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SHORT COMMUNICATION
Year : 2022  |  Volume : 67  |  Issue : 4  |  Page : 399-403
Beads and beyond: An observational study to generate real world evidence on various brands of itraconazole


1 From the Consultant Dermatologist, Rourkela, Odisha, India
2 Department of Dermatology, KPC Medical College and Hospital, Kolkata, West Bengal, India

Date of Web Publication2-Nov-2022

Correspondence Address:
Anupam Das
Department of Dermatology, KPC Medical College and Hospital, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_991_21

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   Abstract 


Background: Rising number of the nonresponding dermatophytic infections raises deep concerns among the dermatologists across the nation. Variations in the quality of itraconazole may be a contributing factor to nonresponse in certain dermatophytic infections. This article will address this issue in a simple way of analyzing things in an OPD and may help us in being aware and taking the right foot forward. Aims and Objectives: To assess the quality of itraconazole brands by observing the morphological properties of pellets/beads in different brands. Methods: In this study, 10 brands of itraconazole that are commonly used in clinical practice were randomly selected. Pellet counts and qualitative morphological analysis of pellets as size (small, large, or mixed), shape (uniform or nonuniform), and presence of amorphous material was performed by three independent observers. Also, dissolution profile of some brands was assessed by adding the pellets in equal quantity of water. Results: The pellet counts of brands varied from 856 pellets per capsule in brand 1 to 109 pellets per capsule in brand 8. Brand 1, brand 2, and brand 7 pellets were small and uniform in morphology. Brand 3, brand 4, and brand 10 pellets were mixed in size but uniform in morphology. Brand 9 pellets were mixed and nonuniform whereas brand 5, brand 6, and brand 8 pellets were mixed in size, nonuniform in shape, and had presence of amorphous material. Dissolution test revealed that brand 5 dissolved rapidly and turned clear water color to milky white. Conclusion: A simple dermoscopy examination of itraconazole pellets may provide thoughtful insights about the quality of itraconazole brand. It may be considered as routine practice for all dermatophytic infection planned for treatment with itraconazole.


Keywords: Dermatophytosis, dermoscopy, generic, innovator, itraconazole, pellet


How to cite this article:
Kar D, Das A. Beads and beyond: An observational study to generate real world evidence on various brands of itraconazole. Indian J Dermatol 2022;67:399-403

How to cite this URL:
Kar D, Das A. Beads and beyond: An observational study to generate real world evidence on various brands of itraconazole. Indian J Dermatol [serial online] 2022 [cited 2022 Dec 10];67:399-403. Available from: https://www.e-ijd.org/text.asp?2022/67/4/399/360373





   Introduction Top


Superficial dermatophytic infections are fairly common in dermatology outpatient clinics. India is witnessing the troublesome menace of chronic and recurrent dermatophytosis since past 4-5 years. The rise in frequency with which such infections are encountered is alarming. Among newly diagnosed dermatophytosis, at least 5--10% is chronic and difficult to treat ones.[1],[2],[3] Comorbidities such as diabetes, atopy, immunosuppression caused by drugs or immunosuppressive disorders, and development of resistance to antifungal agents are probably the major contributory factors.[2] Emergence of resistance has been reported in various studies across the globe.[4],[5],[6],[7] Recent investigations from India reported widespread resistance to antifungal therapies and higher minimal inhibitory concentration (MIC) of itraconazole against dermatophytes.[8],[9] This may contribute to the clinical failure of azoles including itraconazole.

Beside these factors, an important contributor is quality of the drug in a specific brand. Quality of itraconazole can significantly affect its efficacy. It has been supported by the evidence that a nonresponse to one brand may be converted to a clinical response after shifting to another brand.[10],[11] The pharmacokinetic properties inherent to itraconazole (e.g., effect of food intake, water insolubility, and inter-subject variation in oral bioavailability) necessitate drug to be formulated as a capsule containing drug coated pellets.[12] Variation in the quality of different brands might be a cause of clinical failure and emerging resistance with itraconazole. Small, uniform pellet size with minimal pellet size variability indicates better drug quality.[12] Given the rising number of recalcitrant dermatophytic infections, it is important to assess the quality of itraconazole brands, which we have evaluated in the present study by observing the morphological properties of beads in different brands in comparison to innovator brand.


