Application of poly(Clove Oil)-Based Organo-Hydrogels for Drug Delivery Systems

doi:10.21203/rs.3.rs-4275923/v1

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Application of poly(Clove Oil)-Based Organo-Hydrogels for Drug Delivery Systems

https://doi.org/10.21203/rs.3.rs-4275923/v1

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Organo-hydrogels, which are polymeric and biocompatible materials, can control the rate of drug release and enable drugs to reach target sites easily. In the presented study, clove oil-based organo-hydrogels were synthesized for the first-time using agar(A), glycerol(G), and clove oil(ClO), which have biocompatible, antioxidant, and therapeutic properties, and were used as drug release support material for the first time. Gel(AG), hydrogel(p(AG-m) and p(AG-g)), and organo-hydrogels(p(AG-m-ClO) and p(AG-g-ClO) based) were synthesized by redox polymerization technique using N,N, methylenebisacrylamide(MBA) and glutaraldehyde(GA) crosslinkers. In addition, to observe the effect of the amount of clove oil, organo-hydrogels were synthesized with different oil ratios(between 0.1–0.3 mg).In this way were synthesized six different organo-hydrogels. Vitamin D and 5-Fluorouracil(5-Flu) were selected as model drugs. The structure of gel, hydrogel and organo-hydrogels cross-linked with MBA or GA reagent were elucidated by Fourier Transform Infrared Spectroscopy(FTIR),swelling analysis, blood coagulation, hemolysis analysis, and Antioxidant analysis. The FTIR results showed that the structure of Agar and Glycerol based gel and hydrogels was changed after adding clove oil. The results of blood clotting, hemolysis, and antioxidant analysis showed that the organo-hydrogels prepared were blood and biocompatible. The swelling analyses showed that varying amounts of clove oil affected the swelling capacity of organo-hydrogels. The slow-release properties and release kinetics(Zero-order kinetic(ZoKM),First-order kinetic(FoKM),Higuchi(HKM), and Korsmeyer-Peppas model(KPKM)) of organo-hydrogels as a function of pH were also investigated. The results showed that these new organo-hydrogels were not only blood compatible and biocompatible but also had good slow-release properties that can effectively improve the utilization of drugs.

Clove Oil

Organo-hydrogel

release mechanism

Supervised drug delivery systems; are the systems in which the drug active substances are designed to be released from a polymeric matrix to the targeted area in the desired time and amount [1]. Compared to conventional dosage forms, Controlled release systems have many advantages such as improved efficacy, reduced toxicity, and improved patient compliance and comfort [2]. Many studies in recent years have focused on biodegradable polymeric materials for drug release. With such systems, drug therapy control becomes advantageous because these materials can be easily swallowed, injected, or even adapted for the desired release profile, and in some cases, even organ-targeted release can be achieved [3, 4]. For this purpose, biodegradable polymers prepared with natural polymers such as cellulose, chitosan, alginate, gelatin, agar have a wide use as drug carriers in controlled drug release technology [5, 6]. In particular, organo-hydrogels prepared by adding vegetable oils to these polymeric structures have become the most advantageous, effective, and popular drug support material of recent times. Organo-hydrogels can be defined as semi-solid formulations with an immobilized external solvent phase located in a three-dimensional network structure formed by the combination of apolar and polar groups, namely gels (organogels) and hydrogels [7]. Organo-hydrogels are frequently preferred especially in controlled drug release systems, as they can be easily prepared in different geometric forms, are biocompatible and the drug substance is easily loaded into the structure. Thus, the negative parameters affecting the release of drug-active molecules from the structure of organo-hydrogels can be controlled [8–10].

The primary components of clove oil are eugenol 76.8–88%, β-caryophyllene 1.39–17.4%, α-humulene 2.1%, and eugenyl acetate 1.2-8%, caryophyllene 3.56%, 2-heptanone 0.93%, ethyl hexanoate 0.66%, humulenol 0.27%, α-humulene 0.19%, calacorene 0.11% and calamenene 0.10%. Clove oil is a combination of carmine, stomachic, and other drugs with tonic effects, and It can be combined with antitussive, expectorant, and other drugs used in gastrointestinal system diseases. The anticancer effect is known due to sesquiterpenes. Clove oil has traditionally been used in mouth health as an antiseptic and analgesic. It has been observed that eugenol, which is dense in essential oil, has antiseptic, antispasmodic, antihistamine, and anthelmintic properties [11–13].

Vitamin D is a class of steroids that have hormone-like properties. Vitamin D, commonly known as calciferol, belongs to the fat-soluble vitamin group. There are up to 10 distinct compounds that have a Vitamin D action [14]. Cholecalciferol (Vitamin D₃) and ergocalciferol (Vitamin D₂) are the most important physiologically and chemically. Vitamin D differs from other vitamins in several ways. To conclude, 7-dehydrocholesterol may be generated in the body, and 7-dehydrocholesterol converts to Vitamin D₃ in the skin when exposed to UV radiation. Under the same circumstances, ergosterol in vegetable oils converts to Vitamin D₂ [15]. Also, the coenzyme does not have active forms, and they often act on DNA with the formation of certain proteins. Both deficiency and excess of Vitamin D pose serious problems for the body. Vitamin D plays an important role in the absorption of calcium which is one of the main building blocks of bone, in the nervous system, in the functioning of the muscles and in the protection of immunity [16]. Although Vitamin D is not found in nature to a large extent, it is taken in three basic ways. Firstly, Vitamin D is either taken directly from foods or enriched by adding Vitamin D to foods and taken as such. Secondly, Substances containing Vitamin D are enriched in terms of Vitamin D content by exposing them to ultraviolet light as a precursor molecule. Thirdly, Vitamin D deficiency can be prevented by directly exposing the skin to sunlight [8, 17–19].

