Chitosan for digestion -
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More metrics information. Total Views 5. Henceforth, when a weak acid is administered orally, nearly all the drug in the stomach remains unionized, preferring diffusion via the gastric mucosa. Overall, the process by which molecules traverse cell membranes is by passive diffusion, down the concentration gradient.
However large hydrophilic ionic molecules and charged molecules cannot freely traverse the phospholipid bilayer cell membrane passively. Their transport may be confined to protein channels and distinct transport mechanisms present within the membrane [ 25 ].
Such drugs gain access through the membrane by facilitated diffusion whereby molecules integrate with embedded protein carriers to shuttle them across the membrane. This process does not expend energy and is also down the concentration gradient though quicker than would be anticipated by diffusion alone [ 26 ].
A frequent case of facilitated diffusion is the migration of glucose into cells during the production of adenosine triphosphate ATP. Glucose is both large and polar thereby unable to pass the lipid bilayer via simple diffusion. Hence, glucose molecules are delivered into the cell via a unique carrier protein glucose transporter to promote its internalisation in cells [ 27 ].
Active transport is an energy-dependent process that translocates drug molecules against their concentration gradient by a molecular pump [ 20 ]. Carrier-mediated active transport demand energy via ATP hydrolysis or by accompanying the co-transport of counter ions down its electrochemical gradient e.
The most common active transport system is the sodium-potassium pump and receptor-mediated endocytosis. Energy can either be directly provided to the ion pump or indirectly by connecting a pump-action to an activated ionic gradient.
It is often encountered in the gut mucosa, the liver, renal tubules and the blood—brain barrier [ 22 ]. Active transport is typically restricted to drugs that structurally resemble endogenous substances; e.
Targeting drugs to these transporters can enhance their bioavailability and distribution [ 21 ]. Cells control the endocytosis of certain substances via receptor-mediated endocytosis. The use of this form of endocytosis in the GIT is crucial for oral delivery of drugs because it delays the transit of drugs in GIT.
Receptor-mediator endocytosis involves the internalisation of macromolecules by binding the latter to receptors considered as membrane-associated protein [ 30 ].
There are more than 20 different receptors involved in the internalisation of macromolecules [ 31 ]. Following binding to the receptor on the cell surface, the cell will endocytose the portion of the cell membrane enclosing the receptor-ligand complex via a clathrin-dependent endocytic process [ 28 ].
Clathrin plays a significant role in the formation of clathrin-coated pits; invaginated regions of the plasma membrane, and pinch off to form clathrin-coated vesicles that transport molecules within cells [ 31 ].
In summary, drug adsorption may occur passively or via active transport. In either case, absorption occurs predominantly in the small intestine due to its more permeable membrane and larger surface area provided by the microvilli.
Even though, the stomach has a relatively broad epithelial surface, yet the dense mucus layer and transient transit times expended by dosage forms contribute to an impeded absorption. Moreover, the colon with an absorptive surface area of about 5m 2 has negligible contribution to drug absorption in GIT, due to slow caecal arrival times of dosage forms, the presence of numerous gut bacteria and solid stool that impede lateral diffusion.
All in all, absorption of oral drugs is interlinked and controlled by various intrinsic factors; like drug solubility, dissolution and permeability across the mucosal barriers, and physiological factors; such as gastrointestinal transit time, pH and gut microbiome [ 13 , 32 ].
Drug dissolution, solubility and permeability are the three fundamental parameters used in the Biopharmaceutics Classification System BCS to predict the factors limiting drug absorption from GIT [ 33 ].
The BCS is recognised as a useful tool for designing drug delivery systems and is adopted by the US Food and Drug Administration FDA , the European Medicines Agency EMA and the World Health Organization WHO [ 34 ]. According to the BCS, all drug substances are classified into four categories: class I—high soluble and high permeable, class II—low soluble and high permeable, class III—low soluble and high permeable and class IV—low soluble and low permeable [ 35 ].
Drug solubility is crucial outcome in pharmaceutical dosage form. This makes solubility amongst the most important rate limiting parameters in GIT absorption. Drug dissolution reflects a dynamic consequence to drug absorption [ 33 ], whereby drug is released, dissolved and made accessible for absorption.
With the exception of enteric formulations and drugs with low acid solubility, the dissolution process for majority of drugs starts in the stomach where the volume of gastric fluid is sufficient to attain effective drug dissolution [ 37 ].
Thus, the gastric fluid containing the disintegrated immediate-release dosage forms brings the solubilized drug into contact with the absorptive surface of the small intestine as absorption in the stomach is generally minimal. Drug permeability represents the final frontier in the sequence of rate-liming steps to systemic drug availability.
