Mesoporous silica-based amorphous solid dispersions to enhance the oral bioavailability of Neratinib maleate

Neratinib maleate (NM) used in the treatment of breast cancer, has a low and variable oral bioavailability due to its pH-dependent solubility and gut-wall metabolism-restricted permeability. Mesoporous silica based solid dispersion of NM (SD-NM-MSi) was designed to improve its solubility and dissolution rate. SYLOID XDP 3050 was selected as a mesoporous silica carrier based on its higher drug loading (15.7 %) and good flow properties. The extensive surface area of the Mesoporous silica offered a suitable site for drug adsorption. Thermal and diffractometry analysis indicated that NM was adsorbed in an amorphous form. In vitro dissolution studies revealed that the optimized SD-NM-MSi showed a higher rate and extent of drug dissolution compared to plain NM in pH 3.0, pH 4.5, and 6.8, respectively. Similarly, an oral pharmacokinetic study (10 mg/kg) resulted in significantly higher plasma exposure for SD-NM-MSi compared to plain NM, with a 73% (P<0.01) increase in the relative oral bioavailability of NM.

Highlights

• Neratinib maleate (NM) exhibits low oral bioavailability due to its limited solubility in pH > 5.
• Higher doses of NM administered through oral route causes severe gastro-intestinal side effects.
• SYLOID based solid dispersions of NM (SD-NM-MSi) were prepared by solvent evaporation technique.
• Manufacturing process was optimized to increase drug loading and amorphization of the drug.
• SD-NM-MSi were characterized by DSC & pXRD to confirm the amorphization of the NM.
• Amorphization of drug and higher surface area increased drug dissolution at all pH conditions.
• SD-NM-MSi enhanced the oral bioavailability 1.73 times compared to plain NM.

Introduction

New advancements in drug design and synthesis are helping researchers to discover drug molecules that are pharmacologically more potent and efficacious. However, these molecules have significant issues concerning their aqueous solubility, dissolution rate, and intestinal permeability [1]. The oral route is the most widely accepted and patient-compliant route for drug delivery. The new chemical entities entering the market have poor oral bioavailability due to their solubility and permeability issues. Designing oral formulations for drugs with solubility and permeability issues (particularly BCS Class II and IV molecules) is a challenging task [2]. Neratinib maleate (NM), a tyrosine kinase inhibitor, used in breast cancer treatment, has low aqueous solubility and intestinal permeability. NM is known to exhibit pH-dependent solubility. It is highly soluble in the pH between 1-3, sparingly soluble in the pH between 4-6, but insoluble at and above pH 6. Due to these solubility issues and low permeability, NM has less and variable oral bioavailability ranging from 11% to 39% [3]. The recommended oral dose of NM is ∼290 mg (equivalent to 240 mg of neratinib) once daily. The dosing regimen for patients included 6 tablets containing 40 mg at every dose. The therapy has severe dose-dependent gastrointestinal side effects, including Grade III and IV diarrhea. The dose of NM can be scaled down to a minimum of 120 mg (by reducing the number of tablets) until patients can tolerate the drug dose with minimal gastrointestinal side effects. Despite good therapeutic efficacy, the use of this drug has become limited due to its adverse local side effects [4]. Recently, the US FDA approved a prescription treatment with loperamide to reduce the severity of diarrhea in patients receiving NM. However, concomitant therapies are complex to administer. These limitations of the existing treatment create the scope for developing new formulation strategies to improve and reduce the variability in the oral absorption properties of NM. This increase in bioavailability will certainly help to reduce the dose and, thereby, the dose-dependent gastrointestinal side effects, and it will also prevent the need for simultaneous administration of additional drug therapies [5].

Currently, mesoporous silica (MSi), which is widely used as an excipient for tablet manufacturing, has also been repurposed as a carrier for the adsorption of drugs, oils, viscous liquids, etc. [6], [7], [8]. The solubility and dissolution rate of drugs having poor aqueous solubility and high doses can be efficiently resolved using these carrier systems. There are two principles by which this phenomenon occurs: one is due to the conversion of the crystalline form of the active ingredient into an amorphous form, and the other is a larger effective surface area, which is the addition of both the external surface area and the internal pore structure surface area. Based on the size of the pore structure, the powders of silica are classified into three different types, viz. microporous (< 2 nm), mesoporous (2-50 nm), and macroporous (>50 nm) [9], [10]. Smaller pore diameters increase the surface area, whereas small pore diameters restrict the movement of the drug molecules, making it difficult for the drug to change its polymorphic form. The effective surface area might get compromised with larger pore diameters, but they provide free movement for the drug molecules and, hence, better adsorption. MSi offers higher percentages of drug loadings (% DL) for poorly water-soluble drugs [11], [12].

There are commercially available MSi of different grades based on pore size, pore volume, and particle size. Each of them has a considerable effect on the total surface area of the powder and, hence, the dissolution extent and rate achieved by using them. MSi is the best carrier system for increasing the solubility and dissolution rate, with proven evidence in the available literature. Additionally, with good flowability, these drug-loaded carriers can be used in patient-compliant dosage forms such as tablets and capsules [13], [14]. Different methods of manufacturing solid dispersions include solvent evaporation, spray drying, supercritical fluid extraction, and hot melt extrusion. The selection of the manufacturing process impacts the final product characteristics. The extent of the conversion of the crystalline to the amorphous form depends on the process, selection of the solvent, solvent volume, and, most importantly, selection of the carrier [15], [16].

In this research, we employed MSi of various grades under the trade name SYLOID (W. R. Grace, Columbia, MD, USA) to improve NM’s solubility and dissolution rate and increase its oral bioavailability. Based on their particle sizes, we chose three different grades of SYLOID MSi, including SYLOID 244FP, SYLOID XDP 3050, and SYLOID XDP 3150. With preliminary studies including % DL capacity and dissolution rate. Further, we selected one of the three grades for additional investigation to create the ideal solid dispersion with NM-loaded mesoporous silica (SD-NM-MSi). Furthermore, physicochemical characterization was performed, including surface area and pore volume determination, in vitro dissolution studies, and in vivo pharmacokinetic studies. An increase in bioavailability because of improved solubility or dissolution is anticipated to aid in lowering the dose and, consequently, the dose-dependent adverse effects on the GI tract.

Read more here

Materials

Neratinib maleate (NM) and rufinamide (internal standard in the bioanalytical method) were obtained as gift samples from MSN Laboratories Private Limited and Dr. Reddy’s Laboratories (Hyderabad, India), respectively. Different grades of MSi, such as SYLOID 244 FP, SYLOID XDP 3050, and SYLOID XDP 3150, were provided by W. R. Grace & Company (Columbia, MD, USA) as gift samples. Citric acid, NaCl, and various buffer salts were purchased from SD Fine Chemicals Private Limited (Mumbai, India).

Radhika R. Mahajan, Punna Rao Ravi, Mesoporous silica-based amorphous solid dispersions to enhance the oral bioavailability of Neratinib maleate, Journal of Drug Delivery Science and Technology, 2024, 106157, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.106157.

Read also our introduction article:

CPHI Milan 2024 – with a focus on excipients