Formulation, In Vitro Evaluation, and Toxicity Studies of A. vulgaris-co-AAm Carrier for Vildagliptin

Kausar, Samia; Erum, Alia; Tulain, Ume Ruqia; Hussain, Muhammad Ajaz; Farid-ul-Haq, Muhammad; Malik, Nadia Shamshad; Rashid, Ayesha

doi:https://doi.org/10.1155/2021/6634780

Advances in Polymer Technology

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Abstract Introduction Materials and Methods Results and Discussion Conclusions Data Availability Conflicts of Interest Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2021 | Article ID 6634780 | https://doi.org/10.1155/2021/6634780

Formulation, In Vitro Evaluation, and Toxicity Studies of A. vulgaris-co-AAm Carrier for Vildagliptin

Samia Kausar,¹Alia Erum,¹Ume Ruqia Tulain,¹Muhammad Ajaz Hussain,²Muhammad Farid-ul-Haq,²Nadia Shamshad Malik,³and Ayesha Rashid⁴

Academic Editor: Gaurav Sharma

Received20 Nov 2020

Revised17 Jun 2021

Accepted04 Jul 2021

Published23 Jul 2021

Abstract

This study investigated the use of Artemisia vulgaris L. seed mucilage as a new excipient for sustained delivery of Vildagliptin. Copolymeric carrier of A. vulgaris seed mucilage-co-AAm was devised by using acrylamide (AAm) as a monomer, methylene-bis-acrylamide (MBA) as a crosslinker, and potassium persulfate (KPS) as an initiator through free radical polymerization. Different formulations of A. vulgaris-co-AAm were devised by varying contents of polymer, monomer, crosslinking agent, initiator, and reaction temperature. Copolymeric structures were characterized through XRD analysis, Fourier transform infrared (FTIR) spectroscopy, TGA and DSC analysis, and scanning electron microscopy. Porosity, gel fraction, and Vildagliptin loading capacity of copolymers were also established. Swelling and in vitro drug release studies were conducted. XRD evaluation showed the alteration of the crystalline structure of Vildagliptin into an amorphous form. FTIR analysis confirmed the successful grafting of AAm to A. vulgaris seed mucilage backbone. Porosity was increased with increasing polymer concentration and reaction temperature while it was decreased with an increasing amount of AAm, MBA, and KPS. Gel content was decreased with increasing polymer concentration and reaction temperature while it was increased with an increasing amount of AAm, MBA, and KPS. Acute oral toxicity of copolymeric network was done in animal models to evaluate the safety. Copolymers showed the same swelling behavior at all pH 1.2, 4.5, 6.8, and 7.4. Vildagliptin release from copolymer showed a cumulative trend by increasing polymer content and reaction temperature, while a declining trend was observed with increasing contents of monomer, crosslinking agent, and initiator. Sustained release of Vildagliptin was observed from copolymers and release followed the Korsmeyer-Peppas model. From the acute oral toxicity studies, it is evident that newly synthesized copolymeric carriers are potentially safe for eyes, skin, and vital organs.

1. Introduction

Naturapolyceutics is based on interdisciplinary approaches that combine natural polymer and pharmaceutics for advancement in drug delivery design [1]. Since the primal epoch, plants frisked a vibrant character in human daily life from purposeful food to medication [2]. Plant-derivative excipients are constant applicants, which display a spirited part in pharmaceutical product development. Furthermore, the marvelous direction of formulation scientists towards the development of plant instigated excipient offerings a new edge to ascertain, extract, and refine such compounds. Plant polysaccharides, such as gums and mucilages, are commonly used in pharmaceutical, biomedical, and cosmetic industries. Moreover, seed coats of several plants extrude mucilage on potential connection with water [3]. This mucilage comprises complex polysaccharides, which are plentiful with a high degree of biocompatibility, biodegradability, and ability to imitate the natural extracellular matrix (ECM) microenvironment. Due to their diverse nature, these functional materials are in great demand to ripen sustained/controlled/targeted formulations in design and drug delivery [4].

To overcome the drawbacks of the conventional drug delivery system in recent times, the current research area is to develop modified dosage systems to give a more stable and economical dosage form. Among different drug delivery systems, hydrogels are under consideration, which not only decreases the demerits of the conventional dosage form but also provides a stable, more convenient, and biocompatible drug delivery system [5, 6]. Hydrogels have gain attention from the past years due to their extensive applications in medical, biological, and pharmaceutical disciplines [7, 8].

Hydrogels are the copolymeric networks that can swell and keep water within its polymeric network without dissolving in water [7]. Graft copolymers represent surplus benefits, especially stimuli-responsive polymers, such as higher acid-base and thermal resistance and lower crystallinity of natural polymers. Graft copolymers are prepared by first creating free radicals on the biopolymer backbone and then permitting these radicals to function as macroinitiators [9]. As compared to conventional drug delivery systems, hydrogels have prolonged and sustained action. They are biocompatible, biodegradable and provide site-specific drug delivery. This results in improved patient compliance due to reduced frequency of dosing and side effects [8, 10].

A. vulgaris L., commonly known as mugwort, belongs to family Compositae and is native to Europe, Asia, and northern Africa. Artemisia species are used throughout the world for their different kinds of medicinal properties, e.g., anti-inflammatory, antimicrobial, antioxidant, and antimalarial. Artemisia vulgaris seed mucilage, which shows amazing swelling in water, shows stimuli-responsiveness in different physiological conditions, solvents, and electrolytes [11].

Acrylamide is one of the favourite choices due to its excellent compatibility, ease of preparation, noncarcinogenicity, low cost, biocompatibility, and biodegradability [12].

The integral parts of copolymeric carrier synthesis are polymer, monomer, crosslinking agent, and initiator. The swelling behavior of hydrogels depends upon the nature of the polymer, monomer, initiator, and crosslinking agent as well as their concentrations and reaction temperature. The applications of hydrogels mainly depend upon the swelling behavior of the polymeric network of the hydrogel. These formulation parameters are used to alter the swelling behavior of hydrogels to modify the drug release. Extensive studies have been reported to modify swelling properties of crosslinked hydrogels by varying the formulation parameters such as the concentration of polymer, monomer, crosslinking agent, initiator, and various reaction temperatures [13–18].

Vildagliptin is an effective, selective, and orally dynamic dipeptidyl peptidase-4 (DPP-4) inhibitor, which inhibits inactivation of incretion hormones by inhibiting DPP-4 [19]. Its biological half-life is 1 to 3 hours as a result; it entails recurrent management to retain optimum plasma drug level. For the mentioned purpose, a sustained release drug delivery system improves patient compliance by dropping frequency of dosing. Thus, there is a strong clinical prerequisite and market prospective for a dosage form that will provide Vildagliptin in a sustained fashion to a patient demanding therapy. So it could be a potential candidate for safe and effective sustained drug delivery from an ideal dosage form for the treatment of type II diabetes [20].

