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Development of polymeric IPN hydrogels by free radical polymerization technique for extended release of letrozole: Characterization and toxicity evaluation

  • Hammad Yousaf , Ikrima Khalid EMAIL logo , Kashif Barkat , Yasir Mehmood , Syed Faisal Badshah , Irfan Anjum , Hiba-Allah Nafidi , Yousef A. Bin Jardan and Mohammed Bourhia EMAIL logo
Published/Copyright: November 14, 2023
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e-Polymers
From the journal e-Polymers Volume 23 Issue 1

Abstract

This research study’s objective was to formulate interpenetrating pH-sensitive polymeric networks interpenetrating networks (IPNs) based on hydroxypropylmethylcellulose (HPMC)/Primojel for use in the treatment of various malignant conditions. For controlled release, letrozole (LTZ) was selected as a model drug in HPMC and Primojel-based IPN hydrogels. HPMC and Primojel based IPN hydrogels were fabricated through the free radical polymerization method by utilizing HPMC and Primojel as polymers, methacrylic acid as monomer, ammonium persulfate as initiator, and methylenebisacrylamide as cross-linker. For structural characterization, various techniques such as Fourier transform infrared spectroscopy, Scanning electron microscopy (SEM), DSC, TGA, and Powder x-ray diffraction (PXRD) were applied to IPN samples. In vitro and swelling studies were also employed to observe the response of these polymeric networks against 1.2 and 7.4 pH. TGA and DSC of an optimized loaded formulation possess better thermal stability as compared to individual drug. PXRD depicted minor crystallinity and a significant amorphous nature. SEM images show that polymeric networks possess an uneven and porous surface. Significant swelling and enhanced in-vitro outcomes at a high pH of 7.4 confirmed the IPN pH responsive properties. Toxicological studies performed on rabbits revealed no harm in the results. Thus, IPN based on HPMC/Primojel was successfully synthesized and can be used for LTZ’s controlled release.

Keywords: letrozole; primojel; interpenetrating networks; pH-responsive; hydrogels

1 Introduction

Researchers have developed numerous innovative drug delivery systems (DDSs) that utilize advanced technologies to deliver therapeutic substances. The goal of these systems is to deliver active agents to specific locations at controlled rates, ensuring that the active ingredients remain within the desired therapeutic range (1). Some promising DDSs include liposomes, nanoparticles, dendrimers, niosomes, microspheres, microneedles, micelles, and hydrogels. Among these, hydrogel interpenetrating networks (IPN) have been particularly successful due to their hydrophilic polymeric properties (2). IPN is better than simple hydrogels due to its enhanced mechanical strength and improved stability. Hydrogels’ polymeric network contains a variety of functional groups, including carboxylic, amino, and hydroxyl, which give the hydrogels their unique properties. The therapeutic potential of active drugs can be greatly impacted by the means of delivery. Over the past few decades, polymeric network carriers have gained substantial attention because of reported possible alterations within their polymeric network systems resulting in the targeted and appropriate controlled release of the loaded active moiety. Moreover, the polymeric network of such systems holds the capability to accommodate the active moiety within the therapeutic range (3). Responsive hydrogels have been proved to be one of the crucial DDSs among various types of polymeric DDSs. These have been successful in delivering a variety of therapeutic agents for both diagnostic and therapeutic reasons, including genes for diagnosis and tissue-engineering. They are sensitive to chemical, physical, and biological stimuli (4). pH-responsive hydrogels have been particularly effective in monitoring the delivery of therapeutic agents due to variations in body pH during normal and disease states (5). Several pH-sensitive polymeric systems, such as interferon α, insulin, doxorubicin, dexamethasone, and Letrozole (LTZ), have been developed to treat cancer, diabetes, and ophthalmologic conditions. Yousaf et al. prepared a pH-sensitive PVP/hydroxypropylmethylcellulose (HPMC)-based IPN hydrogel using methacrylic acid (MAA) for the controlled release of LTZ (6). Utilizing advanced theranostic technologies can lead to dwindle mortality rates associated with cancer (7). LTZ is a specific anticancer drug used to prevent and cure breast cancer (BC). LTZ, a non-steroidal competitive aromatase enzyme system inhibitor, prevents androgen conversion to estrogen. The gastrointestinal system entirely and quickly absorbs LTZ (8). However, LTZ is known to cause side effects such as hair loss, hot flashes, muscle and bone pain, joint stiffness, exhaustion, sweating, dizziness, nausea, sleep disturbances, weight gain, constipation, headaches, numbness, diarrhea, drowsiness, tingling, weakness, and stiffness in the hands and fingers (9). The design of such carriers and release systems helps to maintain an adequate therapeutic LTZ level within the body, which ultimately leads to the elevated success of these delivery systems. Due to its unique properties, LTZ is perfect for hydrogel loading. By creating and improving their controlled drug delivery method based on magnetic molecularly imprinted nanoparticles, Kazemi and Sarabi have demonstrated their ability to reduce the side effects of LTZ (10). Radwan et al. (11) have also demonstrated improved its therapeutic efficacy of LTZ by loading it into PLGA nanoparticles which resulted in controlled drug release and minimized side effects. Controlled release hydrogel blends majorly incorporate discrete natural polymers. Primojel (sodium starch glycolate) is the cross-linked carboxymethyl starch sodium salt. There are two modifications in Primojel obtained from starch. The first one is substitution which result in increased hydrophilicity and second is crosslinking which leads to reduce water solubility and gel formation (12). When in contact with a solution, the sparingly water-soluble polar polymer HPMC expands and forms a gel mass (13). Additionally, MAA is a hydrophilic polymer. MAA gets ionized and deionized in response to pH which is further due to having carboxylic acid (−COOH) in its structure. This uniqueness further leads to swelling within water (14). In current research, various ratios of Primojel, HPMC and MAA were chemically crosslinked through crosslinker (N,N-methylene bisacrylamide) to formulate pH responsive HPMC and Primojel based IPN hydrogels. These IPN hydrogels were synthesized to deliver loaded model drug (LTZ) in controlled release manner.

