eraga et al., nig. journ. pharm. sci., march, 2018, …eraga et al., nig. journ. pharm. sci., march,...

Eraga et al., Nig. Journ. Pharm. Sci., March, 2018, Vol. 17 No.1, P17-25

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A STUDY OF THE IN VITRO INTERACTION BETWEEN LUMEFANTRINE AND

SOME ANTACIDS AND EDIBLE CLAY

*1Eraga S.O., 2Osahon P.T., 1Mudiaga-Ojemu B.O., 1Ojo M.A. and 1Iwuagwu M.A

1Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, University of

Benin, Benin City, 300001, Nigeria. 2Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, University of Benin,

Benin City, 300001, Nigeria.

*Author for correspondence: [email protected], Tel: +2348030884928

ABSTRACT

There is a growing concern among clinicians and pharmacists of possible interactions between

artemether/lumefantrine combination therapy and antacids. This study was aimed at investigating the in vitro

interactions between lumefantrine and some adsorptive materials used as antacids. Adsorption studies to

determine the extent of adsorption of lumefantrine onto magnesium trisilicate, aluminium hydroxide,

magnesium hydroxide and edible clay was carried out. The effects of the adsorbents and a commercial antacid

preparation (Emtrisil®) on the disintegration time and dissolution profile of a commercial tablet brand

(Lumatem®) were also determined. The adsorption of lumefantrine onto the antacids and edible clay increased

as the concentration of the adsorbents was increased. Adsorption of the drug by the adsorbents followed the rank

order: aluminium hydroxide (99.90 %), > magnesium hydroxide (76.20 %), > magnesium trisilicate (73.21 %),

> edible clay (47.11 %). There was no appreciable increase in the disintegration times of the tablets in the

presence of the adsorptive materials, however there was retardation of dissolution. The rank order of dissolution

retardation was as follows: Emtrisil® > aluminium hydroxide > magnesium hydroxide > magnesium trisilicate >

edible clay. The concomitant administration of these adsorbents with tablets containing lumefantrine should be

discouraged to ensure therapeutic efficacy and reduce the potential for treatment failure.

Keywords: lumefantrine, adsorption, adsorptive antacids, edible clay, dissolution

INTRODUCTION

Lumefantrine is an antimalarial drug usually used in combination with artemether. The combination formulation is sometimes called co-artemether (Toovey et al., 2003). Lumefantrine has a much longer half-life compared to artemether and it is therefore thought to clear any basal parasites that are left after the combination therapy thereby preventing recrudescence (Ashley et al., 2007; Tarning et al., 2013). Amongst other anti-malarial combination therapies,

artemether and lumefantrine combination is one of the safest and effective in the treatment of chloroquine-resistant Plasmodium falciparum infection and a relatively high cure rate has been recorded even in areas where multi-drug resistance exists (Omari et al., 2004; Worldwide Antimalarial Resistant Network, 2015). It is typically not used as a prophylaxis and not administered parenterally. It has been known to be well tolerated in pregnancy and there is often no need to alter the dose in mild or

Nigerian Journal of Pharmaceutical Sciences Vol. 17, No1, 2018, ISSN: 0189-823X All Rights Reserved


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moderate kidney failure (Falade and Manyando, 2009).

Studies have shown that fatty meals have the capability to enhance the absorption of lumefantrine; and substances such as grapefruit juice that influence the activity of the liver enzyme CYP3A4 can influence the blood level of lumefantrine leading to severe side effects or reduced efficacy (van Agtmael et al., 1999; Ashley et al., 2007). Lumefantrine also possesses a dose-dependent absorption kinetics associated with decreasing oral absorption with increasing doses (Ashley et al., 2007). Studies have shown that blood lumefantrine levels are lower when administered concomitantly with lopinavir, ritonavir, efavirenz and nevirapine (Kredo et al., 2011; Askling et al., 2012; Kiang et al., 2013).

Antacids are over the counter (OTC) drugs that have the capability to neutralize stomach hyperacidity, aid in indigestion and also relieve heartburn in ulcer patients (Zajac et al., 2013). Antacids contain alkaline ions that chemically neutralize gastric acid thereby reducing damage to the stomach mucosa. Their co-administration with other drugs can alter the absorption or excretion of these drugs thereby reducing their plasma level and therapeutic effect and in some cases causing toxicity (Mejia and Kraft, 2009). Some studies have shown that antacids are capable of binding to drug in the gastrointestinal tract and thereby inhibiting the dissolution and absorption of the drug and resulting in reduced bioavailability (Granneman et al., 1992; Mersebach et al., 1999; Landmark and Patsalos, 2010; Poudel and Thapa, 2013).