The present work was undertaken to prepare hydrogels from Artemisia vulgaris mucilage and acrylamide blend by the application of free radical polymerization. The purpose of the current study was to evaluate mucilage obtained from Artemisia vulgaris as a new excipient of natural origin for producing smart drug delivery systems such as graft copolymer.

2. Materials and Methods

2.1. Materials

Seeds of Artemisia vulgaris were procured from Seed Needs, LLC. Acrylamide, potassium persulfate, sodium hydroxide, and potassium dihydrogen phosphate were purchased from Sigma-Aldrich, Germany. Methylene-bis-acrylamide was purchased from Fluka, Switzerland. Hydrochloric acid and absolute ethanol were purchased from Riedel-de Haen, Germany. The drug Vildagliptin (99.5% purity) was obtained from M/S Fuxin Long Rui Pharmaceutical Co. Ltd. Distilled water was obtained from the distillation unit of the University of Sargodha. All other chemicals used in this study were of analytical grade.

2.2. Extraction of Artemisia vulgaris Seed Mucilage

The Artemisia vulgaris mucilage was obtained by a hot water extraction method. Extraneous materials were removed by picking and sieving of seeds (200 g). Uncontaminated seeds were soaked in distilled water (1 : 9 ratio) at room temperature for 48 hours. Swollen seeds of Artemisia vulgaris were passed by 40 mesh sieve later heated at 80°C for 30 minutes. The thick exudate was separated by nylon mesh. Defatted mucilage was obtained by n-Hexane (≥98.0% purity, Sigma-Aldrich, Germany) treatment; the resultant was later washed thoroughly with distilled water (repeated thrice) to collect pure mucilage. Dried Artemisia vulgaris mucilage was triturated to obtain even powder of extract and stored in vacuum desiccators [21].

2.3. Determination of Purity of Artemisia vulgaris Seed Mucilage

Aqueous extract was prepared by dissolving Artemisia vulgaris Seed Mucilage powder in distilled water. Molisch’s reagent and sulphuric acid were used to identify the presence of carbohydrates. Molisch’s reagent was added in the aqueous extract of mucilage; then sulphuric acid was added (Malviya et al. [22]). Amino acid presence in extracted powder was checked by dissolving aqueous extract with Ninhydrin reagent (Farooq et al. [23]).

2.4. Synthesis of Artemisia vulgaris-AAm Copolymers

AV seed mucilage was suspended in distilled water with constant stirring at 70°C. KPS was added to it to generate free radicals. A solution of AAm (monomer) and MBA was prepared and transferred to the reaction mixture. The reaction mixture was placed in a water bath for polymerization with continuous rise in temperature from 45 to 70°C by 10°C/h. The temperature was kept at 70°C to complete the reaction. Copolymers attained were cut into discs of 0.5 cm. Ethanol and water (30 : 70) were used to remove an unreacted monomer followed by drying in an oven at 50°C. These discs were kept in a desiccator till further use. A similar method was followed to prepare copolymers at room temperature as a reaction temperature [24].

The composition of all formulations with varying contents is summarized in Table 1.

2.5. Swelling Studies

The swelling ratio (dynamic swelling) of copolymers was performed up to 72 h, and equilibrium swelling of copolymers was continued for 2-3 weeks until a constant weight was achieved in 100 mL buffer solutions of different pH, respectively [25, 26]. Dynamic and equilibrium swelling was calculated from the following formulas: where is the swelling ratio, %ES is the % equilibrium swelling, Ws is the swollen disc weight at time , and Wd is the weight of dried disc [24, 27].

2.6. Gel Fraction

Nonwashed dried copolymer discs were soaked in water for 48 h to remove the insoluble part of copolymer at room temperature followed by drying in an oven at 50°C until constant weight was achieved. Gel fraction was calculated by where W1 is the initial weight of dried disc of copolymer and W0 is the weight of the dried insoluble part of copolymer after extraction with water [24, 26].

2.7. Porosity Measurement

Dried copolymer discs were soaked in absolute ethanol overnight. Excess ethanol on the disc was removed by using a filter paper. Then, the weight of dried disc was taken. The following formula was used to calculate the porosity: where is the weight of dried disc before soaking and is the weight of disc after soaking in ethanol, is the volume of the disc, and is the density of absolute ethanol [28].

2.8. Fourier Transform Infrared (FTIR) Spectroscopy

FTIR spectroscopic analysis of A. vulgaris seed mucilage, acrylamide, Vildagliptin (VLG), loaded, and unloaded copolymer was carried out by using a FTIR spectrometer (IR prestige-21 Shimadzu) between the ranges of 4000-400 cm^-1 [28].

2.9. Thermogravimetric Analysis

Thermogravimetric analysis (TGA) and differential scanning calorimetric (DSC) analysis were done for the evaluation of thermal changes in pure drug, loaded, and unloaded copolymeric networks at a temperature range of ambient to -600°C under nitrogen atmosphere [29, 30].

2.10. Determination of Surface Morphology by Scanning Electron Microscopy (SEM)

Surface morphology of the copolymeric network was examined through a scanning electron microscope (FEI Quanta 250). Copolymer discs were allowed to swell in distilled water at room temperature to constant weight and then freeze-dried. Samples were placed on carbon stub, and after fixing on carbon stub, discs were examined under an electron microscope [31].

2.11. X-Ray Diffraction Analysis (XRD)

XRD of Vildagliptin, loaded, and unloaded copolymers was performed through an X-ray diffractometer (Panalytical, Germany). The XRD was performed by exposing samples to Cu-Kα radiation at the angle between 0 and 50°, and the scan rate was set at 1° per minute at 2Ɵ [29].

2.12. Loading of Drug

The copolymer discs were soaked in a 1% drug solution and allowed to swell for 24 hours at room temperature. After that, the discs were taken out and washed with distilled water. Finally, the drug-loaded discs were placed in an oven to dry at 50°C until the uniform weight was achieved [32, 33].

2.13. Weight Method

The % age drug loading (DL%) was calculated by the weight method after 24 hours by using the following formula: where is the quantity of drug entrapped in the copolymer and is the weight of the dried copolymer discs [34, 35].

2.14. In Vitro Drug Release Measurement

USP-dissolution apparatus II was used to conduct dissolution studies at °C in buffer solution (500 mL) of pH 7.4 by keeping 50 rpm as a stirring rate. Aliquots of 5 mL were pulled out at 0.5, 1, 2, 4, 6, 8, 10, 14, 18, 22, and 24 hours and replenished with fresh media. The samples were filtered, suitably diluted, and analyzed using a UV spectrophotometer at [33, 35].