5-Fluorouracil (5-Flu) is one of the most widely used chemotherapy drugs for years. It is a drug that is active against many types of cancer and effectively inhibits the increase of DNA viruses. 5-Flu is especially used in digestive, breast, and ovarian cancers and metastases [20]. 5-Flu is a drug with side effects, its main side effects are various skin disorders (skin spots, deterioration of nails, hair loss, etc.), neuropsychic disorders (sleepiness, ataxia, etc.), and ocular disorders such as diarrhea and tearing [21]. To eliminate these side effects and to keep the concentration of 5-Flu in blood plasma at a therapeutic level for a long time, the preparation of controlled release forms of the drug is among the popular topics of recent times [8, 22, 23].

In the presented study, it was aimed to synthesize organo-hydrogels that will provide controlled release of the drug in order to both eliminate the side effects of drugs and keep the drug concentration in the body at a therapeutic level for a long time. The originality of the study was increased by using agar, glycerol, and clove oil, which have biocompatible, antioxidant, and therapeutic properties in organo-hydrogel synthesis. Thus, for the first time in the literature, organo-hydrogels based on cross-linked clove oil (in different amounts) were synthesized and used as a controlled drug release support material. Gel(AG), hydrogel(p(AG-m) and p(AG-g)), and organo-hydrogels(p(AG-m-ClO) and p(AG-g-ClO) based) were synthesized by redox polymerization technique using N, N, methylenebisacrylamide(MBA) and glutaraldehyde(GA) crosslinkers. Structure and morphological properties of synthesized new organo-hydrogels, dynamic swelling analysis (ID water, tap water, ethanol, acetone, ethanol/ID water (1:1), acetone/ID water (1:1), gasoline and pH 2–12), FTIR analysis, blood compatibility were separately elucidated by biocompatibility and antioxidant tests. At the same time, the effects of both crosslinkers and different clove oil amounts on the drug release efficiency of the synthesized organo-hydrogels were also investigated. Vitamin D and 5-Flu cancer drugs, which we constantly encounter in daily life, were chosen as target drugs. The release efficiency, release mechanism, and kinetics of these drugs have been studied in detail. In the light of the findings, it can be said that the new clove oil-based organo-hydrogels we have synthesized have a great potential for use as a controlled drug release support material when examined in terms of applicability, biocompatibility, and synthesis from natural materials.

2.1 Reagents

Glycerol (G), agar (99%), N, N, methylenebisacrylamide (MBA, 99%), glutaraldehyde (GA, 25% v/v), ethanol, acetone, calcium chloride (CaCl₂), sodium hydroxide (NaOH) and hydrochloric acid (HCl) (36.5–38% v/v) were purchased from Sigma; ammonium persulfate (APS, 98%), N, N, N’, N’-tetramethylethylenediamine (TEMED, 99%) were purchased from Merck. In terms of analytical grade, all reagents were of the highest cleanliness available, and they were used without additional purification. Clove Oil (ClO), gasoline, D-Vitamin and 5-Fluorouracil were procured from local suppliers. Distilled water (ID water, 18.2 MΩ cm; Human I) was also employed from the beginning to the end of this study.

2.2. Experimental procedures

2.2.1. Synthesis of agar-Glycerol-based gels, hydrogels, and organo-hydrogels based on clove oil

Agar-Glycerol-based gels, hydrogels, and ClO-based organo-hydrogels were obtained using a free radical polymerization technique in an emulsion medium, as described in Tables 1 and 2 [24]. Briefly, gel and hydrogel were synthesized as follows; First, 2% Agar solution (w/v) was prepared by dissolving agar in distilled water at 80°C. Then, 2 mL of 2% agar solution and 0.04 mL of Glycerol were added into the 20 mL reaction flask and mixed thoroughly until it became homogeneous at a mixing speed of 2500 rpm. Then, this mixture was transferred to pipettes with a diameter of 5 mm and waited until the gelation reaction was completed. In the synthesis of hydrogels, two separate 20 mL reaction flasks were taken, and 2 mL of 2% agar solution and 0.04 mL of Glycerol were added separately and mixed well (2500 rpm). MBA (0.01 g) and GA reagent (0.5 mL GA + 0.5 mL ethanol + 0.1 mL HCl) were added separately as crosslinkers to reaction flasks number one and two, respectively, and mixed well. After the MBA crosslinker was added and dissolved well, 10 µL of TEMED and 0.1 mol% APS solution (in 100 µL of ID water) were added to the first reaction flask, respectively, and mixed well. Finally, one and two number reaction mixtures were pipetted separately and waited until the polymerization reaction was completed (approximately 3 hours). Then, the resulting gel and hydrogels were removed from the polymerization medium, cut into 6 mm long cylinders, washed with ID water and dried in an oven at 40°C. The codes of the gels and hydrogels were given in Tables 1 and 2 [17].

Table 1

Codes of different gel, hydrogel and organo-hydrogel
Gel	Code
Agar-Glycerol	AG
Hydrogel	Code
poly(Agar-co-Glycerol)/MBA	p(AG-m)
poly(Agar-co-Glycerol)/GA	p(AG-g)
Organo-hydrogel	Code
poly(Agar-co-Glycerol-co-Clove Oil)/MBA-1	p(AG-m-ClO)¹
poly(Agar-co-Glycerol-co-Clove Oil)/MBA-2	p(AG-m-ClO)²
poly(Agar-co-Glycerol-co-Clove Oil)/MBA-3	p(AG-m-ClO)³
poly(Agar-co-Glycerol-co-Clove Oil)/GA-1	p(AG-g-ClO)¹
poly(Agar-co-Glycerol-co-Clove Oil/GA-2	p(AG-g-ClO)²
poly(Agar-co-Glycerol-co-Clove Oil)/GA-3	p(AG-g-ClO)³