Edible clays are consumed in Papua New Guinea as food because of its nutritive value and in some parts of West Africa, especially among pregnant females in preventing nausea and vomiting as well as in the

discomfort associated with hyperacidity (Iwuagwu and Aloko, 1992; Rowland, 2002). In recent times, they are gaining widespread use in alternative medicine as a detoxifying agent (Clark et al., 1998; Haydel et al., 2008). With the growing use of artemether/lumefantrine combination therapy in the treatment of malaria, clinicians and pharmacists are concerned of possible interactions on their co-administration with antacids or edible clays. The availability of little data addressing this concern has informed the need for this study. Therefore, this study is aimed at investigating any possible in vitro interaction of lumefantrine with some commonly used adsorptive antacids and edible clay with a view to determining the extent to which adsorptive materials affect the in vitro dissolution of lumefantrine.

MATERIALS AND METHODS

Materials Lumefantrine reference standard (Edo Pharmaceutical Ltd, Benin City, Nigeria), magnesium trisilicate, aluminium hydroxide, magnesium hydroxide powders, methanol and concentrated hydrochloric acid (BDH Chemicals Poole, U.K.), Emtrisil®

suspension (Emzor Pharma Ltd. Lagos, Nigeria), Lumartem tablets® (Cipla Ltd. Mumbai, India). Edible clay was purchased from New Benin market, Benin City, Edo State and processed in the Production Laboratory of the Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, University of Benin, Benin City.

Methods

Processing of the edible clay powder The edible clay powder used for the study was processed by breaking lumps of clay into small pieces and soaking in water for about 24 h. The water was decanted several times and replaced with fresh water to


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remove the salt content of the clay. The final wet mass was sun dried and then reduced to fine powder in an electric dry mill. The fine powder was then passed through a sieve of aperture size 0.125 mm (Eraga and Iwuagwu, 2012).

Preparation of calibration curve for lumefantrine Gradient dilutions of lumefantrine ranging from 1.0 - 30 µg/ml were prepared from a 1.0 mg/ml stock solution in 0.1 N HCl/methanol (1:9). The dilutions were subjected to spectrophotometric analysis (Spectronic 21D, Milton Roy, USA) at 234 nm against a blank of 0.1 N HCl/methanol (1:9). Their respective absorbances were plotted against concentrations to generate a line of regression and its equation.

Adsorption studies A series of five conical flasks containing 1.0 g of the antacids or edible clay was added about 80 ml of distilled water. From a 1.0 %w/v solution of lumefantrine previously prepared, five aliquots (0.5, 1.0, 2.0, 3.0 and 4.0 ml) were taken and added to the suspension in the five conical flasks, respectively. The suspensions were made up to 100 ml with sufficient distilled water, shaken and then placed in the water bath at 37 ± 0.5 °C and equilibrated for 4 h, with intermittent shaking. Preliminary experimentation had shown that equilibration is achieved in 2 h. After equilibration, the suspensions were centrifuged at 4000 rpm for 20 min (Techmel and Techmel, USA) and a 2 ml portion of the supernatant was made up to 100 ml with 0.1 N HCl/methanol (1:9) solution. The absorbance of the resultant solution was read in the spectrophotometer at 234 nm against a blank which was similarly prepared without drug (Babalola et al., 2012).

Evaluation of Lumartem® tablets Preliminary tests Preliminary evaluations of the commercial tablets following official protocols were carried out on the Lumartem® tablets (BP, 2009). The following tablet parameters were tested; tablet weight uniformity or variation, hardness, friability and content of active ingredients.

Disintegration time testing The disintegration times of each of ten Lumartem® tablets were determined in distilled water, 0.1 N HCl solution, suspensions of the adsorbents and a commercial product (Emtrisil®) at 37 ± 0.5 °C using a disintegration test unit (Mk IV. Manesty Machines Ltd, UK). The suspension disintegration media used in testing the effect of the adsorbents on the disintegration time of the tablets were prepared by adding 0.5, 1.0 and 2.5 g of the antacids/edible clay and 10, 15 and 20 ml of Emtrisil® to different 500 ml distilled water.

Dissolution studies The dissolution test of Lumartem® tablets was carried out in 900 ml of 0.1 N HCl maintained at 37 ± 0.5 °C using a BP dissolution test apparatus (Caleva ST7, GB Caleva. UK) fitted with a basket rotated of 100 rpm. The effect of the adsorbents on the drug dissolution was studied by adding 2.0 g of the adsorptive antacid or 20 ml of Emtrisil® to the dissolution medium. The effect of different concentrations of aluminium hydroxide on the drug dissolution was equally determined. Samples of 5 ml volume withdrawn at intervals were diluted with more 0.1 N HCl solution and centrifuged at 4000 rpm for 20 min. The concentration of drug in the supernatant was determined spectrophotometrically against a 0.1 N HCl blank at 234 nm. Equal volumes of fresh dissolution medium at 37 ± 0.5 °C were


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used to replace those withdrawn for analysis. Statistical analysis Data generated were subjected to descriptive statistics using Microsoft Excel (2007). Mean and standard deviations of triplicate determinations were computed and reported. Differences between mean was determined using ANOVA, while p ˂ 0.05 was considered significant.

