and University of Basel (Basle, Switzerland) for providing the electron microscopic images.

Authors

Dr. Bastian Arlt

References

[1] http://tain-project.org/

[2] Hydrocortisone, https://www.drugs.com/ (2016)

[3] M.C. Caldato, V.T. Fernandes, C.E. Kater, Arquivos Brasileiros De Endocrinologia E Metabologia. 48 (5), (2004) 705-712.

Theophylline size distribution

Case Study: Layering of Theophylline

Abstract

Theophylline is a powerful active used for the acute treatment of respiratory distress. Its bioavailability and uptake rates are high. Drug carrier systems are pellets made of sugar or microcrystalline cellulose (MCC). This case study will point on the specific advantages of MCC pellets.

Layering on starter pellets

Basically, theophylline is an alkaloid that occurs in nature together with other purine alkaloids such as caffeine and theobromine, but it occurs in comparably small fractions up to 0.25 %. Anyhow, it can be synthetically composed. In application, theophylline is used for the acute treatment of respiratory distress due to airway constriction in bronchial asthma and other obstructive airway diseases.

After oral administration theophylline is rapidly and completely absorbed in the gastrointestinal tract (GIT). Retard preparations are used for long-term treatment, reaching their maximum effect after around six to eight hours [1].

Typical carrier systems are sugar and MCC pellets (Cellets®). By subsequent layering, retard and individual release profiles can be achieved. For both types of starter pellets, a drug solution for 200 g pellets (batch size) was formulated in the following way as listed in Table 1.

Parameter weighted mass
theophylline 8.32 g
PVP K30 0.67 g
distilled water 80.0 g
ammonia 25 % 4.0 g

Table 1: Substances for a drug solution for 200 g batch size.

Process Technology

The formulation results in a drug load of 4.2 %. A Wurster tube at 0.8 cm was used with a processing temperature at 50 °C. In contrast to MCC pellets, sugar pellets are soluble in water. Therefore, process parameters are slightly different, since the process for sugar spheres requires a slower start to avoid sticky particles (Table 2). Obviously, the slower process start required for the sugar pellets results in an additional time consumption of +50 % compared to the Cellets® process.

Parameter Sugar pellets Cellets®
Batch size 200.0 g
Wurster tube 0.8 cm
Fluid bed temperature 50 °C
Inlet air volume (pressure) 0.4 bar 0.35 bar
Atomizing air pressure 2.3 bar 1.8 bar
Spray rate 0.41 g/min 0.73 g/min
Process time 218 min 145 min
Drying period 30 min

Table 2: Process parameter for the formulation with sugar pellets and Cellets®.

Finalized pellets

The processed drug layered pellets show a size distribution as shown in Figure 1. Here, the variation between the batches of the sugar pellets are more pronounced (18.6 %) than for the batches of Cellets® (2.8 %).

The formulation results in a drug load of 4.2 %. A Wurster tube at 0.8 cm was used with a processing temperature at 50 °C. In contrast to MCC pellets, sugar pellets are soluble in water. Therefore, process parameters are slightly different, since the process for sugar spheres requires a slower start to avoid sticky particles (Table 2). Obviously, the slower process start required for the sugar pellets results in an additional time consumption of +50 % compared to the Cellets® process.

Parameter Sugar pellets Cellets®
Batch size 200.0 g
Wurster tube 0.8 cm
Fluid bed temperature 50 °C
Inlet air volume (pressure) 0.4 bar 0.35 bar
Atomizing air pressure 2.3 bar 1.8 bar
Spray rate 0.41 g/min 0.73 g/min
Process time 218 min 145 min
Drying period 30 min

Table 2: Process parameter for the formulation with sugar pellets and Cellets®.

The processed drug layered pellets show a size distribution as shown in Figure 1. Here, the variation between the batches of the sugar pellets are more pronounced (18.6 %) than for the batches of Cellets® (2.8 %).

Theophylline size distribution

Theophylline size distribution

Figure 1: Analysis of batches. From left to right: (1) best batch sugar pellets, (2) worst batch sugar pellets, (3) best batch Cellets®, (4) worst batch Cellets®.

Summary

In this case study, the coating of pellets with theophylline was investigated. A targeted drug load of 4.2 % was reached. By sophisticated formulation, further improvements towards optimized release profiles of the active in the GIT can be performed. Here, MCC pellets are superior to sugar pellets in terms of reproducibility, process time and quality rating after coating.

Acknowledgement

We acknowledge Dr. Riedel (Bayer) for assisting this case study.

Authors

Authors: Dr. Bastian Arlt

References

[1] B. Lemmer, R. Wettengel: Erkrankungen der Atemwege. In: B. Lemmer, K. Brune: Pharmakotherapie – Klinische Pharmakologie. 13. Auflage. Heidelberg 2007, ISBN 978-3-540-34180-2, S. 343–344, S. 349–350.