pH-Sensitive Swelling Behavior and Drug Release Kinetics of Chitosan-Modified Cs/HEMA Hydrogels

doi:10.21203/rs.3.rs-3978283/v1

This study investigates the pH-sensitive swelling behavior and drug release kinetics of Chitosan-modified Cs/HEMA hydrogels. The influence of cross-linking agents, hydrophilicity, and crosslinking density on the swelling behavior and stability of the hydrogel membranes is examined. The Donnan swelling equilibrium is employed to explain the expansion of the hydrogels, which is controlled by the osmotic pressure gradient between the interior and exterior of the hydrogel. The hydrogels exhibit pH responsiveness, with maximum swelling at low pH levels and minimized swelling at high pH levels. Additionally, temperature is found to affect the swelling behavior, with higher temperatures resulting in increased swelling ratios. The release rate of the drug (5-ASA) is observed to be influenced by both pH and temperature, with higher release rates at pH 8 and elevated temperatures. Moreover, the impact of Chitosan concentration on drug release kinetics is investigated, revealing a significant effect. These findings contribute to the understanding of the behavior of Chitosan-modified Cs/HEMA hydrogels and provide valuable insights for the development of pH-responsive and temperature-responsive drug delivery systems.

Nanopolymers

Stimuli responsive polymers

Controlled release

Nano platform

Smart polymers

Colon specific drug delivery

It was thought that the production of materials with novel properties and functions could be accomplished by meticulous design and synthesis, as well as the research of structure-property connections. Nano "drug delivery" systems in the context of colon-specific drug delivery [1-5]. These systems serve as a crucial link amongst the therapeutic needs as well as "drug delivery". Stimuli-responsive polymers show case a non-linear reaction to minor stimuli, leading to notable alterations in their properties and structure [6-8]. Stimuli-sensitive polymers demonstrate a notable alteration in their physicochemical characteristics when subjected to slight modifications in their environment, including temperature, pH, and light. The significance of "colonic drug delivery" is grown in the management of ailments like Crohn's disease, ulcerative colitis, and colon cancer. The progress in polymer-based systems, possessing enhanced adaptability, versatility, and unexplored potential, presents fresh prospects for the advancement of biomedicine. By integrating the notion of intelligence into therapeutically and diagnostically significant systems, a fresh epoch of intelligent therapeutics can be initiated, enhancing the realm of healthcare. This mechanism has been recognized as a responsive framework for dispensing medications precisely at the designated location and moment, owing to its remarkable responsiveness to stimuli.

By integrating the concept of intelligence into therapeutically and diagnostically significant systems, a new era of intelligent therapeutics can be initiated, enhancing the field of healthcare. This responsive framework has been recognized as a mechanism for precise medication dispensing at specific locations and time points, thanks to its remarkable responsiveness to stimuli [9,10]. As one progresses from the stomach (pH 1.5-3) to the terminal ileum (pH 7-8) [11], the pH levels in the gastrointestinal tract gradually increase. pH-sensitive delivery systems utilize polymeric materials that are insoluble in the acidic environment of the upper gastrointestinal tract but dissolve in the higher, nearly neutral pH of the distal gut. Delivery systems activated by microflora are considered more desirable and have shown potential [12]. The human colon is a dynamic and ecologically diverse system that contains over 400 distinct bacterial species [13], which secrete various enzymes [14]. Non-starch polysaccharides serve as the main source of nutrition for bacteria and undergo fermentation in the colon, as they are not significantly degraded in the stomach and small intestine [15]. Currently, natural polysaccharides are commonly used in the production of solid dosage forms for drug delivery to the colon [16]. However, relying solely on pH-sensitive [11] or microflora-activated systems for colon-specific delivery is considered unreliable due to fluctuations in pH or water swelling within the gastrointestinal tract.

Chitosan, a natural polysaccharide with a high molecular weight, possesses numerous desirable properties, including complete biodegradability, non-toxicity, affordability, and favorable gelation characteristics [17]. It is important to note that chitosan is not susceptible to human digestive enzymes in the upper gastrointestinal tract [18,19], but can be hydrolyzed by microbial enzymes in the colon through glycosidic reactions [20,21,22]. Different forms of chitosan, such as capsules [23], matrices [24], hydrogels [25], and microspheres [26], are utilized in colon-targeted drug delivery systems, highlighting its potential as a coating material. However, it is crucial to consider that chitosan dissolves in acidic solutions, which may limit its applications in colon-targeted drug delivery.