RESULTS

The results of the adsorption studies showed appreciable adsorption of lumefantrine by all the adsorptive antacids and edible clay as shown in Figure 1. From the data obtained, the amounts of lumefantrine adsorbed per gram of the adsorbents increased with increase in lumefantrine concentration. The four adsorbents had different adsorption capacities in the order of aluminium hydroxide (99.90 %), > magnesium

hydroxide (76.20 %), > magnesium trisilicate (73.21 %), > edible clay (47.11 %). The results from the preliminary evaluations of the commercial tablets (Lumartem®) showed tablets of minimal weight variations (350.0 ± 0.5 mg), crushing strength or hardness (8.00 ± 0.67 kp), optimal friability values (0.42 ± 0.02 %) and drug content (100.50 ± 0.88 %). Table 1 shows the results from the disintegration time test of Lumartem® tablets in various media at 37 ± 0.5 °C. Rapid disintegration (less than 3.0 min) was observed even in the presence of the antacids and edible clay. There was no significant (p = 0.114) effect on the disintegration times of the tablets at the various concentrations of the adsorbents used when compared with disintegration times obtained using water or 0.1 N HCl solution.

Figure 1: Adsorption of lumefantrine onto magnesium trisilicate (), magnesium hydroxide

(▲), aluminium hydroxide () and edible clay ()


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Table 1: Disintegration times of Lumartem® tablets in various media at 37 ± 0.5 °C

Disintegration medium

Adsorbent concentration

(% w/v)

Disintegration time (min)

Water 0 0.20 ± 0.02 0.1 N HCl 0 0.26 ± 0.02

Magnesium trisilicate 0.10 0.39 ± 0.01 0.20 1.67 ± 0.03 0.50 2.45 ± 0.04

Magnesium hydroxide 0.10 0.36 ± 0.07 0.20 1.61 ± 0.02 0.50 2.30 ± 0.04

Aluminium hydroxide 0.10 0.31 ± 0.03 0.20 1.50 ± 0.05 0.50 1.95 ± 0.02

Edible clay 0.10 0.21 ± 0.02 0.20 0.51 ± 0.02 0.50 1.20 ± 0.06

*Emtrisil® 0.30 0.72 ± 0.03 0.45 1.89 ± 0.02 0.60 2.82 ± 0.04

± Standard deviation *Each ml of Emtrisil® contains 50 mg of magnesium trisilicate, 50 mg of magnesium carbonate and 50

mg of sodium bicarbonate.

The in vitro dissolution studies carried out in the presence of the adsorbent revealed a significant (p = 0.012) inhibitory effect on lumefantrine dissolution from the Lumartem® tablets as shown in Figure 2. The inhibition or retardation of dissolution can be seen in the different amounts of lumefantrine that was dissolved from the tablet within the time frame of the dissolution study. The inhibitory effect on dissolution followed the rank order of Emtrisil® > aluminium hydroxide > magnesium hydroxide > magnesium trisilicate > edible clay. The percentage amount of lumefantrine dissolved in 60 min also followed the same rank order with Emtrisil® (59.50 %) < aluminium hydroxide (62.76 %) < magnesium hydroxide (70.20 %) < magnesium trisilicate (72.80 %) < edible clay (80.92 %) as against 93.80 % in

0.1 N HCl solution. Magnesium trisilicate and magnesium hydroxide had almost the same inhibitory effect on lumefantrine dissolution.

Figure 3 shows the effect of different concentrations of aluminium hydroxide on lumefantrine dissolution. The result showed that the concentration of aluminium hydroxide affects the amount of lumefantrine dissolved. At higher antacid concentration, the inhibitory effect on drug dissolution was more pronounced i.e. the inhibitory effect increased with increased concentration of aluminium hydroxide.