It is a measure of the ease of permeation of the drug across the intestinal wall. There is a positive association between the intestinal permeability and drug solubility GI milieu, which in turn depends on the physicochemical characteristics of the drug [ 38 ], including the pKa, particle size, lipophilicity, as discussed in the sections below.
The ultimate amount of drug absorbed from the GIT also bears dependence on its transit time in the GIT [ 39 ]. The GI pH influences the extent of ionization of drug molecules and thereby impacts on its absorption across the epithelium.
Variations in pH across the GIT can be exploited for delayed drug release in desired section of the GIT in order to achieve efficient absorption.
The fasted stomach is acidic, with pH range of 1—3, which increases upon food or liquid intake. Food is known to buffer the acidic content of the stomach. A rise in pH resumes in response to the continual gastric secretion and then finally, the pH reverts to the original levels due to gastric emptying of content; [ 40 ].
The gastric emptying rate significantly affects the rate of drug absorption because it regulates arrival in the duodenum, where the epithelial surface is suited for absorption [ 41 ].
Moreover, the disparity in gastric pH conditions affects the drug delivery behaviour of modified release dosage forms such as enteric coated products, where the onset of release along with the overall release kinetics may be changed [ 42 ]. The arrival of orally administered dosage forms into the small intestine is met by a pH of about 6 in the duodenum through to pH 7.
This high pH variability is due to duodenal secretion of alkaline bicarbonate. During postprandial state, the initial intestinal pH drops due to the influx of acidic chyme, which is buffered by bicarbonate secretion as it travels distally [ 13 ]. Besides, the mean pH in proximal small intestine during the first hour of transit is usually 6.
Typically, the pH in the caecum drops to just below pH 6 owing to the fermentation processes of the colonic microbiota and then rises to pH 7 at the rectum [ 42 ]. The drop in the amount of short chain fatty acids at the distal colon causes the secretion of colonic mucosal bicarbonate that leads to a neutral pH.
Short chain fatty acids are the end products of fermentation of dietary fibres by the anaerobic intestinal microbiota [ 45 ]. As a consequence of the neutral pH of the colonic luminal fluid, the solubilisation of drug is the rate-limiting factor in colonic drug absorption [ 46 ].
The unspecific interactions of drugs with colonic content e. dietary residues, intestinal secretions or faecal matter all adds to the odds of effective adsorption across the colon [ 47 ].
Generally, the GIT transit time of most orally administered doses through buccal cavity and oesophagus is transient. The stomach is naturally the first segment of the GIT, wherein disintegration and dissolution of solids such as drugs and formulations occur [ 42 ].
The period required for a dosage form to exit the stomach is inconstant and relies on several physiological factors, such as age, body posture, gender and food intake [ 48 ]. Gastric transit can span from 0 to 2 h in the fasted state and can be extended up to 6 h after food intake [ 47 ].
The small intestine is the region of choice for drug absorption with a transit time ranging from 2 to 6 h in healthy individuals. The dissolution of poorly soluble, weakly acidic compounds and lipophilic compounds is greatly enhanced in this region [ 13 ].
In colon-specific drug delivery, the drug has to cross the whole GIT prior to arrival at the colon. Thus, the transit time across the colon can be highly variable, and ranges from 20 to 56 h in healthy humans, although higher variations are also reported in literature amounting up to 72 h [ 42 , 49 , 50 ].
Variations in colonic transit time are affected by dosing time, bowel movements as well as gender, whereby females generally have longer colonic transit times than males [ 51 , 52 ]. Enzymatic and microbial degradation of GIT content affects the amount ultimately made available for absorption.
The active sites for most endogenous enzymes are the stomach and small intestine. Even though these enzymes may affect the stability of orally administered drugs, it is possible to exploit this property for regional drug delivery of formulations in the GIT [ 47 ].
On the other hand, the intestinal microbiome which includes — bacterial species is also important for the digestion of food and the metabolism of drugs [ 53 ]. Therefore, greater number of the intestinal microbiome exists in the anaerobic colon, in which the fermentation of carbohydrates contributes to their nourishment.
Usually, orally administered drugs are transformed to bioactive, bio-inactive, or toxic metabolites by the gut microbial population, all of which can impede the bioavailability of drug. However, gut microflora can improve drug bioavailability by eliminating polar moiety from derived conjugates and thereby promoting biliary recycling of compounds [ 13 ].