The choice of an optimal nano-drug delivery system primarily depends on the biophysical and biochemical properties of the selected drugs for treatment [27]. However, it is important to consider the potential toxicity associated with nanoparticles in the field of nanomedicine. In recent years, there has been a growing trend of combining nanoparticles with natural products to address these toxicity concerns. The use of a green chemistry approach in the development of drug-loaded nanoparticles is strongly recommended as it reduces the presence of hazardous components in the biosynthetic process. Consequently, the use of green nanoparticles for drug delivery has the potential to mitigate the adverse effects of medications [28]. The current investigation aims to develop a drug delivery system using a nanocopolymer (Chitosan-co-HEMA) cross-linked with 1,6-hexandimethacrylate. The focus of this study is to evaluate and determine the drug delivery potential of the developed systems in various pH media.

Materials

1,6-hexanedioldiacrylate (HDODA), 5-Amino salicylic acid(5-ASA) sourced from ALDRICH, Chitosan obtained from HIMEDIA, 2-hydroxyethyl methacrylate (HEMA) provided by ALDRICH, 1-hydroxycyclohexyl phenyl ketone (photoinitiator) also acquired from ALDRICH, nitrogen cleansed, refined water, and phosphate buffer saline (PBS) obtained from HIMEDIA.

Instruments

The NMR spectra were acquired using a Bruker Ultra Shield 300 MHZ Switzerland instrument with Dichloromethane as the solvent. For the thermogravimetric analysis (TGA), the sample underwent heating from 40 to 500 oC at a rate of 10 oC/min in an argon atmosphere The USpicydownlight, (Bow, USND-1801 18W Driven, American, homogenizer(korea), and the American PerkinSTA6000 Differential warm examination (DSC) estimation device were utilized. The industry warmed ultrasonic cleaner warm, TESCAN Mira3 (Geoslovkia) filtering electron magnifying instrument (SEM) was used. The UV Biochrom 118034 Ultraviolet-Visible Spectrophotometer was used in Britain, and the PH-Meter from OHAUS (USA).

Synthesis for all nanopolymers nanocopolymers (Cs-co-HEMA) hydrogel

The hydrogel monomers, Chitosan (Cs) and 2-hydroxyethyl methacrylate (HEMA), were polymerized through free-radical polymerization in the presence of the crosslinking agent HDODA and the photoinitiator PI184. Cs was dissolved in acetic acid, while HEMA did not require this step. The polymerization process was carried out at room temperature for various durations according to Table 1. To remove oxygen from the reaction mixtures, degassing was performed using nitrogen for a period of 30 min. The organic phase was then introduced into an aqueous stabilizer mixture while being stirred with a homogenizer at a speed of 3000 rpm. The resulting emulsion was further stirred at room temperature for 15 min before being homogenized at 12700 rpm for an additional 15 min using a TOPS-SR30 homogenizer. The prepared combination was subsequently exposed to UV light below 365 nm for a duration ranging from 5 to 30 min. Following the polymerization process, the hydrogel lens was soaked in a liquid cleanser containing 20% ethanol to remove any residual photoinitiator and unreacted monomers. To rinse the ethanol from the lens, a sequence of rinses with a solution containing 0.625 wt % HDODA and 0.05 wt % PI184 was performed according to the total formulation.

Table 1: Formulations of Nano polymers hydrogel by monomers.

Sample

"Monomer1 / Wight (mg) "

"Monomer2/ Wight (mg) "

Copolymerization

Time irradiation

(min)

1

Chitosan 20 mg

HEMA / 400 mg

(Cs-co-HEMA)

4

Ultraviolet (UV) Measurements

The stacked and discharged sums of the show sedate Phenacetin were calculated at max 297.0 nm employing a UV/Vis Spectrometer and the Biochrom LDT Show.

pH Measurements

Citric acid/tri sodium citrate as well as sodium dihydrogen phosphate/disodium hydrogen phosphate were utilized, separately for plan buffer arrangements with concentrations of 2, 4, 7, and 8 [29].