2.15. Drug Release Percentage

The drug release percentage from copolymers was measured by using the following formula: where shows the amount of Vildagliptin released at any time and shows the quantity of a drug that was loaded in copolymer discs [26].

2.16. Assessment of Kinetics of Drug Release

The model-dependent approach was used to analyze the release kinetics of Vildagliptin by using a DD solver. The following equations are used for Zero order, First order, Higuchi, Korsmeyer-Peppas, and Hixon-Crowell models [33, 36, 37].

2.17. Acute Oral Toxicity

Swiss female albino mice with weight were allocated into four groups () and were kept in a controlled environment having free access to water and food. A copolymeric network was given a dose of 1 mg/kg, 3 mg/kg, and 5 mg/kg to group 2, group 3, and group 4, respectively, while N/S was taken by group 1 which acted as a control group. The mice of all groups were observed for 48 h for any change in weight and visual sign of mortality, behavioral pattern alteration (skin and fur, the color of urine, fecal consistency, respiration, eyes, salivation, sleep pattern, mucosal membrane variation, convulsion, and finally come), changes in the physical appearance, and further signs of illness on each day while the study was conducted [38]. Fourteen days later, the serum biochemistry analysis was performed, and for tissues (heart, liver, kidney, gastric, small intestine, and colon) of histology studies, mice were sacrificed [39, 40].

3. Results and Discussion

3.1. Synthesis of Artemisia vulgaris-AAm Copolymers

After many trials, it was determined that the optimum concentration of Artemisia seed mucilage for Artemisia vulgaris-AAm copolymers was 2%.

3.2. Swelling Studies

3.2.1. Effect of Polymer Concentration

It was found that copolymers with varying contents of Artemisia vulgaris seed mucilage showed an increase in dynamic and equilibrium swelling with an increase in polymer content (Figure 1, Table 2). This can be explained by the fact that an increase in polymer content results in enhanced pore volume which ultimately causes the penetration of water in the polymer network, thus resulting in enhanced swelling ability as well as an increase in polymer concentration lead to increase in viscosity of solution that results in a reduction in movement of free radicals which ultimately lead to impaired polymerization associated with low crosslinking density. Thus, the formation of interconnected channels results in the high porosity of Artemisia vulgaris-AAm copolymer [41, 42].

3.2.2. Effect of Monomer Concentration

M1, M2, M3, and M4 copolymers are prepared with varying contents of acrylamide, and it was observed that the increase in monomer concentration results in heat-induced auto-crosslinking and branching reaction that causes a reduction in swelling and also inter- and intramolecular self-cross linkage by secondary binding forces is increased due to increase in monomer concentration which is associated with a diminished porous gel structure which prevents the accessibility of more solvent into the polymeric matrix which can be the reason of reduction in the swelling capacity of a copolymer (Figure 2, Table 2) [43–45].

3.2.3. Effect of Crosslinker Concentration

The effect of varying contents of MBA on dynamic swelling was studied, as the crosslinking agent concentration is directly related to the crosslinking density, which markedly affects the dynamic swelling behavior of hydrogels [46]. A clear picture can be seen in Figure 3 (dynamic swelling) and Table 2 (equilibrium swelling) that as the concentration of MBA was increased in feed mixture, the swelling ratio was decreased. This was since there was an increase in the stability of the network and a decrease in network mesh size as the crosslinking agent content was increased in the feed mixture. The eventuating highly crosslinked rigid structure could not be expanded, so this behavior caused a low uptake of fluid by the copolymer and ultimately leads to a lower swelling ratio as well as equilibrium swelling ([47] #84). Findings of other similar studies reported by pioneer researchers revealed that a less porous network structure was produced by a high degree of crosslinking of copolymers which has a low swelling ratio [24, 33, 41].

3.2.4. Effect of Initiator Concentration

The effect of varying initiator concentrations at all pH is presented in Figure 4 and Table 2. The obtained results indicate that by increasing initiator content in feed mixture, swelling ratio, as well as equilibrium swelling, was decreased. This can be attributed to the reason that by increasing initiator contents, the molecular weight of resulting crosslinked copolymers was decreased, which leads to a shortening of macromolecular chains due to the formation of too many radicals and reducing the available free space within the copolymeric network. This causes a decrease in the swelling ratio clearly [48, 49].

3.2.5. Effect of Reaction Temperature

The impact of varying reaction temperatures on swelling ratio (Figure 5) and equilibrium swelling (Table 2) was studied. It was noticed that by increasing reaction temperature, the swelling ratio was increased. The reason for this action is a decomposition of peroxides as a result of irradiation of the base polymer in the air leading to an initial increase in grafting, making the requisite radicals available for grafting. The further decrease in grafting is due to the increased molecular motion with an increase in temperature that causes the increase in radical decay [50]. Besides the optimum increase in temperature, poor selectivity, various hydrogen abstraction, and chain transfer reactions can be the leading cause of graft copolymerization that results in a decrease of percent grafting [51].

3.2.6. Effect of pH on Swelling

There are comparative swelling ratios of different formulations of Artemisia vulgaris-AAm copolymer with varying component concentrations at pH 1.2, 4.5, 6.8, and 7.4. When the pH medium is varied from acidic to basic, swelling behavior did not depict major differences which can be observed in Figures 1–4. This manner is fascinating for the applications of the copolymer. This suggests a high specific surface area of acrylamide, which ensures better solvent interactions and proper swelling. There also was no significant difference in swelling of these hydrogels on varying pH. This could be due to the nonionogenic character of polyacrylamide that leads to pH-independent swelling [52, 53].

3.3. Percent Gel Content

The percent gel content of all Artemisia vulgaris-AAm copolymers is given in Table 3. In all formulations, gel content was decreased with increasing polymer concentration and reaction temperature due to less crosslinked networks while it was increased with increasing contents of AAm, MBA, and KPS. The reason for increased gel content with these respective parameters is that there will be more crosslinking which will ultimately increase the gel strength and hence gel fraction [42, 51].

3.4. Determination of Porosity

Porosity measurement of all Artemisia vulgaris-AAm copolymer formulations is given in Table 3. According to results, the porosity of copolymers was increased with increasing polymer content and decreased with increasing content of acrylamide, MBA, and KPS. This can be explained as the increasing amount of polymer leads to increased viscosity of feed mixture which hindered the free radical movement and caused impair polymerization. So the resulting copolymer network has interconnected channels with low crosslinking density and high porosity [41]. By increasing the amount of AAm, MBA, and KPS, porosity was decreased. As molecular entanglements are increased between a polymer and monomer by increasing crosslinking density which results in a decrease in mesh size of the copolymer and ultimately the porosity ([41, 54]), the porosity of copolymer was increased by increasing reaction temperature from room temperature to 70°C. Grafting is reduced by an increase in temperature, and a copolymer with reduced crosslinked density is developed [51].