2 Materials and methods

2.1 Materials

LTZ was obtained as gift from Novartis Pharma Private Limited Karachi, Pakistan. Primojel, HPMC and MAA were purchased from Sigma Aldrich Chemie GmbH, Steinheim, Germany. Ammonium persulfate (APS), N,N-methylene bisacrylamide (MBA), potassium dihydrogen phosphate, sodium hydroxide, potassium chloride and hydrochloric acid were purchased from Merck, Germany. Ethanol was purchased from BDH Laboratory Supplies Poole, England.

2.2 Synthesis of IPN hydrogels

IPN hydrogels of HPMC/Primojel were prepared by using the free radical polymerization technique. Both the polymers were accurately weighed, as mentioned in Table 1. Polymers (Primojel and HPMC) were transferred separately into purified water. Polymers were dissolved by stirring. Once dissolved, polymer solution poured in each other to form a single polymer solution. Monomer (MAA) was precisely weighed according to Table 1 and poured dropwise into the above-mentioned polymers solution. To start the polymerization reaction, an APS solution was prepared and poured in the mixture of HPMC, Primojel, and MAA. At the end, accurately weighted amount of crosslinker (MBA) was dissolved in water and formed a solution, which was then poured drop by drop in the reaction solution. Final solution was also sonicated to ensure proper mixing. To eliminate any entrapped oxygen, a nitrogen stream was passed through the reaction mixture. The test tubes were filled with the final solution, wrapped in aluminum foil, and submerged in a water bath for 1 h at 45°C, for 2 h at 50°C, for 3 h at 55°C, for 4 h at 60°C, and finally for 24 h at 65°C. To prevent auto acceleration and bubble formation, the temperature was raised gradually. At the end of specified time, test-tubes were removed and cylindrical gel was obtained, which was then sliced into discs of 6–8 mm in size. These hydrogels discs were placed in petri dishes. The cylindrical discs were then sunken in ethanol water (50% v/v) solution for up to 1–2 weeks to completely remove polymers and monomer that remained unreacted. Throughout this duration, solvent was replaced on daily basis. The discs were carefully washed until pH of washing solution remained unchanged. Obtained discs were then dried at room temperature for 24 h following continuous drying at 40–45°C until uniform mass attained. After complete drying, discs were then removed from the oven and were stored in air tight containers (15) (Scheme 1).

Table 1

Composition of formulations

Formulation code Primojel (g) HPMC (g) MAA (g) APS (g) MBA (g)
PHM1 0.4 0.4 6 0.32 0.4
PHM2 0.8 0.4 6 0.32 0.4
PHM3 1.2 0.4 6 0.32 0.4
PHM4 0.8 0.2 6 0.32 0.4
PHM5 0.8 0.4 6 0.32 0.4
PHM6 0.8 0.8 6 0.32 0.4
PHM7 0.8 0.4 6 0.32 0.4
PHM8 0.8 0.4 7 0.32 0.4
PHM9 0.8 0.4 8 0.32 0.4
Scheme 1 Formulation of hydrogel through free radical polymerization technique.
Scheme 1

Formulation of hydrogel through free radical polymerization technique.

2.3 Characterization

2.3.1 Fourier transform infrared spectroscopy (FTIR)

IPN hydrogels were crushed to the desired size for the FTIR investigation of reactants and hydrogels. The use of a Bruker FTIR (Tensor 27 Series – Bruker Corporation – Germany) instrument, utilizing attenuated-total-reflectance technology, along with software OPUS data collecting, has resulted in a value range of 4,000–600 cm−1 for spectrum scans (16,17).

2.3.2 Thermal analysis

Thermal analysis equipment (TA instrument Q2000 Series – West Sussex, UK) was used to perform TGA on the drug and formulation samples. In order to heat samples sufficiently for TGA, they were heated at a rate of 10°C·min−1 until 500°C (18). DSC was performed on Q2000 series thermal analysis system (TA Instrument, Crawley, UK).

2.3.3 Powder X-ray diffraction (PXRD)

The nature of IPN hydrogels was investigated using PXRD. X-ray diffractometer (x-Pert – PAN analytical – The Netherlands) was used to investigate the specimens. The range of the diffraction angle was from 10° to 50°.

