|Year : 2021 | Volume
| Issue : 2 | Page : 72-78
Morphometric analysis of itraconazole pellets of commonly available brands using dermoscopy
Gajanan A Pise, HT Komala, Shilpa V Dastikop, Naveen Manohar, LM Akshay, Vinitha Sanagoudar
Department of Dermatology, Belagavi Institute of Medical Sciences, Belagavi, Karnataka, India
|Date of Submission||22-Mar-2021|
|Date of Decision||28-Sep-2021|
|Date of Acceptance||08-Nov-2021|
|Date of Web Publication||14-Dec-2021|
Room number 24, BIMS Hospital, Belagavi 590002, Karnataka.
Source of Support: None, Conflict of Interest: None
Introduction: Itraconazole (ITZ) is commonly used to treat cutaneous and systemic mycoses. The bioavailability of ITZ capsules varies between individuals; therefore, the quality of ITZ pellets is a major determinant of their absorption and therapeutic efficacy. Morphometric analysis is a surrogate method of evaluating the absorption and efficacy of ITZ capsules, and the number and size of pellets in each capsule are the most important morphometric parameters. Aim: To analyze the morphometric characteristics of commonly available brands of ITZ. Materials and Methods: Commonly available formulations of ITZ in the market were analyzed using a hand-held dermoscope. Morphometric characteristics of 30 and 10 brands of 100-mg and 200-mg formulations were analyzed, respectively. A dermoscope was used to determine the size and the number of pellets per capsule. Furthermore, variations in the size of pellets across brands were compared to that in the global innovator brand. Statistical analysis used was SPSS v. 21 (IBM Inc., Armonk, NY). Results: The capsules included 126–1010 pellets of 788–2343 µm, and dummy pellets and loose powder were found in some brands. Five brands that cost <20 Indian rupees (INR) per capsule included good pellet count, small pellet size, and low size variation. Two other brands included these qualities but were priced at INR 20–30 per capsule. The size variation was the minimum, and no dummy particles or loose powder were observed with the innovator brand; however, it was the costliest. Conclusion: The morphometric characteristics of ITZ formulations varied significantly between brands, which may significantly affect their efficacy.
Keywords: Bioavailability, efficacy, itraconazole, morphometry
|How to cite this article:|
Pise GA, Komala H T, Dastikop SV, Manohar N, Akshay L M, Sanagoudar V. Morphometric analysis of itraconazole pellets of commonly available brands using dermoscopy. Indian J Drugs Dermatol 2021;7:72-8
|How to cite this URL:|
Pise GA, Komala H T, Dastikop SV, Manohar N, Akshay L M, Sanagoudar V. Morphometric analysis of itraconazole pellets of commonly available brands using dermoscopy. Indian J Drugs Dermatol [serial online] 2021 [cited 2022 May 21];7:72-8. Available from: https://www.ijdd.in/text.asp?2021/7/2/72/332429
| Key Messages:|| |
With a plethora of brands available, clinicians could use morphometric analysis as a surrogate marker for choosing the optimum itraconazole formulation to improve therapeutic outcomes.
| Introduction|| |
Itraconazole (ITZ), a synthetic triazole, is commonly used to treat systemic and cutaneous fungal infections. ITZ requires an acidic medium for absorption and has extremely low water solubility; however, its bioavailability can vary between individuals. In India, recalcitrant dermatophytoses have become an epidemic. The number and size of pellets in the ITZ capsule are important indicators of drug dissolution, absorption, and efficacy. Morphometric analysis of the pellets can indicate their absorption profile and efficacy. We aimed to assess the morphometric characteristics of commonly available brands of ITZ and compare them with those of the innovator brand as well as with each other.