Thus, formulation scientist must be cognizant of the interplay between drug and physiological and anatomical manifestations within the GIT when designing orally administered dosage forms. For example, enteric coating can be applied to dosage forms to delay the release of the API in the acidic gastric fluid until pH above 5.
Enteric coating may also be used to shield acid-labile drugs from gastric distress, and upon arrival to the alkaline pH milieu, the enteric polymer coating disintegrates within the intestinal fluid, releasing the drug [ 57 ]. Despite employing such coatings and other conventional interventions, numerous pharmaceuticals still display insufficient bioavailability through the oral route of administration.
This necessitates the use of alternate strategies. One area of research that is gaining traction more recently is the employment of nanoparticles. Nanotechnology has several pharmaceutical and medical applications wherein nanoparticles NPs , with sizes comparable to large biological molecules such as enzymes can be employed in the delivery of therapeutic agents [ 59 ].
The effectiveness of the nanoscale drug delivery vehicles lies on their ability to attain the following key attributes [ 60 ]: The NP must be able to bind or contain the appropriate drug.
The nanocarrier must stay stable in the serum to allow systemic delivery of the therapeutics and only release the drug once at the required site. The NP-drug complex has to reach the required site either via receptor-mediated interactions or by the enhanced permeability and retention EPR effect.
The residual NP carrier should ideally be made of a biological or biologically inert material with a limited lifespan to allow safe degradation.
There are several types of NP drug delivery systems, which may be broadly divided as organic and inorganic NPs [ 61 ]. can be tailored for a diverse applications [ 62 ]. The primary consideration when designing orally administered NP drug delivery system is to maximise drug concentration in the GI therapeutic window.
Organic NP Figure 2 are solid particles comprised of organic compounds usually lipidic or polymeric ranging from 10 nm to 1 μm [ 63 ]. They can be formulated by simple techniques to encapsulate therapeutic agents.
Preferably, compounds used in formulation of organic NPs should be biodegradable and biocompatible [ 61 ]. Manifestations of organic NP include liposomal, polymeric and solid lipid NP, each system possessing requisite features that addresses physiological and anatomic constraints addressed in sections above.
In addition, others systems such as micelles, dendrimers etc. have been also explored as effective nanocarriers for effective deployment of APIs in the GIT [ 14 , 64 ]. Examples of organic nanoparticle platforms for drug delivery.
Inorganic NP represent a wide spectrum of systems synthesized from metals, metal oxides, and metal sulphides [ 65 ].
Gold, silica and superparamagnetic oxide NP are among the long list of inorganic NP Figure 3. They have been studied for use in imaging on nuclear magnetic resonance and high-resolution superconducting quantum interference devices, and their intrinsic properties have been utilised for therapy [ 66 ].
Additionally, their surface composition can be feasibly manipulated to create NP that can escape the reticuloendothelial system [ 67 ]. Even though inorganic NP present good stability characteristics, they have not been the focus of attention in oral NP research, possibly due to concerns on the degradation and elimination end products, which can be potentially toxic [ 68 ].
Examples of inorganic NP platforms for drug delivery. Generally, inorganic NPs differ conceptually from organic NPs in terms of fabrication principles. Inorganic NPs can be formed by the precipitation of inorganic salts, which are linked within a matrix, whilst, most organic NPs are formed by several organic molecules through self-organization or chemical binding [ 61 ].
Notwithstanding, both types of NP are very promising in the formulation of oral delivery system and forms part of the evolutional success in several clinical applications. Polymeric NP arguably presents more desirable attributes as orally delivered NP because of their higher stability, enhanced drug payload and controlled drug release capabilities compared with their colloidal counterparts [ 14 , 69 ].
According to Alexis F. et al. Nanospheres are solid spherical NP with molecules attached or adsorbed to their surface, whilst nanocapsules are vesicular systems with substances confined within a cavity consisting of a liquid core either water or oil surrounded by a solid shell [ 71 ].
Characteristic properties of polymers such as molecular weight, hydrophobicity and crystallinity can be explored to manifest controlled drug release kinetics and entrapment of therapeutic agents [ 72 ].
Polymers also provide significant flexibility in the design of oral NP and many exhibit biodegradability [ 73 ]. In this regard, synthetic and natural variants have been studied. For example poly-lactic-co-glycolic-acid PLGA and poly-lactic-acid PLA are synthetic whilst natural polymers include gelatine, dextran, and chitosan [ 74 ].
The use of natural polymers is preferred over the synthetic ones as the former usually exhibit less toxicity, widely available and have lower production costs [ 75 ]. Chitosan is arguable one of the most studied polymer in NP formulation in view of its distinctive properties.