2.3.4 Scanning electron microscopy (SEM)

SEM was used to examine the surface morphology of IPN polymeric networks. A sample of hydrogel was placed on an aluminium mount and sputtered through gold and palladium. For scanning samples, a 20 kV accelerated voltage with a 5–15 mm space gap was used (19).

2.3.5 Determination of gel% (G%), yield% (Y%), and gel time

In order to determine the percent gelling and percent difference between the actual and theoretical yield, G% and Y% were determined. Both the factors mainly describe the amount of reactant being polymerized during the formulation of hydrogels. First, hydrogels were dried until constant weight (m i) in a vacuum oven. Next, the polymeric network was suitably macerated in water for 7 days, with periodic agitation and shaking to remove any polar components. The polymeric network’s water-impermeable section was then dried in an oven to produce a persistent weight (m d). Gel and yield percent were calculated by following equations:

(1) G % = m d m i × 100

(2) Y % = m d m c × 100

where m c specifies the weight of total reactants of developed IPN formulation (20).

Gelling time was directly calculated with the help of stop-watch. The time at which solution of formulation exhibited no flow was considered as gel time (21).

2.3.6 Swelling study

To determine the dynamic swelling and effect pH sensitivity of formulated hydrogel were first weighed and then placed in 0.1 M HCl solution having a pH 1.2 and in 0.2 M phosphate buffer solution having pH 7.4 with temperature 37°C. Hydrogels were kept in the swelling media with occasional withdrawal to measuring the swollen discs weight at specific time intervals until a constant and uniform weight was reached. Normalized swelling degree “Q” at time “t” have been computed in grams of water per gram of dry gel utilizing the succeeding expression (22).

(3) Q t = m t − m o m o

where m t is the weight of IPN hydrogel after swelling, mo is the weight of IPN hydrogel before swelling (dry gel) and Q t is the weight of water absorbed.

Normalized equilibrium swelling Q ∞ was estimated through following equation:

(4) Q ∞ = m t − m o m o

2.3.7 Loading of LTZ

The IPN polymeric network was immersed in a solution of LTZ, ethanol, and water (1% w/v) (50:50 v/v) for 7 days to accomplish the LTZ loading. The hydrogel discs were allowed to swell till equilibrium and then brought out. The discs were then placed in oven after drying at room temperature, until constant mass was attained (23).

2.3.8 Determination of drug entrapment efficiency

The drug entrapment of LTZ-loaded IPN hydrogels was evaluated by submerging disc with known weights in a 25 mL phosphate buffer with a pH of 7.4 for 24 h then crushing them. To ensure complete extraction of LTZ, the crushed hydrogels containing solution was subjected to sonication for 20 min. The resulting clear supernatant solution was analyzed for LTZ using a UV-Visible Spectrophotometer, with the wavelength set at 240 nm (24). Through following equation, entrapment efficiency of formulated hydrogels for LTZ was estimated (25).

(5) Entrapment efficiency % = Actual drug content in IPN hydrogel Theoretical drug content in IPN hydrogel × 100

2.3.9 Release study

Drug release was determined by using the USP Dissolution Apparatus at basic pH 7.4 and acidic pH 1.2. To maintain a consistent drug concentration within the dissolution medium, a weighed polymer disc was added to 900 mL of dissolution liquid and swirled at 50 rpm. Temperature of dissolution medium was set at 37°C. Samples were withdrawn at certain time intervals up to 24 h. Each time, the sampled volume was replaced with new medium. The maximum 240 λ max was set for determination of the concentration of LTZ in dissolution sample (26). Following formula was used.

(6) Percent drug release = Absorbance of the sample solution Absorbance of the standard solution × 100

2.3.10 Analysis of drug release kinetics

Kosmeyer-Peppas (27), Higuchi (28), first order (29), zero order (30) were selected to determine the drug release mechanism.

2.3.11 Oral acute toxicity study of hydrogel

A hydrogel formulation was optimized on the bases of drug entrapment efficiency and drug release (in-vitro) to determine the safety profile through toxicity study. The toxicity assessment has been confirmed in accordance with reliable norms created by the Organization for Economic Co-operation and Development (OECD). In order to carry out this investigation, 12 healthy adult albino rabbits with weights ranging from roughly 1,500 ± 100 g were purchased through the UVAS Animal Facility Centre in Lahore, Pakistan. Rabbits were divided into two groups (Group A and B), each consisting of six animals. All animals were housed in an animal transitional room, which had a temperature range of 25 ± 2°C, a relative humidity range of 65 ± 5%, and a 12 h light–dark cycle. Each rabbit received unlimited access to water as well as a well-balanced meal. Group A had been kept as control group with the administration of food and water only. Group B had been kept as treatment group and was supplied with hydrogel powder dispersion (in deionized water) via oral administration. Total dose of 2 g·kg−1 bodyweight was administered. The general health and wellness of the rabbits, including changes in body weight, morbidity, and mortality, as well as activity, energy, hair, feces, and behavioral patterns, were regularly monitored and after 14 days, rabbits were sacrificed. Blood samples were collected while preserving them in ethylene diamine tetra acetic acid tubes to conduct hematological as well as biochemical blood analysis measurement. All of the critical organs, including the heart, liver, spleen, kidney, and lungs, had been properly dissected and weighed. All of the organs were preserved in 10% buffered formaldehyde and imbedded in paraffin before being segmented. The paraffin sections were stained via hematoxylin-eosin to conduct histopathological examination.

