**1. Introduction**

Medications are introduced into the human body through various drug delivery routes. For example, administered orally (by mouth), intravenously, intramuscularly, or breathed into the lungs (inhaled). The oral route remains the most popular way of drug administration [1]. In fact, it is the most preferred route by patients due to the ease of self-administration, pain avoidance, and cost-effectiveness. Some other advantages are that the oral ingestion route provides, for the patients, the least amount of sterility constraints, the minimal possibility to introduce systemic infection as a complication of treatment, the versatility to accommodate various types of drugs, and, most importantly, high patient compliance. Hence, it is the most employed route of drug delivery [2,3]. However, an orally administered drug must reach its target site at a concentration sufficient to induce

**Citation:** Aljubailah, A.; Alqahtani, S.M.S.; Al-Garni, T.S.; Saeed, W.S.; Semlali, A.; Aouak, T. Naproxen-Loaded Poly(2-hydroxyalkyl methacrylates): Preparation and Drug Release Dynamics. *Polymers* **2022**, *14*, 450. https://doi.org/10.3390/ polym14030450

Academic Editors: Ariana Hudita and Bianca Galˇ a¸ˇteanu

Received: 30 December 2021 Accepted: 20 January 2022 Published: 23 January 2022

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the desired therapeutic effect. The term "bioavailability" refers to the fractional extent to which an administered dose of drug reaches its site of action or bloodstream from which the drug has access to finally reach its site of action [4,5]. Although the definition applies to any route of administration, practically-speaking the term is usually used for the oral route [6]. A severe drawback of oral ingestion of drugs is the limited absorption of some drugs due to their physical characteristics (e.g., poor aqueous solubility and low membrane permeability) [4]. According to the biopharmaceutical industry, all drugs must meet certain minimal requirements to achieve clinical effectiveness. More than 40% of newly discovered chemical entities entering the drug development pipeline fail to reach therapeutic range due to their poor water solubility, which in turn influences the absorption of the drug from the gastrointestinal tract, thereby leading to low bioavailability [7]. Among the severe drawbacks of oral drug administration is that, in some cases, a significant portion of the drug is destroyed in the stomach (very acidic pH) before reaching the intestines (neutral pH) where it will be absorbed, and, therefore, additional amounts of drug are required to reach the therapeutic threshold, not to mention the side effects that can cause fragments resulting from the degradation of these drugs. Other medications cause direct irritation to the gastric mucosa due to the inhibition of prostaglandins and prostacyclins and thus causes ulceration, epigastric distress, and/or hemorrhage [8]. In order to minimize these inconveniences, several authors have run towards the encapsulation of these drugs in the form of intelligent systems labeled as "drug-carrier" acting according to the environment where they are found. Sustained release of aspirin formulation would reduce the undesired side effects, reduce frequency of administration, and improve patient compliance [9]. Zheng et al. [10] investigated the ibuprofen/montmorillonite intercalation composites as the drug release system, and the in vitro results revealed that the release of ibuprofen from this system was affected by the pH value of the dispersion. The release rate in simulated intestinal fluid (pH = 7.4) was noticeably higher than that in simulated gastric fluid (pH = 1.2).

Polymers have played a key role in the advancement of drug delivery technology. The "in vitro" release of ibuprofen was also investigated by Carreras et al. [11]. These authors encapsulated this drug by poly(ε-caprolactone) using the solvent casting method. The results obtained revealed that the system has low homogeneity in particle size distribution, with a particle size average of 846.9 nm, and, therefore, they are microspheres. Mangindaan et al. [12] developed a controlled release system composed of surface modified porous polycaprolactone (PCL) membranes combined with a layer of tetraorthosilicate (TEOS)–chitosan sol–gel. The drugs chosen in this investigation were silver-sulfadiazine (AgSD) and ketoprofen, which were impregnated in the TEOS–chitosan sol–gel, and the results obtained revealed that the release of AgSD on O2 plasma-treated porous PCL membranes was prolonged when compared with the pristine sample. On the contrary, the release rate of ketoprofen revealed no significant difference on pristine and plasma-treated PCL membranes. Diclofenac sodium(DS) combined with an electrospinning nano-andnanofiber (DS-NNEM) mesh of polycaprolactone (PCL)-chitosan (CH) prepared by the electrospinning technique was the subject of a controlled release study of soluble DS in water [13]. Because of the very slow degradation of nanofiber mats, these authors suggested that DS is released either by diffusion or by permeation through DS-NNEMs structure. In summary, the results suggest that NNEMs technology can potentially serve as a biomimetic platform for loading and the sustained release of biologically active therapeutic compounds and other drugs for prolonged periods.