Preparation of Calibration Curve

To minimize wavelength-setting errors, the researchers selected a wavelength that corresponded to the peak absorption region of the spectrum where only one component in the sample absorbs. This ensures accurate and precise measurements. Under the assumption that the Lambert-Beer law holds true and the drug concentration falls within the linear range of the instrument, two measurement methods were utilized.

For each set of samples, a suitable drug standard was prepared, and if available, a calibration curve passing through zero was established. If this was the case, the average was taken and the samples were measured in a bracketing manner, all at the same concentration, temperature, and solvent conditions, using identical cuvettes.

To establish a linear relationship between the concentration of 5-Amino salicylic acid and absorbance, regression analysis was performed on a standard curve. The standard curve was constructed using solutions prepared within the concentration range of 0.001 to 0.09 g L^-1, with distilled water as the solvent. The absorbance of these solutions was measured at a wavelength of 297.0 nm, with distilled water used as the blank. Similarly, a calibration curve was created using distilled water with a pH value of 7. The absorbance was determined at a wavelength of 297.0 nm.

Swelling Measurement

In this study, the dynamic swelling properties of the hydrogels were investigated in double-distilled water. The equilibrium swelling of the hydrogels was determined by using a gravimeter. Specifically, hydrogel samples weighing 0.1 g were immersed in 100 mL of different pH solutions (pH 2, 4, 7, and 8) for a duration of 10 days at various temperatures (37 and 39 °C) until reaching swelling equilibrium. After the swelling period, the swollen hydrogel samples were occasionally removed from the water, gently blotted with filter paper to remove any excess surface water, and weighed. The weights of the dry sample (Ws) and the swollen gel (Wd) were recorded at a specific time. To calculate the swelling degree of the hydrogels, the formula grams of water per grams of polymer (g/g) was utilized [30]. The swelling degree (g/g) can be determined using the equation:

Swelling Degree = (Ws - Wd) / 100Wd.

Loading Drugs to Nanopolymeric Hydrogels

In the drug loading process, the synthesized hydrogels were used and subjected to the swelling equilibrium technique. The hydrogels were allowed to swell in a predetermined concentration of drug solution for 24 hours at different pH levels (2, 4, 7, and 8). After the swelling period, the hydrogels were dried at room temperature, resulting in the removal of any unabsorbed drug solution from the polymer network. The concentration of the unabsorbed solution was then measured to determine the rate of drug adsorption within the hydrogel framework [31].

In Vitro Drug (5-Amino salicylic acid(5-ASA)) Release Studies

To calculate the amount of 5-Amino salicylic acid (5-ASA) released from the hydrogel matrix, a specific procedure is followed. Initially, a hydrogel sample is prepared by incorporating 100 mg of the drug, such as Benzocaine, into the hydrogel matrix. The sample is then dried and weighed to obtain the initial weight (e.g., 100 mg, 300 mg, or 500 mg). Next, the loaded hydrogel sample is immersed in 100 mL of different pH solutions (pH 2, 4, 7, and 8) for a duration of ten days. Each day, the solution is analyzed using a UV spectrophotometer at a maximum wavelength of 250 nm. The absorbance of the solution is measured, allowing for the determination of the concentration of 5-ASA present. By utilizing a calibration curve or known standards, the concentration of 5-ASA in the solution can be calculated. Multiplying this concentration by the volume of the solution (100 mL) yields the amount of 5-ASA released from the hydrogel on each specific day of the study [32]. The aforementioned steps are repeated for each day of the release study, enabling to track the cumulative amount of 5-ASA released over the ten-day period.