Table 2

Compositions and codes of different gel, hydrogel and organo-hydrogel
Agar	Glycerol	ClO	Crosslinker	Code
2% − 2 mL	0.04 mL	--	--	AG
2% − 2 mL	0.04 mL	---	MBA	p(AG-m)
2% − 2 mL	0.04 mL	---	GA	p(AG-g)
2% − 2 mL	0.04 mL	0.1 mL	MBA	p(AG-m-ClO)¹
2% − 2 mL	0.04 mL	0.2 mL	MBA	p(AG-m-ClO)²
2% − 2 mL	0.04 mL	0.3 mL	MBA	p(AG-m-ClO)³
2% − 2 mL	0.04 mL	0.1 mL	GA	p(AG-g-ClO)¹
2% − 2 mL	0.04 mL	0.2 mL	GA	p(AG-g-ClO)²
2% − 2 mL	0.04 mL	0.3 mL	GA	p(AG-g-ClO)³

Clove oil-based organo-hydrogel synthesis; First, six separate 20 mL reaction flasks were taken, and 2 mL of 2% agar solution and 0.04 mL of Glycerol were added separately and mixed well (2500 rpm). Then, 0.1, 0.2, and 0.3 mL of ClO and 0.01 g of MBA crosslinker were added separately to the first three reaction flasks. After obtaining a homogeneous mixture, 10 µL of TEMED and 0.1 mol% APS solution (in 100 µL of ID water) were added to these three reaction mixtures, respectively, and mixed well. Finally, these three reaction mixtures were pipetted separately and waited until the polymerization reaction was completed (approximately 3 hours). At the same time, 0.1, 0.2, and 0.3 mL ClO and GA reagent (0.5 mL GA + 0.5 mL ethanol + 0.1 mL HCl) were added separately to the other three reaction flasks containing Agar- Glycerol and mixed well. Finally, these three reaction mixtures were pipetted separately and waited until the polymerization reaction was completed (approximately 3 hours). The six different organo-hydrogels obtained were removed from the polymerization medium, cut into 6 mm long cylinders, washed with ID water, and dried in an oven at 40°C. The codes of the synthesized organo-hydrogels are given in Tables 1 and 2.

ClO-based drug-loaded organo-hydrogel synthesis; In order to preserve the effectiveness of the active ingredient, Vitamin D and 5-Fluorouracil were added to the structure during organo-hydrogel synthesis and were physically bound [8, 25]. Therefore, the procedure applied in the synthesis of drug-loaded ClO-based organo-hydrogel was the same as the synthesis procedure described in the previous paragraph. The only difference was that 50 ppm 1mL of Vitamin D and 5-Fluorouracil drugs were added separately to the above-mentioned reaction mixtures at the last moment, mixed well, and pipetted. It waited until the polymerization reaction was completed (approximately 3 hours). The resulting drug-loaded organo-hydrogels were removed from the polymerization medium, cut into 6 mm long cylinders, washed with ID water, and dried in an oven at 40°C.

2.2.2. Swelling analysis

Swelling behavior of gels, hydrogels, and organo-hydrogels synthesized by redox polymerization in emulsion medium, ID water, tap water, ethanol, acetone, ethanol/ID water (1:1), acetone/ID water (1:1), gasoline, and different pH (2–12) were examined with the method suggested by Alpaslan et al. and Dudu et al. [5, 26]. Swelling experiments were performed at 25ºC room temperature.

2.2.3. Fourier transform infrared spectroscopy (FTIR) analysis

FT-IR analyses of the synthesized AG, p(AG-m), p(AG-g), and organo-hydrogels were carried out with Thermo Scientific brand Nicolet iS10 model (USA) Attenuated Total Reflection (ATR) embedded Fourier Transform Infrared Spectroscopy device. FT-IR analysis was performed to identify and examine possible interactions, bond structures, and functional groups among all chemicals used to synthesize the gel, hydrogel, and organo-hydrogels. The gel, hydrogels, and organo-hydrogels were powdered and then put on the ATR sample plate. With a resolution of 4 cm^− 1, the spectral range was examined from 4000 to 650 cm^− 1.

2.2.4. Analysis of blood clotting and hemolysis

It is of great importance to investigate whether the synthesized AG, p(AG-m), p(AG-g), and organo-hydrogels will fulfill the requirements of the intended use and whether they are biologically compatible. Therefore, to evaluate the blood clotting [17, 27] and hemolysis analyzes [8, 28] of AG, p(AG-m), p(AG-g), and organo-hydrogels we synthesized, the analysis methods described in the literature were applied and their biocompatibility performances were examined.

2.2.5. Antioxidant analysis

Whether synthesized AG, p(AG-m), p(AG-g), and organo-hydrogels bind free radicals in the body and reduce their harmful effects is very important in terms of antioxidant activity. For this reason, Folin-Ciocalteu [29, 30] and ABTS [31] techniques, as described in the literature, were used to assess antioxidant activity.

2.3. Vitamin D and 5-Fluorouracil release studies

Vitamin D is very important for maintaining the continuity of body functions. This vitamin, which acts as both a vitamin and a hormone in the body, has many important roles such as healthy bone and tooth development, supporting immune, brain and nervous system health, regulating insulin levels, and supporting diabetes management. 5-Flu, on the other hand, is a drug called antimetabolite, which prevents tumor cells from dividing. It is known to be an effective drug in the treatment of many cancer diseases such as breast, bowel, stomach, head, neck, and pancreas. Since the two drugs mentioned are of great importance for human life, the controlled release of these drugs is of great importance for our study and constitutes our main aim. Therefore, in the present study, the usability of synthesized drug-loaded AG, p(AG-m), p(AG-g), and organo-hydrogels as controlled drug release support materials was investigated. In order to measure the drug release rates of AG, p(AG-m), p(AG-g), and organo-hydrogels synthesized in different formulations, samples containing 50 mg of the drug (50 ppm) were placed separately in 50 mL beakers and buffer solutions prepared at different pH values were added. Release studies were carried out at 37.5°C at certain time intervals at pH 2, 5.5 7.4, and 8 for vitamin D, and pH 7.4 for 5-Flu. In order to determine the amount of vitamin D and 5-Flu drug released from AG, p(AG-m), p(AG-g), and organo-hydrogels, 1 mL sample was taken from the release medium at certain time intervals and the amount of drug released was measured by UV spectrophotometer. The amount of released vitamin D and 5-Flu drug were measured at 237 nm and 268 nm wavelengths, respectively. Each measurement was performed in triplicate and the average was taken with the standard deviation values.