3.5. Fourier Transform Infrared (FTIR) Analysis

FTIR spectra of pure Artemisia vulgaris mucilage, acrylamide, Vildagliptin, unloaded, and loaded Artemisia vulgaris-AAm copolymer were recorded. Artemisia vulgaris seed mucilage (Figure 6(a)) showed peaks at 3795.91 corresponding to OH stretching vibration. NH stretching vibration was observed at 3196.05 and 3263.56/cm ([55]), whereas Vildagliptin spectrum (Figure 6(b)) showed characteristic peaks at 3286.70/cm (OH and NH stretching), 2245.14/cm (CN nitrile stretching), 1660.71/cm (C=O tertiary amide), 1232.51/cm (CN stretching), 1145.72/cm (C-O(H) stretching), and 1037.70/cm (C-O(H) cycloalkane 3-hydroxyadamantane stretching) [56, 57]. FTIR spectroscopic analysis of loaded Artemisia vulgaris-AAm copolymer (Figure 6(c)) showed Vildagliptin peaks were overlapped with a slight band shift which indicated the absence of any interaction between drug and polymer [57, 58]. FTIR spectroscopic analysis also showed the grafting of AAm on to the polymer (Figure 6(d)) due to the presence of a characteristic peak at 1637.56/cm was due to the C=O stretching of amide [59, 60]. Other peaks observed were 3169.04 and 1319.31/cm corresponding to NH stretching and CN stretching [61, 62].

3.6. TGA and DSC

It is evident from the TGA curve (Figure 7) that VLG showed 43.75% weight loss at 315.59°C. At the same temperature, drug-loaded Artemisia vulgaris-AAm copolymer showed a 21.75% weight loss. At 544°C, the drug showed 76.77% weight loss while at this stage drug-loaded Artemisia vulgaris-AAm copolymer showed 71.53% weight loss. Higher remaining mass indicated that the thermal stability of the drug was increased upon loading to copolymer [63]. The results of the DSC analysis are presented in (Figure 8). It can be evident from the results that VLG showed initially flat profile but, when it entered its melting range, a sharp endothermic peak was observed at 164. However, in VLG-loaded Artemisia vulgaris-AAm copolymer, this peak was not evident clearly due to a rigid copolymer network; these observations indicate that VLG was molecularly dispersed in copolymer formulation on loading. These observations indicated that drug and polymer were compatible with each other [56, 64].

3.7. Scanning Electron Microscopy

For determining morphological characteristics of a prepared copolymer, scanning electron microscopy was performed for formulations of Artemisia vulgaris-AAm copolymer with the best swelling results. SEM images (Figure 9) showed dense and compact structure with porous interconnected channels [44, 45, 65].

3.8. X-Ray Diffraction Analysis

It was determined that the crystalline nature of the drug was altered to an amorphous state after its entrapment in the copolymer. An overlay of XRD (Figure 10) of Artemisia vulgaris-AAm copolymer revealed that characteristic peaks of Vildagliptin showed a clear decrease in its intensity. Therefore, results have indicated that Vildagliptin underwent amorphous dispersion [57, 58]. For more characterization and applications of A. vulgaris mucilage, readers are referred to following works of peers [11, 66].

3.9. Loading of Drug

The drug loading capacity of different formulations of Artemisia vulgaris-AAm copolymer is given in Table 4.

3.10. In Vitro Drug Release Measurement

In vitro release profiles of Artemisia vulgaris-AAm copolymers with varying polymer, monomer, crosslinker, initiator, and reaction temperatures at pH 7.4 are presented in Figure 11. Formulations with varying polymer contents showed an increase in drug release with increasing contents of the polymer. As for P1, P2, and P3, Vildagliptin release after 24 hours was 76.84%, 81.81%, and 86.58%, respectively. This significant drug release was observed due to increased porosity of the network with increasing content of polymer [67]. Formulation with varying contents of monomer showed a decrease in drug release with increasing contents of acrylamide. As for M1, M2, M3, and M4, the percentage cumulative drug release observed after 24 h was 89.58%, 79.36%, 75.58%, and 69.41%, respectively. A similar behavior was observed with MBA and KPS. By increasing the contents of the above-mentioned parameters, a more crosslinked network is formed, this behavior of network causes a decrease in chain relaxation and drug release [59, 68, 69]. Also, the impact of varying reaction temperatures was determined. It can be seen in Figure 11 that in the formulation prepared by varying the reaction temperature (T1 and R1), the highest percent of Vildagliptin release was shown by T1 formulation. The drug release pattern was strongly linked with the swelling pattern of copolymers [36].

3.11. Assessment of Drug Release Kinetics

The correlation coefficient and release rates of all formulations were determined. Based on the highest regression coefficient value (), the best fit model found was Korsmeyer-Peppas. This model is applied to determine the release mechanism of drugs, i.e., Fickian diffusion and non-Fickian diffusion [70, 71]. According to the value of the release exponent, i.e., less than 0.5, the drug release mechanism from copolymer was Fickian [72]. Changez et al. prepared poly(acrylic acid)-gelatin hydrogel and reported that gentamicin follows Fickian diffusion from hydrogel [73].

3.12. Acute Oral Toxicity Evaluation

The acute oral toxicity was carried out on Swiss albino mice for the copolymeric network [38]. After 48 h of observation following administration, no change was visible on the skin, fur, and behavioral pattern in all observed groups. Later on, the same parameters were subsequently observed for 14 days to ascertain toxic events macroscopically. There was no significant change in body weight, and no mortality was observed for 14 days. Furthermore, on completion of 14 days, the blood sample was withdrawn from each mouse to conduct CBC and serum biochemistry analysis [74].

3.13. Serum Biochemistry Analysis

Serum biochemistry of Swiss albino mouse blood evaluating acute oral toxicity was determined. Hematology and blood chemistry parameters of mice are shown in Table 5; all the values hemoglobin, liver profile, renal profile, and serum biochemistry shown graphically in Figure 12 are comparable to control and within normal range thus verifying the safety of the copolymeric network [75, 76].

(a)

(b)

(c)

(d)

3.14. Histopathological Evaluation

The macroscopic examination of the heart, gastric tissue, kidney, liver, small intestine, and colon did not display any visible changes or lesion in the tissues of these organs. For further investigation, slides were prepared for each organ (Figure 13) mentioned above for histological exploration. The microscopic examination proved that slides of the heart, gastric tissue, kidney, small intestine, and colon did not show any lesions; the liver was normal and did not present any fatty change or necrosis when compared to control. Hence, the copolymeric network did not turn out to be toxic for these organs and back up the provisions of RFTs and LFTs, thus indicating the safety of the copolymeric network. Conclusively, no gross difference in histopathological observation was found between the control and treatment groups similar to hematological and biochemical biomarkers, credited to the normal functioning of vital organs. The outcomes of acute oral toxicity assessment presented that there was no toxic reaction or histopathological vicissitude instigated after the maximum dose level of A. vulgaris seed mucilage-co-AAm copolymer. Thus, this drug delivery system might be a safe nominee for use in biomedical field, particularly in an oral drug delivery system [77, 78].