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Figure 2: Dissolution profiles of Lumartem® tablets in magnesium trisilicate (), magnesium hydroxide () aluminium hydroxide (▲), edible clay (), Emtrisil® () and 0.1 N HCl ()

Figure 3: Dissolution profiles of Lumartem® tablets in various concentrations of aluminium

hydroxide suspensions (0 (), 0.1 (), 0.2 (▲), 0.5 () %w/v) in 0.1 N HCl. DISCUSSION

The adsorptive ability of antacids forms the basis of their use in medicine to neutralize stomach hyperacidity. It has been

established that adsorptive antacids possess the capability to adsorb certain drugs in the gastrointestinal tract, thereby limiting their absorption into systemic circulation and reducing their therapeutic efficacy


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(Landmark and Patsalos, 2010; Poudel and Thapa, 2013). A large surface area and availability of absorptive sites on the surfaces of powder particles have been implicated in determining the extent of adsorption (Eraga and Iwuagwu, 2012; Adediran et al., 2007). While some studies have reported aluminium hydroxide as having a greater surface area and number of adsorptive sites hence possessing a higher adsorption capacity than all the other adsorbents employed in this study (Iwuagwu and Aloko, 1992; Adediran et al., 2007), others have reported some disparities, attributing a superior capacity for adsorption to magnesium trisilicate (Eraga and Iwuagwu, 2012; Eraga et al., 2014). Based on the results from this study, it can be proposed that another factor, which is the nature of the adsorbate, may be playing a major role in determining the extent of adsorption. Although our results agree with the results of studies that concluded that aluminium hydroxide has a higher capacity for adsorption from its surface area and number of adsorptive sites, we can also add that a higher affinity of lumefantrine for the adsorptive sites on aluminium hydroxide resulting from the structural nature of the drug may have played a significant role to its high adsorption. The fact that magnesium trisilicate has been reported to be a superior adsorbent as a result of its positively charged silica moiety and hydrophobic nature further supports this theory of a higher affinity of lumefantrine for aluminium hydroxide (Depasse, 1978; Onyekweli et al., 2003). Also, the comparable adsorptive capacities of magnesium trisilicate and magnesium hydroxide is another pointer to the fact that lumefantrine affinity for these two antacids are similar in magnitude with all the adsorptive attributes of magnesium trisilicate having no advantage. However, it is expected that Emtrisil® should rank above

all the antacids and edible clay because of the combined adsorptive capacities of the three antacids contained in the formulation.

Results from the evaluation of the commercial Lumartem® tablets would imply tablets of acceptable quality as they complied with official BP specifications with regard to weight uniformity, hardness, friability and content of active (British Pharmacopoeia, 2009). All the tablets disintegrated within 3 min in the presence of the antacids, edible clay and the commercial antacids formulation (Emtrisil®) with no appreciable delays in their disintegration times. The fast disintegration of the tablets and the non-significant effect of the adsorbents on the disintegration times could be attributed to the super-disintegrants (croscamellose sodium and microcrystalline cellulose) incorporated in the tablet formulations (WHO Public Assessment Report, 2010).

Since the tablet disintegration times were not adversely affected by the adsorbents, it is expected that dissolution should follow immediately after disintegration. However, the dissolution profiles of the tablets in the presence of the adsorptive materials would suggest some level of inhibition or retardation of drug dissolution. The different propensities of the adsorbents to adsorb lumefantrine (Fig. 2) seemed to determine the amounts of lumefantrine dissolved from the tablets in the presence of the various adsorbents. These dissolution retardations resulting in reduction in the amounts of drug dissolved would suggest some form of interaction occurring between lumefantrine and the adsorbents forming a drug-adsorbent complex that made the drug unavailable for dissolution to occur (Babalola et al., 2012). There is a higher extent of dissolution inhibition exhibited by Emtrisil® which could be the result of combined effects of the antacids (magnesium trisilicate,


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magnesium carbonate and sodium bicarbonate) contained in the formulation. Also, the varying amounts of lumefantrine dissolved at varying concentrations of the adsorbents showed a direct relationship between antacid concentration and the amount of lumefantrine dissolved (Fig. 3). Therefore, higher doses of the adsorbent would also imply a higher level of drug adsorption with lesser drug available for systemic absorption in the gastrointestinal tract. Some studies have shown similar interactions occurring between artemether/ lumefantrine combination products and antiretrovirals and a dose adjustment or an adequate dosing intervals have been suggested to augment the low plasma levels of lumefantrine resulting from their co-administration (Kredo et al., 2011; Byakika-Kibwika et al., 2012; Hoglund et al., 2014).

CONCLUSION

The study has revealed the evidence of a significant amount of lumefantrine adsorbed onto the studied antacids and edible clay. Even though there were no significant delays in the disintegration times of the Lumartem® tablets used in the study in the presence of the adsorbents, their dissolution retardation potential is a cause for concern in therapeutics. Therefore, the concurrent administration of these adsorbents with tablets containing lumefantrine should be discouraged to ensure therapeutic efficacy and reduce the potentials for the development of resistance by the plasmodium parasite.

Acknowledgement The authors acknowledge the technical support received from the laboratory staff of the Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, University of Benin, Benin City.

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eraga et al., nig. journ. pharm. sci., march, 2018, …eraga et al., nig. journ. pharm. sci., march,...

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