3 Results and discussion

3.1 FTIR

Polymers (Primojel and HPMC), monomer (MAA) and IPN hydrogel (PHM3) discs FTIR spectrums are given in Figure 1. In order to evaluate the crushed samples for FTIR spectroscopy, a scanning range of 4,000−600 cm−1 was used. In the FTIR spectrum of HPMC, band at 3,456, 2,932, and 1,065 cm−1 were observed which depicted the stretching frequency of the –OH, C–H, and C–O bonds/groups respectively. On the other hand, at 1,381 cm−1, bending vibration of –OH groups on the HPMC is shown (31). With respect to Primojel spectrum, at 3,600−2,900 cm−1, a broad band revealed the OH stretching group of the molecule. Overlapping bands at 1,600−1,000 cm−1, reflect stretching (symmetric and asymmetrical) of C–O–C group.

Figure 1 FTIR spectra of Primojel, HPMC, MAA and IPN hydrogel.
Figure 1

FTIR spectra of Primojel, HPMC, MAA and IPN hydrogel.

FTIR spectrum of monomer (MAA) had peaks at about 1,635 cm−1 for carbonyl as well as 1,697 cm−1 for vinyl. Wide band ranging through 3,450−3,000 cm−1 were observed for −OH of COOH (32). In FTIR of IPN hydrogel, small peak at 2,350 cm−1 represented stretching vibration of methanetriyl group of MAA. In the range of 1,250−1,050 cm−1, distinct bands of Primojel, HPMC and MAA were observed. Peaks of individual components showed minor shifting which may be due to crosslinking of polymeric chains. These peaks of cross-linking confirmed the formation of polymeric network.

3.2 SEM

Morphological features of unloaded IPN hydrogel (PHM3) were determined by SEM analysis. Figure 2 present IPN hydrogel micrographs on different magnifications. It is clear from the SEM images that HPMC and Primojel based IPN hydrogel possess porous and uneven surface (Figure 2). Cracks can also be observed all around the uneven surface which may be due to the drying treatment and result in shrinking of polymeric system. These cracks and pores are suitable for invasion of the solvent within IPN hydrogels which result in swelling and subsequent release of LTZ.

Figure 2 SEM images: (a) 100×, (b) 500×, (c) 5,000× of unloaded IPN hydrogel.
Figure 2

SEM images: (a) 100×, (b) 500×, (c) 5,000× of unloaded IPN hydrogel.

3.3 Thermal analysis

Figure 3 presents DSC spectrogram of pure LTZ, unloaded and LTZ loaded IPN formulations (PHM3). Sharp endothermic peak around 100°C in pure LTZ DSC graph corresponds to moisture loss. Peak observed at 240°C indicate breaking of bond among polymeric network (33).

Figure 3 DSC of LTZ (a), unloaded IPN (b) and loaded IPN (c).
Figure 3

DSC of LTZ (a), unloaded IPN (b) and loaded IPN (c).

DSC of IPN formulations (unloaded and loaded) showed parallel thermogram, demonstrates broad peak at 35°C to 130°C that reflects loss of moisture and then leading to bond breakage within polymeric system. It is evident from the thermogram that LTZ possesses higher thermal stability within formulated hydrogel in comparison with pure drug.

LTZ’s TGA thermogram (Figure 4) demonstrated weight decrease in various stages. It lost 10% of its weight during the first step up to 200°C, which may have been caused by water loss. Evaporation of moisture content upon increasing the temperature up to 200°C from drug resulted in slight reduction in the weight of the drug. It displayed a significant weight loss of 75% during the second stage (200°C to 420°C), which corresponded to the partial degradation of LTZ. At this stage, the breakage of the main bonds inside the chemical structure of the drug was initiated and the drug started degradation. The final stage from 420°C to 460°C demonstrated total degeneration. The chemical bonds which were present inside the chemical structure of the drug were broken and hence complete degradation of the drug was found (34). Unloaded IPN hydrogel TGA demonstrates that slight mass loss (10%) occurred up to 220°C. Water evaporation may be the cause of small losses. This indicates that the unloaded IPN (PHM3) sample has a high degree of stability against rising temperatures. Figure 4 shows a significant weight loss from 220°C to 500°C. These findings are almost analogous to de Alvarenga et al. results (35). TGA of LTZ loaded IPN hydrogel (PHM3) showed mass loss in 2 steps. 5% weight loss observed below 310°C temperature. From temperature 310°C to 455°C extensive weight loss represents complete degradation of formulation. Results demonstrated that LTZ in formulated IPN hydrogel possess more thermal stability as that of pure drug. Moreover, from the TGA thermogram, it is also evident that stability of the unloaded formulation was not affected by loading of drug inside it. Thermal stability of the unloaded and loaded IPN hydrogel was comparable and did not show any significant difference.

