Design and Evaluation of Clove Oil-Based Self-Emulsifying Drug Delivery Systems for Improving the Oral Bioavailability of Neratinib Maleate

Abstract

Neratinib maleate (NM), a tyrosine kinase inhibitor, is used in the treatment of breast cancer. NM is orally administered at a high dose of 290 mg due to its low solubility and poor dissolution rate at pH > 3, as well as gut-wall metabolism limiting its bioavailability. Self-emulsifying drug delivery systems (SEDDSs) of NM were developed in the current study to improve its oral bioavailability. The oily vehicle (clove oil) was selected based on the solubility of NM, while the surfactant and the cosurfactant were selected based on the turbidimetric analysis. Three different sets were screened for surfactant selection in the preparation of SEDDS formulations, the first set containing Cremophor^® EL alone as the surfactant, the second set containing a mixture of Cremophor^® EL (surfactant) and Caproyl^® PGMC (cosurfactant), and the third set containing a mixture of Cremophor^® EL (surfactant) and Capmul^® MCM C8 (cosurfactant). Propylene glycol was used as the cosolubilizer in the preparation of SEDDSs. A series of studies, including the construction of ternary phase diagrams to determine the zone of emulsification, thermodynamic stability studies (involving dilution studies, freeze-thaw, and heating–cooling studies), turbidimetric analysis, and physicochemical characterization studies were conducted to identify the two most stable combinations of SEDDSs. The two optimized SEDDS formulations, TP16 and TP25, consisted of clove oil (45% w/w) and propylene glycol (5% w/w) in common but differed with respect to the surfactant or surfactant mixture in the formulations. TP16 was prepared using a mixture of Cremophor^® EL (surfactant) and Caproyl^® PGMC (cosurfactant) in a 4:1 ratio (50% w/w), while TP25 contained only Cremophor^® EL (50% w/w). The mean globule sizes were 239.8 ± 77.8 nm and 204.8 ± 2.4 nm for TP16 and TP25, respectively, with an emulsification time of <12 s for both formulations. In vitro drug dissolution studies performed at different pH conditions (3.0, 4.5, 6.8) have confirmed the increase in solubility and dissolution rate of the drug by TP16 and TP25 at all pH conditions compared to plain NM. An oral pharmacokinetic study in female Wistar rats showed that the relative bioavailability (Frel) values of TP16 and TP25 over the plain NM were 2.18 (p < 0.05) and 2.24 (p < 0.01), respectively.

Introduction

A new class of drugs that bind irreversibly to the adenosine triphosphate binding pocket of the human epidermal growth factor receptor (HER) has emerged in recent years. Epidermal growth factor receptors (EGFR, HER1, or ErbB1), HER2 (ErbB2, neu), HER3 (ErbB3), and HER4 (ErbB4) are the four members of the HER (ErbB) receptor tyrosine kinase family. Numerous cancer types have been linked to the overexpression, mutation, or abnormal activity of these receptors. Neratinib maleate (NM) is a type of tyrosine kinase inhibitor that is used for the treatment of breast cancer. It is also known as a pan-HER inhibitor due to its ability to bind to three of the four mentioned HER receptors, except for HER 3 [1]. NM is marketed under the brand name “Nerlynx” and has a high oral dose of 290 mg because of its low and variable oral bioavailability (BA) of 11–39%. In clinical settings, NM is administered through the oral route as six mini tablets with a total dose of 290 mg. The oral dose of NM is divided into six mini tablets to facilitate dose titration in patients experiencing dose-dependent gastrointestinal side effects such as severe diarrhea. The oral dose of NM is decreased by reducing one tablet (out of the initial six tablets at the start of therapy) at a time until the patient can cope with gastrointestinal side effects. At less than 120 mg, i.e., three tablets, discontinuation of therapy is recommended. Since NM is recommended as chronic therapy for one year, the dose-dependent side effects make it difficult to continue the medication due to patient discomfort, thereby resulting in noncompliance with the therapy [2,3]. Reducing the oral dose of NM by improving its oral absorption can alleviate the dose-dependent side effects of NM, increase patient comfort, and improve compliance with the therapy.