In orally administered NP, chitosan offers added desirability including muco-adhesiveness, augmenting the dissolution rate of poorly water-soluble drugs; useful in drug targeting in the GIT [ 76 ].
It is an N-acetylated derivative of chitin, a natural polysaccharide found in the shells of marine crustaceans. Chitin is chemically inert and thus has fewer applications that chitosan [ 77 ].
The acetamido group of chitin, C 2 H 4 NO can be turned into amino group to yield chitosan by the alkaline deacetylation of chitin. Chitosan is approved as safe by the United States Food and Drug Administration US-FDA for dietary use and wound dressing applications, but its toxicity increases with electrical charge and degree of deacetylation [ 17 ].
Chemically, it comprises of β- [1—4] -linked D-glucosamine and N-acetylated units Figure 4. Chemical structure of chitosan, comprising N-acetyl-D-glucosamine right and D-glucosamine left units. The amine group has pKa of 6.
Positively charged moieties of chitosan also interact with the tight junctions of the intestinal epithelial cells and thus modulate drug permeation and absorption through the interstitial space between epithelial cells [ 79 ].
Moreover, the existence of both hydroxyl and amino groups offers various possibilities for chemical modification.
Chemical modifications give rise to different functional derivatives of chitosan like carboxylation, thiolation, alkylation, acylation etc. that further imparts desirable physiochemical and biopharmaceutical properties, such as solubility, adsorption and pH sensitivity in oral drug delivery [ 80 ].
For example, N-trimethyl chitosan chloride is developed to amplify the intestinal solubility of chitosan; thiolated chitosan is produced to augment the mucoadhesiveness of chitosan; quaternization of chitosan reinforces its impact on the tight junctions of the GIT epithelium whilst grafting carboxylated chitosan with poly methyl methacrylate imparts increased pH sensitivity [ 81 ].
Physical modification through blending with other polymers may be used to enhance desirable physical properties. For example, blending of chitosan with polyethylene glycol PEG and polyvinyl alcohol PVA ameliorate the hydrophilic property of chitosan, while blending of chitosan with cellulose improves its antibacterial properties [ 82 ].
Some of the key desirable features in orally administered dosage forms is delayed GI transit in the duodenum and ability to traverse the epithelium effectively.
In this regard, chitosan-based NP have been shown to possess these attributes. Mucoadhesion refers to the adhesion between two materials, one of which is mucosal [ 83 ]. It can be utilised to prolong the GI transit of dosage forms in the duodenum, thereby improving bioavailability. Delayed transit results from interactions of positively charged moieties in chitosan with negatively charged moieties in sialic acid within mucin [ 81 ].
Chitosan is also capable of physically penetrating the mucous network. Prolonged GI residence results in higher net drug flux across the GIT membrane.
Moreover, chitosan offers controlled drug release capabilities via diffusion from the matrix. Yin et al.
They attributed these results to the disulfide bond formation between the NP and mucin [ 85 ]. Overall, to achieve the desired properties of interest such as particle size, particle size distribution and area of application, the mode of preparation of chitosan NP plays an essential role.
The preparation of chitosan NP is principally divided into two approaches. The first approach is based on a two-step procedure, where an emulsification system is carried out to generate nanodroplets in which organic compounds polymer, monomer, and lipid are solubilized, followed by precipitation or polymerisation into NP [ 61 ].
The second approach involves a one-step procedure where the NP are directly generated via different mechanisms such as nanoprecipitation or ionic gelation [ 86 ]. An example of each of the two general approaches is summarized in the following. Ionic gelation, also known as ionotropic gelation or polyelectrolyte complexation involves the gradual addition of a cross-linking agent tripolyphosphate, glutardehyde etc.
into an aqueous solution of chitosan under continuous stirring to form hydrogels [ 87 ]. The polyanions from the cross-linker forms a meshwork of structures by interacting with the polyvalent cations within chitosan, leading to gelation [ 88 ].
APIs can be loaded into these hydrogels during the production where it becomes encapsulated or added to the formed NP, where it can be adsorbed into the matrix. The choice of the cross-linker should be matched to the desired physical characteristics of the NP, such as mechanical strength, as well as safety profiles.
For example, glutardehyde reported to be toxic when used in high concentrations and results in NP with low mechanical strength.
Genipin is a natural cross-linker obtained from iridoid glucoside geniposide and present in gardenia fruits that can be cross-linked with chitosan. It displays slower degradation rate than glutaraldehyde and possess higher biocompatibility. Sodium tripolyphosphate STPP displays better crosslinker characteristics than each of the above because of its inorganic nature and consequently, results in production of chitosan NP with better mechanical stability.