   Materials and Methods Top


Study design and setting

This observational study was conducted at a single dermatology clinic in Eastern part of India. We do not have any conflict of interest with any brand.

Selection of itraconazole brands

We selected 10 brands of itraconazole that are commercially available in India. Selection was randomly done, from the commonly used drugs in our setting. For avoiding the issues related to storage and environmental conditions, a fresh batch of all brands was bought from local pharmacy and was subjected to evaluation. All brands were well within the limit of date of expiry.

Pellet count and morphological appearance

Pellets from three different random brands were placed over black velvet cloth. Digital photographs were taken for gross observation of the presence of number of pellets. From each capsule strip (itraconazole 100 mg), one capsule was randomly selected and the pellets were taken out in Petri dish. All precautions were taken not to touch the pellets with hands or any instruments. Pellets were counted manually. This was followed by dermoscopy. DermLite3N dermoscope with 10 × magnification was used. Pellets were observed using a polarized light. Three independent observers counted the number of pellets and determined the morphological appearance. Each observer stated the morphology based on three parameters namely size (small, large, or mixed), shape (uniform or nonuniform), and presence of amorphous material.

Dissolution in water

Among the different brands, six were subjected to the solubility test in simple tap water. A 100 ml of clean water was taken in transparent glass beakers. Pellets were added to each beaker separately for each brand. Observations for pellet dissolution were performed at 45 min and 90 min after addition of pellets in the water.


   Results Top


Brands details

Among the 10 brands selected for the observation, two were of international and multinational pharmaceutical companies one of them being an innovator itraconazole brand, and rest eight were Indian generic brands [Table 1].
Table 1: Brands selected for the study

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Pellet count

Pellet count per capsule in different brands is presented in [Figure 1]. The pellet count varied from as high as 856 pellets per capsule in brand 1 to 109 pellets per capsule in brand 8. [Figure 2] confirms these observations showing much higher number of visible pellets in digital photographs of brand 1 in comparison to brand 2 and brand 3.
Figure 1: Distribution by pellet count cut-off of 500 in different brands

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Figure 2: Pellets observed in three different brands

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Pellet morphology using dermoscopy

Pellet morphology observed by three different observers is presented in [Table 2]. All three observers had reported similar morphology for all the brands. Brand 1, brand 2, and brad 7 pellets were small and uniform in morphology. Brand 3, brand 4 and brand 10 pellets were mixed in size but uniform in morphology. Brand 9 pellets were mixed and nonuniform whereas brand 5, brand 6 and brand 8 pellets were mixed in size, nonuniform in shape and had presence of amorphous material. The gross differences in morphology of pellets from four random brands are clearly seen in [Figure 3]. We describe the findings of dermoscopy with a metaphor. In innovator brand, pellets were small and uniform with a very rare broken or dummy pellets indicating an ugly duckling among beautiful swans [Figure 4]a, whereas it was substantially different in one of the generic brands with a few numbers of uniform pellets around the mixed and nonuniform pellets indicating a beautiful swan among ugly ducklings (Metaphor used by author) [Figure 4]b.
Table 2: Pellet morphology reported by three independent observers

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Figure 3: Morphology of pellets observed with dermoscopy. Dermlite DL3, Magnification 10×

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Figure 4: Author's metaphor to describe the pellets morphology (a: Ugly duckling among beautiful swans and b: Beautiful swan among ugly ducklings)

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Dissolution in normal tap water

Dissolution profile of pellets of six different brands is shown in [Figure 5]. There were glaring differences in the amount and rate of dissolution. Brand 5 dissolved rapidly and turned clear water color to milky white (at 45 min and 90 min). Other brands had minimal to no dissolution as seen with naked eyes.
Figure 5: Dissolution profile of pellets of six brands

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   Discussion Top


In this study, we observed that the selected brands substantially varied in the number and morphology of the pellets. There was unanimous agreement in the findings of pellet morphology among the three independent observers. Additionally, dissolution profile also indicated varying rates of water solubility with the pellets of one brand getting dissolved within 90 min. These results indicate there is large variability in the number, morphology, and dissolution profile of itraconazole pellets of different brands. Itraconazole is a weak base and is only ionized at a low pH. It has low solubility and high permeability that may result in poor dissolution rate in the gastrointestinal tract and compromise oral bioavailability.[13] Thus, to overcome this problem, multiparticulate drug delivery systems using pellets/beads are developed. The size of pellets is important for optimum drug availability. Pellet diameter of 600 and 700 μm improves the feasibility of coating process.[14]