Synthesis and Characterization of Nanocopolymers

Synthesis and Characterization of (Cs-co-HEMA)"

The synthesis of the (Cs-co-HEMA) material involves copolymerizing Cs (Copolymerizable surfactant) and HEMA (2-hydroxyethyl methacrylate) using HDODA (1,6-hexanediol diacrylate) as a crosslinking agent and 1-hydroxycyclohexyl phenyl ketone as a photoinitiator. The process begins by mixing Cs, HEMA, HDODA, and the photoinitiator in a reaction vessel, followed by stirring in a dark environment at room temperature. Nitrogen gas is then purged over the mixture for 30 min to remove any dissolved oxygen. The mixture is poured into polypropylene molds to give it the desired shape, and it is cured under a 365 nm UV light for 4 min. This UV light activates the photoinitiator, initiating the polymerization reaction and resulting in the formation of the (Cs-co-HEMA) material. The reaction is illustrated at Scheme 1.

FTIR Spectroscopy of (Cs-co-HEMA)

The FTIR spectrum of (Cs-co-HEMA) exhibits multiple absorption bands at specific wavenumbers, offering information about the molecular structure of the copolymer. Among these absorption bands, important features include an absorption band at 3348 cm^-1, corresponding to the stretching vibration of the hydroxyl (-OH) groups present in the polymer. Additionally, absorption bands at 3292 cm^-1 (N-H stretching of Cs), 2943 cm^-1, and 2887 cm^-1 (C-H stretching of the polymer backbone), 1728 cm^-1 (C=O stretching, ester group), 1620 cm^-1 (N-H-C=O), 1170 cm^-1 and 1083 cm^-1 (C-O-C stretching), 1033 cm^-1 (-C-O of C-OH stretching), and 1170 cm^-1 (C-N stretching) are observed [33-35].

¹HNMR spectrum of (Cs-co-HEMA)

The ¹H NMR spectrum of (HEMA-co-Cs) displayed in Figure 2 exhibits distinct peaks at various chemical shifts, providing insights into the composition and structure of the copolymer. These peaks include a singlet at 0.9δ ppm for 3H of CH₃groups from both HEMA and HDODA, a multiplet ranging from 1.23 to 1.8 δ ppm for 2H of CH₂ groups from both HEMA and HDODA, a singlet at 2.1 δ ppm for 3H of the COCH₃ group, a singlet at 3.4 δ ppm for 1H of the OH group in HEMA, a singlet at 3.58 δ ppm for 2H of the CH₂OH group in HEMA, a multiplet ranging from 3.9 to 4.0 δ ppm for 2H of the COOCH₂ group in HEMA, a multiplet ranging from 4.2 to 4.8 δ ppm for 2H of the COOCH₂ group in HDODA, and a singlet at 5.58 δ ppm for 1H of the NH group in Cs [33-35].

Scanning Electron Microscopy

To examine the surface topography of the nanopolymer used in the study, a scanning electron microscopy (SEM) analysis was performed. In this analysis, the SEM imaging was utilized to investigate the morphology and structure of the nanopolymer. The copolymerization of Cs and HEMA resulted in the formation of a porous framework. These pores play a significant role as they provide regions where water can permeate and interact with the hydrophilic groups of the graft copolymers in response to external stimuli. Figure 3 presents the SEM micrograph, capturing the detailed surface features and dimensions of the nanopolymer at two different magnifications, specifically 200 nm and 500 nm.

X– Ray Diffraction Analysis (XRD)

X-ray Diffraction (XRD) is a widely used analytical technique employed to determine the phase composition, crystal structure, and grain size of various materials. XRD analysis of the catalysts in this study was performed at room temperature, utilizing an X-ray diffractometer with Cu Kα radiation. The measurements were conducted within the Bragg angle range of 10° ≤ 2θ ≤ 90°, with a scan speed of 2° per min. The fundamental principle underlying XRD analysis is described by:

2d_(hkl) sinθ = mλ

where λ represents the wavelength of the X-ray used, θ corresponds to the Bragg diffraction angle of the XRD peak measured in degrees (also known as the scattering angle), m is an integer representing the order of the diffraction peak, and d_(hkl) denotes the inter-plane distance between atoms, ions, or molecules.