The size dimension derived from STPP gelled chitosan NP is of lower order as well. Another attractive feature of STPP is that it is nontoxic, relatively inexpensive, multivalent, has quick gelling property and thus, widely utilised as a crosslinker in chitosan-based NP [ 90 , 91 , 92 ]. Polymeric nano-emulsions are formulated whereby organic solvent is added to a solution of chitosan with surfactant and mixed via sonication [ 93 ].
Basically, the emulsion droplets are converted into NP suspension as the organic solvent evaporates by continuous magnetic stirring at room temperature. The NP suspensions are then centrifuged, washed with distilled water to remove additives such as surfactants and finally lyophilized [ 94 ].
Poovi et al. encapsulated the poorly water-soluble drug, repaglinide, into chitosan NP using the emulsion evaporation for sustained release. They proved that the NP exhibited a controlled release of repaglinide and obtained a high drug loading In another study, Lee et al.
employed solvent evaporation method to formulate polymeric NP from chitosan derivatives fluorescein isothiocyanate FITC - conjugated glycol CSs FGCs using diluted chloroform as the solvent. Size range of — nm were obtained and the NP remained stable in phosphate buffered saline for 20 days at 37°C [ 96 ].
In vitro drug release studies give us insights on the response of formulated delivery systems to challenges in in vivo. The rate and extent of in vitro drug release from chitosan-based NP is influenced by a host of factors, notably, shape and size of the of the delivery system, physicochemical properties of the drug and external media [ 97 ].
Erosion or degradation of polymers lead to successive physical depletion of the polymer as chains and bonds break [ 99 ]. Drug release from the chitosan NP matrix is often pH dependent because of the solubility of chitosan in acidic media [ ].
In acidic media, the matrix swells or disentangles and may act as an effective barrier to drug diffusion. The extent of drug diffusion through this gelled matrix depends on the diffusivity of the drug [ 99 ].
In alkaline media, the polymer matrix does not swell and drug release is controlled mainly by passive diffusion into the medium and the polymer plays an insignificant role in the drug release profile.
If the drug is weakly bound to the surface of the NP, an initial burst release occurs [ 97 ]. In vitro drug release from chitosan NP usually show a two-step pattern with an initial rapid release followed by sustained release [ ].
Patel et al. A good correlation fit was obtained between the cumulative drug released and square root of time, signifying that the drug release from the NP is diffusion-controlled as described by the Higuchi model. They concluded that rifampicin release from chitosan NP is pH dependent, i.
Similarly, Avadi et al. No burst release was observed at higher pH values of 6. The performance of chitosan NP in the GIT depends on its response to the external milieu as discussed above.
Equally important is how the GIT responds to the presence of NP. The following section describes the consequence of NP deployment in the GIT in the management of selected diseases and expected responses.
As mentioned in sections 4. Moreover, due to various characteristics; i. non-toxic, biodegradable, biocompatible, antimicrobial property etc.
Chemotherapeutic APIs usually exhibit low bioavailability following oral administration. Several studies have investigated chitosan-based NP as a possible delivery system to address this issue. For example, doxorubicin Dox , broadly employed to treat breast, bladder and other cancers, is typically delivered intravenously.
The oral bioavailability of Dox is low due to efflux transporter P-glycoprotein, which identifies Dox as a substrate, restraining its cellular uptake [ ]. Simulated digestion of Alg-Chi-TPE hydrogel beads in gastric and intestinal phases was performed according to a previously described method 32 with modification.
Simulated gastric fluid SGF and simulated intestinal fluid SIF were prepared as described below. SGF was prepared by dissolving 2 g of NaCl, 3. The mixture was stirred until homogenized for 1 h before use.
Pepsin is responsible for breaking down protein during gastric digestion, while pancreatic lipase is important in the dietary triacylglycerol breakdown during intestinal digestion. The water uptake of the Alg-Chi-TPE hydrogel beads was performed in two different digestive media: SGF and SIF.
Accurately weighed beads were immersed in 20 mL of respective medium in a sealed conical flask and placed in an incubator shaker rpm at 37°C. The beads were separated from the medium at specific time intervals, wiped gently with filter paper and weighed.
The weight change of the beads to time was determined using the following Equation 4. Where W s is the weight of the beads in swollen state and W i is the initial weight of the untreated beads. The swelling and erosion of the Alg-Chi-TPE hydrogel beads were performed in two different digestive media: SGF and SIF.