Figure 4 TGA of (a) LTZ, (b) unloaded IPN and (c) loaded IPN.
Figure 4

TGA of (a) LTZ, (b) unloaded IPN and (c) loaded IPN.

3.4 PXRD analysis

To confirm the amorphousness or crystallinity of the samples shown in Figure 5, PXRD analyses of LTZ and (PHM3) IPN (unloaded and LTZ loaded) formulations were carried out. Sharp peaks at 2θ = 07.2°, 11.12°, 14.16°, 16.24°, 20.16°, 21°, 21.44°, 23°, 24°, 25.08°, 26.52°, 28.8°, 33.6°, 35°, and 39° are a distinctive feature of LTZ that primarily shows the drug’s crystalline form. The number of peaks affirmed the crystalline nature of LTZ. PXRD graph of unloaded IPN demonstrated no significant peak which verified amorphous nature (36). The PXRD pattern of loaded IPN hydrogel depicted the presence of typical peaks of LTZ (2θ = 11.12°, 14.16°, 16.24°, 21.44°), which indicated the crystalline state of LTZ within loaded hydrogel remains the same. Such conditions predict that drugs are being distributed in the IPN that confirms the requisite necessary for the enhanced DDS.

Figure 5 PXRD of LTZ (a), unloaded IPN (b) and loaded IPN (c).
Figure 5

PXRD of LTZ (a), unloaded IPN (b) and loaded IPN (c).

3.5 Determination of G%, Y% and gel time

Figure 6 demonstrated influence of various ingredients such as polymer (Primojel, HPMC), and monomer (MAA) on G%, Y% and gel time of HPMC-co-poly(MAA)/Primojel IPN hydrogels. Increasing concentration of Primojel and HPMC resulted in increased G% and Y% as presented in Figure 6a and b respectively. It was related to the availability of more radicals for polymerization by increasing concentration of polymers (Primojel & HPMC) (37). Increase in gelling time was possibly due to specific quantity of MBA added in formulation to crosslink Primojel and HPMC with MAA (monomer).

Figure 6 Effect of Primojel (a), HPMC (b) and MAA (c) on G%, Y% and gel time.
Figure 6

Effect of Primojel (a), HPMC (b) and MAA (c) on G%, Y% and gel time.

Figure 6c showed that by increasing the amount of monomer (MAA), Y% and G% increased because of the abundance of functionally active sites on MAA (monomer). Figure 6c showed how a decrease in gelling time was achieved by increasing the MAA ratio in the hydrogel formulation. Greater reaction (polymerization) rate could be the cause of the shorter gelling time (38). These results are in comparison to the previously reported studies.

3.6 Swelling study

This test was performed to evaluate the effects of various polymeric network components on the ability of IPN hydrogel to swell (Figure 7). IPN swelling was significant at 7.4 pH compared to 1.2 pH (Figure 8), where minimum ionization occurred, as a result of increased functional group (carboxyl) ionization. Complete ionization initiated ion repulsion, which caused swelling to grow (39). The formulated system is highly absorptive in nature and have the capability to absorb significant amount of swelling medium. As soon as the formulated system was placed inside the swelling system, then because of pH difference as discussed earlier, extensive ionization at high pH resulted significant repulsion inside the system and hence extensive swelling was resulted. The polymeric chains begin to expand and hence result in swelling of the system.

Figure 7 Swelling index of IPN hydrogels on pH 1.2 and pH 7.4.
Figure 7

Swelling index of IPN hydrogels on pH 1.2 and pH 7.4.

Figure 8 Effect of different pH on swelling of IPN hydrogels.
Figure 8

Effect of different pH on swelling of IPN hydrogels.

From graph, it was noticed that swelling of IPN hydrogels increased by increasing the concentration of Primojel as presented in Figure 9a. This enhanced swelling was possibly due to presence of more radicals availability by increasing polymer concentration (40). Primojel also resulted in changing the extent of cross-linking and carboxymethylation (produced hydrophilicity by weakening hydrogen bonding which led to invasion of water in the molecules) (41). As water is absorbed, the starch polymer chains within Primojel begin to swell and hydrate. The water molecules penetrate the polymer network, causing the intermolecular forces between the starch chains to weaken (42).

Figure 9 Effect of Primojel (a), HPMC (b) and MAA (c) on equilibrium swelling.
Figure 9

Effect of Primojel (a), HPMC (b) and MAA (c) on equilibrium swelling.

Increasing HPMC concentration leads decreased swelling as presented in Figure 9b. Quantity and viscosity of HPMC showed direct relation to swelling. Enhancing HPMC concentration led to more viscous solution that resulted in increased density. Compact polymer structure leads to hindrance in uptake of solvent hence decreased swelling is observed (43). Figure 9c showed that by enhancing MAA concentration in IPN hydrogel results in decreased swelling possibly due to formation of dense/impenetrable linking of polymers via MAA therefore reducing the hydration capacity. These findings are nearly identical to earlier studies where MAA was linked with chondroitin-sulfate (polymer) where researchers also mentioned that decline in swelling (water absorbency) was a result of tight/compact polymeric structure (24).