4. Conclusions

Artemisia vulgaris mucilage-based copolymers were successfully fabricated by a free radical polymerization method. Among various graft copolymer formulations prepared with varying contents of the polymer, monomer, crosslinker, initiator, and reaction temperature, M1 presents superior properties regarding swelling and sustained drug release. Artemisia vulgaris-based copolymers were proved to be a suitable carrier for sustained drug delivery of Vildagliptin. The results of acute oral toxicity evaluation showed that there was no toxic response or histopathological changes caused by A. vulgaris seed mucilage-co-AAm. Thus, the copolymer prepared might be a safe candidate for application in the biomedical field, especially in the oral drug delivery system. The mucilage obtained from Artemisia vulgaris can be used as a new excipient of natural origin for producing smart drug delivery systems such as graft copolymer.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

The authors declare no conflict of interest.

Acknowledgments

Teaching institute (The University of Sargodha) is the only institute that supports only research work-associated cost. The funding provides no support for Open Access fees. Moreover, we all authors are also unable to pay for Open Access fees. We are highly thankful to the Novartis Pharma (Pvt.) Pakistan Ltd. for providing a generous gift of Vildagliptin. We also acknowledge the LCWU Lahore, Pakistan, for the provision of SEM and XRD analysis and expert opinion. The animal houses of The University of Lahore (UOL) and UOS were utilized for animal acute oral toxicity evaluation.