Beads were immersed in 20 mL of respective medium in a sealed conical flask and placed in an incubator shaker rpm at 37°C. The beads were removed from the medium at specific time intervals, wiped gently with filter paper, and the diameter was measured.
The swelling degree and erosion degree of the beads to time were determined using the following Equations 5 and 6 , respectively. Where D s is the diameter of the beads in the swollen state, D i is the initial diameter of the untreated beads, W e is the weight of the dried beads in the swollen state, and W i is the initial weight of the untreated beads.
The microstructures of Alg-Chi-TPE hydrogel beads after gastric digestion and intestinal digestion were observed through a variable pressure scanning electron microscope VP-SEM, Hitachi sN-II, Japan and an upright fluorescent microscope Nikon Eclipse 90i, Nikon Instrument Inc.
For VP-SEM preparation, the samples were air-dried, sputter-coated with gold under a vacuum before analysis. The samples were observed at an accelerating voltage of 10 kV. For the fluorescent microscope, the lipid phase of the emulsions was stained with Nile red 0.
A bead was placed on a microscopic slide and gently covered with a coverslip. The edge of beads was observed. The release of thymoquinone TQ from Alg-Chi-TPE hydrogel beads in gastric digestion and intestinal digestion were evaluated according to the method described in section Measurement of Encapsulation Efficiency EE.
In brief, the hydrogel beads were immersed in 20 mL of respective medium in a sealed conical flask and placed in an incubator shaker rpm at 37°C. The hydrogel beads were treated with SGF for min followed by SIF for another min.
Then, at specific time intervals, 2 mL of the medium was withdrawn from the conical flask and topped up with the fresh medium. The release profiles of TQ were fitted to the Peppas model by the following Equation 7 Thymoquinone TQ was first dissolved in the red palm olein phase before the emulsification process.
The digital images of the wet and dry Alg-Chi-TPE hydrogel beads are shown in Figure 2. However, when lower alginate concentrations were used, the shape of the beads was deformed, resulting in rough and collapsed surface morphology.
This deformation is inevitable when water was evaporated from the wet hydrogel beads during the drying process, causing volume shrinkage of hydrogel beads Figure 2.
Digital images of wet and dry alginate-chitosan hydrogel beads immobilized Pickering emulsion obtained with different alginate concentrations. Table 1 summarizes the percentage of weight change after the drying process. Generally, increasing the alginate ratio in beads formulation causes the beads' amplification and weight change.
However, hydrogel beads obtained with 2. It is worth noting that the colors of the beads became darker when the beads shrink, which could be due to the increase in the concentration of immobilized TPE within the beads after the water has evaporated.
Table 1. The mean sizes and the shrinking ratio of Alg-Chi hydrogel beads were determined by ZEN Blue software. FTIR spectra of thymoquinone-loaded Pickering emulsion TPE , Alg, Alg-TPE, Chi, and Alg-Chi-TPE hydrogel beads are shown in Figure 3A.
The similarities of the palm olein bands revealed no interaction between the Pickering emulsion and wall materials, indicating that the Pickering emulsion is physically entrapped within the Alg-Chi beads system.
On the other hand, the FTIR spectra Figure 3B of Alg-Chi-TPE hydrogel beads with different Alg concentrations displayed similar profiles suggesting that Alg concentration does not affect the physicochemical interactions between the immobilized TPE and the wall materials.
Figure 3. FTIR spectra of A TPE, Alg, Chi, and Alg-Chi-TPE beads B different alginate concentrations 0. A decrease in the encapsulation efficiency could be due to the release of TQ during the ionic gelation and the hardening process.
Figure 4 illustrates the water uptake of Alg-Chi-TPE hydrogel beads with different Alg concentrations in simulated gastric fluid SGF and simulated intestinal fluid SIF. The increase in weight can be justified where the void regions within the hydrogel beads get filled up by water due to osmotic pressure asserting on the hydrogel beads.
The water uptake is minimal at the low pH of gastric fluid because alginate precipitates to form alginic molecules in the form of aggregates linked by hydrogen bonding leading to higher stability When the hydrogel beads were introduced to the gastric digestive fluid, denser alginate structures were believed to be due to the weakened electrostatic repulsion among the alginate molecules.
The pH of the SGF was maintained at pH 1. Figure 4. The water uptake of alginate-chitosan hydrogel beads immobilized Pickering emulsion obtained with different alginate concentrations during A gastric digestion B intestinal digestion.