3.7 Drug entrapment efficiency and release study

As indicated in Table 2, the drug was successfully entrapped in the IPN hydrogels. The swelling of IPN hydrogels and the media’s pH had a direct impact on the drug’s loading. More drug loading was observed on higher pH. Released profile of model drug (LTZ) from IPN hydrogels were attained by conducting dissolution at pH 1.2 and 7.4 for 24 h at different time intervals. Analyses of sample absorbance was done on UV spectrophotometer (Shimadzu, Germany) on particular wavelength (λ max 240 nm). LTZ release was also PH dependent. On 7.4 pH, IPN hydrogels demonstrated greater LTZ release, which was possibly due to ionization of R–COOH (carboxylic) group of MAA. Repulsion was produced due to ionization which generated gaps for up taking water, disc swelling and subsequent LTZ release (44). However, at 1.2 pH, IPN hydrogels showed less LTZ release as a result of protonation of –COOH which result in reduced repulsion within IPN hydrogel and disc swelling (45). LTZ release percentage of PHM3 at 1.2 and 7.4 have been shown in Figure 10.

Table 2

Drug entrapment efficiency (%DEE) and percent drug release on pH 1.2 and pH 7.4

Code Drug entrapment efficiency Percent release of LTZ (for a 24 h period)
pH 1.2 pH 7.4
PHM1 65.21 0.9 69.45
PHM2 74.16 1.2 83.94
PHM3 79.27 1.4 87.46
PHM4 75.26 1.2 82.39
PHM5 71.37 0.8 81.27
PHM6 54.16 0.4 71.18
PHM7 77.19 1.3 75.66
PHM8 72.31 0.9 72.9
PHM9 66.54 0.6 69.16
Figure 10 Drug releases percentage of hydrogel at pH 1.2 and pH 7.4.
Figure 10

Drug releases percentage of hydrogel at pH 1.2 and pH 7.4.

3.8 Kinetic modeling

Release of LTZ through IPN hydrogels were evaluated through dissolution data by applying different kinetic models i.e., zero and first order, Higuchi and Korsmeyer Peppas mathematical models. R 2 (regression-coefficient) value i.e., from 0.9411 to 0.9859 of all the IPN hydrogels were well-matched for release of Zero order. It depicted that constant amount of LTZ was released through IPN hydrogels for prolonged time (46). On applying Higuchi model on LTZ release data, 0.9208–0.9799 R 2 values were obtained which indicated that release of LTZ also followed Higuchi model. Higuchi model demonstrated liberation of active moiety is through diffusion mechanism by the development of pores in the polymeric system (47). R 2 values for Korsmeyer Peppas were in the range from 0.9610 to 0.9953, which indicated that all IPN hydrogels also followed Korsmeyer Peppas release model. It illustrated that release was controlled through water absorbency and following relaxation of matrix (48) (Table 3).

Table 3

Drug release kinetics of HPMC-co-poly(MAA)/Primojel IPN hydrogels

Formulations Zero order First order Higuchi Korsmeyer-Peppas
R 2 R 2 R 2 R 2
PHM1 0.9677 0.3373 0.9735 0.9914
PHM2 0.9619 0.3223 0.9799 0.9898
PHM3 0.9411 0.2931 0.9656 0.9936
PHM4 0.9516 0.3237 0.9569 0.9790
PHM5 0.9601 0.3426 0.9376 0.9721
PHM6 0.9806 0.3432 0.9558 0.9830
PHM7 0.9859 0.3340 0.9569 0.9801
PHM8 0.9592 0.3246 0.9208 0.9601
PHM9 0.9666 0.2924 0.9567 0.9934

3.9 Acute oral toxicity study

To determine the safety of the formulated IPN hydrogels (PHM3) toxicity study was executed on rabbits according to OECD guideline. Twelve healthy rabbits of average 1,600 g weight were randomly placed in two groups, control-group and experimental group, each compromising of six rabbits. All rabbits of same group were retained in isolated cages and labeled as E-group (Experimental group) and C-group (Control group). Rabbits in E-group were administered 2 g·kg−1 disc orally whereas only food and water were consumed by C-group rabbits. Rabbits of both groups were given anesthesia and sacrificed. Spleen, heart, kidney, liver, lungs, and pancreas were weighed after isolation and stored for histopathological examination. Tissue slides of all aforesaid organs were developed and observed. No significant variations were observed as cleared from the Figure 11. Hence the results of toxicity finding assure that IPN hydrogels are nontoxic (Tables 4 and 5).

Figure 11 Histological tissues examination of various organs of control group and experimental group.
Figure 11

Histological tissues examination of various organs of control group and experimental group.