| Materials and Methods|| |
This study was approved by the Institutional Review Board of our institution (approval number: BIMS-IEC/886/2020–21). We evaluated 30 brands of 100-mg formulations and 10 brands of 200-mg formulations of ITZ. First, a single capsule from a standard strip of each brand was opened, and the contents were emptied on a clean tray. After observing for the presence of any loose powder within the capsule, the pellets were counted manually [Figure 1]. Subsequently, we used a dermoscope (AM7013, VideoDermoscope, Dino-Lite Europe, Almere, The Netherlands) to evaluate the presence of dummy pellets based on ivory white appearance—instead of the pure white pellets—as well as the regularity of the surface [Figure 2]. Additionally, we randomly selected 50 pellets from capsules of each brand and evaluated the following parameters: the average size of 50 pellets of each brand, range of size, and the mean average variation in the sizes of all brands. Furthermore, we compared these parameters with those of the innovator brand. Lastly, we assessed the mean difference in the average size of the pellets between brands with different pellet counts (>500, 300–500, and <300 pellets per capsule) using analysis of variance [Figure 3]. P values < 0.05 were considered significant. Statistical analyses were performed using SPSS v. 21 (IBM Inc., Armonk, NY).
|Figure 1: The pellets were removed from the capsules, and the presence of powder was recorded|
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|Figure 2: The color of the pellets was observed for variations. Black arrowhead, dummy pellet|
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|Figure 3: The average pellet size and pellet count in 100-mg formulations|
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| Results|| |
The morphometric characteristics of the pellets in the 100-mg and 200-mg formulations are summarized in [Table 1] and [Table 2], respectively.
Results of 100-mg Formulations
The number of pellets per capsule ranged from 126 in brand #30 to 1010 in brand #1. The pellet count was >500 in 16/30 (53.3%) and 2/10 (20%) brands of 100-mg and 200-mg formulations, respectively, whereas it was 300–500 in 5/30 (16.6%) and 3/10 (30%) brands of 100-mg and 200-mg formulations, respectively. Additionally, the count was very less, <300, in 9/30 (30%) and 5/10 (2%) brands of 100-mg and 200-mg formulations, respectively.
The average size of the pellets in a capsule varied from 788 µm in brand #1 to 2343 µm in brand #30. The brands with more than 500 pellets per capsule had a lower average pellet size compared with those with less than 500 pellets per capsule [Table 3]. Brands #22, 23, 24, 25, 26, 27, 28, 29, and 30 had very large pellets (>1500 µm). Additionally, the pellet size in 18 brands (#1–17 and #21) was within 25% (up to 1243 µm) of that of the innovator brand. However, two of these brands (#17 and #21) had fewer than 500 pellets per capsule. A negative relationship was observed between the pellet count and average pellet size [Figure 4]. This is expected because a large number of small pellets can be filled within the fixed outer shell of the capsule. Furthermore, on comparing the brands grouped according to their pellet count (>500, 300–500, and <300 pellets per capsule), a significant difference was observed in the average pellet size between the first (>500 pellets) and third (<300 pellets) (P = 0.0001) as well as the second (300–500 pellets) and third (<300 pellets) groups (P = 0.002) [Table 3]. The difference between the smallest and the largest pellet was 1555 µm. Additionally, this range varied between brands as well; it was 788 µm in brand #1 and 2343 µm in brand #30. The loose powder was found in one brand (#23), and dummy particles were observed in 14 brands (#1, 4, 5, 7, 8, 13, 16, 18, 19, 21, 22, 26, 27, and 29).
|Table 3: Investigation of pellet size in brands grouped according to pellet count|
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|Figure 4: The mean variations in the size of various brands compared with the mean variation in size of the innovator brand|
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As of January 2021, 21/30 (70%) of the analyzed brands cost between Indian rupees (INR) 10–20 per capsule, whereas 6/30 (20%) brands cost more than INR 20 per capsule, and only 3/30 (10%) brands cost less than INR 10 per capsule. The mean size variation—the mean of the variation in the size of 50 individual pellets used to estimate the average pellet size—varied from 78.7 µm in brand #17 to 267 µm in brand #19. Furthermore, the mean size variation was <25% of that of the innovator brand in 12/30 (40%) brands, 25%–30% in 4/30 (13.3%) brands, and 30%–50% in four brands. However, the mean size variation in nine brands was more than 50% of that of the innovator brand [Figure 4].