NM is a highly lipophilic drug with a Log P of 4.7. It exhibits pH-dependent solubility in the pH range of 1.2 to 7.4. It has good solubility under low pH conditions, with a saturation solubility (Cs) of 100 ± 1 and 22 ± 0.5 mg/mL at pH 1.2 and 3.5, respectively. The solubility of NM decreases significantly as the pH increases. The drug is insoluble at pH 6 (Cs = 90 μg/mL) and above. The low and variable oral BA of NM is primarily due to its poor solubility in intestinal pH conditions and extensive CYP3A4-related metabolism in the gut wall during its intestinal absorption process. To address the problems associated with the available conventional therapy, researchers have designed a few modified or novel drug delivery systems. Fadilah S.A. et al. developed neratinib-loaded polyamidoamine dendrimer nanocapsules coated with trastuzumab to target breast cancer cells. The researchers could increase the drug concentration at the site of action and decrease its cytotoxicity with the nanocapsules compared to the conventional formulation of neratinib [4]. Mohamed R. et al. designed effervescent floating tablets of neratinib to enhance the solubility and residence time of the drug in the upper GIT and, thereby, the oral bioavailability [5]. Our research group has made efforts to enhance the oral BA of NM and thereby reduce the dose and dose-dependent side effects using lipid-based drug delivery systems (LBDDS). To date, no LBDDS has been explored for the treatment of breast cancer with NM. The current research aims to improve the solubility, dissolution rate, and oral absorption properties of NM.
Self-emulsifying drug delivery systems (SEDDSs) are LBDDS that are capable of dissolving and delivering large doses of lipophilic drugs in solubilized form. A SEDDS contains oil, a surfactant, and a cosurfactant or cosolubilizer. Several approved marketed formulations showcase the translational capabilities of SEDDSs which include Agenerase® (amprenavir) by Glaxo Group, United Kingdom; Depakene® (valproic acid) by AbbVie Inc., IL, USA; Rocaltrol® (calcitriol) by Validus Pharmaceuticals, NJ, USA; Vesanoid® (tretinoin) and Accutane® (isotretinoin) by Roche, Basel, Switzerland; and Aptivus® (tipranavir) by Boehringer Ingelheim, Rhein, Germany, etc. [6,7,8,9]. These systems rapidly form an emulsion upon dilution with water [10]. Suppose the sizes of the globules formed by the SEDDSs in the emulsion are >1 µm or between 0.1 µm and 0.8 µm. In that case, the SEDDSs are classified as self-microemulsifying drug delivery systems (SMEDDS) or self-nanoemulsifying drug delivery systems (SNEDDS), respectively. During the digestion process, gastric lipase in the stomach partially digests lipid components, whereas pancreatic lipase in the small intestine completes the digestion of lipids. The bile salts and cholesterol secreted as a part of the bile secretions through the biliary duct into the duodenum help in the micellar solubilization of the lipophilic drug. These micelles prevent drug precipitation and keep the drug in a solubilized form for the entire course of absorption in the gastrointestinal tract (GIT). The SEDDS formulations are reported to enhance the solubility, dissolution rate, and BA of lipophilic drugs such as atorvastatin, naringenin, cefpodoxime, and talinolol [11,12,13,14].

The objective of the current research was to design and optimize NM-loaded SEDDSs to improve the oral BA of the drug. The components used in the formulations were finalized scientifically. The NM-loaded SEDDSs were characterized for physicochemical properties, in vitro drug release, and stability to identify the optimized formulation with the desired characteristics. Finally, oral pharmacokinetic studies were conducted in Wistar rats to determine the efficacy of the optimized NM-loaded SEDDSs over the conventional formulation of NM in improving the BA of the drug.

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Materials

Neratinib maleate (NM) and Rufinamide (internal standard in the bioanalytical method) were obtained from MSN Laboratories Pvt. Ltd. (Hyderabad, India) and Dr. Reddy’s laboratories (Hyderabad, India), respectively. Excipients like Gelucire® 59/14 (Mixture of Lauroyl Polyoxyl-32 glycerides and PEG 6000), Gelucire® 44/14 (Lauroyl polyoxyl-32 glycerides), Gelucire® 48/16 (Polyoxyl-32 stearate (type I)), and Lauroglycol™ FCC (Propylene glycol monolaurate (type I, monoesters > 45%)), and solubilizing solvents such as Transcutol® (diethylene glycol monoethyl ether) and Labrasol® (Caprylocaproyl macrogol-8 glycerides) were generously gifted by Gattefosse (Mumbai, India). Capmul® MCM C8 (propylene glycol monolaurate) and Capryol® PGMC (Propylene Glycol Mono and Dicaprylate) were gift samples from Abitec corporation (Columbus, OH, USA). Additionally, BASF provided kind support by providing Cremophor® EL (Polyethoxylated castor oil). A variety of essential oils were purchased from Naturalis (Leiden, The Netherlands), RM Herbals (Chennai, India), and Natures Natural (Ghaziabad, India). Clove oil and glacial acetic acid were procured from Sisco Research Laboratories, Pvt. Ltd. (Mumbai, India). Citric acid, sodium chloride (NaCl), and various buffer salts were obtained from SD Fine Chemicals Pvt. Ltd. (Mumbai, India). HPLC grade solvents acetonitrile (ACN) and methanol (MeOH) were purchased from Qualigens Pharma Pvt. Ltd. (Mumbai, India). Filtered Milli-Q water was obtained from our institute’s central Millipore (Millipore®, Bedford, MA, USA) unit facility. Female albino Wistar rats were procured from Vyas Biosciences (Hyderabad, India). Isoflurane (anesthesia) was obtained from UMA Enterprises (Hyderabad, India).

Mahajan, R.R.; Ravi, P.R.; Marathe, R.K.; Dongare, A.G.; Prabhu, A.V.; Szeleszczuk, Ł. Design and Evaluation of Clove Oil-Based Self-Emulsifying Drug Delivery Systems for Improving the Oral Bioavailability of Neratinib Maleate. Pharmaceutics 2024, 16, 1087. https://doi.org/10.3390/pharmaceutics16081087

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