Table 4

Clinical observations from the acute oral toxicity test for the optimized hydrogel

Observation Control-group (C) n = 3 Mean ± SD Experimental-group (tested with 2 g·kg−1 IPN hydrogel) n = 3 Mean ± SD
Signs of illness Nil Nil
Body weight (kg)
Pretreatment 1,576.66 ± 110.47 1,578.32 ± 105.04
Day 1 1,573.32 ± 105.59 1,575.32 ± 105.16
Day 7 1,579.66 ± 100.24 1,579.32 ± 115.38
Day 14 1,577.66 ± 115.66 1,576.32 ± 115.37
Water intake (mL)
Pretreatment 205.33 ± 2.42 191.34 ± 3.15
Day 1 200.67 ± 1.43 200.00 ± 1.11
Day 7 195.33 ± 3.16 195.33 ± 1.43
Day 14 195.00 ± 3.61 200.67 ± 2.18
Food intake (g)
Pretreatment 70.56 ± 0.68 76.51 ± 1.32
Day 1 75.17 ± 1.44 80.01 ± 0.91
Day 7 75.59 ± 1.33 73.30 ± 1.20
Day 14 76.89 ± 2.29 75.41 ± 0.45
Dermal irritation Nil Nil
Ocular toxicity: simple irritation or corrosion Nil Nil
Mortality Nil Nil
Table 5

Biochemical analysis of blood of rabbits treated with blank hydrogel formulation

Hematology Group I (control) Group II (treated with hydrogel at 2 g·kg−1)
Hb (g·dL−1) 12.87 ± 1.15 12.71 ± 1.76
White cells × 103 cmm−1 3.24 ± 0.51 2.92 ± 0.50
Total RBCs (3.8–7.9 × 106 mm−3) 5.45 ± 0.51 5.25 ± 0.56
Monocytes (%) 3.85 ± 0.33 3.47 ± 0.39
Lymphocytes (43–80%) 76.25 ± 2.17 78.05 ± 1.04
MCV (%) 61.83 ± 1.76 61.45 ± 0.79
MCH (pg) 20.49 ± 0.73 21.42 ± 1.17
MCHC (%) 30.58 ± 1.09 32.77 ± 1.74
Total Cholesterol (1–80 mg·dL−1) 35.61 ± 2.79 36.20 ± 2.59
Triglycerides (mg·dL−1) 58.35 ± 3.16 60.84 ± 0.28
Uric acid (1–4.3 mg·dL−1) 2.47 ± 0.47 2.39 ± 0.54
Urea (mcg·dL−1) 51.39 ± 3.53 42.61 ± 1.24
Creatinine (mg·dL−1) 0.88 ± 0.15 0.91 ± 0.15
ALT (55–210 IU·L−1) 104.52 ± 1.36 104.87 ± 3.42
AST (10–98 IU·L−1) 65.13 ± 3.88 68.39 ± 2.74

All values are expressed as mean ± SD (n = 3).

4 Conclusion

It is concluded that HPMC/Primojel based IPN hydrogels were successfully fabricated through free radical polymerization technique. Primojel and HPMC were cross-linked with MAA via MBA. Characteristics like swelling and release of drug from IPN hydrogels showed pH sensitivity. PHM3 appeared to be best among all the formulated IPN hydrogel on the basis of drug loading and its release characteristics. IPN hydrogel was analyzed by FTIR, SEM, DSC and TGA. In vitro LTZ release studies showed that liberation of drug is directly proportional to the swelling of IPN hydrogels. Kinetic modeling explains that all IPN hydrogels followed zero order, Korsemeyer Peppas and Higuchi drug release models. Oral acute toxicity study results confirmed that IPN hydrogels were nontoxic. Therefore, all results suggest that HPMC-co-poly(MAA)/Primojel IPN hydrogels can be used as potential carrier for controlled release of model drug (LTZ) in treatment of BC.

  1. Funding information: The authors are thankful for the contribution of the Government College University Faisalabad Pakistan for providing the finances and facilities for performing studies. The authors would like to extend their sincere appreciation to the Researchers Supporting Project , King Saud University, Riyadh, Saudi Arabia for funding this work through the project number (RSP2023R457).

  2. Author contributions: Hammad Yousaf: Methodology, research work, writing original draft and formal analysis; Ikrima Khalid: Project design, supervision and project administration; Kashif Barkat, Hiba-Allah Nafidi, Yousef A. Bin Jardan, Mohammed Bourhia: Provision of facilities, editing, review and scientific writing; Yasir Mehmood: Data procuration, review and editing; Syed Faisal Badshah: Manuscript handling, compiling of data and reviewing results according to format; Irfan Anjum: Assisted in scientific writing, provision of access to various apparatuses and instruments, highlighted the typographic mistakes and correction.

  3. Conflict of interest: The authors state no conflict of interest.

  4. Compliance with ethical standards: Animal studies were conducted in accordance with the approved guidelines of Pharmacy Animal Ethics Committee (PAEC).