2.3.1. Drug release kinetics

For soluble matter release from controlled release systems, many theories and kinetic models have been developed. The release rate and diffusion behavior of the soluble component from the polymer may be easily established by comparing experimentally acquired release data with theoretically constructed release kinetic models. To illuminate the drug release mechanism in the prepared AG, p(AG-m), p(AG-g), and organo-hydrogel-drug transport system, experimentally obtained release data were applied to four different release kinetics models as zero order kinetic model (ZoKM) (Eq. (11)) [32], first order kinetic model (FoKM) (Eq. (12)) [32], Higuchi Model (HKM) (Eq. (13)) [33] and Korsmeyer-Peppas Model (KPKM) (Eq. (14)) [34] (In Table 3 were given).

Table 3

Mathematical models for drug release.
Model	Mathematical Equation	Release Mechanism	Codes
Zero order kinetic model	\({\text{C}}_{\text{r}}={\text{C}}_{0}-{\text{k}}_{0}.\text{t}\)	Diffusion Mechanism	ZoKM
First order kinetic model	\(\text{l}\text{n}{\text{C}}_{\text{r}}=\text{l}\text{n}{\text{C}}_{0}-{\text{k}}_{1}.\text{t}\)	Fick’s first law, diffusion Mechanism	FoKM
Higuchi Model	\(\frac{{\text{C}}_{\text{r}}}{{\text{C}}_{{\infty }}}={\text{k}}_{\text{H}}.\sqrt{\text{t}}\)	Diffusion medium based Mechanism in Fick’s first law	HM
Korsemeyer-Peppas Model	\(\text{l}\text{n}\frac{{\text{C}}_{\text{r}}}{{\text{C}}_{{\infty }}}=\text{l}\text{n}{\text{k}}_{\text{K}\text{P}}+\text{n}.\text{l}\text{n}\text{t}\)	Semi empirical model, diffusion-based mechanism	KPM
C_r is concentration of drug release in time t (mg/L); C₀ is the initial concentration of drug in the solution (most times, C₀ = 0) (mg/L); k₀ is the zero order release constant expressed in units of concentration/time (mg/(L.min)); t is time (min); k₁ is the first order release constant (1/min); C_∞ is concentration of drug release in equilibrium (mg/L); k_H is Higuchi release rate constant (1/\(\sqrt{\text{m}\text{i}\text{n}}\)); k_KP is Korsmeyer-Peppas release rate constant; n is release exponent which is indicative of the transport mechanism (M_t/M_∞ < 0.6 should only be used.

3.1. Bonding mechanism of gel, hydrogel, organo-hydrogels

In the presented study, gel, hydrogel, organo-hydrogel, and drug-loaded support materials, which had different formulations, were synthesized using agar, glycerol, and clove oil. Agar, which is a polyanionic carbohydrate and abundant -OH groups, was used because of its ability to gel at low concentrations and its naturalness. Glycerol, on the other hand, was preferred because it is active in preserving the structure of biological macromolecules, promoting protein self-assembly through preferential hydration, and easily changing the viscosity of a liquid over a wide range due to its hydrogen bond structure. In particular, glycerol-water systems are known as hydrogen bonding fluids due to the presence of oriented H-bonds, and their mixtures have a special place among complex systems. Therefore, by forming H-bonds between agar-glycerol-water, the AG gel, which we call gel, was synthesized and the relatively easy rearrangement property of H bonds, unlike covalent bonds, was exploited. [24, 35, 36] In hydrogel synthesis, MBA and GA reagents were added as crosslinkers to the agar-glycerol-water system and the polymerization was strengthened by cross-links. These structures with both hydrogen bonds and cross-links were called hydrogels. By adding clove oil to the hydrogel structure, structures that we call organo-hydrogel, in which both hydrophilic and organic structures are combined, were synthesized. With the CH₂ = CH₂ groups in the clove oil structure, the number of cross-links was increased, and a nested network structure was obtained. At the same time, the presence of H-bonds in the environment strengthened the bond structure. In the synthesis of drug-loaded support materials, Vitamin D and 5-Flu drugs were physically bound to the structure. The physical binding of drugs was supported by drug release data.

3.2. Swelling test

After the cross-linked, networked polymers are placed in the appropriate solvent environment, hydrophilic groups in the molecule interact with each other when the solvent enters the structure, and swelling begins. As a result of diffusion of solvent, hydrogen bonds between polymer molecules weaken and solvent-polymer hydrogen bonds are formed instead of these intramolecular hydrogen bonds. After a certain time, the rate of solvent entering the gel and the rate of release from the gel become equal. This situation: is the equilibrium state where the maximum swelling value is reached. It is important to examine the swelling kinetics and elucidate the swelling mechanism in the characterization of network polymers that exhibit swelling behavior.

