Friday, 15 November 2013 15:55

Taste-Masking for Paediatric Medicines

Written by T.H. Hoang Thi and M.P. Flament
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Introduction

Following the implantation of European regulation with respect to medicinal products for paediatric use, scientist community has to speed up for making medicine available for children by encountering multiple problems of paediatric formulation [1]. Indeed, the taste of oral medicine is one of the most crucial factors influencing adherence to therapeutic regimens and therapeutic outcomes [2].

 

Spray-drying is a well-established, inexpensive and straightforward technology which permits to mask the unpleasant taste of certain ingredients through encapsulation [3,4]. During this process, appropriate encapsulating materials enable the film formation at the droplet surface as water evaporates. The functional properties of encapsulating agent have an important role on resultant product characteristics e.g solubility, and therefore the taste-masking efficiency.

Objectives

To produce and characterize taste-masked powders of acetaminophen (used as model drug) prepared by spray-drying using potentially tolerable and safe excipients for paediatric use, i.e. sodium or calcium caseinate, and lecithin. Taste assessment is approached in vitro by an indirect method through drug release studies. We developed a method with a syringe pump using small volumes of aqueous medium and low flow rates, to mimic the behavior in the mouth (figure 1). We consider the percentage of drug release amount during the first 2 minutes since the taste-masking is achieved if, within the frame of 1-2 minutes, the drug substance is either not released or released amount is below the human threshold for identifying its bad taste. This method is compared to the Astree electronic tongue analysis (Alpha MOS).

Taste-masking with sodium caseinate and lecithin

Particles of acetaminophen covered by an association of sodium caseinate and lecithin (1:0.5 or 5:1.5) were produced by spray-drying with a Mini Spray-dryer Buchi B-190. The DSC curves (figure 2) show that no particular peak is recorded for the 5:1.5 spray-dried powder, which indicates that drug might exist under molecular state. It can be explained by the fact that drug molecules in the solution of droplet remain dispersed in the dried particle by the higher amount of available excipients, i.e. sodium caseinate and lecithin. The results are confirmes by X-ray diffraction. To evaluate the composition of the surface around the acetaminophen core, we used X-ray photoelectron spectroscopy (XPS) (figure 3). The XPS is a well-established technique that allows getting greater insight about the 10 nm-outermost layer composition of particles which may determine the product properties such as flowability, stability, wettability and even solubility. The XPS results imply the presence of sodium caseinate at the surface of both spray-dried powders (table 1). The figure 3 indicates an over-representation of sodium caseinate on the surface of the 5:1.5 spray-dried powder. The 1:0.5 formulation generates particles with all components in the bulk composition found on the surface, whereas the 5:1.5 particle surface is mostly covered by sodium caseinate.

The “coating” consisted of sodium caseinate and lecithin has a significant role in decreasing the release of drug (figure 4). Indeed, during first 2 minutes, the 1:0.5 and 5:1.5 formulations demonstrate lower released amounts at 1.7 and 2.5 folds less than the unmasked drug, respectively, which is in favor of taste-masking.

The general taste of taste-masked formulations is also evaluated by means of Astree e-tongue. Figure 5 plots the responses of seven sensors to sample through the last three replicates. Based on the 7-dimensional data set obtained from these sensors, a principal component analysis (PCA) is applied in order to reduce the dimensional space without losing information. As shown in the figure 6, the PC1 and PC2 explain 91.96% and 7% of data variance, respectively. It appears that both 1:0.5 and 5:1.5 formulations are closer to the corresponding placebo, in comparison to the reference of pure drug, therefore reflect a better taste improvement for taste-masked formulations. The masking efficiency is particularly remarkable for the 5:1.5 formulation which represents the lowest distance. Interestingly, this is in good accordance with results obtained from the drug release study.

The simplex design (figure 8) made it possible to determine an optimal formulation: O4 containing 1.6% of sodium caseinate and 2.5% of lecithin. This was confirmed by the drug release profiles (figure 9).

Optimizing the taste-masked formulation by experimental design

The aim was (i) to evaluate the effects of various processing and formulation parameters on the taste-masking efficiency, i.e. inlet temperature, spray flow, sodium caseinate amount, lecithin amount, by using a full factorial design and (ii) to determine the optimal formulation for optimal taste-masking effect by means of a simplex design.

Figure 7 shows that an inlet temperature of 130°C and a spray flow of 300 L/h produced the optimal response.

Then, calcium caseinate was compared to sodium caseinate using a 24 full factorial design. SEM micrographs (figure 10) show that despite the type of caseinate, the particle morphology differs from each other and is dependent upon the caseinate/lecithin ratio in the dispersion being spray-dried. The lowest level of caseinate and lecithin is shown not to efficiently encapsulate the acetaminophen, so that drug crystals readily expose on the outer surface (Figure 10a and 10e). It is worth noting that the formulations containing 5% of caseinate exhibit typically corrugated morphology as a result of protein accumulation at the particle surface [5]. Particularly, the powders show a tendency to form aggregates since the content of lecithin increases as can be seen in Figure 10c and 10g.

All spray-dried formulations are demonstrated to delay the drug release, in comparison to “uncoated” drug. Interestingly, calcium caseinate-based formulations lower the release profiles to a higher extent compared to sodium caseinate-based formulations (Figure 11), in particular after the first two minutes (paired samples t-test, p < 0.05).

Outlook

The taste-masked product is intended to develop a multi-particulate dosage form for pediatric use. Our aim is to develop fast disintegrating pellets, produced by the association of extrusion/spheronization and freeze-drying technologies. The first results are promising.

References

[1] Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL. Developing paediatric medicines: identifying the needs and recognizing the challenges. J. Pharm. Pharmacol. 2007; 59: 1043–1055.

[2] Matsui D. Current issues in pediatric medication adherence. Paediatr. Drugs. 2007; 9: 283–288.

[3] Gouin S. Microencapsulation: industrial appraisal of existing technologies and trends. Trends in Food Science & Technology. 2004; 15: 330–347.

[4] Gharsallaoui A, Roudaut G, Chambin O, Voilley A, Saurel R. Applications of spray-drying in microencapsulation of food ingredients: An overview. Food Research International. 2007; 40: 1107–1121.

[5] R. Vehring, W. R. Foss, and D. Lechuga-Ballesteros, “Particle formation in spray-drying,” J Aerosol Sci, vol. 38, no. 7, pp. 728–746, 2007.

 

PSSRC Facilities

The research group of Professor Juergen Siepmann (U 1008) focuses on the development of novel types of advanced drug delivery systems and biomaterials allowing for an accurate control of the resulting drug release kinetics during periods ranging from a few minutes up to several years. We work on different types of systems, in particular:

  • Coated pellets which are orally administered and allow for site specific drug delivery to the colon. This is of major benefit for the treatment of inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis
  • Biodegradable microparticles for parenteral administration, especially for the treatment of brain diseases (e.g., cancer and neurodegenerative disorders)
  • Lipid implants for the controlled delivery of fragile protein drugs (e.g., growth factors)
  • Drug eluting stents with improved biocompatibility
  • Implants releasing antibiotics and anesthetics in a time controlled manner for dental surgery
  • Scaffolds releasing incorporated drugs at a pre-determined rate for bone substitution in facial surgery.
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