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Received: 2023-04-18
Revised: 2023-08-27
Accepted: 2023-08-29
Published Online: 2023-11-14

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/epoly-2023-0033
Keywords for this article
letrozole; primojel; interpenetrating networks; pH-responsive; hydrogels
Creative Commons
BY 4.0

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  43. High-strength polyvinyl alcohol-based hydrogel by vermiculite and lignocellulosic nanofibrils for electronic sensing
  44. Impacts of micro-size PbO on the gamma-ray shielding performance of polyepoxide resin
  45. Influence of the molecular structure of phenylamine antioxidants on anti-migration and anti-aging behavior of high-performance nitrile rubber composites
  46. Fiber-reinforced polyvinyl alcohol hydrogel via in situ fiber formation
  47. Preparation and performance of homogenous braids-reinforced poly (p-phenylene terephthamide) hollow fiber membranes
  48. Synthesis of cadmium(ii) ion-imprinted composite membrane with a pyridine functional monomer and characterization of its adsorption performance
  49. Impact of WO3 and BaO nanoparticles on the radiation shielding characteristics of polydimethylsiloxane composites
  50. Comprehensive study of the radiation shielding feature of polyester polymers impregnated with iron filings
  51. Preparation and characterization of polymeric cross-linked hydrogel patch for topical delivery of gentamicin
  52. Mechanical properties of rCB-pigment masterbatch in rLDPE: The effect of processing aids and water absorption test
  53. Pineapple fruit residue-based nanofibre composites: Preparation and characterizations
  54. Effect of natural Indocalamus leaf addition on the mechanical properties of epoxy and epoxy-carbon fiber composites
  55. Utilization of biosilica for energy-saving tire compounds: Enhancing performance and efficiency
  56. Effect of capillary arrays on the profile of multi-layer micro-capillary films
  57. A numerical study on thermal bonding with preheating technique for polypropylene microfluidic device
  58. Development of modified h-BN/UPE resin for insulation varnish applications
  59. High strength, anti-static, thermal conductive glass fiber/epoxy composites for medical devices: A strategy of modifying fibers with functionalized carbon nanotubes
  60. Effects of mechanical recycling on the properties of glass fiber–reinforced polyamide 66 composites in automotive components
  61. Bentonite/hydroxyethylcellulose as eco-dielectrics with potential utilization in energy storage
  62. Study on wall-slipping mechanism of nano-injection polymer under the constant temperature fields
  63. Synthesis of low-VOC unsaturated polyester coatings for electrical insulation
  64. Enhanced apoptotic activity of Pluronic F127 polymer-encapsulated chlorogenic acid nanoparticles through the PI3K/Akt/mTOR signaling pathway in liver cancer cells and in vivo toxicity studies in zebrafish
  65. Preparation and performance of silicone-modified 3D printing photosensitive materials
  66. A novel fabrication method of slippery lubricant-infused porous surface by thiol-ene click chemistry reaction for anti-fouling and anti-corrosion applications
  67. Development of polymeric IPN hydrogels by free radical polymerization technique for extended release of letrozole: Characterization and toxicity evaluation
  68. Tribological characterization of sponge gourd outer skin fiber-reinforced epoxy composite with Tamarindus indica seed filler addition using the Box–Behnken method
  69. Stereocomplex PLLA–PBAT copolymer and its composites with multi-walled carbon nanotubes for electrostatic dissipative application
  70. Enhancing the therapeutic efficacy of Krestin–chitosan nanocomplex for cancer medication via activation of the mitochondrial intrinsic pathway
  71. Variation in tungsten(vi) oxide particle size for enhancing the radiation shielding ability of silicone rubber composites
  72. Damage accumulation and failure mechanism of glass/epoxy composite laminates subjected to repeated low velocity impacts
  73. Gamma-ray shielding analysis using the experimental measurements for copper(ii) sulfate-doped polyepoxide resins
  74. Numerical simulation into influence of airflow channel quantities on melt-blowing airflow field in processing of polymer fiber
  75. Cellulose acetate oleate-reinforced poly(butylene adipate-co-terephthalate) composite materials
  76. Radiation shielding capability and exposure buildup factor of cerium(iv) oxide-reinforced polyester resins
  77. Recyclable polytriazole resins with high performance based on Diels-Alder dynamic covalent crosslinking
  78. Adsorption and recovery of Cr(vi) from wastewater by Chitosan–Urushiol composite nanofiber membrane
  79. Comprehensive performance evaluation based on electromagnetic shielding properties of the weft-knitted fabrics made by stainless steel/cotton blended yarn
  80. Review Articles
  81. Preparation and application of natural protein polymer-based Pickering emulsions
  82. Wood-derived high-performance cellulose structural materials
  83. Flammability properties of polymers and polymer composites combined with ionic liquids
  84. Polymer-based nanocarriers for biomedical and environmental applications
  85. A review on semi-crystalline polymer bead foams from stirring autoclave: Processing and properties
  86. Rapid Communication
  87. Preparation and characterization of magnetic microgels with linear thermosensitivity over a wide temperature range
  88. Special Issue: Biodegradable and bio-based polymers: Green approaches (Guest Editors: Kumaran Subramanian, A. Wilson Santhosh Kumar, and Venkatajothi Ramarao)
  89. Synthesis and characterization of proton-conducting membranes based on bacterial cellulose and human nail keratin
  90. Fatigue behaviour of Kevlar/carbon/basalt fibre-reinforced SiC nanofiller particulate hybrid epoxy composite
  91. Effect of citric acid on thermal, phase morphological, and mechanical properties of poly(l-lactide)-b-poly(ethylene glycol)-b-poly(l-lactide)/thermoplastic starch blends
  92. Dose-dependent cytotoxicity against lung cancer cells via green synthesized ZnFe2O4/cellulose nanocomposites
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