Swelling analyzes were carried out in different water types to observe the change in swelling values of dry AG, p(AG-m), p(AG-g) and organo-hydrogels in water and organic solvent mixtures as a function of solvent concentration and to determine equilibrium swelling values. The results of the swelling analysis performed in different water and organic solvent mixtures were given in detail in Fig. 1a-b. In the swelling analyzes performed in ID water, tap water, ethanol, acetone, ethanol/ID water, acetone/ID water and gasoline, it was determined that AG, p(AG-m), p(AG-g) exhibited low swelling ability in organic solvents. At the same time, the swelling capacity in ID water and tap water media increased by 15% and 53%, respectively, after the AG gel was crosslinked with MBA. Moreover, after crosslinking the AG gel with the GA reagent, the swelling capacity in ID water and tap water media increased by 25% and 27%, respectively. In contrast to gels and hydrogels, clove oil-based organo-hydrogels have been observed to exhibit swelling ability not only in distilled water and tap water, but also in other organic solvent media. A remarkable increase was observed especially in ethanol/ID water (1:1) and acetone/ID water (1:1) environments. When the charts were examined, the percentage of swelling values changed with the change of Clove oil amount in organo-hydrogels. When Fig. 1b is examined, it is concluded that organo-hydrogels, especially in ID water, tap water, ethanol/ID water (1:1) and acetone/ID water (1:1) media, exhibit similar swelling behavior. The maximum swelling capacities of p(AG-m-ClO)¹, p(AG-m-ClO)², p(AG-m-ClO)³, p(AG-g-ClO)¹, p(AG-g-ClO)² and p(AG-g-ClO)³ organo-hydrogels were found to be 65% (tap water), 60% (ID water), 39% (ID water), 67% (ID water), 49% (tap water) and 36% (ID water), respectively. In the light of the findings, it can be said that the most important factors affecting the swelling capacity of clove oil-based organo-hydrogens are the excess of functional groups from ClO and crosslinker.

In addition, swelling behavior of AG, p(AG-m), p(AG-g) and organo-hydrogels in liquid media prepared between pH 2 and 12 at room temperature were determined and the results were given in Figs. 1c-d. When Fig. 1c was examined, it was observed that AG is not sensitive to pH since it does not contain ionizable groups in the gel structure [9]. However, when MBA and GA crosslinkers were added to the AG gel structure, it was observed that the number of ionizable groups increased and became sensitive to changes in pH values. According to Fig. 1c, AG gel and p(AG-m) and p(AG-g) hydrogels were found to exhibit similar swelling behavior when compared among themselves. The highest swelling values of AG, p(AG-m), and p(AG-g) were 89% (pH 10), 121% (pH 12) and 103% (pH 10), respectively. When the swelling balance values of p(AG-m-ClO) and p(AG-g-ClO) organo-hydrogels at different pH values are compared (Fig. 1d); It was observed that the swelling values decreased as the ClO ratio increased. The decrease in pH sensitivity as the amount of clove oil increases can be explained by the fact that the active functional groups in the structure are affected by the ion mobility in the environment and negatively affect the swelling ability. The fact that AG, p(AG-m), p(AG-g) and organo-hydrogels exhibit different swelling abilities in different liquid and pH environments reveals the idea that the synthesized materials will offer ease of use in multifunctional areas.

3.3. Fourier transform infrared spectroscopy (FTIR)

Necessary spectroscopic studies to elucidate the chemical structures of AG, p(AG-m), p(AG-g), and organo-hydrogels and to examine possible bond structures were made with FT-IR spectrophotometer and their spectra are given in Fig. 2. When Fig. 2 was examined, the broad and strong peaks that appeared at 3750 − 3000 cm^− 1 are ascribed to the -OH band of agar, glycerol, and clove oil. Also, the OH stretch peak attributable to the intermolecular hydrogen bonding between the hydroxyl groups on the Agar and glycerol structures shifted slightly to a lower region after clove oil was added (from 3328 cm^− 1 to 3260 cm^− 1 for p(AG-m-ClO³) and from 3328 cm^− 1 to 3311 cm^− 1 for p(AG-g-ClO³)). It was determined that the peaks observed in approximately 2928 cm^− 1, 2927 cm^− 1, 2925 cm^− 1, 2922 cm^− 1, 2880 cm^− 1, 2877 cm^− 1, 2856 cm^− 1, and 2853 cm^− 1 in all spectra belonged to the C-H stretch band and the intensity of these peaks increased after the addition of clove oil. In addition, it was observed that the peaks observed at 1646 cm^− 1, 1646 cm^− 1, and 1654 cm^− 1 in the spectra of AG, p(AG-m), and p(AG-g) belonged to the C = O band and these peaks shifted to 1743 cm^− 1 after adding clove oil to the structure. It can be said that new bonds are formed between 1679 cm^− 1 and 1437 cm^− 1 after the clove oil is added and these bonds belong to C = C, O-H, and C-H (belong to alkane and alkene) bonds. In addition, it was observed that the intense peaks observed at approximately 1035 cm^− 1 belonged to the C-O bond and the intensity of this bond changed with the addition of clove oil. When all FTIR spectra were examined, it was concluded that with the addition of clove oil to the structure, remarkable new bonds were formed in the structure and the strength of the existing bonds changed and shifted, and organo-hydrogels with new properties were successfully synthesized.

3.4. Blood clotting and hemolysis tests

Since the developed biomaterials remain in contact with the blood for a long time and/or constantly, the harmful effects of these materials on the blood should be evaluated before being used widely. Biomaterial design for biological environments is extremely difficult due to the presence of a dynamic element that interacts with each other. Chief among these factors is the chemical structure of the biomaterial surface and its response to the interaction of the biomaterial-blood interface layer. Therefore, hemolysis and blood coagulation analyze were performed to see the response of the interaction between AG, p(AG-m), p(AG-g), ClO, and organo-hydrogels and blood. The findings of the blood compatibility and hemolysis tests were reported in Fig. 3. Hemolysis results for AG, AG-m, AG-g, ClO, p(AG-m-ClO)¹, p(AG-m-ClO)², p(AG-m-ClO)³, p(AG-g-ClO)¹, p(AG-g-ClO)², and p(AG-g-ClO)³ at 5 mg/mL concentration were calculated as 0.65%, 0.17%, 0.54%, 0.67%, 0.79%, 0.33%, 0.18%, 0.34%, 0.91% and 0.91%, respectively. A hemolysis rate of less than 5% indicates that there is no hemolytic effect. [17] Therefore, it was predicted that gel, hydrogel, organo-hydrogel, and ClO had hemolysis values less than 1% even at high concentrations such as 5 mg/mL, and these materials had a high potential to be used as safe biomaterials in terms of hemolysis. At the same time, another way to evaluate the blood compatibility of gel, hydrogel, organo-hydrogel, and ClO is to determine the blood clotting index (BCI). When Fig. 3b is examined, it is seen that AG, AG-m, AG-g, ClO, p(AG-m-ClO)¹, p(AG-m-ClO)², p(AG-m-ClO)³, p(AG-g-ClO)¹, p(AG-g-ClO)², and p(AG-g-ClO)³ have blood coagulation indices of 5.8%, 5.7%, 3.1%, 2.2%, 5.8%, 6.1%, 6.8%, 5.7%, 6.1%, and 2.5%, respectively. In the light of the obtained hemolysis and blood clotting data, it can be said that gel, hydrogel, organo-hydrogel, and ClO are compatible with blood.