Results of 200-mg Formulations
Of the 10 brands that were analyzed, six included dummy pellets, and none had loose powder. The pellet size ranged between 929 and 2305 µm, which was similar to the range in the 100-mg formulations. Additionally, there was a wide variation in the pellet number in relation to the pellet count [Figure 5]. The sizes of both 100-mg and 200-mg capsules of the same brands were almost the same [Figure 6]. No innovator brand was available to compare the mean size variations among the 200-mg formulations.
|Figure 5: The average pellet size and pellet count in 200-mg formulations|
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|Figure 6: The average size of 100-mg and 200-mg capsules of the same brand|
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| Discussion|| |
Our findings revealed that based on the criteria of ≥500 pellets per capsule and low size variability, only five brands (#3, 7, 10, 11, and 15) were comparable to the innovator brand. However, the number of pellets per capsule was the highest in the innovator brand.
Several factors affect the absorption and efficacy of ITZ. One of them is that ITZ requires gastric acid for dissolution and adequate absorption. Other factors that have been demonstrated to negatively affect the absorption and efficacy of ITZ are incomplete drug release and poor aqueous solubility., One study found that the relative bioavailability of generic ITZ, compared with that of the innovator brand, was only 3.5% ± 2.8% (range = 0.5%–8.2%)., Although there are several manufactural measures that can improve the bioavailability of ITZ, pelletization is the commonest one used by pharmaceutical manufacturers. Furthermore, variations in the gastric emptying time, as well as transit time, can be reduced with pellets, which in turn reduce the inter-patient and intra-patient variabilities.
The manufacturing of pellets is a time-consuming, expensive, and complicated process that requires strict quality control. At the elementary level, the number and size of the pellets in an ITZ capsule are the crucial visually assessable characteristics; therefore, they can be used as surrogate indicators of the quality of the respective formulation. The pellets in an ITZ capsule are made of sucrose or cellulose beads with an ideal size of 600–700 µm in diameter. Beads with diameter <600 µm cannot be coated uniformly, whereas those with diameter >700 µm result in a small surface area for drug dissolution. The beads are coated with a polymer mixture of the drug using a complex layering technique. Within a capsule, ITZ is present as a molecular dispersion in amorphous hydroxypropyl methylcellulose (HPMC) polymer. It has been reported that ITZ and HPMC should ideally be in a ratio of approximately 40:60. This ratio is based on the observations that a higher proportion of the drug may hamper its release, whereas a lower proportion may result in ineffectiveness and unstable binding. Lastly, in order to prevent agglutination of the formulation in the gut, a secondary coating of polyethylene glycol (PEG) 20000 is added.
A previous study reported that the dissolution rate of ITZ can be increased by increasing the number of pellets in a capsule. Therefore, a large pellet number can be achieved using smaller pellets, which was also observed in our findings. In this study, the average size of the pellets significantly increased from brands with >500 pellets to those brands with 300–500 pellets and <300 pellets [Table 3]. Brands #22–30 had unusually big pellets (1512–2343 µm), which resulted in a very low pellet count (126–227). Of the 30 brands evaluated in this study, 16, 9, and 5 brands had a pellet number of >500, <300, and 300–500, respectively. The difference in the sizes of the pellets was significant between the first and third as well as the second and third groups (P < 0.001 for both).
The quality of the manufacturing process can be estimated based on the variation in the size of individual pellets., Some of the factors that reflect poor quality control are the presence of inert dummy particles or powder within the capsule because these characteristics are not observed with the innovator brand. Low mean size variation of <95 µm reflects the optimum concentration of HPMC, which was observed with brands #3, 7, 10, 11, and 15 in this study., Consequently, variation in the size of individual pellets may be considered an indirect marker of optimal HPMC concentration that in turn affects the drug release and absorption. Therefore, clinicians can derive the approximate gastrointestinal absorption profile of a brand based on the variation in the size of pellets.