Figure 4 displays the XRD spectra of the (Cs-co-HEMA) nanocopolymer. The analysis of the patterns revealed that the compounds exhibit a crystalline crystal structure. The diffraction peaks were observed within the range of 10°-75° in 2θ. Notably, all the nanocopolymer samples exhibited distinct peaks, including those at 2θ values of 29.7728, 31.800, 32.2032, 34.014640.2146, 45.6535, 56.9997, 66.5896, and 75.6692. Additionally, a broad peak was observed in these compounds. The diffraction peaks observed in the nanocopolymer samples can be attributed to the monoclinic system crystalline structure and nanostructure of (Cs-co-HEMA). This is evident not only from the peak positions but also from the relative intensity of the characteristic peaks. The crystalline nature of the (Cs-co-HEMA) nanocopolymer was confirmed by the XRD analysis. The crystallite size (D) of the nanocopolymer was calculated using:

D = (0.94 λ) / (β cosθ)

The calculation involved determining the full width at half maximum (FWHM) (β) of the preferred orientation diffraction peak. The Debye-Sherrer's equation was utilized for this purpose. The calculated crystallite sizes are presented in Table 2. The obtained results are in good agreement with the analysis conducted, confirming the crystalline nature of the (Cs-co-HEMA) nanocopolymer.

Table (2): X-ray diffraction parameters for Cs-co-HEMA.

Pos. [°2Th.]	Height [cts]	FWHM [°2Th.]	d-spacing [Å]	Rel. Int. [%]	Tip width [°2Th.]	D(nm)
29.7728	51.06	3.0867	2.99840	8.35	3.7040	0.47372
31.8000	611.63	0.1465	2.81173	100.00	0.1758	9.9834
32.2032	435.57	0.2223	2.77744	71.21	0.2667	6.58
34.0146	34.28	0.2316	2.63356	5.60	0.2780	6.315
40.2146	8.54	1.5168	2.24068	1.40	1.8201	0.9640
45.6535	399.26	0.4222	1.98558	65.28	0.5066	3.4639
56.9997	56.67	2.1676	1.61435	9.27	2.6011	0.6745
66.5896	24.08	1.2299	1.40323	3.94	1.4759	1.1888
75.6692	51.55	1.4130	1.25582	8.43	1.6956	1.0348

Degree of swelling of Cs-co-HEMA as function of Cs: HEMA composition ratio

Figure 5 depicts the time-dependent swelling behavior of the hydrogel PHEMA at different pH levels. The introduction of chitosan into the hydrogel formulation results in an increase in water content. This can be attributed to the presence of hydroxyl (-OH) and amino (-NH) groups in chitosan, which have the ability to form hydrogen bonds with water molecules. Consequently, the hydrogel exhibits a higher capacity to absorb and retain water. The Swelling Ratio, which is a measure of the amount of water absorbed by the hydrogel, reaches a value of 356. This significant increase in the Swelling Ratio indicates a substantial improvement in the hydrogel's water absorption capability. The incorporation of hydrophilic monomers, such as chitosan, proves to be effective in enhancing the water uptake capacity of hydrogels [36].

Analysis of drug (5-Amino salicylic acid) (5-ASA)

In drug-related work, accuracy and precision in analytical techniques are of utmost importance. Therefore, an initial UV-visible method was developed to analyze the component 5-Amino salicylic acid (5-ASA) in drug loading and release media. 5-Amino salicylic acid is commercially available in a crystalline form. To prepare a stock solution, the compound (5-ASA) can be dissolved in an organic solvent that has been purged with an inert gas. Although it is insoluble in ethanol, (5-ASA) can be dissolved in organic solvents such as dimethyl sulfoxide (DMSO) and dimethyl formamide (DMF). The solubility of (5-ASA) in DMSO is approximately 4 mg/ml, while in DMF it is around 1.6 mg/ml. Upon dissolution in either of these solvents, (5-ASA) forms a yellow-colored solution [37].

The effect of pH on the release of drug (5-ASA)

The release rates of 5-Amino salicylic acid (5-ASA) from Cs/HEMA hydrogels were measured at different pH levels (2, 4, 7, and 8), as depicted in Figures 6. Notably, the highest release rate of 5-ASA was observed at pH 8, which can be attributed to the hydrogels' greater swelling ratio. This can be explained by the presence of a high concentration of H⁺ ions, which promotes the ionization of NH₂groups and increases the overall ion number concentration within the gel matrix. Consequently, the hydrogels exhibit an enhanced ability to interact with water molecules through increased solvation. On the other hand, at a low pH of 2, the amino groups of Chitosan undergo protonation. This protonation leads to repulsion between the polymer chains and subsequent release of the drug. The decrease in release observed at pH 2 can be attributed to the diminished swelling ratio of the hydrogels. This reduction is a result of the deprotonation of the amino groups, which leads to a decrease in repulsion between the polymer chains and causes the hydrogels to shrink [39].