3.5. Antioxidant analysis

Clove is a plant with strong antioxidant properties. Eugenol is a major part of clove extract and is the antioxidative element of clove oil. In many studies on the subject, it has been stated that clove has a strong antioxidative effect as BHT (butylated hydroxy toluene) and BHA (butylated hydroxy anisole) [37]. Table 4 showed the gallic acid equivalent value of the antioxidant activity of ClO and organo-hydrogel. According to the results obtained, it was observed that organo-hydrogels cross-linked with GA reagent exhibited a higher antioxidant effect than the others. Although ClO alone exhibits a high antioxidant effect, a significant amount of antioxidant activity was achieved after adding clove oil to the organo-hydrogel structure. It has been determined that the clove oil-based organo-hydrogels we synthesized have higher antioxidant activity than the other vegetable oil-based organo-hydrogels synthesized in the literature [6, 8–10, 18].

Table 4

Total phenol content values.
Substance	Total phenol (mg)
Organo-hydrogel
p(AG-m-ClO)¹	1663
p(AG-m-ClO)²	1274
p(AG-m-ClO)³	2207
p(AG-g-ClO)¹	3421
p(AG-g-ClO)²	3421
p(AG-g-ClO)³	3927
Oil
Clove Oil	7141

3.6. Vitamin D and 5-Fluorouracil release studies

Controlled release systems must be able to regulate the rate at which dissolved substances are released as a function of time. Organo-hydrogels, which are among the materials that can be used, have very suitable properties for this application. Therefore, the release of bioactive compounds may be controlled in pharmaceutical applications, which is one of the most significant uses of organo-hydrogels. Organo-hydrogels are a useful carrier in the release of biomolecules due to their many unique properties.

Drug release behaviors of organo-hydrogels loaded with 50 ppm drug (vitamin D or 5-Fluorouracil) at different pHs (2, 5.5, 7.4, 8) at 37.5°C were investigated as a function of time and the results were shown in Fig. 4. Considering the delivery methods of drugs to the human body, in vitro gastric, intestinal, oral blood, and skin environments were imitated to perform vitamin release from vitamin D-loaded organo-hydrogels, while the oral blood environment was imitated for 5-Flu release. In the study presented by Alpaslan et al., vitamin D release by AG, p(AG-m), and p(AG-g) was found to be 2.79% (pH 5.5), 6.07% (pH 2-7.4), and 4.43% (pH 7.4), respectively. [17] In addition, in the study presented by Olak et al., 5-Flu release of AG, p(AG-m), and p(AG-g) was found to be 0.73% (pH 7.4), 0.71%, (pH 7.4), and 0.8% (pH 7.4), respectively [5]. In this study, vitamin D and 5-Flu drug release behaviors of clove oil-based organo-hydrogels were examined in detail. When looking at Fig. 4, it was founded that the Vitamin D and 5-Flu drug release rates of all organo-hydrogels were quick at first due to the concentration difference, but then slowed after 600 minutes. Initially, as the solution enters the structure, the dry organo-hydrogels begin to swell, and at the same time, it can be said that the drug molecules diffuse into the solvent environment by reverse diffusion. As the solvent-drug diffusion approaches the equilibrium position, it decreases over time and reaches a constant value after a while. After this stage, drug molecules are released by structural degradation in residual organo-hydrogels. When the Vitamin D release graphs were examined, it was observed that organo-hydrogels generally exhibited better release behavior at pH values above 5.5. The maximum vitamin D release for p(AG-m-ClO)¹, p(AG-m-ClO)², p(AG-m-ClO)³, p(AG-g-ClO)¹, p(AG-g-ClO)², and p(AG-g-ClO)³ organo-hydrogels was 46% (pH 7.4), 88% (pH 7.4), 97% (pH 8), 43%(pH 8), 63% (pH 7.4), and 81% (pH 8), respectively. When the release behavior of organo-hydrogels was evaluated in terms of cross-linking agents, it was determined that organo-hydrogels cross-linked with MBA exhibited better release behavior. In addition, it was observed that the amount of clove oil and the amount of vitamin D released changed in direct proportion. When Fig. 4e was examined, it was observed that all organo-hydrogels exhibited similar 5-Flu drug release behavior. The highest 5-Flu drug release amount reached after 600 minutes was found as 30%, 30%, 37%, 21%, 25%, and 40% for p(AG-m-ClO)¹, p(AG-m-ClO)², p(AG-m-ClO)³, p(AG-g-ClO)¹, p(AG-g-ClO)², and p(AG-g-ClO)³, respectively. The obtained 5-Flu drug release results show that clove oil-based organo-hydrogels have a very slow-release feature for 5-Flu drug and some of the drugs in the structure will be released into the environment as a result of structural degradation. It was observed that the amount of 5-Flu drug release increased with the increasing amount of clove oil. In line with the release data obtained, it can be said that the structural functionality increases with the increase in the amount of clove oil added to the structure, and in parallel with this, the amount of both bound and released drug increases. Similar findings have been reported in the literature [38–45].