C The visual appearance of beads before and after gastric and intestinal digestion. Error bars represent the standard deviation of three replicates. A comparison was made between 2.
The water uptake of beads was accelerated during intestinal digestion, which is ideal for digesting oils. Hydrogel beads obtained with 0. Generally, the water uptake ability of all beads during intestinal digestion improved with increasing alginate concentration.
The water uptake ratios of 2. The calcium ions dissociate and form calcium phosphate salts which no longer crosslink with the alginate matrix, leading to the structural degradation of the hydrogel matrix. On the other hand, the ionization of alginate at intestinal pH produces electrostatic repulsion forces between alginate chains, increasing weight gain Table 2 shows the swelling and erosion degrees of Alg-TPE and Alg-Chi-TPE hydrogel beads after min of gastric digestion and up to min of intestinal digestion.
The swelling degree measures the diameter of the swollen beads after treatment. The swelling degree for both hydrogel beads reduced after min of gastric digestion, demonstrating the shrinking of beads. This observation is in line with other studies where alginate-based hydrogel beads shrunk during gastric digestion and swell during intestinal digestion, possibly due to the changes in electrostatic forces of the wall matrix at different pH 31 , It is worth noting that the hydrogel beads with chitosan illustrated a lower swelling degree than the hydrogel beads without chitosan.
The addition of chitosan onto alginate leads to the formation of a more entangled system developed by the blending of both polymers forming polyelectrolyte complexes between the amino groups of chitosan and carboxylate groups of alginate These factors improved the stability of Alg-Chi-TPE hydrogel beads and exhibited increased resistance to osmotic pressure.
Table 2. The swelling and erosion degrees of alginate hydrogel beads and alginate-chitosan hydrogel beads during gastric digestion and intestinal digestion. On the other hand, the erosion degree measures the weight loss of the dried hydrogel beads after treatment.
From Table 2 , the erosion degrees for both Alg-TPE and Alg-Chi-TPE hydrogel beads after gastric digestion were 8. A significant reduction in the weight of hydrogel beads can be related to the syneresis effect in an acidic environment where shrinkage is favored Nevertheless, the erosion degree of the hydrogel beads in an alkaline environment begins to rise with time, with the maximum erosion degree of The erosion degree for hydrogel beads coated with chitosan was lower than hydrogel beads without chitosan, demonstrating enhanced stability of the hydrogel beads when chitosan was introduced.
As the treatment continues, the degradation, and dissolution of the bead matrix were enhanced over time. As a result, the final weight of the dried and treated hydrogel beads became lower, displaying time-dependent erosion properties. The hydrogel beads prepared by 2.
Scanning electron micrographs of dry alginate hydrogel Alg-TPE beads, chitosan-coated alginate Alg-Chi-TPE beads and Alg-Chi-TPE beads after specific digestion in SGF or SIF are illustrated in Figure 5. The Alg-TPE and Alg-Chi-TPE hydrogel beads exhibited spherical shape after air drying, and a detailed examination of the surface structure revealed a rough and folded appearance.
There was not much difference between alginate and alginate-chitosan beads in terms of surface structure. However, a closer observation on SEM images with higher magnification x illustrated the presence of more rough surfaces with irregular dents on the crosslinked alginate-chitosan hydrogel beads Figures 5b,d.
This could be attributed to the effect of chitosan polymer coating onto the surface of the alginate matrix, creating patchy-like textures associated with a shielding effect by the insoluble chitosan layer.
The results can be correlated to the lower swelling profile of chitosan-coated alginate beads than the uncoated beads [swelling degree of 85 vs. Figure 5. SEM images of a,b 2. As shown in Figures 5d,f , there is no significant variation in the microstructure of beads after gastric digestion with similar roughness and compact surfaces.
This observation agrees with the swelling behaviors of hydrogel beads, where alginate displayed excellent stability in a medium of low pH. The stability of the alginate-chitosan beads or capsules depends strongly on the differences in their assembly 43 and the amount of chitosan bound to the capsules The present study employed a one-step preparative procedure by dropping the emulsion-alginate mixture into a chitosan solution containing calcium chloride.
Hydrogel bead formation was achieved by the ionic gelation effect, and chitosan formed the outer layer of the beads. An earlier study reported that the chitosan molecules could diffuse into the alginate matrix, creating a 3D hydrogel network interconnected by alginate molecules, chitosan polymer bridges, and cationic calcium ions The SEM micrographs revealed minimal changes in the surface morphology of alginate-chitosan beads upon min exposure to SGF.