References

U. R. Tulain, M. Ahmad, and A. Rashid, “Development, in vitro and in vivo evaluation of hydrogel based system of carboxymethyl arabinoxylan for controlled delivery of rabeprazole sodium,” Polymer-Plastics Technology and Engineering, vol. 57, no. 17, pp. 1771–1783, 2018.
View at: Publisher Site | Google Scholar
C. I. Abuajah, A. C. Ogbonna, and C. M. Osuji, “Functional components and medicinal properties of food: a review,” Journal of Food Science and Technology, vol. 52, no. 5, pp. 2522–2529, 2015.
View at: Publisher Site | Google Scholar
M. T. Haseeb, M. A. Hussain, S. H. Yuk, S. Bashir, and M. Nauman, “Polysaccharides based superabsorbent hydrogel from linseed: dynamic swelling, stimuli responsive on-off switching and drug release,” Carbohydrate Polymers, vol. 136, pp. 750–756, 2016.
View at: Publisher Site | Google Scholar
V. Gopinath, S. Saravanan, A. R. al-Maleki, M. Ramesh, and J. Vadivelu, “A review of natural polysaccharides for drug delivery applications: special focus on cellulose, starch and glycogen,” Biomedicine & Pharmacotherapy, vol. 107, pp. 96–108, 2018.
View at: Publisher Site | Google Scholar
S. Karna, S. Chaturvedi, V. Agrawal, and M. Alim, “Formulation approaches for sustained release dosage forms: a review,” Asian Journal of Pharmaceutical and Clinical Research, vol. 8, pp. 46–53, 2015.
View at: Google Scholar
S. Khan, A. Ullah, K. Ullah, and N.-U. Rehman, “Insight into hydrogels,” Designed Monomers and Polymers, vol. 19, no. 5, pp. 456–478, 2016.
View at: Publisher Site | Google Scholar
E. M. Ahmed, “Hydrogel: preparation, characterization, and applications: a review,” Journal of Advanced Research, vol. 6, no. 2, pp. 105–121, 2015.
View at: Publisher Site | Google Scholar
N. M. Ranjha, G. Ayub, S. Naseem, and M. T. Ansari, “Preparation and characterization of hybrid pH-sensitive hydrogels of chitosan-co-acrylic acid for controlled release of verapamil,” Journal of Materials Science: Materials in Medicine, vol. 21, no. 10, pp. 2805–2816, 2010.
View at: Publisher Site | Google Scholar
U. R. Tulain, M. Ahmad, A. Rashid, M. Z. Malik, and F. M. Iqbal, “Fabrication of pH-responsive hydrogel and it’s in vitro and in vivo evaluation,” Advances in Polymer Technology, vol. 37, no. 1, p. 304, 2018.
View at: Publisher Site | Google Scholar
A. Singh, P. K. Sharma, V. K. Garg, and G. Garg, “Hydrogels: a review,” International Journal of Pharmaceutical Sciences Review and Research, vol. 4, pp. 97–105, 2010.
View at: Google Scholar
M. Farid-Ul-Haq, M. A. Hussain, M. T. Haseeb et al., “A stimuli-responsive, superporous and non-toxic smart hydrogel from seeds of mugwort (Artemisia vulgaris): stimuli responsive swelling/deswelling, intelligent drug delivery and enhanced aceclofenac bioavailability,” RSC Advances, vol. 10, no. 34, pp. 19832–19843, 2020.
View at: Publisher Site | Google Scholar
D. Swantomo, R. Rochmadi, K. T. Basuki, and R. Sudiyo, “Synthesis and characterization of graft copolymer rice straw cellulose-acrylamide hydrogels using gamma irradiation,” Atom Indonesia, vol. 39, no. 2, p. 57, 2013.
View at: Publisher Site | Google Scholar
S. Benamer, M. Mahlous, A. Boukrif, B. Mansouri, and S. L. Youcef, “Synthesis and characterisation of hydrogels based on poly(vinyl pyrrolidone),” Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, vol. 248, no. 2, pp. 284–290, 2006.
View at: Publisher Site | Google Scholar
O. Hazer, C. Soykan, and Ş. Kartal, “Synthesis and swelling behavior analysis of poly(acrylamidoxime‐co‐2‐acrylamido‐2‐methylpropane sulfonic acid) hydrogels,” Journal of Macromolecular Science, Part A: Pure and Applied Chemistry, vol. 45, no. 1, pp. 45–51, 2007.
View at: Publisher Site | Google Scholar
S. Ilic-Stojanovic S., L. Nikolic, V. Nikolic et al., “Influence of monomer and crosslinker molar ratio on the swelling behaviour of thermosensitive hydrogels,” Chemical Industry and Chemical Engineering Quarterly, vol. 18, no. 1, pp. 1–9, 2012.
View at: Publisher Site | Google Scholar
A. Martinez-Ruvalcaba, J. C. Sanchez-Diaz, F. Becerra, L. E. Cruz-Barba, and A. Gonzalez-Alvarez, “Swelling characterization and drug delivery kinetics of polyacrylamide-co-itaconic acid/chitosan hydrogels,” Express Polymer Letters, vol. 3, no. 1, pp. 25–32, 2009.
View at: Publisher Site | Google Scholar
J. Mudassir and N. M. Ranjha, “Dynamic and equilibrium swelling studies: crosslinked pH sensitive methyl methacrylate-co-itaconic acid (MMA-co-IA) hydrogels,” Journal of Polymer Research, vol. 15, no. 3, pp. 195–203, 2008.
View at: Publisher Site | Google Scholar
H. R. Norouzi, H. Azizpour, S. Sharafoddinzadeh, and A. Barati, “Equilibrium swelling study of cationic acrylamide-based hydrogels: effect of synthesis parameters, and phase transition in polyelectrolyte solutions,” Journal of Chemical and Petroleum Engineering, vol. 45, pp. 13–25, 2011.
View at: Google Scholar
N. Sree, B. Aldhubiab, I. Alhaider, M. Attimarad, and A. Nair, “Carbopol 934-P loaded with vildagliptin for diabetic delivery: in vitro and in vivo evaluation of nanoparticles,” Current Nanoscience, vol. 9, no. 5, pp. 642–647, 2013.
View at: Publisher Site | Google Scholar
K. Pangavhane and R. Saudagar, “Formulation, development and evaluation of controlled porosity osmotic tablet of vildagliptin,” The Pharma Innovation Journal, vol. 7, no. 8, pp. 187–191, 2018.
View at: Google Scholar
M. T. Haseeb, M. A. Hussain, S. Bashir, M. U. Ashraf, and N. Ahmad, “Evaluation of superabsorbent linseed-polysaccharides as a novel stimuli-responsive oral sustained release drug delivery system,” Drug Development and Industrial Pharmacy, vol. 43, no. 3, pp. 409–420, 2017.
View at: Publisher Site | Google Scholar
J. Malviya, V. Joshi, and K. Singh, “Antimicrobial activity of some ethno-medicinal plants used by Baiga Tribes from Amarkantak, India,” Advances in Life Science and Technology, vol. 4, pp. 19–26, 2012.
View at: Google Scholar
U. Farooq, R. Malviya, and P. K. Sharma, “Extraction and characterization of okra mucilage as pharmaceutical excipient,” Academic Journal of Plant Sciences, vol. 6, no. 4, pp. 168–172, 2013.
View at: Publisher Site | Google Scholar
U. R. Tulain, M. Ahmad, A. Rashid, and F. M. Iqbal, “Development and characterization of smart drug delivery system,” Acta Poloniae Pharmaceutica, vol. 73, no. 4, pp. 1009–1022, 2016.
View at: Google Scholar
M. U. Ashraf, M. A. Hussain, S. Bashir, M. T. Haseeb, and Z. Hussain, “Quince seed hydrogel (glucuronoxylan): evaluation of stimuli responsive sustained release oral drug delivery system and biomedical properties,” Journal of Drug Delivery Science and Technology, vol. 45, pp. 455–465, 2018.
View at: Publisher Site | Google Scholar
F. Shabir, A. Erum, U. R. Tulain, M. A. Hussain, M. Ahmad, and F. Akhter, “Preparation and characterization of pH sensitive crosslinked linseed polysaccharides-co-acrylic acid/methacrylic acid hydrogels for controlled delivery of ketoprofen,” Designed Monomers and Polymers, vol. 20, no. 1, pp. 485–495, 2017.