3.7. Drug release kinetics

Release kinetics and mechanisms are of great importance for the design of controlled slow-release systems and can be easily explained by mathematical modeling. In this study, four different mathematical models were used to find drug release kinetics and the calculated model constants and R² values were given in Tables 5 and 6. The highest correlation coefficient value represents the most appropriate mathematical model showing drug release kinetics. As shown in Table 5, the Vitamin D release kinetics of the organo-hydrogels were found to generally match HKM, KPKM, and FoKM at all pH values. 5-Flu release kinetics were found to be more suitable for HKM (Table 6). The diffusional constant (n) values reflecting the release mechanism predicted using the KPKM were founded as either less than 0.45 or between 0.45 and 0.89, as shown in Table 5. As a result, with n values less than 0.45, the Fickian diffusion mechanism is effective, and the relaxation time of the organo-hydrogel is less than the diffusion time of water. It may be concluded that a non-Fickian (abnormal) diffusion mechanism is effective for n values between 0.45 and 0.89 and that diffusion and relaxation are effective in the release process [26]. When Table 6 was examined, it was found that the diffusion constant values of 5-Flu drug release were either between 0.45 and 0.89 or greater than 0.89. These results prove that the synthesized clove oil-based organo-hydrogels will provide advantages in drug delivery systems and that drug release can be controlled by changing the amount of clove oil.

Table 5

Release kinetic and mechanism of Vitamin D release.
p(AG-m-ClO)¹		2	5.5	7.4	8	p(AG-g-ClO)¹		2	5.5	7.4	8
ZoKM	Co	2.819	2.864	6.882	6.341	ZoKM	Co	6.685	2.893	0.573	4.140
	ko	-0.007	-0.010	-0.021	-0.028		ko	-0.017	-0.010	-0.019	-0.023
	R²	0.835	0.979	0.836	0.961		R²	0.746	0.928	0.988	0.981
FoKM	Co	0.945	0.913	4.933	4.967	FoKM	Co	2.127	1.212	3.57	4.613
	k1	-0.002	-0.002	-0.028	-0.031		k1	-0.001	-0.002	-0.019	-0.022
	R²	0.945	0.913	0.841	0.914		R²	0.748	0.860	0.988	0.991
HKM	kh	0.034	0.020	0.008	0.028	HKM	kh	0.048	0.032	0.036	0.037
	R²	0.997	0.965	0.959	0.959		R²	0.990	0.975	0.991	0.993
KPKM	n	0.316	0.347	0.329	0.354	KPKM	n	0.196	0.418	0.486	0.505
	kkp	9.729	15.007	15.927	12.767		kkp	3.452	16.718	24.073	33.315
	R²	0.977	0.955	0.958	0.896		R²	0.805	0.954	0.996	0.996
p(AG-m-ClO)²		2	5.5	7.4	8	p(AG-g-ClO)²		2	5.5	7.4	8
ZoKM	Co	2.440	0.550	10.183	7.404	ZoKM	Co	2.366	2.544	9.160	11.166
	ko	-0.007	-0.016	-0.023	-0.024		ko	-0.014	-0.011	-0.034	-0.029
	R²	0.968	0.973	0.946	0.987		R²	0.919	0.951	0.997	0.981
FoKM	Co	7.833	11.147	0.451	1.074	FoKM	Co	0.987	1.079	9.160	12.0
	k1	-0.002	-0.003	-0.019	-0.023		k1	-0.003	-0.002	-0.034	-0.027
	R²	0.994	0.970	0.824	0.994		R²	0.748	0.853	0.997	0.994
HKM	kh	0.039	0.029	0.024	0.028	HKM	kh	0.036	0.037	0.038	0.038
	R²	0.996	0.828	0.952	0.959		R²	0.997	0.969	0.992	0.992
KPKM	n	0.427	0.825	0.102	0.393	KPKM	n	0.468	0.593	0.467	0.233
	kkp	17.633	218.176	2.451	13.150		kkp	26.706	47.527	22.354	5.232
	R²	0.938	0.973	0.991	0.989		R²	0.974	0.970	0.986	0.964
p(AG-m-ClO)³		2	5.5	7.4	8	p(AG-g-ClO)³		2	5.5	7.4	8
ZoKM	Co	2.641	1.183	3.724	0.932	ZoKM	Co	1.443	1.252	4.046	6.985
	ko	-0.019	-0.013	-0.029	-0.024		ko	-0.023	-0.014	-0.035	-0.038
	R²	0.854	0.943	0.937	0.906		R²	0.930	0.957	0.964	0.899
FoKM	Co	1.263	0.664	5.009	5.308	FoKM	Co	1.430	1.048	5.712	11.307
	k1	-0.003	-0.003	-0.025	-0.021		k1	-0.002	-0.002	-0.031	-0.028
	R²	0.687	0.838	0.986	0.989		R²	0.832	0.969	0.999	1.000
HKM	kh	0.025	0.039	0.030	0.025	HKM	kh	0.030	0.033	0.036	0.036
	R²	0.944	0.994	0.989	0.953		R²	0.985	0.977	0.994	0.994
KPKM	n	0.426	0.544	0.422	0.422	KPKM	n	0.626	0.533	0.560	0.409
	kkp	16.715	39.977	16.655	14.495		kkp	61.393	44.961	40.948	15.276
	R²	0.964	0.917	0.930	0.960		R²	0.914	0.966	0.988	0.989
Fickian diffusion mechanism n ≤ 0.45, non-Fickian (anomalous) diffusion mechanism.0.45 < n < 0.89, Case II diffusion mechanism n > 1.