A similar observation was also made in a previous work conducted by Li et al. In addition, Chew et al. concluded that the chitosan-alginate coacervated beads appear to resist in an acidic medium where the structure remains intact because of the ionic bonds of calcium-alginate-chitosan complexation through electrostatic interactions The micrographs of Alg-Chi-TPE hydrogel beads at a different time point of intestinal digestion are illustrated in Figures 5g—n.
After 30min of intestinal digestion, the microstructure of hydrogel beads displayed a smoother surface, indicating the degradation of the hydrogel bead wall materials Figures 5g,h.
The compact structure gradually transforms into a heterogeneous structure with disorderly folded and significant dents when the intestinal digestion time increased to min. The change in the microstructures of hydrogel beads could be due to the swelling process, which coincides with the erosion and dissolution of swollen beads A slight deformation on the morphology of hydrogel beads spherical to oval after 60 min of intestinal digestion Figures 5i,j could be related to the swelling process and erosion of beads where the degradation of chitosan-coated alginate matrix as the wall materials of the beads has begun.
At min of intestinal digestion, micrographs of hydrogel beads Figures 5m,n with severe cleavages and uneven surfaces could be observed in the later stage. As shown in Figure 6 , the fluorescent micrographs showed a similar microstructure of beads after gastric digestion without any substantial difference.
However, the micrographs of beads displayed significant changes at different time points of intestinal digestion. The original compact surface has gradually transformed into a loose structure, indicating the loss of lipid phase from the beads.
These results suggest that the digestion could start from the surface toward the center of the beads 48 , causing the release of immobilized Pickering emulsion within the beads into the external medium.
Figure 6. Fluorescent images of alginate-chitosan hydrogel beads immobilized Pickering emulsion surface after gastric and intestinal digestion scale bar, μm. The release of encapsulated thymoquinone TQ from the hydrogel beads was achieved during gastrointestinal digestion.
The introduction of intestinal fluid at an alkaline pH and the extensive water uptake properties of the hydrogel beads could account for the initial rapid release In addition, the presence of lipase in SIF could initiate the lipolysis process, breaking down lipid droplets into triacylglycerol molecules, mixed micelles, non-digested fat droplets, or smaller fractions of free fatty acids 49 , 50 , thus releasing TQ in short-chain fatty acids that could be absorbed in the small intestine.
Figure 7. In vitro release profiles of thymoquinone from alginate-chitosan hydrogel beads immobilized Pickering emulsion in SGF, SIF, and 2 h in SGF followed by SIF. When the hydrogel beads were soaked in the SGF medium, a syneresis process occurs, resulting in the shrinking of beads.
These shrunk beads with lesser volume were later transferred into the SIF medium to initiate intestinal digestion. Then, the encapsulated TQ can be released by diffusion process through the increasingly large openings.
During the later stage 60— min , the rate of swelling of the beads decreased, and the diffusion process determines the amount of bioactive release.
The results were analyzed using the Peppas model to distinguish the release mechanisms of TQ from the alginate beads. For hydrogel beads, the diffusional exponent n specifies the mechanism of release.
Chitosan oligosaccharides Chitosan for bone health have shown positive effects on host digestiln health and Chitosqn on diegstion microbial community. Chitosan for digestion, the bioactivity and mechanism of COS on gut microbiota is still poorly understood. Creatine for performance digestin vitro fermentation of Dkgestion by mice gut microbiota, digeston bacterial population figestion decreased Fasting for Enhancing Autophagy 8-h COS treatment but was returned to the normal level after extended incubation. Consumption of COS and production of SCFAs suggested that COS were utilized by the microbe, although the consumption of chitosan pentasaccharides was obviously slower than others. In vivo animal study indicated that COS reduced population of probiotic genera LactobacillusBifidobacterium and harmful genus Desulfovibrioand increased abundance of genus Akkermansia. Phylum Proteobacteria was significantly inhibited by COS both in the animal model and in vitro fermentation. Our findings suggested that COS could reform the community structure of gut microbiota.Video
Her Weight-Loss Video Went Viral On TikTok. Here's What She Learned. Open Fleet Fuel Efficiency peer-reviewed digewtion. Submitted: Chitosaj September Creatine for performance 04 December Published: 23 December com fod cbspd. Sigestion clinical treatment outcomes Chitosan for digestion on achieving optimal systemic delivery of therapeutics. The oral route of administering Active Pharmaceutical Ingredients API remains formidable because of ease to the patient and convenience. Yet, the gastrointestinal tract GIT poses several barriers that need to be surmounted prior to systemic availability, especially for Class IV type drugs.
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