View at: Publisher Site | Google Scholar
O. Cevik, D. Gidon, and S. Kizilel, “Visible-light-induced synthesis of pH-responsive composite hydrogels for controlled delivery of the anticonvulsant drug pregabalin,” Acta Biomaterialia, vol. 11, pp. 151–161, 2015.
View at: Publisher Site | Google Scholar
N. M. Ranjha and U. F. Qureshi, “Preparation and characterization of crosslinked acrylic acid/hydroxyl propyl methyl cellulose hydrogels for drug delivery,” International Journal of Pharmacy and Pharmaceutical Sciences, vol. 6, 2014.
View at: Google Scholar
S. Bashir, Y. Y. Teo, S. Naeem, S. Ramesh, and K. Ramesh, “pH responsive N-succinyl chitosan/poly (acrylamide-co-acrylic acid) hydrogels and in vitro release of 5-fluorouracil,” PLoS One, vol. 12, no. 7, article e0179250, 2017.
View at: Publisher Site | Google Scholar
X. Qi, J. Li, W. Wei et al., “Cationic Salecan-based hydrogels for release of 5-fluorouracil,” RSC Advances, vol. 7, no. 24, pp. 14337–14347, 2017.
View at: Publisher Site | Google Scholar
N. Shah and K. Patel, “Formulationanddevelopmentofhydrogelforpolyacrylamide-co-acrylic acid,” Journal of Pharmaceutical and Bio Sciences, vol. 4, pp. 114–120, 2014.
View at: Google Scholar
G. A. Mahmoud, D. E. Hegazy, and H. Kamal, “In-vitro release of ketoprofen behavior loaded in polyvinyl alcohol/acrylamide hydrogels prepared by gamma irradiation,” Arab Journal of Nuclear Sciences and Applications, vol. 47, pp. 28–40, 2014.
View at: Google Scholar
N. M. Ranjha, M. Hanif, Z. Afzal, and G. Abbas, “Diffusion coefficient, porosity measurement, dynamic and equilibrium swelling studies of acrylic acid/polyvinyl alcohol (AA/PVA) hydrogels,” Pakistan Journal of Pharmaceutical Research, vol. 1, no. 2, pp. 48–57, 2015.
View at: Publisher Site | Google Scholar
A. Bajpai and A. Giri, “Water sorption behaviour of highly swelling (carboxy methylcellulose-g- polyacrylamide) hydrogels and release of potassium nitrate as agrochemical,” Carbohydrate Polymers, vol. 53, no. 3, pp. 271–279, 2003.
View at: Publisher Site | Google Scholar
M. Pandey, M. C. I. Mohd Amin, N. Ahmad, and M. M. Abeer, “Rapid synthesis of superabsorbent smart-swelling bacterial cellulose/acrylamide-based hydrogels for drug delivery,” International Journal of Polymer Science, vol. 2013, Article ID 905471, 10 pages, 2013.
View at: Publisher Site | Google Scholar
M. F. Akhtar, N. M. Ranjha, and M. Hanif, “Effect of ethylene glycol dimethacrylate on swelling and on metformin hydrochloride release behavior of chemically crosslinked pH– sensitive acrylic acid–polyvinyl alcohol hydrogel,” DARU Journal of Pharmaceutical Sciences, vol. 23, no. 1, 2015.
View at: Publisher Site | Google Scholar
N. M. Ranjha, J. Mudassir, and N. Akhtar, “Methyl methacrylate-co-itaconic acid (MMA-co-IA) hydrogels for controlled drug delivery,” Journal of Sol-Gel Science and Technology, vol. 47, no. 1, pp. 23–30, 2008.
View at: Publisher Site | Google Scholar
U. Saleem, B. Ahmad, M. Ahmad, A. Erum, K. Hussain, and N. Irfan Bukhari, “Is folklore use of Euphorbia helioscopia devoid of toxic effects?” Drug and Chemical Toxicology, vol. 39, no. 2, pp. 233–237, 2016.
View at: Publisher Site | Google Scholar
T. Singh, N. Sinha, and A. Singh, “Biochemical and histopathological effects on liver due to acute oral toxicity of aqueous leaf extract of ecliptaalba on female Swiss albino mice,” Indian Journal of Pharmacology, vol. 45, no. 1, pp. 61–65, 2013.
View at: Publisher Site | Google Scholar
R. J. Vandebriel, E. C. M. Tonk, L. J. de la Fonteyne-Blankestijn et al., “Immunotoxicity of silver nanoparticles in an intravenous 28-day repeated-dose toxicity study in rats,” Particle and Fibre Toxicology, vol. 11, no. 1, p. 21, 2014.
View at: Publisher Site | Google Scholar
N. M. Ranjha, A. Madni, A. A. Bakar, N. Talib, S. Ahmad, and H. Ahmad, “Preparation and characterization of isosorbide mononitrate hydrogels obtained by free-radical polymerization for site-specific delivery,” Tropical Journal of Pharmaceutical Research, vol. 13, pp. 1979–1985, 2015.
View at: Publisher Site | Google Scholar
S. A. Shah, M. Sohail, M. U. Minhas et al., “pH-responsive CAP-co-poly (methacrylic acid)-based hydrogel as an efficient platform for controlled gastrointestinal delivery: fabrication, characterization, in vitro and in vivo toxicity evaluation,” Drug Delivery and Translational Research, vol. 9, no. 2, pp. 555–577, 2019.
View at: Google Scholar
J. Chen, M. Liu, H. Liu, and L. Ma, “Synthesis, swelling and drug release behavior of poly(N,N -diethylacrylamide-co- N -hydroxymethyl acrylamide) hydrogel,” Materials Science and Engineering: C, vol. 29, no. 7, pp. 2116–2123, 2009.
View at: Publisher Site | Google Scholar
R. Jindal, B. S. Kaith, and H. mittal, “Rapid synthesis of acrylamide onto xanthan gum based hydrogels under microwave radiations for enhanced thermal and chemical modifications,” Polymers from Renewable Resources, vol. 2, no. 3, pp. 105–116, 2011.
View at: Publisher Site | Google Scholar
R. Prabhakar and D. Kumar, “Investigation on poly (acrylate-co- acrylamide)/poly aniline conducting hydrogel,” American Journal of Polymer Science & Engineering, vol. 3, pp. 1–14, 2015.
View at: Google Scholar
Y. Murali Mohan, K. Sudhakar, P. Keshava Murthy, and K. Mohan Raju, “Swelling properties of chemically crosslinked poly (acrylamide-co-maleic acid) hydrogels,” International Journal of Polymeric Materials, vol. 55, no. 7, pp. 513–536, 2006.
View at: Publisher Site | Google Scholar
M. Sadeghi and B. Heidari, “Crosslinked graft copolymer of methacrylic acid and gelatin as a novel hydrogel with pH-responsiveness properties,” Materials, vol. 4, no. 3, pp. 543–552, 2011.
View at: Publisher Site | Google Scholar
E. Karadağ, Ö. Bariş Üzüm, and D. Saraydin, “Water uptake in chemically crosslinked poly(acrylamide- co -crotonic acid) hydrogels,” Materials & Design, vol. 26, no. 4, pp. 265–270, 2005.
View at: Publisher Site | Google Scholar
D. Yiamsawas, W. Kangwansupamonkon, O. Chailapakul, and S. Kiatkamjornwong, “Synthesis and swelling properties of poly[acrylamide- co -(crotonic acid)] superabsorbents,” Reactive and Functional Polymers, vol. 67, no. 10, pp. 865–882, 2007.
View at: Publisher Site | Google Scholar
A. Bhattacharya and B. Misra, “Grafting: a versatile means to modify polymers: techniques, factors and applications,” Progress in Polymer Science, vol. 29, no. 8, pp. 767–814, 2004.
View at: Publisher Site | Google Scholar
B. Raj Sharma, V. Kumar, and P. L. Soni, “Ceric ammonium nitrate-initiated graft copolymerization of acrylamide ontoCassia tora gum,” Journal of Applied Polymer Science, vol. 86, no. 13, pp. 3250–3255, 2002.
View at: Publisher Site | Google Scholar
R. Bera, A. Dey, and D. Chakrabarty, “Synthesis, characterization, and drug release study of acrylamide-co-itaconic acid based smart hydrogel,” Polymer Engineering & Science, vol. 55, no. 1, pp. 113–122, 2015.