Table 6

Release kinetic and mechanism of 5-Flu release.
p(AG-m-ClO)¹		7.4	p(AG-g-ClO)¹		7.4
ZoKM	Co	1.978	ZoKM	Co	0.327
	ko	0.018		ko	0.013
	R²	0.946		R²	0.913
FoKM	Co	3.051	FoKM	Co	1.352
	k1	0.003		k1	0.003
	R²	0.946		R²	0.954
HKM	kh	0.034	HKM	kh	0.048
	R²	0.997		R²	0.990
KPKM	n	0.424	KPKM	n	0.955
	kkp	22.156		kkp	462.109
	R²	0.953		R²	0.860
p(AG-m-ClO)²		7.4	p(AG-g-ClO)²		7.4
ZoKM	Co	3.702	ZoKM	Co	0.240
	ko	0.015		ko	0.027
	R²	0.997		R²	0.994
FoKM	Co	4.456	FoKM	Co	2.227
	k1	0.002		k1	0.004
	R²	0.980		R²	0.936
HKM	kh	0.039	HKM	kh	0.036
	R²	0.996		R²	0.997
KPKM	n	0.513	KPKM	n	0.899
	kkp	28.236		kkp	325.805
	R²	0.980		R²	0.986
p(AG-m-ClO)³		7.4	p(AG-g-ClO)³		7.4
ZoKM	Co	1.759	ZoKM	Co	2.969
	ko	0.018		ko	0.021
	R²	0.948		R²	0.936
FoKM	Co	2.872	FoKM	Co	5.146
	k1	0.003		k1	0.002
	R²	0.875		R²	0.992
HKM	kh	0.025	HKM	kh	0.022
	R²	0.944		R²	0.915
KPKM	n	0.694	KPKM	n	0.411
	kkp	86.505		kkp	17.947
	R²	0.946		R²	0.903
Fickian diffusion mechanism n ≤ 0.45, non-Fickian (anomalous) diffusion mechanism.0.45 < n < 0.89, Case II diffusion mechanism n > 1.

In this study, Agar/Glycerol based gel and hydrogel with biocompatible, antioxidant, and therapeutic properties and six different novel organo-hydrogels based on Agar/Glycerol/Clove Oil were synthesized. At the same time, in order to support the long-term preservation of the effects of Vitamin D and 5-Fluorouracil drugs in the body, their use as controlled drug release support materials in the in vitro environment was focused on. In experimental studies, both the effects of two different crosslinkers and the amount of clove oil on the structural and drug release behavior of organo-hydrogels were investigated separately. In contrast to gels and hydrogels, clove oil-based organo-hydrogels have been observed to exhibit swelling ability not only in distilled water and tap water but also in other organic solvent media. In addition, it was founded that there were remarkable changes in swelling values with the change in the amount of Clove oil in the organo-hydrogels. According to the swelling analysis results in different solvents and different pH values, it can be said that the most important factors affecting the swelling capacity of clove oil-based organo-hydrogens are the functional groups from ClO and crosslinker. The results of blood clotting, hemolysis, and antioxidant analysis proved that the synthesized organo-hydrogels were blood compatible and biocompatible. When the drug release results were examined, it was determined that Vitamin D was released more than 5-Fluorouracil. This result leads to the conclusion that the 5-Fluorouracil drug binds more tightly to the organo-hydrogel structure and is released more slowly. It was also determined that the swing behavior can be controlled by changing the amount of clove oil added to the structure. Since synthesized organo-hydrogels exhibit different swelling and release behavior in different pH environments, and have biocompatible and antioxidant properties, they are promising in terms of transporting different drugs to different target sites.

Conflict of interest

There is no conflict of interest.

Author Contribution

Tuba Ersen Dudu is an Assistant Professor Doctor at the Chemical Engineering Department of Faculty of Engineering, Van Yuzuncu Yıl University, Van, Turkey, and her specialty is polymeric materials, water consumption, plant growth, nanotechnology, energy, chemical engineering, and wastewater treatment.Duygu Alpaslan is an Assistant Professor Doctor at the Chemical Engineering Department of Faculty of Engineering, Van Yuzuncu Yıl University, Van, Turkey, and her specialty is polymeric materials, water consumption, plant growth, nanotechnology, energy, food engineering, microbiology, and wastewater treatment.Nahit Aktas is a Professor at the Chemical Engineering Department of Faculty of Engineering, Van Yuzuncu Yıl University, Van, Turkey, and his specialty is chemical engineering, energy, wastewater treatment, polymer, and fuel cell.Abdullah Turan is a doctorated student at the Molecular Biology and Genetics Department of Science Faculty, Van Yuzuncu Yıl University, Van, Turkey, and his specialty is molecular biology, antioxidants, obesity, and drug release.

Acknowledgements

This work is supported by the Van Yuzuncu Yıl University BAP with grant # FBA-2022-9783.

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Application of poly(Clove Oil)-Based Organo-Hydrogels for Drug Delivery Systems

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Abstract

Figures

1. Introduction

2. Materials and Methods

2.1 Reagents

2.2. Experimental procedures

2.2.1. Synthesis of agar-Glycerol-based gels, hydrogels, and organo-hydrogels based on clove oil

2.2.2. Swelling analysis

2.2.3. Fourier transform infrared spectroscopy (FTIR) analysis

2.2.4. Analysis of blood clotting and hemolysis

2.2.5. Antioxidant analysis

2.3. Vitamin D and 5-Fluorouracil release studies

2.3.1. Drug release kinetics

3. Results and Discussion

3.1. Bonding mechanism of gel, hydrogel, organo-hydrogels

3.2. Swelling test

3.3. Fourier transform infrared spectroscopy (FTIR)

3.4. Blood clotting and hemolysis tests

3.5. Antioxidant analysis

3.6. Vitamin D and 5-Fluorouracil release studies

3.7. Drug release kinetics

4. Conclusion

Declarations

Conflict of interest

Author Contribution

Acknowledgements

References

Additional Declarations

Status:

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