The effect of temperature on the release of drug (5-ASA)

The influence of temperature on the release of 5-Amino salicylic acid (5-ASA) has also been investigated in this study. According to Figure 7, it has been observed that the release rate is higher at 39 °C compared to 37 °C. This temperature-dependent variation can be attributed to the hydrogen bonding interactions among the amino groups present in the Chitosan chains. As the temperature increases, the polymer chains tend to unwind, leading to the disruption of secondary interactions such as intramolecular hydrogen bonding. This allows for a greater penetration of water into the gel network. Consequently, the swelling ratio of all hydrogels increases with the rise in temperature. This increase in the swelling ratio can have a significant impact on the release rate of 5-ASA by expanding the diffusion pathways within the superabsorbent material. The combined effect of increased water penetration and expanded diffusion pathways is believed to enhance the release rate of 5-ASA as the temperature rises [39].

The effect of amount of loading on release of drug (5-ASA)

In this study, a porous Cs/HEMA hydrogel was loaded with varying amounts of 5-Amino salicylic acid (5-ASA), and its release profile was examined at different pH levels (2, 4, 7, and 8). The results, illustrated in Figure 8, indicate that the loading capacity of 5-ASA increases as the concentration of the active agent in the loading medium is increased. Additionally, the release profiles demonstrate that the amount of 5-ASA released also increases with higher loading of the active agent. The speed at which the solvent front enters the hydrogel surface, known as the release rate, increases as the loading of 5-ASA increases. This phenomenon can be attributed to the presence of empty spaces or voids within the hydrogel matrix, which act as diffusion barriers and restrict the transportation of 5-ASA molecules. As the loading of 5-ASA increases, these empty spaces become more pronounced, hindering the release of the drug. It's important to note that the release of drugs through microspheres, such as the porous Cs/HEMA hydrogel in this study, is influenced by multiple factors. These factors include particle size, polymer crystallinity, surface properties, molecular weight, polymer composition, swelling ratio, degradation rate, drug binding affinity, and hydrogel rate [40].

In summary, the study concludes that the pH-sensitive swelling behavior and stability of Chitosan-modified hydrogel membranes are influenced by the cross-linking agent selection, hydrophilicity, and crosslinking density. The Donnan swelling equilibrium explains the expansion of Cs/HEMA hydrogels, controlled by the osmotic pressure gradient between the interior and exterior of the hydrogel. The hydrogels exhibit pH responsiveness, with maximum swelling at low pH levels and minimized swelling at high pH levels. Temperature also affects the swelling behavior, with higher temperatures leading to increased swelling ratios. The release rate of the drug (5-ASA) is influenced by pH and temperature, with higher release rates observed at pH 8 and elevated temperatures. Chitosan concentration was found to impact the drug release rate. These findings provide valuable insights for the development of pH-responsive and temperature-responsive drug delivery systems using Cs/HEMA hydrogels.

Data Availability

Not applicable.

Funding

Not applicable.

Author contributions

All authors contributed to the study’s conception and design. HSM wrote the first draft of the manuscript. SMA commented on first versions of the manuscript. All authors read and approved the final manuscript.

Ethics declarations

Research Involving Humans and Animals

None.

Informed Consent

None.

Competing Interests

The authors declare no competing interests.

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Scheme 1 is available in the Supplementary Files section.

No competing interests reported.

scheme1.png
Scheme 1: Synthesis of Cs-co-HEMA

pH-Sensitive Swelling Behavior and Drug Release Kinetics of Chitosan-Modified Cs/HEMA Hydrogels

Status:

Version 1

Abstract

Figures

Introduction

EXPERIMENTAL

Results and discussion

Conclusion

Declarations

References

Scheme

Additional Declarations

Supplementary Files

Status:

Version 1