The cost of the ITZ varies widely between various brands. We found that certain brands with adequate parameters were cheaper than some poorly formulated ones. Additionally, a few multinational pharmaceutical brands included poor values of the measured factors, whereas a few indigenous brands demonstrated superior values in the same factors. Therefore, the cost of ITZ capsules alone is not a maker of their effectiveness. Of the 30 brands that were analyzed, six (20%) brands cost >20 INR per capsule and three (10%) brands cost <10 INR per capsule; however, a majority of the brands (21/30, 70%) cost 10–20 INR. Therefore, a 15-day course (100 mg per day) can approximately cost 196–1284 INR. However, in routine practice, the dosages as well as durations are much higher than the approved parameters. Furthermore, prescribing capsules of 200 mg and higher formulations may result in suboptimal responses; unfortunately, the Indian market is flooded with such formulations. The reason for the suboptimal response is that a larger capsule size is required for a 200‑mg formulation with the standard pellet size. However, changing the pellet size—by removing the PEG 20000 layer or modifying the drug–polymer ratio—results in unstable formulations and reduced bioavailability of the drug. According to our findings, brand #9 was the best brand because it cost <20 INR per capsule and included a good pellet count (>500), small pellet size (within 25% of that of the innovator brand), and small mean size variation (within 25% of that of the innovator brand). Although the innovator brand (brand 1) had the best values in most of the characteristics, it was also the most expensive one (57.5 INR per capsule).
Interestingly, maintaining the same pellet size and technology in 200-mg formulations as that in 100-mg formulations would require a much larger capsule size. However, our analysis of 10 brands of 200-mg formulations revealed that the capsule size was almost the same as that of 100-mg formulations [Figure 6]. Although six brands of 200-mg formulations included dummy pellets, the average size of the pellets was almost the same as that in 100-mg formulations. The variation in the pellet size was greater when compared with the corresponding variation in the pellet count, and none of them included any loose powder. However, there was no innovator brand to compare the mean size variation with. Therefore, any change in the capsule size by altering the manufacturing process would lead to unstable formulations with reduced bioavailability.
A dermoscope is an essential part of a dermatologist’s toolkit. Dermoscopic examination of various brands of ITZ can be performed easily in a clinic or an office. A simple exercise to determine the characteristics of different brands of the drug is to examine them using a dermoscope to identify variations in the size of pellets and the presence of dummy pellets and loose powder. A dummy pellet will be almost perfectly smooth with ivory white coating [Figure 2], which is easily visible in contrast with the ideal pellets. Therefore, this simple exercise can help dermatologists identify the surrogate efficacy of a brand by comparing these characteristics with those of the innovator brand. Therefore, the ideal choice of the brand of ITZ should contain pellets of ideal size and number at an affordable price and no dummy pellets or loose powder [Figure 7] and [Figure 8].
|Figure 7: Dermoscopic image demonstrating variations in size (solid arrow) and color (hollow arrow) of the dummy pellets|
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|Figure 8: Dermoscopic image demonstrating loose powder in a capsule of ITZ|
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This study included some limitations. First, the parameters of the capsules may vary based on the batch of production. However, we only evaluated one batch of brands, which may not accurately reflect their average parameters. Second, scientific parameters can be used to compare various brands more accurately, such as the layering technology, type of bead, type of base, variations in size using scanning microscopy, and polymer‑to‑drug ratio. We were unable to perform these assessments because they were beyond the scope of resources available. Additionally, we focused on using simple parameters that clinicians can evaluate themselves. However, we believe that our simple approach does provide some insights into the expected efficacy of the drug based on such surrogate markers.
In conclusion, we aimed to investigate the variations in the quality between a few commonly available ITZ brands using morphometric analyses. Our findings may be used to identify the optimal brands, which can be prescribed for the stipulated duration with reduced costs, increased compliance, and reduced drug resistance. Additionally, they demonstrate at least one of the reasons for recalcitrant dermatophytosis and its epidemic in India. It should be noted that only the 100-mg capsule formulations of ITZ have been approved by the US Food and Drugs Administration as well as the Drug Controller General of India/Central Drugs Standard Control Organisation,; therefore, formulations of higher doses (200 and 400 mg) may include inherent quality issues. Poor quality control was observed in the form of wide variability in the quality of the available 100-mg formulations. The pharmacokinetics of ITZ in the skin demonstrates that 100 mg is a sufficient dose; therefore, if ITZ pellets are manufactured according to the predefined parameters, it may be unnecessary to prescribe it in doses exceeding 100 mg/day.
The authors thank Dr. Ashwini G. S., Assistant Professor, Department of Community Medicine, BGS Global Institute of Medical Sciences, Kengeri, Bengaluru.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3]