Naproxen (NPX), also known by its trade name "Proxen" (Scheme 1), belongs to the family of aryl propanoic acids such as ibuprofen, ketoprofen and diclofenac. This medication is a potent nonsteroidal anti-inflammatory drug (NSAIDs) that is used to treat acute pain, inflammation, as well as pain related to arthritis and rheumatic diseases [14,15]. However, the pharmaceutical applications of Naproxen is hampered by its poor water solubility [16]. Naproxen is a weak acid drug (pKa 4.2) that belongs to BCS class II drugs. It is a highly lipophilic drug (log P 3.18) with an aqueous solubility of 0.0159 mg·mL−<sup>1</sup> at 25 ◦C [15,17].

**Scheme 1.** Chemical structure of Naproxen.

Among the polymers that have attracted the attention of many researchers in the biomedical field, poly(2-hydroxyethyl methacrylate)(pHEMA) was found as a suitable compatible biomaterial [18,19] and a good candidate for drug delivery [20–26] and bone implantation [27–30]. This material can be prepared by bulk polymerization with low water content or by suspension polymerization to form microbeads [31,32]. pHEMA is usually reported to be biocompatible but less biodegradable [33]. However, for oral administration of this polymer, it must not be biodegradable.

Although pHEMA has been extensively studied in the biomedical field, its analog with additional methyl group, poly (2-hydroxypropyl methacrylate)(pHPMA) is very little known in this field. Therefore, it will be curious to know the reasons why this polymer has not been able to place itself among polymers selected as potential candidates as a carrier in drug delivery or as scaffolds used in the biomedical field.

In order to have an idea on the performance of pHPMA in the drug release domain, a comparative study on the effect of the 2-hydroxyalkyl methacrylate substituent on the release dynamics of Naproxen from the Naproxen/poly (2-hydroxyalkyl methacrylate) drug carrier system was carried out. To reach this goal, two series of composites involving Naproxen combined with pHEMA and Naproxen combined with pHPMA as polymer composites were prepared with different compositions by solvent casting route. The distribution of NPX particles in the resulted systems were studied by FTIR, DSC, XRD, and SEM methods, while the cell viability and the cell adhesions were examined by MTT test and LDH essay. A comparative study of the efficiency of these two drug carrier systems was carried out on the release dynamic of Naproxen by varying different parameters that affect the release performance of NPX, such as the percentage of medication incorporated in the polymer matrix and the pH media. The improvement in the solubility of Naproxen in the different pH media was also deduced from the release process.

#### **2. Materials and Methods**

#### *2.1. Chemicals*

HEMA (purity, ≥99%), HPMA (purity, ≥99%), and AIBN (purity, 98%) were provided by Sigma Aldrich (Taufkirchen, Germany). Proxen tablets manufactured by GRUNEN-THAL were purchased from Riyadh Pharma (Saudi Arabia). Monomers were purified from hydroquinone (inhibitor) by distillation under reduced pressure. AIBN was purified three times by dissolution and recrystallization in ethanol. Human oral cancer cell line Ca9-22 cells were obtained from the laboratory of Dr. Abdelhabib Semlali (GREB–laval University, Quebec City, QC, Canada). RPMI-1640 medium was purchased from ThermoFisher (Burlington, ON, Canada), and the fetal bovine serum (FBS, Gibco) and 1% penicillin/streptomycin solution were from Sigma Aldrich (St. Louis, MO, USA).