View at: Publisher Site | Google Scholar
M. V. Risbud and R. R. Bhonde, “Polyacrylamide-chitosan hydrogels: in vitro biocompatibility and sustained antibiotic release studies,” Drug Delivery, vol. 7, no. 2, pp. 69–75, 2000.
View at: Publisher Site | Google Scholar
S. Lin-Gibson, H. J. Walls, S. B. Kennedy, and E. R. Welsh, “Reaction kinetics and gel properties of blocked diisocyinate crosslinked chitosan hydrogels,” Carbohydrate Polymers, vol. 54, no. 2, pp. 193–199, 2003.
View at: Publisher Site | Google Scholar
B. Sundararajan and B. D. Ranjitha Kumari, “Novel synthesis of gold nanoparticles using Artemisia vulgaris L. leaf extract and their efficacy of larvicidal activity against dengue fever vector Aedes aegypti L.,” Journal of Trace Elements in Medicine and Biology, vol. 43, pp. 187–196, 2017.
View at: Publisher Site | Google Scholar
H. Khan, A. R. Khan, S. Maheen et al., “Preparation and in vitro evaluation of sustained release microparticles of an antidiabetic drug,” Latin American Journal of Pharmacy, vol. 34, pp. 1931–1939, 2015.
View at: Google Scholar
J. B. Naik and M. R. Waghulde, “Development of vildagliptin loaded Eudragit® microspheres by screening design: in vitro evaluation,” Journal of Pharmaceutical Investigation, vol. 48, no. 6, pp. 627–637, 2018.
View at: Publisher Site | Google Scholar
M. Waghulde and J. Naik, “Comparative study of encapsulated vildagliptin microparticles produced by spray drying and solvent evaporation technique,” Drying Technology, vol. 35, no. 13, pp. 1644–1654, 2017.
View at: Publisher Site | Google Scholar
B. B. Mandal, S. Kapoor, and S. C. Kundu, “Silk fibroin/polyacrylamide semi-interpenetrating network hydrogels for controlled drug release,” Biomaterials, vol. 30, no. 14, pp. 2826–2836, 2009.
View at: Publisher Site | Google Scholar
E. K. P. Š. P. Šimon and A. Gatial, “Confirmation of polymerisation effects of sodium chloride and its additives on acrylamide by infrared spectrometry,” Journal of Food and Nutrition Research, vol. 46, pp. 39–44, 2007.
View at: Google Scholar
Y. Guo and P. Wu, “FTIR spectroscopic study of the acrylamide states in AOT reversed micelles,” Journal of Molecular Structure, vol. 883-884, pp. 31–37, 2008.
View at: Publisher Site | Google Scholar
A. Moin, T. Hussain, and D. V. Gowda, “Enteric delivery of diclofenac sodium through functionally modified poly (acrylamide-grafted-ghatti gum)-based pH-sensitive hydrogel beads: development, formulation and evaluation,” Journal of Young Pharmacists, vol. 9, no. 4, pp. 525–536, 2017.
View at: Publisher Site | Google Scholar
K. Sharma, V. Kumar, B. Chaudhary, B. S. Kaith, S. Kalia, and H. C. Swart, “Application of biodegradable superabsorbent hydrogel composite based on gum ghatti-co-poly(acrylic acid-aniline) for controlled drug delivery,” Polymer Degradation and Stability, vol. 124, pp. 101–111, 2016.
View at: Publisher Site | Google Scholar
M. M. F. A. Baig, S. Khan, M. A. Naeem, G. J. Khan, and M. T. Ansari, “Vildagliptin loaded triangular DNA nanospheres coated with eudragit for oral delivery and better glycemic control in type 2 diabetes mellitus,” Biomedicine & Pharmacotherapy, vol. 97, pp. 1250–1258, 2018.
View at: Publisher Site | Google Scholar
A. Pourjavadi, P. E. Jahromi, F. Seidi, and H. Salimi, “Synthesis and swelling behavior of acrylatedstarch-g-poly (acrylic acid) and acrylatedstarch-g-poly (acrylamide) hydrogels,” Carbohydrate Polymers, vol. 79, no. 4, pp. 933–940, 2010.
View at: Publisher Site | Google Scholar
M. Farid-ul-Haq, M. T. Haseeb, M. A. Hussain et al., “A smart drug delivery system based on _Artemisia vulgaris_ hydrogel: Design, on-off switching, and real-time swelling, transit detection, and mechanistic studies,” Journal of Drug Delivery Science and Technology, vol. 58, article 101795, 2020.
View at: Publisher Site | Google Scholar
C. S. Brazel and N. A. Peppas, “Mechanisms of solute and drug transport in relaxing, swellable, hydrophilic glassy polymers,” Polymer, vol. 40, no. 12, pp. 3383–3398, 1999.
View at: Publisher Site | Google Scholar
R. Chouhan and A. Bajpai, “Real time in vitro studies of doxorubicin release from PHEMA nanoparticles,” Journal of Nanobiotechnology, vol. 7, no. 1, p. 5, 2009.
View at: Publisher Site | Google Scholar
K. Sohail, I. U. Khan, Y. Shahzad, T. Hussain, and N. M. Ranjha, “pH-sensitive polyvinylpyrrolidone-acrylic acid hydrogels: impact of material parameters on swelling and drug release,” Brazilian Journal of Pharmaceutical Sciences, vol. 50, no. 1, pp. 173–184, 2014.
View at: Publisher Site | Google Scholar
R. W. Korsmeyer and N. A. Peppas, “Macromolecular and modeling aspects of swelling-controlled systems,” Controlled Release Delivery Systems, vol. 1983, pp. 77–90, 1983.
View at: Google Scholar
S. S. Vaghani, M. M. Patel, and C. S. Satish, “Synthesis and characterization of pH-sensitive hydrogel composed of carboxymethyl chitosan for colon targeted delivery of ornidazole,” Carbohydrate Research, vol. 347, no. 1, pp. 76–82, 2012.
View at: Publisher Site | Google Scholar
B. Singh and N. Sharma, “Development of novel hydrogels by functionalization of sterculia gum for use in anti-ulcer drug delivery,” Carbohydrate Polymers, vol. 74, no. 3, pp. 489–497, 2008.
View at: Publisher Site | Google Scholar
M. Changez, K. Burugapalli, V. Koul, and V. Choudhary, “The effect of composition of poly(acrylic acid)-gelatin hydrogel on gentamicin sulphate release: in vitro,” Biomaterials, vol. 24, no. 4, pp. 527–536, 2003.
View at: Publisher Site | Google Scholar
M. F. Sohail, H. S. Sarwar, I. Javed et al., “Cell to rodent: toxicological profiling of folate grafted thiomer enveloped nanoliposomes,” Toxicology Research, vol. 6, no. 6, pp. 814–821, 2017.
View at: Publisher Site | Google Scholar
C. Y. Gong, S. Shi, P. W. Dong et al., “Biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive PCL -PEG-PCL hydrogel: part 1–synthesis, characterization, and acute toxicity evaluation,” Journal of Pharmaceutical Sciences, vol. 98, no. 12, pp. 4684–4694, 2009.
View at: Publisher Site | Google Scholar
C. Patel, P. Dadhaniya, L. Hingorani, and M. G. Soni, “Safety assessment of pomegranate fruit extract: acute and subchronic toxicity studies,” Food and Chemical Toxicology, vol. 46, no. 8, pp. 2728–2735, 2008.
View at: Publisher Site | Google Scholar
N. Malik, M. Ahmad, M. Minhas et al., “Toxicological evaluation of xanthan gum based hydrogel formulation in wistar rats using single dose study,” Acta Poloniae Pharmaceutica, vol. 77, no. 2, pp. 353–360, 2020.
View at: Publisher Site | Google Scholar
L. Tan, X. Xu, J. Song, F. Luo, and Z. Qian, “Synthesis, Characterization, and Acute Oral Toxicity Evaluation of pH- Sensitive Hydrogel Based on MPEG, Poly(ε-caprolactone), and Itaconic Acid,” BioMed research international, vol. 2013, Article ID 239838, 9 pages, 2013.
View at: Publisher Site | Google Scholar

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