This size dimension is critical as lesser diameter may be coated properly whereas increasing the pellet diameter reduces the surface area for drug dissolution.[14] As we observed a significant variation in the size of pellets by qualitative analysis, each brand may behave differently in their pharmacokinetics. In a similar study from Sardana et al.[15] 22 brands of itraconazole were assessed. They observed significantly large variation in the pellet size across different brands. Pellet numbers varied from 121 to 820 and average size varied from 959 to 1845 μm. Combined with our observations, these data clearly indicate large differences in morphometric characteristics of itraconazole pellets may hamper its quality. During development of a 200 mg capsule of itraconazole, limitations such as instability, larger capsule size, increased risk for agglutination, and gel formation were not taken into consideration and such formulations should be strongly discouraged.[14]

The poor quality of itraconazole brands is mostly responsible for the clinical failure with particular brand. Study from Pasqualotto et al.[10] indicates that substitution of innovator brand with generic itraconazole in the treatment of aspergillosis resulted in treatment failure due to inadequate plasma levels. They also observed that it may lead to resistance to itraconazole in a patient. In a randomized two-way cross over study, Pierard-Franchimont et al.[11] demonstrated that the relative bioavailability of generic itraconazole to innovator itraconazole was only 3.5 ± 2.8% (range: 0.5%–8.2%). This indicates poor absorption of the itraconazole from generic brand. Insufficient bioavailability of itraconazole can be the result of poor drug quality, concomitant use of antacids or use in immunocompromised patients.[14] Increasing rates of treatment failures with itraconazole are concerning. Itraconazole being the last knight, its quality becomes questionable especially with the generic brands. Using guideline-directed treatment of itraconazole with deferred use of topical steroids in management of dermatophytosis, development of treatment failure may be reduced to this one of commonly preferred antifungal.[16]

Mehta et al.[17] had carried out a similar office-based procedure to assess the different brands of itraconazole. However, our study has taken into consideration, a larger sample size and more number of brands of itraconazole, and therefore, the external validity of our study is better, both in terms of quantity and quality.

Limitations

In our study, we did not measure the diameter of the pellets which would have provided objective analysis of the pellet morphology. Though, pellet diameter was not measured, a qualitative analysis of morphology by three different observers provides valuable insights on brands. Comparison of clinical parameters including treatment response with different brands would have provided additional insights. A cross-over bioavailability study would shed further lights on absorption kinetics of different brands which was not feasible for us because of technical reasons.


   Conclusion Top


A simple morphometric analysis of itraconazole pellets provides greater insights in to the quality of different itraconazole brands. Adequate number of pellets and their uniform size is a key to enhance the bioavailability of itraconazole. Highlighting these findings to the manufacturers and regulatory authorities may help in streamlining the quality of itraconazole brands. By this observation, we urge dermatologists across India to incorporate habit of dermoscopic examination of brands in use.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Pasqualotto AC, Denning DW. Generic substitution of itraconazole resulting in sub-therapeutic levels and resistance. Int J Antimicrob Agents 2007;30:93-4.  Back to cited text no. 10
    
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Pierard-Franchimont G, De Doncker P, Van de VV, Jacqmin P, Arrese JE, Pierard GE. Paradoxical response to itraconazole treatment in a patient with onychomycosis caused by Microsporum gypseum. Ann Soc Belg Med Trop 1995;75:211-7.  Back to cited text no. 11
    
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Sirisha KVR, Sri KV, Suresh K, Reddy GK. Devanna N. A review of pellets and pelletization process-A multiparticulate drug delivery system. Int J Pharm Sci Res 2013;4:2145-58.  Back to cited text no. 12
    
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Heykants J, Van PA, Van de VV, Van RP, Meuldermans W, Lavrijsen K, et al. The clinical pharmacokinetics of itraconazole: An overview. Mycoses 1989;32(Suppl 1):67-87.  Back to cited text no. 13
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2]



 

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